bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mental healthcare in primary and community-based settings: evidence beyond the WHO Mental Health Gap Action Programme (mhGAP) Intervention Guide
Authors: Keynejad Roxanne C , Spagnolo Jessica , Thornicroft Graham 
Published: May 2022

ObjectivesThe WHO’s Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) has been widely used in low and middle-income countries. We reviewed literature describing interventions and training programmes beyond the mhGAP-IG, in primary healthcare (PHC) and community-based healthcare (CBH).DesignWe searched studies excluded from our updated mhGAP-IG systematic review, and included in other relevant systematic reviews, for evidence and experience of initiatives integrating mental health into PHC and CBH. Our 24 November 2020 mhGAP-IG search encompassed MEDLINE, Embase, PsycINFO, Web of Knowledge, Scopus, CINAHL, LILACS, ScieELO, Cochrane, PubMed databases, 3ie and Google Scholar. Although heterogeneity prevented meta-analysis, we descriptively summarised the evidence-base.ResultsOut of 1827 results, we identified 208 relevant records. They described randomised controlled trials of mental health interventions (98 studies, n=55 523 participants), non-randomised studies measuring clinical outcomes (22 studies, n=7405), training outcomes (36 studies, n=12 280) and implementation outcomes (21 studies, n=1090), plus descriptive accounts (18 studies, n=2526), baseline surveys and exploratory studies (6 studies, n=17 093) and commentaries (7 studies). Most (40%) were conducted in the African region, region of the Americas (16%), and South-East Asia (13%). Randomised and non-randomised studies reported improved symptoms, substance use, functioning, parenting and child outcomes. Non-randomised studies reported improved clinical knowledge, confidence and skills following training.ConclusionsThe literature beyond the mhGAP-IG is extensive and shares common findings. Future priorities are less-studied regions, interventions for severe mental illness, exploring ways that mhGAP-IG and alternative approaches complement each other in different contexts and scaling-up mental health integration.PROSPERO registration numberCRD42017068459.
Guided digital health intervention for depression in Lebanon: randomised trial
Authors: Cuijpers Pim , Heim Eva , Ramia Jinane Abi , Burchert Sebastian , Carswell Kenneth , Cornelisz Ilja , Knaevelsrud Christine , Noun Philip , van Klaveren Chris , van’t Hof Edith , Zoghbi Edwina , van Ommeren Mark , El Chammay Rabih 
Published: May 2022

BackgroundMost people with mental disorders in communities exposed to adversity in low-income and middle-income countries (LMICs) do not receive effective care. Digital mental health interventions are scalable when digital access is adequate, and can be safely delivered during the COVID-19 pandemic.ObjectiveTo examine the effects of a new WHO-guided digital mental health intervention, Step-by-Step, supported by a non-specialist helper in Lebanon, in the context of concurring economic, humanitarian and political crises, a large industrial disaster and the COVID-19 pandemic.MethodsWe conducted a single-blind, two-arm pragmatic randomised trial, comparing guided Step-by-Step with enhanced care as usual (ECAU) among people suffering from depression and impaired functioning. Primary outcomes were depression (Patient Health Questionnaire 9 (PHQ-9)) and impaired functioning (WHO Disability Assessment Schedule-12 (WHODAS)) at post-treatment.Findings680 people with depression (PHQ-9>10) and impaired functioning (WHODAS>16) were randomised to Step-by-Step or ECAU. Intention-to-treat analyses showed effects on depression (standardised mean differences, SMD: 0.71; 95% CI: 0.45 to 0.97), impaired functioning (SMD: 0.43; 95% CI: 0.21 to 0.65), post-traumatic stress (SMD: 0.53; 95% CI: 0.27 to 0.79), anxiety (SMD: 0.74; 95% CI: 0.49 to 0.99), subjective well-being (SMD: 0.37; 95% CI: 0.12 to 0.62) and self-identified personal problems (SMD: 0.56; 95% CI 0.29 to 0.83). Significant effects on all outcomes were retained at 3-month follow-up.ConclusionsGuided digital mental health interventions can be effective in the treatment of depression in communities exposed to adversities in LMICs, although some uncertainty remains because of high attrition.Clinical implicationsGuided digital mental health interventions should be considered for implementation in LMICs.Trial registration numberClinicalTrials.govNCT03720769.
Impact of prehospital opioid dose on angiographic and clinical outcomes in acute coronary syndromes
Authors: Fernando Himawan , Nehme Ziad , Dinh Diem , Andrew Emily , Brennan Angela , Shi William , Bloom Jason , Duffy Stephen James , Shaw James , Peter Karlheinz , Nadurata Voltaire , Chan William , Layland Jamie , Freeman Melanie , Van Gaal William , Bernard Stephen , Lefkovits Jeffrey , Liew Danny , Stephenson Michael , Smith Karen , Stub Dion 
Published: May 2022

BackgroundAn adverse interaction whereby opioids impair and delay the gastrointestinal absorption of oral P2Y12inhibitors has been established, however the clinical significance of this in acute coronary syndrome (ACS) is uncertain. We sought to characterise the relationship between prehospital opioid dose and clinical outcomes in patients with ACS.MethodsPatients given opioid treatment by emergency medical services (EMS) with ACS who underwent percutaneous coronary intervention (PCI) between 1 January 2014 and 31 December 2018 were included in this retrospective cohort analysis using data linkage between the Ambulance Victoria, Victorian Cardiac Outcomes Registry and Melbourne Interventional Group databases. Patients with cardiogenic shock, out-of-hospital cardiac arrest and fibrinolysis were excluded. The primary end point was the risk-adjusted odds of 30-day major adverse cardiac events (MACE) between patients who received opioids and those that did not.Results10 531 patients were included in the primary analysis. There was no significant difference in 30-day MACE between patients receiving opioids and those who did not after adjusting for key patient and clinical factors. Among patients with ST-elevation myocardial infarction (STEMI), there were significantly more patients with thrombolysis in myocardial infarction (TIMI) 0 or 1 flow pre-PCI in a subset of patients with high opioid dose versus no opioids (56% vs 25%, p<0.001). This remained significant after adjusting for known confounders with a higher predicted probability of TIMI 0/1 flow in the high versus no opioid groups (33% vs 11%, p<0.001).ConclusionsOpioid use was not associated with 30-day MACE. There were higher rates of TIMI 0/1 flow pre-PCI in patients with STEMI prescribed opioids. Future prospective research is required to verify these findings and investigate alternative analgesia for ischaemic chest pain.
Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea
Authors: Camilleri Michael , Carlson Paula , BouSaba Joelle , McKinzie Sanna , Vijayvargiya Priya , Magnus Yorick , Sannaa Wassel , Wang Xiao Jing , Chedid Victor , Zheng Ting , Maselli Daniel , Atieh Jessica , Taylor Ann , Nair Asha A , Kengunte Nagaraj Nagaswaroop , Johnson Stephen , Chen Jun , Burton Duane , Busciglio Irene 
Published: May 2022

ObjectiveThere are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD).AimTo compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL).DesignIn patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM.ResultsCompared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation ofSLC44A5(a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes (CLDN2), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter (FABP6; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation.ConclusionThough sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes.
Excess mortality among essential workers in England and Wales during the COVID-19 pandemic
Authors: Matz Melissa , Allemani Claudia , van Tongeren Martie , Nafilyan Vahé , Rhodes Sarah , van Veldhoven Karin , Pembrey Lucy , Coleman Michel P , Pearce Neil 
Published: May 2022

BackgroundExposure to SARS-CoV-2, subsequent development of COVID-19 and death from COVID-19 may vary by occupation, and the risks may be higher for those categorised as ‘essential workers’.MethodsWe estimated excess mortality by occupational group and sex separately for each month in 2020 and for the entire 12 months overall.ResultsMortality for all adults of working age was similar to the annual average over the previous 5 years. Monthly excess mortality peaked in April, when the number of deaths was 54.2% higher than expected and was lowest in December when deaths were 30.0% lower than expected.Essential workers had consistently higher excess mortality than other groups throughout 2020. There were also large differences in excess mortality between the categories of essential workers, with healthcare workers having the highest excess mortality and social care and education workers having the lowest. Excess mortality also varied widely between men and women, even within the same occupational group. Generally, excess mortality was higher in men.ConclusionsIn summary, excess mortality was consistently higher for essential workers throughout 2020, particularly for healthcare workers. Further research is needed to examine excess mortality by occupational group, while controlling for important confounders such as ethnicity and socioeconomic status. For non-essential workers, the lockdowns, encouragement to work from home and to maintain social distancing are likely to have prevented a number of deaths from COVID-19 and from other causes.
Network analysis of genes associated with esophageal squamous cell carcinoma progression
Authors: Li Xu , Xia Zhenkun 
Published: May 2022

This study aims to identify possible genes associated with esophageal squamous cell carcinoma (ESCC) by bioinformatics tool and further explore the function of immunoglobulin heavy chain variable family 4 gene (IGHV4)-28 in the ESCC progression. The ESCC-related genes in Cancer Genome Atlas (TCGA) database were analyzed by bioinformatics tools, which finally identified IGHV4-28. The expression levels of IGHV4-28 in TE-4 and EC9706 cells were detected by quantitative reverse transcription-PCR (qRT-PCR). Then oe-IGHV4-28 or sh-IGHV4-28 was transfected into TE-4 and EC9706 cells to verify the effect on cell proliferation, migration, invasion, and apoptosis rate. In vivo, a nude mouse model of ESCC was developed, whereby the tumor volume and weight were calculated to evaluate the impact of IGHV4-8 on tumor growth. Bioinformatics analysis using TCGA database showed that IGHV4-28, IGLV6-57, and KPRP were all associated with ESCC progression. Kaplan-Meier (KM) analysis showed overexpression of IGHV4-28 is substantially associated with the survival rate of patients with ESCC. IGHV4-28 was highly expressed in TE-4 and EC9706 cell lines and overexpression of IGHV4-28 enhanced cell proliferation, invasion, and migration, as well as decreased apoptosis rate. Moreover, nude mice transplanted with IGHV4-28-silencing TE-4 cells showed restrained tumor weight and volume. In summary, IGHV4-28 was increasingly expressed in ESCC and may serve as a therapeutic target in the treatment of ESCC.
Intrahepatic inflammatory IgA+PD-L1high monocytes in hepatocellular carcinoma development and immunotherapy
Authors: Sung Pil Soo , Park Dong Jun , Roh Pu Reun , Mun Kyoung Do , Cho Sung Woo , Lee Gil Won , Jung Eun Sun , Lee Sung Hak , Jang Jeong Won , Bae Si Hyun , Choi Jong Young , Choi Jonghwan , Ahn Jaegyoon , Yoon Seung Kew 
Published: May 2022

BackgroundIgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepatic inflammatory IgA+ monocytes in the development of hepatocellular carcinoma (HCC).MethodsPatient cohorts including steatohepatitis cohort (n=61) and HCC cohort (n=271) were established. Patients’ surgical and biopsy specimens were analyzed using immunohistochemistry. Multicolor flow cytometry was performed with a subset of patient samples. Single-cell RNA-Seq analysis was performed using Gene Expression Omnibus (GEO) datasets. Additionally, we performed in vitro differentiation of macrophages, stimulation with coated IgA, and RNA sequencing. Hepa1-6 cells and C57BL/6N mice were used to obtain HCC syngeneic mouse models.ResultsSerum IgA levels were associated (p<0.001) with fibrosis progression and HCC development in patients with chronic liver diseases. Additionally, immunohistochemical staining of inflamed livers or HCC revealed IgA positivity in monocytes, with a correlation between IgA+ cell frequency and IgA serum levels. Compared with IgA− monocytes, intrahepatic IgA+ monocytes expressed higher levels of programmed death-ligand 1 (PD-L1) in inflamed livers and in HCC tumor microenvironment. Single-cell RNA sequencing using NCBI GEO database indicated an upregulation in inflammation-associated genes in the monocytes of patients whose plasma cell IGHA1 expression was greater than or equal to the median value. Bulk RNA sequencing demonstrated that in vitro stimulation of M2-polarized macrophages using coated IgA complex induced PD-L1 upregulation via YAP-mediated signaling. In vivo blockade of IgA signaling decreased the number of tumor-infiltrating IgA+PD-L1high macrophages and increased the number of CD69+CD8+ T cells to enhance antitumor effects in HCC mice models.ConclusionsOverall, the findings of this study showed that serum IgA levels was correlated with intrahepatic and intratumoral infiltration of inflammatory IgA+PD-L1high monocytes in chronic liver diseases and HCC, providing potential therapeutic targets.
Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome
Authors: Gorris Mark A J , van der Woude Lieke L , Kroeze Leonie I , Bol Kalijn , Verrijp Kiek , Amir Avital L , Meek Jelena , Textor Johannes , Figdor Carl G , de Vries I Jolanda M 
Published: May 2022

BackgroundImmune checkpoint inhibitors (ICI) can lead to long-term responses in patients with metastatic melanoma. Still many patients with melanoma are intrinsically resistant or acquire secondary resistance. Previous studies have used primary or metastatic tumor tissue for biomarker assessment. Especially in melanoma, metastatic lesions are often present at different anatomical sites such as skin, lymph nodes, and visceral organs. The anatomical site may directly affect the tumor microenvironment (TME). To evaluate the impact of tumor evolution on the TME and on ICI treatment outcome, we directly compared paired primary and metastatic melanoma lesions for tumor mutational burden (TMB), HLA-ABC status, and tumor infiltrating lymphocytes (TILs) of patients that received ipilimumab.MethodsTMB was analyzed by sequencing primary and metastatic melanoma lesions using the TruSight Oncology 500 assay. Tumor tissues were subjected to multiplex immunohistochemistry to assess HLA-ABC status and for the detection of TIL subsets (B cells, cytotoxic T cells, helper T cells, and regulatory T cells), by using a machine-learning algorithm.ResultsWhile we observed a very good agreement between TMB of matched primary and metastatic melanoma lesions (intraclass coefficient=0.921), such association was absent for HLA-ABC status, TIL density, and subsets thereof. Interestingly, analyses of different metastatic melanoma lesions within a single patient revealed that TIL density and composition agreed remarkably well, rejecting the hypothesis that the TME of different anatomical sites affects TIL infiltration. Similarly, the HLA-ABC status between different metastatic lesions within patients was also comparable. Furthermore, high TMB, of either primary or metastatic melanoma tissue, directly correlated with response to ipilimumab, whereas lymphocyte density or composition did not. Loss of HLA-ABC in the metastatic lesion correlated to a shorter progression-free survival on ipilimumab.ConclusionsWe confirm the link between TMB and HLA-ABC status and the response to ipilimumab-based immunotherapy in melanoma, but no correlation was found for TIL density, neither in primary nor metastatic lesions. Our finding that TMB between paired primary and metastatic melanoma lesions is highly stable, demonstrates its independency of the time point and location of acquisition. TIL and HLA-ABC status in metastatic lesions of different anatomical sites are highly similar within an individual patient.
Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion
Authors: Song Byong-Sop , Moon Ji Sun , Tian Jingwen , Lee Ho Yeop , Sim Byeong Chang , Kim Seok-Hwan , Kang Seul Gi , Kim Jung Tae , Nga Ha Thi , Benfeitas Rui , Kim Yeongmin , Park Sanghee , Wolfe Robert R. , Eun Hyuk Soo , Shong Minho , Lee Sunjae , Kim Il-Young , Yi Hyon-Seung 
Published: May 2022

BackgroundMitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer.MethodsWe used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively.ResultsSingle-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression.Crif1deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells.Crif1deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production.ConclusionsHepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.
Discrepancy between disability and reported well-being after traumatic brain injury
Authors: Retel Helmrich Isabel Rosalie Arianne , van Klaveren David , Andelic Nada , Lingsma Hester , Maas Andrew , Menon David , Polinder Suzanne , Røe Cecilie , Steyerberg Ewout W , Van Veen Ernest , Wilson Lindsay 
Published: May 2022

BackgroundFollowing traumatic brain injury (TBI), the clinical focus is often on disability. However, patients’ perceptions of well-being can be discordant with their disability level, referred to as the ‘disability paradox’. We aimed to examine the relationship between disability and health-related quality of life (HRQoL) following TBI, while taking variation in personal, injury-related and environment factors into account.MethodsWe used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury study. Disability was assessed 6 months post-injury by the Glasgow Outcome Scale-Extended (GOSE). HRQoL was assessed by the SF-12v2 physical and mental component summary scores and the Quality of Life after Traumatic Brain Injury overall scale. We examined mean total and domain HRQoL scores by GOSE. We quantified variance in HRQoL explained by GOSE, personal, injury-related and environment factors with multivariable regression.ResultsSix-month outcome assessments were completed in 2075 patients, of whom 78% had mild TBI (Glasgow Coma Scale 13–15). Patients with severe disability had higher HRQoL than expected on the basis of GOSE alone, particularly after mild TBI. Up to 50% of patients with severe disability reported HRQoL scores within the normative range. GOSE, personal, injury-related and environment factors explained a limited amount of variance in HRQoL (up to 29%).ConclusionContrary to the idea that discrepancies are unusual, many patients with poor functional outcomes reported well-being that was at or above the boundary considered satisfactory for the normative sample. These findings challenge the idea that satisfactory HRQoL in patients with disability should be described as ‘paradoxical’ and question common views of what constitutes ‘unfavourable’ outcome.
Shift of multiple sclerosis onset towards older age
Authors: Prosperini Luca , Lucchini Matteo , Ruggieri Serena , Tortorella Carla , Haggiag Shalom , Mirabella Massimiliano , Pozzilli Carlo , Gasperini Claudio 
Published: May 2022

ObjectiveTo explore whether age at onset increased over time despite a shortened interval from the initial clinical demyelinating event to the diagnosis of multiple sclerosis (MS), as promoted by updated diagnostic criteria.MethodsThis was an independent, multicentre, retrospective study based on data from 4345 patients with relapsing-onset MS attending three tertiary MS Clinics in Italy. After stratifying the year of MS onset into four periods (<1991, 1991–2000, 2001–2010, 2011–2021), we analysed the temporal trends in age at onset and interval from onset to diagnosis; we then explored the female-to-male ratio and onset location across different classes of age at onset.ResultsWe observed an increased mean age at onset, and a shortened mean interval to diagnosis over time (p<0.0001). Accordingly, there were more MS onsets at the older age classes of 40-49, 50–59 and ≥60 years (p<0.0001). In cases with age at onset ≥40 years, we also found an increased female-to-male ratio (p=0.007), more frequent spinal cord (p=0.0004) and less frequent supratentorial onset (p=0.008).ConclusionOur study shows a forward shift towards an older age at onset of MS, thus suggesting considerable thought on the place-in-therapy of most currently used disease-modifying treatments, and on the standard of care to an older population.