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Disparities in cardiovascular outcomes between Aboriginal and Torres Strait Islander Australians and non-Indigenous Australians persist. This has previously been attributed to a combination of differences in burden of cardiovascular disease risk factors, and inpatient access to guideline-recommended care.To assess differences in inpatient access to guideline-recommended acute coronary syndrome (GR-ACS) treatment between Aboriginal and Torres Strait Islander and non-indigenous patients admitted to Royal Darwin Hospital (RDH) with index ACS event.This retrospective study included index ACS admissions (n = 288) to RDH between January 2016 and June 2017. Outcomes included rates of coronary angiography, percutaneous coronary intervention (PCI), surgical revascularisation, GR-ACS medications prescribed on discharge and short-term outcomes (30-day mortality and ACS readmissions; 12-month all cardiac-related readmissions).Two hundred and eighty-eight patients, including 109 (37.85%) Aboriginal and Torres Strait Islander patients, were included. Compared with non-indigenous patients, they were younger (median age 48 years vs 60 years; P 0.01), with a greater burden of comorbidities, including diabetes (39% vs 19%; P 0.01), smoking (68% vs 35%; P 0.01) and chronic kidney disease (29% vs 5%; P 0.01). There were no differences in rates of coronary angiography (98% vs 96%; P = 0.24) or PCI (47% vs 57%; P = 0.12), although there was a trend towards surgical revascularisation in Aboriginal and Torres Strait Islander patients (16% vs 8%; P = 0.047). There were no differences in 30-day mortality (1.8% vs 1.7%; P = 0.72), 12-month ACS readmissions (7% vs 4%; P = 0.20) or 12-month cardiac-related readmissions (7% vs 13%; P = 0.11).Aboriginal and Torres Strait Islander patients received similar inpatient ACS care and secondary prevention medication at discharge, with similar short-term mortality outcomes as non-indigenous patients. While encouraging, these outcomes may not persist long term. Further outcomes research is required, with differences compelling consideration of other primary and secondary prevention contributors.

Background: Major depression is found in around ten percent of patients attending cancer clinics. One of the symptoms of major depression, defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), is ‘thoughts of death or suicide’. In order to implement depression screening programs for patients with cancer, we need to know the prevalence not only of this broadly defined symptom, but also of more specific suicidal thoughts, as only the latter clearly indicates the need for specialist psychiatric assessment and management of suicide risk. Methods: We analyzed data from a routine two-stage depression screening program that operated in three UK cancer centers, linked with demographic and clinical data obtained from a national cancer registry. We included data on 2,217 patients with common cancers and comorbid, interview-diagnosed, major depression. We determined the percentage of patients with: (a) the DSM-IV symptom ‘thoughts of death or suicide’ and (b) suicidal thoughts, defined as an affirmative response to the question ‘have you had thoughts of ending your life?’ We investigated the associations of patients’ demographic and clinical characteristics with each of these using logistic regression models. Results: We found that 29% (641/2,217) of patients had the DSM symptom ‘thoughts of death or suicide’ and 9% (207/2,217) had suicidal thoughts. Of the demographic and clinical characteristics that we studied, none had statistically significant associations with having the DSM symptom. Only younger age and primary cancer were associated with having suicidal thoughts. Conclusions: We found that almost one third of patients with cancer and comorbid major depression, have the DSM symptom ‘thoughts of death or suicide’. However, only a third of the patients with this symptom report suicidal thoughts. These findings suggest that around one in ten patients found by a screening program to have major depression will have suicidal thoughts requiring a psychiatric assessment. The staffing of depression screening programs should be designed with these data in mind.

Objective The purpose of this study was to assess the ability of intraspinal microstimulation, triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury. Approach Experiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. Four weeks after SCI, and under ketamine/xylazine anesthesia, fine wire electromyographic (EMG) electrodes were implanted into four muscles of the right hindlimb. After exposure of the left motor cortex hindlimb area and laminectomy of the T13-L1 vertebrae, intracortical microstimulation (ICMS) and intraspinal microstimulation (ISMS) were used to determine the location of evoked hip movements in cortex and spinal cord, respectively. For activity-dependent stimulation sessions, a single shank, 16-channel, recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. Spinal cord injured rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Activity-dependent stimulation sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using ICMS to examine the number of spikes evoked in spinal cord neurons during five minute test bouts. Evoked spikes were recorded, sorted, and displayed in post-stimulus spike histograms in 1-ms bins. Post-stimulus spike histograms and EMG recordings were characterized using stimulus triggered averaging techniques. Main results The results showed that activity-dependent stimulation resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord, including the ventral horn, in the vicinity of motor neurons. Changes were evident in some conditions as early as 1 hour after conditioning. EMG responses were never evoked with ICMS pre-or post-conditioning. Significance These results show that after a spinal cord contusion injury, activity-dependent stimulation, consisting of cortical spike-driven ISMS, can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This suggests that activity-dependent stimulation may serve as an effective therapeutic approach for enhancing descending motor control after spinal cord injury.

Background: Echocardiography is the diagnostic modality for assessing cardiac systolic and diastolic function to diagnose and manage heart failure. However, manual interpretation of echocardiograms can be time consuming and subject to human error. Therefore, we developed a fully automated deep learning workflow to classify, segment, and annotate two-dimensional (2D) videos and Doppler modalities in echocardiograms. Methods: We developed the workflow using a training dataset of 1145 echocardiograms and an internal test set of 406 echocardiograms from the prospective heart failure research platform (Asian Network for Translational Research and Cardiovascular Trials; ATTRaCT) in Asia, with previous manual tracings by expert sonographers. We validated the workflow against manual measurements in a curated dataset from Canada (Alberta Heart Failure Etiology and Analysis Research Team; HEART; n=1029 echocardiograms), a real-world dataset from Taiwan (n=31 241), the US-based EchoNet-Dynamic dataset (n=10 030), and in an independent prospective assessment of the Asian (ATTRaCT) and Canadian (Alberta HEART) datasets (n=142) with repeated independent measurements by two expert sonographers. Findings: In the ATTRaCT test set, the automated workflow classified 2D videos and Doppler modalities with accuracies (number of correct predictions divided by the total number of predictions) ranging from 0·91 to 0·99. Segmentations of the left ventricle and left atrium were accurate, with a mean Dice similarity coefficient greater than 93% for all. In the external datasets (n=1029 to 10 030 echocardiograms used as input), automated measurements showed good agreement with locally measured values, with a mean absolute error range of 9–25 mL for left ventricular volumes, 6–10% for left ventricular ejection fraction (LVEF), and 1·8–2·2 for the ratio of the mitral inflow E wave to the tissue Doppler e' wave (E/e' ratio); and reliably classified systolic dysfunction (LVEF

The role of PET and integrated PET-CT in the diagnostic workup of suspected malignant pleural effusions is unknown. Earlier systematic reviews (published 2014 and 2015) both included pleural pathology without effusion, and reached contradictory conclusions. Five studies have been published since the latest review. This systematic review and meta-analysis aims to summarise the evidence of PET and integrated PET-CT in predicting pleural malignancy in patients suspected of having malignant pleural effusions. A meta-analysis based on a systematic literature search in Cochrane Library, Medline, EMBASE and Clinicaltrials.gov was performed. Diagnostic studies evaluating the performance of PET or PET-CT in patients with suspected malignant pleural effusion, using pleural fluid cytology or histopathology as the reference test, and presenting sufficient data for constructing a 2x2 table were included. The quality of the studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 score. Subgroup analyses on image modality, interpretation method and known malignancy status pre index-test application were planned. Seven studies with low risk of bias were included. The pooled ability to separate benign from malignant effusions varied with image modality, interpretation method and known malignancy status pre index-test application. In studies using PET-CT, visual/qualitative image analysis was superior to semi-quantitative with positive (LR + ) and negative likelihood ratio (LR-) of 9.9 (4.5–15.3) respectively 0.1 (0.1–0.2). There was considerable heterogeneity among studies. In conclusion, visual/qualitative image analysis of integrated PET-CT seems to add relevant information in the work-up of suspected malignant pleural effusions with LR + and LR- close to rigorous pre-set cut-offs of > 10 and < 0.1. However, the quality of evidence was low due to inter-study heterogeneity, and inability to assess meta-bias. Clinical Trial Registration: The protocol was uploaded to the PROSPERO database (CRD42020213319) on the 13th of October 2020.

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France

Neurologic manifestations associated with a COVID-19 diagnosis are common and often occur in severe and critically ill patients. In these patients, the neurologic symptoms are confounded by critical care conditions, such as acute respiratory distress syndrome. Patients with dual diagnoses of COVID-19 and neurologic changes such as myopathy, polyneuropathy, and stroke are likely at a higher risk to experience deficits with swallowing, communication, and/or cognition. Speech-language pathologists are an integral part of both the critical care and neurological disorders multi-disciplinary teams, offering valuable contributions in the evaluation, treatment, and management of these areas. Patients in intensive care units (ICUs) who require mechanical ventilation often experience difficulty with communication and benefit from early speech-language pathology intervention to identify the most efficient communication methods with the medical team and caregivers. Moreover, patients with neurologic manifestations may present with cognitive-linguistic impairments such as aphasia, increasing the need for communication-based interventions. Difficulties with voice and swallowing after extubation are common, often requiring frequent treatment sessions, possibly persisting beyond ICU discharge. After leaving the ICU, patients with COVID-19 often experience physical, cognitive, and mental health impairments collectively called post-intensive care syndrome. This is often a lengthy road as they progress toward full recovery, requiring continued speech-language pathology treatment after hospital discharge, capitalizing on the principles of neuroplasticity. This article is protected by copyright. All rights reserved.

Cohort study.To study the clinical outcome, complications and subsequent surgery rate of DA for lumbar spinal stenosis (LSS) with DS.There is still no consensus regarding the treatment approach for LSS with DS.We performed a retrospectively designed cohort study on prospectively collected data from a single high productive spine surgical center. Results from the Swedish Spine Registry and a local register for complications were used for the analyses. Patients with LSS and DS (3 mm) who underwent DA during January 2012 to August 2017 were included. Patient reported outcome measures at baseline and 2 years after surgery were analyzed. Complications within 30 days of surgery and all subsequent surgery in the lumbar spine were registered.We identified and included 346 patients with completed 2-year follow-up registration. At 2-year follow-up there was a significant improvement in all outcome measures. The global assessment success rate for back and leg pain was 68.3% and 67.6% respectively. Forty-one patients had at least 1 intra- or postoperative complication (11.9%). Nine patients (2.6%), underwent subsequent surgery within 2 years of the primary surgery whereof 2 underwent fusion. During the whole period of data collection, that is, as of June 2020, 28 patients had undergone subsequent surgery (8.1%) whereas 8 of them had had 2 surgeries. Fifteen patients underwent fusion.DA provides good clinical outcome at 2-year follow-up in patients with LSS and DS with low rate of intra- and postoperative complications and subsequent surgery. Our data supports the evidence that DA is effective and safe for LSS with DS.Level of Evidence: 3.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

In a span of twenty years, two of the autocephalous churches of the Orthodox Christian world released documents addressing the social realities of contemporary life: the Russian Orthodox Church's Basis of the Social Concept (2000) and the Ecumenical Patriarch's For the Life of the World: Toward a Social Ethos of the Orthodox Church (2020). This article offers a side-by-side comparison and analysis of the documents’ treatments of matters of birth and death, including childbirth, abortion, miscarriage, end-of-life care, euthanasia, suicide, and a vision of a good death. Detailed comparison demonstrates remarkable accord between the two churches on many of these matters. Differences of omission and emphasis appear to be indicative of contrasting demographic and historical situations, with the exception of one, notable divergence between the churches, all of which are discussed. The striking degree and depth of consonance between the documents offers potential for cooperation and unity as the two churches negotiate their conflicts while also seeking to guide their flocks and offer Orthodox Christian witness in an increasingly desacralized world.

Background Syringe services programs (SSPs) complement substance use disorder treatment in providing services that improve the health of people who use drugs (PWUD). Buprenorphine treatment is an effective underutilized opioid use disorder treatment. Regulations allow buprenorphine prescribing from office-based settings, potentially including SSPs although few studies have examined this approach. Our objective was to assess the attitudes among PWUD toward the potential introduction of buprenorphine treatment in an SSP. Methods In this qualitative study, we recruited 34 participants who were enrolled at a New York City-based SSP to participate in one of seven focus group sessions. The focus group facilitators prompted participants to share their thoughts in five domains: attitudes toward (1) medical clinics; (2) harm reduction in general; (3) SSP-based buprenorphine treatment; (4) potential challenges of SSP-based treatment; and (5) logistical considerations of an SSP-based buprenorphine treatment program. Four researchers analyzed focus group transcripts using thematic analysis. Results Of the 34 participants, most were white (68%), over the age of 40 years old (56%), and had previously tried buprenorphine (89%). Common themes were: 1) The SSP is a supportive community for people who use drugs; 2) Participants felt less stigmatized at the SSP than in general medical settings; 3) Offering buprenorphine treatment could change the SSP's culture; and 4) SSP participants receiving buprenorphine may be tempted to divert their medication. Participants offered suggestions for a slow intentional introduction of buprenorphine treatment at the SSP including structured appointments, training medical providers in harm reduction, and program eligibility criteria. Conclusion Overall, participants expressed enthusiasm for onsite buprenorphine treatment at SSPs. Research on SSP-based buprenorphine treatment should investigate standard buprenorphine treatment outcomes but also any effects on the program itself and medication diversion. Implementation should consider cultural and environmental aspects of the SSP and consult program staff and participants.

Background - Body mass index (BMI) increases while cardiometabolic risk factors decrease in individuals in high-income countries. This paradoxical observation raises the question of whether current measures of overweight and obesity properly identify cardiometabolic risk. Methods - A total of 3675 participants (59% women) aged 40–84 years with whole-body dual-energy x-ray absorptiometry scans from the seventh survey of the Tromsø Study were included to examine the association between visceral adipose tissue (VAT) in grams and BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Further, their association with single cardiometabolic risk factors (blood pressure, triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, glycated hemoglobin, high-sensitivity C-reactive protein), modified single components from the ATP Ⅲ criteria for metabolic syndrome (hypertension, diabetes, high triglycerides, and low HDL cholesterol), and metabolic syndrome were examined. Results - VAT mass was strongly correlated with BMI (r ≥ 0.77), WC (r ≥ 0.80), WHR (r ≥ 0.58), and WHtR (r ≥ 0.78). WC was the strongest predictor for VAT (area under the curve: 0.90). Compared to anthropometric measures, the associations between VAT and metabolic syndrome as well as single components of metabolic syndrome were statistically significantly stronger, but the clinical differences were likely minor. Conclusion - Although VAT mass showed statistically stronger associations with cardiometabolic risk compared to traditional anthropometrics, the clinical importance was likely small. Simple, clinically available tools seem to satisfactory substitute for VAT to identify cardiometabolic risk.

Hoarding disorder is marked by strong attachments to everyday objects, extreme difficulties discarding, and impairing levels of clutter. We examined the associations between hoarding symptoms and associated clinical features using network analysis in a large sample of individuals with established hoarding disorder (n = 217) and matched healthy controls (n = 130). Network nodes included the three core features of hoarding (difficulties discarding, clutter, and acquiring), along with comorbid symptoms, impairment, and saving and acquiring motives. Models showed hoarding and comorbid symptoms as separate syndromes. Healthy and patient networks differed significantly in both global network strength and structure. For the hoarding patient network, the comorbidity and hoarding clusters were connected by acquiring and anxiety, which served as bridge symptoms. Clutter was the only hoarding node associated with impairment. Hoarding beliefs were not central to the model, and only difficulties discarding was associated with saving and acquiring motives, including emotional attachment and wastefulness beliefs. Our findings indicate that the network approach to mental disorders provides a new and complementary way to improve our understanding of the etiological model of hoarding, and may present novel hypotheses to examine in treatment development research.

Funder: Gerald Kerkut Charitable Trust; FundRef: http://dx.doi.org/10.13039/100012166, Funder: Rank Prize, Funder: NIHR Clinical Lectureship, Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy., CS was funded by a Gerald Kerkut Charitable Trust studentship and BA by Rank Prize and University of Southampton Vice Chancellor���s Studentships plus the MRC. KMG was supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator [NF-SI-0515-10042], NIHR Southampton 1000DaysPlus Global Nutrition Research Group [17/63/154], and NIHR Southampton Biomedical Research Centre [IS-BRC-1215-20004]), British Heart Foundation (RG/15/17/3174) and the US National Institute on Aging of the National Institutes of Health (Award No. U24AG047867). KSJ was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (ISBRC-1215-20014). The NIHR Cambridge Biomedical Research Centre is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Experimental work performed by KSJ and FH at MRC. EWL was supported by Dr Ann Prentice (UK Medical Research Council U105960371). The SWS has been supported by grants from Medical Research Council (MRC) (4050502589 [MRC LEU]), Dunhill Medical Trust, British Heart Foundation, Food Standards Agency, National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, NIHR Oxford Biomedical Research Centre, University of Oxford, and the European Union���s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition, under grant agreement 289346 and the European Union���s Horizon 2020 research and innovation program (LIFECYCLE, grant agreement no. 733206). EC has been supported by the Wellcome Trust (201268/Z/16/Z) and an NIHR Clinical Lectureship. Work leading to these results was supported by the BBSRC (HDHL-Biomarkers, BB/P028179/1), as part of the ALPHABET project, supported by an award made through the ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL), Horizon 2020 grant agreement number 696295. The proteomic analyses (SDG and AM) were financially supported by the National Institutes of Health (R21AI122389) and the Beckman Institute at the California Institute of Technology. This project has received funding from the European Union���s Horizon 2020 research and innovation program under the Marie Sk��odowska-Curie grant agreement InvADeRS no. 841172 to JMF. The electron microscopy image in Figure 2 was produced with help of the Biomedical imaging unit, Faculty of Medicine, University of Southampton.

There is a critical need for new ways to illuminate the geospatial context of the lived experience of people with dementia in their local neighbourhoods. This chapter reports on research that used qualitative geographic information systems (GIS) to understand experiences of place for people with dementia when they are ‘out and about’ in their local community. Conducted in Kiama, an Australian seaside town popular with retirees, the research aimed to understand the geospatial elements of these movements using two qualitative mapping methods: semi-structured, sketch mapping interviews and a crowdsourced online map for wider publics. Results provided grounded understandings of the everyday usage of a range of important places, including physical and social settings that variously supported or hindered civic participation and social engagement. Crowdsourced online maps, while less rich in detail, supported access to map-making. The resulting data was useful to inform advocacy and local targets for environmental action. Research using qualitative GIS provided a much-needed geospatial element and was a valuable complementary method to interviewing and walk-arounds, foregrounding how the everyday lives of people living with dementia are constituted relationally through social and material interactions in place.

BackgroundMost regions in Indonesia experience annual dengue epidemics. However, the province of East Nusa Tenggara has consistently reported low incidence. We conducted a dengue molecular epidemiology study in Kupang, the capital of the province.MethodsDengue patients were recruited from May 2016 to September 2017. Dengue virus (DENV) screening was performed using NS1 and immunoglobulin G (IgG)/IgM detection. Serotype was determined using reverse transcription polymerase chain reaction and the envelope genes were sequenced to infer the genetic identity and phylogeny.ResultsFrom 119 patients, dengue was confirmed in 62 (52%). Compared with official data, underreporting of dengue incidence was observed. The majority (36%) of patients were children ConclusionsThe low dengue incidence was most likely caused by sustained local circulation of endemic viruses. This study provides information on the epidemiology of dengue in a low-endemicity setting that should help future mitigation and disease management.

Introduction Pembrolizumab is a highly effective standard of care in PD-L1 overexpressing (≥ 50%) non–small-cell lung cancer. However, a substantial share of patients from everyday clinical practice is treated without clear evidence from clinical trials. Patients and Methods We performed a retrospective multicentric study including all consecutive patients from 6 certified lung cancer centers in Berlin, Germany, having received pembrolizumab as first-line palliative therapy from January 1 until December 31, 2017. Aims were to validate published clinical trials with a special focus on efficacy and outcome in patients with reduced performance status (PS), brain metastases, and steroids. Results A total of 153 patients were included (median age 69 years, 58% men, 69% adenocarcinoma). Rates for PS ≥ 2, brain metastases, and steroids were 24.8%, 20.9%, and 24.2%, respectively. Median objective response rate, progression-free and overall survival were 48.5%, 8.2 and 22.0 months for all patients and 52.4%, 8.8 and 29.2 months in patients fulfilling the inclusion criteria for the KEYNOTE-024 trial. Patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases requiring upfront radiotherapy, or baseline steroids had significantly reduced survival. In contrast, durable responses occurred with a tumor-related PS ≥ 2 or asymptomatic brain metastases. Grade 3/4 and 5 immune-related adverse events affected 13.7% and 2.0% of patients. Conclusion Real-world and clinical trial efficacy with upfront pembrolizumab correspond well. Pembrolizumab may sufficiently control asymptomatic brain metastases and may improve a cancer-related reduced PS. However, the frail share of patients with a comorbidity-defined PS ≥ 2, symptomatic brain metastases, or baseline steroids derives no relevant benefit.

Predicció de risc de càncer de mama; Dones europees; Variant patògena heterozigota Predicción del riesgo de cáncer de mama; Mujeres europeas; Variante patógena heterocigota Breast cancer risk prediction; European women; Heterozygous pathogenic variant Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.

Background Over the past decades, approaches for diagnosing and treating cancer have seen significant improvement. However, the variability of patient and tumor characteristics has limited progress on methods for prognosis prediction. The development of high-throughput omics technologies now provides multiple approaches for characterizing tumors. Although a large number of published studies have focused on integration of multi-omics data and use of pathway-level models for cancer prognosis prediction, there still exists a gap of knowledge regarding the prognostic landscape across multi-omics data for multiple cancer types using both gene-level and pathway-level predictors. Methods In this study, we systematically evaluated three often available types of omics data (gene expression, copy number variation and somatic point mutation) covering both DNA-level and RNA-level features. We evaluated the landscape of predictive performance of these three omics modalities for 33 cancer types in the TCGA using a Lasso or Group Lasso-penalized Cox model and either gene or pathway level predictors. Results We constructed the prognostic landscape using three types of omics data for 33 cancer types on both the gene and pathway levels. Based on this landscape, we found that predictive performance is cancer type dependent and we also highlighted the cancer types and omics modalities that support the most accurate prognostic models. In general, models estimated on gene expression data provide the best predictive performance on either gene or pathway level and adding copy number variation or somatic point mutation data to gene expression data does not improve predictive performance, with some exceptional cohorts including low grade glioma and thyroid cancer. In general, pathway-level models have better interpretative performance, higher stability and smaller model size across multiple cancer types and omics data types relative to gene-level models. Conclusions Based on this landscape and comprehensively comparison, models estimated on gene expression data provide the best predictive performance on either gene or pathway level. Pathway-level models have better interpretative performance, higher stability and smaller model size relative to gene-level models.

Total daily energy expenditure (“total expenditure”, MJ/d) reflects daily energy needs and is a critical variable in human health and physiology, yet it is unclear how daily expenditure changes over the life course. Here, we analyze a large, globally diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 yr. We show that total expenditure is strongly related to fat free mass in a power-law manner and identify four distinct metabolic life stages. Fat free mass-adjusted daily expenditure accelerates rapidly in neonates (0-1yr) to ~46% above adult values at ~1 yr, declines slowly throughout childhood and adolescence (1-20 yr) to adult levels at ~20 yr, remains stable in adulthood (20-60 yr) even during pregnancy, and declines in older adults (60+ yr). These changes in total expenditure shed new light on human development and aging and should help shape nutrition and health strategies across the lifespan.

ObjectiveAortic valve calcification (AVC) and coronary artery calcification (CAC) are predictors of cardiovascular disease (CVD), presumably sharing risk factors. Our objectives were to determine the prevalence and extent of AVC in a large population of men aged 60–74 years and to assess the association between AVC and cardiovascular risk factors including CAC and biomarkers.MethodsParticipants from the DANish CArdioVAscular Screening and intervention trial (DANCAVAS) with AVC and CAC scores and without previous valve replacement were included in the study. Calcification scores were calculated on non-contrast CT scans. Cardiovascular risk factors were self-reported, measured or both, and further explored using descriptive and regression analysis for AVC association.Results14 073 men aged 60–74 years were included. The AVC scores ranged from 0 to 9067 AU, with a median AVC of 6 AU (IQR 0–82). In 8156 individuals (58.0%), the AVC score was >0 and 215 (1.5%) had an AVC score ≥1200. In the regression analysis, all cardiovascular risk factors were associated with AVC; however, after inclusion of CAC ≥400, only age (ratio of expected counts (REC) 1.07 (95% CI 1.06 to 1.09)), hypertension (REC 1.24 (95% CI 1.09 to 1.41)), obesity (REC 1.34 (95% CI 1.20 to 1.50)), known CVD (REC 1.16 (95% CI 1.03 to 1.31)) and serum phosphate (REC 2.25 (95% CI 1.66 to 3.10) remained significantly associated, while smoking, diabetes, hyperlipidaemia, estimated glomerular filtration rate and serum calcium were not.ConclusionsAVC was prevalent in the general population of men aged 60–74 years and was significantly associated with all modifiable cardiovascular risk factors, but only selectively after adjustment for CAC ≥400 AU.Trial registration numberNCT03946410 and ISRCTN12157806.

Background: Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab. Methods: This observational, dose-finding study was done in a clinical trials facility in Melbourne (VIC, Australia). Groups of healthy volunteers aged 18–40 years, at low risk of complicated S pyogenes disease, and without high type-specific anti-emm75 IgG antibodies against the challenge strain were challenged and closely monitored as inpatients for up to 6 days, and then as outpatients for 6 months. Antibiotics were started upon diagnosis (clinical signs and symptoms of pharyngitis and a positive rapid molecular test) or after 5 days in those without pharyngitis. Rapid test results were confirmed by standard bacterial culture. After a sentinel participant, cohorts of five and then ten participants were challenged, with protocol-directed dose-escalation or de-escalation for subsequent cohorts. The primary outcome was the proportion of participants at each dose level with pharyngitis by day 5 after challenge. The study is registered with ClinicalTrials.gov, NCT03361163. Findings: Between July 10, 2018, and Sept 23, 2019, 25 healthy adults were challenged with emm75 S pyogenes and included in analyses. Pharyngitis was diagnosed in 17 (85%; 95% CI 62–97) of 20 participants at the starting dose level (1–3 × 105 colony-forming units [CFU]/mL). This high proportion prompted dose de-escalation. At the lower dose level (1–3 × 104 CFU/mL), pharyngitis was diagnosed in one of five participants. Immunological, biochemical, and microbiological results supported the clinical picture, with acute symptomatic pharyngitis characterised by pharyngeal colonisation by S pyogenes accompanied by significantly elevated C-reactive protein and inflammatory cytokines (eg, interferon-γ and interleukin-6), and modest serological responses to streptolysin O and deoxyribonuclease B. There were no severe (grade 3) or serious adverse events related to challenge. Interpretation: We have established a reliable pharyngitis human infection model with reassuring early safety findings to accelerate development of vaccines and other interventions to control disease due to S pyogenes. Funding: Australian National Health and Medical Research Council., SCOPUS: ar.j, info:eu-repo/semantics/published

Jan Anker Jahnsen,1– 3 Sofia Frost Widnes,1,2 Jan Schjøtt1– 3 1Regional Medicines Information and Pharmacovigilance Centre (RELIS Vest), Haukeland University Hospital, Bergen, Norway; 2Department of Clinical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; 3Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, NorwayCorrespondence: Jan Anker JahnsenRegional Medicines Information and Pharmacovigilance Centre (RELIS Vest), Haukeland University Hospital, Bergen, NorwayTel +47-48182071Email jan.anker.jahnsen@helse-bergen.noPurpose: The second-generation antipsychotic quetiapine has been associated with misuse and dependency. We aimed to review questions to the Norwegian network of drug information centers concerning this potential drug safety problem.Methods: We conducted a Boolean search in the database of the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS) combining the indexed categories “quetiapine” and “adverse drug reaction” with the text words “misuse” or “dependency”. Question–answer pairs (Q/As) in the full-text, searchable RELIS database were defined as cases. Cases were analyzed for drug safety issues linked to use of quetiapine, including off-label use, polypharmacy and other patient risk factors.Results: The search resulted in 54 cases. Forty-six cases (85%) were patient-related, and a majority came from physicians working in hospitals. Twenty-nine cases (54%) concerned patients with a history of addiction, 14 cases (26%) had polypharmacy, and off-label use of quetiapine for insomnia was identified in 14 of the cases (26%). Only three of the cases included a specific question about patient dependency of quetiapine, and these cases were all associated with insomnia.Conclusion: We conclude that our case series from the Norwegian network of drug information centres reflects that quetiapine frequently involves clinical narratives of a history of addiction, polypharmacy or insomnia (off-label use). However, the case series did not reveal new information about the drug’s addictive potential.Keywords: off-label, insomnia, drug safety, addiction, abuse

Objectives In patients with NSCLC, current ESTS and ESMO guidelines recommend invasive lymph node (LN) staging with EBUS-TBNA even if FDG-PET/CT is negative for mediastinal LNs if at least one of three risk factors is present (cN1, non-peripheral primary or primary >3 cm). Modified workflows to avoid unnecessary invasive procedures were evaluated. Materials and methods Monocentric retrospective analysis of pretherapeutic FDG-PET/CT in 247 patients with NSCLC (62 % male; age, 68 [43–88] years) using an analog or digital PET/CT scanner. PET windowing was standardized. LNs were positive if ‘LN uptake > mediastinal blood pool’ or short axis >10 mm. Surgery or EBUS-TBNA served as reference for diagnostic accuracy per LN station. In all patients with negative mediastinal LNs by PET/CT, LN histology from surgery was available. Results Among 700 L N stations analyzed, 180 were malignant. Sensitivity and specificity of PET/CT per LN station were 93 % and 71 %. Following current guidelines, 76 patients with mediastinal negative PET/CT required confirmatory invasive staging. Only 5/76 patients had unexpected pN2 (all had adenocarcinoma). In a modified approach, confirmatory invasive staging was confined to patients with mediastinal negative PET/CT who showed all three risk factors. Using this modification, EBUS-TBNA could have been omitted in 62 (82 %) of the 76 patients who required EBUS-TBNA based on current recommendation. Among these 62 patients, only one patient had unsuspected pN2 (single-level) while the remaining 61 of 62 omitted EBUS-TBNA were deemed unnecessary because mediastinal LNs were confirmed to be negative. No multi-level pN2 would have been missed. Conclusion In the current analysis, 82 % of EBUS-TBNA procedures in patients with mediastinal negative PET/CT could have been omitted by modifying the current guideline workflow as proposed (i.e., restricting EBUS-TBNA in patients with cN0/1 to those with all three risk factors). This was consistent with different PET/CT scanners. Prospective confirmation is required.

Background Severe anaemia (haemoglobin Methods Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. Results Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63–3.78), p p p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21–1.69), p p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47–0.76), p p p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23–2.44) and 1.46(1.18–1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. Conclusions Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. Trial registration ISRCTN ISRCTN84086586.

Aims Incident atrial fibrillation (AF) is an adverse prognostic indicator in heart failure (HF); identifying modifiable targets may be relevant to reduce the incidence and morbidity of AF. Therefore, we examined the association between quality of HF care and risk of AF. Methods and results Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed between 2008 and 2018 and without history of AF. Quality of HF care was assessed by seven process performance measures, including echocardiographic examination, New York Heart Association classification, treatment with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blockers, and mineralocorticoid antagonists, physical training, and patient education. In the main analysis, we examined adherence with all measures in a cohort of 25 100 patients (mean age 68.5 ± 13.2 years; 33.6% women). The median follow-up was 3.1 years. Cox proportional hazard regressions estimated the hazard ratios (HRs) with 95% confidence intervals (95% CIs) between the number of fulfilled measures and incident AF. In a multivariable-adjusted analysis with 0 fulfilled performance measures as reference, the HRs (95% CIs) were 1: 0.78 (0.61–1.00), 2: 0.63 (0.49–0.80), 3: 0.53 (0.36–0.80), 4: 0.64 (0.44–0.94), 5: 0.56 (0.39–0.82), 6: 0.51 (0.35–0.74), and 7: 0.49 (0.33–0.73), with a significant decreasing linear trend (P Conclusion In patients with incident HF, fulfilment of guideline-based process performance measures was associated with decreased long-term risk of AF. This study supports initiatives to improve the quality of care for patients with HF to prevent incident AF.

Aims Coronary artery calcification (CAC) measured on cardiac computed tomography (CT) is an important risk marker for cardiovascular disease (CVD) and has been included in the prevention guidelines. The aim of this study was to describe CAC score reference values in the middle-aged and elderly population and to develop a freely available CAC calculator. Methods and results All participants from two population-based cardiac CT screening cohorts (DanRisk and DANCAVAS) were included. The CAC score was measured as a part of a screening session. Positive CAC scores were log-transformed and non-parametrically regressed on age for each gender, and percentile curves were transposed according to proportions of zero CAC scores. Men had higher CAC scores than women, and the prevalence and extend of CAC increased steadily with age. An online CAC calculator was developed, http://flscripts.dk/cacscore. After entering sex, age, and CAC score, the CAC score percentile and the coronary age are depicted including a figure with the specific CAC score and 25%, 50%, 75%, and 90% percentiles. The specific CAC score can be compared to the entire background population or only those without prior CVD. Conclusion This study provides modern population-based reference values of CAC scores in men and woman and a freely accessible online CAC calculator. Physicians and patients are very familiar with blood pressure and lipids, but unfamiliar with CAC scores. Using the calculator makes it easy to see if a CAC value is low, moderate, or high, when a physician in the future communicate and discusses a CAC score with a patient.

Few studies have examined the post-discharge benefits associated with recover-oriented programs delivered in inpatient and sub-acute mental health settings. The aim of this study was to evaluate the medium-term outcomes of a 6-week sub-acute inpatient intervention program for 27 service users with a diagnosis of serious mental illness (mean age = 33.22 years, 70.4% with a psychosis diagnosis). Recovery data were collected on admission, at discharge, and at 3- and 6-months post-discharge using self-report, collaborative and clinical measures. The three clinician-rated measures (assessing therapeutic engagement, functioning, and life skills) revealed linear improvements from admission to 6-month follow-up (with mean z-change ranging from 0.72 to 1.35), as did the self-reported social connection measure (Mental Health Recovery Star, MHRS; mean z-change: 1.05). There were also curvilinear improvements in self-determination and self-reported MHRS symptom management and functioning scores; however, only modest changes were detected in hope (Herth Hope Index) and MHRS self-belief scores. Change scores based on self-reported and clinician-rated measures tended to be uncorrelated. An exploration of client-level outcomes revealed three recovery trajectory subgroups: transient (21.7%), gradual (34.8%), or sustained (43.5%) improvement; with members of the latter group tending to have longer illness durations. The study’s findings are encouraging, to the extent that they demonstrate recovery-focused sub-acute inpatient programs can promote clinical recovery and aspects of personal recovery. However, they also suggest that recovery perspectives differ between clients and clinicians, and that far more work is required to understand the psychological factors that generate and sustain the hope that recovery is possible.

Syringe services programs (SSPs) are essential to preventing injection drug use-related infections and overdose death among people who use drugs (PWUD). The novel coronavirus (COVID-19) pandemic initially impeded SSPs' operations. To effectively support these programs, information is needed regarding SSPs' experiences adapting their services and the challenges posed by COVID-19. We conducted qualitative interviews with leadership and staff from a sample of 31 U.S. SSPs. Respondents discussed urgent concerns including reduced reach of services, suspended HIV/hepatitis C testing, high COVID-19 risk among PWUD, and negative impacts of isolation on overdose and mental health. They also noted opportunities to improve future services for PWUD, including shifting to evidence-based distribution practices and maintaining regulatory changes that increased access to opioid use disorder medications post-pandemic. Findings can inform efforts to support SSPs in restoring and expanding services, and provide insight into SSPs' role in engaging PWUD during the COVID-19 response and future emergencies.Los programas de servicios de jeringas (reconocido como SSP en inglés) son esenciales para prevenir las infecciones relacionadas con el consumo de drogas inyectables y la muerte por sobredosis entre las personas que consumen drogas (reconocidos como PWUD en ingles). La nueva pandemia del coronavirus (COVID-19) inicialmente impidió las operaciones de los SSP. Para apoyar eficazmente estos programas, se necesita información sobre las experiencias de los SSP que adaptan sus servicios y los desafíos que plantea COVID-19. Realizamos entrevistas cualitativas con el liderazgo y el personal de una muestra de 31 SSPs de EE.UU. Los encuestados discutieron las preocupaciones urgentes, incluyendo la reducción del alcance de los servicios, la suspensión de las pruebas de VIH/hepatitis C, el alto riesgo de COVID-19 entre la PWUD, y los impactos negativos del aislamiento en las sobredosis y la salud mental. También identificaron las oportunidades de mejorar los servicios futuros para las PWUD, incluyendo el cambio a prácticas de distribución basadas en evidencias y el mantenimiento de cambios regulatorios que aumentaran el acceso a medicamentos para el trastorno por consumo de opiáceos después de la pandemia. La información que se encontró en este estudio se puede utilizar junto los esfuerzos para apoyar a los SSP en la restauración y expansión de los servicios, y proporcionar información sobre el papel de los SSP en la participación de PWUD durante la respuesta covid-19 futuras emergencias.

Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)—a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability—is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.

BackgroundAround 40% of patients with bipolar disorder (BD) additionally have anxiety disorder. The prevalence of anxiety in patients with newly diagnosed BD and their first-degree relatives (UR) has not been investigated.ObjectiveTo investigate (1) the prevalence of a comorbid anxiety diagnosis in patients with newly diagnosed BD and their UR, (2) sociodemographic and clinical differences between patients with and without a comorbid anxiety diagnosis and (3) the association between smartphone-based patient-reported anxiety and observer-based ratings of anxiety and functioning, respectively.MethodsWe recruited 372 patients with BD and 116 of their UR. Daily smartphone-based data were provided from 125 patients. SCAN was used to assess comorbid anxiety diagnoses.FindingsIn patients with BD, the prevalence of a comorbid anxiety disorder was 11.3% (N=42) and 10.3% and 5.9% in partial and full remission, respectively. In UR, the prevalence was 6.9%. Patients with a comorbid anxiety disorder had longer illness duration (p=0.016) and higher number of affective episodes (p=0.011). Smartphone-based patient-reported anxiety symptoms were associated with ratings of anxiety and impaired functioning (pLimitationsThe SCAN interviews to diagnose comorbid anxiety disorder were carried out regardless of the participants’ mood state.Clinical implicationsThe lower prevalence of anxiety in newly diagnosed BD than in later stages of BD indicates that anxiety increases with progression of BD. Comorbid anxiety seems associated with poorer clinical outcomes and functioning and smartphones are clinically useful for monitoring anxiety symptoms.Trial registration numberClinicalTrials.gov Registry (NCT02888262).

BACKGROUND Randomized trials of antenatal steroids (ANS) included women at 24-33 weeks gestational age (GA); however, few women had preeclampsia and women with diabetes mellitus (DM) were excluded. METHODS Cohort study including preterm births at 230/7-286/7 weeks GA before (Epoch-1) and after (Epoch-2) expansion of ANS administration to women with DM and hypertensive disorders (HTN). We compared Group-A (neither DM nor HTN) and Group-B (DM and/or HTN). RESULTS Among 747 neonates the adjusted odds ratio (aOR) for surfactant administration, in-hospital mortality, severe intraventricular hemorrhage (IVH) and death or severe IVH were lower in ANS-exposed neonates than unexposed neonates. In Group-B, ANS administration was independently associated with less severe IVH and less death or severe IVH, but not less surfactant use or mortality. CONCLUSIONS Increased ANS administration in women with DM and/or HTN was independently associated with less severe IVH and less death or severe IVH but without decrease in surfactant administration.

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐2 (GLP‐2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP‐ and GLP‐2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed‐meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal‐ and GIP‐ but not the GLP‐2‐induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP‐2 receptor (GLP‐2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP‐2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP‐2R were expressed in parathyroid tissue. Our findings suggest that the GIP‐induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP‐2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP‐2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Background The impact of COVID-19 restrictions on people living with dementia and their carers is an emerging focus of recent research determining how we can best support this population. People living with dementia have faced service curtailment, increased risk for COVID-19, as well as potential heightened deterioration. This study reports the experiences of people living with dementia and their family carers during the early months of the COVID-19 pandemic in England and the impact on them. Methods We recruited and remotely interviewed 30 people living with dementia in their own homes and 31 family carers, via video or telephone call in mid-2020. Data were transcribed and analysed using thematic analysis. Results People living with dementia often had a basic understanding of COVID-19 restrictions but could have difficulty translating this into personalised risk-appraisal of their own actions. Managing COVID-19 risks facing people living with dementia at home was largely done by family carers, exemplified by changes to living arrangements, which could strain or sustain caring relationships. Well-established familial caring relationships contributed to the wellbeing of the person living with dementia and their carer, as well as keeping to simple routines that included leaving the home for exercise and stimulation. People living with dementia reported some negative psychological and cognitive effects due to the imposed restrictions, such as increased apathy, irritability, or anxiety, which were fuelled by lack of social engagement. Conclusions Structuring routine (remote) social interactions where possible could increase social engagement and improve wellbeing for people living with dementia, especially those with limited familial support in a post-COVID-19 context. As some care relationships had been restructured to manage COVID-19 risks, additional carer strain may emerge as a result of the impact on the independence of the person living with dementia and come to the attention of professionals in health and care services. People living with dementia and their carers highlighted the importance of maintaining or adapting routines which may be useful learning for professionals, although additional support may be necessary for those who are impacted by more severe or worsening symptoms of dementia.

Background: Promising approaches for reduction of childhood obesity include interventions such as Connect for Health, a scalable, primary care-based intervention to improve family-centered outcomes for children ages 2-12 years. Substantial gaps remain in the adoption of proven-effective interventions particularly in settings that care for low-income children. Methods: We used the Consolidated Framework for Implementation Research to examine contextual determinants of implementation of Connect for Health in four organizations that deliver primary care to low-income children in Boston, MA, Denver, CO, and Greenville, SC. The Connect for Health program includes (1) electronic health record (EHR)-based clinical decision support tools to guide clinicians; (2) family educational materials; and (3) text messages for parents to support behavior change. We used the RE-AIM framework to guide our mixed-methods evaluation. Using a quasi-experimental design, we will examine the effectiveness of stakeholder-informed strategies in supporting program adoption and child outcomes. At baseline, we abstracted EHR data from the organizations to describe characteristics of children ages 2-12 years with a BMI ≥ 85th percentile.Results: During the 15-month period prior to implementation, 26,161 children with a BMI ≥ 85th percentile ages 2-12 years were seen for a primary care visit. Across the organizations, 79% of children with a BMI ≥ 85th percentile had public insurance, 49% were Hispanic, and 18% were Black. Approximately 37% of children had a BMI ≥ 95th percentile and 15% had a BMI in the severe obesity category. Childhood obesity ICD-10 diagnostic codes were used more for children with obesity (44%) and severe obesity (60%) than children with overweight (17%); nutrition (7%) and physical activity (6%) counseling codes were seldom used. Referrals for weight management programs were less than 17% and less than 16% for nutrition services. Laboratory evaluations were ordered more often for children with obesity (39%) and severe obesity (64%) than children with overweight (29%)Discussion: A majority of children with overweight and obesity lacked recommended diagnosis codes, referrals, and laboratory evaluations for assessment and management of obesity and related co-morbidities. These findings suggest the need to augment current approaches to increase uptake of proven-effective weight management programs. Trial Registration: Clinicaltrials.gov, NCT04042493, Registered on August 2, 2019; https://clinicaltrials.gov/ct2/show/NCT04042493

Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.

PURPOSE Helicobacter pylori could theoretically induce ocular adnexal lymphoma (OAL) via 2 mechanisms: the first is that of infection within the ocular adnexa and the second is that of infection within the gastric mucosa, leading to the malignant transformation of lymphocytes that migrate to the ocular adnexa, forming a primary "ectopic" cancer. This study investigated if an association exists between gastric H. pylori or ocular adnexal H. pylori and OAL. METHODS Prospective case-control study including cases with OAL and controls with nonlymphomatous pathologies. Gastric H. pylori infection was assessed via serologic antibody testing. Ocular adnexal infection was assessed via polymerase chain reaction testing for H. pylori and Chlamydia psittaci within ocular adnexal samples. RESULTS Seventy-two patients were enrolled, of whom 18 had lymphoma and 54 nonlymphomatous pathologies. H. pylori antibodies were present in 5 cases (28%) and 18 controls (33%) (95% CI, 0.24%-2.50%, p = 0.78). All ocular adnexal specimens were negative for H. pylori and C. psittaci infection. The only relevant statistically significant difference between cases and controls was a history of gastric ulcer (95% CI, 1.23%-44.80%, p = 0.03). CONCLUSIONS In the study's population, infection of gastric mucosa with H. pylori does not appear to influence the development of OAL. Also, H. pylori or C. psittaci infection within the ocular adnexa does not appear to influence the development of OAL. In the study's practice, authors do not recommend antibiotic administration or routine gastroscopy for patients with OAL. The authors do recommend referral of OAL patients with gastric symptoms to a gastroenterologist.

BACKGROUND A nocturnal non-dipping pattern has been associated with hypertension-mediated organ damage (HMOD), morbidity and mortality. Retinal imaging through application of modern technologies including optical coherence tomography angiography (OCT-A) can provide detailed insights into early vascular damage. In this observational study, we investigated the relationship of microscopic vascular density in the retina measured with OCT-A and nocturnal blood pressure (BP) dipping. METHODS Retinal OCT-A and ambulatory BP monitoring (ABPM) data prospectively obtained from 142 patients referred to a tertiary hypertension clinic were analysed with regression models for associations between BP night-time dipping and retinal capillary vascular density in three different zones around the fovea. RESULTS More pronounced nocturnal SBP and DBP dipping was significantly associated with increased vascular density in the central foveal area of the retina. These associations were robust to adjustment for other available risk factors including mean daytime BP. Parafoveal and whole image vascular density did not show equivalent significant associations with nocturnal BP dipping. The results were reproducible when assessed in a subgroup of patients who had concomitant type 2 diabetes. CONCLUSION Foveal vascular density was associated with the nocturnal BP dipping pattern in hypertensive patients. These associations were robust to adjustment of relevant factors such as daytime BP. Our findings highlight the importance of nocturnal BP features reflected in ambulatory BP monitoring in the assessment of HMOD. Whether routine assessment of retinal damage markers may improve risk management of hypertensive patients remains to be determined.

ObjectiveTo examine the effect of the consumption of ultraprocessed food on diet quality, and cardiometabolic risk (CMR) in an occupational cohort.DesignCross-sectional.SettingOccupational cohort.Participants53 163 British police force employees enrolled (2004–2012) into the Airwave Health Monitoring Study. A total of 28 forces across the UK agreed to participate. 9009 participants with available 7-day diet record data and complete co-variate data are reported in this study.Main outcome measuresA CMR and Dietary Approaches to Stop Hypertension score were treated as continuous variables and used to generate measures of cardiometabolic health and diet quality. Secondary outcome measures include percentage of energy from fat, saturated fat, carbohydrate, protein and non-milk extrinsic sugars (NMES) and fibre grams per 1000 kcal of energy intake.ResultsIn this cohort, 58.3%±11.6 of total energy intake was derived from ultraprocessed (NOVA 4) foods. Ultraprocessed food intake was negatively correlated with diet quality (r=−0.32, pConclusionsUltraprocessed food consumption is associated with a deterioration in diet quality and positively associated with CMR, although this association is mediated by and dependent on the quality of the diet. The negative impact of ultraprocessed food consumption on diet quality needs to be addressed and controlled studies are needed to fully comprehend whether the relationship between ultraprocessed food consumption and health is independent to its relationship with poor diet quality.

BACKGROUND: Enlargement of left atrium (LA) is a valuable marker of cardiovascular events, and LA size is readily available while performing non-contrast cardiac computed tomography (NCCT) for preventive purposes. We aimed to evaluate the predictive value of a single LA area from NCCT in a population-based cohort.METHOD: Mainly men aged 60-75 years from DANCAVAS were included. Traditional risk factors were recorded, and an NCCT scan performed at baseline. Coronary artery calcifications (CAC) score and the largest LA area were measured. LA was indexed to body surface area and categorised into four groups. Data on incident atrial fibrillation (AF), thromboembolic events, heart failure (HF) and death were obtained from Danish national registries.RESULTS: In total, 14,557 individuals were eligible, excluding those without LA measurement (N = 232) and with heart valve replacement (N = 197). Known AF or HF were respectively excluded from follow-up. Median follow-up time was 2.1 to 3.4 years. In total, 304 developed AF, 149 had thromboembolism, 129 developed HF and 482 died. In adjusted analysis, LA enlargement was associated with AF (HR (95% CI): large 1.99 (1.46-2.71) and very large LA 3.77 (2.31-6.14)) and HF (large 2.40 (1.50-3.85) and very large LA 6.54 (4.07-10.51)). A very large LA significantly increased mortality (HR: 2.01 (1.44-2.82)), and was associated with a two-fold increased risk of thromboembolism; however, not significantly in adjusted analysis (p = 0.09).CONCLUSION: We demonstrated that determination of LA area from NCCT was an important predictor of AF, HF and death. This knowledge could inform current risk assessment beyond CAC score.

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as primary ovarian insufficiency, hypothalamic amenorrhea, congenital hypogonadotropic hypogonadism, and early menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin, and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly aging population., Graphical Abstract Graphical Abstract

The management of complicated ventral hernias (CVH), namely ventral hernias in actively or recently infected/contaminated operative fields, and open abdomens in which the native fascia cannot be primarily reapproximated, pose a surgical challenge. Fetal Bovine and Porcine Acellular Dermal Matrix (BADM and PADM) biologic meshes are being increasingly used in these scenarios. A comparison, however, of clinically relevant outcomes between the two is lacking. With this investigation, we aim to review and compare clinically relevant outcomes in patients that underwent abdominal wall herniorrhaphy with either BADM or PADM at a tertiary urban academic institution over a 5-year period. Patients who had a BADM or PADM implanted during CVH over a 5-year period at a tertiary urban academic hospital were identified. Baseline clinical and hernia characteristics, as well as postoperative outcomes were compared after a retrospective chart review. Phone interviews were also conducted to assess for recurrence, followed by in-person visits as indicated. Cox Proportional Hazard regression was fitted to identify risk factors for recurrence. Of the 140 patients who underwent biologic mesh implantation for CVH, 109 were for ventral hernia repair and 31 for open abdomen bridging. Mean age was 52.7 ± 14.2 and males constituted 57.9% of our sample, while 25.1% had undergone > 5 prior abdominal operations. Thirty percent were active smokers, and another 30% required emergency surgery. Only immunosuppression was a risk factor for recurrence [HR 13.3 (1.04–169.2), p = 0.047] on Cox Proportional Hazard regression, while mesh selection had no effect. Both BADM and PADM meshes perform well in CVH, with satisfactory recurrence rates, only slightly higher compared to traditional synthetic mesh repairs.

Background Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder. Effective long-term treatment options are limited, which warrants increased focus on potential modifiable risk factors. The aim of this study was to investigate associations between maternal diet quality during pregnancy and child diet quality and child ADHD symptoms and ADHD diagnosis. Methods This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). We assessed maternal diet quality with the Prenatal Diet Quality Index (PDQI) and Ultra-Processed Food Index (UPFI) around mid-gestation, and child diet quality using the Diet Quality Index (CDQI) at 3 years. ADHD symptoms were assessed at child age 8 years using the Parent Rating Scale for Disruptive Behaviour Disorders. ADHD diagnoses were retrieved from the Norwegian Patient Registry. Results In total, 77,768 mother-child pairs were eligible for studying ADHD diagnoses and 37,787 for ADHD symptoms. Means (SD) for the PDQI, UPFI and CDQI were 83.1 (9.3), 31.8 (9.7) and 60.3 (10.6), respectively. Mean (SD) ADHD symptom score was 8.4 (7.1) and ADHD diagnosis prevalence was 2.9% (male to female ratio 2.6:1). For one SD increase in maternal diet index scores, we saw a change in mean (percent) ADHD symptom score of − 0.28 (− 3.3%) (CI: − 0.41, − 0.14 (− 4.8, − 1.6%)) for PDQI scores and 0.25 (+ 3.0%) (CI: 0.13, 0.38 (1.5, 4.5%)) for UPFI scores. A one SD increase in PDQI score was associated with a relative risk of ADHD diagnosis of 0.87 (CI: 0.79, 0.97). We found no reliable associations with either outcomes for the CDQI, and no reliable change in risk of ADHD diagnosis for the UPFI. Conclusions We provide evidence that overall maternal diet quality during pregnancy is associated with a small decrease in ADHD symptom score at 8 years and lower risk for ADHD diagnosis, with more robust findings for the latter outcome. Consumption of ultra-processed foods was only associated with increased ADHD symptom score of similar magnitude as for overall maternal diet quality, and we found no associations between child diet quality and either outcome. No causal inferences should be made based on these results, due to potential unmeasured confounding.

Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.

Introduction:The inverse relationship between benign prostate hypertrophy and incidence/severity of prostate cancer is well documented in the clinical literature. However, this phenomenon i...

Accurate staging of non-small cell lung cancer (NSCLC) is crucial for allocation to surgical, medical or multimodal treatment. EUS and endobronchial ultrasound (EBUS) have gained ground in the diagnosis and staging of lung cancer in addition to radiological imaging (e.g., computed tomography, fluoroscopy, and magnetic resonance imaging), nuclear medicine techniques (e.g. positron emission tomography, PET), combined techniques (e.g., fluorodesoxyglucosepositron emission tomography scanning), and sonographic imaging including conventional transcutaneous mediastinal and lung ultrasound. By using one single echoendoscope in both the trachea and the esophagus, surgical staging procedures (e.g. mediastinoscopy and video assisted thoracoscopy) can be avoided in a considerable proportion of patients with NSCLC.

BackgroundCOVID-19 has accelerated remote healthcare provision in primary care, with changes potentially permanent. The implementation of remote provision of health care needs to be informed by vulnerable populations, such as people living with dementia.AimTo understand the remote healthcare experiences of patients living with dementia and their family carers during the COVID-19 pandemic.Design and settingQualitative interviews with community-based patients living with dementia and their carers were carried out between May–August 2020, while the COVID-19 pandemic was ongoing in England.MethodSemi-structured interviews were conducted remotely by telephone or video call with 30 patients living with dementia and 31 carers. Data were analysed using thematic analysis.ResultsThree main themes were derived relating to: proactive care at the onset of COVID-19 restrictions; avoidance of healthcare settings and services; and difficulties with remote healthcare encounters. People living with dementia and their carers felt check-up calls were reassuring but limited in scope and content. Some avoided healthcare services, wishing to minimise COVID-19 risk or reduce NHS burden, or encountering technological barriers. Difficulties in remote consultations included lack of prompts to remember problems, dealing with new emerging difficulties, rescheduling/missed calls, and inclusion of the voice of the person with dementia.ConclusionWhile remote consultations could be effective, proactive calls could be more structured around needs. Consideration should be given to replace non-verbal prompts to describe problems, particularly for new health concerns. In continuing remote consultations, it is important to facilitate engagement with patients living with dementia and their carers to ensure good practice.