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Background The survival benefit of neoadjuvant therapy in resectable carcinoma esophagus has been elucidated. We performed a meta-analysis in light of new studies and long-term results of past trials. The search strategy was refined to include only “neoadjuvant” so that any bias by adjuvant treatment is eliminated. Methods A detailed search of MEDLINE, Embase, and Cochrane Library was done. Only published randomized English language trials were included. Data were categorized as neoadjuvant concurrent chemoradiation (NACRT), neoadjuvant chemotherapy (NACT), neoadjuvant radiotherapy (NART), and neoadjuvant sequential chemoradiotherapy (SCRT). Meta-analysis was done using odds ratio (OR) and 95% CI using fixed/random effects model. Heterogeneity was tested by chi-square and I 2 test. Z probability calculated significant difference across subgroups. Outcomes assessed were overall survival (OS) and disease-free survival (DFS) at 3 and 5 years, respectively, mortality (30/90 day) and failures (local/systemic). Results Twenty-five randomized trials involving 5272 patients were included for quantitative analysis. NACRT was evaluated in 12 studies (2676 patients). Superior 3-year OS (OR = 0.68 CI 0.52–0.90, p = 0.007), 3-year DFS (OR = 0.55 CI 0.45–0.68, p = 0.00001), and 5-year DFS (OR = 0.59 CI 0.47–0.74, p = 0.00001), with lower failures (OR = 0.52 CI 0.37–0.73, p = 0.0001), were seen in favor of NACRT at the cost of increased perioperative mortality (OR = 1.79 CI 1.15–2.80, p = .01). However, 5-year OS (OR = 0.78 CI 0.60–0.1.01, p = 0.06) was not found to be significantly superior. NACT, NART, and SCRT were not found to have any benefit over surgery alone. Conclusion This meta-analysis presents strong evidence favoring NACRT over upfront surgery. It also shows no survival advantage of neoadjuvant chemotherapy.

Background Sedentary behaviour (SB; time spent sitting) is associated with musculoskeletal pain (MSP) conditions; however, no prior systematic review has examined these associations according to SB domains. We synthesised evidence on occupational and non-occupational SB and MSP conditions. Methods Guided by a PRISMA protocol, eight databases (MEDLINE, CINAHL, PsycINFO, Web of Science, Scopus, Cochrane Library, SPORTDiscus, and AMED) and three grey literature sources (Google Scholar, WorldChat, and Trove) were searched (January 1, 2000, to March 17, 2021) for original quantitative studies of adults ≥ 18 years. Clinical-condition studies were excluded. Studies’ risk of bias was assessed using the QualSyst checklist. For meta-analyses, random effect inverse-variance pooled effect size was estimated; otherwise, best-evidence synthesis was used for narrative review. Results Of 178 potentially-eligible studies, 79 were included [24 general population; 55 occupational (incuding15 experimental/intervention)]; 56 studies were of high quality, with scores > 0.75. Data for 26 were meta-synthesised. For cross-sectional studies of non-occupational SB, meta-analysis showed full-day SB to be associated with low back pain [LBP – OR = 1.19(1.03 – 1.38)]. Narrative synthesis found full-day SB associations with knee pain, arthritis, and general MSP, but the evidence was insufficient on associations with neck/shoulder pain, hip pain, and upper extremities pain. Evidence of prospective associations of full-day SB with MSP conditions was insufficient. Also, there was insufficient evidence on both cross-sectional and prospective associations between leisure-time SB and MSP conditions. For occupational SB, cross-sectional studies meta-analysed indicated associations of self-reported workplace sitting with LBP [OR = 1.47(1.12 – 1.92)] and neck/shoulder pain [OR = 1.73(1.46 – 2.03)], but not with extremities pain [OR = 1.17(0.65 – 2.11)]. Best-evidence synthesis identified inconsistent findings on cross-sectional association and a probable negative prospective association of device-measured workplace sitting with LBP-intensity in tradespeople. There was cross-sectional evidence on the association of computer time with neck/shoulder pain, but insufficient evidence for LBP and general MSP. Experimental/intervention evidence indicated reduced LBP, neck/shoulder pain, and general MSP with reducing workplace sitting. Conclusions We found cross-sectional associations of occupational and non-occupational SB with MSP conditions, with occupational SB associations being occupation dependent, however, reverse causality bias cannot be ruled out. While prospective evidence was inconclusive, reducing workplace sitting was associated with reduced MSP conditions. Future studies should emphasise prospective analyses and examining potential interactions with chronic diseases. Protocol registration PROSPERO ID # CRD42020166412 (Amended to limit the scope)

Objectives. We examined associations of attractiveness, size, and proximity of multiple neighborhood open spaces (NOSs) with recreational walking. Methods. Adults participating in the Residential Environments (RESIDE) study (n = 1366) in Perth, Australia, reported time spent engaging in recreational walking within their neighborhoods. Park audit data and geographic information systems were used to identify the most attractive, largest, and nearest NOS within a 1.6-km radius from each participant's residential location. Regression analysis was used to examine attributes (attractiveness, size, and proximity) of these open spaces and their associations with participants’ recreational walking. Results. Shorter distance to attractive open spaces was associated with doing any recreational walking, but adults with larger attractive open spaces within 1.6 km of their home were more likely to walk 150 minutes or more in a week. Conclusions. For adults, the presence of a large, high-quality park within walking distance of one's home may be more important in promoting sufficient amounts of walking for health benefits than is the presence of an open space within a shorter distance.

Detrimental associations of sedentary behaviour (time spent sitting) with musculoskeletal pain (MSP) conditions have been observed. However, findings on those with, or at risk of, type 2 diabetes (T2D) have not been reported. We examined the linear and non-linear associations of device-measured daily sitting time with MSP outcomes according to glucose metabolism status (GMS). Cross-sectional data from 2827 participants aged 40-75 years in the Maastricht Study (1728 with normal glucose metabolism (NGM); 441 with prediabetes; 658 with T2D), for whom valid data were available on activPAL-derived daily sitting time, MSP [neck, shoulder, low back, and knee pain], and GMS. Associations were examined by logistic regression analyses, adjusted serially for relevant confounders, including moderate-to-vigorous intensity physical activity (MVPA) and body mass index (BMI). Restricted cubic splines were used to further examine non-linear relationships. The fully adjusted model (including BMI, MVPA, and history of cardiovascular disease) showed daily sitting time to be significantly associated with knee pain in the overall sample (OR = 1.07, 95%CI: 1.01-1.12) and in those with T2D (OR = 1.11, 95%CI: 1.00-1.22); this was not statistically significant in those with prediabetes (OR = 1.04, 95%CI: 0.91-1.18) or NGM (OR = 1.05, 95%CI: 0.98-1.13). There were no statistically significant associations between daily sitting time and neck, shoulder, or low back pain in any of the models. Furthermore, the non-linear relationships were statistically non-significant. Among middle-aged and older adults with T2D, daily sitting time was significantly associated with higher odds of knee pain, but not with neck, shoulder, or low back pain. No significant association was observed in those without T2D for neck, shoulder, low back, or knee pain. Future studies, preferably those utilising prospective designs, could examine additional attributes of daily sitting (e.g., sitting bouts and domain-specific sitting time) and the potential relationships of knee pain with mobility limitations.

Proton pump inhibitors reduce ulcer recurrence in non-steroidal anti-inflammatory drug (NSAID) users, but their impact in at-risk ulcer-free patients using the current spectrum of prescribed agents has not been clearly defined. We assessed esomeprazole for ulcer prevention in at-risk patients (> or = 60 yr and/or ulcer history) taking NSAIDs, including COX-2 inhibitors. Such studies are particularly relevant, given that concerns regarding adverse cardiovascular outcomes among COX-2 inhibitor users may prompt re-evaluation of their use. We conducted two similar double-blind, placebo-controlled, randomized, multicenter studies; VENUS (United States) and PLUTO (multinational). A total of 844 and 585 patients requiring daily NSAIDs, including COX-2 inhibitors were randomized to receive esomeprazole (20 or 40 mg) or placebo, daily for 6 months. In the VENUS study, the life table estimated proportion of patients who developed ulcers over 6 months (primary variable, intent-to-treat population) was 20.4% on placebo, 5.3% on esomeprazole 20 mg (p < 0.001), and 4.7% on esomeprazole 40 mg (p < 0.0001). In the PLUTO study, the values were 12.3% on placebo, 5.2% with esomeprazole 20 mg (p = 0.018), and 4.4% with esomeprazole 40 mg (p = 0.007). Significant reductions were observed for users of both non-selective NSAIDs and COX-2 inhibitors. Pooled ulcer rates for patients using COX-2 inhibitors (n = 400) were 16.5% on placebo, 0.9% on esomeprazole 20 mg (p < 0.001) and 4.1% on esomeprazole 40 mg (p= 0.002). Esomeprazole was well tolerated and associated with better symptom control than placebo. For at-risk patients, esomeprazole was effective in preventing ulcers in long-term users of NSAIDs, including COX-2 inhibitors.

Aims/hypothesis The associations of sitting, standing, physical activity and sleep with cardiometabolic health and glycaemic control markers are interrelated. We aimed to identify 24 h time-use compositions associated with optimal metabolic and glycaemic control and determine whether these varied by diabetes status. Methods Thigh-worn activPAL data from 2388 participants aged 40–75 years (48.7% female; mean age 60.1 [SD = 8.1] years; n =684 with type 2 diabetes) in The Maastricht Study were examined. Compositional isometric log ratios were generated from mean 24 h time use (sitting, standing, light-intensity physical activity [LPA], moderate-to-vigorous physical activity [MVPA] and sleeping) and regressed with outcomes of waist circumference, fasting plasma glucose (FPG), 2 h plasma glucose, HbA 1c , the Matsuda index expressed as z scores, and with a clustered cardiometabolic risk score. Overall analyses were adjusted for demographics, smoking, dietary intake and diabetes status, and interaction by diabetes status was examined separately. The estimated difference when substituting 30 min of one behaviour with another was determined with isotemporal substitution. To identify optimal time use, all combinations of 24 h compositions possible within the study footprint (1st–99th percentile of each behaviour) were investigated to determine those cross-sectionally associated with the most-optimal outcome (top 5%) for each outcome measure. Results Compositions lower in sitting time and with greater standing time, physical activity and sleeping had the most beneficial associations with outcomes. Associations were stronger in participants with type 2 diabetes ( p <0.05 for interactions), with larger estimated benefits for waist circumference, FPG and HbA 1c when sitting was replaced by LPA or MVPA in those with type 2 diabetes vs the overall sample. The mean (range) optimal compositions of 24 h time use, considering all outcomes, were 6 h (range 5 h 40 min–7 h 10 min) for sitting, 5 h 10 min (4 h 10 min–6 h 10 min) for standing, 2 h 10 min (2 h–2 h 20 min) for LPA, 2 h 10 min (1 h 40 min–2 h 20 min) for MVPA and 8 h 20 min (7 h 30 min–9 h) for sleeping. Conclusions/interpretation Shorter sitting time and more time spent standing, undergoing physical activity and sleeping are associated with preferable cardiometabolic health. The substitutions of behavioural time use were significantly stronger in their associations with glycaemic control in those with type 2 diabetes compared with those with normoglycaemic metabolism, especially when sitting time was balanced with greater physical activity. Graphical Abstract

Background Bodily pain is a common presentation in several chronic diseases, yet the influence of sedentary behaviour, common in ageing adults, is unclear. Television-viewing (TV) time is a ubiquitous leisure-time sedentary behaviour, with a potential contribution to the development of bodily pain. We examined bodily pain trajectories and the longitudinal relationships of TV time with the bodily pain severity; and further, the potential moderation of the relationships by type 2 diabetes (T2D) status. Method Data were from 4099 participants (aged 35 to 65 years at baseline) in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), who took part in the follow-ups at 5 years, 12 years, or both. Bodily pain (from SF36 questionnaire: a 0 to 100 scale, where lower scores indicate more-severe pain), TV time, and T2D status [normal glucose metabolism (NGM), prediabetes, and T2D] were assessed at all three time points. Multilevel growth curve modelling used age (centred at 50 years) as the time metric, adjusting for potential confounders, including physical activity and waist circumference. Results Mean TV time increased, and bodily pain worsened (i.e., mean bodily pain score decreased) across the three time points. Those with T2D had higher TV time and more-severe bodily pain than those without T2D at all time points. In a fully adjusted model, the mean bodily pain score for those aged 50 years at baseline was 76.9(SE: 2.2) and worsened (i.e., bodily pain score decreased) significantly by 0.3(SE: 0.03) units every additional year ( p <0.001). Those with initially more-severe pain had a higher rate of increase in pain severity. At any given time point, a one-hour increase in daily TV time was significantly associated with an increase in pain severity [bodily pain score decreased by 0.69 (SE: 0.17) units each additional hour; p <0.001], accounting for the growth factor (age) and confounders’ effects. The association was more-pronounced in those with T2D than in those without (prediabetes or NGM), with the effect of T2D on bodily pain severity becoming more apparent as TV time increases, significantly so when TV time increased above 2.5 hours per day. Conclusion Bodily pain severity increased with age in middle-aged and older Australian adults over a 12-year period, and increments in TV time predicted increased bodily pain severity at any given period, which was more pronounced in those with T2D. While increasing physical activity is a mainstay of the prevention and management of chronic health problems, these new findings highlight the potential of reducing sedentary behaviours in this context.

Ipilimumab has been shown to improve survival in patients with previously treated metastatic melanoma. In this study, ipilimumab plus dacarbazine improved survival in patients with previously untreated metastatic melanoma. The survival rate for patients with metastatic melanoma is low, with an expected 2-year survival rate of 10 to 20%. 1 – 3 Although dacarbazine has never been shown to improve survival in randomized, controlled studies, it has been the drug most frequently compared with new agents or combination therapies in randomized trials involving patients with melanoma. 4 , 5 High-dose interleukin-2 is associated with durable, complete responses, with a survival benefit, in a small subgroup of patients with metastatic melanoma. 6 , 7 Ipilimumab, a fully human, IgG1 monoclonal antibody, blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negative regulator of T cells, and thereby augments . . .

This study explores the effect of emotional intelligence (assessed by the Schutte Emotional Intelligence Scale) on work-related psychological health (assessed by the two scales of the Francis Burnout Inventory) among 364 Anglican clergy serving in the Church in Wales (264 clergymen, 93 clergywomen, and 7 who did not disclose their sex). After controlling for personal factors (sex and age) and for personality dimensions (extraversion, neuroticism, and psychoticism), the data suggested that higher levels of emotional intelligence enhanced work-related psychological health both in terms of lowering negative affect (emotional exhaustion in ministry) and in terms of increasing positive affect (satisfaction in ministry). These findings suggest that there may be benefits in professional development programmes designed to develop emotional intelligence among clergy.

David Goldstein, Mohamad Mikati and colleagues report identification of de novo mutations in ATP1A3 in alternating hemiplegia of childhood, which is a rare neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3 .