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As antimicrobial susceptibility of common bacterial pathogens decreases, ensuring optimal dosing may preserve the use of older antibiotics in order to limit the spread of resistance to newer agents. Beta-lactams represent the most widely prescribed antibiotic class, yet most were licensed prior to legislation changes mandating their study in children. As a result, significant heterogeneity persists in the pediatric doses used globally, along with quality of evidence used to inform dosing. This review summarizes dosing recommendations from the major pediatric reference sources and tries to answer the questions: Does beta-lactam dose heterogeneity matter? Does it impact pharmacodynamic target attainment? For three important severe clinical infections—pneumonia, sepsis, and meningitis—pharmacokinetic models were identified for common for beta-lactam antibiotics. Real-world demographics were derived from three multicenter point prevalence surveys. Simulation results were compared with minimum inhibitory concentration distributions to inform appropriateness of recommended doses in targeted and empiric treatment. While cephalosporin dosing regimens are largely adequate for target attainment, they also pose the most risk of neurotoxicity. Our review highlights aminopenicillin, piperacillin, and meropenem doses as potentially requiring review/optimization in order to preserve the use of these agents in future.

Genomic sequencing is rapidly transitioning into clinical practice, and implementation into healthcare systems has been supported by substantial government investment, totaling over US$4 billion, in at least 14 countries. These national genomic-medicine initiatives are driving transformative change under real-life conditions while simultaneously addressing barriers to implementation and gathering evidence for wider adoption. We review the diversity of approaches and current progress made by national genomic-medicine initiatives in the UK, France, Australia, and US and provide a roadmap for sharing strategies, standards, and data internationally to accelerate implementation.

This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.

Objective: The Health and Social Care Act 2012 ('HSCA 2012') introduced a new, statutory, form of regulation of competition into the National Health Service (NHS), while at the same time recognising that cooperation was necessary. NHS England's policy document, The Five Year Forward View ('5YFV') of 2014 placed less emphasis on competition without altering the legislation. We explored how commissioners and providers understand the complex regulatory framework, and how they behave in relation to competition and cooperation. Design: We carried out detailed case studies in four clinical commissioning groups, using interviews and documentary analysis to explore the commissioners'and providers' understanding and experience of competition and cooperation. Setting/participants: We conducted 42 interviews with senior managers in commissioning organizations and senior managers in NHS and independent provider organisations (acute and community services). Results: Neither commissioners nor providers fully understand the regulatory regime in respect of competition in the NHS, and have not found that the regulatory authorities have provided adequate guidance. Despite the HSCA 2012 promoting competition, commissioners chose mainly to use collaborative strategies to effect major service reconfigurations, which is endorsed as a suitable approach by providers. Nevertheless, commissioners are using competitive tendering in respect of more peripheral services in order to improve quality of care and value for money. Conclusions: Commissioners regard the use of competition and cooperation as appropriate in the NHS currently, although collaborative strategies appear more helpful in respect of large-scale changes. However, the current regulatory framework contained in the HSCA 2012, particularly since the publication of the 5YFV, is not clear. Better guidance should be issued by the regulatory authorities.

Introduction: Community pharmacy increasingly features in global strategies to modernise the delivery of primary healthcare. Medicine Use Reviews (MURs) form part of the English Government's medicines management strategy to improve adherence and reduce medicine waste. MURs provide space for patient-pharmacist dialogue to discuss the well-known problems patients experience with medicine taking. However, 'underserved' communities (eg, black and minority ethnic communities, people with mental illness), who may benefit the most, may not receive this support. This study aims to develop, implement and evaluate an e-learning education intervention which is coproduced between patients from underserved communities and pharmacy teams to improve MUR provision. Methods and analysis: This mixed-methods evaluative study will involve a 2-stage design. Stage 1 involves coproduction of an e-learning resource through mixed patient-professional development (n=2) and review (n=2) workshops, alongside informative semistructured interviews with patients (n=10) and pharmacy staff (n=10). Stage 2 involves the implementation and evaluation of the intervention with community pharmacy staff within all community pharmacies within the Nottinghamshire geographical area (n=237). Online questionnaires will be completed at baseline and postintervention (3 months) to assess changes in engagement with underserved communities and changes in self-reported attitudes and behaviour. To triangulate findings, 10 pharmacies will record at baseline and postintervention, details of actual numbers of MURs performed and the proportion that are from underserved communities. Descriptive and inferential statistics will be used to analyse the data. The evaluation will also include a thematic analysis of one-to-one interviews with pharmacy teams to explore the impact on clinical practice (n=20). Interviews with patients belonging to underserved communities, and who received an MUR, will also be conducted (n=20). Ethics and dissemination: The study has received ethical approval from the NHS Research Ethics Committee (East Midlands-Derby) and governance clearance through the NHS Health Research Authority. Following the evaluation, the educational intervention will be freely accessible online.

Objective: Combat Stress, a UK national charity for veterans with mental health problems, has been funded by the National Health Service (NHS) to provide a national specialist service to deliver treatment for post-traumatic stress disorder (PTSD). This paper reports the efficacy of a PTSD treatment programme for UK veterans at 6 months follow-up. Design: A within subject design. Setting: UK veterans with a diagnosis of PTSD who accessed Combat Stress. Participants: 246 veterans who received treatment between late 2012 and early 2014. Intervention: An intensive 6-week residential treatment programme, consisting of a mixture of individual and group sessions. Participants were offered a minimum of 15 individual trauma-focused cognitive behavioural therapy sessions. In addition, participants were offered 55 group sessions focusing on psychoeducational material and emotional regulation. Main outcome measures: Clinicians completed measures of PTSD and functional impairment and participants completed measures of PTSD, depression, anger and functional impairment. Results: We observed significant reductions in PTSD scores following treatment on both clinician completed measures (PSS-I: -13.0, 95% CI -14.5 to -11.5) and self-reported measures (Revised Impact of Events Scale (IES-R): -16.5, 95% CI -19.0 to -14.0). Significant improvements in functional impairment were also observed (eg, Health of the Nation Outcome Scales (HONOS): -6.85, 95% CI -7.98 to -5.72). There were no differences in baseline outcomes between those who completed and those who did not complete the programme, or post-treatment outcomes between those we were able to follow-up at 6 months and those lost to follow-up. Conclusions: In a naturalistic study we observed a significant reduction in PTSD scores and functional impairment following treatment. These improvements were maintained at 6 month follow-up. Our findings suggest it may be helpful to take a closer look at combining individual trauma-focused cognitive behaviour therapy and group sessions when treating veterans with PTSD. This is the first UK study of its kind, but requires further evaluation.

Background Melanoma incidence often shows an increasing latitudinal gradient from north to south among white European populations. Objectives To assess emerging regional melanoma incidence patterns in England. Methods All primary invasive cutaneous melanomas diagnosed in England in people aged 10-89 years, in 1996-2006, were ascertained. Age-standardized incidence rates by sex, age and Government Office Region were calculated for the entire population and for the white population only. Rates according to socioeconomic deprivation were further calculated among those aged under 30 years. Regional heterogeneity and latitude and deprivation trends were assessed by Poisson regression and tests for trend. Results Overall, melanoma incidence in England was highest in the South West (overall, 18·75; white, 19·03 per 100 000) and lowest in London (overall, 8·85; white, 11·22 per 100 000). Incidence significantly increased with more southerly latitudes in all white adults aged over 30 years (P <0·0001), except women aged 30-49 years (1·8%, P = 0·10). However, these north-south latitude trends were reversed in white 10-29 year olds, with sex-specific analyses showing an absence of trend in male subjects (2·7%, P = 0·41) and a strong decreasing trend (-9·8%, P <0·0001) in female subjects. The highest rates in the young female population occurred in the North West (5·46 per 100 000), and specifically in the second most deprived (5·69 per 100 000) and the second most affluent (6·48 per 100 000) groups. Conclusions Melanoma incidence is high in young people in northern England, including among the moderately deprived, reversing the expected north-south incidence gradients. Prevalent sunbed use in northern England and holiday sun exposure abroad may explain these emerging trends. What's already known about this topic? Increasing trends in melanoma incidence from north to south have been noted in England and other northern countries. Melanoma predominantly affects white, affluent populations; however, neither ethnic groups nor socioeconomic status are uniformly distributed across England. What does this study add? This study describes a striking reversal in the well-established north-south latitude trend in melanoma incidence among young women in England. Incidence was high among young people in northern regions, and particularly among moderately deprived female subjects. © 2013 British Association of Dermatologists.

Objective: To compare all cause mortality between the north and south of England over four decades. Design: Population wide comparative observational study of mortality. Setting: Five northernmost and four southernmost English government office regions. Population: All residents in each year from 1965 to 2008. Main outcome measures: Death rate ratios of north over south England by age band and sex, and northern excess mortality (percentage of excess deaths in north compared with south, adjusted for age and sex and examined for annual trends, using Poisson regression). Results: During 1965 to 2008 the northern excess mortality remained substantial, at an average of 13.8% (95% confidence interval 13.7% to 13.9%). This geographical inequality was significantly larger for males than for females (14.9%, 14.7% to 15.0% v 12.7%, 12.6% to 12.9%, P

Objectives Military organizations are keen to address barriers to mental health care yet stigma and barriers to care remain little understood, especially potential cultural differences between Armed Forces. The aim of this study was to compare data collected by the US, UK, Australian, New Zealand and Canadian militaries using Hoge et al.'s perceived stigma and barriers to care measure (Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. New Engl J Med 2004;351:13-22). Design Each member country identified data sources that had enquired about Hoge et al.'s perceived stigma and perceived barriers to care items in the re-deployment or immediate post-deployment period. Five relevant statements were included in the study. Setting US, UK Australian, New Zealand and Canadian Armed Forces. Results Concerns about stigma and barriers to care tended to be more prominent among personnel who met criteria for a mental health problem. The pattern of reported stigma and barriers to care was similar across the Armed Forces of all five nations. Conclusions Barriers to care continue to be a major issue for service personnel within Western military forces. Although there are policy, procedural and cultural differences between Armed Forces, the nations studied appear to share some similarities in terms of perceived stigma and barriers to psychological care. Further research to understand patterns of reporting and subgroup differences is required.

Objective: To evaluate the quality of patient information leaflets provided with dispensed medications in the United States, United Kingdom, and Australia. Design: Quantitative survey by an expert panel. Setting: United States, United Kingdom, and Australia. Participants: Not applicable. Intervention: Patient information leaflets for atenolol, glyburide (glibenclamide), atorvastatin, and nitroglycerin (glyceryl trinitrate) from the United States, United Kingdom, and Australia. Main outcome measures: Leaflets were evaluated against U. S. consensus criteria for both clinical information and general criteria, including the design of the leaflets. Results: Leaflets from Australia received a mean overall score of 90% (range 83%-94%) adherence with criteria, those from the United Kingdom a score of 81% (range 73%-84%), and those from the United States a score of 68% (range 65%-77%). The U. S. leaflets achieved 50% or less adherence for contraindication and precaution information. Omissions included warnings about preexisting allergy and illness and information about drug interactions. The U. S. leaflets also scored poorly (60%) for legibility and comprehensibility. The lower U. K. score reflected shortcomings in information about how to use and monitor the medications (46% adherence) and on adverse drug reactions (64%), largely due to the lack of clear advice about urgency of action in relation to adverse drug reactions. Conclusion: Leaflet quality varied more among the three countries than within each country, reflecting the regulatory context. The Australian leaflets performed well across all criteria, whereas the U. S. leaflets had significant shortcomings with the omission of vital information for the safe and effective use of the medications. A repeat survey is needed to assess whether new legislation and guidance in all three countries successfully addresses the shortcomings identified.

This article considers the role of treatment in the provision of mental health care in England and Wales. The current legislative position with regard to the making of treatment choices following compulsory commitment will be examined. Consideration will also be given to the position of the informal hospitalised patient, as in the case of R v. Bournewood Community and Mental Health NHS Trust, ex parte L and finally, the role of the common law in establishing (in)capacity in relation to the non-consensual provision of treatment for physical conditions. Attention will then be given to the reform process, which is currently ongoing in England and Wales, and its likely impact on treatment provision. The Mental Capacity Act 2005 received Royal Assent on the 7th April 2005, while the draft Mental Health Bill 2004 underwent detailed examination by the Joint Scrutiny Committee, a report of which was published on the 23rd March 2005. On the 13th July 2005 the British Government outlined its response following the publication of the Scrutiny Committee's recommendations and despite it accepting many of the recommendations put forward, some significant areas of concern remain making the draft Mental Health Bill 2004 "a long way from acceptable legislation". © 2005 Elsevier Inc. All rights reserved.

This paper argues that the HFEA's recent report on sex selection abdicates its responsibility to give its own authentic advice on the matters within its remit, that it accepts arguments and conclusions that are implausible on the face of it and where they depend on empirical claims, produces no empirical evidence whatsoever, but relies on reckless speculation as to what the "facts" are likely to be. Finally, having committed itself to what I call the "democratic presumption", that human freedom will not be constrained unless very good and powerful reasons can be produced to justify such infringement of liberty, the HFEA simply reformulates the democratic presumption as saying the opposite-namely that freedom may only be exercised if powerful justifications are produced for any exercise of liberty.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Background: Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone. Methods: In this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27. Findings: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1–24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment. Interpretation: Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up. Funding: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Children's Hospital Zurich.

Background: Telecare could greatly facilitate chronic disease management in the community, but despite government promotion and positive demonstrations its implementation has been limited. This study aimed to identify factors inhibiting the implementation and integration of telecare systems for chronic disease management in the community. Methods. Large scale comparative study employing qualitative data collection techniques: semi-structured interviews with key informants, task-groups, and workshops; framework analysis of qualitative data informed by Normalization Process Theory. Drawn from telecare services in community and domestic settings in England and Scotland, 221 participants were included, consisting of health professionals and managers; patients and carers; social care professionals and managers; and service suppliers and manufacturers. Results: Key barriers to telecare integration were uncertainties about coherent and sustainable service and business models; lack of coordination across social and primary care boundaries, lack of financial or other incentives to include telecare within primary care services; a lack of a sense of continuity with previous service provision and self-care work undertaken by patients; and general uncertainty about the adequacy of telecare systems. These problems led to poor integration of policy and practice. Conclusion: Telecare services may offer a cost effective and safe form of care for some people living with chronic illness. Slow and uneven implementation and integration do not stem from problems of adoption. They result from incomplete understanding of the role of telecare systems and subsequent adaption and embeddedness to context, and uncertainties about the best way to develop, coordinate, and sustain services that assist with chronic disease management. Interventions are therefore needed that (i) reduce uncertainty about the ownership of implementation processes and that lock together health and social care agencies; and (ii) ensure user centred rather than biomedical/service- centred models of care. © 2011 May et al; licensee BioMed Central Ltd.