bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-sectional survey on researchers’ experience in using accelerometers in health-related studies
Authors: Albrecht Birte Marie , Flaßkamp Fabian Tristan , Koster Annemarie , Eskofier Bjoern M , Bammann Karin
Published: May 2022

Objectives

Accelerometers are widely applied in health studies, but lack of standardisation regarding device placement, sampling and data processing hampers comparability between studies. The objectives of this study were to assess how accelerometers are applied in health-related research and problems with accelerometer hardware and software encountered by researchers.

Methods

Researchers applying accelerometry in a health context were invited to a cross-sectional web-based survey (August 2020–September 2020). The questionnaire included quantitative questions regarding the application of accelerometers and qualitative questions on encountered hardware and software problems. Descriptive statistics were calculated for quantitative data and content analysis was applied to qualitative data.

Results

In total, 116 health researchers were included in the study (response: 13.7%). The most used brand was ActiGraph (67.2%). Independently of brand, the main reason for choosing a device was that it was the standard in the field (57.1%–83.3%). In children and adolescent populations, sampling frequency was higher (mean: 73.3 Hz ±29.9 Hz vs 47.6 Hz ±29.4 Hz) and epoch length (15.0s±15.6s vs 30.1s±25.9s) and non-wear time (42.9 min ±23.7 min vs 65.3 min ±35.4 min) were shorter compared with adult populations. Content analysis revealed eight categories of hardware problems (battery problems, compliance issues, data loss, mechanical problems, electronic problems, sensor problems, lacking waterproofness, other problems) and five categories of software problems (lack of user-friendliness, limited possibilities, bugs, high computational burden, black box character).

Conclusions

The study confirms heterogeneity regarding accelerometer use in health-related research. Moreover, several hardware and software problems were documented. Both aspects must be tackled to increase validity, practicability and comparability of research.
Risk assessment and implementation of risk reduction measures is not associated with increased transmission of SARS-CoV-2 compared with standard isolation at professional golf events
Authors: Robinson Patrick Gordon , Murray Andrew , Watson Matt , Close Graeme , Kinane Denis F
Published: May 2022

Objectives

The purpose of this prospective study was to report incidence and transmission of SARS-CoV-2, among professional golfers and essential support staff undergoing risk assessment and enhanced risk reduction measures when considered a close contact as opposed to standard isolation while competing on the DP World Tour during the 2021 season.

Methods

This prospective cohort study included all players and essential support staff participating in 26 DP World Tour events from 18 April 2021 to 21 November 2021. High-risk contacts were isolated for 10 days. Moderate-risk contacts received education regarding enhanced medical surveillance, had daily rapid antigen testing for 5 days, with reverse transcriptase-polymerase chain reaction (RT-PCR) tesing on day 5, mandated mask use and access to outside space for work purposes only. Low-risk contacts typically received rapid antigen testing every 48 hours and RT-PCR testing on day 5.

Results

The total study cohort compromised 13 394 person-weeks of exposure. There were a total of 30 positive cases over the study period. Eleven contacts were stratified as ‘high risk’. Two of these subsequently tested positive for SARS-CoV-2. There were 79 moderate-risk contact and 73 low-risk contacts. One moderate-risk contact subsequently tested positive for SARS-CoV-2 but did not transmit the virus. All other contacts, remained negative and asymptomatic to the end of the tournament week.

Conclusions

A risk assessment and risk reduction-based approach to contact tracing was safe in this professional golf event setting when Alpha and Delta were the predominant variants. It enabled professional golfers and essential support staff to work.
Assisted dying and medical practice: questions and considerations for healthcare organisations
Authors: Worthington Ana , Finlay Ilora , Regnard Claud
Published: May 2022

Objectives

Most clinical teams and organisations have not openly or formally discussed how they would react if physician-assisted suicide were to be legalised. This paper aims to discuss some of the potential challenges of introducing ‘assisted dying’ into medical care and produces a table of questions and considerations in light of such evidence so as to promote necessary discussion.

Methods

An analysis of recent quantitative and qualitative studies from jurisdictions where ‘assisted dying’ is practised was conducted, with particular attention paid to studies which focus on the impact of legalising ‘assisted dying’ on clinical care.

Results

‘Assisted dying’ can have a significant impact on clinical practice by complicating patient care and increasing clinician workload, potentially causing stress on patient care.

Conclusions

If physician-assisted suicide was to be legalised as part of existing healthcare, there are many questions that healthcare organisations must consider. Such considerations are tabulated in order to encourage awareness and discussion on the topic.
Serotonin syndrome
Authors: Maitland Stuart , Baker Mark
Published: May 2022

The serotonin syndrome is a life-threatening adverse drug reaction resulting from excess serotonergic agonism due to interactions between multiple drugs, poisoning, or less commonly due to therapeutic action of a single drug. The central triad of features in serotonin syndrome are altered mental state, autonomic hyperactivity, and neuromuscular abnormalities in the context of a patient with new/altered serotonergic therapy, although not all these features are consistently present in all patients. The severity of serotonin syndrome can be assessed clinically based on the number and severity of features. Severe serotonin syndrome warrants more careful management on a high-dependency unit. In case of temperature exceeding 38.5°C, urgent cooling measures and sedation should be employed, progressing to rapid sequence intubation and paralysis if cooling measures are ineffective.
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

Objectives

The 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).

Design

We 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.

Results

Out 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.

Conclusions

The 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 number

CRD42017068459.
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

Background

Most 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.

Objective

To 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.

Methods

We 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.

Findings

680 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.

Conclusions

Guided 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 implications

Guided digital mental health interventions should be considered for implementation in LMICs.

Trial registration number

ClinicalTrials.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

Background

An 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.

Methods

Patients 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.

Results

10 531 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).

Conclusions

Opioid 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

Objective

There 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).

Aim

To 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).

Design

In 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.

Results

Compared 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.

Conclusion

Though 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

Background

Exposure 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’.

Methods

We estimated excess mortality by occupational group and sex separately for each month in 2020 and for the entire 12 months overall.

Results

Mortality 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.

Conclusions

In 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.
Prognostic Utility of Biomarker Levels and Clinical Severity Scoring in Sepsis: A Comparative Study
Authors: Makkar Nayani , Soneja Manish , Arora Umang , Sood Rita , Biswas Sagnik , Jadon Ranveer Singh , Biswas Ashutosh , Wig Naveet
Published: May 2022

Procalcitonin (PCT) is one of the best validated biomarkers in the management of sepsis. However, its prognostic utility remains poorly studied. The present study sought to assess the prognostic utility of serial PCT assessments in patients with sepsis, and to compare the prognostic predictive capability of serial measurements of PCT with conventional markers of inflammation and validated intensive care unit (ICU) severity scoring systems. We recruited consecutive patients admitted to the medical units of a tertiary care center with suspected or proven bacterial infection and sepsis. Measurement of serum PCT levels, inflammatory markers, and ICU severity scores were performed at admission and repeated every 48 hours subsequently for the duration of hospital stay. 99 patients with bacterial infection and sepsis were recruited and followed until death or discharge. Median serum PCT level was similar between survivors and non-survivors on day 1, but was significantly lower at days 3, 5 and 7 in the survivors. The analysis found Acute Physiology and Chronic Health Evaluation (APACHE IV) score on all days (1, 3, 5, and 7), PCT on days 5 and 7, and Sequential Organ Failure Assessment score at 24 hours to have good predictive accuracy for adverse patient outcome. PCT clearance on days 3 and 5 of admission was measured and demonstrated predictive accuracy comparable to day-matched APACHE IV scores. While serial levels of serum PCT in patients with sepsis are accurate in the prediction of adverse patient outcome, they do not offer any additional clinical benefit over existing severity of illness scores and may be cost prohibitive in resource-limited settings. While serial levels of serum PCT in patients with sepsis are accurate in the prediction of adverse patient outcome, they do not offer any additional clinical benefit over existing severity of illness scores and may be cost prohibitive in resource-limited settings.
Time 2EVOLVE: predicting efficacy of engineered T-cells – how far is the bench from the bedside?
Authors: Guedan Sonia , Luu Maik , Ammar Delphine , Barbao Paula , Bonini Chiara , Bousso Philippe , Buchholz Christian J , Casucci Monica , De Angelis Biagio , Donnadieu Emmanuel , Espie David , Greco Beatrice , Groen Richard , Huppa Johannes B , Kantari-Mimoun Chahrazade , Laugel Bruno , Mantock Mary , Markman Janet L , Morris Emma , Quintarelli Concetta , Rade Michael , Reiche Kristin , Rodriguez-Garcia Alba , Rodriguez-Madoz Juan Roberto , Ruggiero Eliana , Themeli Maria , Hudecek Michael , Marchiq Ibtissam
Published: May 2022

Immunotherapy with gene engineered CAR and TCR transgenic T-cells is a transformative treatment in cancer medicine. There is a rich pipeline with target antigens and sophisticated technologies that will enable establishing this novel treatment not only in rare hematological malignancies, but also in common solid tumors. The T2EVOLVE consortium is a public private partnership directed at accelerating the preclinical development of and increasing access to engineered T-cell immunotherapies for cancer patients. A key ambition in T2EVOLVE is to assess the currently available preclinical models for evaluating safety and efficacy of engineered T cell therapy and developing new models and test parameters with higher predictive value for clinical safety and efficacy in order to improve and accelerate the selection of lead T-cell products for clinical translation. Here, we review existing and emerging preclinical models that permit assessing CAR and TCR signaling and antigen binding, the access and function of engineered T-cells to primary and metastatic tumor ligands, as well as the impact of endogenous factors such as the host immune system and microbiome. Collectively, this review article presents a perspective on an accelerated translational development path that is based on innovative standardized preclinical test systems for CAR and TCR transgenic T-cell products.
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

Background

IgA 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).

Methods

Patient 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.

Results

Serum 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.

Conclusions

Overall, 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

Background

Immune 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.

Methods

TMB 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.

Results

While 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.

Conclusions

We 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

Background

Mitochondria 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.

Methods

We 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.

Results

Single-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.

Conclusions

Hepatic 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

Background

Following 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.

Methods

We 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.

Results

Six-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%).

Conclusion

Contrary 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

Objective

To 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.

Methods

This 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.

Results

We 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).

Conclusion

Our 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.
Risk factors of disease flares in a Chinese lupus cohort with low-grade disease activity
Authors: Sun Fangfang , Zhao Liling , Wang Haiting , Zhang Danting , Chen Jie , Wang Xiaodong , Li Ting , Ye Shuang
Published: May 2022

Objective

Recurrent disease flare is one of the key problems in lupus patients. A Chinese Flare-Prevention Lupus Initiative Cohort (FLIC) was established. Risk factors of disease flare were evaluated accordingly.

Methods

Patients with low-grade disease activity (the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) =≤6, daily prednisone ≤20 mg, no British Isles Lupus Assessment Group A or no more than one B organ domain score) from January 2014 to August 2020 were included in the FLIC. Disease flares were defined by the modified SELENA-­SLEDAI Flare Index. Low disease activity status (LDAS) and remission were also assessed. The cumulative flare rate was estimated by an event per 100 person-years analysis. Cox proportional hazards models were performed to identify risk factors of subsequent disease flares after adjusting clinical confounders. Survival was assessed with the Kaplan-Meier method.

Results

448 eligible patients with low-grade disease activity were included in FLIC. During a mean follow-up of 30.4 months, 170 patients flared. The cumulative lupus flare rate was 22.2 events per 100 patient-years. Compared with patients without flare, those with lupus flares were taking more prednisone, had higher disease activity index and with less patients attained LDAS/remission at baseline. They also had higher rates of antiphospholipid antibodies (aPLs) and antiribosomal P antibody. Cox regression analysis confirmed that attainment of either LDAS or remission at baseline were independent protective factors against subsequent disease flare (LDAS but not in remission: HR 0.58, 95% CI 0.38~0.88; remission: HR 0.46, 95% CI 0.30~0.69), while aPL was a risk factor of lupus flares (HR 1.95, 95% CI 1.36~2.78). Kaplan-Meier curves indicated that attaining LDAS or remission and absence of aPL at baseline had the least flare risk.

Conclusions

In our real-world cohort study, not attaining LDAS or remission at baseline and aPL positivity was associated with higher risk of disease flares in patients with low-grade SLE.
Two kinds of embryo research: four case examples
Authors: Savulescu Julian , Labude Markus , Barcellona Capucine , Huang Zhongwei , Leverentz Michael Karl , Xafis Vicki , Lysaght Tamra
Published: May 2022

There are ethical obligations to conduct research that contributes to generalisable knowledge and improves reproductive health, and this should include embryo research in jurisdictions where it is permitted. Often, the controversial nature of embryo research can alarm ethics committee members, which can unnecessarily delay important research that can potentially improve fertility for patients and society. Such delay is ethically unjustified. Moreover, countries such as the UK, Australia and Singapore have legislation which unnecessarily captures low-risk research, such as observational research, in an often cumbersome and protracted review process. Such countries should revise such legislation to better facilitate low-risk embryo research.

We introduce a philosophical distinction to help decision-makers more efficiently identify higher risk embryo research from that which presents no more risks to persons than other types of tissue research. That distinction is between future person embryo research and non-future person embryo research. We apply this distinction to four examples of embryo research that might be presented to ethics committees.

Embryo research is most controversial and deserving of detailed scrutiny when it potentially affects a future person. Where it does not, it should generally require less ethical scrutiny. We explore a variety of ways in which research can affect a future person, including by deriving information about that person, and manipulating eggs or sperm before an embryo is created.
Research ethics and public trust in vaccines: the case of COVID-19 challenge trials
Authors: Eyal Nir
Published: May 2022

Despite their clearly demonstrated safety and effectiveness, approved vaccines against COVID-19 are commonly mistrusted. Nations should find and implement effective ways to boost vaccine confidence. But the implications for ethical vaccine development are less straightforward than some have assumed. Opponents of COVID-19 vaccine challenge trials, in particular, made speculative or empirically implausible warnings on this matter, some of which, if applied consistently, would have ruled out most COVID-19 vaccine trials and many non-pharmaceutical responses.
Clinical law: what do clinicians want to know? The demography of clinical law
Authors: Wheeler Robert , Hall Nigel
Published: May 2022

This is the first description of the questions that clinicians ask a department of clinical law, relating to the legal rules applicable to the care of their patients.

Objectives

To describe in detail the demography of clinical legal enquiries made by clinicians of all professions concerning the care of their patients. To collate and categorise the varieties of enquiry, to identify phenotypic patterns. To provide colleges, regulators, commissioners, educators and the NHS with an insight into hitherto undescribed subject matter, better to understand and respond to this aspect of clinical practice.

Design

Prospective collection of all clinical legal referrals recorded in writing over 12 years by a department of clinical law.

Setting

An English Tertiary Hospital NHS Trust.

Participants

Clinical staff of the regulated professions, all seeking to have their clinical legal enquiries answered.

Main outcome measures

The description of the demography of clinical law.

Results

1251 written records were identified and reviewed. These were divided into nine broad clinical legal subject areas (domains): mental disorders, parents and children, incapacity, consent for treatment, disclosure of private information, other statutory, regulated practice, professional practice, clinical practice. Within these, 149 clinical legal phenotypes were identified to which each case could be assigned.

Conclusions

Among a broad range of enquiries, recognisable clinical legal phenotypes exist and have for the first time been described and categorised. These are clinical situations which clinicians need to be able to recognise and equipped to deal with. Doing so will likely facilitate timely and better treatment.
Combined anterior and posterior circulation approach for stent-assisted coiling of a recurrent basilar tip aneurysm
Authors: Domingo Ricardo A , Ramos-Fresnedo Andres , Ravindran Krishnan , Tawk Rabih G
Published: May 2022

Endovascular treatment of recurrent basilar aneurysms is challenging due to significant changes in the configuration of the aneurysm and adjacent vessels from prior interventions.1 Coil compaction is a common cause of recurrence and alters the aneurysm morphology significantly.2–4 Stenting of the basilar artery into a posterior cerebral artery modifies the angles between these vessels.5 In this video, we discuss a combined approach via the anterior and posterior circulation for stent-assisted coiling of a recurrent basilar tip aneurysm (Video 1) . A patient in their 40s with a history of ruptured aneurysm underwent multiple endovascular interventions including coiling, stent-assisted coiling, and Woven Endobridge (WEB) device. The patient presented with worsening headaches and underwent treatment with stent-assisted coiling for recurrence. After encountering challenges with direct access from the basilar artery, a combined anterior and posterior circulation approach was used.6 The stent was deployed through the posterior communicating artery and a snare was used to navigate the complex anatomy.

Video 1
Comparison of cancer incidence and mortality in the Norwegian Fire Departments Cohort, 1960–2018
Authors: Marjerrison Niki , Jakobsen Jarle , Demers Paul A , Grimsrud Tom K , Hansen Johnni , Martinsen Jan Ivar , Nordby Karl-Christian , Veierød Marit B , Kjærheim Kristina
Published: May 2022

Objectives

Elevated risk of cancer at several sites has been reported among firefighters, although with mixed findings. The purpose of this study was to calculate standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs) for cancer and compare them to assess whether use of the different measures could be a source of inconsistencies in findings.

Methods

The Norwegian Fire Departments Cohort, comprising 4295 male employees who worked at 15 fire departments across Norway, was linked to health outcome registries for the period 1960–2018. SIRs and SMRs were derived using national reference rates.

Results

Overall, we observed elevated incidence of colon cancer (SIR, 95% CI 1.27, 1.01 to 1.58), mesothelioma (2.59, 1.12 to 5.11), prostate cancer (1.18, 1.03 to 1.34) and all sites combined (1.15, 1.08 to 1.23). Smaller, non-significant elevations were found for mortality of colon cancer (SMR, 95% CI 1.20, 0.84 to 1.67) and mesothelioma (1.66, 0.34 to 4.86), while SMR for prostate cancer was at unity. Potential errors were observed in some of the mortality data, notably for mesothelioma cases. Among those who died of cancer, 3.7% (n=14) did not have a prior diagnosis of malignancy at the same site group.

Conclusions

Assessment of incidence or mortality did not greatly influence the interpretation of results. The most prominent differences in SIR and SMR appeared to be due to inconsistencies between sites of cancer diagnosis and cause of death. The difference in SIR and SMR for prostate cancer suggested a detection bias from differential screening practices.
Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease
Authors: Guyatt Anna , John Catherine , Williams Alexander T , Shrine Nick , Reeve Nicola F ,   SpiroMeta consortium, Sayers Ian , Hall Ian , Wain Louise V , Sheehan Nuala , Dudbridge Frank , Tobin Martin D
Published: May 2022

Rationale

Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood.

Objectives

We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections.

Methods

We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils.

Measurements and main results

Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1(weighted median estimator, SD FEV1/FVC: −0.054 (95% CI −0.078 to −0.029), effect only prominent in individuals with asthma).

Conclusions

Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.