Whittington Health NHS Trust

BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. METHODS: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. RESULTS: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). CONCLUSIONS: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191.

BACKGROUND: Advancing age is independently associated with poor postoperative outcomes. The ageing of the general population is a major concern for healthcare providers. Trends in age were studied among patients undergoing surgery in the National Health Service in England. METHODS: Time trend ecological analysis was undertaken of Hospital Episode Statistics and Office for National Statistics data for England from 1999 to 2015. The proportion of patients undergoing surgery in different age groupings, their pooled mean age, and change in age profile over time were calculated. Growth in the surgical population was estimated, with associated costs, to the year 2030 by use of linear regression modelling. RESULTS: Some 68 205 695 surgical patient episodes (31 220 341 men, 45·8 per cent) were identified. The mean duration of hospital stay was 5·3 days. The surgical population was older than the general population of England; this gap increased over time (1999: 47·5 versus 38·3 years; 2015: 54·2 versus 39·7 years). The number of people aged 75 years or more undergoing surgery increased from 544 998 (14·9 per cent of that age group) in 1999 to 1 012 517 (22·9 per cent) in 2015. By 2030, it is estimated that one-fifth of the 75 years and older age category will undergo surgery each year (1·49 (95 per cent c.i. 1·43 to 1·55) million people), at a cost of €3·2 (3·1 to 3·5) billion. CONCLUSION: The population having surgery in England is ageing at a faster rate than the general population. Healthcare policies must adapt to ensure that provision of surgical treatments remains safe and sustainable.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. DATA COLLECTION AND ANALYSIS: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. MAIN RESULTS: The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). SECONDARY OUTCOMES: Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events. OBJECTIVES: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies. SEARCH METHODS: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention. DATA COLLECTION AND ANALYSIS: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses. MAIN RESULTS: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). AUTHORS' CONCLUSIONS: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

BACKGROUND: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

The influence of acute mental stress on cardiovascular responses and concentrations of inflammatory cytokines up to 2 h later was assessed in 12 subjects exposed to stress and in eight control subjects. Beat-by-beat recordings of finger blood pressure and heart rate were made at rest and during two behavioural tasks (colour-word interference and mirror tracing). Blood was drawn after adaptation and at 45 min and 2 h after the tasks, and assayed for interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1Ra), C-reactive protein (CRP) and haematocrit. Saliva was sampled periodically and assayed for free cortisol. The tasks were rated as stressful by the participants. The stress group showed significant increases in systolic and diastolic blood pressure (mean rises of 16.4+/-12.3 and 12.6+/-6.9 mmHg respectively) and heart rate (5.39+/-5.3 beats/min); these values returned to baseline during the recovery period. The IL-6 concentration was increased by 56% at 2 h after the tasks (P<0.05), while IL-1Ra was increased by 12.3% (P<0.01). No changes in cardiovascular variables or cytokine concentrations were observed in the control subjects, and haematocrit did not change. The magnitude of blood pressure responses during tasks was correlated positively with the IL-6 concentration after 45 min (r=0.70, P<0.05), and with the IL-1Ra concentration after 2 h (r=0.63, P<0.05). Increases in TNF-alpha after 2 h were correlated with heart rate responses to tasks (r=0.66, P<0.05). Associations between IL-6 and IL-1Ra concentrations were also recorded. This study indicates that inflammatory cytokines respond to acute mental stress in humans with delayed increases, and suggest that individual differences in cytokine responses are associated with sympathetic reactivity.

Patient-reported outcomes (PROs) reflect the patient's perspective and are used in rheumatoid arthritis (RA) routine clinical practice. Patient global assessment (PGA) is one of the most widely used PROs in RA practice and research and is included in several composite scores such as the 28-joint Disease Activity Score (DAS28). PGA is often assessed by a single question with a 0-10 or 0-100 response. The content can vary and relates either to global health (e.g., how is your health overall) or to disease activity (e.g., how active is your arthritis). The wordings used as anchors, i.e., for the score of 0, 10, or 100 according to the scale used, and the timing (i.e., this day or this week) also vary. The different possible ways of measuring PGA translate into variations in its interpretation and reporting and may impact on measures of disease activity and consequently achievement of treat-to-target goals. Furthermore, although PGA is associated with objective measures of disease activity, it is also associated with other aspects of health, such as psychological distress or comorbidities, which leads to situations of discordance between objective RA assessments and PGA. Focusing on the role of PGA, its use and interpretation in RA, this review explores its validity and correlations with other disease measures and its overall value for research and routine clinical practice.

OBJECTIVE: Structured patient education programs can reduce the risk of diabetes-related complications. However, people appear to have difficulties attending face-to-face education and alternatives are needed. This review looked at the impact of computer-based diabetes self-management interventions on health status, cardiovascular risk factors, and quality of life of adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We searched The Cochrane Library, Medline, Embase, PsycINFO, Web of Science, and CINAHL for relevant trials from inception to November 2011. Reference lists from relevant published studies were screened and authors contacted for further information when required. Two authors independently extracted relevant data using standard data extraction templates. RESULTS: Sixteen randomized controlled trials with 3,578 participants met the inclusion criteria. Interventions were delivered via clinics, the Internet, and mobile phones. Computer-based diabetes self-management interventions appear to have small benefits on glycemic control: the pooled effect on HbA1c was -0.2% (-2.3 mmol/mol [95% CI -0.4 to -0.1%]). A subgroup analysis on mobile phone-based interventions showed a larger effect: the pooled effect on HbA1c from three studies was -0.50% (-5.46 mmol/mol [95% CI -0.7 to -0.3%]). There was no evidence of improvement in depression, quality of life, blood pressure, serum lipids, or weight. There was no evidence of significant adverse effects. CONCLUSIONS: Computer-based diabetes self-management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control, and this effect was larger in the mobile phone subgroup. There was no evidence of benefit for other biological, cognitive, behavioral, or emotional outcomes.

Patients with β-thalassemia major (BTM) require regular blood transfusions, supported by appropriate iron chelation therapy (ICT), throughout their life. β-thalassemia is a global disease that is most highly prevalent in Southeast Asia, Africa, and Mediterranean countries. However, the global distribution of patients with β-thalassemia is changing due to population migration, and Northern European countries now have significant thalassemia populations. Globally, many patients with BTM have limited access to regular and safe blood transfusions. A lack of voluntary nonremunerated blood donors, poor awareness of thalassemia, a lack of national blood policies, and fragmented blood services contribute to a significant gap between the timely supply of, and demand for, safe blood. In many centers, there is inadequate provision of antigen testing, even for common red cell antigens such as CcEe and Kell. Policies to raise awareness and increase the use of red blood cell antigen testing and requesting of compatible blood in transfusion centers are needed to reduce alloimmunization (the development of antibodies to red blood cell antigens), which limits the effectiveness of transfusions and the potential availability of blood. Patients with BTM are also at risk of transfusion-transmitted infections unless appropriate blood screening and safety practices are in place. Hence, many patients are not transfused or are undertransfused, resulting in decreased health and quality-of-life outcomes. Hemovigilance, leukoreduction, and the ability to thoroughly investigate transfusion reactions are often lacking, especially in resource-poor countries. ICT is essential to prevent cardiac failure and other complications due to iron accumulation. Despite the availability of potentially inexpensive oral ICT, a high proportion of patients suffer complications of iron overload and die each year due to a lack of, or inadequate, ICT. Increased awareness, training, and resources are required to improve and standardize adequate blood transfusion services and ICT among the worldwide population of patients with BTM. ICT needs to be available, affordable, and correctly prescribed. Effective, safe, and affordable new treatments that reduce the blood transfusion burden in patients with β-thalassemia remain an unmet need.

BACKGROUND: Prolonged sitting is an emerging health risk. However, multi-country comparative sitting data are sparse. This paper reports the prevalence and correlates of sitting time in 32 European countries. METHODS: Data from the Eurobarometer 64.3 study were used, which included nationally representative samples (n = 304-1,102) from 32 European countries. Face-to-face interviews were conducted during November and December 2005. Usual weekday sitting time was assessed using the International Physical Activity Questionnaire (short-version). Sitting time was compared by country, age, gender, years of education, general health status, usual activity and physical activity. Multivariable-adjusted analyses assessed the odds of belonging to the highest sitting quartile. RESULTS: Data were available for 27,637 adults aged 15-98 years. Overall, mean reported weekday sitting time was 309 min/day (SD 184 min/day). There was a broad geographical pattern and some of the lowest amounts of daily sitting were reported in southern (Malta and Portugal means 194-236 min/day) and eastern (Romania and Hungary means 191-276 min/day) European countries; and some of the highest amounts of daily sitting were reported in northern European countries (Germany, Benelux and Scandinavian countries; means 407-335 min/day). Multivariable-adjusted analyses showed adults with low physical activity levels (OR = 5.10, CI₉₅ = 4.60-5.66), those with high sitting in their main daily activity (OR = 2.99, CI₉₅ = 2.74-3.25), those with a bad/very bad general health state (OR = 1.87, CI₉₅ = 1.63-2.15) and higher education levels (OR = 1.48, CI₉₅ = 1.38-1.59) were more likely to be in the highest quartile of daily sitting time. Adults within Greece (OR = 2.91, CI₉₅ = 2.51-3.36) and Netherlands (OR = 2.56, CI₉₅ = 2.22-2.94) were most likely to be in the highest quartile. High-sit/low-active participants comprised 10.1% of the sample. Adults self-reporting bad/very bad general health state (OR = 4.74, CI₉₅ = 3.97-5.65), those within high sitting in their main daily activities (OR = 2.87, CI₉₅ = 2.52-3.26) and adults aged ≥65 years (OR = 1.53, CI₉₅ = 1.19-1.96) and were more likely to be in the high-sit/low-active group. CONCLUSIONS: Weekday sitting time and its demographic correlates varied considerably across European countries, with adults in north-western European countries sitting the most. Sitting is prevalent across Europe and merits attention by preventive interventions.

STUDY QUESTION: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? METHODS: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. STUDY ANSWER AND LIMITATIONS: The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. WHAT THIS STUDY ADDS: The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. FUNDING, COMPETING INTERESTS, DATA SHARING: Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.

The influence of acute mental stress on cardiovascular responses andconcentrations of inflammatory cytokines up to 2 h later was assessed in 12 subjects exposed to stress and in eight control subjects. Beat-by-beat recordings of finger blood pressure and heart rate were made at rest and during two behavioural tasks (colour–word interference and mirror tracing). Blood was drawn after adaptation and at 45 min and 2 h after the tasks, and assayed for interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1Ra), C-reactive protein (CRP) and haematocrit. Saliva was sampled periodically and assayed for free cortisol. The tasks were rated as stressful by the participants. The stress group showed significant increases in systolic and diastolic blood pressure (mean rises of 16.4±12.3 and 12.6±6.9 mmHg respectively) and heart rate (5.39±5.3 beats/min); these values returned to baseline during the recovery period. The IL-6 concentration was increased by 56% at 2 h after the tasks (P&lt; 0.05), while IL-1Ra was increased by 12.3% (P&lt; 0.01). No changes in cardiovascular variables or cytokine concentrations were observed in the control subjects, and haematocrit did not change. The magnitude of blood pressure responses during tasks was correlated positively with the IL-6 concentration after 45 min (r = 0.70, P&lt; 0.05), and with the IL-1Ra concentration after 2 h (r = 0.63, P&lt; 0.05). Increases in TNF-α after 2 h were correlated with heart rate responses to tasks (r = 0.66, P&lt; 0.05). Associations between IL-6 and IL-1Ra concentrations were also recorded. This study indicates that inflammatory cytokines respond to acute mental stress in humans with delayed increases, and suggest that individual differences in cytokine responses are associated with sympathetic reactivity.

BACKGROUND: Evidence on how to implement new interventions into complex healthcare environments is often poorly reported and indexed, reducing its potential to inform initiatives to improve healthcare services. Using the implementation of a digital intervention within routine National Health Service (NHS) practice, we provide an example of how to develop a theoretically based implementation plan and how to report it transparently. In doing so we also highlight some of the challenges to implementation in routine healthcare. METHODS: The implemented intervention was HeLP-Diabetes, a digital self-management programme for people with Type 2 Diabetes, which was effective in improving diabetes control. The target setting for the implementation was an inner city London Clinical Commissioning Group in the NHS comprised of 34 general practices. HeLP-Diabetes was designed to be offered to patients as part of routine diabetes care across England. Evidence synthesis, engagement of local stakeholders, a theory of implementation (Normalization Process Theory), feedback, qualitative interviews and usage data were used to develop an implementation plan. RESULTS: A new implementation plan was developed to implement HeLP-Diabetes within routine practice. Individual component strategies were selected and developed informed by Normalization Process Theory. These strategies included: engagement of local opinion leaders, provision of educational materials, educational visits, educational meetings, audit and feedback and reminders. Additional strategies were introduced iteratively to address barriers that arose during the implementation. Barriers largely related to difficulties in allocating resources to implement the intervention within routine care. CONCLUSION: This paper provides a worked example of implementing a digital health intervention. The learning from this work can inform others undertaking the work of planning and executing implementation activities in routine healthcare. Of particular importance is: the selection of appropriate theory to guide the implementation process and selection of strategies; ensuring that enough attention is paid to planning implementation; and a flexible approach that allows response to emerging barriers.

Stunting is a global burden affecting nearly 160 million children younger than five years of age. Whilst the linkages between nutrition and stunting are well recognized, there is a need to explore environmental factors such as water and sanitation, which may influence feeding practices and result in potential infection pathways. This paper explores the linkages between stunting and water, sanitation and hygiene (WASH) factors in Ethiopia, which is a relatively understudied context. The research draws upon baseline data for children under the age of five from 3200 households across four regions in Ethiopia as part of a wider study and integrated program led by the United Nations Children's Fund (UNICEF). Using World Health Organization (WHO) z-scoring, the average stunting rate in the sample is 47.5%. This paper also takes into account demographic and social behavioural factors such as the age, gender of children, and gender of the primary caregiver, in addition to handwashing behaviour and drinking water facilities. The evidence recommends efforts to improve handwashing behaviour for mothers and children with a focus on access to clean water. Higher stunting rates with an increase in the age of children highlight the need for continued interventions, as efforts to improve nutrition and WASH behaviours are most effective early on in promoting long-term health outcomes for children.

OBJECTIVE: To compare the effectiveness of a nurse-led hypertension clinic with conventional community care in general practice in the management of uncontrolled hypertension in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 120 men and women outpatient attendees (61% non-Caucasian) with type 2 diabetes and a seated blood pressure (BP) >or=140/80 mmHg. All patients were being treated for hypertension, and 71% had increased urinary albumin excretion (UAE). Patients were allocated to either a nurse-led hypertension clinic or conventional primary care. The primary outcome measure was a change in systolic BP. Secondary outcome measures were total cholesterol, HDL cholesterol, total triglycerides, HbA(1c), UAE, serum creatinine, and changes in absolute stroke and coronary heart disease (CHD) risk scores. RESULTS: The mean (95% CI) difference in the decrement of systolic BP was 12.6 mmHg (5.9-19.3) (P = 0.000) in favor of the nurse-led group, whose patients were three times more likely to a reach target systolic BP <140 mmHg compared with conventional care (P = 0.003). A significant fall in 10-year CHD (P = 0.004) and stroke risk (P = 0.000) scores occurred only in the nurse-led group. There were no significant differences in the reduction of diastolic BP or any of the other secondary outcome measures at 6 months. CONCLUSIONS: Compared with conventional care, a nurse-led hypertension clinic is a more effective intervention for patients with type 2 diabetes and uncontrolled hypertension. A target systolic BP <140 mmHg is more readily achieved and may be associated with significant reductions in 10-year cardiovascular disease risk scores.

Healthcare workers (HCWs) have a theoretically increased risk of contracting severe acute respiratory coronavirus virus 2 (SARS-CoV-2) given their occupational exposure. We tested 2,167 HCWs in a London Acute Integrated Care Organisation for antibodies to SARS-CoV-2 in May and June 2020 to evaluate seroprevalence. We found a seropositivity rate of 31.6% among HCWs.

OBJECTIVES: To describe self-reported characteristics and symptoms of treatment-seeking patients with post-COVID-19 syndrome (PCS). To assess the impact of symptoms on health-related quality of life (HRQoL) and patients' ability to work and undertake activities of daily living. DESIGN: Cross-sectional single-arm service evaluation of real-time user data. SETTING: 31 post-COVID-19 clinics in the UK. PARTICIPANTS: 3754 adults diagnosed with PCS in primary or secondary care deemed suitable for rehabilitation. INTERVENTION: Patients using the Living With Covid Recovery digital health intervention registered between 30 November 2020 and 23 March 2022. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the baseline Work and Social Adjustment Scale (WSAS). WSAS measures the functional limitations of the patient; scores of ≥20 indicate moderately severe limitations. Other symptoms explored included fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), depression (Patient Health Questionnaire-Eight Item Depression Scale), anxiety (Generalised Anxiety Disorder Scale, Seven-Item), breathlessness (Medical Research Council Dyspnoea Scale and Dyspnoea-12), cognitive impairment (Perceived Deficits Questionnaire, Five-Item Version) and HRQoL (EQ-5D). Symptoms and demographic characteristics associated with more severe functional limitations were identified using logistic regression analysis. RESULTS: 3541 (94%) patients were of working age (18-65); mean age (SD) 48 (12) years; 1282 (71%) were female and 89% were white. 51% reported losing ≥1 days from work in the previous 4 weeks; 20% reported being unable to work at all. Mean WSAS score at baseline was 21 (SD 10) with 53% scoring ≥20. Factors associated with WSAS scores of ≥20 were high levels of fatigue, depression and cognitive impairment. Fatigue was found to be the main symptom contributing to a high WSAS score. CONCLUSION: A high proportion of this PCS treatment-seeking population was of working age with over half reporting moderately severe or worse functional limitation. There were substantial impacts on ability to work and activities of daily living in people with PCS. Clinical care and rehabilitation should address the management of fatigue as the dominant symptom explaining variation in functionality.