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Background Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. Methods We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO(2)) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 mu g/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 mu g/L, which had been increasing over the previous 24 h, or lyrnphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 mu g/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 x 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. Findings Between April 4, and Dec 6,2020,342 patients were randomly assigned to IL-1 blockade n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0.94 [95% CI 0.73-1.21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1.00[0-78-1-29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. Interpretation Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Belgian Health Care Knowledge Center; VIB Grand Challenges program The authors acknowledge professional support and committed efforts from various organisations and individuals involved in this trial and thank all trial participants and clinicians involved in patient recruitment at the different participating sites. This study was funded by KCE, and KCE was involved in various aspects of the study design, management, and execution (Nelle Stocquart, Jillian Harrison). The VIB Grand Challenges Program (Sofie Bekaert) funded measurements of cytokines and the Ghent University Special Research Fund (BOF) supported the clinical follow-up of patients at Ghent University Hospital (UZ Ghent). The clinical trial team of the Department of Respiratory Medicine at UZ Ghent (Stefanie Vermeersch, Benedicte Demeyere, Anja Delporte) were involved in protocol development, amendment filing, and eCRF construction. The Health Innovation and Research Institute of UZ Ghent was involved in eCRF design, protocol design, ethical committee reporting, drug dispensing, trial monitoring, data cleaning, and sponsor site management (Charlotte Clauwaert, Dries Loncke, Hanife Kokur, Lieselot Van Landuyt, Joke Tommelein, Hélène De Naeyer). The hospital pharmacy of UZ Ghent dispensed drugs to all study sites (Els Kestens). Team members of the Primary Immune Deficiency laboratory (Karlien Claes, Veronique Debacker, Lisa Roels, Zara Declercq) handled samples from all study sites. The authors acknowledge the insights of the data safety monitoring board (Drs Renaat Peleman, Geert Leroux-Roels, Steven Callens, Frank Vermassen, Piet Hoebeke, Karim Vermaelen, A Dupont, Tomasz Burzykowski, and Marnik Vuylsteke under the chairmanship of SR).

Background Increased awareness of gastric cancer risk, easy access to upper endoscopy, and high definition endoscopes with virtual chromoendoscopy may have led to the increase in early diagnosis of gastric cancer observed in recent years in Europe, which may be associated with improved survival. Currently, no data exist on the impact of early diagnosis on survival at a populational level in Europe. Our aim was to assess gastric cancer incidence, early diagnosis, and survival in northwestern and southern European countries with a low-to-moderate incidence of gastric cancer. Methods Data on 41 138 gastric cancers diagnosed in 2007–2016 were retrieved from national cancer registries of Belgium, the Netherlands, and northern Portugal. Age-standardized incidence and mortality rates were assessed and expressed per 100 000 person-years. Early diagnosis was defined as T1 tumors. Net survival estimates for 2007–2011 vs. 2012–2016 were compared. Results Age-standardized incidence and mortality decreased over time in Belgium, northern Portugal, and the Netherlands (relative incidence decrease 8.6 %, 4.5 %, and 46.8 %, respectively; relative mortality decrease 22.0 %, 30.9 %, and 50.0 %, respectively). Early gastric cancer diagnosis increased over time for all countries. Net 1-year survival improved significantly between the two time periods in all countries, and at 5 years in Belgium and Portugal. Conclusions This is the first study comparing trends (2007–2016) in gastric cancer incidence and mortality in some European countries. We found an increasing proportion of T1 gastric cancers and a decrease in age-standardized mortality over time, supporting the use of secondary prevention strategies.

Villages are changing as a consequence of global processes of transformation, as well as a summation of small-scale and individual decisions. Village communities are challenged by the way identities change, and search for ways to reflect and exchange ideas on what has disappeared, what aspects of life remain and will be possible. Our aim was to support individual villagers in order to better understand what is changing and to collectively define a future image. The methodology of action research brings in a future-forming orientation: to discuss what might become and to reflect on what is already there. Combined with aspects of participatory design, we set up different actions in Hoepertingen, a village in Haspengouw. Through walking with villagers, generating scenarios, envisioning, enacting, prototyping and more, we assembled and compared different meaning constructs, experimented with possible solutions and developed dialogues about these scenarios. In this paper, we will discuss the ways in which these participatory actions supported us to envision how public places in villages change and generate reflection, and debate about how inhabitants can contribute to this change.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Introduction Converting a high-volume primary stroke center (PSC) into a stroke center that can perform emergency endovascular treatment (EVT) could reduce the time to thrombectomy . We report the first results of a newly established EVT facility at the Perpignan PSC and their comparison with the targets defined by the established guidelines. Patients and method For this comprehensive observational study, data of patients with acute ischemic stroke (AIS) due to proximal large vessel occlusion (LVO) and treated by EVT at the Perpignan PSC from December 5, 2019 to September 15, 2020 were extracted from an ongoing prospective database. Results During the study period, 37 patients underwent EVT at the Perpignan PSC. The median (range) symptom-onset to recanalization time was 262 min (100–485 min). The median (range) intra-hospital times were: 20 min (2–58 min) for door-to-imaging, 57 min (30–155 min) for imaging-to-puncture, 55 min (15–180 min) for puncture-to-recanalization, and 137 min (59–319 min) for door-to-recanalization. At 3 months post-AIS, the favorable outcome (modified Ranking Score: 0–2) rate was 50% and the mortality rate was 19.4%. These results are comparable to those of previous clinical trials, and meet the targets defined by the current consensus statements for EVT. Discussion and conclusion Our results show the feasibility and safety of EVT in a PSC for patients with AIS due to LVO. The implementation of this strategy may be important for shortening the time to thrombectomy.

Background: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16 & ndash;26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27 & ndash;45 versus 16 & ndash;26 years of age. Methods: This international, open-label study (NCT03158220) was conducted in women 16 & ndash;45 years of age. Participants (16 & ndash;26 years, n = 570 and 27 & ndash;45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study. Results: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27 & ndash;45 years were compared to those in women 16 & ndash;26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27 & ndash;45 years to 16 & ndash;26 years) was 0.60 & ndash;0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27 & ndash; 45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16 & ndash;26 years, and 85.2% and 24.1% of women 27 & ndash; 45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study. Conclusions: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27 & ndash;45 years compared with women 16 & ndash;26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16 & ndash;26 years to women 27 & ndash;45 years of age. Clinical trial registration NCT03158220. (c) 2021 Elsevier Ltd. All rights reserved.

INTRODUCTION: The global COVID-19 vaccine rollout has highlighted inequities in the accessibility of countries to COVID-19 vaccines. Populations in low- and middle-income countries have found it difficult to have access to COVID-19 vaccines. AREAS COVERED: This perspective provides analyses on historical and contemporary policy trends of vaccine development and immunization programs, including the current COVID-19 vaccination drive, and governance challenges. Moreover, we also provide a comparative health system analysis of the COVID-19 vaccine deployment in some countries from different continents. It recommends that the international Access to COVID-19 Tools Accelerator (ACT-A) partnership requires a strong governance mechanism and urgent financial investment. EXPERT OPINION: All WHO member states should agree on technology transfer and voluntary license-sharing via a commonly governed technology access pool and supported by a just Intellectual Property regime. Contextualized, dynamic understandings and country-specific versions of health systems strengthening are needed to improve vaccine equity in a sustainable matter

BackgroundThis meta-analysis aims to: (i) describe the pooled prevalence of diabetes in people with intellectual disabilities, (ii) investigate the association with demographic, clinical and treatment-related factors and (iii) compare the prevalence versus age- and gender-matched general population controls.MethodsPubmed, Embase and CINAHL were searched until 01 May 2021. Random effects meta-analysis and an odds ratio analysis were conducted to compare rates with controls.ResultsThe trim- and fill-adjusted pooled diabetes prevalence amongst 55,548 individuals with intellectual disabilities (N studies = 33) was 8.5% (95% CI = 7.2%–10.0%). The trim- and fill-adjusted odds for diabetes was 2.46 times higher (95% CI = 1.89–3.21) (n = 42,684) versus controls (n = 4,177,550).Older age (R2 = .83, p p = .009) and co-morbid depression (R2 = .18, p = .04), anxiety (R2 = .97, p R2 = 0.29, p ConclusionsOur findings demonstrate that people with intellectual disabilities are at an increased risk of diabetes, and therefore routine screening and multidisciplinary management of diabetes is needed.

Background OVX836 is a recombinant protein vaccine targeting the highly conserved influenza nucleoprotein (NP), which could confer broad-spectrum protection against this disease. Methods A randomized, placebo-controlled, double-blind, dose-escalating, single- center, first-in-human study was conducted in 36 healthy adults aged 18–49 years. Twelve subjects per cohort (9 vaccine and 3 placebo) received 2 OVX836 intramuscular administrations on days 1 and 28 at the dose level of 30 µg, 90 µg, or 180 µg. Safety and immunogenicity were assessed after each vaccination and for 150 days in total. Results OVX836 was safe and well tolerated at all dose levels, with no difference in solicited local and systemic symptoms, and unsolicited adverse events between the first and second administration, or between dose levels. All subjects presented pre-existing NP-specific immunity at baseline. OVX836 induced a significant increase in NP-specific interferon-gamma T cells and anti-NP immunoglobulin G at all dose levels after the first vaccination. The second vaccination did not further increase the response. There was a trend for a dose effect in the immune response. Conclusions The safety and reactogenicity profile, as well as the humoral and cellular immune responses, encourage further evaluation of OVX836 in a larger Phase 2a study.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

BACKGROUND: Although hereditary ataxias are a group of clinically and genetically heterogeneous disorders, specific clinical clues can sometimes incriminate certain genes. This can trigger genetic testing in sporadic patients or prompt dissecting certain genes more thoroughly when initial genetic testing is negative. Also for the assembly of gene panels and interpretation of the results, genotype-phenotype correlations remain important to establish. METHODS: We clinically evaluated a Belgian family with autosomal dominant inherited sensory ataxia and variable pyramidal involvement and performed targeted clinical exome sequencing. Secondly, we retrospectively screened sequencing data of an in-house cohort of 404 patients with neuromuscular disorders for variants in the identified gene RNF170. RESULTS: All affected family members showed sensory ataxia on examination. Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings. We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family. We did not find additional pathogenic variants in RNF170 in our in-house neuromuscular cohort. CONCLUSIONS: We confirm the heterozygous variant p.Arg199Cys in RNF170 in a Belgian family with autosomal dominant sensory ataxia and variable pyramidal involvement. This constitutes a rare but clinically recognizable phenotype that warrants testing of RNF170. Unlike the distinctive bi-allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia. It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP. ispartof: EUROPEAN JOURNAL OF NEUROLOGY vol:29 issue:1 pages:345-349 ispartof: location:England status: published

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Vaccine‐induced human papillomavirus (HPV) antibodies originating from cervicovaginal secretions were recently shown to be detectable in first‐void (FV) urine. This presents a novel opportunity for noninvasive sampling to monitor HPV antibody status in women participating in large epidemiological studies and HPV vaccine trials. With a view towards method optimization, this study compared the measurement of HPV antibodies in FV urine using a multiplex L1/L2 virus‐like particles (VLP)‐based ELISA (M4ELISA) with previously reported results using a glutathione S‐transferase (GST)‐L1‐based immunoassay (GST‐L1‐MIA). We tested 53 paired FV urine and serum samples from 19‐ to 26‐year‐old healthy women, unvaccinated (n = 17) or vaccinated with either the bivalent or quadrivalent HPV‐vaccine during adolescence (n = 36). HPV6/11/16/18 antibodies were measured using M4ELISA and compared with GST‐L1‐MIA results. Inter‐assay and inter‐specimen correlations were examined using the Spearman's rank test (rs). As expected, lower HPV antibody concentrations were found in FV urine than in serum. Vaccinated women had significantly higher HPV6/11/16/18 antibody levels in both FV urine and serum compared with those unvaccinated (M4ELISA; FV urine P = .0003; serum P ≤ .0001). HPV antibody levels in FV urine and serum showed a significant positive correlation (M4ELISA anti‐HPV6/11/16/18, r s = 0.85/0.86/0.91/0.79, P ≤ .001). Despite assay differences, there was moderate to good correlation between M4ELISA and GST‐L1‐MIA (FV urine anti‐HPV6/11/16/18, r s = 0.86/0.83/0.89/0.53, P ≤ .0001; serum anti‐HPV6/11/16/18, r s = 0.93/0.89/0.94/0.75, P ≤ .0001). FV urine HPV antibody detection is comparable with both assays, further supporting this noninvasive sampling method as a possible option for HPV vaccine assessment. Approaches to improve the sensitivity and larger studies are warranted to determine the feasibility of FV urine for vaccine‐induced HPV antibody detection., Highlights First‐void urine HPV antibody detection is comparable with both assays.Urine of vaccinees contain higher antibody levels as opposed to unvaccinated women.Urinary HPV6/11/16/18 antibodies correlate significantly with paired sera.Urine might offer a non‐invasive tool to assess serum antibody transudate.Approaches to improve the sensitivity of vaccine‐induced HPV antibody detection in FV urine are required.

Background Primary health care providers (PHCPs) are assumed to be at high risk of a COVID-19 infection, as they are exposed to patients with usually less personal protective equipment (PPE) than other frontline health care workers (HCWs). Nevertheless, current research efforts focussed on the assessment of COVID-19 seroprevalence rates in the general population or hospital HCWs. Objective We aimed to determine the seroprevalence in PHCPs during the second SARS-CoV-2 wave in Flanders (Belgium) and compared it to the seroprevalence in the general population. We also assessed risk factors, availability of PPE and attitudes towards the government guidelines over time. Methods A prospective cohort of PHCPs (n = 698), mainly general practitioners, was asked to complete a questionnaire and self-sample capillary blood by finger-pricking at five distinct points in time (June–December 2020). We analysed the dried blood spots for IgG antibodies using a Luminex multiplex immunoassay. Results The seroprevalence of PHCPs remained stable between June and September (4.6–5.0%), increased significantly from October to December (8.1–13.4%) and was significantly higher than the seroprevalence of the general population. The majority of PHCPs were concerned about becoming infected, had adequate PPE and showed increasing confidence in government guidelines. Conclusions The marked increase in seroprevalence during the second COVID-19 wave shows that PHCPs were more at risk during the second wave compared to the first wave in Flanders. This increase was only slightly higher in PHCPs than in the general population suggesting that the occupational health measures implemented provided sufficient protection when managing patients.

In 2019, an estimated 14 million persons in the World Health Organization (WHO) European Region* (EUR) were chronically infected with hepatitis B virus (HBV), and approximately 43,000 of these persons died from complications of chronic HBV infection (1). In 2016, the WHO Regional Office for Europe set hepatitis B control program targets for 2020, including 1) ≥90% coverage with 3 doses of hepatitis B vaccine (HepB3), 2) ≥90% coverage with interventions to prevent mother-to-child transmission (MTCT) of HBV,† and 3) ≤0.5% prevalence of HBV surface antigen (HBsAg)§ in age groups eligible for vaccination with hepatitis B vaccine (HepB) (2-4). This report describes the progress made toward hepatitis B control in EUR during 2016-2019. By December 2019, 50 (94%) of 53 countries in EUR provided routine vaccination with HepB to all infants or children aged 1-12 years (universal HepB), including 23 (43%) countries that offered hepatitis B birth dose (HepB-BD) to all newborns. In addition, 35 (73%) of the 48 countries with universal infant HepB vaccination reached ≥90% HepB3 coverage annually during 2017-2019, and 19 (83%) of the 23 countries with universal birth dose administration achieved ≥90% timely HepB-BD coverage¶ annually during that period. Antenatal hepatitis B screening coverage was ≥90% in 17 (57%) of 30 countries that selectively provided HepB-BD to infants born to mothers with positive HBsAg test results. In January 2020, Italy and the Netherlands became the first counties in EUR to be validated to have achieved the regional hepatitis B control targets. Countries can accelerate progress toward hepatitis B control by improving coverage with HepB and interventions to prevent MTCT and documenting achievement of the HBsAg seroprevalence target through representative serosurveys or, in low-endemicity countries, antenatal screening.

Background Quality human resources constitute an essential pillar of an effective health system. This paper analyzes the outcomes of blended learning for post-Ebola capacity strengthening of health professionals in Guinea. Methods Two courses lasting 3 months each (7–8 modules) were developed and implemented: one in Primary Health Care (eSSP) and the other in Sexual and Reproductive Health Services Management (eSSR). Both eSSP and eSSR courses were offered online on the Moodle platform, followed by a face-to-face capacity-building workshop. A cross-sectional study using a mixed-methods approach was conducted in 2018–19. As outcomes, we described learners’ sociodemographic characteristics, course completion and success, and perceptions of the courses and support from the instructors, analyzed the factors associated with learners’ successful completion and reported on learners’ feedback on their blended learning experience. Quantitative data were analyzed using the STATA 15 software, and qualitative data were analyzed through content analysis. Results Overall, 282 health professionals were enrolled for both eSSP and eSSR courses. The completion rate was 69.5% (196/282). The success rate for learners who completed the courses was 80% (156/196), and the overall success rate for enrollees was 55% (156/282). The dropout and abstention rates were 22 and 9%, respectively. On both eSSP and eSSR courses, the success rate of women enrolled was higher than or equal to men’s. The success rate of medical doctors enrolled (53% for eSSP and 67% for eSSR) was higher than for other health professionals, in particular nurses (9% for eSSP) and midwives (40% for eSSR). Course type was associated with success (AOR = 1.93; 95% CI = 1.15–3.24). Most learners strongly agreed that the courses are relevant for targeted health professionals (81 to 150/150), pdf course materials are well-structured and useful (105/150), the content of the modules is relevant, comprehensible, and clear (90/150), self-assessment quizzes are helpful (105/150), summative assessment assignments are relevant (90/150), the course administrators and IT manager were responsive to learners’ concerns (90/150), they will recommend the courses to colleagues and friends (120/150). Conclusion Two blended courses for capacity strengthening of health professionals were successfully developed and implemented in Guinea.

Background Many definitions and operationalisations of frailty exclude psychosocial factors, such as social isolation and mental health, despite considerable evidence of the links between frailty and these factors. This study aimed to investigate the health domains covered by frailty screening tools. Methods A systematic search of the literature was conducted in ac­cordance with PRISMA guidelines. MEDLINE, CINAHL, EMBASE, and PsycInfo were searched from inception to December 31, 2018. Data related to the domains of each screening tool were extracted and mapped onto a framework based on the biopsychosocial model of Lehmans et al. (2009) and Wade & Halligans (2017). Results Sixty-seven frailty screening tools were captured in 79 arti­cles. All screening tools assessed biological factors, 73% assessed psychological factors, 52% assessed social factors, and 78% assessed contextual factors. Under half (43%) of the tools evaluated all four domains, 33% evaluated three of four domains, 12% reported two of four domains, and 13% reported one domain (biological). Conclusion This review found considerable variation in the assessment domains covered by frailty screening tools. Frailty is a broad construct, and frailty screening tools need to cover a wide var­iety of domains to enhance screening and outcomes assessment.

Distribution centres are becoming more and more relevant for spatial planning, due to their rapidly increasing size and number. There is little literature, however, that provides a generalized analysis of the size and functional attributes of distribution centres, and none that discusses the relationships between these attributes. Our aim is to fill this gap by providing new evidence and analysis to understand this relationship. We make use of an extensive database of 2888 DCs in the Netherlands to develop a new typology of DCs based on the geographical location of DCs, their functional attributes and client sector characteristics. The analysis shows that the context in which medium sized DCs are operating is more heterogeneous than in the case of very large and small size DCs. This study is a first attempt to analyse this relationship between facility size and functions based on a rich and extensive dataset of large population of DCs. The results can serve as input for further quantitative statistical analysis and international comparison.

Key Points Question What genetic variants are associated with juvenile amyotrophic lateral sclerosis (ALS)? Findings In this family-based genetic study, exome sequencing was performed in 3 patients diagnosed with juvenile ALS and failure to thrive; this identified de novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient). Variants in SPTLC1 are a known cause of hereditary sensory and autonomic neuropathy, type 1A, and these data extend the phenotype associated with this gene. Meaning De novo variants in the SPTLC1 gene are associated with juvenile ALS, a fatal neurological disorder., This genetic association study identifies genetic variants associated with juvenile amyotrophic lateral sclerosis., 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 & Aims Approximately 5%-10% of the general population respond inadequately to licensed recombinant hepatitis B vaccines. We assessed the immunogenicity and safety of a new HBAI20 vaccine, consisting of a new AI20 adjuvant (20-mu g recombinant human IL-2 attached to 20-mu g aluminium hydroxide) in combination with HBVaxPro (R)-10 mu g.Methods In a double-blinded, randomised, controlled phase 2 trial, 18- to 59-year-old healthy non-responders (titre = 10 mIU/ml) measured 1-3 months following the third vaccination.Results A total of 133 participants were randomised to receive either HBAI20 vaccine (n = 101) or HBVaxPro (R)-10 mu g (n = 32). In the modified intention-to-treat analysis, the seroprotection rate after the third vaccination was 92.0% (80/87) in the HBAI20 group and 79.3% (23/29) in the HBVaxPro (R)-10-mu g group, P = .068. Using a generalised linear mixed model to adjust for stratification factors, a higher odds of seroprotection with HBAI20 vaccine was shown (adjusted odds ratio = 3.48, P = .028). Frequency of mild and moderate local adverse events was greater in the HBAI20 group than in the HBVaxPro (R)-10 mu g. Rates of severe local adverse events and systemic adverse events were low and similar in both groups.Conclusions In this group of hepatitis B vaccine non-responders, the HBAI20 vaccine demonstrated a higher seroprotection rate when adjusting for stratification factors and a similar safety profile compared to the licensed recombinant HBVaxPro (R)-10 mu g. The study was partially sponsored by CyTuVax BV, and the sponsor was involved in the study design, interpretation of the data, review and approval of the manuscript in accordance with good clinical practice. The funding source had no input in data collection and statistical analysis of the data. ÖK, CK, NH and AOL had full access to all the data in the study and the corresponding CyTuVax BV sponsored the study. The authors would like to thank the many participants and would like to acknowledge Mohannad Altabban (CyTuVax BV, Maastricht, the Netherlands), the staffs of the Ease Travel Clinic & Health Support (Maastricht, the Netherlands), the Department of Gastroenterology and Hepatology (Genk, Belgium) and Centre for the Evaluation of Vaccination, Vaccine & Infectious Disease Institute (Antwerp, Belgium) for their careful performance of the study.

Background Limited data exist on the impact of maternal tetanus, diphtheria, acellular pertussis (Tdap) vaccination for preterm born infants. We report its effect at birth and on antibody-mediated immune responses to a DTaP-IPV-HB-PRP~T vaccine in preterm compared with term infants. Methods Women delivering at term or prematurely were either vaccinated with a Tdap vaccine (Boostrix; GSK) during pregnancy or not vaccinated in the last 5 years. Cord and maternal blood were collected at delivery. Infants were vaccinated with DTaP-IPV-HB-PRP~T vaccine (Hexyon; Sanofi Pasteur) and blood collected before and 1 month after primary (8-12-16 weeks) and before and 1 month after booster vaccination (13 or 15 months for preterm and term, respectively). Immunoglobulin G antibodies against all antigens included in DTaP-IPV-HB-PRP~T vaccine were measured (NCT02511327). Results Cord blood geometric mean concentrations (GMCs) in preterm infants from Tdap-vaccinated women were significantly higher than in term and preterm infants from unvaccinated women. A longer time interval between maternal vaccination and delivery resulted in higher cord blood GMCs in preterm infants. Equal GMCs in term and preterm infants from Tdap-vaccinated women were observed after primary vaccination. After boosting, significantly lower GMCs were seen for pertussis toxin, filamentous hemagglutinin, and tetanus toxoid in preterm compared with term infants from Tdap-vaccinated women, yet still comparable to GMCs in both term and preterm infants from unvaccinated women. Conclusions Preterm infants profit from maternal Tdap vaccination. Prematurity did not influence primary immune responses in the presence of maternal antibodies but was associated with a lower booster immune response.

Background Guinea undertook health workforce reform in 2016 following the Ebola outbreak to overcome decades-long shortages and maldistribution of healthcare workers (HCWs). Specifically, over 5000 HCWs were recruited and deployed to rural health districts and with a signed 5-year commitment for rural medical practice. Governance structures were also established to improve the supervision of these HCWs. This study assessed the effects of this programme on local health systems and its influence on HCWs turnover in rural Guinea. Methods An exploratory study design using a mixed-method approach was conducted in five rural health districts. Data were collected through semi-structured questionnaires, in-depth interview guides, and documentary reviews. Results Of the 611 HCWs officially deployed to the selected districts, 600 (98%) took up duties. Female HCWs (64%), assistant nurses (39%), nurses (26%), and medical doctors (20%) represented the majority. Findings showed that 69% of HCWs were posted in health centres and the remaining in district hospitals and the health office (directorate); the majority of which were medical doctors, nurses, and midwives. The deployment has reportedly enhanced quality and timely data reporting. However, challenges were faced by local health authorities in the posting of HCWs including the unfamiliarity of some with primary healthcare delivery, collaboration conflicts between HCWs, and high feminization of the recruitment. One year after their deployment, 31% of the HCWs were absent from their posts. This included 59% nurses, 29% medical doctors, and 11% midwives. The main reasons for absenteeism were unknown (51%), continuing training (12%), illness (10%), and maternity leave (9%). Findings showed a confusion of roles and responsibilities between national and local actors in the management of HCWs, which was accentuated by a lack of policy documents. Conclusion The post-Ebola healthcare workers policy appears to have been successfully positive in the redistribution of HCWs, quality improvement of staffing levels in peripheral healthcare facilities, and enhancement of district health office capacities. However, greater attention should be given to the development of policy guidance documents with the full participation of all actors and a clear distinction of their roles and responsibilities for improved implementation and efficacy of this programme.

PURPOSE: Understanding enablers of and barriers for physical activity (PA) participation in people with intellectual disability (ID) is an essential first step to develop effective interventions. This systematic review examined correlates of PA across the socio-ecological model (i.e., intra-personal, inter-personal, environmental and policy level) in people with ID across the lifespan. MATERIAL AND METHODS: Major electronic databases were searched from inception until 15 February 2021. Keywords included "physical activity" or "exercise" and "intellectual disability" or "mental retardation." A summary coding was used to analyze the data for adolescents (

Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.

Introduction Myositis-specific autoantibodies (MSAs) are thought to be mutually exclusive in patients with idiopathic inflammatory myopathies (IIM) based on studies with immunoprecipitation-based (IP) detection methods. Recently, detection of multiple MSAs in unique patients is increasingly reported, but the extent of this phenomenon remains unclear. Methods At our centre, we reviewed results from two line immunoassays and one dot immunoassay in 145 IIM patients and 240 controls for the presence of multiple MSAs. Pubmed and Embase were systematically searched for articles mentioning detection of multiple MSAs in IIM patients, published until February 2019. We assessed the frequency, detection method, the precise combinations and clinical phenotypes of participants with multiple MSAs. Results At our centre, detection of multiple MSAs occurred in 3.4-8.3% of patients with IIM, depending on the assay. However, no cases with full concordance across all three assays were identified. Forty-four articles reported detection of multiple MSAs, representing a total of 133 cases, including four patients with a connective tissue disease other than IIM and two healthy controls. In 101 cases all MSAs were detected using only one detection method: 40 cases with IP-based methods (most frequently used technique) and 61 cases with other assay types. In most cases the phenotype of patients with multiple MSAs matched the predicted presentation associated with one MSA and in few cases the phenotype matched with both MSAs. Conclusion Detection of multiple MSAs in unique IIM patients is less rare than commonly accepted. Specificity issues of the commercially available multiplex immunoassays may, at least partly, explain the higher frequency compared to IP-based methods. ‘True multiple MSA-positive’ patients may exist, though they are most likely rare.

INTRODUCTION: The development of quality human resources for health is an essential pillar of an effective health system. The objective of this study was to describe the implementation process and the results of an eLearning approach for capacity strengthening of health professionals in Guinea. METHOD: A descriptive cross-sectional study using a mixed research method was conducted from January 15, 2018 to January 15, 2019. RESULTS: A team from the National Training and Research Centre in Rural Health of Maferinyah in Guinea has been trained in the development of online courses. Two courses lasting three months each (7 to 8 modules), entirely offered online on the Moodle platform, have been developed, one on Primary Health Care (eSSP) and the other on the Management of Sexual and Reproductive Health Services (eSSR). Overall, 282 health professionals have been enrolled for both courses, with a completion rate of 69.5%. The success rate for learners who completed the courses was 79.6% and the success rate for enrollees was 55.3%. The dropout and abstention rates were 21.6% and 8.9%, respectively. The strengths, weaknesses and challenges of the organization and the success of such a training were reported. CONCLUSIONS: The eLearning approach for capacity strengthening of health professionals is feasible and gives good findings in low-income contexts like that of Guinea.

Purpose: To describe experience with partial nephrectomy combined with brachytherapy as part of the local management of bilateral Wilms tumor (WT) including a review of the available literature.Results (methods and case description): Between 2011 and 2014, three highly selected patients (age nine months, 16 months, and 4 years) with bilateral WT (two synchronous and one metachronous) underwent enucleation and perioperative brachytherapy to the tumor bed. With a minimum follow-up of 5 years, all three patients are in continuous complete remission with preserved kidney function.Conclusions: Although nephron sparing surgery aiming at tumor free-margins remains the gold standard for bilateral WT, tumor enucleation followed by brachytherapy may be considered in carefully selected patients at high risk for end-stage kidney failure. Given the rarity and complexity of the procedure, concentration of care of such patients is mandatory.

Objective:. Exercise has established efficacy in people with anxiety and stress-related disorders. Dropouts from randomized controlled trials (RCT's) pose a threat to the validity of the evidence, with dropout rates varying across studies. We conducted a meta-analysis to investigate the prevalence and predictors of dropout rates among adults with anxiety and stress-related disorders participating in exercise RCT's. Methods:. Two authors searched major electronic databases up to 07/2020. We included RCT's of exercise interventions in people with anxiety and stress-related disorders that reported dropout rates. A random effects meta-analysis and meta-regression were conducted. Results:. Fourteen RCT's involving 16 exercise interventions (n=369, mean age 20.7 to 67.7years; 38.4% male) were included. The trim-and-fill-adjusted prevalence of dropout across all studies was 22.4% (95%CI = 15.0% to 32.0%). Applying controlled motivation strategies (P2 = 0%; N=16). Limitations:. Potentially important moderators of dropout, such as the severity of mental health symptoms and illness duration were insufficiently available. Conclusions:. Exercise is well tolerated by people with anxiety and stress-related disorders and drop out in RCT's is comparable to control conditions. Thus, exercise is a feasible treatment, in particular when autonomous motivation strategies are included and when the intervention is delivered by healthcare professionals with expertise in exercise prescription.

A quadrivalent high-dose inactivated influenza vaccine (IIV4-HD) is licensed for adults ≥65y of age based on immunogenicity and efficacy studies. However, IIV4-HD has not been evaluated in adults aged 60–64y. This study compared immunogenicity and safety of IIV4-HD with a standard-dose quadrivalent influenza vaccine (IIV4-SD) in adults aged ≥60y. This Phase III, randomized, modified double-blind, active-controlled study enrolled 1,528 participants aged ≥60y, randomized 1:1 to a single injection of IIV4-HD or IIV4-SD. Hemagglutination inhibition (HAI) geometric mean titers (GMTs) were measured at baseline and D 28 and seroconversion assessed. Safety was described for 180d after vaccination. The primary immunogenicity objective was superiority of IIV4-HD versus IIV4-SD, for all four influenza strains 28d post vaccination in participants aged 60–64 and ≥65y. IIV4-HD induced a superior immune response versus IIV4-SD in terms of GMTs in participants aged 60–64 y and those aged ≥65y for all four influenza strains. IIV4-HD induced higher GMTs in those aged 60–64 y than those aged ≥65 y. Seroconversion rates were higher for IIV4-HD versus IIV4-SD in each age-group for all influenza strains. Both vaccines were well tolerated in participants ≥60y of age, with no safety concerns identified. More solicited reactions were reported with IIV4-HD than with IIV4-SD. IIV4-HD provided superior immunogenicity versus IIV4-SD and was well tolerated in adults aged ≥60 y. IIV4-HD is assumed to offer improved protection against influenza compared with IIV4-SD in adults aged ≥60 y, as was previously assessed for adults aged ≥65y.

Introduction: Flat epithelial atypia (FEA), classical lobular neoplasia (LN), papillary lesions (PL), radial scars (RS) and atypical ductal hyperplasia (ADH) are lesions of uncertain malignant potential in the breast, which are described as B3 lesions in the B classification system of the European Working Group for Breast Cancer Screening Pathology. Current standard for management of B3 lesions on core needle biopsy (CNB) or vacuum assisted biopsy (VAB), is wide local excision (WE). However, recent consensus-based guidelines no longer recommend WE for all such lesions, but propose surveillance following CNB or VAB to be sufficient in some cases. In the absence of a Belgian guideline on the treatment of B3 lesions, this study was conducted to identify which B3 lesions have the lowest likelihood for breast malignancy and could therefore be spared from WE. Methods: Using data from the Belgian Cancer Registry (BCR), all patients with a new diagnosis of a B3 lesion on CNB or VAB between 2013-2016 and who had a histological follow up with VAB or WE after CNB or WE after VAB were included. Histological follow-up was retrieved from BCR and limited to 12 months following diagnosis. Histology was compared between the first- and follow-up investigation to determine the upgrade risk to ductal carcinoma in situ (DCIS) or invasive breast cancer (IC) according to the type of B3 lesion. Patients with synchronous (pre-) invasive lesions were excluded. Results: Between 2013-2016 there were 812 B3 lesions available for upgrade analysis after initial diagnosis. After CNB 551 lesions had WE or VAB as follow up and after VAB 261 lesions had WE. After primary diagnosis on CNB, the total upgrade risk was 19,0%. There was histological agreement in 57,9% and no B3 lesion or upgrade was reported in 21,8%. Per B3 lesion subtype the upgrade risk to DCIS - IC after diagnosis on CNB was: ADH 17,1%-12,4%, FEA 21,1% - 18,4%, LN 18,9% -21,6%, RS 14,3% - 11,4%, and PL 7,2% - 3,2%. After initial diagnosis on VAB the total upgrade risk was 14,9%. There was histological agreement in 52,9% and no B3 lesion or upgrade was found in 31,4%. Per B3 subtype the upgrade risk to DCIS - IC after diagnosis on VAB was: ADH 17,3%- 2,7%, FEA 11,7%- 5,9%, LN 0,0% - 4,3%, PL 10,4% - 2,1%. We found no upgrade for RS. (Table 1). Conclusions: In a series of B3 lesions with a histological follow-up, we notice that overall upgrade risk is higher for lesions detected on CNB than on VAB: 19,0% vs. 14,9%. The majority of lesions showed histological agreement between initial B3 diagnosis and histological follow-up: 57,9% after CNB and 53,5% after VAB. More investigation is needed to make a proper risk assessment as to which B3 lesions can be followed with regular surveillance. Also, further prospective research is needed to get a better understanding of associated risk factors for upgrade, upgrade risk and lifetime risk of developing breast cancer after diagnosis of a B3 lesion. Table 1: Upgrade risk per B3 subtype after diagnosis on CNB or VABSubtypeNumberCNB followed by VAB or WEDCISICTotal Upgrade riskCNBNumberVAB followed by WEDCISICUpgrade riskVAB followed by WEADH10517,1%12,4%29,5%11017,3%2,7%20,0%FEA3821,1%18,4%39,5%5111,7%5,9%17,6%LN3718,9%21,6%40,5%460%4,3%4,3%PL3367,2%3,2%10,4%4810,4%2,1%12,5%RS3514,3%11,4%25,7%60%0%0%Total551261Upgrade105/55119,0%39/26114,9%B3 lesion319/55157,9%138/26152,9%No B3 lesion120/55121,8%82/26131,4%Result not available7/5511,3%2/2610,8% Citation Format: Nynke Willers, Patrick Neven, Giuseppe Floris, Cecile Colpaert, Eva Oldenburger, Sileny Han, Chantal Van Ongeval, Ann Smeets, Francois Duhoux, Hans Wildiers, Petra Denolf, Isabel De Brabander, Nancy Van Damme, Harlinde De Schutter. The upgrade risk to (pre-)invasive breast cancer for B3 lesions diagnosed on core needle or vacuum assisted biopsy. A Belgian retrospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-52.

Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with 6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N=65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p=0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients’ progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.

Background Silicone adhesive multilayer foam dressings are used as adjuvant therapy to prevent hospital-acquired pressure ulcers (PUs). Objectives To determine whether silicone foam dressings in addition to standard prevention reduce the incidence of PUs of category 2 or worse compared with standard prevention alone. Methods This was a multicentre, randomized controlled medical device trial conducted in eight Belgian hospitals. At-risk adult patients were centrally randomized (n = 1633) to study groups based on a 1 : 1 : 1 allocation: experimental groups 1 (n = 542) and 2 (n = 545) - pooled as the treatment group - and the control group (n = 546). The experimental groups received PU prevention according to hospital protocol, and a silicone foam dressing on the relevant body sites. The control group received standard of care. The primary endpoint was the incidence of a new PU of category 2 or worse at the studied body sites. Results In the intention-to-treat population (n = 1605), PUs of category 2 or worse occurred in 4·0% of patients in the treatment group and 6·3% in the control group [relative risk (RR) 0·64, 95% confidence interval (CI) 0·41-0·99, P = 0·04]. Sacral PUs were observed in 2·8% and 4·8% of the patients in the treatment group and the control group, respectively (RR 0·59, 95% CI 0·35-0·98, P = 0·04). Heel PUs occurred in 1·4% and 1·9% of patients in the treatment and control groups, respectively (RR 0·76, 95% CI 0·34-1·68, P = 0·49). Conclusions Silicone foam dressings reduce the incidence of PUs of category 2 or worse in hospitalized at-risk patients when used in addition to standard of care. The results show a decrease for the sacrum, but no statistical difference for the heel and trochanter areas.

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], 22.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, 26.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843. © 2020 by The American Society of Hematology This study was supported by Bayer AG and Janssen Research and Development.

The economic literature provides evidence thatgrowth is associated with positive performance of the financial sector. This aspect is particularly important for developing countries. This study aims to investigate whether, in an environment of growing competition and regulation, the maintenance of their social mission may have led microfinance institutions (MFIs) to compromise their performance, in terms of efficient production of credit services. To this purpose, we use a two-stage approach to analyze the relationship between outreach and efficiency of MFIs in Bangladesh. In the first stage, a dynamic data envelopment analysis is exploited to measure the efficiency of MFIs from 2009 to 2014. The results show that most of the MFIs are operationally inefficient over the period, suggesting a considerable potential for future improvement. In the second stage, the study examines the potential trade-off between MFIs’ commitment to financial inclusion and depth of outreach on the one hand and efficiency on the other hand, using a double bootstrapping methodology that helps in limiting the problems arising from the endogenous nature of the measures of outreach with respect to efficiency. The results show that financial inclusion is positively associated with MFIs’ efficiency, whereas the relationship between deepening and efficiency turns up negative, providing partial evidence in support of ‘mission drift’ in the Bangladesh microfinance industry.This may be indicative of the fact that MFIs with stronger commercial objectives have expanded their business and their margins of efficiency to compete with other intermediaries. In contrast, the MFIs with a more intense social strategy may have suffered a decrease in their operating efficiency in order to maintain their social mission. Policy implications point towards a greater degree of awareness on the part of the regulatory authorities of the consequences of imposing constraints on the operating mechanisms of the microfinance industry, such as interest rate caps. We also suggest that rules disciplining competition should not be uniform, but rather tailored to specific outreach indicators.

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Hypereosinophilia (HE) is rare but often secondary to a nonhematologic disease such as allergic disorders and parasitic infections. HE can also be associated with hematologic malignancies and be the result of a clonal proliferation or reactive to another hematologic condition. Association of HE with acute lymphoblastic leukemia (ALL) is rare in children. We reported a case of a teenager presented with HE secondary to B-ALL who experienced severe cardiac complications with severe absolute eosinophil count. We compared his clinical evolution with other published cases and we reported 2 mutations linked to B-ALL never described before in this context.

Africa is urgently in need of adequate basic infrastructure and housing, and it is one of the continents where massive construction activities are on the rise. There is a vast variety of potentially viable resources for sustainable construction on the continents, and consequently, the continent can bring innovative, greener technologies based on local sources effectively into practice. However, unlike established concrete constituents from industrialised countries in the global North, most of the innovation potentials from the African continent have not yet been the focus of intensive fundamental and applied research. This clearly limits the implementation of more sustainable local technologies. This paper presents a case for the need to first appreciate the rich diversity and versatility of the African continent which is often not realistically perceived and appreciated. It discusses specific innovation potentials and challenges for cementitious materials and concrete technology based on local materials derived from sources on the African continent. The unique African materials solutions are presented and discussed, from mineral binders over chemical admixtures and fibres to reinforcement and aggregates. Due to the pressing challenges faced by Africa, with regards to population growth and urbanisation, the focus is not only put on the technological (durability, robustness and safety) and environmental sustainability, but also strongly on socio-economic applicability, adaptability and scalability. This includes a review of alternative, traditional and vernacular construction technologies such as materials-saving structures that help reducing cementitious materials. Eventually, a strategic research roadmap is hypothesised that points out the most relevant potentials and research needs for quick implementation of more localised construction materials.

Introduction: Vaccination of pregnant women protects both women and their newborns against some infectious diseases. Thailand implemented tetanus toxoid (TT) vaccination of pregnant women in 1977, which was replaced by tetanus-diphtheria toxoid (dT) vaccination in 2005. The tetanus-diphtheria-acel lular pertussis (Tdap) vaccine has been recommended for pregnant women at 27-36 weeks of gestation since 2012 in several countries. Data on antibody responses to diphtheria toxoid (DT), TT, and Hemophilus influenzae type b (Hib) induced by combined vaccines in children born to TT-vaccinated and/or Tdapvaccinated mothers are limited. Material and methods: We investigated anti-DT, anti-TT, and anti-Hib IgG responses in a cohort of Thai children (ClinicalTrial.gov NCT02408926) born to mothers who received a TT-containing and/or the Tdap vaccine during pregnancy. Children born to Tdap-vaccinated mothers were randomized to receive either a hexavalent (Infanrix-hexa) or pentavalent (Quinvaxem) vaccine, whereas children born to TT-vaccinated mothers received only Quinvaxem vaccine at 2, 4, 6, and 18 months of age. IgG levels were evaluated at birth (cord blood), 2 (pre-primary), 7 (post-primary), 18 (pre-booster), and 19 months of age (post-booster) using a commercially available enzyme-linked immunoassay. Results: Seroprotective concentrations of anti-DT, anti-TT, and anti-Hib IgG were achieved in >90% and >99% of children following primary and booster vaccination, respectively. Among children born to Tdap-vaccinated mothers, the pentavalent vaccine induced higher levels of anti-Hib IgG than the hexavalent vaccine after primary and booster vaccination. Significantly higher anti-Hib IgG levels were observed among children receiving the pentavalent vaccine and who were born to TT-vaccinated mothers than among children receiving the pentavalent vaccine and born to Tdap-vaccinated mothers after primary and booster vaccination. Conclusions: Vaccination with a TT-containing and/or the Tdap vaccine during pregnancy did not compromise the seroprotection rate achieved following primary and booster immunization in individuals receiving either the pentavalent or hexavalent vaccine. (c) 2020 Elsevier Ltd. All rights reserved.

Aim To compare foot joint kinetics and energetics in male paediatric boys with and without blood-induced ankle joint destruction to these of matched control groups. Methods A cross-sectional study was conducted in which 3D gait analysis data were collected from thirty-five male children (6-21 years) with severe or moderate haemophilia and twenty-six typically developing boys. Structural integrity of the tarsal foot joints of all haemophilic patients was assessed using the IPSG-MRI scale. All participants walked barefoot while adopting a physiological gait pattern. Three subgroups were created based on the IPSG-MRI scores: a group with no joint involvement (HealthyHaemo), with uni- or bilaterally involvement (PathoHaemo) and with only unilaterally involvement (Haemo_Unilateral_Patho). Results The PathoHaemo group presented a significant lower Lisfranc peak dorsiflexion angular velocity (34.7°/s vs 71.4°/s, P = .000, Cohen d = 1.31) and a significantly higher Lisfranc peak plantarflexion angular velocity (-130.5°/s vs -51.8°/s, P = .000, Cohen d = 0.98) compared to the control group. The Haemo_Unilateral_Patho side had a significant higher Chopart peak dorsiflexion angular velocity compared to the Haemo_Unilateral_Healthy side (41.7°/s vs 31.9°/s, P = .002, Cohen d = 1.16). Conclusion No evidence for mild and severe gait deviations could be demonstrated. Internal moments, used as a surrogate measure of joint loading, quantified by the multi-segment foot model were found to be similar within the three subanalyses. We suggest that the ongoing musculoskeletal development in children compensates for structural damage to the ankle joint.

Nonlinear reduced-order models are being investigated for use as digital twins for advanced aircraft and spacecraft. In concept, the digital twin would be tuned to accurately describe the behavior ...

Highlights • Darunavir showed no in vitro antiviral activity against SARS-CoV-2 (EC50 > 100 μM) • Remdesivir demonstrated potent antiviral activity, confirming validity of the assay • Overall, the data do not support use of darunavir for treatment of COVID-19, Objectives Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Methods Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. Results DRV showed no activity against SARS-CoV-2 at clinically relevant concentrations (EC50 >100 μM). Remdesivir, used as a positive control, showed potent antiviral activity (EC50 = 0.38 μM). Conclusions Overall, the data do not support the use of DRV for treatment of COVID-19.

COVID-19 is a severe acute respiratory syndrome-related corona-virus SARS-CoV-2, that constitutes a pandemic threat to global public health. Unfortunately, there are no specific available therapies. This research work presents the findings of an investigation on traditional Cameroonian remedies of respiratory tract infections, malaria and viral infections, and also recipes that could serve as a baseline for the prevention, alleviate symptoms, treatment and perhaps may help for the anti-COVID-19 drugs discovery. Data on the medicinal plants were collected from traditional healers, Cameroonian medicinal plants books, the internet, and in addition to our personal experience as researchers and herbalists. Details of 85 plant species used to manage these three mentioned diseases in Cameroon and their pharmacological properties are recorded. Due to their ethnomedicinal uses and pharmacological activities, twenty-eight (28) plant species and 13 recipes are suggested for COVID-19 prevention, alleviate symptoms, treatment and baseline for anti-COVID-19 drug discovery. Amongst the proposed plants we have the following, Curcuma longa, Azadirachta indica, Zingiber officinale, Allium sativum and Ocimum gratissimum which were reported to possess certain inhibition properties against COVID-19 protease.

Background Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administratio...

To determine whether Gleason scores were concordant between prostate biopsies (bGS) and the definitive resection specimen (pGS) excised with robot-assisted radical prostatectomy (RARP); to identify clinical and pathological factors that might predict upgrading; and to evaluate how upgrading affected outcome. Between 2009 and 2016, 25 Belgian centers participated in collecting prospective data for patients that underwent RARP. We analyzed the concordance rate between the bGS and the pGS in 8021 patients with kappa statistics, and we compared concordance rates from different centers. We assessed the effect of several clinical and pathological factors on the concordance rate with logistic regression analysis. The concordance rate for the entire population was 62.9%. Upgrading from bGS to pGS occurred in 27.3% of patients. The number of biopsies was significantly associated with concordance. Older age (>60 y), a higher clinical T stage (≥cT2), a higher PSA value at the time of biopsy (>10 ng/ml), and more time between the biopsy and the radical prostatectomy were significantly associated with a higher risk of upgrading. Positive margins and PSA relapse occurred more frequently in upgraded patients. Center size did not significantly affect the concordance rate (p = 0.40).This prospective, nationwide analysis demonstrated a Gleason score concordance rate of 62.9%. Upgrading was most frequently observed in the non-concordant group. We identified clinical and pathological factors associated with (non)-concordance. Upgrading was associated with a worse oncological outcome. Center volume was not associated with pathological accuracy.

Introduction and aim The ankle joint remains vulnerable in children with haemophilia and is the primary joint affected. The purpose of this study was to dynamically characterize the segmental foot and ankle kinematics of male children, adolescents and young adults with or without ankle arthropathy. Methods The barefoot multi-segment foot kinematics of 70 ankles from 35 haemophilia subjects between 6 and 20 years old were captured with the Rizzoli Multi-Segment Foot Model. Joint damage of the tibiotalar and subtalar joints was scored using the IPSG-MRI score. The feet of patients with or without evidence of ankle arthropathy were compared with those of matched typically developing boys via a nonpaired comparison. The differences between the affected and nonaffected sides of patients with unilateral ankle arthropathy were assessed using a paired comparison. Results Subjects without arthropathy demonstrated a nonsignificant trend towards a higher frontal plane range of motion (RoM) at the midfoot upon loading response and a lower sagittal plane RoM at the midfoot during midstance. No differences were observed between the affected side group and their matched control group. The affected side of unilaterally affected subjects exhibited a nonsignificant tendency towards a higher frontal plane RoM at the ankle joint upon loading response and terminal stance compared to the healthy side. Conclusion Most patients maintained physiological rocker function of the ankle and had no (mal)adaptive motion patterns in the more distal joints of the foot. Therefore, established structural lesions may remain subclinical with respect to moderate functional activities like walking.

Objective Examine the associations of training volume and longest endurance run with (half‐)marathon performance and running‐related injuries (RRIs) in recreational runners. Materials and Methods During the preparation for and directly after the running event, 556 participants of a half marathon and 441 participants of a marathon completed three questionnaires on RRIs, average weekly training volume and the longest endurance run. With finish time, decline in pace during the running event and RRIs as dependent variables, linear and logistic regression analyses were performed to test the associations with weekly training volume and the longest endurance run. Results In half‐marathon runners, a high training volume (>32 km/wk) (β −4.19, 95% CI: −6.52;−1.85) and a long endurance run (>21 km) (β −3.87, 95% CI: −6.31;‐−1.44) were associated with a faster finish time, while a high training volume (β −1.81, 95% CI: −3.49;−0.12) and a long endurance run (β −1.89, 95% CI: −3.65;−0.12) were also related to less decline in pace. In marathon runners, a low training volume (65 km/wk) to a faster finish time (β −14.09, 95% CI: −22.47;−5.72), while a longest endurance run of

Background Low- and middle-income countries (LMICs) account for a higher burden of noncommunicable diseases (NCD) and home to a higher number of premature deaths (before age 70) from NCDs. NCDs have become an integral part of the global development agenda; hence, the scope of action on NCDs extends beyond just the health-related sustainable development goal (SDG 3). However, the organization and integration of NCD-related health services have faced several gaps in the LMIC regions such as India. Although the national NCD programme of India has been in operation for a decade, challenges remain in the integration of NCD services at primary care. In this paper, we have analysed existing gaps in the organization and integration of NCD services at primary care and suggested plausible solutions that exist. Method The identification of gaps is based out of a review of peer-reviewed articles, reports on national and global guidelines/protocols. The gaps are organized and narrated at four levels such as community, facility, health system, health policy and research, as per the WHO Innovative Care for Chronic Conditions framework (WHO ICCC). Result The review found that challenges in the identification of eligible beneficiaries, shortage and poor capacity of frontline health workers, poor functioning of community groups and poor community knowledge on NCD risk factors were key gaps at the community level. Challenges at facility level such as poor facility infrastructure, lack of provider knowledge on standards of NCD care and below par quality of care led to poor management of NCDs. At the health system level, we found, organization of care, programme management and monitoring systems were not geared up to address NCDs. Multi-sectoral collaboration and coordination were proposed at the policy level to tackle NCDs; however, gaps remained in implementation of such policies. Limited research on the effect of health promotion, prevention and, in particular, non-medical interventions on NCDs was found as a key gap at the research level. Conclusion This paper reinforces the need for an integrated comprehensive model of NCD care especially at primary health care level to address the growing burden of these diseases. This overarching review is quite relevant and useful in organizing NCD care in Indian and similar LMIC settings.

Background Gestational diabetes mellitus (GDM) is associated with an increased risk for a future type 2 diabetes mellitus in women and their children. As linkage between maternal health and non-communicable diseases, antenatal care plays a key role in the primary and secondary prevention of GDM associated adverse outcomes. While implementing a locally adapted GDM screening and management approach through antenatal care services at the primary level of care, we assessed its acceptability by the implementing health care providers. Methods As part of a larger implementation effectiveness study assessing a decentralized gestational diabetes screening and management approach in the prefecture of Marrakech and the rural district of Al Haouz in Morocco, we conducted four focus group discussions with 29 primary health care providers and seven in-depth interviews with national and regional key informants. After transcription of data, we thematically analyzed the data using a combined deductive and inductive approach. Results The intervention of screening and managing women with gestational diabetes added value to existing antenatal care services but presented an additional workload for first line health care providers. An existing lack of knowledge about gestational diabetes in the community and among private health care physicians required of public providers to spend more time on counselling women. Nurses had to adapt recommendations on diet to the socio-economic context of patients. Despite the additional task, especially nurses and midwives felt motivated by their gained capacity to detect and manage gestational diabetes, and to take decisions on treatment and follow-up. Conclusions Detection and initial management of gestational diabetes is an acceptable strategy to extend the antenatal care service offer in Morocco and to facilitate service access for affected pregnant women. Despite its additional workload, gestational diabetes management can contribute to the professional motivation of primary level health care providers. Trial registration clinicaltrials.gov; NCT02979756.

This study scrutinizes if detained girls with psychiatric disorders were at risk for future violent arrests during adolescence. A structured diagnostic interview was performed to determine the presence of various psychiatric disorders in 313 detained girls. Official juvenile arrest records were collected. With three exceptions that are in need of replication, psychiatric disorders (e.g., post-traumatic stress disorder, subtypes of conduct disorder), psychiatric disorder categories (e.g., anxiety disorders), and psychiatric comorbidity patterns were not prospectively related to future violent arrests. Our findings suggest that detained girls with psychiatric disorders should not be considered more dangerous than their counterparts without disorders, at least not during adolescence.

The Appellate Body report in EU–PET (Pakistan) raises distinct questions regarding the need for findings in relation to expired measures, the conditions under which duty drawback schemes may constitute subsidies and the causation methodology to apply under the SCM Agreement. We conclude that the report offers no clear guidance on whether the function and design of WTO dispute settlement require or preclude findings in case of expired measures. We welcome the Appellate Body's conclusion that, in case of duty drawback schemes, the financial contribution element of the subsidy is limited to the excess remission or drawback of import charges. Finally, although the Appellate Body rightly found that authorities are free to choose the methodology for the causation analysis provided that the analysis is complete and objective, the methodology used by the investigating authority in this case shows a number of deficiencies that were not recognized by the Appellate Body.