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Background The long-term impact of universal home-based testing and treatment as part of universal testing and treatment (UTT) on HIV incidence is unknown. We made projections using a detailed individual-based model of the effect of the intervention delivered in the HPTN 071 (PopART) cluster-randomised trial. Methods In this modelling study, we fitted an individual-based model to the HIV epidemic and HIV care cascade in 21 high prevalence communities in Zambia and South Africa that were part of the PopART cluster-randomised trial (intervention period Nov 1, 2013, to Dec 31, 2017). The model represents coverage of home-based testing and counselling by age and sex, delivered as part of the trial, antiretroviral therapy (ART) uptake, and any changes in national guidelines on ART eligibility. In PopART, communities were randomly assigned to one of three arms: arm A received the full PopART intervention for all individuals who tested positive for HIV, arm B received the intervention with ART provided in accordance with national guidelines, and arm C received standard of care. We fitted the model to trial data twice using Approximate Bayesian Computation, once before data unblinding and then again after data unblinding. We compared projections of intervention impact with observed effects, and for four different scenarios of UTT up to Jan 1, 2030 in the study communities. Findings Compared with standard of care, a 51% (95% credible interval 40–60) reduction in HIV incidence is projected if the trial intervention (arms A and B combined) is continued from 2020 to 2030, over and above a declining trend in HIV incidence under standard of care. Interpretation A widespread and continued commitment to UTT via home-based testing and counselling can have a substantial effect on HIV incidence in high prevalence communities. Funding National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

The HPTN 071 (PopART) trial of universal HIV testing and treatment to reduce HIV incidence was conducted in nine communities in South Africa and 12 in Zambia. The trial's primary outcome results were complicated to explain. Dissemination of these complicated results in participating communities in Zambia was done using a community dialogue approach. The approach, which involved interactive activities and a gradual and systematic approach to discussion of results in each community, facilitated respect and inclusion of participants in the dissemination process. The use of local language, pictures, images, and familiar analogies enhanced comprehension of the findings and created a two-way communication process between researchers and participants. The dialogue approach enabled both groups to use community perspectives, lived experiences, and local socio-structural features to interpret the trial results. Further, community members reflected on what the results meant to them individually and collectively. Although this community dialogue was both productive and appreciated, making this community interpretation apparent across disciplines in key quantitative scientific outputs remained a challenge.

In this qualitative study, we examined how community members of the Dutch reformed pietist community coped with the COVID-19 pandemic, and which religious sources of meaning making and resilience they used during this time of crisis. Based on seven in-depth interviews, we found that the representation of God being ‘above all things’ was prominent in times of close encounter with the coronavirus. In actively interpreting the pandemic, community members tended to stay away from concrete eschatological or ecological interpretations. Rather, the general theme of ‘malleability’ was used and linked to notions of calling and punishment. Furthermore, we identified the importance of community and scepticism towards the government as sources of resilience, whereas thinking about the future of the church was a source of fear and concern.

BackgroundTo explore whether differences between men and women in the sensitivity to (strength of the association) and/or in the exposure to determinants (prevalence) contribute to the difference in physical functioning, with women reporting more limitations.MethodsData of the Doetinchem Cohort Study was used (n = 5856, initial ages 26–70 years), with follow-up measurements every 5 years (up to 20). Physical functioning (subscale SF-36, range:0–100), sex (men or women) and a number of socio-demographic, lifestyle- and health-related determinants were assessed. Mixed-model multivariable analysis was used to investigate differences between men and women in sensitivity (interaction term with sex) and in exposure (change of the sex difference when adjusting) to determinants of physical functioning.ResultsThe physical functioning score among women was 6.55 (95%CI:5.48,7.61) points lower than among men. In general, men and women had similar determinants, but pain was more strongly associated with physical functioning (higher sensitivity), and also more prevalent among women (higher exposure). The higher exposure to low educational level and not having a paid job also contributed to the lower physical functioning score among women. In contrast, current smoking, mental health problems and a low educational level were more strongly associated with a lower physical functioning score among men and lower physical activity and higher BMI were more prevalent among men.ConclusionsAlthough important for physical functioning among both men and women, our findings provide no indications for reducing the difference in physical functioning by promoting a healthy lifestyle but stress the importance of differences in pain, work and education.

In the recent COVID-19 pandemic, a wide range of epidemiological modelling approaches were used to predict the effective reproduction number, R(t), and other COVID-19-related measures such as the daily rate of exponential growth, r(t). These candidate models use different modelling approaches or differing assumptions about spatial or age-mixing, and some capture genuine uncertainty in scientific understanding of disease dynamics. Combining estimates using appropriate statistical methodology from multiple candidate models is important to better understand the variation of these outcome measures to help inform decision-making. In this paper, we combine estimates for specific UK nations/regions using random-effects meta-analyses techniques, utilising the restricted maximum-likelihood (REML) method to estimate the heterogeneity variance parameter, and two approaches to calculate the confidence interval for the combined estimate: the standard Wald-type and the Knapp and Hartung (KNHA) method. As estimates in this setting are derived using model predictions, each with varying degrees of uncertainty, equal-weighting is favoured over the standard inverse-variance weighting to avoid potential up-weighting of models providing estimates with lower levels of uncertainty that are not fully accounting for inherent uncertainties. Both equally-weighted models using REML alone and REML+KNHA approaches were found to provide similar variation for R(t) and r(t), with both approaches providing wider, and therefore more conservative, confidence intervals around the combined estimate compared to the standard inverse-variance weighting approach. Utilising these meta-analysis techniques has allowed for statistically robust combined estimates to be calculated for key COVID-19 outcome measures. This in turn allows timely and informed decision-making based on all available information.

Contains fulltext : 251275.pdf (Publisher’s version ) (Open Access) Objective: To evaluate a pilot implementation of an organizational-level intervention. The Participatory Approach (PA) was used to create a supportive work environment for employees with chronic conditions, with a key role for occupational physicians (OPs). Methods: 28 semi-structured interviews were conducted with OPs and stakeholders within their organizations. Furthermore, observational data and research notes were gathered. Data analysis occurred through content analysis. Results: Recruitment of organizations was challenging, with a reach of 25%. Dose delivered, dose received and fidelity differed across the three organizations. Organizations were positive about the PA as a method to improve support for employees with chronic conditions. Conclusions: The PA could be of added value for creating a supportive work environment. However, research is needed on activating organizations to improve support for employees with chronic conditions. 10 p.

Contains fulltext : 282573.pdf (Publisher’s version ) (Open Access) Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 10(9) /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to

Introduction: Obstetric hemorrhage-related deaths are rare in high income countries. Yet, with increasing incidences of obstetric hemorrhage in these countries, it is of utmost importance to learn lessons from each obstetric hemorrhage-related death to improve maternity care. Our objective was to calculate the obstetric hemorrhagerelated maternal mortality ratio (MMR), assess causes of obstetric hemorrhage-related deaths, and identify lessons learned.Material and methods: Nationwide mixed-methods prospective case-series with confidential enquiries into maternal deaths due to obstetric hemorrhage in the Netherlands from January 1, 2006 to December 31, 2019.Results: The obstetric hemorrhage-related MMR in the Netherlands in 2006–2019was 0.7 per 100 000 livebirths and was not statistically significantly different compared with the previous MMR of 1.0 per 100 000 livebirths in 1993–2005 (odds ratio 0.70, 95% confidence interval 0.38–1.30). Leading underlying cause of hemorrhage was retained placenta. Early recognition of persistent bleeding, prompt involvement of a senior clinician and timely management tailored to the cause of hemorrhage with attention to coagulopathy were prominent lessons learned. Also, timely recourse to surgical interventions, including hysterectomy, in case other management options fail to stop bleeding came up as an important lesson in several obstetric hemorrhagerelated deaths.Conclusions: The obstetric hemorrhage-related MMR in the Netherlands in 2006–2019 has not substantially changed compared to the MMR of the previous enquiry in1993–2005. Although obstetric hemorrhage is commonly encountered by maternity care professionals, it is important to remain vigilant for possible adverse maternal outcomes and act upon an ongoing bleeding following birth in a more timely and adequate manner. Our confidential enquiries still led to important lessons learned with clinical advice to professionals as how to improve maternity care and avoid maternal deaths. Drawing lessons from maternal deaths should remain a qualitative and moral imperative.

Duodenal mucosal resurfacing (DMR) is a new endoscopic ablation technique aimed at improving glycemia and metabolic control in patients with type 2 diabetes mellitus (T2DM). DMR appears to improve insulin resistance, which is the root cause of T2DM, but its mechanism of action is largely unknown. Bile acids function as intestinal signaling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signaling [e.g., via fibroblast growth factor 19 (FGF19)], and are linked to metabolic health. We investigated the effect of DMR and glucagon-like peptide-1 (GLP-1) on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at the baseline and 6 mo after the DMR procedure. The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycemic and metabolic health. We found increased postprandial unconjugated bile acid responses (all P < 0.05), an overall increased secondary bile acid response (P = 0.036) and a higher 12a-hydroxylated:non-12a-hydroxylated ratio (P < 0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-a-hydroxy-4-cholesten-3-one (C4) concentrations decreased postintervention (both P < 0.01). Our study demonstrates that DMR with GLP-1 modulates the postprandial bile acid response. The alterations in postprandial bile acid responses may be the result of changes in the microbiome, ileal bile acid uptake and improved insulin sensitivity. Controlled studies are needed to elucidate the mechanism linking the combination treatment to metabolic health and bile acids. NEW & NOTEWORTHY Glycemic and metabolic improvements are seen in patients with type 2 diabetes after replacing their insulin therapy with DMR and GLP-1. These changes are accompanied by changes in postprandial bile acid concentrations: increased unconjugated and secondary bile acids.

Contains fulltext : 248292.pdf (Publisher’s version ) (Open Access) BACKGROUND: Skin microvasculature changes are crucial in psoriasis development and correlate with perfusion. The noninvasive Handheld Perfusion Imager (HAPI) examines microvascular skin perfusion in large body areas using laser speckle contrast imaging (LSCI). OBJECTIVES: To (i) assess whether increased perilesional perfusion and perfusion inhomogeneity are predictors for expansion of psoriasis lesions and (ii) assess feasibility of the HAPI system in a mounted modality. METHODS: In this interventional pilot study in adults with unstable plaque psoriasis, HAPI measurements and color photographs were performed for lesions present on one body region at week 0, 2, 4, 6 and 8. The presence of increased perilesional perfusion and perfusion inhomogeneity was determined. Clinical outcome was categorized as increased, stable or decreased lesion surface between visits. Patient feedback was collected on a 10-point scale. RESULTS: In total, 110 lesions with a median follow-up of 6 (IQR 6.0) weeks were assessed in 6 patients with unstable plaque psoriasis. Perfusion data was matched to 281 clinical outcomes after two weeks. A mixed multinomial logistic regression model revealed a predictive value of perilesional increased perfusion (OR 9.90; p

Introduction: Dementia prevalence in older women is higher than that in men. The purpose of the present study was to investigate whether there is a female disadvantage in cognitive functioning at adult age and/or whether a female disadvantage develops with age. Methods: Data of 5,135 women and 4,756 men from the Longitudinal Aging Study Amsterdam (LASA) and the Doetinchem Cohort Study (DCS) were used. In the LASA, memory, processing speed, fluid intelligence, and global cognitive function were measured every 3–4 years since 1992 in persons aged 55+ years for up to 23 years. In the DCS, memory, processing speed, cognitive flexibility, and global cognitive function were measured every 5 years since 1995 in persons aged 45+ years for up to 20 years. Sex differences in cognitive aging were analyzed using linear mixed models and also examined by the 10-year birth cohort or level of education. Results: Women had a better memory, processing speed, flexibility, and, in the DCS only, global cognitive function than men (p’s < 0.01). However, women showed up to 10% faster decline in these cognitive domains, except for flexibility, where women showed 9% slower decline. In the LASA, women scored poorer on fluid intelligence (p < 0.01), but their decline was 10% slower than that in men. Female advantage was larger in later born cohorts; adjustment for the educational level increased the female advantage. Conclusion: Women have better memory and processing speed than men at middle age. This female advantage becomes smaller with aging and has increased in more recent birth cohorts.

Background and Purpose: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. Methods: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. Results: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P =0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52–2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13–2.15]) than patients without stroke. Conclusions: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

Background For working patients with a lower socioeconomic position, health complaints often result from a combination of problems on multiple life domains. To prevent long-term health complaints and absence from work, it is crucial for general and occupational health professionals to adopt a broad perspective on health and to collaborate when necessary. This study aimed to evaluate how the ‘Grip on Health’ intervention is implemented in general and occupational health practice to address multi-domain problems and to promote interprofessional collaboration. Method A process evaluation was performed among 28 general and occupational health professionals, who were trained and implemented the Grip on Health intervention during a six-month period. The ‘Measurement Instrument for Determinants of Innovations’ was used to evaluate facilitators and barriers for implementing Grip on Health. Data included three group interviews with 17 professionals, a questionnaire and five individual interviews. Results While most health professionals were enthusiastic about the Grip on Health intervention, its implementation was hindered by contextual factors. Barriers in the socio-political context consisted of legal rules and regulations around sickness and disability, professional protocols for interprofessional collaboration, and the Covid-19 pandemic. On the organizational level, lack of consultation time was the main barrier. Facilitators were found on the level of the intervention and the health professional. For instance, professionals described how the intervention supports addressing multi-domain problems and has created awareness of work in each other’s healthcare domain. They recognized the relevance of the intervention for a broad target group and experienced benefits of its use. The intervention period was, nevertheless, too short to determine the outcomes of Grip on Health. Conclusion The Grip on Health intervention can be used to address problems on multiple life domains and to stimulate interprofessional collaboration. Visualizing multi-domain problems appeared especially helpful to guide patients with a lower socioeconomic position, and a joint training of general and occupational health professionals promoted their mutual awareness and familiarity. For a wider implementation, stakeholders on all levels, including the government and professional associations, should reflect on ways to address contextual barriers to promote a broad perspective on health as well as on collaborative work.

Background Age and comorbidities increase COVID-19 related in-hospital mortality risk, but the extent by which comorbidities mediate the impact of age remains unknown. Methods In this multicenter retrospective cohort study with data from 45 Dutch hospitals, 4806 proven COVID-19 patients hospitalized in Dutch hospitals (between February and July 2020) from the CAPACITY-COVID registry were included (age 69[58–77]years, 64% men). The primary outcome was defined as a combination of in-hospital mortality or discharge with palliative care. Logistic regression analysis was performed to analyze the associations between sex, age, and comorbidities with the primary outcome. The effect of comorbidities on the relation of age with the primary outcome was evaluated using mediation analysis. Results In-hospital COVID-19 related mortality occurred in 1108 (23%) patients, 836 (76%) were aged ≥70 years (70+). Both age 70+ and female sex were univariably associated with outcome (odds ratio [OR]4.68, 95%confidence interval [4.02–5.45], OR0.68[0.59–0.79], respectively;both pp Conclusions Age is the main determinant of COVID-19 related in-hospital mortality, with negligible mediation effect of pre-existing comorbidities. Trial registration CAPACITY-COVID (NCT04325412)

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin

Aims Patients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality. Methods and results We used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existing heart disease and in-hospital mortality. A total of 16 511 patients with COVID-19 were included (21.1% aged 66–75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male, and often had other comorbid conditions when compared with those without. Mortality was higher in patients with cardiac disease (29.7%; n = 1545 vs. 15.9%; n = 1797). However, following multivariable adjustment, this difference was not significant [adjusted risk ratio (aRR) 1.08, 95% confidence interval (CI) 1.02–1.15; P = 0.12 (corrected for multiple testing)]. Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure (aRR 1.19, 95% CI 1.10–1.30; P Conclusion Considerable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare during hospitalization.

Purpose Health problems among employees with a lower socioeconomic position (SEP) often result from an interplay of problems on multiple life domains. Contextual factors greatly affect implementation of interventions that aim to solve these type of problems. The aim of this study was to gain insight into the organizational and socio-political context for implementation of preventive interventions that consider multiple life domains among employees with a lower SEP. Methods In total 16 semi-structured interviews were conducted with stakeholders at organizational level, occupational health service (OHS) level, and at socio-political macro level. Thematic analysis was performed to identify themes that describe the perceptions of stakeholders about the impact of contextual factors on implementation. Results The following themes were identified: (1) the importance of addressing problems on multiple life domains among employees with a lower SEP, (2) unclarity of responsibilities for solving problems on multiple life domains, (3) necessity of better collaboration between occupational and curative healthcare, (4) insufficient investments in prevention by employers, (5) difficulties in early identification of employees at risk for health problems, and (6) risk of conflicting role for supervisors in addressing problems on multiple life domains. Conclusions Implementation of preventive interventions considering multiple life domains among lower SEP employees is challenging, due to various contextual factors. To improve the feasibility, many different stakeholders both in- and outside occupational health practice need to be involved, collaborate, and need to be convinced of the added value to prevent problems on multiple life domains among employees with a lower SEP.

Purpose: Magnetic resonance imaging-detected extramural venous invasion (mrEMVI) and tumor deposits (TDs) are risk factors for the development of local recurrence and distant metastases (DMs) in rectal cancer. However, little is known about their response to neoadjuvant treatment and its relation to oncologic outcomes. This study evaluated the incidence and features of mrEMVI and TDs before and after neoadjuvant treatment in relation to the development of local recurrence and DMs.Methods and Materials: Patients with cT3/4 rectal cancer without synchronous metastases who underwent surgery in a tertiary referral hospital were retrospectively analyzed. MRI scans were re-evaluated for the presence of mrEMVI, the occurrence of TDs, and response to neoadjuvant therapy (mr-vTRG).Results: In total, 277 patients were included, of whom 163 (58.8%) presented with mrEMVI. TDs were present in 56.4% of mrEMVI-positive and 9.6% of mrEMVI-negative patients (P < .001). The 5-year DM rate was significantly higher in mrEMVI-positive patients with and without TDs (45.2% and 35.9%, respectively) compared with mrEMVI-negative patients (25.7%; P = .012). After neoadjuvant treatment, the 5-year DM rate of patients with mr-vTRG 3-5 was 46.1%, whereas good responders (mr-vTRG 1-2) had a DM rate similar to mrEMVI-negative patients (25.7% and 25.7%, respectively; P = .002). The occurrence of TDs and larger mrEMVI size resulted in a lower likelihood of regression of mrEMVI.Conclusions: The prevalence of mrEMVI and TDs in cT3-4 rectal cancer is high and is associated with worsened oncologic outcomes. mrEMVI regression (mr-vTRG 1-2), which occured in 25% of the cases, leads to oncologic outcomes similar to those in patients without mrEMVI on baseline MRI. (C) 2021 The Author(s). Published by Elsevier Inc.

To assess the normal healing process of limbal–conjunctival autograft (LCA) after pterygium removal during the early postoperative period using anterior segment optical coherence tomography angiography (OCTA). Prospective case series of seven patients undergoing pterygium removal with LCA transplantation procedure, imaged with anterior segment OCTA, and anterior segment colour photos prior to the procedure and on postoperative day (POD) 1, 3, 7 and 30. Revascularization of the graft was analysed quantitatively and qualitatively to estimate patterns of blood vessel growth. Association between revascularization to graft thickness was also investigated. On POD 1, all autografts showed either minimal flow signal or no signal at all (Mean 7.1 ± 3.3%). Regrowth of blood vessels into the graft was detected on OCTA scans on POD3 (8.7 ± 3.6%) to 7 (14.3 ± 4.1%), as nonorganised vessels formation in their appearance. Blood vessels were seen growing in a centrifugal pattern towards the surrounding conjunctiva, originating from the underlying episcleral vessels. Revascularization flow signal was seen throughout nearly all graft extent on day 30 (21.6 ± 2.2%). Graft oedema was evident on the first week (Mean 611 ± 120 μm, 695 ± 84 μm, 639 ± 96 μm of POD 1, 3 and 7, respectively), reducing substantially by day 30 (300 ± 108 μm). OCTA imaging can be used to assess the LCA healing process during the early postoperative period. Revascularization occurring as early as 3–7 days post-surgery, seems to originate from the underlying episcleral vessels. Therefore, careful handling of the bare scleral surface during surgery may be prudent for achieving an adequate healing process.

Background Akkermansia muciniphila is a member of the human gut microbiota where it resides in the mucus layer and uses mucin as the sole carbon, nitrogen and energy source. A. muciniphila is the only representative of the Verrucomicrobia phylum in the human gut. However, A. muciniphila 16S rRNA gene sequences have also been found in the intestines of many vertebrates. Results We detected A. muciniphila-like bacteria in the intestines of animals belonging to 15 out of 16 mammalian orders. In addition, other species belonging to the Verrucomicrobia phylum were detected in fecal samples. We isolated 10 new A. muciniphila strains from the feces of chimpanzee, siamang, mouse, pig, reindeer, horse and elephant. The physiology and genome of these strains were highly similar in comparison to the type strain A. muciniphila MucT. Overall, the genomes of the new strains showed high average nucleotide identity (93.9 to 99.7%). In these genomes, we detected considerable conservation of at least 75 of the 78 mucin degradation genes that were previously detected in the genome of the type strain MucT. Conclusions The low genomic divergence observed in the new strains may indicate that A. muciniphila favors mucosal colonization independent of the differences in hosts. In addition, the conserved mucus degradation capability points towards a similar beneficial role of the new strains in regulating host metabolic health.

Introduction: The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics. Methods: All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was per -formed based on the aforementioned characteristics. Results: Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013). Conclusion: Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prog-nostically poor characteristics. (c) 2021 Elsevier Ltd, BASO -The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Mutant Peptide eXtractor and Informer (MuPeXI), by Bjerregaard et al. (Cancer Immunol Immunother CII 66:1123-1130, 2017), is a program which identifies tumor-specific peptides and assesses their potential to be neoepitopes. MuPeXI takes as input a VCF file and a list of human leukocyte antigen (HLA) types and optionally a gene expression profile to assess a peptide's potential to be a neoepitope. MuPeXI can be downloaded and run both locally and on a web server. Here, we describe a pipeline for processing the input data so that it can be used for MuPeXI and how to run MuPeXI both locally and as a web server.

ObjectivesThe aim of this study was to develop an index to measure older adults’ exposure to the COVID-19 pandemic and to study its association with various domains of functioning.DesignCross-sectional study.SettingThe Longitudinal Aging Study Amsterdam (LASA), a cohort study in the Netherlands.ParticipantsCommunity-dwelling older adults aged 62–102 years (n=1089) who participated in the LASA COVID-19 study (June–September 2020), just after the first wave of the pandemic.Primary outcome measuresA 35-item COVID-19 exposure index with a score ranging between 0 and 1 was developed, including items that assess the extent to which the COVID-19 situation affected daily lives of older adults. Descriptive characteristics of the index were studied, stratified by several sociodemographic factors. Logistic regression analyses were performed to study associations between the exposure index and several indicators of functioning (functional limitations, anxiety, depression and loneliness).ResultsThe mean COVID-19 exposure index score was 0.20 (SD 0.10). Scores were relatively high among women and in the southern region of the Netherlands. In models adjusted for sociodemographic factors and prepandemic functioning (2018–2019), those with scores in the highest tertile of the exposure index were more likely to report functional limitations (OR: 2.24; 95% CI: 1.48 to 3.38), anxiety symptoms (OR: 3.14; 95% CI: 1.82 to 5.44), depressive symptoms (OR: 2.49; 95% CI: 1.55 to 4.00) and loneliness (OR: 2.97; 95% CI: 2.08 to 4.26) than those in the lowest tertile.ConclusionsAmong older adults in the Netherlands, higher exposure to the COVID-19 pandemic was associated with worse functioning in the physical, mental and social domain. The newly developed exposure index may be used to identify persons for whom targeted interventions are needed to maintain or improve functioning during the pandemic or postpandemic.

A substantial number of patients report persisting symptoms after a COVID-19 infection: so-called post-COVID-19 syndrome. There is limited research on patients’ perspectives on post-COVID-19 symptoms and ways to recover. This qualitative study explored the illness perceptions and recovery strategies of patients who had been hospitalised for COVID-19. Differences between recovered and non-recovered patients were investigated. Semi-structured in-depth interviews were held with 24 participating patients (8 recovered and 16 non-recovered) 7 to 12 months after hospital discharge. Data were interpreted using reflexive thematic analysis. Four overarching themes were identified: (I) symptoms after hospital discharge; (II) impact of COVID-19 on daily life and self-identity; (III) uncertainty about COVID-19; and (IV) dealing with COVID-19. Formerly hospitalised post-COVID-19 patients seem to have difficulties with making sense of their illness and gaining control over their recovery. The majority of non-recovered participants continue to suffer mostly from weakness or fatigue, dyspnoea and cognitive dysfunction. No notable differences in illness beliefs were observed between recovered and non-recovered participants

Background The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. Methods This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. Discussion This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. Trial registration Clinicaltrials.gov: NCT04838496, registered on 02–04-2021 Netherlands Trial Register: NL9790. Protocol version Version 3 dd 11–4-2022.

Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype-phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are beta-thalassemia carriers presenting with features of beta-thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated alpha-globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haplo-insufficiency of a non-linked gene SUPT5H on chromosome 19q, first described in two Dutch families with beta-thalassemia trait without variants in the HBB gene.

Background: Colchicine reduces risk of cardiovascular events in patients post–myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). Objectives: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. Methods: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. Results: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). Conclusions: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684)

Background and Aims Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt–FGF19 axis. Approach and Results Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7‐α‐hydroxy‐4‐cholesten‐3‐one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up‐regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course. Conclusions CR in patients with IF‐TDE restored bile salt–FGF19 signaling and improved gut–liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt–FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.

The aim of the current study was to compare cancellations or postponement of medical care among older adults during the COVID-19 pandemic between 2021 and 2020.Data of respondents aged ≥ 62 years were used from the longitudinal aging study Amsterdam (LASA), collected in 2020 and 2021, directly after the main COVID-19 waves in the Netherlands. A questionnaire assessed cancellations of medical care and postponed help-seeking behavior. Descriptive analyses were performed.Overall, cancellations declined from 35% in 2020 (sample n = 1128) to 17% in 2021 (sample n = 1020). Healthcare-initiated cancellations declined from 29 to 8%. Respondent-initiated cancellations declined from 12 to 7%. Postponed help-seeking remained around 8%.In 2021, less cancellations were reported compared to just after the first wave of the pandemic in 2020, while postponed help-seeking remained the same. It is important to investigate how cancellations and postponed help-seeking can be prevented in future pandemics.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909–2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3–4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53–2·33; p

PURPOSE: The PopART for Youth (P-ART-Y) study was nested within the HPTN 071 (PopART) trial, a three-arm community randomized trial in 21 communities in Zambia and South Africa. The P-ART-Y study evaluated the acceptability and uptake of a combination HIV prevention package among young people. We report on the HIV care cascade for adolescents aged 10-19 years from 14 communities receiving the full HIV prevention package in Zambia and South Africa. METHODS: Adolescents were offered participation in the PopART intervention, which included universal home-based HIV testing, linkage to care, antiretroviral therapy (ART) adherence, and other services. Data were collected from September 2016 to December 2017, covering the third round (R3) of the intervention. RESULTS: We enumerated (listed) 128,241 adolescents (Zambia: 95,295 and South Africa: 32,946). Of the adolescents offered HIV testing, 81.9% accepted in Zambia and 70.3% in South Africa. Knowledge of HIV status was higher among older adolescents and increased from 31.4% before R3 to 88.3% at the end of R3 in Zambia and from 28.3% to 79.5% in South Africa. Overall, there were 1,710 (1.9%) adolescents identified as living with HIV by the end of R3 (515 new diagnoses and 1,195 self-reported). Of the new diagnoses, 335 (65.0%) were girls aged 15-19 years. The median time to initiate ART was 5 months. ART coverage before and after R3 increased from 61.3% to 78.7% in Zambia and from 65.6% to 87.8% in South Africa, with boys having higher uptake than girls in both countries. CONCLUSIONS: The PopART intervention substantially increased coverage toward the first and second UNAIDS 90-90-90 targets in adolescents.

Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34+ hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141+CLEG9A+ cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients.

Background & aims: To investigate the acute effects of intravenous vs enteral meal administration on circulating bile acid and gut hormone responses.Methods: In a randomized crossover design, we compared the effects of duodenal (via a nasoduodenal tube) vs parenteral (intravenous) administration over 180 min of identical mixed meals on circulating bile acid and gut hormone concentrations in eight healthy lean men. We analysed the bile acid and gut hormone responses in two periods: the intraprandial period from time point (T) 0 until T180 during meal administration and the postprandial period from T180 until T360, after discontinuation of meal administration.Results: Intravenous meal administration decreased the intraprandial (AUC (mmol/L*min) duodenal 1469 +/- 284 vs intravenous 240 +/- 39, p < 0.01) and postprandial bile acid response (985 +/- 240 vs 223 +/- 5, p < 0.05) and was accompanied by decreased gut hormone responses including glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, glucagon-like peptide 2 and fibroblast growth factor 19. Furthermore, intravenous meal administration elicited greater glucose concentrations, but similar insulin concentrations compared to enteral administration.Conclusions: Compared to enteral administration, parenteral nutrition results in lower postprandial bile acid and gut hormone responses in healthy lean men. This was accompanied by higher glucose concentrations in the face of similar insulin concentrations exposing a clear incretin effect of enteral mixed meal administration. The alterations in bile acid homeostasis were apparent after only one intravenous meal. (C) 2020 The Authors. Published by Elsevier Ltd.

BackgroundCarcinoembryonic antigen is overexpressed in colorectal cancer (CRC), making it an optimal target for fluorescence imaging. A phase I/II study was designed to determine the optimal imaging dose of SGM-101 for intraoperative fluorescence imaging of primary and recurrent CRC.MethodsPatients were included and received a single dose of SGM-101 at least 24 h before surgery. Patients who received routine anticancer therapy (i.e., radiotherapy or chemotherapy) also were eligible. A dedicated near-infrared imaging system was used for real-time fluorescence imaging during surgery. Safety assessments were performed and SGM-101 efficacy was evaluated per dose level to determine the most optimal imaging dose.ResultsThirty-seven patients with CRC were included in the analysis. Fluorescence was visible in all primary and recurrent tumors. In seven patients, no fluorescence was seen; all were confirmed as pathological complete responses after neoadjuvant therapy. Two tumors showed false-positive fluorescence. In the 37 patients, a total of 97 lesions were excised. The highest mean intraoperative tumor-to-background ratio (TBR) of 1.9 (p = 0.019) was seen in the 10-mg dose. This dose showed a sensitivity of 96%, specificity of 63%, and negative predictive value of 94%. Nine patients (24%) had a surgical plan alteration based on fluorescence, with additional malignant lesions detected in six patients.ConclusionsThe optimal imaging dose was established at 10 mg 4 days before surgery. The results accentuate the potential of SGM-101 and designated a promising base for the multinational phase III study, which enrolled the first patients in June 2019.

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Background In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes. Methods Patients with low cT3–4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response. Results More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P Conclusion Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes. Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.

Introduction: Transdermal analysis patches (TAPs) noninvasively measure soluble proteins in the stratum corneum. Ultimately, such local protein profiles could benefit the search for biomarkers to improve personalized treatment in psoriasis. This study aimed to explore the patient friendliness and protein detection by TAP in pediatric psoriasis in daily clinical practice. Methods: In this observational study, TAPs measuring CXC chemokine ligand (CXCL)-1/2, CC chemokine ligand (CCL)-27, interleukin (IL)-1RA, IL-23, IL-1α, IL-8, IL-4, IL-22, IL-17A, vascular endothelial growth factor (VEGF), human beta-defensin (hBD)-2, hBD-1, and kallikrein-related peptidase (KLK)-5 were applied on lesional, peri-lesional, and non-lesional skin sites of psoriasis patients aged >5 to Results: Thirty-two patients (median age 14.0 years) were included, of which 19 were treated with solely topical agents and 13 with systemic treatment. The median VAS of discomfort during TAP removal was 1.0 (interquartile range 1.0). Significantly higher levels in lesional versus non-lesional skin were found for IL-1RA, VEGF, CXCL-1/2, hBD-2, and IL-8, whereas lower levels were found for IL-1α. Skin surface proteins were measured in both treatment groups, with significant higher lesional levels of KLK-5, IL-1RA, hBD-2, IL-1α, IL-23, and CCL-27 in the systemic treatment group. Conclusion: The TAP platform holds the potential for patient-friendly and noninvasive monitoring of skin-derived proteins in pediatric psoriasis patients in daily clinical practice.

BackgroundPandemics, even more than other medical problems, require swift integration of knowledge. When caused by a new virus, understanding the underlying biology may help finding solutions. In a setting where there are a large number of loosely related projects and initiatives, we need common ground, also known as a “commons.” Wikidata, a public knowledge graph aligned with Wikipedia, is such a commons and uses unique identifiers to link knowledge in other knowledge bases. However, Wikidata may not always have the right schema for the urgent questions. In this paper, we address this problem by showing how a data schema required for the integration can be modeled with entity schemas represented by Shape Expressions.ResultsAs a telling example, we describe the process of aligning resources on the genomes and proteomes of the SARS-CoV-2 virus and related viruses as well as how Shape Expressions can be defined for Wikidata to model the knowledge, helping others studying the SARS-CoV-2 pandemic. How this model can be used to make data between various resources interoperable is demonstrated by integrating data from NCBI (National Center for Biotechnology Information) Taxonomy, NCBI Genes, UniProt, and WikiPathways. Based on that model, a set of automated applications or bots were written for regular updates of these sources in Wikidata and added to a platform for automatically running these updates.ConclusionsAlthough this workflow is developed and applied in the context of the COVID-19 pandemic, to demonstrate its broader applicability it was also applied to other human coronaviruses (MERS, SARS, human coronavirus NL63, human coronavirus 229E, human coronavirus HKU1, human coronavirus OC4).

Background Following the World Health Organization’s (WHO) 2015 guidelines recommending initiation of antiretroviral therapy (ART) irrespective of CD4 count for all people living with HIV (PLHIV), many countries in sub-Saharan Africa have adopted this strategy to reach epidemic control. As the number of PLHIV on ART rises, maintenance of viral suppression on ART for over 90% of PLHIV remains a challenge to government health systems in resource-limited high HIV burden settings. Non facility-based antiretroviral therapy (ART) delivery for stable HIV+ patients may increase sustainable ART coverage in resource-limited settings. Within the HPTN 071 (PopART) trial, two models, home-based delivery (HBD) or adherence clubs (AC), were offered to assess whether they achieved similar viral load suppression (VLS) to standard of care (SoC). In this paper, we describe the trial design and discuss the methodological issues and challenges. Methods A three-arm cluster randomized non-inferiority trial, nested in two urban HPTN 071 trial communities in Zambia, randomly allocated 104 zones to SoC (35), HBD (35), or AC (34). ART and adherence support were delivered 3-monthly at home (HBD), adherence clubs (AC), or clinic (SoC). Adult HIV+ patients defined as “stable” on ART were eligible for inclusion. The primary endpoint was the proportion of PLHIV with virological suppression (≤ 1000 copies HIV RNA/ml) at 12 months (± 3months) after study entry across all three arms. Viral load measurement was done at the routine government laboratories in accordance with national guidelines, annually. The study was powered to determine if either of the community-based interventions would yield a viral suppression rate drop compared to SoC of no more than 5% in its absolute value. Both community-based interventions were delivered by community HIV providers (CHiPs). An additional qualitative study using observations, interviews with PLHIV, and FGDs with community HIV providers was nested in this study to complement the quantitative data. Discussion This trial was designed to provide rigorous randomized evidence of safety and efficacy of non-facility-based delivery of ART for stable PLHIV in high-burden resource-limited settings. This trial will inform policy regarding best practices and what is needed to strengthen scale-up of differentiated models of ART delivery in resource-limited settings. Trial registration ClinicalTrials.gov NCT03025165. Registered on 19 January 2017

BackgroundA one-stop shop for disaster response services provides a central location for information and advice in an accessible way. Yet little is known about its organization and outcomes. After the MH17 airplane crash, the one-stop shop concept was realized through a digital environment called the Information and Referral Center (IRC). The aim of this study was to evaluate the experiences of users and providers in regard to the IRC and to identify improvement points for future IRCs.MethodData was collected among affected ones as well as involved organizations, using interviews, focus groups, surveys and online user information. Existing evaluation and quality models were combined to design the study and analyze the data.ResultsFirst, affected ones and a variety of organizations involved were positive about the merits of the IRC. Affected ones indicated they perceived the IRC as a reliable source of information and appreciated the referral possibilities. Second, the feature of the IRC to serve as a community where affected ones could meet, share experiences and support each other was hardly used according to participants. Lastly, tracking evolving psychosocial needs and problems through the IRC was hampered due to difficulty in accessing relevant data.ConclusionsThe IRC helped organizations to structure and align their services. Affected ones were positive about its reliability and accessibility. An IRC has to be embedded within the established care structures. Future research could indicate whether an IRC is useful in other event types and population contexts as well.

BACKGROUND: We nested a seroprevalence survey within the TREATS (Tuberculosis Reduction through Expanded Antiretroviral Treatment and Screening) project. We aimed to measure the seroprevalence of SARS-CoV-2 infection and investigate associated risk factors in one community (population ∼27,000) with high prevalence of TB/HIV in Zambia. METHODS: The study design was cross-sectional. A random sample of 3592 individuals aged ≥15 years enrolled in the TREATS TB-prevalence survey were selected for antibody testing. Randomly selected blocks of residence were visited between October 2020 and March 2021. Antibodies against SARS-CoV-2 were detected using Abbott- ARCHITECT SARS-CoV-2 IgG assay. RESULTS: A total of 3035/3526 (86.1%) individuals had a blood sample taken. Antibody testing results were available for 2917/3035 (96.1%) participants. Overall, 401/2977 (13.5%) individuals tested positive for IgG antibodies. Seroprevalence was similar by sex (12.7% men vs 14.0% women) and was lowest in the youngest age group 15-19 years (9.7%) and similar in ages 20 years and older (∼15%). We found no evidence of an association between seroprevalence and HIV-status or TB. There was strong evidence (p

BackgroundPrevious phylogeographic studies of the lion (Panthera leo) have improved our insight into the distribution of genetic variation, as well as a revised taxonomy which now recognizes a northern (Panthera leo leo) and a southern (Panthera leo melanochaita) subspecies. However, existing whole range phylogeographic studies on lions either consist of very limited numbers of samples, or are focused on mitochondrial DNA and/or a limited set of microsatellites. The geographic extent of genetic lineages and their phylogenetic relationships remain uncertain, clouded by massive sampling gaps, sex-biased dispersal and incomplete lineage sorting.ResultsIn this study we present results of low depth whole genome sequencing and subsequent variant calling in ten lions sampled throughout the geographic range, resulting in the discovery of >150,000 Single Nucleotide Polymorphisms (SNPs). Phylogenetic analyses revealed the same basal split between northern and southern populations, as well as four population clusters on a more local scale. Further, we designed a SNP panel, including 125 autosomal and 14 mitochondrial SNPs, which was tested on >200 lions from across their range. Results allow us to assign individuals to one of these four major clades (West & Central Africa, India, East Africa, or Southern Africa) and delineate these clades in more detail.ConclusionsThe results presented here, particularly the validated SNP panel, have important applications, not only for studying populations on a local geographic scale, but also for tracing samples of unknown origin for forensic purposes, and for guiding conservation management of ex situ populations. Thus, these genomic resources not only contribute to our understanding of the evolutionary history of the lion, but may also play a crucial role in conservation efforts aimed at protecting the species in its full diversity.

Religious coping can be seen as a method which applies religious resources, including prayer, and trust and appeals to God, in order to deal with stressful situations.To gain insight into the associations between religious coping styles and mental health and to investigate whether the use of the coping styles differs between mental health care clients and non-mental health care clients with a Christian background.The sample consisted of 655 Dutch participants with a Christian worldview, aged 18 to 79 years (M = 42.6, SD = 14.2). 60.9% were female and 49.5% higher educated. Intra- and extramural clients in mental health care were involved. A cross-sectional, online survey was used, combined with an available client database.More use of the collaborative coping style was associated with less psychological complaints. More use of the (passive-)deferring and selfdirecting coping styles was associated with more psychological complaints. Christian mental health care clients used the collaborative and the deferring coping styles less often compared to Christian non-clients.The collaborative religious coping style is positively associated with mental health. Mental health care clients amongst them use this style less often compared to non-clients. Awareness of religious coping styles and appropriate support are indicated.

Introduction: To calculate the maternal mortality ratio (MMR) for 2006-2018 in the Netherlands and compare this with 1993-2005, and to describe women's characteristics, causes of death and improvable factors. Material and Methods: We performed a nationwide, cohort study of all maternal deaths between January 1, 2006 and December 31, 2018 reported to the Audit Committee Maternal Mortality and Morbidity. Main outcome measures were the national MMR and causes of death. Results: Overall MMR was 6.2 per 100 000 live births, a decrease from 12.1 in 1993-2005 (risk ratio [RR] 0.5). Women with a non-western ethnic background had an increased MMR compared with Dutch women (MMR 6.5 vs. 5.0, RR 1.3). The MMR was increased among women with a background from Surinam/Dutch Antilles (MMR 14.7, RR 2.9). Half of all women had an uncomplicated medical history (79/161, 49.1%). Of 171 pregnancy-related deaths within 1 year postpartum, 102 (60%) had a direct and 69 (40%) an indirect cause of death. Leading causes within 42 days postpartum were cardiac disease (n = 21, 14.9%), hypertensive disorders (n = 20, 14.2%) and thrombosis (n = 19, 13.5%). Up to 1 year postpartum, the most common cause of death was cardiac disease (n = 32, 18.7%). Improvable care factors were identified in 76 (47.5%) of all deaths. Conclusions: Maternal mortality halved in 2006-2018 compared with 1993-2005. Cardiac disease became the main cause. In almost half of all deaths, improvable factors were identified and women with a background from Surinam/Dutch Antilles had a threefold increased risk of death compared with Dutch women without a background of migration.

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30–39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955.

Background Across Sub-Saharan Africa, adolescents and young people (AYP) aged 15-24 have limited access to sexual and reproductive health (SRH) services, including HIV testing services (HTS). In response, the Yathu Yathu study was implemented in two high-density communities in Lusaka, Zambia. Yathu Yathu provides comprehensive, community-based, peer-led SRH services, including differentiated HTS (finger-prick and HIV self-testing) and comprehensive sexuality education (CSE). We describe adaptations to the Yathu Yathu intervention in response to the COVID-19 epidemic, and implications on uptake of HTS among AYP. Methods Yathu Yathu provides SRH services through community-based peer-led spaces. AYP in study communities were offered prevention points cards (PPC), which incentivizes and tracks service use. Social media (WhatsApp©/Facebook©) is used to engage and inform AYP about SRH. Due to COVID-19, hubs closed from April-June 2020. We describe adaptations in response to COVID-19 and, using routinely collected PPC data, describe uptake of HTS before (September 2019-March 2020) and after (July-December 2020) adaptations in response to COVID-19. We describe reach of the Yathu Yathu Facebook page and use qualitative data to describe AYP experiences of SRH service access. Results During hub closures, CSE was delivered via video on social media, resulting in an increase in Facebook page followers from 539(April) to 891(June). WhatsApp groups evolved as a platform to deliver CSE and COVID-19 information, with higher participation among young people aged 20-24. Key service delivery adaptations included: reducing the number of participants in hubs, mandatory handwashing before entry, use of personal protective equipment by staff and provision of facemasks to AYP. HTS were provided as normal. Adaptations led to fewer AYP attending hubs. Uptake of HTS among AYP visiting hubs for the first time after COVID-19-related closures was higher (73.2%) compared to uptake before adaptations (65.9%; adjOR=1.24 95%CI 0.99, 1.56, p=0.06). Despite disappointments with some aspects of service delivery, AYP expressed happiness that hubs had reopened. Conclusions Social media can be a useful additional platform to reach AYP with HIV prevention information during COVID-19. With proper infection control in place, HTS can safely be provided to, accessed and accepted by AYP in community-based settings during COVID-19. Trial Registration National Clinical Trials NCT04060420,19th August 2019. Current Controlled Trials ISRCTN75609016, 14th September 2021, retrospectively registered.

Background Access to affordable and effective menstrual hygiene products (MHP) is critical to the menstrual health of adolescent girls and young women (AGYW). In this mixed-methods analysis, we use data from a programme delivering comprehensive sexual and reproductive health (SRH) services to describe access to MHP and how COVID-19-related closures affected access to MHP; we use qualitative data to understand AGYW’s experience accessing products during the study. Methods Between September 2019-January 2021, we used data routinely collected from ten Yathu Yathu hubs offering community-based, peer-led SRH services to adolescents and young people aged 15–24. Hubs offered free MHP (primarily disposable pads) as a service. To incentivise service access, a “loyalty” card system was embedded within Yathu Yathu, allowing individuals to gain points for services accessed and redeem rewards using these points. Branded pads, tampons and reusable pads were among available rewards. We describe access to service pads and to reward MHP, and use logistic regression to investigate factors associated with accessing pads and reward products before (Sept 2019-March 2020) and after (July 2020-Jan 2021) COVID-19-related closures. Focus group discussions explored accessibility of offering MHP through hubs. Results Between September 2019-January 2021, 6374 AGYW made 34,116 hub visits to access an SRH service and/or redeem a reward. At 30% of these visits, AGYW accessed any MHP. Before COVID19-closures, an average of 17% of monthly visits were for freely-available disposable pads compared to 34% after hubs reopened (p Conclusion Availability of MHP through Yathu Yathu provided a large number of AGYW with access to these products. Hubs seemed particularly important for adolescent girls. Community-based, peer-led hubs should be considered as spaces to provide AGYW access to affordable and effective MHP.

BACKGROUND: Localized-type tenosynovial giant cell tumor (TGCT) is a rare, neoplastic disease with only limited data supporting treatment protocols. We describe treatment protocols and evaluate their oncological outcome, complications, and functional results in a large multicenter cohort of patients. A secondary study aim was to identify factors associated with local recurrence after surgical treatment.METHODS: Patients with histologically proven localized TGCT of a large joint were included if they had been treated between 1990 and 2017 in 1 of 31 tertiary sarcoma centers. Of 941 patients with localized TGCT, 62% were female. The median age at initial treatment was 39 years, and the median duration of follow-up was 34 months. Sixty-seven percent of the tumors affected the knee, and the primary treatment at the tertiary center was 1-stage open resection in 73% of the patients. Proposed factors for predicting a first local recurrence after treatment in the tertiary center were tested in a univariate analysis, and those that demonstrated significance were subsequently included in a multivariate analysis.RESULTS: The localized TGCT recurred in 12% of all cases, with local-recurrence-free rates at 3, 5, and 10 years of 88%, 83%, and 79%, respectively. The strongest factor for predicting recurrent disease was a prior recurrence (p < 0.001). Surgical treatment decreased pain and swelling in 71% and 85% of the patients, respectively, and such treatment was associated with complications in 4% of the patients. Univariate and multivariate analyses of the patients who had not undergone therapy previously yielded positive associations between local recurrence and a tumor size of ≥5 cm versus CONCLUSIONS: Factors associated with recurrence after resection of localized-type TGCT were larger tumor size and initial treatment with arthroscopy. Relatively low complication rates and good functional outcomes warrant an open approach with complete resection when possible to reduce recurrence rates in high-risk patients.LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.