The true cost of antimicrobial resistance.

antibioticpills_0Almost as soon as antibiotics were discovered, we knew that bacteria were able to develop resistance against them.1 This is not necessarily a problem, as long as there are other antimicrobials to take their place. During the latter half of the 20th century this was the predominant situation, but no longer.2 A rapid decrease in the number of new drugs approved and numerous withdrawals on quality and safety grounds have left the well dry, and it is clear that “the existing classes of antibiotics are probably the best we will ever have.”3

In light of this, there have been efforts to support interventions that encourage more conservative and appropriate use of antibiotics in an attempt to halt or slow the progress of resistance.4 However, this action is often too little and may be too late.

Given that the dangers of resistance are widely acknowledged, why isn’t more being done? One reason is that antibiotic resistance has fallen victim to evidence based policy making, which prioritises health problems by economic burden and cost effectiveness of interventions.5 Health economists have been unable to show that antibiotic resistance costs enough to be a health priority.

Limitations of health economic research

Ten years ago we published a systematic review on the economics of resistance.6We asked two questions: what is the cost of resistance and what is the cost effectiveness of interventions to reduce it? The lack of research meant we could investigate only the second question.7 And even here we concluded that the evidence for the cost effectiveness of interventions for resistance was poor.


Source: BMJ


Your five worst medical nightmares.

Carry on Doctor

From a doctor amputating the wrong leg, to a woman given the wrong baby, hospital treatment does not always go to plan. Luckily, though, mistakes are rare


t sounds like a classic nightmare – waking up during an operation to find you can’t move. But that’s what happened to one patient, Sarah Newton. “I was trying to scream. I tried to wiggle my toes desperately hard but I couldn’t move anything.” Thankfully, “accidental awareness”, as it is known, is rare. A survey from the Royal College of Anaesthetists says it occurs once in every 15,000 operations under general anaesthetic, or 153 times in 2011 – and is usually brief and painless. But what of our other medical terrors?


Wrong site surgery

Usually the cause is a catastrophic series of administrative errors, such as when Dr Rolando Sanchez, a Florida surgeon, was told by a nurse that he was amputating the wrong leg of his patient just as he finished cutting through it. Luckily, with only 70 incidents recorded by theNHS in the year 2011-12, it is extremely unusual.


Wrong patient surgery

Never mind the wrong limb. How about operating on the wrong body? Sometimes there may be a mix-up over two people with the same name. Or similar procedures. The reality may not be as scary as it sounds – recently a patient in Cambridgeshire was given another patient’s lens during eye surgery, although this was soon corrected. Plus there were fewer than 10 incidents reported in the UK during 2011-2.

Retained instruments


Leaving surgical instruments inside patients occurred 161 times in 2011-12. Often it’s a sponge, which can lead to serious infections. The risk arises in emergency surgery, and in surgery on obese patients, but it is still very unlikely to happen to you.

Baby mix-ups


Despite being a common storyline in films or stories, there are few documented cases of mothers sent home with the wrong baby. But you have to ask: how would they know? In Romania in 2008, Cristina Zahariuc noticed because the daughter she was sent home with turned out to have a penis. Despite a few awful stories, the risk will be lower now that most babies stay with their parents immediately after birth.

Being treated by an impostor

Well, it has happened. In September 2011, 17-year-old Matthew Scheidt was convicted, of impersonating a physician’s assistant in Florida. He dressed wounds, attended surgery, examined naked patients and even administered CPR. While New Zealander Richmal Oates-Whitehead treated victims of the 7 July 2005 bombings in London, despite not beingmedically qualified.

Ferdinand Waldo Demara managed fairly well when he conducted a series of major operations by speed-reading textbooks during the Korean war. And a man called Gerald Barnes even managed to impersonate a doctor, and be convicted of it, five times. Thankfully pretenders do tend to get caught.


Source: Guardian.Uk

Malignant and premalignant lesions of the penis.


  • Penile cancer has potentially devastating functional and psychological consequences for the patient
  • Penile cancer is thought to be associated with foreskin and genital infection with human papillomavirus types 16 and 18
  • Most patients present with a penile lump (47%), ulcer (35%), or erythematous lesion (17%)
  • Carcinoma in situ of the penis is treated initially with topical chemotherapy or lasers; surgery is reserved for unresponsive cases and men with extensive premalignant changes
  • In invasive penile cancer, penile preserving surgery minimises voiding and sexual dysfunction and psychological sequelae; more radical penile surgery is reserved for advanced cases
  • Metastatic inguinal lymph node involvement is the most important prognostic factor

Penile cancer can have devastating mutilating and psychological consequences for those affected. It is important for clinicians to be aware of the condition. Differentiation of benign genital dermatoses from premalignant penile lesions and early stage penile cancer, with prompt specialist referral, usually prevents progression, improves prognosis, and results in improved functional and cosmetic outcomes for affected men. A retrospective single centre study of all penile cancer cases in a specialist unit over five years found that general practitioners initiated most referrals, but that about 20% of patients were initially referred to specialties other than urology, such as genitourinary medicine, dermatology, or plastic surgery.1This error delayed diagnosis by up to six months and potentially adversely affected quality of life, prognosis, and survival. Our article, written for the non-specialist, aims to provide an evidence based review of the causes and current trends in the diagnosis and management of premalignant and malignant penile lesions.





Mental disorders and vulnerability to homicidal death: Swedish nationwide cohort study.


Objective To determine the risk of people with mental disorders being victims of homicide.

Design National cohort study.

Setting Sweden.

Participants Entire adult population (n=7 253 516).

Main outcome measures Homicidal death during eight years of follow-up (2001-08); hazard ratios for the association between mental disorders and homicidal death, with adjustment for sociodemographic confounders; potential modifying effect of comorbid substance use.

Results 615 homicidal deaths occurred in 54.4 million person years of follow-up. Mortality rates due to homicide (per 100 000 person years) were 2.8 among people with mental disorders compared with 1.1 in the general population. After adjustment for sociodemographic confounders, any mental disorder was associated with a 4.9-fold (95% confidence interval 4.0 to 6.0) risk of homicidal death, relative to people without mental disorders. Strong associations were found irrespective of age, sex, or other sociodemographic characteristics. Although the risk of homicidal death was highest among people with substance use disorders (approximately ninefold), the risk was also increased among those with personality disorders (3.2-fold), depression (2.6-fold), anxiety disorders (2.2-fold), or schizophrenia (1.8-fold) and did not seem to be explained by comorbid substance use. Sociodemographic risk factors included male sex, being unmarried, and low socioeconomic status.

Conclusions In this large cohort study, people with mental disorders, including those with substance use disorders, personality disorders, depression, anxiety disorders, or schizophrenia, had greatly increased risks of homicidal death. Interventions to reduce violent death among people with mental disorders should tackle victimisation and homicidal death in addition to suicide and accidents, which share common risk factors.




Cognitive function and other risk factors for mild traumatic brain injury in young men: nationwide cohort study.


Objective To investigate cognitive function and other risk factors for mild traumatic brain injury in young men.

Design Nationwide prospective cohort study.

Setting Sweden.

Participants 305 885 men conscripted for military service from 1989 to 1994.

Main outcome measure mild traumatic brain injuries in relation to cognitive function and other potential risk factors assessed at conscription and follow-up.


Results Men with one mild traumatic brain injury within two years before (n=1988) or after cognitive testing (n=2214) had about 5.5% lower overall cognitive function scores than did men with no mild traumatic brain injury during follow up (P<0.001 for both). Moreover, men with at least two mild traumatic brain injuries after cognitive testing (n=795) had 15% lower overall cognitive function scores compared with those with no such injury (P<0.001). Independent strong risk factors (P<1×10−10) for at least one mild traumatic brain injury after cognitive testing (n=12 494 events) included low overall cognitive function, a previous mild traumatic brain injury, hospital admission for intoxications, and low education and socioeconomic status. In a sub-cohort of twin pairs in which one twin had a mild traumatic brain injury before cognitive testing (n=63), both twins had lower logical performance and technical performance compared with men in the total cohort with no mild traumatic brain injury (P<0.05 for all).


Conclusion Low cognitive function, intoxications, and factors related to low socioeconomic status were strong independent risk factors for mild traumatic brain injuries in men. The low cognitive function in twin pairs discordant for mild traumatic brain injury suggests a genetic component to the low cognitive function associated with such injuries. The study included only men, so inferences to women should be made with caution.



Primary Prevention of Cardiovascular Disease with a Mediterranean Diet.


Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events.


In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.



A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported.



Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events.




Magnetic Resonance Imaging in Follow-up Assessment of Sciatica.


Magnetic resonance imaging (MRI) is frequently performed during follow-up in patients with known lumbar-disk herniation and persistent symptoms of sciatica. The association between findings on MRI and clinical outcome is controversial.


We studied 283 patients in a randomized trial comparing surgery and prolonged conservative care for sciatica and lumbar-disk herniation. Patients underwent MRI at baseline and after 1 year. We used a 4-point scale to assess disk herniation on MRI, ranging from 1 for “definitely present” to 4 for “definitely absent.” A favorable clinical outcome was defined as complete or nearly complete disappearance of symptoms at 1 year. We compared proportions of patients with a favorable outcome among those with a definite absence of disk herniation and those with a definite, probable, or possible presence of disk herniation at 1 year. The area under the receiver-operating-characteristic (ROC) curve was used to assess the prognostic accuracy of the 4-point scores regarding a favorable or unfavorable outcome, with 1 indicating perfect discriminatory value and 0.5 or less indicating no discriminatory value.


At 1 year, 84% of the patients reported having a favorable outcome. Disk herniation was visible in 35% with a favorable outcome and in 33% with an unfavorable outcome (P=0.70). A favorable outcome was reported in 85% of patients with disk herniation and 83% without disk herniation (P=0.70). MRI assessment of disk herniation did not distinguish between patients with a favorable outcome and those with an unfavorable outcome (area under ROC curve, 0.48).



MRI performed at 1-year follow-up in patients who had been treated for sciatica and lumbar-disk herniation did not distinguish between those with a favorable outcome and those with an unfavorable outcome.



Regulatory Innovation and Drug Development for Early-Stage Alzheimer’s Disease.

In reviewing new-drug applications for the treatment of Alzheimer’s disease, the Food and Drug Administration (FDA) has maintained that claims of improved cognition should be accompanied by evidence of improvement in function. However, the premise that effective cognitive improvement will be manifested in the functional assessment of patients is untenable in the case of early-stage Alzheimer’s disease, which is increasingly the target of drug-development efforts. We simply do not yet have drug-development tools that are validated to provide measures of function in patients with Alzheimer’s disease before the onset of overt dementia. Improvement in function, moreover, could lag substantially behind cognitive improvement mediated by pharmacologic agents early in the course of the disease. In view of the devastating effects of this disease on patients and their families, along with its growing prevalence, innovative approaches to trial design and end-point selection are urgently needed, especially as the drug-development community turns its sights on early stages of the disease.

The current landscape of research and drug development in Alzheimer’s disease offers a study in contrasts. On the positive side, numerous discoveries over the past decade have begun to unmask complex pathophysiological processes that underlie disease progression. Such advances have, in part, resulted from large, well-organized observational studies, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), that have elucidated various disease biomarkers that reflect, or even predict, the progression of disease. On the negative side, drug discovery has been disappointing. Despite all best efforts to translate mechanistic insights concerning Alzheimer’s disease into new drug products, several candidate agents have failed to demonstrate efficacy in large, well-designed, phase 3 clinical trials of late-stage disease.

The hallmark pathological feature of Alzheimer’s disease is the presence of brain plaques, consisting primarily of β-amyloid peptide aggregates. Accordingly, the abnormal production and aggregation of β-amyloid peptide, associated particularly with late-stage disease, has been the principal target of many drug-development efforts, including the recent phase 3 efforts that failed to result in new drug products. To account for these disappointing results of trials involving patients with overt dementia, a leading theory posits that the attempts at intervention may have been made too late in the progression of disease, at a stage when neuronal damage had become too widespread. According to some models, levels of β-amyloid peptide in the brain reach a plateau before the earliest symptoms of Alzheimer’s disease are apparent.1 A further hurdle to interpreting clinical failures is our limited understanding of how β-amyloid production may contribute to the pathophysiology of the disease. Because the biologic role of β-amyloid peptides is uncertain, researchers are also investigating alternative targets of intervention at various stages of progression.

The focus of drug development in Alzheimer’s disease has increasingly been earlier disease stages, before overt dementia. This refinement of focus, however, raises important new challenges because the subtleties of cognitive impairment in patients with early-stage Alzheimer’s can be difficult to assess. Moreover, the range of focus must extend to healthy people who are merely at risk for the disease but could benefit from preventive therapies. In recognition of these shifting challenges, the FDA has developed guidance for the design and execution of clinical trials involving patients who do not present with dementia.

One aspect of the FDA guidance covers the selection of patients for trials in early-stage Alzheimer’s disease. In particular, we have acknowledged the consensus emerging within the Alzheimer’s research community that clinical diagnosis of early cognitive impairment might be paired productively with appropriate biomarkers of disease — criteria that have been delineated and are being validated by various working groups. Such biomarkers might include brain amyloid load (e.g., as measured by positron-emission tomography) and cerebrospinal fluid levels of β-amyloid and tau proteins. Ongoing efforts by the research community to qualify biomarkers in clinical trial designs and methods for enriching study populations with patients with early-stage Alzheimer’s disease reflect important FDA priorities.

A specific suggestion that is also offered in the agency’s guidance for trials focusing on patients in whom overt dementia seems imminent is the use of a single scale that combines assessment of both cognition and function, such as the score on the Clinical Dementia Rating Sum of Boxes (CDR-SB), which rates patients on a series of six domains covering various aspects of cognition and daily functioning.5 For patients whose disease is at an even earlier clinical stage, so that functional impairment would be more difficult to assess, it might be feasible to approve a drug through the FDA’s accelerated approval pathway on the basis of assessment of cognitive outcome alone. The accelerated-approval mechanism allows drugs that address an unmet medical need to be approved on the basis of a surrogate end point or an intermediate clinical end point (e.g., a sensitive cognitive measure), with the stipulation that post approval studies will be conducted to verify the clinical benefit. Such a regulatory process may hold promise for facilitating the approval of treatments that appear to be effective in early Alzheimer’s disease, when patients might be expected to derive the greatest benefit .


our growing understanding of the relationship between various disease-based biomarkers and the clinical course of Alzheimer’s disease, it remains unclear whether the effect of a drug on one or more such biomarkers can actually predict a meaningful clinical benefit. This concern was reinforced by the recent phase 3 trials of amyloid-lowering agents that failed to improve cognition despite appearing to interact with putative targets in the brain. It remains possible that an effect of an intervention on one or more biomarkers could someday be accepted as predictive of a clinical benefit, but further research will clearly be needed before the effect of an intervention on a single biomarker alone could be considered an adequate surrogate measure for the purposes of accelerated approval of a candidate drug for early Alzheimer’s disease.

As the focus of drug development has shifted to earlier stages of Alzheimer’s disease, many new and challenging scientific questions have emerged, and the regulatory framework under which such therapies are evaluated should evolve accordingly. The FDA remains committed to innovative approaches to the evaluation of drugs that are in clinical development. Effective treatments for the devastating disorder that is Alzheimer’s disease are urgently needed, as the world’s population continues to age.



‘Chemical cosh’ drugs given to the elderly triple the risk of stroke.

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Antipsychotic drugs given to the elderly could triple the risk of potentially fatal strokes, The Alzheimer’s Society claims.

The charity also suggests that the medication could double the risk of death and leave patients unable to walk or talk.

Antipsychotics, which are prescribed to elderly patients to treat symptoms such as agitation, psychosis, anxiety, insomnia and depression, should only be given for a limited period.

But they are often seen by care home staff as an easy way to calm dementia patients.

Previous research has suggested that at least 1,800 dementia sufferers die each year from the ‘chemical cosh’ drugs.

Just one in five of the 180,000 dementia patients prescribed the anti-psychotic drugs benefit, meaning nearly 150,000 are given them needlessly, the government-commissioned report found.

Now, new research suggests that antipsychotics can raise the risk of a potentially fatal stroke.

Researchers at the National Taiwan University claim that stroke risk is greatest in patients who are older or who have dementia.

Writing in the journal Biological Psychiatry, they found that the risk is also linked to the duration and dosage of treatment.

Patients who received high doses of antipsychotic treatment, or who were treated for a short period of time, were at greater risk of stroke.

The researchers believe this suggests the risk is highest in the initial weeks of antipsychotic treatment and for those with a higher average daily dose.

In their study, the Taiwanese scientists focused on the wide range of brain mechanisms targeted by antipsychotic medications.

‘The stroke risk profiles from this study suggest that it may be possible to use antipsychotics more safely in the elderly,’ said Dr John Krystal, Editor of Biological Psychiatry.

The researchers recommended that doctors start antipsychotics at low dosages, closely monitoring for side-effects in the initial treatment, particularly for individuals who are older or who have dementia.

An Alzheimer’s Society spokesperson said: ‘Tens of thousands of people with dementia are having their lives put at risk every day by being inappropriately prescribed this “chemical cosh” which can double the risk of death, treble the risk of stroke and can leave people unable to walk or talk.

‘Whatever the situation, antipsychotics should only ever be used as a last resort. They should be prescribed at low dosages and should be closely monitored.

‘Only by empowering staff with the knowledge they need to understand dementia and the person behind the condition can we ensure that the inappropriate prescribing of these harmful is stamped out for good.’

Dr Clare Walton, Research Communication Officer from the Stroke Association, said: ‘This research shows doctors need to be cautious about the dose and type of antipsychotics they prescribe, especially for older people or anyone at risk of stroke.

‘If antipsychotics are being used, we recommend patients are closely monitored for the first few weeks when stroke risk seems to be highest.’

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, added: ‘This study provides yet more evidence highlighting the potential dangers of antipsychotics for people with dementia.

‘Research funded by Alzheimer’s Research UK revealed in 2009 that long-term use of these drugs increases the risk of death for people with dementia, and we have since seen positive steps to reduce their use.

‘Where antipsychotics are prescribed for these people it’s vital that their use is closely monitored. Symptoms such as agitation and aggression can be extremely difficult for doctors and carers to deal with, and research must continue into alternative treatments for these symptoms.’