Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study.


Summary

Background

Roughly 70–80% of patients with advanced stage Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin’s lymphoma.

Methods

We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin’s lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.

Findings

Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vstwo [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).

Interpretation

Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin’s lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin’s lymphoma.

Source:http://www.thelancet.com

Cutting salt could reduce need to urinate at night, study finds.


Cutting salt intake could reduce people’s need to get up in the night to urinate, says a preliminary study presented at the European Association of Urology congress in London.1

The Japanese study included 321 men and women with a mean age of 64.3 who experienced nocturia during sleep time and had a high dietary salt intake (≥8 g/day in men and ≥7 g/day in women).The participants were given written guidance and support on reducing their salt intake and were followed up for 12 weeks.

The volume and frequency of urination were measured on a frequency volume chart, and daily salt intake was estimated by examining the sodium and creatinine concentrations of spot urine samples using a formula that was adjusted for height, weight, and age.

The study found that 223 members of the group (69.5%) managed to reduce their salt intake from a mean of 10.7 g/day to 8.0 g/day. In this group the average night time frequency of urination improved, falling from 2.3 times to 1.4 times (P<0.001). In contrast, 98 subjects increased their average salt intake from a mean of 9.6 g/day to 11.0 g/day, and they found that the need to urinate increased from 2.3 times to 2.7 times a night (P<0.001).

The need to urinate during the day also reduced when salt in the diet was reduced, the researchers found. Quality of life as measured by a standard questionnaire also improved significantly from 3.6 points to 2.7 points (P<0.001) among the group who cut their salt intake.

The study has not been published in a journal so has not gone through a peer review process. However, it was reviewed for suitability and accuracy by the European Association of Urology communications group and by a specialist in the field.

The study author, Matsuo Tomohiro, of Nagasaki University in Japan, said, “This is the first study to measure how salt intake affects the frequency of going to the bathroom, so we need to confirm the work with larger studies. Night time urination is a real problem for many people, especially as they get older. This work holds out the possibility that a simple dietary modification might significantly improve the quality of life for many people.”

Marcus Drake, professor of physiological urology from the University of Bristol, UK, and lead of the European Association of Urology’s working group on nocturia, commented, “This is an important aspect of how patients potentially can help themselves to reduce the impact of frequent urination. Research generally focuses on reducing the amount of water a patient drinks, and the salt intake is generally not considered.

“Here we have a useful study showing how we need to consider all influences to get the best chance of improving the symptom.”

Figure1

References

Source:http://www.bmj.com

Is it time to reassess current safety standards for glyphosate-based herbicides? 


Abstract

Use of glyphosate-based herbicides (GBHs) increased ∼100-fold from 1974 to 2014. Additional increases are expected due to widespread emergence of glyphosate-resistant weeds, increased application of GBHs, and preharvest uses of GBHs as desiccants. Current safety assessments rely heavily on studies conducted over 30 years ago. We have considered information on GBH use, exposures, mechanisms of action, toxicity and epidemiology. Human exposures to glyphosate are rising, and a number of in vitro and in vivo studies challenge the basis for the current safety assessment of glyphosate and GBHs. We conclude that current safety standards for GBHs are outdated and may fail to protect public health or the environment. To improve safety standards, the following are urgently needed: (1) human biomonitoring for glyphosate and its metabolites; (2) prioritisation of glyphosate and GBHs for hazard assessments, including toxicological studies that use state-of-the-art approaches; (3) epidemiological studies, especially of occupationally exposed agricultural workers, pregnant women and their children and (4) evaluations of GBHs in commercially used formulations, recognising that herbicide mixtures likely have effects that are not predicted by studying glyphosate alone.

Introduction

Glyphosate is an active ingredient in a number of commercially available herbicides, including several that are used in concert with genetically modified crops. The herbicidal action of glyphosate derives from its inhibition of a key plant enzyme, 5-enolpyruvylshikimate-3-phosphate synthase, which is involved in the synthesis of aromatic amino acids. Since this enzyme is not present in vertebrates, it has long been believed that glyphosate would not affect non-target species, including humans. However, multiple lines of evidence suggest that this contention is inaccurate.

Methods used in environmental health sciences to examine the potential health effects of chemicals, including pesticides, have undergone substantial changes over the past 30 years. Cutting-edge tools currently employed by federally funded scientists bear little resemblance to the archaic standardised assays required by regulatory agencies and used in formal risk assessments.1 We are concerned that the assays used to assess glyphosate safety, including the toxicity studies requested by the US Environmental Protection Agency (EPA) in 2009, may be insufficient to address the full complement of health effects that could be induced by exposure to glyphosate-based herbicides (GBHs).

In this commentary, we summarise these key findings as well as trends in increased use of GBHs. Since commercial applications of GBHs began four decades ago, their use has diversified and expanded considerably. We offer recommendations on how to reduce significant uncertainties concerning GBH risks.

Glyphosate use has increased since safety evaluations were conducted

Glyphosate was registered in 1974 in the USA as a broad-spectrum contact herbicide to kill weeds in fields prior to the planting of crops. It was also approved for weed control in a variety of non-crop settings. Glyphosate use is the highest of any pesticide in the USA, with rapid increases in use over the last two decades; worldwide estimates of use suggest that enough GBH was applied in 2014 to spray nearly 0.5 kg glyphosate on every hectare of cropland on the planet.2

In addition to their use as weed-control herbicides, GBHs are now used as desiccants prior to harvest3 to accelerate natural drying of seeds. These use patterns are expected to increase glyphosate residue levels in harvested products. Although such effects still need to be evaluated in controlled studies, residues of glyphosate and aminomethylphosphonic acid (AMPA) (the major bioactive metabolite of glyphosate) are now routinely detected in soybeans, wheat, barley, and many other crops and foods.4 ,5

Although GBH use has increased dramatically in the last 10 years, most of the science used in the risk assessment process to support its safety was conducted more than 30 years ago. In the US EPA’s 1993 registration review of GBHs,6 for example, 73% of the almost 300 citations were published prior to 1985; importantly, only 11 were peer-reviewed. A search of PubMed (conducted 6 November 2016) reveals more than 1500 published studies on glyphosate in the last decade alone. It is incongruous that safety assessments of the most widely used herbicide on the planet rely largely on fewer than 300 unpublished, non-peer-reviewed studies while excluding the vast, modern literature on glyphosate effects.

Considering the ∼100-fold increase in GBH use in the last four decades, increased human exposure is almost certain. Unfortunately, no systematic data have tracked changes in glyphosate or AMPA concentrations in human tissues or bodily fluids during this period. For this reason, we recommend that glyphosate and AMPA should be monitored by the US Centers for Disease Control and Prevention (US CDC) in its National Health and Nutrition Examination Survey (NHANES) biomonitoring programme, as well as other biomonitoring programmes around the world. Studies of the general population to evaluate actual exposures via diet (rather than hypothetical inferred exposures), as well as studies in occupationally exposed individuals (eg, pesticide sprayers as well as production workers), are both needed.

Are humans affected by GBHs?

There are few human epidemiology studies examining the impact of glyphosate on human diseases. Unexplained chronic kidney disease has killed thousands of rice farm workers in Sri Lanka7 and sugarcane workers in Central America;8 exposure to herbicides including GBHs has been documented in some of these populations.9 Some epidemiologists have hypothesised that epidemics of chronic kidney disease among male agricultural workers result from the interactions of the herbicide with hard drinking water and associated metals.7 ,9 Others have attributed these health conditions to dehydration.10 Neither explanation is plausible because such plantation work in these regions has been going on for centuries while the epidemic of kidney failure and herbicide use are recent phenomena.

A number of other studies have evaluated the association between exposures to GBHs and other health effects in humans including cancer. In fact, some of the most compelling studies in human populations suggest associations between GBHs and non-Hodgkin lymphoma.11 ,12 Cancer end points will be discussed later in this commentary.

Without appropriate epidemiological and biomonitoring studies, any association between glyphosate and AMPA concentrations found in human tissues and fluids with disease will remain uncertain. Epidemiological studies are urgently needed to augment the ability of risk assessors to draw better conclusions about the safety of GBHs. Such studies should evaluate short-term and long-term health outcomes including DNA damage and cancer.

Recent studies raise new questions about GBH safety

In laboratory animals, glyphosate can disrupt reproductive development in male rats,13 and male and female fish.14 ,15 Studies in fish and the amphibian Xenopus laevis demonstrate that developmental exposures to GBHs induce malformations in craniofacial structures and the brain, although the mechanism underlying these effects is not fully understood.16 ,17 Research from controlled laboratory studies also suggests that GBHs may contribute to liver,18 hepatorenal19–22 and cardiovascular damage;23 ,24 some of these effects may be due to altered ion flux in these tissues.25 GBHs are also recognised to cause serious eye damage based on evaluation of six separate studies.26 Finally, GBH exposures have been shown to induce oxidative stress27 and genotoxicity28 in vitro and in vivo.

In a previous consensus statement, we analysed these data and raised concerns over the setting of ‘safe’ levels of exposure by regulatory agencies around the world;29 other comprehensive reviews of the toxicity literature also provide an excellent overview of the effects of glyphosate and GBHs on a range of end points.30 ,31

Recently, there has been debate over the possibility that glyphosate is an endocrine disruptor.13 ,14 ,32–34 Studies in cell culture showed that glyphosate induces endocrine-mediated effects on end points relevant to toxicity, as well as cell proliferation.32 ,33 In contrast, using their Endocrine Disruptor Screening Program (EDSP), the US EPA’s recent review of glyphosate dismissed statistically significant differences consistent with oestrogenic activity in some assays (eg, altered vitellogenin levels in a fish short-term reproduction assay) because they followed a non-monotonic dose response.35 The final conclusion of the US EPA was that ‘there was no convincing evidence’ that glyphosate interacts with endocrine pathways. Significant criticisms of the EDSP assays have been raised by endocrinologists, and others have expressed concern about the failure of the EPA to acknowledge non-monotonic dose responses, which have been documented for other endocrine disruptors.36 Other agencies including the European Food Safety Authority (EFSA) have used the EDSP data to suggest that there is not sufficient evidence to conclude that glyphosate is an endocrine disruptor, but the 2015 EFSA report does note that ‘signs of endocrine activity… could not be completely ruled out’ in some of these assays.37

In December 2009, the US EPA issued a ‘Glyphosate Final Work Plan (FWP) registration review’38 that identified uncertainties about the toxicity of glyphosate. For example, the EPA announced its plan to require that registrants conduct acute and subchronic neurotoxicity studies as well as an immunotoxicity study. The EPA also acknowledged that AMPA had not been evaluated for ecological risk assessments. Since this testing is supposed to be conducted by the registrants, it is unclear whether testing is underway, will actually be completed, or will be published in the peer-reviewed literature. Thus, additional studies, using state-of-the-art approaches, are needed to better elucidate the effects of glyphosate and GBHs on non-target species. We recommend that scientists and entities independent of the registrants, (eg, the US National Toxicology Program (NTP)) should prioritise glyphosate and GBHs for hazard assessments. In fact, the US EPA also proposed a collaborative research plan with the NTP, which calls for NTP to help provide answers to four research questions: (1) comparisons of the toxicity of glyphosate versus GBH formulations; (2) provide publicly available data on glyphosate’s effects on cancer-related end points; and (3) non-cancer end points; (4) finally, investigate the mechanisms by which glyphosate and GBHs induce toxic and adverse effects.39 Several of these points are addressed further below.

GBHs are chemical mixtures, and may be more toxic than glyphosate alone

GBHs are always used as a mixture of glyphosate plus numerous other so called inert ingredients, which are added to alter the herbicide’s physicochemical properties and enhance its herbicidal action. Some inert ingredients or chemicals are used to enhance the adhesion of glyphosate to plant surfaces (eg, alkyl polyglycosides), whereas others facilitate its penetration of plant cell walls and into plant tissues (eg, ethoxylated tallow amines) to exert its herbicidal effects. Unfortunately, the full list of these chemicals, collectively known as adjuvants or coformulants, is treated as a trade secret by the manufacturers; the composition of GBHs are unknown and available data on the hazards posed by different mixtures remain limited.

Chemical mixtures can have effects that are more potent than the effects of individual ingredients.40 GBHs have been shown to be more toxic than glyphosate.41–44 It also should be noted that some of the studies discussed in the previous section of this review evaluated GBHs, and thus likely reveal effects that may not be observed if studies examined only the active ingredient. These results reveal that GBH safety evaluations focused on glyphosate alone can underestimate toxicity and are insufficient to assess relevance to human and environmental exposures. Although the number of commercial formulations is extensive and will be difficult to study comprehensively, we propose that the most widely applied GBH formulations should be tested in parallel with glyphosate alone.

Is glyphosate a human carcinogen?

Over the last few years, glyphosate has received significant attention by the public as well as regulatory agencies around the world. In the European Union, safety evaluations on glyphosate have recently been conducted by the European Chemicals Agency (ECHA) and EFSA; in the USA, meetings by evaluation committees within the US EPA scheduled for fall 2016 were cancelled so the agency could supplement the panel of experts with additional members who have expertise in epidemiology. In December 2016, an EPA scientific advisory panel was charged with evaluating the human carcinogenic potential of glyphosate only, not GBHs. The conclusions of this panel have not yet been released.

The WHO’s International Agency for Research on Cancer (IARC) working group’s 2015 decision to classify glyphosate as a grade 2A probable human carcinogen followed an extensive review and evaluation of the weight of all available evidence.45 The outcome was driven by: (1) limited human evidence from case–control epidemiology studies, including high-quality studies reporting a link with non-Hodgkin lymphoma;11 ,12 (2) sufficient evidence from unpublished animal studies analysed by the US EPA, which identified an elevated frequency of rare kidney tumours in male mice, hemangiosarcoma in male mice, pancreatic islet-cell adenoma in male rats, and skin tumours and other non-malignant growths in mice and (3) strong mechanistic evidence, such as numerous studies demonstrating that glyphosate is genotoxic and can induce oxidative stress in humans, human cells, non-human mammals and non-mammalian species (data reviewed in depth in ref. 46). Other data from unpublished studies that have been reviewed in the peer-reviewed literature could not be evaluated by IARC because the data were not publicly available; some of these studies also suggest increases in lymphoma in male mice exposed even to the lowest doses evaluated (14.5 mg/kg/day) (see study 13 evaluated in ref. 47).

A joint meeting on pesticides residues (JMPR) in the WHO used the IARC hazard assessment evaluation (eg, concluding that glyphosate is a probable human carcinogen) to establish a safe level of exposure for humans. In their most recent evaluation, JMPR would not exclude the possibility that glyphosate is a human carcinogen, but concluded that it ‘is unlikely to pose a carcinogenic risk to humans from exposure through the diet’.48 The JMPR did not conduct a quantitative assessment to estimate cancer risk at current dietary exposures, and, more crucially, did not evaluate actual dietary exposures in any population.

The IARC classification was made based on an analysis of the entire body of evidence, including the evaluation of GBH (mixtures) and not glyphosate alone, as IARC requires that ‘the body of evidence is considered as a whole…’.49 A 2016 review of the carcinogenic potential of glyphosate by EFSA contrasts with the IARC conclusions.37 EFSA concluded that ‘glyphosate is unlikely to pose a carcinogenic hazard to humans’ but notes that it drew its conclusions based only on studies of glyphosate alone; studies of GBHs were not included in the EFSA assessment. Other agencies in the European Union, including the German Federal Institute for Risk Assessment, have similarly focused on studies of the active ingredient, failing to consider all studies of GBHs.50 Furthermore, the EFSA monograph notes that studies that demonstrate the genotoxicity of glyphosate that were considered by IARC were not considered by EFSA because they did not follow prescribed guidelines for study reporting (eg, good laboratory practices, or GLP);37this argument has also been made to eliminate studies conducted within academia in other risk assessments,1 despite evidence that academic laboratory research can be well designed and properly reported in the absence of GLP.51 Importantly, studies conducted according to GLP (including study 13 evaluated in ref. 47) that suggest causal links between glyphosate and cancer in exposed rodents have been dismissed by agencies including the EPA and EFSA due to speculation about a viral infection in the animal colony, even though no adverse health effects of such an infection have been shown.26

After the release of the IARC and EFSA expert conclusions, there were a number of public discussions and articles written for lay audiences describing how these organisations could come to conflicting results after reviewing the same literature. These discussions revealed that the same literature often was not evaluated: IARC examined studies of GBH and glyphosate whereas EFSA only evaluated studies of glyphosate; IARC examined all studies whereas EFSA gave priority to studies conducted according to GLP. Finally, IARC has strict conflict of interest rules about the experts that serve on its panels, whereas other agencies including EFSA do not exclude experts that have received monetary compensation from chemical manufacturers. There is evidence that the presence of individuals with conflicts of interest on regulatory panels can influence the integrity of decision making.52 ,53

Where does the burden of proof of safety lie?

The EFSA report, evaluating only studies of glyphosate and not GBH mixtures, concluded that there was no evidence to conclude that it is a carcinogen.37 The European Commission has not yet accepted the EFSA conclusion; in 2016, because European Union member states failed to take action against glyphosate, the European Commission extended its approval for its use under certain circumstances for 18 months, giving ECHA this time to review glyphosate’s classification. In the interim, the Commission recommended that an adjuvant, ethoxylated tallow amine, be banned from GBHs; that spraying of public parks, playgrounds and gardens be minimised; and that preharvest uses be minimised.54 It will be up to the individual member states to approve and enforce these recommendations.

In the USA, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA, (7 U.S.C. §136 et seq. (1996))) requires chemical manufacturers to demonstrate that a pesticide will not cause ‘unreasonable adverse effects on the environment’. Although FIFRA allows risks to humans and the environment to be balanced by the benefits of a pesticide’s use, this can only be accomplished if sufficient data are available to support safety. It also can only be accomplished if the full costs of exposure, including costs to human health, are quantified (see ref. 55 for a discussion of the costs of other environmental chemicals).

FIFRA places the burden to demonstrate that a pesticide is safe on the manufacturers and registrants. Yet the knowledge gaps that currently exist preclude the drawing of conclusions that GBHs are safe as currently used. FIFRA provides the US EPA with the means to restrict the use of pesticides, to update registered pesticides (like glyphosate) with new safety information, and to take action when new evidence of adverse environmental or human health effects are reported (7 U.S.C. §136 et seq. (1996)). The studies we have outlined in this commentary, together with the burden of proof for safety on the chemical manufacturer, clearly suggests that such actions are needed.

Conclusions

In this commentary, we have identified factors that heighten concerns over the adequacy of safety assessments, and by extension, permitted levels of exposure to glyphosate and GBHs. These factors include increased use of GBHs on crops and for non-crop weed control, leading to measurable concentrations of glyphosate and AMPA in foodstuffs and likely increases in human exposures. The lack of biomonitoring data and epidemiological studies remain important data gaps. A small number of controlled laboratory studies using contemporary scientific approaches have identified adverse effects of glyphosate and GBHs at much lower doses than those used to make risk assessment decisions. Although there is controversy and debate regarding the carcinogenic and endocrine disrupting potential of these compounds, conclusions such as those drawn by IARC call into question the safety of GBHs beyond ‘reasonable certainty of no harm’. Considering what is now known about glyphosate from studies published over the last three decades, as well as the knowledge gaps that continue to raise concerns, we conclude that current safety standards for GBHs are outdated and may fail to protect public health and the environment.

What is already known

  • Glyphosate is a widely used herbicide, and its use continues to rise

  • Epidemiology studies suggest associations between GBH exposures and adverse health outcomes including chronic kidney disease and some cancers

  • A small number of rodent studies suggest that glyphosate can induce cancers

  • The effects of chemical mixtures can be more toxic than the effects of individual compounds

What this study adds

  • We call for improved biomonitoring of glyphosate and its metabolites in human populations

  • We recommend that hazard assessments using state-of-the-art technical approaches be conducted on glyphosate and GBHs

  • Epidemiological studies examining occupationally exposed workers, pesticide manufacturers, and vulnerable populations are needed

  • After review of all evaluations, we conclude that the current safety standards are outdated and fail to protect public health and the environment.

Acknowledgments

The authors gratefully acknowledge support from the World Federation of Scientists, which funded travel for many of the authors to attend the 48th Session of the International Seminars on Planetary Emergencies and Associated Events, where work on this manuscript was conducted.

References

Source: BMJ

Richard Lehman’s journal review.


Stem cells for AMD

For sufferers of age-related macular degeneration who were hoping for a stem cell cure, this week’s New England Journal brings bad news and shocking news. The bad news comes in a case report showing zero improvement after transplanting a sheet of retinal pigment epithelial cells differentiated from induced pluripotent stem cells in a patient with neovascular age-related macular degeneration. The 41 authors of this paper took the utmost care to test the material which they then implanted under the retina of one patient, after removing all neovascular membrane. At one year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular oedema was present.

That is a great deal better than what happened to patients receiving intravitreal injections of “stem cells” derived from the patients’ own adipose tissue. The American clinics who offer this treatment perform the injections under the auspices of patient-funded, institutional review board–approved research. The research is listed on ClinicalTrials.gov without an investigational new drug application with the FDA. Three case reports describe how the recipients became blind after the procedure.

PCSK9 inhibitorzzzzz

The future of cardiology happened at 13h00 GMT on Friday 17 March 2017. This was when the results of the FOURIER trial of evolocumab for the prevention of cardiovascular events were presented at the American College of Cardiology. The BBC immediately declared a massive breakthrough. All my American commentator friends sprang into action. In this new era, it would take, er, $2million or more to avoid one event in a high risk population over two years. The effect on all cause mortality would be, er, zero or worse. They had seen the future and it was, er, pants. Pants that cost $15,000 per person per year. As ever, I was awe-struck by the mastery of the commentaries and data synthesis produced within hours by Harlan Krumholz, Larry Husten, Gary Schwitzer, James McCormack and Vinay Prasad. By evening the future had become the familiar past. We need longer trials. We need to look at how drugs are priced. We need to look beyond lipid-lowering if we are to reduce cardiovascular disease further.

So before you all go to sleep, what were we actually looking at here? You will all, I imagine, have heard of PCSK9 inhibitors and their remarkable ability to lower low density lipid cholesterol by binding to proprotein convertase subtilisin–kexin type 9 in the liver. Three antibodies were developed to achieve this: evolocumab, alirocumab, and bococizumab. The first two are fully human antibodies and are rarely treated as foreigners by the immune system. But bococizumab is a humanized rather than a human antibody: it contains 3% of mouse material and sadly for its manufacturers, this is sufficient to induce counter-antibodies in most people. This is described in a report of the SPIRE trials, which were duly discontinued.

Evolocumab and alirocumab will continue to stumble on expensively. I imagine their main use will be to treat the severer forms of hereditary hypercholesterolaemia. Expect more hyping of the “statin intolerance” concept too, as this will create another market sector. If you want more detail, look up the superb commentaries I mentioned. And if you want a new lipid-lowering horse to put your money on, there’s now inclisiran. It’s a chemically synthesized small interfering RNA designed to target–you guessed it–PCSK9 messenger RNA. Could be transformational. Needs big phase 3 trials. Might end up costing a lot. May transform preventive cardiology. May bomb. You just never know.

JAMA  14 Mar 2017  Vol 317

Parturient montes, nascetur ridiculus mus

The FOURIER trial was a good example of massive hype and enormous effort followed by an underwhelming result. “A mountain had gone into labour and was groaning terribly. Such rumours excited great expectations all over the country. In the end, however, the mountain gave birth to a mouse,” wrote the Latin poet Phaedrus, though the story is better known from a pithy line by Horace (see heading). A mighty coalition of East Coast American institutions decided to address the mountainous issue of whether a professionally delivered intervention plus education aimed at mouse infestation might reduce asthma symptoms among mouse-sensitized children and adolescents with persistent asthma compared with education alone. The mountain groaned for five years. Mice were sacrificed, or fled in terror. But at the end of the trial, asthma symptoms did not differ between groups.

Testing fails to predict preterm birth

Spontaneous labour is preceded by shortening of the cervix and a rise in vaginal levels of fetal pronectin. So perhaps by measuring these things, one might be able to predict premature labour, ran the hypothesis. But a study of 9410 nulliparous women with singleton pregnancies showed that this combination predicted less than a quarter of preterm onset of labour, and is not fit for clinical use.

Poor anticoagulation in AF precedes stroke

A study of 94 474 North American patients with acute ischemic stroke who had a known history of atrial fibrillation shows the importance of adequate anticoagulation. 84% did not receive guideline-recommended therapeutic anticoagulation preceding the stroke. The 16% who had received adequate treatment with warfarin or DOACs had less severe strokes and lower in-hospital mortality.

JAMA Intern Med  Mar 2017 Vol 177

Kidney outcomes & BP control in non-diabetics

Here’s a meta-analysis of nine randomized clinical trials with 8127 patients and a median follow-up of 3.3 years. It aims to answer the question of whether aiming for a BP of <130/80 mm Hg (intensive control) prevents kidney disease progression better than standard control (<140/90). Every week, I look at about 20 meta-analyses, deliberately leaving aside most technical aspects and concentrating on what might be important for decision-making with patients. High blood pressure is a very common cardiorenal risk factor: end-stage renal failure is a very rare complication of high blood pressure. There is every likelihood that different BP lowering agents confer different levels of protection, and that this will differ among subgroups e.g. by ethnicity, duration, age etc. How will this review help me to reach decisions with real people, using specific drugs? Not a bit, I would suggest. It relies on surrogate end-points and compares one general strategy with another over too short a period. That’s not the fault of the authors. But it is their fault when they go on to stretch even this meagre evidence beyond anything it can support: “Targeting blood pressure below the current standard is not consistently warranted, but may benefit nonblack patients or those with heavy proteinuria.” If something hasn’t reached statistical significance, don’t make a strapline of it. It will only confuse the troops. Bury it in the conclusion, as a suggestion for further research.

The Lancet 18 Mar 2017 Vol 389

Our statin war correspondent writes

I know some people like to watch a good fight, but for me the statin wars between The Lancet and The BMJ, seemed endlessly tiresome and pointless. Even now, the two central lessons don’t seem to have emerged clearly: firstly, taking a statin is an individual choice, not a herd intervention; and secondly, the effect is not a herd effect at all but accrues maximally to a few individuals while leaving most with no benefit at all. But in this overheated argument, the issue has been depicted as a moral crusade to make people take pills for their own good and tell them that any adverse effects they experience must be in their imagination. Many months after The Lancet published a review by Rory Collins, which was to settle the matter, the journal publishes responses from dissenters, including the BMJ authors whose article triggered the war and Fiona Godlee who stood by them. She writes: “So despite Horton and Collins and colleagues wanting to shut down the discussion and award themselves the final word, the debate about statins in primary prevention is alive and kicking. It is a debate that needs to be resolved as thoughtfully, objectively, and openly as possible, and not by eminence-based narrative reviews, however extensive, based on meta-analysis of data that only Collins, his fellow trialists, and industry sponsors have seen. This absence of independence and transparency is not unusual in medicine—indeed it is sadly still very much the norm.” Bravissima! And praise to The Lancet for printing this. Can we look forward to calm and good sense from now on?

Hip screws i’FAITH

The Lancet has published a study comparing two kinds of screw fixation for hip fractures. Hip fractures are common and often presage immobility and death in old people, so a good treatment is of interest to all of us. The FAITH trial concludes that “in terms of reoperation rates the sliding hip screw shows no advantage, but some groups of patients (smokers and those with displaced or base of neck fractures) might do better with a sliding hip screw than with cancellous screws.” Useful knowledge.

BLISTERingly good

If you ever get the chance to hear Hywel Williams talk about his work, don’t miss it. He talks a wonderful talk, but he walks an even more wonderful walk. The BLISTER trial is a classic example from his Centre of Evidence Based Dermatology in Nottingham. Bullous pemphigoid is a distressingly itchy auto-immune skin disease of older people, whose incidence has doubled in the last decade and now stands somewhere between 14 and 42 new patients per million inhabitants of the UK and Europe. Too rare and too cheaply treated to be of any interest to the pharmaceutical industry: but Hywel and his colleagues did a systematic review and found that there was no clear evidence to choose between treatment with oral steroids or tetracyclines. They talked to patients; they collected a group of colleagues from across the UK to conduct a trial, and they found funding from a non-pharma source. This is what they always do. Go thou, dear reader, and do likewise. Oh, and what did they find? That starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Truly useful knowledge. Go forth, dear reader, and discover something of your own that really benefits patients.

The BMJ 18 Mar 2017 Vol 356

Hot fresh microbiome

A single-author review from the USA sets out to describe how our understanding of our microbial communities (microbiota) has developed over recent years. “Perhaps the most radical change is the realization that most of the microbes that inhabit our body supply crucial ecosystem services that benefit the entire host-microbe system. These services include the production of important resources, bioconversion of nutrients, and protection against pathogenic microbes.” I like this analogy between the microbiome and a service industry. It can work both ways. This article, though long and occasionally hard to penetrate, is good reading for a rainy afternoon. It ends on a note of American optimism. “The insights gained through the study of our indigenous microbiota are leading the way to a better understanding of the mechanisms by which microbes can maintain health and trigger disease. With this greater understanding it is hoped that we will be in a position to develop new ways to prevent and treat a wide range of diseases and to foster health by tending to our microbial symbionts.” Little cuties. Now please wash your hands.

Plant of the Week: Forsythia suspensa var sieboldii

I’m all for people growing the plants they enjoy, but I suspect that most of the shouty yellow forsythias that appear at this time of year are not there for pleasure but are just mistakes which nobody has thought to correct. Our neighbour planted one in a prominent spot near our common drive a few years ago. In the interests of internecine tranquillity, I said nothing and raised not an eyebrow in his direction. Fortunately he is a man of order and soon tired of its wild and straggling habit: an inoffensive little barberry now marks the place where once it blazed bad yellow at the March winds.

The forsythias which clash inexcusably with the early cherry and magnolia trees are usually of the intermediagroup, but from time to time I catch sight of paler forsythias which make me want to stop the car and admire them, perhaps also surreptitiously helping myself to a branch while nobody is looking. What stops me doing this is the fact that we don’t have any room for another large straggling shrub. If we had, I would probably go for F suspensa var sieboldii, placed on a bank, though I may be relying too much on book descriptions and Google images. “Introduced c.1857. This unique Forsythia is distinguished by its arching, rambling, lax habit; its pleasing, light yellow flowers are borne all along the vigorous new shoots as well as on the old twigs; it is by far the most desirable for cutting for the house,” wrote Graham Stuart Thomas (1992), who was never wrong.

Source:BMJ

 

Worldwide trends in volume and quality of published protocols of randomized controlled trials


Abstract

Introduction

Publishing protocols of randomized controlled trials (RCT) facilitates a more detailed description of study rational, design, and related ethical and safety issues, which should promote transparency. Little is known about how the practice of publishing protocols developed over time. Therefore, this study describes the worldwide trends in volume and methodological quality of published RCT protocols.

Methods

A systematic search was performed in PubMed and EMBASE, identifying RCT protocols published over a decade from 1 September 2001. Data were extracted on quality characteristics of RCT protocols. The primary outcome, methodological quality, was assessed by individual methodological characteristics (adequate generation of allocation, concealment of allocation and intention-to-treat analysis). A comparison was made by publication period (First, September 2001- December 2004; Second, January 2005-May 2008; Third, June 2008-September 2011), geographical region and medical specialty.

Results

The number of published RCT protocols increased from 69 in the first, to 390 in the third period (p<0.0001). Internal medicine and paediatrics were the most common specialty topics. Whereas most published RCT protocols in the first period originated from North America (n = 30, 44%), in the second and third period this was Europe (respectively, n = 65, 47% and n = 190, 48%, p = 0.02). Quality of RCT protocols was higher in Europe and Australasia, compared to North America (OR = 0.63, CI = 0.40–0.99, p = 0.04). Adequate generation of allocation improved with time (44%, 58%, 67%, p = 0.001), as did concealment of allocation (38%, 53%, 55%, p = 0.03). Surgical protocols had the highest quality among the three specialty topics used in this study (OR = 1.94, CI = 1.09–3.45, p = 0.02).

Conclusion

Publishing RCT protocols has become popular, with a five-fold increase in the past decade. The quality of published RCT protocols also improved, although variation between geographical regions and across medical specialties was seen. This emphasizes the importance of international standards of comprehensive training in RCT methodology.

Soure:plos.org

Virology: Fighting for a cause.


When Judy Mikovits found links between chronic fatigue syndrome and a virus, the world took notice. Now, she’s caught between the patients who believe her work and the researchers who don’t.

On a sunny January afternoon in Santa Rosa, California, a small crowd waits patiently for Judy Mikovits to arrive. She is scheduled to deliver a talk on a mysterious virus called XMRV, which she believes underlies chronic fatigue syndrome. Although she’s two hours late — held up by fog at San Francisco International Airport — not a single person has left. And when she arrives, they burst into applause.

To a rapt audience, she gives a chaotic and wide-ranging talk that explores viral sequences, cell-culture techniques and some of the criticisms that have been thrown at her since she published evidence1 of a link between XMRV and chronic fatigue in 2009. Afterwards, Mikovits is swarmed by attendees. A middle-aged woman who spent most of the talk in a motorized scooter stands up to snap pictures of her with a digital camera. Ann Cavanagh, who has chronic fatigue and has tested positive for XMRV, says that she came in part for information and in part to show her support for Mikovits. “I just wish there were a hundred of her,” Cavanagh says.

The event was “surreal”, says Mikovits, a viral immunologist at the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Reno, Nevada. She is discomfited by the attention from patients, which at times borders on adulation. But her reception among scientists has been markedly cooler. Numerous follow-up studies have found no link between the virus and the disease; no group has published a replication of her findings; and some scientists argue that XMRV is an artefact of laboratory contamination. Now, even some of Mikovits’s former collaborators are having second thoughts.

Mikovits has dug in, however, attacking her critics’ methods and motives. She says that their distrust of her science stems from doubts about the legitimacy of chronic fatigue syndrome itself. Chronic fatigue, also known as myalgic encephalomyelitis, affects an estimated 17 million people worldwide, but it is extremely difficult to diagnose. Many with the disorder are told that their symptoms — which include exhaustion, joint and muscle pain, cognitive issues, and heart and respiratory problems — are psychosomatic. “I had no idea there was that much bias against this disease,” Mikovits says.

The stakes are high and many are taking the risks seriously. Several countries have barred people with chronic fatigue from donating blood in case the virus spreads (see ‘Something in the blood’). And the US government has launched a US$1.3-million study to investigate the link. Patients are already being tested for XMRV, and some are taking antiviral drugs on the assumption that the virus causes chronic fatigue by attacking their immune defences. Many say that such action is premature, but Mikovits is steadfast. “We’re not changing our course,” she says.

First findings

In October 2007, Mikovits attended a prostate-cancer meeting near Lake Tahoe, Nevada, where she met Robert Silverman, a virologist at the Cleveland Clinic in Ohio. Silverman co-discovered XMRV, which stands for xenotropic murine leukaemia virus-related virus2. While examining human prostate tumours, he and his collaborators found genetic sequences that resemble retroviruses found in the mouse genome. Like all retroviruses, XMRV rewrites its RNA genome into DNA on infection, then slips the DNA into the genomes of host cells. Ancient remnants of such viruses litter animal genomes. But the only active retroviruses conclusively linked to human disease are HTLV-1, which causes leukaemia, and HIV.

At the meeting, Silverman was presenting research linking XMRV to deficiencies in a virus-defence pathway. Mikovits recalled that the same pathway was weakened in some patients with chronic fatigue. She wondered whether the prostate-tumour virus could also be behind chronic fatigue. After the meeting, Silverman sent Mikovits reagents to test for XMRV.

The idea excited Mikovits, but she had other priorities. After stints in industry and at the US National Cancer Institute (NCI) in Maryland, she had recently joined the WPI to lead its research programme. The WPI was founded in 2006 by physician Daniel Peterson, an expert on chronic fatigue, and by Annette Whittemore, the wife of a well-connected Nevada businessman, whose daughter Andrea has had chronic fatigue for more than 20 years. The Whittemores spent $5 million establishing the WPI, and several million more to support Mikovits’s research, which has attracted few other grants.

At the WPI, Mikovits established a sample collection from Peterson’s patients and began screening it for signs of an infection. A litany of pathogens has been linked to chronic fatigue over the years, including Epstein-Barr virus, Borna disease virus, human herpes virus 6 and HTLV-2. None panned out. Still, the disorder bears some hallmarks of an infection. Many patients report acute illness before chronic symptoms appear, and their bodies often show signs of an immune system at war. The disease can also crop up in apparent outbreaks, including one characterized by Peterson near Lake Tahoe in the 1980s.

Just before Christmas 2008, Mikovits turned her attention to Silverman’s reagents. She and her postdoc, Vincent Lombardi, known as Vinny, asked a graduate student to test for XMRV DNA in white blood cells from some of the most seriously ill people being studied at the WPI.

The first try turned up just two positives out of 20. But by tweaking the conditions of the test, Mikovits says her team found XMRV in all 20. “Vinny and I looked at each other and said, ‘Well, that’s interesting’,” she says. They spent the next few weeks convincing themselves that they were onto something, and soon conscripted Silverman and Mikovits’s former mentor at the NCI, Frank Ruscetti, to help prove that XMRV infection was behind chronic fatigue.

“We really retooled our entire programme and did nothing but focus on that,” she says. They kept the effort under wraps, dubbing it ‘Project X’. Even Peterson and the Whittemores weren’t clued in. Mikovits says that the secrecy was necessary because her team also found XMRV in the blood of some healthy people, raising concerns about blood products. She hoped to build an airtight case because she worried that sceptical public-health officials would undermine her work.

In May 2009, the team submitted a paper to Science reporting the identification of XMRV genetic material in two-thirds of the 101 patients with chronic fatigue they had tested and in 3.7% of 218 healthy people. They also included data suggesting that infected white blood cells could pass the virus on to uninfected cells.

“They call me every single day. I spend so much time trying to understand the patients, to understand this disease.”

Reviewers wanted more evidence: a clear electron micrograph of virus-infected cells, proof that patients mounted an immune response to the virus, an evolutionary tree showing XMRV’s relationship to other viruses and the locations where viral DNA was integrating into patient genomes. Mikovits’s team went to work. “None of us took any time off, not even a weekend,” she says. They resubmitted the paper in early July with everything the reviewers had asked for, except the DNA integration sites, which many scientists consider a gold standard in proving a retroviral infection.

Later that month, NCI officials who had learned about the work invited Mikovits to give a talk at a closed-door meeting with other XMRV researchers and government scientists. “When I finished speaking you could’ve heard a pin drop,” she says. Mikovits says she thinks at least one of her manuscript’s reviewers was at the meeting, because soon after, she got a call from a Science editor. Their paper had been accepted.

Jonathan Stoye, a retrovirologist at the MRC National Institute for Medical Research in London, wrote a commentary about the paper for Science3. He had never heard of Mikovits, but Frank Ruscetti’s name on the paper gave him confidence, he says, and “if it were true, it was clearly very important”. Stoye’s co-author John Coffin, a retrovirologist at Tufts University in Boston, Massachusetts, says he was satisfied with the data and thought it was time to “let the field and public chew on them”.

The BBC, US National Public Radio, The New York Times, The Wall Street Journal and dozens of other news outlets covered the research. “Prostate cancer pathogen may be behind the disease once dubbed ‘yuppie flu’,” Nature announced on its news website the day the paper came out. Phoenix Rising, a forum for patients with chronic fatigue that has become a hub for all things XMRV, called the work a “game changer”, and patients flocked to learn more about a virus that they hoped would explain their condition. But others, including Britain’s leading chronic fatigue patient group, urged caution until more research buttressed the link.

The first negative findings started to arrive in January 2010 — failing to find XMRV in 186 people with chronic fatigue from the United Kingdom4. A month later, a team including Stoye published a paper5showing no evidence of XMRV in more than 500 blood samples from patients with chronic fatigue and healthy people. One day later, theBritish Medical Journal accepted a paper reporting more negative results in Dutch patients6. Studies began piling up so fast that Coffin made a scorecard to show at talks. “I’ve lost count now,” he says.

Mikovits says that the discrepancies can be explained by differences in the geographical distribution of XMRV or in the methods used.

Judy Mikovits says that she will not abandon the hypothesis that XMRV and related viruses cause chronic fatigue syndrome, despite a growing chorus of critics.

The most common way to detect XMRV is PCR, or polymerase chain reaction, which amplifies viral DNA sequences to a level at which they can be identified. Mikovits and her team used this method to detect XMRV in some of their patients, but she contends that the most sensitive way to detect the virus is to culture patients’ blood cells with a cell line in which the virus replicates more quickly. This should create more copies of the virus, making it easier to detect with PCR and other techniques. She says that none of the negative studies applied this method exactly, a fact that annoys her. “Nobody’s tried to rep-li-cate it,” she says, sounding out each syllable for emphasis.

In summer 2010, some evidence emerged in Mikovits’s corner. Harvey Alter, a hepatitis expert at the NIH’s Clinical Center, and his team identified viruses similar to XMRV in 32 of 37 people with chronic fatigue and in 3 of 44 healthy people. They were preparing to publish their results in the Proceedings of the National Academy of Sciences. But scientists at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, were about to publish a negative report. The authors delayed publication of both papers7,8for several weeks to assess discrepancies. The move agitated Mikovits as well as the chronic-fatigue community, who suspected that important data were being suppressed.

When Alter’s work came out in late August7, Mikovits was ecstatic, and the WPI released a YouTube video of her touting it. For other researchers, however, the new paper had shortcomings. The viral sequences from Alter’s paper differed from XMRV, says Greg Towers, a retrovirologist at University College London. “He doesn’t get variation, he gets a totally different virus.” Towers says that mouse DNA, which is chock-full of virus sequences like those Alter’s team found, probably contaminated their samples, which were collected in the 1990s. But Alter says that his team found no contamination from mouse DNA and recovered the same viral sequences from the same patients sampled a decade later.

Contamination became a dirty word for Mikovits. Just before Christmas 2010, Retrovirology published four papers9,10,11,12 that highlighted laboratory contamination as a possible explanation for her findings. One showed, for example, that mouse DNA contaminates an enzyme from a commercial kit commonly used for PCR. Coffin, an author on two of the Retrovirology papers, urges caution against over-extrapolating. These papers do not say that contamination explains Mikovits’s results, he says, just that extreme care is required to avoid it.

Towers and his colleague Paul Kellam, a virologist at the Wellcome Trust Sanger Institute near Cambridge, UK, are less charitable, however. Their study12 showed that the XMRV sequences that Mikovits and Silverman had extracted from patients lacked the diversity expected of a retrovirus that accumulates mutations as it passes between patients. “This doesn’t look like an onwardly transmittable infectious virus,” says Kellam. A press release for the paper issued by the Sanger Institute put it more bluntly: “Chronic fatigue syndrome is not caused by XMRV.”

Mikovits is riled when the topic turns to Towers’s paper over dinner one night in Reno — “Christmas garbage”, she calls it. Contamination cannot explain why her team can reproduce its results both in her lab in Reno and at Ruscetti’s at the NCI, she says. Her team checks for contamination in reagents and in the cells it grows the patients’ samples with. She says that her team has also collected viral sequences that will address Towers’s and Kellam’s criticism but that it hasn’t yet been able to publish them. Meanwhile, an unpublished study of patients in Britain with chronic fatigue bears out the link to XMRV, she says. “I haven’t for one second seen a piece of data that convinced me they’re not infected.”

Jay Levy, a virologist at the Univer­sity of California, San Francisco, has a window in his closet-sized office that looks out into the laboratory where, in the 1980s, he became one of the first scientists to isolate HIV. After his discovery was scooped by other researchers, Levy turned his attention to chronic fatigue and started a long but fruitless search for an infectious cause.

Now, Levy is putting the finishing touches on what could be the most thorough response yet to Mikovits’s Science paper, adopting the same cell-culture techniques to detect the virus and using samples from the same patients. He’s done this with the help of Daniel Peterson, who left the WPI in 2010 for what Peterson says are “personal reasons”. Peterson has questioned the institute’s singular pursuit of XMRV, a research direction that was pursued without his consultation.

Mikovits says that she kept the XMRV work secret from Peterson over fears he would tell his patients, and left his name off the original Science manuscript until a reviewer questioned the omission. When asked whether that episode contributed to his departure, he says, “I was surprised at the secrecy and lack of collaboration.” As for his motivation to team up with Levy: “I’m just trying to get to the truth. It’s my only motive, because this is such a deserving group of patients who need to know what’s going on.”

Others, too, are rallying for a definitive answer. Ian Lipkin, a microbial epidemiologist at Columbia University in New York, has a reputation for getting to the bottom of mysterious disease–pathogen links. His team debunked the association between Borna disease virus and chronic fatigue, for example. Now he is spearheading the $1.3-million effort funded by the US government. He is leaving the testing to three labs: Mikovits’s at the WPI, Alter’s at the NIH and the CDC. Each will receive coded samples of white blood cells and plasma from 150 patients with chronic fatigue and from 150 healthy controls. The labs will test for XMRV using their method of choice. Lipkin will crunch the data and unblind the samples.

But even if a study confirms the link to chronic fatigue, it won’t be able to determine whether the virus is the cause. XMRV could, for example, be an opportunistic infection affecting those whose immune systems are already dampened by chronic fatigue. Even Mikovits can only hypothesize as to how it might cause disease.

The virus might not even exist as a natural infection. At a retrovirus conference this month in Boston, Massachusetts, Coffin and his colleague Vinay Pathak at the NCI in Frederick, Maryland, presented data showing that XMRV emerged in the 1990s, during the development of a prostate-tumour cell line called 22Rv1. Developing the line involved implanting a prostate-tumour sample into mice, retrieving cells that might divide indefinitely and repeating the process. But looking back at DNA samples taken throughout the cell-line’s development showed that human cells became infected only after passing through several different mice. Importantly, XMRV’s sequence seems to have come from two different mouse strains. “They just sort of snapped together like two puzzle pieces,” says Coffin, an event extremely unlikely to have happened twice.

Bumper stickers are just one of the supportive gifts given to the WPI.D. 

XMRV sequences retrieved from patients with prostate cancer and chronic fatigue — including some who have had chronic fatigue since the mid-1980s — are nearly identical to the virus from 22Rv1 cells. The implication, says Coffin, is that this virus, born in a laboratory, has probably been infecting samples for more than a decade, but not people. “Although people on the blogs aren’t going to believe me, I’m afraid this is by far the most reasonable explanation for how XMRV came to be,” says Coffin, who hoped that the association with chronic fatigue would pan out and still thinks some pathogen other than XMRV could explain the disease.

Silverman, who no longer works with Mikovits, says that he wasn’t using 22Rv1 cells when XMRV was discovered. Nonetheless, the work has rattled his confidence in XMRV’s link to both prostate cancer and chronic fatigue.

Mikovits, however, is undeterred. The WPI owns a company that charges patients up to $549 to be tested for XMRV, and Mikovits believes that patients who test positive should consult their doctors about getting antiretroviral drugs normally prescribed to those with HIV. Levy and others worry that she is overreaching. “That’s scary for me. These antiretroviral drugs are not just like taking an aspirin,” he says. Mikovits argues that they might be some patients’ only hope. “The people who we know they’re infected should have a right to get therapy,” she says, “They have nothing. They have no other choice.”

Context and debate

Back in her Reno laboratory two days after the talk in Santa Rosa, Mikovits examines a stack of small plastic flasks under a microscope. Some contain patient cells that she hopes will turn into cell lines and churn out XMRV. “On Wednesdays I get to take care of my cells, and that’s where I’m the happiest,” she says.

She has just come off the phone from a sobbing patient infected with XMRV whose symptoms had worsened. “They call me every single day,” Mikovits says. “I don’t do science any more. I spend so much time trying to understand the patients, to understand this disease. People have moved to Reno to be here,” she says. They’ve left gifts: stuffed animals, and stacks of bumper stickers that say “Today’s Discoveries, Tomorrow’s Cures” and, more boldly, “It’s the virus XMRV”.

Mikovits clearly shares in the frustration of those with chronic fatigue who have been marginalized over the years and told that their disease is not real. She says that this disbelief in the disorder drives the criticism of her work. Kellam and the others say that this isn’t true. They don’t deny the existence of the syndrome or even the possibility of an infectious origin. “What we’re trying to understand is the aetiology,” Kellam says. “It’s a scientific debate.”

ADVERTISEMENT

Mikovits says that she’s analysed all the papers critical of her work and found flaws in each of them. Nevertheless, she’s quick to endorse findings that support her work. She claims that Coffin and Pathak’s study, for example, “says nothing about human infection”. Yet new work presented at a different meeting that found XMRV using next-generation DNA sequencing offers “no doubt it’s not contamination — that the whole story’s real”, she says.

Despite the growing choir of sceptics, Mikovits says that she has simply seen too many data implicating XMRV and other related viruses in chronic fatigue to change her mind. For her supporters, that steadfastness offers legitimacy and hope. “The scientists are moving forward,” she announced at her talk in Santa Rosa, “and I think the politics will go away shortly.” The crowd responded with vigorous applause. 

Ewen Callaway writes for Nature from London.

  • References

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    2. Urisman, A. et al. PLoS Pathog. 2, e25 (2006). | Article | PubMed | ChemPort |
    3. Coffin, J. M. & Stoye, J. P. Science 326, 530-531 (2009). | Article | PubMed | ChemPort |
    4. Erlwein, O. et al. PLoS ONE 5, e8519 (2010). | Article | PubMed | ChemPort |
    5. Groom, H. C. et al. Retrovirology 7, 10 (2010). | Article | PubMed | ChemPort |
    6. Van Kuppeveld, F. J. et al. Br. Med. J. 340, c1018 (2010).
    7. Lo, S. C. et al. Proc. Natl Acad. Sci. USA 107, 15874-15879 (2010).
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    12. Hué, S. et al. Retrovirology 7, 111 (2010).

Source: Nature.com

Biomarkers for Identifying Risk of Immune Reconstitution Inflammatory Syndrome


In the last 10–20 years, access to antiretroviral therapy (ART) has improved worldwide, resulting in substantial reduction in HIV-associated mortality and increased life expectancy, especially in low and middle-income countries. However, immune reconstitution inflammatory syndrome (IRIS), the clinical deterioration in patients with HIV initiating ART, is a common complication of ART initiation. The manifestations of IRIS depend on the type of opportunistic infection. With HIV-1 as the strongest predisposing factor to tuberculosis (TB) and TB as the commonest cause of death in HIV-1 infected persons in Africa, the otherwise beneficial dual therapy for HIV-1 and TB is frequently complicated by the occurrence of TB-immune reconstitution inflammatory syndrome (TB-IRIS) (Walker et al., 2015). Two forms of TB-IRIS are recognized: paradoxical, which occurs in patients established on anti-tuberculosis therapy before ART, but who develop recurrent or new TB symptoms and clinical features after ART initiation; and unmasking TB-IRIS in patients not receiving treatment for TB when ART is started, but who present with active TB within 3 months of starting ART (Meintjes et al., 2008). Paradoxical TB-IRIS affects approximately 15.7% of all HIV-1-infected patients commencing ART while on TB treatment, and up to 52% in some populations, causing considerable morbidity and mortality (Namale et al., 2015).

While the clinical features are relatively well-described, specific diagnostic tools and treatments for TB-IRIS are lacking. The diagnosis of IRIS is clinical, and excluding other causes for a clinical deterioration, such as other opportunistic infections and drug-resistance, is challenging, especially in a resource-limited setting. While risk factors for IRIS have been identified, such as low CD4 count pre-ART initiation and the presence of a disseminated opportunistic infection, there are no biomarkers that predict which patients will develop IRIS. The identification of biomarkers for IRIS prediction may help elucidate the mechanism of IRIS pathogenesis, which may in turn facilitate the development of specific therapies and additionally, allow high-risk patients that would benefit from specific preventative strategies to be identified.

A large number of investigations have addressed the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis, reviewed in Lai et al. (2015a)). A recent unbiased whole-blood transcriptomic profiling of HIV-TB co-infected patients commencing ART showed that inflammation in TB-IRIS is driven by innate immune signaling and activation of the inflammasome, which triggers the activation of transcription factors leading to hypercytokinemia, resulting in systemic inflammation (Lai et al., 2015b). Other recent work also suggests that extracellular matrix destruction by matrix metalloproteinases may play a role in paradoxical TB-IRIS (Tadokera et al., 2014, Shruthi Ravimohan, 2015). Immunosuppressive corticosteroid therapy improves symptoms and reduces hospital admissions but is not without adverse events, and is potentially detrimental in cases of drug-resistant TB (Meintjes et al., 2010). Therefore therapeutic strategies that offer greater immune specificity should be explored.

The CADIRIS study, a double-blind, randomized, placebo-controlled trial, investigated the use of maraviroc (a CCR5 antagonist) for IRIS prevention, based on the hypothesis that inflammatory cytokines and chemokines mediate the influx of CCR5-expressing immune cells in IRIS and CCR5 blockade would prevent these inflammatory cells leaving the circulation, reducing local inflammatory reactions leading to IRIS. The study recruited HIV-infected participants with advanced immunosuppression (CD4 count <100/μl) from five clinical sites in Mexico and one in South Africa and followed them for 1 year. Patients were assigned to receive either maraviroc (600 mg twice daily) or placebo in addition to ART, the primary outcome being time to an IRIS event by 24 weeks. Maraviroc had no significant effect on development of IRIS after ART initiation. While this CCR5 inhibitor has proven antiviral activity, safety and tolerability as part of an ART regimen, its use as an immune-modulator to prevent IRIS appears un-warranted (Sierra-Madero et al., 2014).

Well-conducted clinical trials, even if their outcome is negative, are an enormously valuable resource for further studies, such as identifying correlates of risk and/or protection. In this issue of EBioMedicine, Musselwhite and colleagues (Musselwhite et al., 2016) investigate plasma biomarkers predictive of IRIS in samples banked at enrolment from HIV-infected patients entering the CADIRIS trial. With the hypothesis that the risk of IRIS is most likely already present before starting ART, and can be predicted from measuring biomarkers in plasma samples collected before starting ART, they assessed twenty biomarkers in an exploratory way, and retrospectively associated them with the risk of developing IRIS. Of the 267 patients with banked plasma samples, 62 developed IRIS within 6 months of ART initiation, 31% of them TB-IRIS specifically, within median of 13 days of ART. The results indicate that baseline concentrations of vitamin D and higher concentrations of D-dimer, as well as markers of T cell and monocyte activation (interferon-γ and sCD14) were independently associated with risk of IRIS in general. Vitamin D deficiency was prevalent. Higher vitamin D levels were associated with protection against IRIS events, suggesting vitamin D plays an immune-modulatory role. However, vitamin D and D-dimer concentrations were not associated with TB-IRIS specifically, perhaps due to lack of power for this sub-analysis. TB-IRIS was associated with higher concentrations of CRP, sCD14, and interferon-γ and lower hemoglobin than other forms of IRIS and these parameters were used in a composite score to predict TB-IRIS over Other IRIS, with an area under the curve of 0.85 (CI 0.79-0.92) on Receiver Operator Characteristics (ROC) analysis.

The strength of this study lies in reasonable power to assess predictors of IRIS and the availability of plasma samples prior to starting ART on two different continents, contributing to the generalizability of the findings. Interesting comparisons are drawn between TB-IRIS and other causes of IRIS, demonstrating heterogeneity in IRIS pathophysiology. As patients with CD4 counts ≥100/μl and those with critical illness (e.g. severe laboratory abnormalities, CNS infections) were excluded, generalizability of the findings to these groups is unknown. Further work is required to confirm the findings in these and other at-risk patient populations.

References

  1. Lai, R.P., Meintjes, G., and Wilkinson, R.J. HIV-1 tuberculosis-associated immune reconstitution inflammatory syndrome. Semin. Immunopathol. 2015;
  2. Lai, R.P., Meintjes, G., Wilkinson, K.A., Graham, C.M., Marais, S., Van der Plas, H., Deffur, A., Schutz, C., Bloom, C., Munagala, I., Anguiano, E., Goliath, R., Maartens, G., Banchereau, J., Chaussabel, D., O’Garra, A., and Wilkinson, R.J. HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling. Nat. Commun. 2015; 6: 8451
  3. Meintjes, G., Lawn, S.D., Scano, F., Maartens, G., French, M.A., Worodria, W., Elliott, J.H., Murdoch, D., Wilkinson, R.J., Seyler, C., John, L., van der Loeff, M.S., Reiss, P., Lynen, L., Janoff, E.N., Gilks, C., and Colebunders, R. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect. Dis. 2008; 8: 516–523
  4. Meintjes, G., Wilkinson, R.J., Morroni, C., Pepper, D.J., Rebe, K., Rangaka, M.X., Oni, T., and Maartens, G. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010; 24: 2381–2390
  5. Musselwhite, Laura W., BBA, Ellenberg, Susan S., Tierney, Ann, Belaunzaran-Zamudio, Pablo F., Rupert, Adam, Lederman, Michael M., Sanne, Ian, Madero, Juan G. Sierra, and Sereti, Irini. Vitamin D, d-dimer, interferon γ, and sCD14 levels are independently associated with immune reconstitution inflammatory syndrome: a prospective, international study. EBioMedicine. 2016; 4: 115–123
  6. Namale, P.E., Abdullahi, L.H., Fine, S., Kamkuemah, M., Wilkinson, R.J., and Meintjes, G. Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis. Future Microbiol. 2015; 10: 1077–1099
  7. Shruthi Ravimohan, N.T., Kung, Shiang-Ju, Nfanyana, Kebatshabile, Steenhoff, Andrew P., Gross, Robert, Weissman, Drew, and Bisson, Gregory P. Matrix metalloproteinases in tuberculosis-immune reconstitution inflammatory syndrome and impaired lung function among advanced HIV/TB co-infected patients initiating antiretroviral therapy. EBioMedicine. 2015; 3: 100–107
  8. Sierra-Madero, J.G., Ellenberg, S., Rassool, M.S., Tierney, A., Belaunzaran-Zamudio, P.F., Lopez-Martinez, A., Pineirua-Menendez, A., Montaner, L.J., Azzoni, L., Benitez, C.R., Sereti, I., Andrade-Villanueva, J., Mosqueda-Gomez, J.L., Rodriguez, B., Sanne, I., Lederman, M.M., and team Cs. A randomized, double-blind, placebo-controlled clinical trial of a chemokine receptor 5 (CCR5) antagonist to decrease the occurrence of immune reconstitution inflammatory syndrome in HIV-infection: the CADIRIS study. Lancet HIV. 2014; 1: e60–e67
  9. Tadokera, R., Meintjes, G.A., Wilkinson, K.A., Skolimowska, K.H., Walker, N., Friedland, J.S., Maartens, G., Elkington, P.T., and Wilkinson, R.J. Matrix metalloproteinases and tissue damage in HIV-tuberculosis immune reconstitution inflammatory syndrome. Eur. J. Immunol. 2014; 44: 127–136
  10. Walker, N.F., Scriven, J., Meintjes, G., and Wilkinson, R.J. Immune reconstitution inflammatory syndrome in HIV-infected patients. HIV AIDS (Auckl.). 2015; 7: 49–64

Source:http://www.ebiomedicine.com

Drug-Resistant Tuberculosis


Executive Summary

“Practices for the management of individual patients in settings with a high tuberculosis burden are not sufficient to prevent the emergence, amplification, and spread of drug-resistant tuberculosis” is one of the key messages from The Lancet Respiratory Medicine Commission, led by Keertan Dheda from the University of Cape Town, South Africa. The Commission focuses on multidrug-resistant, extensively drug-resistant, and incurable tuberculosis, and highlights the growing burden of disease, its implications for patient management, as well as social and legal aspects. The authors also provide practical solutions for tackling emerging resistant cases—an exponentially increasing concern in high-burden countries.

Read more: http://thelancet.com/commissions/drug-resistant-tuberculosis?dgcid=twitter_social_lancet

source: the Lancet

David Oliver: Getting real about care closer to home.


There’s a growing consensus about how we must change to ensure sustainable future health services. Its essence is: let’s focus more on public health, prevention, and wellbeing; enhance primary and wider community support for people with long term conditions; and, during acute crises, help patients spend less time in hospitals—or none at all—repurposing resources and staff away from hospital buildings.

In England we see such ambitions and rhetoric in political pronouncements and in key documents such as the NHS Five Year Forward View,1 sustainability and transformation plans (STPs),2 and position papers from professional organisations.34

These grand ideas aren’t new, but they remain unmatched by grand actions. This isn’t surprising, when service leaders must balance imagined future benefits against tangible current pressures in broke, full acute hospitals—admitting that they can no longer hit high profile and politically sensitive performance targets.5

These grand ideas aren’t new, but they remain unmatched by grand actions

The health announcements in the chancellor’s March 2017 spring budget further exposed this dissonance.6 First, Philip Hammond promised an extra £100m for GPs based in emergency department triage—even though upstream conventional primary care, with the potential to help keep patients away from them, is experiencing workforce and workload crises and has 100 fewer GPs this year despite plans to recruit 5000 more.7

Social care was promised a further £2bn uplift over the next three years. But this announcement was clearly labelled in terms of reducing delayed transfers from—you guessed it—acute hospitals.8 Senior NHS leaders encouraged these hospitals to “get lippy” about use of the social care money.9 Little mention, then, of supporting people and their carers to stay at home in the first place, although this is at the core of social care’s purpose.

Hammond promised an additional £325m of capital expenditure for “leading” STPs (again, more on buildings rather than on staff and services in people’s own homes).10 Some £800m in funds held by clinical commissioning groups and earmarked for primary and mental health was then repurposed by NHS England to meet hospital deficits and pressures.11

Opinion polls show that responsive, urgent care tops public concerns about the NHS.12 Politicians and journalists reinforce this by discussing it predominantly in terms of hospitals and beds. This high visibility and the narrow focus on acute care performance become a distorting, overvalued idea.

If we’re serious about a shift towards the preventive and coordinated care we claim to want, we can’t keep pumping all additional new funds into supporting hospitals. We’ll need to relax our expectations of hospital performance and be honest about what they can no longer offer, let alone improve.

Maybe in the autumn statement we’ll put our money where our mouth is. Platitudes don’t help patients.

Footnotes

References

Source:BMJ

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis


Summary

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms—including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions—are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Conclusion

MDR tuberculosis, XDR tuberculosis, and resistance beyond XDR tuberculosis remains a major threat to global tuberculosis control because of the increasing burden it creates on health-care systems, economies, and societies, the threat to health-care workers in tuberculosis-endemic countries, the high mortality, and the unsustainably high costs of treating drug-resistant tuberculosis. Additionally, the development of totally drug-resistant or programmatically incurable tuberculosis has raised several ethical and medicolegal challenges. The global epidemiology of drug-resistant tuberculosis shows a worrying increase in the prevalence and incidence of drug-resistant tuberculosis in several countries and regions. Also, the proportion of cases of tuberculosis that are MDR and fluoroquinolone-resistant or aminoglycoside-resistant—ie, pre-XDR—or that are programmatically incurable has increased greatly. New molecular tools such as next-generation whole-genome sequencing are shedding further light on the transmission, diagnosis, and pathogenesis of drug-resistant tuberculosis.522Particularly, several lines of evidence challenge the traditional view that resistance is acquired through non-adherence promoted by poor programmatic functioning. Although adherence is clearly important for the prevention of drug-resistant tuberculosis, several other factors that promote pharmacokinetic mismatch drive the acquisition of drug-resistant tuberculosis even when adherence is good. However, newer methods to enable whole-genome sequencing directly from sputum and to assess its effect on clinical outcomes are needed.

Furthermore, a paradigm shift is required to take testing from the clinical setting into the community, thus promoting active case finding, and the detection of the undiagnosed and unsuspected cases of community-based drug-resistant tuberculosis. Newer drugs have improved the efficacy of the treatment of MDR and XDR tuberculosis, and therefore the prognosis, but resistance amplification will need to be minimised through strengthening tuberculosis programmes and other innovative approaches to prevent pharmacokinetic mismatch. Novel ways to reduce or eliminate the transmission of drug-resistant tuberculosis and to understand the fundamental biology of transmission are urgently required. These key messages are summarised in panel 11, and timeline-orientated research priorities and goals for drug-resistant tuberculosis are shown in table 15. All these priorities will need to be urgently addressed in tandem with the strengthening of health systems, reduction of poverty, and changing of political will.

Key messages

  • Resistance to antituberculosis drugs is a global problem of considerable public health importance that threatens to derail efforts to eradicate the disease. Advocacy is needed in national and transnational fora to ensure the urgency of the situation is understood and that appropriate funding is made available.

  • Practices for the management of individual patients in settings with a high tuberculosis burden are not sufficient to prevent the emergence, amplification, and spread of drug-resistant tuberculosis. These practices include empirical treatment with standardised second-line drug regimens for people who are found to have rifampicin-resistant tuberculosis.

  • Access to drug resistance testing is scarce in most countries and urgently needs to be expanded to allow curative second-line treatment regimens to be implemented.

  • Knowledge regarding the safe use—including dose and length of treatment—of new and repurposed drugs must be improved through clinical trials.

  • Models of care for people with drug-resistant tuberculosis, including programmatically incurable disease, must ensure that the rights and dignity of individual patients are respected.

  • Assessment of the performance, health effects, and potential economic benefits of molecular tools such as genome sequencing for detecting resistance, must be accelerated to facilitate effective implementation.

  • Greater investment is needed in the development of new drugs and diagnostics.

Source:Lancet