Glaring Absence of Women


More women are now faculty in physical medicine and rehabilitation, but why so few awards?

 

 

While the proportion of full-time female faculty in physical medicine and rehabilitation has risen to more than 40 percent over the last two decades, the proportion of women receiving awards and honors from a major professional association in the field has fallen, with no women receiving any awards in several recent years, and none receiving awards in some categories over the past decade, according to a new study by Harvard Medical School researchers at Spaulding Rehabilitation Network.

The findings were published the American Journal of Physical Medicine and Rehabilitation.

This is the second study in the field of physical medicine and rehabilitation to demonstrate an underrepresentation of awards presented to women physicians and the first of its kind in any medical specialty to study this disparity in academic physicians specifically.

“In this study we demonstrated that the underrepresentation of women physicians as recognition award recipients was not limited to one medical society but was a bigger problem within the specialty,” said Julie Silver, lead author of this study and the earlier one  and HMS associate professor of physical medicine and rehabilitation and associate chair for strategic initiatives at Spaulding Rehabilitation Network. “We hope that our research will be a wake-up call for physician- supported societies to use metrics that include, but also extend beyond, recognition awards to assess diversity and inclusion—not just for women but for all physicians.”

The study involved a review of 27 years’ worth of data from the Association of Academic Physiatrists. The list contained all major recognition award recipients from 1990 to 2016 with a total of 85 individual awards presented to physicians.

No woman physician has received the outstanding resident/fellow award since its inception in 2010. While the proportion of awards given to women from 1990 to 2016 has decreased from 21.7 percent to 17.9 percent, the proportion of full-time female physician faculty in physical medicine and rehabilitation has increased from 38 percent in 1992 to 41 percent in 2013.

The authors say that recognition awards from specialty societies are a useful rubric to measure the ability of women physicians to navigate key resources needed for career advancement. Among other things, medical specialty societies own or control medical journals, scientific speaking opportunities, leadership training and leadership positions on task forces, committees and boards.

previous study by the same group of researchers published in the journal PM&R found that over a 48-year period women physicians received only 15.9 percent of the awards from the American Academy of Physical Medicine and Rehabilitation. A key finding was that women were the most underrepresented group for prestigious lectureship awards to speak at national conferences. The study found that women received lectureships in eight of the 48 years studied.

There are many documented gender disparities for physicians in academia, including pay and promotions. This study highlights the role of medical societies as gatekeepers of crucial resources that doctors need to advance their careers and identifies a glaring gap for women physicians.

The researchers—including five men and six women who are all affiliated with HMS—intend to publish further reports that explore the unique challenges and barriers for underrepresented physician groups. The researchers also plan on working collaboratively with physician colleagues throughout the U.S. and with national medical societies to establish and implement metrics that focus on measuring diversity and inclusion.

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The role of TDP-43 in amyotrophic lateral sclerosis and frontotemporal dementia


Purpose of review

We examine current evidence that the TAR DNA binding protein, TDP-43, plays a pathogenic role in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Recent findings

TDP-43 was recently identified as the major pathological protein in sporadic ALS and in the most common pathological subtype of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions (FLTD-U). In these conditions, abnormal C-terminal fragments of TDP-43 are ubiquitinated, hyperphosphorylated and accumulate as cellular inclusions in neurons and glia. Cells with inclusions show absence of the normal nuclear TDP-43 localization. Recently, missense mutations in the gene encoding TDP-43 have been identified in patients with sporadic and familial ALS.

Summary

The recent discovery of pathological TDP-43 in both ALS and FTLD-U confirms that these are closely related conditions within a new biochemical class of neurodegenerative disease, the TDP-43 proteinopathies.

Keywords: TDP-43, amyotrophic lateral sclerosis, frontotemporal dementia, FTLD-U

Introduction

There is growing evidence that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are closely related conditions with overlapping clinical, genetic and neuropathological features [1]. The recent identification of the transactive response (TAR) DNA binding protein with Mr 43 kDa (TDP-43) as the major pathological protein, in both ALS and the most common pathological subtype of FTD (frontotemporal lobar degeneration with ubiquitinated inclusions, FTLD-U) [2••,3••], provides the strongest evidence to date that these conditions are part of a clinicopathological spectrum of disease. Furthermore, this discovery provides important new insights into the pathogenesis of these conditions and the potential for the development of new diagnostic tests and therapies.

TDP-43 is the pathological protein in ALS and FTLD-U

One of the most characteristic neuropathological features of ALS is the presence of ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions (NCI) in the degenerating motor neurons [4]. A significant proportion of ALS patients develop cognitive deficits, often with prominent frontal lobe features [5], and are found to have additional ub-ir NCI and neurites in the frontotemporal neocortex and hippocampus [6,7]. Similar ub-ir, tau- and α-synuclein-negative cortical pathology (FTLD-U) is now recognized to also be the most common pathological substrate for clinical FTD, in the absence of motor features [8,9]. Until recently, it was uncertain whether FTLD-U represented a single disease process, or if it included a number of discrete entities in which the ubiquitinated protein was different. The recognition of several identifiable subtypes of FTLD-U pathology, each with relatively specific clinical and molecular genetic correlations, was initially interpreted as suggesting that FTLD-U was a heterogeneous collection of diseases [10,11]. However, this issue was finally resolved, in late 2006, when two groups independently identified the pathological protein in both FTLD-U and ALS as being TDP-43 [2••,3••].

In those initial studies, immunoblot analysis performed on the high Mr insoluble protein fraction from postmortem FTLD-U brain tissue identified disease specific bands that were excised and analyzed by liquid chromatography-mass spectrometry [2••,3••]. The resulting peptides were found to correspond to amino acid sequences in the C-terminal region of TDP-43. Commercially available antibodies against TDP-43 were found to consistently label the ub-ir inclusions in cases of FTLD-U and also ALS (Figure 1), but not the characteristic inclusions in a variety of other neurodegenerative conditions. An interesting observation, with possible functional implications, was the fact that neurons that contained TDP-43 inclusions showed an absence of the normal diffuse nuclear staining pattern [3••]. In addition to the normal 43 kDa band, TPD-43 immunoblot analysis of FTLD-U and ALS tissue, demonstrated disease specific bands at ~25 and 45 kDa, as well as a high Mr smear (Figure 2). The pathological proteins were shown to represent abnormal C-terminal fragments of TDP-43 that were ubiquitinated and phosphorylated.

Fig. 1

TDP-43 immunohistochemistry in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS)
Fig. 2

Biochemical analysis of pathologic TDP-43 in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)

A number of subsequent studies have confirmed that most clinical and pathological subtypes of FTLD-U and ALS are characterized by TDP-43 immunoreactive inclusions [12••,13• ,14,15••,16,17]. Moreover, by virtue of its greater sensitivity and specificity, TDP-43 immunohistochemistry has proved to be a powerful new tool for investigating the neuropathology of these conditions, demonstrating changes that were not previously recognized. These include TDP-43-immunoreactive cytoplasmic inclusions in glial cells of presumed oligodendroglial lineage [2••,15••,16,18•], granular neuronal cytoplasmic “pre-inclusions” [19], dystrophic neurites in the CA1 region in cases with hippocampal sclerosis [20] and more extensive extramotor pathology in cases of ALS, with and without dementia [19]. Antibodies raised against phosphorylated epitopes of TDP-43 have proven to be even more sensitive and specific, as they only identify the pathological forms of the protein [21•] while the use of C-terminal and N-terminal specific antibodies has suggested that the pathological inclusions in different populations of neurons may be composed of different forms of TDP-43 [22•]. As a result, FTLD-U and ALS are now recognized as representing a clinicopathological spectrum within a new biochemical class of neurodegenerative disease, the TDP-43 proteinopathies.

Normal function of TDP-43 in nervous system

TDP-43 is a 414 amino acid nuclear protein that is encoded by the TARDBP gene on human chromosome 1p36.2. It is highly conserved and ubiquitously expressed in a variety of tissues including brain [23]. TDP-43 contains 2 RNA-recognition motifs (RRM1: ~aa 106–175 and RRM2: ~aa 191–262) and a glycine-rich C-terminal region (~aa 274–413) that allow it to bind single stranded DNA, RNA and proteins [23,24]. It was initially cloned as a human protein capable of binding to the TAR DNA of human HIV-1, where it acts as a transcription repressor [25]. It was subsequently identified as part of a complex involved in splicing the cystic fibrosis transmembrane conductance regulator gene [23] and also the apoA-II gene [26]. The exon skipping and splicing inhibitory activity requires the glycine-rich C-terminal domain that binds to several members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family [24,27]. TDP-43 has also been shown to act as a scaffold for nuclear bodies through an interaction with survival motor neuron protein [28]. It may also be involved in mRNA stability, microRNA biogenesis, apoptosis and cell division [29•]. In the brain, TDP-43 is normally localized to the nucleus of neurons and some glial cells [3••]. Although, its physiological function in the nervous system is not currently known, one recent study has suggested it may act as a neuronal activity-response factor, involved in the regulation of neuronal plasticity [30].

The spectrum TDP-43 proteinopathies

Although the initial reports suggested that pathological TDP-43 is both a specific and sensitive marker of all subtypes of FTLD-U and ALS [2••,3••,13•], subsequent studies have identified some important exceptions. While the vast majority of sporadic FTLD-U cases are found to be TDP-43-positive, most large series have identified a small proportion in which the ub-ir pathology is negative [12••,20]. Two recent papers have provided detailed description of these “atypical” cases (aFTLD-U), which represented 10 – 20 % of all FTLD-U in the respective series [31•,32]. In contrast to TDP-43-positive cases, all aFTLD-U cases were sporadic with very early onset FTD, characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathology consisted of NCI and unique neuronal intranuclear inclusions that were only reactive for ubiquitin. Based on the unusual and highly consistent clinical phenotype and neuropathology, the authors suggested that aFTLD-U represents a newly recognized and specific disease entity.

In familial FTLD-U, different patterns of TDP-43 pathology have been found to correlate with most of the known genetic causes, including mutations in the genes encoding progranulin and valosin-containing protein and in families with FTD and MND linked to chromosome 9p21-13 [12••,14,17]. An exception is FTD linked to chromosome 3, caused by a mutation in the gene encoding the charged multi-vesicular body protein gene (CHMP2B), which is characterized by ub-ir NCI in hippocampal granule cells, that are not reactive for TDP-43 [12••,33•].

In ALS, TDP-43 positive inclusions, in both lower motor neurons and glia, are a consistent feature of all sporadic cases and familial cases without SOD1 mutations [15••,16]. However, the absence of immunohistochemical or biochemical evidence of pathological TDP-43 in human cases and animal models with SOD1 mutations suggests that neurodegeneration in these cases may have a different pathogenesis [15••,16,34•].

A number of recent studies have also raised questions about the disease specificity of TDP-43 pathology by demonstrating some degree of positivity in a variety of conditions, outside the usual spectrum of FTD and ALS. TDP-43 immunoreactivity is reported to be a consistent feature of ALS-parkinsonism-dementia complex of Guam [35•,36•] and present in a significant proportion of cases of hippocampal sclerosis dementia [12••,37••,38], classical Pick’s disease [39], corticobasal degeneration [40], Alzheimer’s disease [37••,40,41], Parkinson’s disease and dementia with Lewy bodies [41,42]. In most of these conditions, the TDP-43 pathology is anatomically restricted to mesial temporal structures, shows only partial co-localization with the other pathological changes and is of uncertain clinical relevance [37••,3842].

It is anticipated that our understanding of the spectrum of TDP-43 proteinopathies will continue to evolve as more cases and additional conditions are examined. Rather than diminish the importance of this protein in the pathogenesis of ALS and FTD, this new information will help to clarify the relationship between different ALS and FTD subtypes and their relationship with other neurodegenerative conditions.

Mutations in TARDBP cause ALS but not dementia

Rare pathogenic missense mutations and multiplications have been identified in genes encoding the major constituents of the pathological deposits in several neurodegenerative diseases [4345]. The gene encoding TDP-43 (TARDBP) therefore represents an excellent candidate for causing or increasing the risk to develop a disease in the spectrum of TDP-43 proteinopathies. Initial sequence analyses of TARDBP in patients with sporadic FTD and ALS, as well as familial FTD, failed to identify mutations [46]. Similarly, no evidence of genetic variation in TARDBP increasing risk for FTD or ALS was observed [4648]. However, subsequent large population-based TARDBP mutation screenings, by us and by others, have identified 16 different missense mutations in 19 genealogically unrelated ALS patients, which were absent in healthy controls [49•,50•,51••,52,53•] (Figure 3). Eight mutations have been found in familial ALS patients [49•,50•,51••,52,53•], while eight others were identified in patients with sporadic ALS [50•,51••]. Mutations c.1077G>A (p.A315T), c.1009A>G (p.M337V) and c.1278G>A (p.A382T) were identified in two families each and haplotype sharing studies supported a common genetic origin for mutations p.M337V and p.A382T. TARDBP mutations were not restricted to Caucasians ALS populations; mutation c.892G>A (p.G298S) was identified in a Chinese family [53•] and c.1028A>G (p.Q343R) in a Japanese family [52].

Fig. 3

Missense mutations in the gene encoding TDP-43 (TARDBP) cause ALS

Depending on the study, the overall TARDBP mutation frequency in ALS has ranged from 3% to 6%, with the exception of the initial report by Sreedharan et al. [51••], in which a much lower TARDBP mutation frequency of 0.6% (3/526) was identified. Both population-based studies in which sporadic mutation carriers were identified, described comparable TARDBP frequencies for sporadic and familial ALS [50•,51••]; however mutation analyses in a large clinical series of sporadic ALS patients of European descent did not identify mutations [54] and other studies have identified TARDBP mutations exclusively in familial ALS [49•,52,53•]. Without supportive functional data, the pathogenic character of each of the TARDBP mutations identified in a single sporadic ALS patient remains uncertain.

The clinical phenotype of TARDBP mutation carriers resembles classical adult onset ALS. Based on the current published literature, the mean onset age for mutation carriers was 56.3 ± 12.1 years (N=30; range 30–83 years) with similar onset ages in familial (N=22; 55.8 ± 12.1 years) and sporadic (N=8; 57.5 ± 12.8 years) cases [49•,50•,51••,52,53•]. The mean duration of disease was 4.3 ± 3.6 years (N=18; range 1–12 years). Even within a single family, the age of onset varied significantly (by as much as 35 years) [53•], suggesting that additional genetic and/or environmental factors determine the disease expression of TARDBP mutations. Thirty-three percent of mutation carriers (11/33) had bulbar onset and 67% (22/33) limb-onset ALS, a distribution comparable to non-TARDBP mutation carriers [55,56]. Interestingly, despite the common co-occurrence of cognitive symptoms in ALS patients [5], none of the TARDBP mutation carriers identified to date, have had a personal or family history of dementia. In agreement with this finding, TARDBP mutations have not been identified in patients with FTD, FTD-ALS or AD, characterized by TDP-43 pathology [50•,53•].

Thus far, pathological examination has only been performed in two families with TARDBP mutations [52,53•]. The neuropathological changes in patients from both families were characteristic of ALS, with motor neuron loss, gliosis and the presence of Bunina bodies. As expected, TDP-43-positive NCIs and glial cytoplasmic inclusions were observed in the anterior horn cells of the spinal cord and in various other regions of the central nervous system. In one family the authors suggested a higher frequency of TDP-43-positive “pre-inclusions” compared to other patients with sporadic ALS [53•]. Biochemical analyses of TDP-43 protein extracted from the spinal cord of the autopsied case carrying the p.Q343R mutation showed elevated levels of the abnormal molecular-weight fragments of ~25 and 45kDa, that were previously observed in sporadic ALS and in SOD-1 negative familial ALS, suggesting TARDBP mutations may accelerate the production of these fragments [52]. Whether these neuropathological findings are characteristic of all TARDBP mutation carriers needs further confirmation.

All but one of the reported mutations cluster in TARDBP exon 6, encoding the highly conserved C-terminal region of TDP-43 (Figure 3). Four mutations involve glycine residues, in close proximity of each other, in the glycine-rich region, while the other mutations affect conserved residues in the remaining portion of the C-terminal domain. No clustering of familial versus sporadic mutations in specific regions of the gene has been observed and no effect of the location of the mutations on the age of onset or disease duration has been demonstrated.

Role of TDP-43 in neurodegeneration

Little is currently known about the pathogenic role of TARDBP mutations or TDP-43 pathology in neurodegeneration. Analogous to other neurodegenerative diseases, characterized by the accumulation of mis-folded protein, the critical step will be to determine whether disease results from a loss-of-function, a toxic gain-of-function or both.

The abnormal localization of TDP-43 to the cytoplasm in affected neurons in FTD and ALS, irrespective of the presence of a genetic mutation, suggests a pathogenic mechanism associated with the loss of the normal nuclear TDP-43 function in regulating transcription, splicing and mRNA stability [29•,57]. In support of this hypothesis, loss of TDP-43 in human cells has been shown to induce morphological nuclear defects and increased apoptosis [58••]. Alternatively, sequestration of TDP-43 in cellular inclusions may induce a toxic gain-of-function, independent of the basic biological role of TDP-43. A study in which TDP-43 was overexpressed in yeast suggested that only aggregating forms of TDP-43 were toxic, although the toxicity depended on an intact RNA recognition motif [59•]. Factors that affect the normal intracellular trafficking of TDP-43, between the cytoplasm and nucleus, may predispose to both the formation of abnormal aggregates (inclusions) and the loss of nuclear localization [60•].

The identification of TARDBP mutations in ALS has provided important clues to the possible pathogenic mechanisms involved in TDP-43 proteinopathies. The clustering of mutations in exon 6, that encodes the highly conserved C-terminal domain, suggests that TARDBP mutations may interfere with the normal protein-protein interactions of TDP-43, affect its transport through the nuclear pore or influence its exon skipping or transcriptional repression activity [50•,51••]. Numerous potential phosphorylation sites have been predicted to occur in the C-terminal region of TDP-43 and some mutations, especially the six substitutions to serine and threonine residues, may increase phosphorylation and aggregation. A single mutation c.640A>T (p.D169G) was identified in TARDBP exon 4 encoding RRM1 [50•]. This mutation may abrogate the RNA binding to this region; however, because it lies outside of exon 6 and lacks evidence of segregation with disease, it may also represent a rare benign sequence variant. Finally, a study of mutant TDP-43 in cell culture and in vivo revealed increased generation of detergent-insoluble TDP-43 fragments that could aggregate and cause a toxic gain-of-function [50•,51••]. Given the multifaceted role of TDP-43, multiple disease mechanism may well be involved.

Conclusions

The identification of pathological TDP-43 in FTLD-U and ALS confirms that these conditions are part of a disease spectrum with a common underlying biochemical mechanism. This insight has helped to clarify the relationship among the various genetic, clinical and pathological subtypes of FTD and ALS and has suggested possible mechanistic links with other neurodegenerative disorders. A better understanding of the role of TDP-43 in neurodegeneration will be crucial to the development of targeted therapeutic strategies for these conditions. Central to this process will be the use of experimental animals and cell systems, expressing pathogenic mutations in TARDBP or FTLD-U causing genes. The recent identification of elevated plasma levels of TDP-43, in some patients with neurodegenerative disease [61•], supports the possible use of TDP-43 as an in vivo biomarker to aid in diagnosis and monitoring the effects of therapy. In summary, the discovery that TDP-43 plays a central role in the pathogenesis of FTD and ALS has been a major advance towards the effective management of these devastating neurodegenerative conditions.

Diabetes, cardiovascular disease, and chronic kidney disease in South Asia: current status and future directions


South Asians are more susceptible to diabetes and cardiovascular diseases and have worse outcomes than other ethnicities, say Anoop Misra, Tazeen Jafar, and colleagues. They call for urgent action to provide screening and treatment, complemented by population level lifestyle modifications.

All South Asian countries have adopted the World Health Organization’s Global Action Plan for the Prevention and Control of Non-Communicable Diseases, which recommends a 25% relative reduction in the prevalence of raised blood pressure by 2025 and a halt to the rise in diabetes and obesity. Although considerable diversity exists between countries, all South Asians have markedly elevated risks of diabetes and variably elevated risks of cardiovascular disease compared with other ethnicities.12 In this paper, we review the burden of diabetes, cardiovascular disease, and chronic kidney disease in the region and policies to mitigate this burden. We identify key actions for health authorities and governments to attenuate the rise in non-communicable diseases and meaningfully improve outcomes for the millions of people with, or expected to develop, these diseases.

Methods

We gathered data on characteristics of populations and health systems from publicly available World Bank reports and WHO’s country profiles. Information on death and disability from cardiovascular disease, diabetes, and chronic kidney disease and their attributable risk factors came from Health Metrics and Evaluation’s data visualisation tool of the Global Burden of Disease Study 2015. We searched PubMed and Google scholar for relevant literature up to January 2017, using the terms “South Asians”, “diabetes”, “cardiovascular disease”, “myocardial infarction”, “stroke”, “renal”, and “kidney disease”. We formulated this paper by drawing from our collective experience in this field and the available literature.

Current epidemiology and trends

Cardiovascular disease, diabetes, and chronic kidney disease now account for 27%, 4.0%, and 3.0% of deaths, respectively, in South Asia (table 1).3456 Notwithstanding the limited quality and breadth of data, ischaemic heart disease is the leading cause of death in India, Pakistan, Nepal, and Sri Lanka, and stroke is the leading cause in Bangladesh.

The age standardised years of life lost as a result of cardiovascular disease has increased in South Asia in contrast to most other regions, where the reverse is true.5 In part, this is because cardiovascular disease events are more common in South Asia than in high income countries.78 Furthermore, acute myocardial infarction occurs six years earlier in South Asians than in European counterparts, probably owing to earlier onset of risk factors. Case fatality rates are higher in South Asia, especially in younger adults, thereby increasing the years of life lost.78 Stroke and chronic kidney disease may also occur earlier in South Asians.91011 The effect of lives lost due to premature cardiovascular disease is far worse in South Asia than elsewhere, as more than half of the population lives in conditions of poverty.3

Susceptibility to diabetes, cardiovascular diseases, and chronic kidney disease

The region has experienced rapid demographic, epidemiological, environmental, and economic transitions. These, coupled with unhealthy lifestyles of physical inactivity and consumption of a calorie dense diet, have increased the risk of non-communicable diseases. In addition, social disparities, wealth inequalities, and conflicts in the region contribute to high rates of stress associated behaviours including smoking.1112 Evidence from multi-country case-control studies indicates that hypertension, dyslipidaemia, smoking, obesity, diabetes, physical inactivity, low fruit and vegetable intake, and psychosocial stress attribute up to 90% of the population risk of cardiovascular disease in South Asians.1314 Age standardised blood pressure and cholesterol levels and prevalence of diabetes have increased in South Asia over the past decades.151617 High blood pressure and high blood glucose are the leading attributable risk factors for deaths from chronic kidney disease in every South Asian country (table 2).

Adverse metabolic factors are evident in South Asians at an early age. South Asian children have been shown to have adverse metabolic factors (hyperinsulinaemia, dyslipidaemia) compared with British children of similar age and body mass index and higher blood pressure than white children in the US.1819 Physical inactivity, dietary imbalances, and increasing obesity amplify this (fig 1).2021

 

Fig 1 Interacting risk pathways contributing to higher risks of diabetes and cardiovascular disease (CVD) in South Asians, acting over the life course. This begins with poor maternal nutrition and adverse programming, with neonates born at lower average birth weights yet higher fat to lean mass ratios compared with white children. This phenotype worsens over time, with greater weight gain and lower activity levels in South Asian children and adults, leading, in turn, via greater insulin resistance and CVD risk factors, to higher rates of diabetes and CVD, respectively. The parallel societal, political, and health considerations, as well as life course considerations, are also shown. BMI=body mass index; BP=blood pressure; CKD=chronic kidney disease

“>Figure1

Fig 1

 Interacting risk pathways contributing to higher risks of diabetes and cardiovascular disease (CVD) in South Asians, acting over the life course. This begins with poor maternal nutrition and adverse programming, with neonates born at lower average birth weights yet higher fat to lean mass ratios compared with white children. This phenotype worsens over time, with greater weight gain and lower activity levels in South Asian children and adults, leading, in turn, via greater insulin resistance and CVD risk factors, to higher rates of diabetes and CVD, respectively. The parallel societal, political, and health considerations, as well as life course considerations, are also shown. BMI=body mass index; BP=blood pressure; CKD=chronic kidney disease

 South Asian adults have greater risks of cardiovascular disease and diabetes, both of which tend to manifest around 5-10 years earlier than in white Europeans.10 The risk of cardiovascular disease is independent of that predicted by established risk factors. Possible mechanisms, among others, include an atherogenic dyslipidaemia driven by high concentrations of triglycerides and low concentrations of high density lipoprotein cholesterol, a pro-coagulant tendency, and higher concentrations of inflammatory cytokines.22 Further work is needed to define mechanisms for this excess cardiovascular disease risk. The risk factors vary by socioeconomic strata, geographical region, and migration.

Of particular importance, South Asian adults are more insulin resistant at any given body mass index and may experience more rapid β cell failure.2 They may progress more rapidly from a state of high risk of diabetes to frank diabetes and may have accelerated microvascular damage, with evidence of earlier diabetic nephropathy and retinopathy.2

Effects of poor and inconsistent treatment

Significant treatment gaps exist in South Asian populations. Studies report that less than half of all people with hypertension have received a diagnosis or treatment and less than a third have their blood pressure controlled with drugs.232425 The rates of diabetes awareness (50%), glycaemic control (<30%), and chronic kidney disease awareness (<15%) are suboptimal.24262728

Delay or prevention of diabetes in South Asians will require earlier intervention—that is, at lower levels of glycaemia. This requires wider testing and earlier use of antihyperglycaemic treatment, complemented with population-wide strategies to drive change in dietary habits and physical activity. Although antihypertensive, antidiabetic, and lipid lowering drugs are part of WHO’s list of essential medicines, availability in government primary care facilities is poor and patients must often pay out of pocket for these drugs. Social insurance schemes in countries are not available to the majority of the population,2930 and they tend to cover hospital based treatment and do not provide for standardised screening and medical management of these conditions in primary care.

Under-diagnosis and under-treatment result in higher rates of myocardial infarction and stroke, with adverse outcomes due to poor access to standardised and affordable treatment. Most patients with acute ischaemic heart disease are brought to the hospital too late to qualify for reperfusion therapy.31 Management in primary care is less than satisfactory, and many patients do not receive appropriate drugs owing to gaps in the knowledge and practices of healthcare providers.323334 The situation is much worse in rural areas, where an acute event is more likely to be fatal.3135

Health policies are not geared to respond to the rising challenge

Non-communicable diseases have been a recent addition to the policy agenda in all South Asian countries. Public health expenditure varies across countries, but overall investment is insufficient to support services for the prevention and management of cardiovascular disease, diabetes, and chronic kidney disease (table 3).36Implementation has been slow owing to donor agencies having limited interest in investing in non-communicable diseases and lack of engagement between governments and professional organisations in this field.

Table 3

Characteristics of health systems and policies for management of cardiovascular diseases and diabetes in South Asia

 In India, the National Programme for Prevention and Control of Cancer, Diabetes, CVD and Stroke has piloted opportunistic screening of risk factors for non-communicable diseases for people over 30 years of age. Furthermore, as part of the national health mission, the Indian government has outlined an operational plan for universal screening for hypertension and diabetes.31 A model of opportunistic screening for diabetes in patients with tuberculosis is being evaluated in Sri Lanka.37 Examples of successful public-private partnerships for non-communicable disease healthcare in the region are limited. Pakistan’s National Action Plan for Non-communicable Diseases is one such model,38 which involved a tripartite collaboration with Heartfile, a not for profit organisation, in formulation of policy and implementation in partnership with the government and WHO.

Recommendations

Progress towards the targeted reductions in death and disability from cardiovascular disease, diabetes, and chronic kidney disease would not be possible without concerted, multi-sectoral efforts by various government entities and non-government partners. We recommend the following essential policy and health system interventions.

Implementation of taxes on unhealthy foods

A tax of 20% on sugar sweetened drinks in India is projected to reduce the prevalence of overweight and obesity by 3.0% (95% confidence interval 1.6% to 5.9%) and the incidence of type 2 diabetes by 1.6% (1.2% to 1.9%) over the period 2014-23, assuming that consumption increases in line with current trends.39 In Mexico, an excise tax of 10% on sugar sweetened drinks decreased consumption by an average of 6% over one year.40 The Indian state of Kerala recently announced a “fat tax” on pizzas, burgers, sandwiches, and tacos sold through branded food outlets.41 Such strategies must be adopted in cities of South Asia that experience widespread marketing and consumption of unhealthy fast foods.

Furthermore, a 20% tax on palm oil purchases in India is projected to avert approximately 363 000 (95% confidence interval 247 000 to 479 000) deaths from myocardial infarctions and strokes over the period 2014-23 (1.3% reduction in cardiovascular deaths).42 Palm oil is consumed widely in low and middle income countries. It is high in saturated fat and causes a large increase in cholesterol concentrations. Empirical data from Mauritius show a reduction of 1 mmol/L in cholesterol concentrations through substitution of palm oil with soya oil.43 This reduction in cholesterol and low density lipoprotein cholesterol would equate to a 22% lower risk for cardiovascular disease, a huge effect by any standards.44

Strengthening of health system capacity to deliver care for non-communicable diseases

Strengthening of health systems and a well designed quality of care improvement framework are essential for concerted efforts to manage hypertension and diabetes for prevention of cardiovascular disease and chronic kidney disease. Shifting management of chronic diseases and risk factors from doctors to community healthcare workers holds promise and is being tested in rural areas in South Asia.34 Studies from Pakistan and India have shown that involving trained health workers in home health education on diet and physical activity and training general practitioners led to earlier diagnosis and better management of patients with hypertension or diabetes, and it was also cost effective.454647 Scaling up similar models is likely to offer substantial reductions in cardiovascular disease and chronic kidney disease in the medium to long term.

Screening populations at high risk (such as people who are sedentary, overweight, or smokers; those with hypertension; those with a family history of diabetes or premature cardiovascular disease in first degree relatives; and women with a history of gestational diabetes) is essential for early diagnosis. Low cost strategies such as validated simple screening questionnaires, blood pressure measurement, and, if possible, fasting or random blood glucose measurement, urinary dipstick for protein, and non-fasting cholesterol measurement, may be used. Although the cost effectiveness of opportunistic screening compared with universal screening is likely to vary according to the characteristics of the population, its value cannot be overstated for countries with a high prevalence of diabetes.48

Making antihypertensives, statins, and diabetes drugs available for free or at low cost in primary healthcare centres should be prioritised. This is consistent with achievement of universal health coverage, including access to quality and affordable essential medicines for all, as advocated in the United Nations’ sustainable development goals.49High quality generic drugs produced in the region can help to make this sustainable. Fixed dose drug combinations may improve coverage and long term adherence in people with established disease, but their widespread use in primary prevention is still debated.50 Health insurance reforms must provide for screening and primary care for these conditions to reduce out of pocket expenditure.51

Evidence is growing for m-health (mobile health technologies) interventions in improving adherence to treatment, maintaining appointments, data collection, and supporting health workers.52 More than 80% of the population of South Asia have mobile phones, and a large majority of villages are connected with mobile technology.53 This platform should be strongly considered in risk communication strategies and integration of care delivery for non-communicable diseases where feasible.

Public-private partnerships for non-communicable disease care should be encouraged to provide for unmet needs. Setting standards for long term public sector engagement; having transparent goals, inputs, and expectations; good governance of costs and fair allocation of profits; a shared vision and trust; and agreed processes for negotiation on common interests of partners are crucial to their success. The Sindh Institute of Urology and Transplantation in Karachi, Pakistan, providing dialysis services, and Aravind Eye Care System in India are good examples of successful public-private partnerships in the region.5455

Consideration of population based strategies to promote a healthy lifestyle

Community based interventions to promote a healthy diet and physical activity and reduce smoking and stress will go a long way in delaying the onset of these diseases. The Indian Diabetes Prevention Program, and more recently the D-CLIP study, showed the effectiveness of lifestyle intervention in reducing the development of diabetes in people at high risk, while concurrently tackling problems with community acceptability and long term sustainability.5657

School health programmes, encouraged by WHO to inform children about risk factors for non-communicable diseases and promote physical activity, have been hindered by low education budgets and poor infrastructure. There are no restrictions on advertising unhealthy food to minors.58 Such legislation must be complemented with multi-sectoral action including involvement of schools and workplaces to influence diet and physical activity.

Investment in surveillance and research

Surveillance and monitoring are critical to raise awareness and inform policy and implementation. Although the WHO STEPS instrument (www.who.int/chp/steps/instrument/en/) for collecting data on risk factors for non-communicable diseases has been used in community based studies in South Asia, national implementation is lacking.59 All South Asian countries must institutionalise risk factor surveillance and establish robust cardiovascular disease, diabetes, and chronic kidney disease registries to track trends and monitor progress. Surveillance data must be shared publicly to create awareness.

Evidence on effective interventions to prevent and control non-communicable diseases in the region is very limited. The effect of school, workplace, and community based interventions must be evaluated. Research comparing single versus multiple risk factor screening, as well as opportunistic and targeted screening versus universal screening in all adults, will help to tailor screening strategies. Policy initiatives such as taxes and diet substitution must be rigorously evaluated for their feasibility and impact at a population level.

Conclusion

Capacity building, financing, and a strong quality assurance framework are crucial for the effectiveness, scalability, and long term sustainability of initiatives to curb non-communicable diseases in the South Asia region.

Key messages

  • South Asians are more likely than other ethnicities to develop diabetes, cardiovascular disease, and chronic kidney disease, and these often have an earlier onset and poor outcomes

  • Strategies for early diagnosis and treatment including awareness generation, opportunistic screening, availability of low cost drugs, and task shifting to health workers must be prioritised

  • Countries must consider taxation on unhealthy foods, restrictions on advertising, and appropriate food labelling.

source: BMJ

107 studies published in a cancer journal have just been retracted 


In a massive cleanup, 107 articles have just been retracted from the open-access cancer research journal Tumor Biology.

“After a thorough investigation we have strong reason to believe that the peer review process was compromised,” writes editor-in-chief Torgny Stigbrand in the retraction notice.

Peer review is one of the golden standards that help sort the wheat from pseudoscientific babbling, making the process an integral part of academic publishing.

But there is massive publishing pressure in the scientific community, and with about 2.5 million papers published each year, some of those inevitably end up cutting corners. In this case, the transgression was what’s known as ‘fake peer review’.

Scientists are often asked to provide recommendations for potential reviewers of their work. While that sounds like an obvious invitation to cheat, it actually makes sense when the work is really specific and few others do similar research.

But it’s easy to game the system by providing a fake reviewer email address, impersonating an actual researcher and sending the journal a super-positive review in their name.

“The articles were submitted with reviewer suggestions, which had real researcher names but fabricated email addresses,” Springer representative Peter Butler told Yan Jie at Sixth Tone.

It’s a pretty massive lot of retractions all at once, but a few of the big academic publishers have been sweeping their portfolios for potential breaches, including fake peer review, plagiarism, data fabrication and more.

This time, the 107 papers were published between 2012 and 2016, and most were authored by Chinese researchers, although that doesn’t automatically reflect poorly on their scientific work.

Chinese scientists are known to rely on third-party agencies that provide language editing services, which give the papers a polish, increasing the chance of getting accepted. But it’s possible those companies have also done the authors a massive disservice.

“There is some evidence that so-called third-party language-editing services play a role in manipulating the reviewing process,” an unnamed Springer spokesperson told Cathleen O’Grady at Ars Technica.

While we don’t have details on whether any of the authors had a hand in contributing fake reviews, experts are willing to chalk at least some of the breaches up to those third-party companies, some of which are known to operate unethically.

“If the authors didn’t realise that this is what the editing company was doing, then I feel the authors should have a fair chance,” Elizabeth Wager, editor of the journal Research Integrity & Peer Review, told Ars Technica.

“There’s probably nothing wrong with the research; it just hasn’t been peer reviewed.”

China is one of the biggest scientific contributors in the world, producing more than 300,000 papers every year. With strides in nuclear fusion and revolutionary CRISPR experiments, Chinese researchers are major players in the international research scene.

But any large industry gets its share of scandals. For example, just last year news broke that 80 percent of data in Chinese clinical trials had been fabricated.

As for Tumor Biology, the journal actually moved from Springer to SAGE late last year, and the new publisher was made aware of the investigation into potential peer review fraud. The journal is run by the International Society of Oncology and BioMarkers.

“The society were open about the past instances of peer review fraud, and as part of the relaunch they wanted to address the underlying reasons,” a SAGE spokesperson told Alison McCook at Retraction Watch.

“As part of their transition to a new publisher, the Tumor Biology editorial team have already introduced new robust peer review practices expected from all SAGE journals.”

Generic drugs: Review and experiences from South India


Abstract

The cost of pharmaceuticals, as a percentage of total healthcare spending, has been rising worldwide. This has resulted in strained national budgets and a high proportion of people without access to essential medications. Though India has become a global hub of generic drug manufacturing, the expected benefits of cheaper drugs are not translating into savings for ordinary people. This is in part due to the rise of branded generics, which are marketed at a price point close to the innovator brands. Unbranded generic medicines are not finding their way into prescriptions due to issues of confidence and perception, though they are proven to be much cheaper and comparable in efficacy to branded medicines. The drug inventory of unbranded generic manufacturers fares reasonably when reviewed using the World Health Organization-Health Action International (WHO-HAI) tool for analysing drug availability. Also, unbranded generic medicines are much cheaper when compared to the most selling brands and they can bring down the treatment costs in primary care and family practice. We share our experience in running a community pharmacy for an urban health center in the Pathanamthitta district of Kerala State, which is run solely on generic medicines. The drug availability at the community pharmacy was 73.3% when analyzed using WHO-HAI tool and the savings for the final consumers were up to 93.1%, when compared with most-selling brand of the same formulation.

Keywords: Drug availability, drug industry/legislation and jurisprudence, drugs, economic competition, essential medicines, generic*, generic medicines, global health, India, patents as topic/legislation and jurisprudence*, poverty, unbranded generics

Introduction

The World Health Organization (WHO) estimates that almost 30% of the world population lacks access to essential medicines and that the figure will rise to more than 50% in some countries of Africa and Asia.[1] The cost of the pharmaceuticals is the main factor that hampers access to medicines and the governments in poor countries seem to be doing very little to counter this problem. The public sector availability of essential medicines was less than 50% in most of the countries of Africa and Asia.[2] This is appalling in the face of increases in healthcare expenditure in most of the developing nations, mostly financed through secured loans by international development banks and consortia.

The situation in India is not very different than that of other developing nations. Healthcare expenditures have been growing in India, both in real terms and also when considered as a proportion of the Gross Domestic Product (GDP).[3] However, even with this recent increase in healthcare spending, India’s expenditure on health is nowhere near that of OECD (Organisation for Economic Cooperation and Development) nations.[4] The total public spending on healthcare in India accounted for only around 1.2% of GDP in 2012, with the per-capita spending on health around USD 160. This is a miniscule amount when compared against the OECD per-capita healthcare spending of USD 3,484 in 2012.[3,4] This shows that the healthcare spending in the country is set to rise further in the coming years and the healthcare industry is all set for a boom time.

The cost of medicines and pharmaceuticals as a percentage of total healthcare spending has also been rising worldwide.[5] It is the fastest-growing item in the healthcare budgets worldwide and it varies between 20-60% in various healthcare budgets of countries.[6] By 2020, the prescription drug market in United States of America is set to grow to USD 700 billion (B) and China will be USD 260 B.[5] Though no credible predictions about the Indian pharmaceutical industry are available, it is quite safe to assume that Indian pharmaceutical industry will also grow manifold. The growth of the pharmaceutical market worldwide and its increased share in total healthcare spending will reignite the age-old debate on how to balance the cost of innovation in drug research and universal access to the fruits of that research.[7]

Rise of Generics

The role of generic medicines in reducing the healthcare expenditure has been recognised for a long time. Multiple studies have proven that saving through substitution of originator brands by cheaper generic medicines, savings in the range of 10-90% can be achieved.[8] Most national governments have been encouraging the use of generic medicines worldwide and many healthcare systems have policies of substituting expensive branded original medications with generic medicines.[9] In the United States, generic substitution (GS) is an accepted practice and at the end of 2012, almost 80% of all the prescriptions were of generic medications. This has resulted in a substantial moderation of expenditure growth in widely used drugs and significant savings to the economy.[6] In the United Kingdom, GS is now a standard practice in hospitals operated by the National Health Service (NHS) and medical schools have included generic prescribing as a part of their medical training.[10]

In India, the procurement price of essential medicines is generally lower than the mean International Reference Pricing (IRP) but availability of these drugs in the public sector has always been a problem. The exorbitant cost of some of the commonly used medications in private pharmacies makes it inaccessible to majority of the poor.[11] Also, the difference between procurement prices and retail prices in case of some of the generic medicines, were as high as 28 times, which shows a very high margin of profit-taking in view of limited price control mechanisms.[11] It is in this light, that the government revised the National Pharmaceutical Pricing Policy in 2012. It gave methods to calculate ceiling prices for drugs which are under the National List of Essential Medicines (NLEM) which was modified in 2011. It gave a formula for deciding the ceiling prices for drugs under NLEM, using a market-based pricing (MBP) method, taking into account the prices of all manufacturers having a market share of more than 1% nationally.[12] The Drug Price Control Order of 2013 was a follow-up to the National Pharmaceutical Pricing Policy and gave the price ceiling for 348 drugs and over 600 formulations. However, the action was considered inadequate by many activists lobbying for cheaper drugs and they termed it as a sell-out to international pharmaceutical companies.[13]

Indian Pharmaceutical Industry

The multiplicity of brands and manufacturers makes it difficult to decipher the actual market dynamics and the structural issues in the Indian pharmaceutical industry. The complexity of the market and the intensity of the competition between companies in India have made the country a hub for manufacture of generic medicines, earning a sobriquet “pharmacy of the developing world.”[14] This, along with a favorable governmental stance has made India a powerhouse in this field, bringing it into direct confrontation with certain developed nations where most of the big multinational pharmaceutical companies are located[14] There have been many instances when the Indian Patents Office and the Supreme Court of India effectively used certain flexibilities of the Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement of the World Trade Organization and also the safeguards embedded in the Indian Patents Act. The compulsory licensing of Sorafenib, a drug used in treatment of advanced liver and renal cancer and the rejection of patent application for Imatinib, a drug used in the treatment of leukaemia, were considered as landmark decisions by many state and non-state organizations involved in pharmaceutical sector.[15,16]

Considering the Indian scenario, we can divide the brands into innovator brands (IB), most-selling generics (MSG), and least-priced generics (LPG).[17] The IBs will be at the highest price point, followed by MSGs and LPGs. A new category of generic drugs known as unbranded generics (UB) are also coming into the market now. These drugs are usually manufactured by not-for-profit organizations or are subsidised by certain non-governmental organizations (NGO).[18] Though the price points of these different categories of drugs are different, their efficacies are comparable. This fact has been proved by multiple studies all over the world and it belittles the reasoning which goes behind differential pricing of the same drug.[19,20] Even though it has been proved that there is not much difference in efficacy between the above categories of drugs, physicians tend to prescribe drugs manufactured by highly-reputed companies. Their trust is often misplaced as most of these leading companies market drugs manufactured by less-known manufacturers.[18]

A Model Community Pharmacy: Experiences from South India

Pushpagiri Medical College, which is a teaching hospital in Kerala state of India partnered with a social organization, Bodhana Social Service Society, involved in poverty alleviation and income generation programmes, to start an urban health center with an objective to improve patient accessibility to cost-effective medical care. The urban health center serves a population of 10,000, spread over 5 municipal wards of Tiruvalla municipality and was intended as a model for cost-effective primary care. A comprehensive population survey was carried out before the start of the project and the health center started functioning in September 2014. As a part of the initiative, a community pharmacy was opened to stock unbranded generic drugs manufactured by two non-governmental organizations. Low-Cost Standard Therapeutics (LOCOST), Baroda and Comprehensive Medical Supplies India (CMSI), Chennai were the two NGOs providing us with the drugs which were needed at the community pharmacy.[21,22] The drugs were provided to us at a nominal cost, after we provided an undertaking that the Pushpagiri Medical College is a charitable institution with no intention of making profits. Also, the physicians working at the health center made a collective decision to prescribe all the drugs generically and the pharmacist was advised to dispense the cheapest generic brand.

The drug inventory available with these not-for-profit manufacturers were fairly comprehensive when reviewed using the World Health Organization-Health Action International (WHO-HAI) tool for quantifying availability of essential medicines.[23] The WHO-HAI tool is a validated method for measuring availability of drugs in a health system and includes 30 core medicines: 14 essential medicines for global burden of disease and 16 medicines specific to the WHO region [Table 1].[24]

Table 1

Drug inventory of LOCOST, Baroda and CMSI, Chennai: Review using WHO-HAI tool for WHO South East Asian Region

The WHO-HAI tool showed a drug availability of 73.3% for LOCOST, Baroda and 43.3% for CMSI, Chennai. This is much better when compared to drug inventory in public hospitals in other parts of India, assessed using the same methodology.[11] There are a multitude of companies and NGOs manufacturing UB medicines and the drug inventory of a health system can be made comprehensive through a mixed purchase model where procurement is done from multiple vendors.[23]

Similarly, unbranded generic drugs offered significant savings to the health system in terms of costs involved for procurement. When reviewed against the MSBs, UB medicines were costing only a fraction of the maximum retail price (MRP) of MSPs [Table 2].

Table 2

Comparison of drug prices of most-selling brands and their generic counterparts: drugs identified by WHO-HAI tool for WHO South East Asian Region[17,25]

The community pharmacy has been in operation since September 2014, and stocks over 120 formulations manufactured by unbranded generic manufacturers. In addition, it also supplies LSG to augment the drug inventory of the pharmacy. There is a family physician and a general practitioner who run the center, apart from regular specialist visits from Pushpagiri Medical College Hospital. The urban health center has an outpatient load of 20-25 patients a day within 6 months of starting operations. The staff from the center is providing services to 3 old-age homes and a few surrounding schools and the drugs from the community pharmacy is being used for free supply during the medical camps conducted by the department of community medicine.

The patients and the physicians have responded positively to this novel initiative and the general acceptability has been found to be high, though objective studies to assess the same are yet to be done. Some physicians have suggested replicating this model in other similar health initiatives also. The financial sustainability of the model is still unproven, and the urban health center along with the community pharmacy is being sustained with large subsidies provided by Pushpagiri Medical College and Bodhana Social Service Society. The cost of setting-up such a facility was around INR 500,000, which includes the furniture, basic medical equipment, basic lab accessories, and first round of procurement for the community pharmacy and is exclusive of the capital expenditure on the building. The average monthly expenditure in running the health center, has been around INR 150,000 a month, including salaries, cost of consumables and medicines and exclusive of building rent and depreciation. The income earned by the center is around INR 40,000, and there is an excess of expenditure over income to the range of more than INR 100,000 a month, which is subsidised by Pushpagiri Medical College and Bodhana Social Service Society. Both the organizations are charitable societies run by a prominent religious group and the subsidies are meant to further their commitment to social causes.

The community pharmacy concept faced the following key challenges:

  • Absence of intermediaries for drug procurement results in inordinate delays in transit, mainly on account of the tardy services rendered by private logistics companies
  • Advance payment in full has to be remitted to the bank accounts of these NGOs for supply of drugs, which goes against the standard practice of procurement followed in hospitals. This has been an issue with the internal audit department
  • The difference between procurement price and the MRP is minimal and this is causing worries of long-term financial sustainability of the community pharmacy model
  • Packaging of the drugs is unattractive in some cases, resulting in difficulty to convince patients about the efficacy of the drug
  • We have faced difficulty in convincing some of the specialist doctors on the quality of the drug, despite providing ample literature proving the efficacy of unbranded generic drugs.

The Way Forward

Many studies have revealed apprehensions among physicians in prescribing UB medicines to their patients. Most of these apprehensions are related to quality of the product and the fear of losing patients.[26] Along with these unfounded concerns, poor patient acceptability due to various issues like poor packaging, lack of brand promotion initiatives, etc., are affecting the extend of penetration of UB drugs in the country, even though India is becoming a lifeline for all developing countries in the supply of generic medicines.[27] The government and the policy makers in India and other similar developing countries should focus on building the confidence of physicians and the patients regarding unbranded generic medications. The demand side management should include a multifaceted approach in which issues of different stakeholders are addressed and affirmative actions taken in favour of unbranded generic medicine manufacturers.[27] Another important issue is concerning the inherent deficiencies and implementation status of the Drug Price Control Order of 2013. The said order has been criticised extensively for being myopic in its approach, as the number of formulations included is less than 20% of the whole pharmaceutical market. Also, it gave ample space for pharmaceutical companies to tweak their marketing strategies by focussing on formulations and dosages not covered by the Drug Price Control Order. It also leaves out the important area of fixed-dose combinations (FDCs), a potential loop-hole for the pharmaceutical companies to exploit fully. It is indeed distressing to note that more than 90% of the diabetic drug market is out of the purview of this order.[13] The policy makers in the country needs to get a realisation that the share of drugs in out-of-pocket expenditure (OPP) is around 80% in India and a tighter regulatory framework is needed to protect the consumers against exploitation.[28]

In the future, we intend to do a study on the perception about generic drugs, among the treating physicians and the patients who form the clientele of the community pharmacy. This can help us to understand the issues which affect the actual stakeholders and find means to improve the acceptability and penetration of generic medicines. Also, after the yearly financial audit, we plan to do a cost-benefit analysis to objectively analyse the efficacy of the model in monetary terms.

References

1. The World Medicines Situation 2011. The World Health Organisation. [Last accessed on 2015 Mar 2]. Available from: http://apps.who.int/medicinedocs/documents/s18772en/s18772en.pdf .
2. Cameron A, Ewen M, Ross-Degnan D, Ball D, Laing R. Medicine prices, availability, and affordability in 36 developing and middle-income countries: A secondary analysis. Lancet. 2009;373:240–9. [PubMed]
3. Health Expenditure, Total (% of GDP) | Data | Table. [Last accessed on 2015 Mar 2]. Available from: http://data.worldbank.org/indicator/SH.XPD.TOTL.ZS .
4. Microsoft Word-Briefing-Note-INDIA-2014-doc-Briefing-Note-INDIA-2014.pdf. [Last accessed on 2015 Mar 2]. Available from: http://www.oecd.org/els/health-systems/Briefing-Note-INDIA-2014.pdf .
5. Daemmrich A, Mohanty A. Healthcare reform in the United States and China: Pharmaceutical market implications. J Pharm Policy Pract. 2014;7:9. [PMC free article] [PubMed]
6. Hoffman JM, Li E, Doloresco F, Matusiak L, Hunkler RJ, Shah ND, et al. Projecting future drug expenditures–2012. Am J Health Syst Pharm. 2012;69:405–21. [PubMed]
7. Sax P. Spending on medicines in Israel in an international context. Isr Med Assoc J. 2005;7:286–91.[PubMed]
8. Cameron A, Mantel-Teeuwisse AK, Leufkens HG, Laing RO. Switching from originator brand medicines to generic equivalents in selected developing countries: How much could be saved? Value Health. 2012;15:664–73. [PubMed]
9. Hassali MA, Alrasheedy AA, McLachlan A, Nguyen TA, Al-Tamimi SK, Ibrahim MI, et al. The experiences of implementing generic medicine policy in eight countries: A review and recommendations for a successful promotion of generic medicine use. Saudi Pharm. 2014;22:491–503. [PMC free article][PubMed]
10. Duerden MG, Hughes DA. Generic and therapeutic substitutions in the UK: Are they a good thing? Br J Clin Pharmacol. 2010;70:335–41. [PMC free article] [PubMed]
11. Kotwani A, Ewen M, Dey D, Iyer S, Lakshmi PK, Patel A, et al. Prices and availability of common medicines at six sites in India using a standard methodology. Indian J Med Res. 2007;125:645–54.[PubMed]
12. Copy of f1.pdf – NPPPNotification.pdf [Internet] [Cited 2015 Mar 2, Last accessed on 2015 Mar 2]. Available from: http://www.nppaindia.nic.in/NPPPNotification.pdf .
13. Paying the Price – The Hindu. [Last accessed on 2015 Mar 2]. Available from: http://www.thehindu.com/opinion/op-ed/paying-the-price/article4912732.ece .
14. Kapczynski A. Engineered in India–patent law 2.0. N Engl J Med. 2013;369:497–9. [PubMed]
15. Bhaumik S. India’s rejection of Novartis’s patent is but a small step in the right direction. BMJ. 2013;346:f2412. [PubMed]
16. Lancet Oncology. Is India ready to lead the battle for fair access to medicines? Lancet Oncol. 2013;14:437. [PubMed]
17. Bhargava A, Kalantri SP. The crisis in access to essential medicines in India: Key issues which call for action. Indian J Med Ethics. 2013;10:86–95. [PubMed]
18. Amit G, Rosen A, Wagshal AB, Bonneh DY, Liss T, Grosbard A, et al. Efficacy of substituting innovator propafenone for its generic formulation in patients with atrial fibrillation. Am J Cardiol. 2004;93:1558–60. [PubMed]
19. Kesselheim AS, Stedman MR, Bubrick EJ, Gagne JJ, Misono AS, Lee JL, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: A systematic review and meta-analysis. Drugs. 2010;70:605–21. [PMC free article] [PubMed]
20. Asia Pacific Ecumenical News-News. [Last accessed on 2015 Mar 2]. Available from: http://apenews.org/newsread.asp?nid=163 .
21. LOCOST: Medicines within the Common Man’s Reach | The Alternative. [Last accessed on 2015 Mar 2]. Available from: http://www.thealternative.in/business/locost- affordable-medicine-drugscommon-man-reach .
22. Where Are We Now: Assessing the Price, Availability and Affordability of Essential Medicines in Delhi as India Plans Free Medicine for All. [Last accessed on 2015 Mar 2]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733775 . [PMC free article] [PubMed]
23. Madden JM, Meza E, Ewen M, Laing RO, Stephens P, Ross-Degnan D. Measuring medicine prices in Peru: Validation of key aspects of WHO/HAI survey methodology. Rev Panam Salud Publica. 2010;27:291–9. [PubMed]
24. Drug Price List. List of Generic Names in Alphabetical Order. [Last accessed on 2015 Mar 2]. Available from: http://www.medindia.net/drug-price .
25. Generic Index | DrugsUpdate India. [Last accessed on 2015 Mar 2]. Available from: http://www.drugsupdate.com/generic/listing .
26. Waning B, Diedrichsen E, Moon S. A lifeline to treatment: The role of Indian generic manufacturers in supplying antiretroviral medicines to developing countries. J Int AIDS Soc. 2010;13:35. [PMC free article][PubMed]
27. Shrank WH, Choudhry NK, Liberman JN, Brennan TA. The use of generic drugs in prevention of chronic disease is far more cost-effective than thought, and may save money. Health Aff (Millwood) 2011;30:1351–7. [PubMed]
28. Thakkar KB, Billa G. Light at the end of the tunnel: The Great Indian Pharmacoeconomics story. Front Pharmacol. 2013;4:153. [PMC free article] [PubMed]
Source:www.ncbi.nlm.nih.gov

Preoperative ACE and ARB: To hold or to withhold?


Treating physicians of patients undergoing (non-cardiac) surgery frequently decide to withhold both angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) before the operation, mostly out of concern regarding intraoperative hypotension. But does the continuing administration / withholding of these drugs really affect clinical outcomes? The current US-Canadian-British prospective cohort study says yes: Withholding ACE inhibitors and ARBs before surgery decreased the likelihood of 30-day all-cause mortality, stroke and myocardial injury by 18 percent.

The study was based on data from approximately 14,700 patients (including 4,800 ACE inhibitor / ARB users) who underwent non-cardiac surgery between 2007 and 2011. The primary composite outcome was all-cause death, stroke, or myocardial injury after non-cardiac surgery at 30 days; secondary outcomes included intraoperative and postoperative clinically important hypotension.

Compared to patients who continued their preoperative use of ACE-inhibitors and ARBs, the users who stopped their drugs in the 24 hours before surgery were less likely to experience the primary composite outcome (12.0 % versus 12.9 %; adjusted relative risk [aRR] 0.82; P = 0.01) and intraoperative hypotension (aRR, 0.80; P < 0.001). By contrast, both groups had a similar risk of postoperative hypotension (aRR, 0.92; P = 0.36).

Withholding ACE inhibitors and ARBs before major non-cardiac surgery is associated with a lower risk of death and postoperative vascular events, but a large randomized trial is required to confirm these findings. Until then, the authors recommend that patients withhold these two drugs in the 24 hours before undergoing surgery.

Abstract

Background: The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown.

Methods: In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes.

Results: Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery.

Conclusions: Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24 h before surgery.

What We Already Know about This Topic
  • Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are commonly withheld before surgery for concern over intraoperative hypotension, but whether this affects clinical outcomes is unclear

What This Article Tells Us That Is New
  • In a secondary analysis of 4,802 patients on these drugs in the Vascular events In noncardiac Surgery patIents cOhort evaluatioN prospective cohort study, those in whom the drugs were withheld in the 24 h before surgery were less likely to suffer a composite outcome of 30-day all-cause death, stroke, or myocardial injury (18% adjusted relative risk reduction)

MORE than 200 million people have major noncardiac surgery worldwide each year.1  Of those, millions die or suffer a major vascular complication during the perioperative period.2,3 Perioperative hypotension has been associated with myocardial infarction (MI), stroke, and death.2,4–6 
By blunting the effect of the sympathetic system on vascular tone, anesthesia may increase reliance on the renin–angiotensin and vasopressor systems to maintain blood pressure. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), which are commonly used in patients with a history of, or risk factors for, cardiovascular disease, block the physiologic renin–angiotensin response to hypotension.7 
Current guidelines from the American College of Cardiology and American Heart Association recommend continuing ACEI/ARBs in the setting of noncardiac surgery; these recommendations are based on data from small randomized trials and observational studies with significant risk of bias.8  By contrast, many anesthesia groups routinely withhold ACEI/ARBs on the day of surgery to avoid intraoperative hypotension.9,10  Without strong evidence, the practice of withholding ACEI/ARBs on the day of surgery appears to depend largely on provider preference and local policy.
The primary objective of this study was to test the hypothesis that withholding ACEI/ARBs (compared to continuing them on the day of surgery) is associated with a lower risk of the 30-day composite outcome of all-cause death, myocardial injury after noncardiac surgery (MINS), and stroke. Secondary objectives included determining the relationship between withholding ACEI/ARBs and perioperative clinically important hypotension and the association between perioperative clinically important hypotension and the 30-day risk of the composite outcome of all-cause death, MINS, and stroke.
Materials and Methods
Cohort
We conducted analyses in a sample from the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) study—a prospective international cohort study—that included 16,079 patients from 12 centers in eight countries (throughout North and South America, Australia, Asia, and Europe) recruited from August 2007 to January 2011 (ClinicalTrials.gov identifier: NCT00512109). The research ethics board at each site approved the protocol before patient recruitment.
Previous reports have described the VISION cohort study.11–13 Briefly, participants at least 45 yr old undergoing noncardiac surgery who required an overnight hospital admission with general or regional anesthetic were screened sequentially, and if eligible and consenting, they answered a series of questions regarding their past medical, surgical, and social history. Study personnel reviewed medical charts for additional history.
Outcomes
Our primary outcome was a composite of 30-day all-cause death, MINS,12  and stroke. These components were selected to fulfill the requirements for a valid composite outcome (i.e., including mortality avoided competing risks, each component could influence clinical practice as they all impact 30-day mortality, and one would anticipate that they would be affected by ACEI/ARBs similarly).14 MINS was defined as any peak non–high sensitivity cardiac troponin T (cTnT) value greater than or equal to 0.03 ng/ml resulting from myocardial ischemia (i.e., without evidence of a nonischemic etiology) that occurred within the first 30 days after surgery.12 Stroke was defined as a new focal neurologic deficit thought to be vascular in origin with signs and symptoms lasting more than 24 h.
Throughout each patient’s hospital stay, research personnel performed clinical evaluations and reviewed medical records. We measured cTnT using the Roche fourth-generation Elecsys assay (Germany) to assess for myocardial injury 6 to 12 h postoperatively and on the first 3 days after surgery. Research staff obtained other information on death and stroke from in-hospital follow-up, review of medical records, and a follow-up telephone interview conducted with the patients or their caregivers 30 days after surgery. If the patient interview indicated the occurrence of an outcome, their primary care physicians were contacted to obtain further documentation. Physicians experienced in perioperative medicine adjudicated death, MINS, and stroke.
Secondary outcomes of interest included clinically important intraoperative and postoperative hypotension, defined a priori as systolic blood pressure (sBP) less than 90 mmHg for any duration for which an intervention was initiated (including initiation or intensification of intravenous fluids, use of vasopressors or inotropes, blood transfusion, or intraaortic balloon pump therapy) that occurred during surgery (intraoperative hypotension) and during postoperative days 0 to 3 (postoperative hypotension).
Definitions for all variables are available in Supplemental Digital Content 1, http://links.lww.com/ALN/B326, under Variable Definitions.
Analyses
We performed the analyses using Stata (version 13.1 MP; Stata Corp, USA). All hypothesis tests were two sided; P < 0.05 denoted statistical significance.
Primary Objective
Relationship between Withholding versus Continuing Preoperative ACEI/ARBs and the Composite of Death, MINS, or Stroke.
Among patients who used ACEI/ARBs during the 7 days before surgery (i.e., baseline users), we compared outcomes of patients who did not take ACEI/ARBs within 24 h before surgery to the outcomes of those who did. We used multivariable modified Poisson regression15  to estimate relative risks adjusted for a large set of potential confounders (listed in table 1 and table S1 in Supplemental Digital Content 1, http://links.lww.com/ALN/B326), including patient characteristics, preoperative use of antihypertensive medications and antiplatelet agents or anticoagulants that may contribute to perioperative bleeding (use vs. no use 1 to 7 days before surgery), continuation, withholding, or new initiation of these medications on the day of surgery, and the type and the timing of surgery (elective vs. urgent or emergency surgery). We also accounted for potential center effects using a cluster-robust variance estimator16  with study centers as clusters. We used restricted cubic spline functions to model continuous variables (preoperative sBP, age, body mass index, and estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration equation).17  We did not study the effects of withholding ACEI/ARBs or other antihypertensive medications after surgery because the timing of postoperative medication use was not captured with sufficient precision in VISION.
Table 1.

Abridged Cohort Characteristics

Abridged Cohort Characteristics

Secondary Objectives
Effect of Preoperative sBP on the Relationship between Withholding of Preoperative ACEI/ARBs and the Composite of Death, MINS, or Stroke.
We tested whether the relationship between withholding versuscontinuing ACEI/ARBs and the primary outcome was consistent across different levels of preoperative sBP. We used tests of interaction in a multivariable fractional polynomial approach with the algorithm outlined by Royston and Sauerbrei18  to search for the optimal functional form of preoperative sBP that would significantly modify the effect of withholding ACEI/ARBs, where sBP was analyzed as a continuous variable.
Relationship between Clinically Important Hypotension and Withholding Preoperative ACEI/ARBs and Separately the Composite of Death, MINS, or Stroke.
We undertook multivariable modified Poisson regression analyses as the primary objective to explore the relationship between clinically important intraoperative and, separately, postoperative hypotension and withholding versus continuing ACEI/ARBs in the 24 h before surgery.
In all patients (not limited to ACEI/ARB users), we undertook similar multivariable modified Poisson regression analyses to study the relationship between intraoperative and, separately, postoperative clinically important hypotension and the composite of death, MINS, and stroke.
Variation in Withholding Preoperative ACEI/ARBs.
We estimated the proportion of variation in the practice of withholding or continuing ACEI/ARBs preoperatively that could be explained by study center, patient, and surgical factors. We first constructed a multivariable logistic regression model to predict the preoperative withholding of ACEI/ARBs with demographics, clinical factors, surgical factors, and the study center as independent variables. We next constructed a model that included only surgical factors and study center, and we compared it to the full model that also included demographics and clinical factors using a likelihood ratio test to determine whether clinical factors made a significant independent contribution to the explained variation. If the test was statistically significant, we estimated the independent contribution of clinical factors by subtracting the R2 of the model without clinical factors (calculated using the method of McKelvey and Zavoina19 ) from the full model. We repeated the same process for surgical factors and study center. We took variation that could not be explained by these factors as reflecting provider preference.
Sensitivity Analyses
To test for residual confounding, we performed tracer analyses with significant intraoperative bleeding that resulted in intraoperative blood transfusion and significant bleeding within 30 days that required transfusion of blood products or reoperation. These common outcomes were associated with increased risk of our primary outcome but are unlikely to be influenced by withholding ACEI/ARBs. Failing to detect these associations would lend support for a causal nature to our primary results.20,21 
We additionally looked for associations between withholding versuscontinuing other antihypertensive agents and our primary outcome. If withholding of several of these agents was associated with the primary outcome in the same direction as withholding of ACEI/ARBs, this may again suggest residual confounding.
We also conducted three post hoc sensitivity analyses in response to comments from peer reviewers. First, we repeated our main analyses using logistic regression in place of modified Poisson regression. Second, we repeated our main analyses based on the composite outcome of all-cause death, MI, and stroke at 30 days after surgery. Third, we examined the effect of progressively longer durations of intraoperative hypotension on the primary composite of death, MINS, or stroke at 30 days after surgery and performed a statistical test to assess for trend.
Approach to Missing Data
We excluded patients who did not have complete preoperative medication data or postoperative blood pressures recorded or (among those who did not die or experience a stroke) did not have a cTnT level measured or recorded correctly (e.g., recorded as less than 0.04 ng/ml instead of exact value). We imputed all other missing data using single stochastic conditional imputation with predictive mean matching for continuous variables22  and logistic regression for any other missing variables, both with fully conditional specification.23  We included all variables and outcomes in the imputation model.
Results
We analyzed data from 14,687 (91.3%) of the 16,079 recruited patients (fig. 1) of whom 1,409 (9.6%) died or suffered a nonfatal stroke or MINS; MINS occurred in 1,160 patients (7.9%), stroke in 90 (0.6%), and death in 302 (2.1%). We imputed missing baseline characteristics (mostly serum creatinine, height, and weight) for 10.3% of the included patients. The prevalence of most baseline characteristics differed among patients who suffered an event compared to those who did not (table 1 and table S1 in Supplemental Digital Content 1, http://links.lww.com/ALN/B326). Table S2 (Supplemental Digital Content 1, http://links.lww.com/ALN/B326) shows that the 8.7% of patients who were omitted from the analysis for missing data were similar to those included.
Fig. 1.
Participant flowchart. VISION = Vascular events In noncardiac Surgery patIents cOhort evaluatioN.

Participant flowchart. VISION = Vascular events In noncardiac Surgery patIents cOhort evaluatioN.

Six thousand eight hundred fifty-six (46.7%) patients were taking an antihypertensive agent at baseline (i.e., within 1 to 7 days before surgery); 4,120 (60.1%) used a single agent; 2,131 (31.1%) used two medications; and 605 (8.8%) used three or more. Four thousand eight hundred two patients took ACEI/ARBs at baseline; 2,275 of them (47.4%) were also using at least one other antihypertensive medication. Among all antihypertensive medication users, 1,794 (26.2%) had at least one of these medications withheld on the day of surgery (table 2). Typically only one antihypertensive agent was withheld (79.3% of patients), even in patients taking multiple agents at baseline. Patients with lower preoperative blood pressure were more likely to have their medications withheld on the day of surgery (table S3, Supplemental Digital Content 1, http://links.lww.com/ALN/B326).
Table 2.

Number of Antihypertensive Medications That Patients Were Using at Baseline and the Number and Proportion Withheld on the Day of Surgery

Number of Antihypertensive Medications That Patients Were Using at Baseline and the Number and Proportion Withheld on the Day of Surgery

Results for the Primary Objective
Patients in whom ACEI/ARBs were withheld (n = 1,245; 25.9%) were largely similar to those in whom ACEI/ARBs were continued but were less likely to have very high preoperative blood pressure, less likely to undergo major urogenital surgery, and more likely to undergo major general and urgent or emergency surgery.
Among the 4,802 patients who took ACEI/ARBs at baseline, withholding ACEI/ARBs on the day of surgery was associated with an 18% reduction in the relative risk of the composite outcome of death, stroke, or MINS (adjusted relative risk [aRR], 0.82; 95% CI, 0.70 to 0.96; P = 0.01) with the results qualitatively consistent across the component outcomes (fig. 2).
Fig. 2.
(A) Adjusted association between withholding versus continuing preoperative angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) with postoperative 30-day death from any cause, myocardial injury after noncardiac surgery (MINS), or stroke, intraoperative and postoperative (day 0 to 3) hypotension, and the exploratory outcome myocardial infarction (MI) in 4,802 patients taking these medications at baseline. (B) Association between hypotension and postoperative death and vascular events in all 14,687 patients. aRR = adjusted relative risk.

(A) Adjusted association between withholding versus continuing preoperative angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) with postoperative 30-day death from any cause, myocardial injury after noncardiac surgery (MINS), or stroke, intraoperative and postoperative (day 0 to 3) hypotension, and the exploratory outcome myocardial infarction (MI) in 4,802 patients taking these medications at baseline. (B) Association between hypotension and postoperative death and vascular events in all 14,687 patients. aRR = adjusted relative risk.

Results for Secondary Objectives
The relationship between withholding ACEI/ARBs and the primary composite outcome was consistent across preoperative sBP readings; the P value for interaction was nonsignificant (i.e.P > 0.2).
Withholding ACEI/ARBs was also associated with a 20% relative reduction in the risk of intraoperative hypotension (aRR, 0.80; 95% CI, 0.73 to 0.88; P < 0.001) but was not associated with postoperative hypotension (aRR, 0.92; 95% CI, 0.77 to 1.10; P = 0.36).
Among all patients (regardless of ACEI/ARB use), those who experienced clinically important hypotension during surgery (n = 4,162; 28.3%) were more likely to develop clinically important hypotension after surgery (aRR, 1.65; 95% CI, 1.48 to 1.84; P < 0.001). Adjusted for postoperative hypotension, intraoperative hypotension was not significantly associated with the composite outcome of death, MINS, or stroke within the 30 days after surgery (aRR, 1.11; 95% CI, 0.98 to 1.25; P = 0.09).
In total, 2,860 of 14,687 patients (19.5%) experienced at least one episode of clinically important postoperative hypotension; 2,728 (95.4%) of them experienced their first episode of postoperative hypotension by day 3 and the remainder between day 4 and discharge (fig. 3). Postoperative hypotension occurred in the postanesthesia care unit in 3.4% (n = 493) of patients; in the hours immediately after transfer out of the postanesthesia care unit in 6.3% (n = 931); and during the next day in 11.6% (n = 1,711). Patients who experienced clinically important hypotension by the third postoperative day (n = 2,728; 18.6%) were more likely to die or suffer a vascular event compared to their counterparts without postoperative hypotension (aRR, 1.68; 95% CI, 1.53 to 1.85; P < 0.001).
Fig. 3.
Clinically significant hypotension in the postoperative period. In total, 2,860 of 14,687 patients (19.5%) experienced at least one episode of clinically significant hypotension after their surgery; 2,728 (95.4%) of those patients experienced a hypotensive episode by postoperative day (POD) 3. OR = operating room; PACU = postanesthesia care unit.

Clinically significant hypotension in the postoperative period. In total, 2,860 of 14,687 patients (19.5%) experienced at least one episode of clinically significant hypotension after their surgery; 2,728 (95.4%) of those patients experienced a hypotensive episode by postoperative day (POD) 3. OR = operating room; PACU = postanesthesia care unit.

Only 6.62% of the propensity to withhold ACEI/ARBs on the day of surgery could be explained by available demographic and clinical information (explained 0.02%), surgical information (explained 0.6%), and center information (explained 6.0%). Figure S1 (Supplemental Digital Content 1, http://links.lww.com/ALN/B326) shows that the percentage of baseline ACEI/ARB users who had these medications withheld ranged from 9% to 44% across countries included in the study. Although these estimates are based on just 12 hospitals and relatively few patients, much variation likely reflects provider preference.
Sensitivity Analyses
Clinically significant bleeding during surgery occurred in 278 (5.8%) baseline ACEI/ARB users and was significantly associated with the composite of death and vascular events (aRR, 1.49; 95% CI, 1.13 to 1.97; P = 0.004) but not associated with withholding these medications (aRR, 0.94; 95% CI, 0.70 to 1.26; P = 0.69). Significant bleeding within 30 days of surgery occurred in 955 (19.9%) ACEI/ARB users and was significantly associated with the primary outcome (aRR, 2.05; 95% CI, 1.63 to 2.59; P < 0.001) but not associated with withholding these medications (aRR, 1.04; 95% CI, 0.92 to 1.18; P = 0.56). Withholding of other antihypertensive medications was not significantly associated with the primary outcome (fig. S2, Supplemental Digital Content 1, http://links.lww.com/ALN/B326), with wide CIs around the estimates. Both of these sensitivity analyses suggest that our primary results are specific to ACEI/ARBs and not explained by residual confounding.
A similar analysis suggested that some residual confounding affected the relationship between hypotension and the primary outcome, but the results remained qualitatively similar after adjusting for bleeding (Supplemental Digital Content 1, http://links.lww.com/ALN/B326, heading Sensitivity analysis for relationship between hypotension and the primary outcome).
The sensitivity analysis with logistic regression yielded results similar to our prespecified analyses (table S2, Supplemental Digital Content 1, http://links.lww.com/ALN/B326). The sensitivity analysis based on the composite outcome of death, MI, or stroke demonstrated similar results to the analyses based on the primary outcome. The association between withholding ACEI/ARB versuscontinuing these drugs before surgery and the composite outcome of death, MI, or stroke produced essentially the same point estimate of effect as seen with the primary composite outcome; however, the result in the sensitivity analysis was not statistically significant (aRR, 0.81; 95% CI, 0.62 to 1.03; P = 0.08). The sensitivity analysis had less power than the primary analysis because 205 (4.3%) baseline ACEI/ARB users suffered an MI, whereas 531 (11.1%) suffered MINS. The composite outcome of death, MI, or stroke was more likely to occur in patients who experienced intraoperative hypotension (aRR, 1.23; 95% CI, 1.03 to 1.47; P = 0.03) and postoperative hypotension (aRR, 2.01; 95% CI, 1.72 to 2.33; P < 0.001).
Figure S3 (Supplemental Digital Content 1, http://links.lww.com/ALN/B326) demonstrates a graded relationship between progressively longer durations of intraoperative hypotension and increasing risk of death, MINS, or stroke (P value for trend less than 0.001).
Discussion
One third of patients having major noncardiac surgery in this large prospective cohort study used ACEI/ARB on a regular basis. Of these patients, a quarter did not receive their ACEI/ARBs in the 24 h before surgery and had a lower adjusted risk of death or vascular events (aRR, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and of clinically important intraoperative hypotension (aRR, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The negligible association between clinical and surgical factors and the withholding of ACEI/ARBs suggests that clinician discretion, independent of patient characteristics, predominantly determined the decision to withhold.
Recent perioperative guidelines suggest continuing ACEI/ARBs before noncardiac surgery,8  citing a meta-analysis and a retrospective cohort study. The meta-analysis included three small randomized trials (20 to 30 patients per arm) limited to cardiac and vascular surgery and two retrospective observational studies (n = 434 patients) undergoing nonemergency surgery.24  The results suggested that patients given ACEI/ARBs before surgery were more likely to develop hypotension requiring a vasopressor during or shortly after induction of anesthesia (relative risk, 1.50; 95% CI, 1.15 to 1.96). The incidence of perioperative MI did not differ significantly in patients who continued or withheld ACEI/ARBs, but the CI was very wide and thus compatible with substantial benefit or harm (relative risk, 0.41; 95% CI, 0.07 to 2.53). A more recent meta-analysis arrived at similar conclusions.25 
In a cohort analysis that matched 9,028 baseline ACEI users to 9,028 nonusers on a propensity score for baseline ACEI use, ACEI use was not associated with either 30-day mortality (odds ratio, 0.93; 95% CI, 0.73 to 1.19) or the composite of in-hospital morbidity and mortality (odds ratio, 1.06; 95% CI, 0.97 to 1.15).26  The analysis had four limitations that we avoided in our analysis. First, patients who adhere to preventive medications (or placebo) have better health outcomes than those who have indications to take them but do not27–29 —a “healthy user” bias that may counteract an increase in risk associated with taking ACEI. In contrast, we limited our comparisons to patients who were already taking these medications at baseline. Second, outcomes were collected as part of routine care, whereas VISION employed central adjudication of the primary outcomes and active surveillance for myocardial injury with serial cTnT measurements. Third, the study was conducted in a single center, while VISION was a multicenter, international study. Finally, we obtained information on whether medication was withheld directly from patients and medication records.
We found that hypotensive episodes were common in the hours and days after surgery. Postoperative hypotension was independently associated with a greater risk of death or vascular events. Intraoperative hypotension was also common but was not significantly associated with mortality and vascular events after adjustment for postoperative hypotension.
Our findings regarding postoperative hypotension parallel the results from the 10,010-patient PeriOperative ISchemic Evaluation (POISE)-2 trial. In POISE-2, 37.1% of patients in the placebo arm experienced clinically important hypotension; hypotension was associated with perioperative MI (hazard ratio, 1.37; 95% CI, 1.16 to 1.62).30  The association between intraoperative hypotension and death or vascular events was not statistically significant in our analysis. Larger studies have reported an association between intraoperative hypotension, kidney and myocardial injury,4  and mortality.5  The difference from our findings may relate to these studies’ use of lower thresholds to define intraoperative hypotension, our adjustment for postoperative hypotension, or insufficient power in our study.
Study Strengths
We used prospectively collected data from a representative sample of patients undergoing a broad range of surgeries in several countries, actively monitored and centrally adjudicated outcomes, ensured minimal loss-to-follow-up, had a comprehensive approach to missing data, adjusted for a wide range of potential confounders, and had no evidence of substantial residual confounding in sensitivity analyses. Our study is the first to assess the effect of preoperative ACEI/ARB management on the incidence of a cardiovascular outcome that includes MINS distinct from MI. Only 15.8% of patients suffering MINS experience an ischemic symptom, and the remaining 84.2% of events would likely go undetected without systematic postoperative troponin monitoring.12 Accordingly, the third universal definition of MI consensus statement recommends monitoring perioperative troponin measurements in high-risk patients undergoing noncardiac surgery.31  Among baseline ACEI/ARB users, 205 (4.3%) suffered an MI, whereas 531 (11.1%) suffered MINS. Given the almost identical point estimate of apparent effect in the sensitivity analysis, this lower incidence of MI is almost certainly the reason that the association between withholding ACEI/ARBs versus continuing these drugs before surgery and the composite outcome of death, MI, or stroke was not statistically significant (aRR, 0.81; 95% CI, 0.62 to 1.03; P = 0.08).
Study Limitations
Residual confounding is possible in any observational study. We adjusted for many variables and failed to detect substantial residual confounding in sensitivity analyses. Patients in whom ACEI/ARBs were withheld were generally similar to those in whom they were continued in unadjusted comparisons of baseline characteristics but notably appeared more likely to undergo urgent or emergency surgery. Urgent or emergency surgeries were those performed within 72 h of the acute event that led to surgery. Patients were admitted more than 24 h before many of these surgeries during which time clinicians could withhold their blood pressure medications. After adjusting for the type of surgery and patient characteristics and accounting for center effects, patients who underwent urgent or emergency surgery were not significantly more likely to have their ACEI/ARBs withheld than patients who underwent elective surgery (P = 0.29).
We excluded 8.7% of patients due to missing data on cTnT, postoperative blood pressure, or preoperative medication use. Included and excluded patients had similar baseline characteristics. We imputed missing data for baseline characteristics in 10.3% of included patients. Our findings regarding withholding versuscontinuing ACEI/ARBs were likely robust to this small amount of missing confounder data because clinical variables explained very little of the variation in this practice (i.e., they were very weak confounders), and we made appropriate imputation efforts.
The need to control for many potential confounders and the correlation between them limited the statistical power of our analyses.32  We could not reliably estimate the effects of withholding antihypertensive medications other than ACEI/ARBs and of starting medications not already used before the day of surgery or study potentially relevant subgroups such as patients with heart failure or known cardiovascular disease. Sample size may also have limited our statistical power to detect differential effects of withholding ACEI/ARBs at different levels of preoperative blood pressure. Regression results demonstrated wide CIs for outcomes with a limited number of events (i.e., stroke and MI), but the direction of their point estimates was consistent with the composite outcome.
We relied on a crude dichotomous definition of hypotension (sBP less than 90 mmHg of any duration accompanied by intervention) rather than actual values. Our blood pressure threshold may have been too high, short durations of sBP slightly below 90 mmHg may not be prognostically significant, and the associations with death and vascular events may be driven by episodes with lower sBP or of a long duration. We relied on routine measurements commonly conducted at 4-h or longer intervals in the postoperative period and have likely missed some hypotensive episodes. Surveillance bias may have inflated the associations between postoperative hypotension and clinical outcomes because patients who develop complications are monitored more closely.
We could not evaluate renal outcomes in this subsample of VISION. Three randomized controlled trials totaling 64 patients studied renal outcomes of preoperative ACEI in cardiac and vascular surgery but detected no acute kidney injury events.33  A prospective cohort study of 1,594 cardiac surgery patients found a graded increase in the risk of acute kidney injury across three groups of preoperative ACEI/ARB exposure (none, 31%; held, 34%; continued, 42%; P for trend 0.03).34  The study suggested that, if anything, withholding of ACEI/ARBs is associated with a reduction in kidney injury.
We did not study the effects of withholding antihypertensive medications after surgery because the timing of postoperative medication use was not captured with sufficient precision in VISION.
Implications
We estimate that, if all patients who continue to take ACEI/ARBs on the day of surgery were to instead withhold them, 5.9% (95% CI, 1.2 to 10.1)—or over 500,000 patients per year—would avoid death, MINS, or stroke within 30 days of their operation. This estimate assumes that 100 million of the 200 million people who undergo major noncardiac surgery annually are at least 45 yr old,1,36 that 9.6% die or suffer an adverse perioperative vascular event, that our data accurately represents the international patient population and clinical practice, and that the relationship we observed is causal. Even if these assumptions are violated, our results have substantial global importance.

Lung ultrasound to manage fluid volume in dialysis.


Volume overload is an important, but often hidden risk factor for all-cause and cardiovascular death in end stage renal disease (ESRD) patients. Monitoring lung water could be used as a biomarker for detecting and monitoring lung congestion in populations at risk for pulmonary edema, as substantial lung water accumulation may occur before clinical symptoms of heart failure and in other conditions appear, explains the author of the present Italian study. Until recently, measuring lung water meant using costly radioactive compounds, X-rays or placing catheter into the pulmonary artery. But as the present study shows, ultrasound (US) could also allow valid, reproducible estimates of lung water.

Why ultrasound? Water accumulates in the lung interstitium, thickening the interlobular septa and thereby generating visible bundles in the ultrasound. These bundles are a US equivalent of B lines (BL-US) detected in chest radiographs – which means that simply counting BL-US could offer an estimate of lung water. Studies have also shown that the number of BL-US is associated with parameters such as LV filling pressure, larger LV end-diastolic and end-systolic diameters, LV mass index, left atrial volume index, tricuspid regurgitation velocity and estimated pulmonary artery systolic pressure in heart failure (HF) patients. And: Ultrasound could also be particularly valuable in intensive care patients, where it could be used to discriminate moderate and severe lung congestion.

Ultrasound (US) is a well-validated technique that allows reliable estimates of lung water in the care of hemodialysis patients at high cardiovascular risk, summarizes the author.

 

Abstract

Volume overload is a hidden, pervasive complication in dialysis patients with dyspnea and pulmonary edema being its main clinical manifestations. Measuring lung water has clinical potential because it allows timely treatment of lung congestion at a preclinical stage. Chest ultrasound (US) is a novel, well-validated technique that allows reliable estimates of lung water in clinical practice. The application of this technique in dialysis patients has shown that an unsuspectedly high proportion of these patients have moderate to severe lung congestion which is usually asymptomatic. Furthermore, lung congestion in these patients is only loosely associated with fluid excess as measured by bioimpedance (BIA). Lung congestion is associated with a high death risk in dialysis patients and therefore represents a potential treatment target. The “Lung water by Ultra-Sound guided Treatment to prevent death and cardiovascular complications in high risk ESRD patients with cardiomyopathy” (LUST) study will provide important information about the clinical value of this technique in the care of hemodialysis patients at high cardiovascular risk.

Volume overload is considered a main, hidden risk factor for all-cause and cardiovascular death in end stage renal disease (ESRD) patients [1]. Observational studies support the hypothesis that chronic volume expansion is per se (i.e., above and beyond blood pressure and other risk factors) a strong, direct predictor of the risk of death in hemodialysis patients [2, 3]. A major reason hindering optimization of fluid volume status in dialysis patients is the almost universal presence of LVH and its associated LV diastolic and systolic dysfunction [4] which makes these patients hypotension-prone and unable to mount a successful counter-regulatory hemodynamic response to the volume removal at the UF rate applied in standard dialysis schedules.

Estimates of fluid volume in dialysis patients are being increasingly applied to guide the prescription of ultrafiltration and dietary sodium intake in dialysis patients. These estimates include the measurement of total and extracellular fluid volume by bio-impedance (BIA) [5], inferior vena cava diameter, plasma volume changes across dialysis by the Crit-Line system and circulating levels of cardiac natriuretic peptides. All these biomarkers still have a low evidentiary basis supporting their systematic use in ESRD. Though small trials based on surrogates seem to support the use of BIA [6, 7] we still lack trials based on clinical endpoints documenting the usefulness of this technique. Inferior vena cava diameter does not provide useful information for probing dry weight [8]. As with BIA, there are no clinical trials using valid clinical endpoints which test the value of this measurement in clinical practice. In a clinical trial testing the application of Crit-Line to guide UF, the Crit-Line Intradialytic Monitoring Benefit (CLIMB) study, adverse events in the active arm of the trial were significantly higher than in the control arm [9]. Finally, cardiac natriuretic peptides, ANP, BNP and Pro-BNP, largely reflect left ventricular (LV) myocardial mass and LV end-diastolic pressure rather than circulating volume [10, 11].

It should be noted that, however, reliable and accurate a technique might be, the derived estimates of global fluid volumes may be insufficient to guide clinical decisions about fluid volume optimization in ESRD patients. Fluid accumulation in critical organs like the lung is of particular importance. Until recently, no easily applicable method for measuring fluid accumulation in this organ was available. Overall, notwithstanding the large majority of nephrologists who have no doubt about the paramount importance of body fluid volume optimization in the care of dialysis patients, most dialysis centers have no established clinical policy for evaluating and monitoring fluid volume status [12].

Fluid Excess, Hemodynamic, and Pulmonary Congestion

Together with the heart, the lung is the organ where fluid excess poses the major health hazards. Accumulation of fluid in a dialysis patient’s lungs entails a high risk for pulmonary edema [13, 14]. Superficially, pulmonary edema might be equated with volume overload. However, fluid overload apart, lung water content also depends on two additional, quite relevant factors: left ventricular (LV) function and lung permeability. In both LV systolic and diastolic dysfunction, LV end-diastolic pressure and hence left atrial pressure are high; retrograde transmission of this pressure to pulmonary veins and lung capillaries results into high pulmonary capillary wedge pressure — “hemodynamic congestion”. Hemodynamic congestion sets the stage for extravasation of fluid into the lung interstitium and into the alveoli, resulting into “pulmonary congestion”.

Even though pulmonary congestion is, in most cases, attributable to high pulmonary capillary pressure concomitant with fluid overload, this alteration may also occur without fluid overload pointing to fluid redistribution triggered by systemic arterial and/or venous vasoconstriction. In this regard, it cannot be overemphasized that fluid removal in patients with decompensated heart failure has just a loose relationship with the improvement of dyspnea [15]. In the same vein, application of continuous intrathoracic impedance monitoring in these patients showed that pulmonary congestion may antedate by 2 weeks frank pulmonary edema in these patients. Of note, a high degree of tolerance to fluid accumulation in the lung without superimposed dyspnea is well-documented in patients with nephrotic syndrome where an estimated average lung water excess as high as 1.7 l can remain asymptomatic [16]. Yet, in the vast majority of cases, particularly in patients with LV disorders, congestion eventually triggers clinical lung congestion, i.e., dyspnea, a symptom most often leading to hospitalization.

The relevance of the second factor that may facilitate lung congestion in patients with kidney diseases, lung permeability, is obvious in acute kidney injury a condition where, independently of fluid overload, systemic inflammation may dramatically increase alveolo-capillary permeability and trigger life-threatening congestion [17]. Furthermore, pulmonary capillaries are recognized as a vulnerable segment of the cardiopulmonary circulation in patients with heart disease [18] which has obvious implications in dialysis patients, a population where cardiomyopathy is almost universal [4].

Measuring Lung Congestion

Because substantial lung water accumulation may occur before clinical symptoms in heart failure and in other conditions, monitoring lung water has prima facie credibility as a biomarker for detecting and monitoring lung congestion in populations at risk for pulmonary edema. However, until recently measuring lung water entailed either the use of costly radioactive compounds [19], exposure to X-rays [20] or the placement of a catheter into the pulmonary artery to apply the thermo-dilution technique [21]. The discovery that ultrasound (US) may allow valid, reproducible estimates of lung water as well as corollary information on other pulmonary alterations has been a breakthrough in pulmonary medicine [22].

The rationale for adopting ultrasound to measure lung water is that water accumulation in the lung interstitium thickens the interlobular septa. This thickening produces a reverberation of the US beam and generates visible bundles at narrow basis going from the probe to the edge of the echotomography screen. These bundles are a true US equivalent of B lines [BL-US] detected in chest roentgenograms and their simple count provides an estimate of lung water [23] (Fig. 1). The number of BL-US is associated with LV filling pressure [23] as well as with larger LV end-diastolic and end-systolic diameters, LV mass index, left atrial volume index, tricuspid regurgitation velocity and estimated pulmonary artery systolic pressure in heart failure (HF) patients with dyspnea as well as in those without overt cardiac decompensation [24]. Beyond heart failure, the technique is of particular value in intensive care patients where it is a powerful instrument to discriminate moderate and severe lung congestion (areas under the ROC curves of 0.94 and 0.96 respectively) [25].

Figure 1.

Ultrasound B lines in interstitial lung edema are generated because the US beam reverberates against the thickened (edematous) interlobular septa.

Lung Congestion in ESRD

Lung US has specifically been validated in ESRD patients where it holds high intra and interobserver reproducibility as well as high technical reproducibility, i.e. it provides reproducible results with different echo-tomography machines [26]. Measuring the degree of lung congestion in dialysis patients has clinical potential for various reasons. Lung congestion is common both in hemodialysis [26-28] and in peritoneal dialysis [29] patients where it is usually asymptomatic. There is a dose–response relationship in dialysis patients between the number of US B lines and both the risk of mortality and cardiovascular complications which is largely independent of other risk factors ([27, 28]). In addition, the number of US-B lines is strongly associated with various echocardiography parameters including left atrial volume, pulmonary artery pressure, Ee’ ratio (an index of diastolic function) and, particularly, with the ejection fraction; these associations hold true both predialysis and postdialysis implying that the relationships are largely independent of volume overload [26].

Lung auscultation to detect crackles at the lung bases is a cornerstone for the diagnosis and the monitoring of congestion in patients with heart failure and in those with chronic kidney failure [30]. However, as with several other time honored clinical signs [31], the reliability of auscultation for the diagnosis of lung congestion has not, until very recently, been specifically assessed in the dialysis population. Investigators of the “Lung water by Ultra-Sound guided Treatment to prevent death and cardiovascular complications in high risk ESRD patients with cardiomyopathy” (LUST) [32], a randomized trial testing whether the use of lung US in high risk hemodialysis patients may improve clinical outcomes and echocardiographic indicators of cardiomyopathy in these patients, adopted lung sonography as a reference test to examine the diagnostic reliability of crackles as a sign of pulmonary congestion [33] in over 1000 paired measurements of lung water by US with simultaneous standardized auscultation of the thorax. These analyses showed that crackles were quite insensitive in detecting interstitial lung edema found by lung US [26].

Lung congestion in heart failure is a gradual phenomenon and pulmonary edema may supervene after one or more weeks of insidious accumulation of fluid in the lung [34]. This is of particular relevance in dialysis patients, a population where lung water (as measured US-B lines) only weakly correlated with total body water (by BIA) and interdialysis weight gain10. Furthermore, dialysis patients have increased alveolo-capillary permeability [35] and the average estimated interstitial lung water in ESRD patients is about 1.2 l, an unsuspectedly high degree of pulmonary congestion [23].

The application of lung US has relevant clinical potential. However, its usefulness in patients needs to be tested in a randomized trial comparing a treatment policy guided by this technique with that using the standard approach. Currently, the usefulness of targeting asymptomatic lung congestion remains unproven. The CLIMB study is a cautionary tale about accepting on purely physiologic grounds the use of medical devices and the lack of proper trials testing their impact on clinical endpoints.

Lung US is a well-validated, simple and low-cost technique which can be easily applied by nephrologists at the bedside by using virtually all, old and new, US machines [36] including affordable hand-held US devices. The LUST study is currently testing whether the use of lung US by nephrologists may improve clinical outcomes in high risk dialysis patients. It will provide important information about the clinical value of this technique in the care of hemodialysis patients at high cardiovascular risk.

Source:http://onlinelibrary.wiley.com

Richard Lehman’s journal review.17 April 2017


NEJM  13 Apr 2017  Vol 376
Diabetes, death, and cardiovascular disease in Sweden
“Diabetes mellitus is a complex and heterogeneous group of chronic metabolic diseases that are characterized by hyperglycemia.” That’s a good intelligent sentence to begin a good intelligent analysis of outcomes in Sweden for people labelled with diabetes over the period 1998-2012.

Figure two summarises what happens to people with type 1 and 2 diabetes in a civilised country with decent modern healthcare. For cardiovascular outcomes, the story is one of steady improvement: events and hospital admissions for all patients with diabetes are falling compared with population controls. The main exception, however, is all cause death (per two year period) in people with the label of type 2 diabetes. This was going down up until 2008 and then something happened to stop it dropping. I would love to know why. Were the Swedes doing something right and then started doing something wrong? What non-cardiovascular factors are causing this anomaly? It should be very easy to check from the mortality registers on this database.

Diabetes in American youth
And now, with due foreboding, let’s fly to the US. Here the incidence of diabetes is rising, especially in the young. In this survey of Americans aged 10-19, the overall rise between 2002 and 2012 was 1.4% annually for type 1, and 7.1% annually (4.8% after adjustment) for type 2. But for two ethnic groups, the rise in T2DM was spectacularly larger than for white American youth: native Americans and black Americans. Early onset T2DM has a pretty terrible prognosis, even when ideally treated—and optimal treatment is unlikely to be affordable for many of those worst affected. Here is another driver towards ever greater health disparities by race in the US.

JAMA 11 Apr 2017  Vol 317
Middle life risk factors for later brain amyloid
Florbetapir: the word to remember this week. Florbetapir is a chemical that crosses the blood-brain barrier and attaches itself to amyloid. It is produced in a cyclotron in the morning and will have decayed by the evening, because the crucial ingredient is 19F, an isotope of fluorine with a half-life of 109 minutes. That’s just enough time to get your subject into a positron emission scanner and look for amyloid in the brain. Over two years, this was done to 322 participants in the Atherosclerosis Risk in Communities cohort, which was set up in 1987-9 and measured cardiovascular risk factors sequentially in US adults without overt cardiovascular disease at baseline. Now this is very impressive, but bear in mind that florbetapir uptake on positron emission tomography (PET) is just a surrogate for amyloid deposition, which in turn is just a surrogate for so called Alzheimer’s disease. This in turn has become a catch-all label for dementia, and is very different from the case described by Alzheimer in 1906. Florbetapir uptake is very common in older people: in this cohort of mean age 76, it was present in 31% of those with no CV risk factors in midlife and in 61% with two or more risk factors. So this study shows two things: florbetapir PET picks up a lot of brain amyloid that has no obvious clinical meaning, and amyloid deposition is associated strongly with traditional CV risk factors rather than being something which discriminates clearly between “vascular” and “Alzheimer’s” dementia.

Back pain & manipulation
When I get back pain I become tetchy and needy. I want somebody to take it away so that I can become the calm, amiable, easy to live with person I would like to be. Fortunately, I don’t often get back pain. Instead I find other excuses for being tetchy and needy. But if I got back pain all the time, I can see why I would be manipulated, although this systematic review provides a weak signal that spinal manipulation can help in acute episodes of back pain. As with so many kinds of symptom relief, it’s not the population effect I’d be looking for if I were the person with back pain, it’s what might work for me. That is why the world is full of manipulators for when you become tetchy and needy.

JAMA Int Med  Apr 2017  Vol 
Hospital based primary care is more wasteful
I’m a strong advocate of breaking down the barriers between primary and secondary care in Britain. It would be nice to think that the good features of general practice could spread into hospitals: a broader view of diagnosis, more continuity of care, acceptance of uncertainty, frugality with testing, give and take based on personal knowledge of patients. But there are dangers too, as this American survey shows. “Primary care” in the US is something else, and it is often co-located with hospital services that make money from doing things to patients. This large sample of primary care visits by Americans shows that those who go to hospital based clinics are more likely to be overinvestigated, especially using radiography and MRI, and referred needlessly to specialists. Primary care doctors can be infected by their environment. When the NHS is forced into its next phase of disintegration, it could easily happen here. And you will be paying a lot more for it.

US hospital initiative works
Just occasionally, incentives achieve what they set out to do. An example seems to be the Medicare Hospital Readmission Reduction Program in the US. This was a voluntary scheme, which provided financial incentives to reduce readmissions in participating hospitals. It had a number of components and it proved very popular. In 2010, none of the 2837 hospitals in this study were participating in the programs. By 2015, all of them were involved with some of the components. Using some sophisticated analytics, the investigators show that the degree of participation correlates with a fall in 30 day readmissions following myocardial infarction, heart failure, and pneumonia.

The Lancet  15 Apr 2017  Vol 389
Alcohol in England
Here is a wide ranging and well written survey of how alcohol affects the health of people in England. It is modestly billed as “A rapid evidence review of the effectiveness and cost-effectiveness of alcohol control policies: an English perspective,” but it is much more than that. It provides a panoramic survey of what is known about drinking in England and how public institutions assess its costs and harms. As for interventions, the evidence is sensibly summarised at the start: “Although there is variability in research design and measured outcomes, evidence supports the effectiveness and cost-effectiveness of policies that address affordability and marketing. An adequate reduction in temporal availability, particularly late night on-sale availability, is effective and cost-effective. Individually-directed interventions delivered to at-risk drinkers and enforced legislative measures are also effective. Providing information and education increases awareness, but is not sufficient to produce long lasting changes in behaviour.”

Death from breathing
Now from drinking to smoking, and from England to the world. A quarter of men around the world still smoke, which is a 28% reduction from 1990. Smoking has fallen everywhere since then, except for Congo and Azerbaijan (for men) and Kuwait and Timor-Leste (for women). Despite the absolute decline, the relative contribution of smoking to overall disease burden is growing, especially in lower income countries. There is no excuse for this. Nicotine addiction can be satisfied in safe ways, which don’t involve the inhalation of toxins. Selling combustible tobacco is mass murder.

There is slightly more excuse for air pollution, which is largely a legacy of our long dependence on burning hydrocarbons for energy. Another Gates funded global survey lists particulate air pollution as the fifth ranking mortality risk factor in 2015. Again, successes in rich countries are counterbalanced by increases in pollution in low to middle income countries. At least there is the general will to find technological solutions for this, based as much on a common fear of global warming as on concern for people inhaling toxic air.

Celecoxib vs naproxen in high risk patients
So here’s a fairly common clinical scenario: you have a patient who’s had a cardiovascular event for which aspirin is indicated. They also would like to take a non-steroidal anti-inflammatory drug (NSAID) for arthritis. But they have had an episode of upper gastrointestinal bleeding. So if you continue their present treatment, they will need to take a proton pump inhibitor. As for the NSAID, you could opt for naproxen, because of its greater cardiovascular safety, or celecoxib, because of its greater GI safety. Which is it to be? A hospital in Hong Kong collected 514 such patients over seven years and randomised them to one or the other, in addition to aspirin and esomeprazole. The title blazons the fact that this was an industry independent trial. Good. But it wasn’t sufficiently powered to determine cardiovascular events. It did, however, show that celecoxib was significantly less likely than naproxen to cause upper GI bleeds over an 18 month period.

The BMJ 15 Apr 2017  Vol 357
Quick-Wee
Attentive readers of The BMJ will remember reading about Quick-Wee in Minerva last September. And here is Quick-Wee again, in a biggish randomised trial rather than the earlier 40 baby series in the Emergency Medicine Journal. Infants were randomised to either gentle suprapubic cutaneous stimulation (n=174) using gauze soaked in cold fluid (the Quick-Wee method) or standard clean catch urine with no additional stimulation (n=170), for five minutes. The method resulted in a significantly higher rate of voiding within five minutes compared with standard clean catch urine (31% v 12%, P<0.001). I like the pee value. It means we can agree that Quick-Wee is a wee improvement in getting wee tots to pee when we see the need to test their wee.    

Short course steroids are not harmless
“A few days on pred to see them through” is a very common strategy in the US, as I’m sure it is here. In fact, one fifth out of a million and a half adults in an American commercial insurance plan were given prescriptions for short term use of oral corticosteroids during a three year period. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The absolute risk may be small, but these relative risks are pretty alarming, especially for sepsis.

Uncertain about adult tonsillectomy
It’s nice to see an Uncertainties article in this week’s BMJ, especially a meaty one with some good graphics. It covers the evidence base for tonsillectomy in adults with recurrent tonsillitis. There are some rather poor randomised trials and some good retrospective case series. The tables are good, but where is the decision tool to be used directly with patients? I hope that future articles will go the whole way and put The BMJ right at the forefront of shared decision making by turning evidence synthesis into adaptable, shareable infographics.

Plant of the Week: Koelreuteria paniculata “Coral Sun”
The Indian Golden Rain tree is named in honour of Joseph Gottlieb Kölreuter (1733 –1806), who spent most of his life doing experiments on hybridisation in plants. This form of it is not a hybrid but a natural mutation with red stems and coral-pink finely divided leaves in spring, which turn pale green in the summer and are then joined by sprays of yellow flowers. In autumn, red returns to the leaves and the flowers will have turned into interesting bladder-like fruits.

So here is a tree for all seasons: well, three seasons anyway. And in nurseries it is becoming commoner and cheaper by the year. When we saw one on sale for £12.99 the other day, we bought it at once, though we have no idea where to put it. Our garden is not very warm, and our life expectancy is not infinite, so we will be lucky to see it grow to 3m, perhaps. In a favoured spot, over a longer time, you could easily double that. I suspect that the further north in England you go, the less well this tree will perform. It likes sun. Somewhere above Nottingham, it will probably just get mardy* and die.

I haven’t yet seen this particular variety in a garden, but perhaps in time it will be as common a sight in our suburbs as laburnum. General practitioners of the future may look forward to its shrimpy leaves in April and its rain of golden flowers in August, as they drive along familiar town roads to familiar town patients. It will take a decade or more to tell if this is the kind of tree you want in your own front garden or would rather see in other peoples’.

*Mardy is a word of obloquy, which creeps in around Nottingham and Derby and is used sporadically in other places that Southern people rarely visit. It means sulky and unsociable. Often (but not necessarily) combined with “baby,” “bugger,” “bum,” or “pants.”

Management of the Crooked Nose- Study


The study has been published in International Journal of Head and Neck Surgery

Patients with crooked nose suffer from functional ailments, most significant nasal obstruction, as well as esthetic concerns which may impact their self-image as well as others’ perception of them. As such, management of the crooked nose is an especially challenging task in that it demands careful attention to both nasal function and appearance. There are a plethora of surgical technique..

Read more at Medical Dialogues: Management of the Crooked Nose- Study http://speciality.medicaldialogues.in/management-of-the-crooked-nose-study/

Citation: Scordino JW, Stucker FJ. Management of the Crooked Nose. Int J Head Neck Surg 2016;7(3):168-172.

Coca-Cola’s secret influence on medical and science journalists.


A series of journalism conferences on obesity received covert funding from Coca-Cola.

 Paul Thacker investigates

Industry money was used to covertly influence journalists with the message that exercise is a bigger problem than sugar consumption in the obesity epidemic, documents obtained under freedom of information laws show. The documents detail how Coca-Cola funded journalism conferences at a US university in an attempt to create favourable press coverage of sugar sweetened drinks. When challenged about funding of the series of conferences, the academics involved weren’t forthcoming about industry involvement.

For drinks manufacturers such as Coca-Cola the idea that consuming their products is fine as long as you exercise—reinforced with expensive advertising campaigns associated with sport—has been an important one. As Yoni Freedhoff, assistant professor of medicine at the University of Ottawa, told The BMJ, “For Coca-Cola the ‘energy balance’ message has been a crucial one to cultivate, as its underlying inference is that, even for soda drinkers, obesity is more a consequence of inactivity than it is of regularly drinking liquid candy.”

The six figure bill for funding these journalism conferences was more than repaid in favourable press coverage, say critics. Documented evidence of the industry’s covert influence on the media is rare. In 2004, researchers examined secret documents made public during tobacco litigation. Attempting to derail the effect of the US Environmental Protection Agency’s 1993 report on secondhand smoke, the tobacco industry successfully placed stories in major print publications about the report’s “scientific weakness” to help “build considerable reasonable doubt . . . particularly among consumers,” the researchers wrote.1 They concluded that even journalists can fall victim to well orchestrated public relations efforts, regardless of the quality of the science used in these PR exercises.

Source:bmj.com