title: Pandemic inequity in a megacity: a multilevel analysis of individual, community, and health care vulnerability risks for COVID-19 mortality in Jakarta, Indonesia

abstract:
BackgroundThe 33 recognized megacities comprise approximately 7% of the global population, yet account for 20% COVID-19 deaths. The specific inequities and other factors within megacities that affect vulnerability to COVID-19 mortality remain poorly defined. We assessed individual, community-level and health care factors associated with COVID-19-related mortality in a megacity of Jakarta, Indonesia, during two epidemic waves spanning March 2, 2020, to August 31, 2021.

MethodsThis retrospective cohort included all residents of Jakarta, Indonesia, with PCR-confirmed COVID-19. We extracted demographic, clinical, outcome (recovered or died), vaccine coverage data, and disease prevalence from Jakarta Health Office surveillance records, and collected sub-district level socio-demographics data from various official sources. We used multi-level logistic regression to examine individual, community and sub-district-level health care factors and their associations with COVID-19-mortality.

FindingsOf 705,503 cases with a definitive outcome by August 31, 2021, 694,706 (98{middle dot}5%) recovered and 10,797 (1{middle dot}5%) died. The median age was 36 years (IQR 24-50), 13{middle dot}2% (93,459) were <18 years, and 51{middle dot}6% were female. The sub-district level accounted for 1{middle dot}5% of variance in mortality (p<0.0001). Individual-level factors associated with death were older age, male sex, comorbidities, and, during the first wave, age <5 years (adjusted odds ratio (aOR) 1{middle dot}56, 95%CI 1{middle dot}04-2{middle dot}35; reference: age 20-29 years). Community-level factors associated with death were poverty (aOR for the poorer quarter 1{middle dot}35, 95%CI 1{middle dot}17-1{middle dot}55; reference: wealthiest quarter), high population density (aOR for the highest density 1{middle dot}34, 95%CI 1{middle dot}14-2{middle dot}58; reference: the lowest), low vaccine coverage (aOR for the lowest coverage 1{middle dot}25, 95%CI 1{middle dot}13-1{middle dot}38; reference: the highest).

InterpretationIn addition to individual risk factors, living in areas with high poverty and density, and low health care performance further increase the vulnerability of communities to COVID-19-associated death in urban low-resource settings.

FundingWellcome (UK) Africa Asia Programme Vietnam (106680/Z/14/Z).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on November 22, 2021, for articles that assessed individual, community, and healthcare vulnerability factors associated with coronavirus disease 2019 (COVID-19) mortality, using the search terms ("novel coronavirus" OR "SARS-CoV-2" OR "COVID-19") AND ("death" OR "mortality" OR "deceased") AND ("community" OR "social") AND ("healthcare" OR "health system"). The 33 recognized megacities comprise approximately 7% of the global population, yet account for 20% COVID-19 deaths. The specific inequities and other factors within megacities that affect vulnerability to COVID-19 mortality remain poorly defined. At individual-level, studies have shown COVID-19-related mortality to be associated with older age and common underlying chronic co-morbidities including hypertension, diabetes, obesity, cardiac disease, chronic kidney disease and liver disease. Only few studies from North America, and South America have reported the association between lower community-level socio-economic status and healthcare performance with increased risk of COVID-19-related death. We found no studies have been done to assess individual, community, and healthcare vulnerability factors associated with COVID-19 mortality risk, especially in lower-and middle-income countries (LMIC) where accessing quality health care services is often challenging for substantial proportions of population, due to under-resourced and fragile health systems. In Southeast Asia, by November 22, 2021, COVID-19 case fatality rate had been reported at 2{middle dot}2% (23,951/1,104,835) in Vietnam, 1{middle dot}7% (47,288/2,826,853) in Philippines, 1{middle dot}0% (20,434/2,071,009) in Thailand, 1{middle dot}2% (30,063/2,591,486) in Malaysia, 2{middle dot}4% (2,905/119,904) in Cambodia, and 0{middle dot}3% in Singapore (667/253,649). Indonesia has the highest number of COVID-19 cases and deaths in the region, reporting 3{middle dot}4% case fatality rate (143,744 /4,253,598), with the highest number of cases in the capital city of Jakarta. A preliminary analysis of the first five months of surveillance in Jakarta found that 497 of 4265 (12%) hospitalised patients had died, associated with older age, male sex; pre-existing hypertension, diabetes, or chronic kidney disease; clinical diagnosis of pneumonia; multiple (>3) symptoms; immediate intensive care unit admission, or intubation.

Added value of this studyThis retrospective population-based study of the complete epidemiological surveillance data of Jakarta during the first eighteen months of the epidemic is the largest studies in LMIC to date, that comprehensively analysed the individual, community, and healthcare vulnerability associated with COVID-19-related mortality among individuals diagnosed with PCR-confirmed COVID-19. The overall case fatality rate among general population in Jakarta was 1{middle dot}5% (10,797/705,503). Individual factors associated with risk of death were older age, male sex, comorbidities, and, during the first wave, age <5 years (adjusted odds ratio (aOR) 1{middle dot}56, 95%CI 1{middle dot}04-2{middle dot}35; reference: age 20-29 years). The risk of death was further increased for people living in sub-districts with high rates of poverty (aOR for the poorer quarter 1{middle dot}35, 95%CI 1{middle dot}17-1{middle dot}55; reference: wealthiest quarter), high population density (aOR for the highest density 1{middle dot}34, 95%CI 1{middle dot}14-2{middle dot}58), and low COVID-19 vaccination coverage (aOR for the lowest coverage 1{middle dot}25, 95%CI 1{middle dot}13-1{middle dot}38; reference: the highest).

Implications of all available evidenceDifferences in socio-demographics and access to quality health services, among other factors, greatly influence COVID-19 mortality in low-resource settings. This study affirmed that in addition to well-known individual risk factors, community-level socio-demographics and healthcare factors further increase the vulnerability of communities to die from COVID-19 in urban low-resource settings. These results highlight the need for accelerated vaccine rollout and additional preventive interventions to protect the urban poor who are most vulnerable to dying from COVID-19.


title: The COVID-19 pandemic and temporal change in metabolic risk factors for cardiovascular disease: a natural experiment within the HELIUS study.

abstract:
ObjectiveWe studied the association between the coronavirus disease 2019 (COVID-19) pandemic, including the restrictive measures, and metabolic risk factors for cardiovascular disease (CVD) in women and men. Next, we analysed whether changes in these metabolic risk factors were mediated by psychological and behavioural mechanisms.

DesignIn this natural experiment, we assessed changes from baseline in metabolic CVD risk factors in the exposed group (whose follow-up measurements were taken during the pandemic), and compared these to the changes in the control group (whose follow-up measurements were taken before the pandemic).

ParticipantsThis study used data from 6962 participants from six different ethnic groups (Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan) of the HELIUS study, based in Amsterdam, the Netherlands. We included women and men without prior CVD, who participated in both the baseline (2011-2015) and follow-up measurements (2019-2021).

Outcome measuresChanges between baseline and follow-up measurements in six metabolic CVD risk factors were calculated for systolic and diastolic blood pressure (SBP, DBP), total cholesterol (TC), fasting plasma glucose (FPG), haemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR).

ResultsThe exposed group experienced somewhat less favourable changes over time in SBP, DBP and FPG (the latter only in women) than the control group, while temporal changes in HbA1c and eGFR were more favourable among the control group. For instance, SBP was 1.119 mmHg [0.046, 2.193] higher in exposed than non-exposed women, and 1.380 [0.288, 2.471] in men. Changes in SBP and DBP were partially mediated by changes in behavioural factors, most notably BMI and alcohol consumption.

ConclusionsThe COVID-19 pandemic, including the restrictive lockdown measures, is associated with a deterioration of several CVD risk factors in women and men. These findings may aid in decision making concerning the management of and the recovery following the pandemic.

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThe COVID19 pandemic lockdown measures led to a pause in the data collection for the prospective, population-based HELIUS study, which shaped a natural experiment.
C_LIO_LINatural experiments, as quasi-experimental designs, are generally considered stronger than cross-sectional studies.
C_LIO_LIThrough inverse-probability weighting, this study aimed to account for baseline differences between the control and exposed group.
C_LIO_LIWe could not adjust for differences in follow-up time that occurred as a result of the restrictive measures, which may have affected estimates of variables that change with age.
C_LIO_LIThe effects of certain mediators may be underestimated, as the data available for defining these variables were largely based on self-reports.
C_LI

category: public and global health


title: Effects of drinking water, sanitation, handwashing and nutritional interventions on stress physiology, oxidative stress, and epigenetic programming in young children living in rural Bangladesh: A randomized clinical trial

abstract:
ImportanceA regulated stress response is essential for healthy trajectories, but the integrated effects of early childhood environmental and nutritional interventions on stress physiology are unknown.

ObjectiveTo assess the effects of a combined nutritional, water, sanitation, and handwashing intervention on physiological stress response, oxidative stress, and DNA methylation.

Design, Setting, and ParticipantsIn a trial in rural Bangladesh, we randomized geographical clusters of pregnant women and their in-utero children into either the combined nutritional, water, sanitation, and handwashing intervention or the control group. Physiological stress response, oxidative stress, and methylation levels of 757 children were measured at ages one and two years. Analysis was intention-to-treat.

InterventionsThe intervention group received combined nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap (N+WSH). The control group did not receive interventions.

Main Outcomes and MeasuresWe measured four isomers of urinary F2-isoprostanes [iPF(2)-III; 2,3-dinor-iPF(2)-III; iPF(2)-VI; 8,12-iso-iPF(2)-VI] at year one. At year two, we measured pre- and post-stressor concentrations of salivary alpha-amylase and cortisol, overall methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including methylation levels at the nerve growth factor-inducible protein A (NGFI-A) binding site, mean arterial pressure, and resting heart rate.

ResultsChildren in the N+WSH group had lower levels of F2-isoprostanes compared to controls (difference -0.16 to -0.19 log ng/mg of creatinine, P<0.01). Compared to the control group, post-stressor cortisol levels were elevated (0.24 log g/dl; 95% CI, 0.07 to 0.4; P<0.01) and the residualized gain score for cortisol was higher (0.06 g/dl; 95% CI, 0.01 to 0.12; P=0.023) in the N+WSH group. Children in the N+WSH group exhibited decreased logit-transformed methylation of the NGFI-A transcription factor binding site (-0.04; 95% CI, -0.08 to 0; P=0.037).

Conclusions and RelevanceA nutritional, water, sanitation, and handwashing intervention reduced oxidative stress, enhanced hypothalamic-pituitary-adrenocortical axis activity, and reduced methylation levels in a transcription factor binding site of the glucocorticoid receptor gene. A targeted environmental and nutritional intervention affected the set point, reactivity, and regulation of the physiological stress system in early childhood, which may have implications for long-term health and developmental trajectories.

Trial RegistrationClinicalTrials.gov NCT01590095

Key PointsO_ST_ABSQuestionC_ST_ABSDo intensive nutritional and environmental interventions alter physiological stress response, oxidative stress levels, and epigenetic programming during the first two years of life?

FindingsIn this cluster randomized clinical trial of 757 children, a combined nutritional, drinking water, sanitation, and handwashing intervention significantly reduced oxidative stress, enhanced the cortisol response, and reduced methylation levels in a transcription factor binding site of the glucocorticoid receptor gene.

MeaningThe integrated nutritional, drinking water, sanitation, and handwashing intervention enhanced adaptive responses of the physiological stress system in early childhood, which may have implications for long-term health and developmental trajectories.


title: A slow road from meat dominance to more sustainable diets: an analysis of purchase preferences

abstract:
BackgroundAchieving a sustainable and healthy diet requires increased replacement of red meat with more sustainable foods. There is a call for novel methodologies to assess the potential of different interventions and policies in enhancing the transition from the current to more sustainable choices.

ObjectiveWe aimed to characterize consumer clusters with similar preferences in protein sources, to compare the purchase prices of these foods, and to identify ongoing transitions from one protein source to another.

DesignGrocery purchase data with individual attributes on 29,437 consenting loyalty card holders were analyzed over 2.3 year period. We designed a sequence analysis to group participants to clusters with similar purchase preferences over the follow-up period and to estimate transition probabilities between preferences. We studied the determinants of prevalent purchase profiles by ordinal logistic models.

ResultsWe identified six participant profiles with similar preferences in four protein sources: red meat, poultry, fish, and plant-based foods. Red meat dominated the purchase preferences and showed the highest persistence over time. The majority (70%) of the participants demonstrated somewhat mixed purchase profiles. A step-by-step transition from red meat towards plant-based food preference seems most likely via poultry and fish. Overall, low income was not a barrier to a more sustainable purchase profile, while price may deter the purchase of fish. The most important resources in choosing more sustainable profiles were education and stage of family life.

ConclusionsSocietal incentives for sustainable food choices seem most crucial at transition stages of life course and for the less educated. Here we also demonstrate that grocery purchase data offer a valuable tool for monitoring the progressive transition towards a healthy and sustainable food system.

category: nutrition


title: Macrophage polarization in cesarean scar diverticulum

abstract:
AimsTo determine immunohistochemical features and correlations between M1/M2 polarization status with disease severity of post-cesarean scar diverticulum (CSD).

MethodsHistological and immunohistological staining were performed and inflammatory (CD16, CD163, and TNF-), fibrosis (-SMA), and angiogenic (CD31) markers were examined in uterine tissues collected from patients with uterine scar diverticula (CSD) (n=37) and cesarean section (CS) (n=3).

ResultsCSD tissues have higher expression of -SMA, TNF-, CD16, and CD31 and lower expression of CD163 than CS tissue (P <0.05). Compared with adjacent tissues, thick-walled blood vessels, glands, and fibrotic sites have higher expression of -SMA, TNF-, and CD16. Statistical correlation was observed between the expression of CD16 and TNF- (R = 0.693, P <0.001), -SMA (R = 0.404, P <0.05), and CD31 (R = 0.253, P <0.05) in CSD tissues, especially with the ratio of CD16/CD163 (R = 0.590, P <0.01). A more significant difference was observed between the expression of CD16/CD163 and -SMA (R = 0.556, P <0.001), TNF- (R = 0.633, P <0.0001) and CD31 (R = 0.336, P <0.05) Statistical correlation.

ConclusionIn this study, TNF-, -SMA, CD16, and CD31 proteins were overexpressed in all CSD cases, and CD16/CD163 was positively correlated with tissue inflammation, fibrosis, and neovascularization. Abnormal mononuclear macrophage infiltration may be involved in the origin and progression of CSD.

category: obstetrics and gynecology


title: Population-level changes in the mental health of UK workers during the COVID-19 pandemic: A longitudinal study using Understanding Society

abstract:
ObjectivesThe COVID-19 pandemic has substantially affected workers mental health. We investigated changes in UK workers mental health by industry, social class, and occupation and differential effects by UK country of residence, gender and age.

MethodsWe used representative Understanding Society data from 6,474 adults (41,207 observations) in paid employment who participated in pre-pandemic (2017-2020) and at least one COVID-19 survey. The outcome was psychological distress (General Health Questionnaire-12; score>=4). Exposures were industry, social class and occupation and are examined separately. Mixed-effects logistic regression was used to estimate relative (OR) and absolute (%) increases in distress before and during pandemic. Differential effects were investigated for UK countries of residence (Non-England/England), gender (Male/female), and age (Younger/Older) using 3-way interaction effects.

ResultsPsychological distress increased in relative terms most for  professional, scientific and technical (OR:3.15, 95% CI 2.17-4.59) industry in the pandemic versus pre-pandemic period. Absolute risk increased most in  hospitality (+11.4%). For social class,  small employers/self-employed were most affected in relative and absolute terms (OR:3.24, 95% CI 2.28-4.63; +10.3%). Across occupations  Sales and customer service (OR:3.01, 95% CI 1.61-5.62; +10.7%) had the greatest increase. Analysis with 3-way interactions showed considerable gender differences, while for UK country of residence and age results are mixed.

ConclusionsPsychological distress increases during the COVID-19 pandemic were concentrated among  professional and technical and  hospitality industries,  small employers/self-employed and  sales and customers service workers. Female workers often exhibited greater differences in risk by industry and occupation. Policies supporting these industries and groups are needed.

O_TEXTBOXWhat is already known about this subject?Employment has been disrupted by the COVID-19 pandemic and non-pharmaceutical interventions (e.g. national and regional  lockdowns) introduced to control the pandemic. The pandemic has impacted on different occupational groups in different ways and has been linked to substantial deteriorations in mental health.

What are the new findings?The effect of the COVID-19 pandemic on mental health has been particularly pronounced for those working in professional and technical industries, hospitality, customer service occupations, small employers and the self-employed as well as female workers.

How might this impact on policy or clinical practice in the foreseeable future?Policies should prioritise support to certain industries, occupations, the self-employed/small business owners, and particular demographic groups (e.g., women in sales and customer service occupations, younger  construction or non-England workers in  Public Administration and Defence) with high risk.

C_TEXTBOX

category: occupational and environmental health


title: Life course traumas, phenotypic aging, and cardiovascular disease: retrospective analysis of 104,939 UKB participants

abstract:
BackgroundWhile childhood and adulthood traumatic experiences have been linked to subsequent cardiovascular disease (CVD), the relationship between life course traumas and CVD and the underpinning pathways are poorly understood. This study aimed to: (1) examine the associations of childhood, adulthood, and lifetime traumas with CVD; (2) examine the associations between diverse life course traumatic profiles and CVD; and (3) examine the extent to which Phenotypic Age (PhenoAge), a well-developed phenotypic aging measure, mediates these associations.

MethodsWe included 104,939 participants from the UK Biobank who completed the 2016 online mental health questionnaire. CVD outcomes including ischemic heart disease, myocardial infarction, and stroke were ascertained. Childhood, adulthood, and lifetime traumas were categorized into three subgroups (mild, moderate, and severe), respectively. Four life course traumatic profiles were defined as non-severe traumas across life course, non-severe childhood and severe adulthood traumas, severe childhood and non-severe adulthood traumas, and severe traumas across life course based on both childhood and adulthood traumas. PhenoAge was measured using an equation previously developed. Multivariable logistic models and formal mediation analyses were performed.

ResultsOf 104,939 participants, 7,398 (7.0%) were diagnosed with CVD. Subgroups of childhood, adulthood, and lifetime traumas were associated with CVD, respectively. Furthermore, life course traumatic profiles were significantly associated with CVD. For instance, compared with subgroups experiencing non-severe traumas across life course, those who experienced non-severe childhood and severe adulthood traumas, severe childhood and non-severe adulthood traumas, and severe traumas across life course had higher odd of CVD, with odds ratios of 1.07 (95% confidence interval [CI]: 1.00, 1.15), 1.17 (95% CI: 1.09, 1.25), and 1.33 (95% CI: 1.24, 1.43), respectively. Formal mediation analyses suggested that PhenoAge partially mediated the above associations. For instance, PhenoAge mediated 5.8% of increased CVD events in subgroups who experienced severe childhood traumas, relative to those experiencing mild childhood traumas.

ConclusionsChildhood, adulthood, and lifetime traumas, as well as diverse life course traumatic profiles, were associated with CVD. Furthermore, phenotypic aging partially mediated these associations. These findings suggest a potential pathway from life course traumas to CVD through phenotypic aging, and underscore the importance of policy programs targeting traumatic events over the life course in ameliorating inequalities in cardiovascular health.

category: epidemiology


title: Predicting Post-operative Pain in Lung Cancer Patients using Pre-operative Peak Alpha Frequency

abstract:
Aims and ObjectivesExperimental models of neuropathic pain suggest that individual peak alpha frequency (PAF), measured using electroencephalography (EEG), can predict future pain sensitivity in experimental settings. Here, we tested whether PAF could predict future pain severity in a clinical setting in patients undergoing thoracotomy.

MethodsRecorded using wearable around the ear electrodes (cEEGrids), the feasibility and efficacy of pre-operative PAF as a neuro-marker for post-operative pain was assessed in 16 patients undergoing thoracic surgery for lung cancer (age = 67.53 {+/-} 4.38 [SD]). Patients also provided numerical ratings (0-10) of current, average, and worst pain pre-operatively as well as within three days post-operatively

Results and SignificancePre-operative PAF of less than 9 Hz was highly sensitive (1.0) and specific (0.86) in identifying patients who would go on to experience severe (>7/10) worst pain. Moreover, PAF was negatively correlated with patients current, average, and worst post-operative pain. PAF was significantly higher for those reporting lower pain severity compared to those reporting higher pain severity in the immediate post-operative period. This suggests that PAF is a promising neuro-marker to pre-operatively assess individual susceptibility to severe pain in the immediate post-operative period, possibly enabling more informed assessment of an individuals suitability for surgery.

category: pain medicine


title: Transcriptomic-based clustering of advanced atherosclerotic plaques identifies subgroups of plaques with differential underlying biology that associate with clinical presentation

abstract:
Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved sub- phenotyping. We hypothesized that unbiased clustering of plaques based on gene expression results in an alternative categorization of late-stage atherosclerotic lesions.

We analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These novel plaque phenotypes associated with clinical presentation (p<0.001) and showed differences in cellular compositions. Validation in coronary segments showed that the molecular signature of these plaques was linked to coronary ischemia. One of the plaque types with most severe clinical symptoms pointed to both inflammatory and fibrotic cell lineages. This highlighted plaque phenotype showed high expression of genes involved in active inflammatory processes, neutrophil degranulation, matrix turnover, and metabolism. For clinical translation, we did a first promising attempt to identify circulating biomarkers that mark these newly identified plaque phenotypes.

In conclusion, the definition of the plaque at risk for a thrombotic event can be fine-tuned by in- depth transcriptomic based phenotyping. These differential plaque phenotypes prove clinically relevant for both carotid and coronary artery plaques and point to differential underlying biology of symptomatic lesions.

category: cardiovascular medicine


title: Insights from an autism imaging biomarker challenge: promises and threats to biomarker discovery

abstract: MRI has been extensively used to identify anatomical and functional differences in Autism Spectrum Disorder (ASD). Yet, many of these findings have proven difficult to replicate because studies rely on small cohorts and are built on many complex, undisclosed, analytic choices. We conducted an international challenge to predict ASD diagnosis from MRI data, where we provided preprocessed anatomical and functional MRI data from > 2,000 individuals. Evaluation of the predictions was rigorously blinded. 146 challengers submitted prediction algorithms, which were evaluated at the end of the challenge using unseen data and an additional acquisition site. On the best algorithms, we studied the importance of MRI modalities, brain regions, and sample size. We found evidence that MRI could predict ASD diagnosis: the 10 best algorithms reliably predicted diagnosis with AUC[~]0.80 - far superior to what can be currently obtained using genotyping data in cohorts 20-times larger. We observed that functional MRI was more important for prediction than anatomical MRI, and that increasing sample size steadily increased prediction accuracy, providing an efficient strategy to improve biomarkers. We also observed that despite a strong incentive to generalise to unseen data, model development on a given dataset faces the risk of overfitting: performing well in cross-validation on the data at hand, but not generalising. Finally, we were able to predict ASD diagnosis on an external sample added after the end of the challenge (EU-AIMS), although with a lower prediction accuracy (AUC=0.72). This indicates that despite being based on a large multisite cohort, our challenge still produced biomarkers fragile in the face of dataset shifts.

category: radiology and imaging


title: A COMPREHENSIVE GUIDE TO MEGA-PRESS FOR GABA MEASUREMENT

abstract:
BackgroundThe aim of this guideline is to provide a series of evidence-based recommendations that allow those new to the field of MEGA-PRESS to produce high-quality data for the measurement of GABA levels using edited magnetic resonance spectroscopy with the MEGA-PRESS sequence at 3T. GABA is the main inhibitory neurotransmitter of the central nervous system and has been increasingly studied due to its relevance in many clinical disorders of the central nervous system. MEGA-PRESS is the most widely used method for quantification of GABA at 3T, but is technically challenging and operates at a low signal-to-noise ratio. Therefore, the acquisition of high-quality MRS data relies on avoiding numerous pitfalls and observing important caveats.

MethodsThe guideline was developed by a working party that consisted of experts in MRS and experts in guideline development and implementation, together with key stakeholders. Strictly following a translational framework, we first identified evidence using a systematically conducted scoping literature review, then synthesised and graded the quality of evidence that formed recommendations. These recommendations were then sent to a panel of 21 world leaders in MRS for feedback and approval using a modified-Delphi process across two rounds.

ResultsThe final guideline consists of 23 recommendations across six domains essential for GABA MRS acquisition (Parameters, Practicalities, Data acquisition, Confounders, Quality/reporting, Post-processing). Overall, 78% of recommendations were formed from high-quality evidence, and 91% received agreement from over 80% of the expert panel.

ConclusionThese 23 expert-reviewed recommendations and accompanying extended documentation form a readily usable guideline to allow those new to the field of MEGA-PRESS to design appropriate MEGA-PRESS study protocols and generate high-quality data.


title: Synthesis of High-Resolution Research-Quality MRI Data from Clinical MRI Data in Patients with COVID-19

abstract: Pathophysiological mechanisms of neurological disorders in patients with coronavirus disease 2019 (COVID-19) are poorly understood, partly because of a lack of high-resolution neuroimaging data. We applied SynthSR, a convolutional neural network that synthesizes high-resolution isotropic research-quality data from thick-slice clinical MRI data, to a cohort of 11 patients with severe COVID-19. SynthSR successfully synthesized T1-weighted MPRAGE data at 1 mm spatial resolution for all 11 patients, each of whom had at least one brain lesion. Correlations between volumetric measures derived from synthesized and acquired MPRAGE data were strong for the cortical grey matter, subcortical grey matter, brainstem, hippocampus, and hemispheric white matter (r=0.84 to 0.96, p[≤]0.001), but absent for the cerebellar white matter and corpus callosum (r=0.04 to 0.17, p>0.61). SynthSR creates an opportunity to quantitatively study clinical MRI scans and elucidate the pathophysiology of neurological disorders in patients with COVID-19, including those with focal lesions.

category: neurology


title: Prophylactic Magnesium Supplementation and New-Onset Atrial Fibrillation in a General Critical Care Population: A Prescribing Preference Instrumental Variable Analysis

abstract:
AimsAtrial fibrillation is frequently encountered in critical illness and causes adverse effects including haemodynamic decompensation, stroke and longer hospital stay. It is common to supplement serum magnesium for the purpose of preventing new-onset atrial fibrillation. However, no randomised studies support this practice in the non-cardiac surgery critical care population, and its effectiveness is unclear. We sought to investigate the effectiveness of magnesium supplementation in preventing new-onset atrial fibrillation in a mixed critical care population.

MethodsWe conducted a single centre retrospective observational study of adult critical care patients. We employed a natural experiment design, using the supplementation preference of the bedside critical care nurse as an instrumental variable.

Using the electronic patient record, magnesium supplementation opportunities were defined and linked to the bedside nurse. Nurse preference for administering magnesium was obtained using multilevel modelling. The results were used to define  pro and  anti supplementation groups, which were inputted into an instrumental variable regression to obtain an estimate of the effect of magnesium supplementation.

Results9,114 magnesium supplementation opportunities were analysed, representing 2,137 critical care admissions for 1,914 patients. There was significant variation in magnesium supplementation practices attributable to the individual nurse, after accounting for covariates. The instrumental variable analysis showed magnesium supplementation was associated with a 3% decreased chance of experiencing new-onset atrial fibrillation (95% CI -0.06 to -0.04, p = 0.03).

ConclusionsThis study supports the strategy of routine magnesium supplementation, but further work is required to identify optimal serum magnesium targets for prophylaxis of atrial fibrillation.

Whats New?O_LIRoutine administration of supplemental magnesium sulphate is associated with a reduced chance of developing new-onset Atrial Fibrillation, in a general critical care cohort.
C_LIO_LIThis finding agrees with previous Randomised Controlled Trial results which are limited to the cardiac critical care population.
C_LIO_LIThis finding disagrees with previously published observational studies, which is likely due to better control of unmeasured confounding.
C_LIO_LIThere is significant variation in serum magnesium supplementation attributable to the individual bedside critical care nurse.
C_LIO_LIElectronic health records offer the ability to evaluate the effectiveness of routinely administered treatments which lack evidence in an affordable way.
C_LIO_LINatural experiments and instrumental variable analysis offer the opportunity to derive causally robust estimations of treatment effectiveness by better accounting for unobserved confounding.
C_LI

category: intensive care and critical care medicine


title: Actionable absolute risk prediction of atherosclerotic cardiovascular disease: a behavior-management approach based on data from 464,547 UK Biobank participants

abstract:
Cardiovascular diseases (CVDs) are the primary cause of all global death. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae, via risk prediction model, is a central pillar of preventive cardiology. However, currently available models only consider a limited set of risk factors and outcomes, do not focus on providing actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making a high percentage of occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. We developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure).

Our two best performing absolute atherosclerotic risk prediction models provided higher performance than Framingham and QRisk3. Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and could allow continuous personalized predictions with automated intervention suggestions.


title: Postprandial dynamics of proglucagon cleavage products and their relation to metabolic health

abstract:
While oral glucose ingestion typically leads to a decrease in circulating glucagon levels, a substantial number of persons display stable or rising glucagon concentrations when assessed by radioimmunoassay (RIA). However, these assays show cross-reactivity to other proglucagon cleavage products. Recently, more specific assays became available, therefore we systematically assessed glucagon and other proglucagon cleavage products and their relation to metabolic health. We used samples from 52 oral glucose tolerance tests (OGTT) that were randomly selected from an extensively phenotyped study cohort.

Glucagon concentrations quantified with RIA were non-suppressed at 2 hours of the OGTT in 36 % of the samples. Non-suppressors showed lower fasting glucagon levels compared to suppressors (p=0.011). Similar to RIA measurements, ELISA-derived fasting glucagon was lower in non-suppressors (p<0.001). Glucagon 1-61 as well as glicentin kinetics were significantly different between suppressors and non-suppressors (p=0.004 and p=0.002, respectively) with higher concentrations of both hormones in non-suppressors. Levels of insulin, C-peptide, and free fatty acids were comparable between groups. Non-suppressors were leaner and had lower plasma glucose concentrations (p=0.03 and p=0.047, respectively). Despite comparable liver fat content and insulin sensitivity (p[≥]0.3), they had lower 2-hour post-challenge glucose (p=0.01).

Glucagon 1-61, glicentin and GLP-1 partially account for RIA-derived glucagon measurements due to cross-reactivity of the assay. However, this contribution is small, since the investigated proglucagon cleavage products contribute less than 10% to the variation in RIA measured glucagon. Altered glucagon levels and higher post-challenge incretins are associated with a healthier metabolic phenotype that is known to be indicative for reduced cardiovascular risk, cancer incidence, and mortality.

category: endocrinology


title: Future prevalence of type 2 diabetes - a comparative analysis of chronic disease projection methods

abstract:
BackgroundAccurate projections of the future number of people with chronic diseases are necessary for effective resource allocation and health care planning in response to changes in disease burden.

AimTo introduce and compare different projection methods to estimate the number of people with diagnosed type 2 diabetes (T2D) in Germany in 2040.

MethodsWe compare three methods to project the number of males with T2D in Germany in 2040. Method 1) simply combines the sex- and age-specific prevalence of T2D in 2010 with future population distributions projected by the German Federal Statistical Office (FSO). Methods 2) and 3) additionally account for the incidence of T2D and mortality rates using partial differential equations (PDEs). Method 2) models the prevalence of T2D employing a scalar PDE which incorporates incidence and mortality rates. Subsequently, the estimated prevalence is applied to the population projection of the FSO. Method 3) uses a two-dimensional system of PDEs and estimates future case numbers directly while future mortality of people with and without T2D is modelled independently from the projection of the FSO.

ResultsMethod 1) projects 3.6 million male people with diagnosed T2D in Germany in 2040. Compared to 2.8 million males in 2010, this equals an increase by 29%. Methods 2) and 3) project 5.9 million (+104% compared to 2010) and 6.0 million (+116%) male T2D patients, respectively.

ConclusionsThe results of the three methods differ substantially. It appears that ignoring temporal trends in incidence and mortality may result in misleading projections of the future number of people with chronic diseases. Hence, it is essential to include these rates as is done by method 2) and 3).


title: The effects of walking in nature on negative and positive affect in adult psychiatric outpatients with major depressive disorder: A randomized-controlled study

abstract:
BackgroundWhile walking in nature has been shown to improve affect in adults from the community to a greater extent than walking in urban settings, it is unknown whether such findings can be generalized to individuals suffering from depression. Using a parallel group design, this randomized controlled trial examined the effects of a single walk in nature versus urban settings on negative and positive affect in adult psychiatric outpatients diagnosed with major depressive disorder (MDD).

MethodParticipants recruited from a psychiatric outpatient clinic for adults with MDD were randomly assigned to a nature or urban walk condition. Thirty-seven adults (mean age=49 years) completed a single 60-minute walk. Negative and positive affect were assessed using The Positive and Negative Affect Schedule or PANAS at 6 time points: before the walk, halfway during the walk, immediately post-walk, at home before bedtime, 24 hours post-walk, and 48 hours post-walk.

ResultsControlling for baseline levels of affect before the walk, individuals who walked in nature experienced overall lower levels of negative affect, F(1, 35.039)=4.239, p=.047, compared to those who walked in urban settings. Positive affect did not differ across walk conditions.

LimitationsThe generalizability of results are limited by the small sample size and the presence of more female than male participants.

ConclusionsWalking in nature might be a useful strategy to improve the affect of adults with MDD. Future research should investigate different ways to integrate the beneficial effects of nature exposure into existing treatment plans for psychiatric outpatients with MDD.

category: psychiatry and clinical psychology


title: The relationship of COVID-19 related stress and media consumption with schizotypy, depression and anxiety

abstract:
Studies report a strong impact of the COVID-19 pandemic and related stressors on the mental wellbeing of general population. In this paper, we investigated whether COVID-19 related concerns and social adversity affected schizotypal traits, anxiety and depression using structural equational modelling. In mediation analyses, we furthermore explored whether these associations were mediated by healthy (sleep and physical exercise) or unhealthy behaviours (drug and alcohol consumption, excessive media use).

We assessed schizotypy, depression and anxiety as well as, healthy and unhealthy behaviours and a wide range of sociodemographic scores using online surveys from residents of Germany and the United Kingdom over one year during the COVID-19 pandemic. Four independent samples were collected (April/ May 2020: N=781, September/ October 2020: N=498, January/ February 2021: N=544, May 2021: N= 486). The results revealed that COVID-19 related life concerns were significantly associated with schizotypy in the autumn 2020 and spring 2021 surveys, and with anxiety and depressive symptoms in all surveys; and social adversity significantly affected the expression of schizotypal traits in all but the spring 2020 survey, and depressive and anxiety symptoms in all samples. Importantly, we found that excessive media consumption (>4h per day) fully mediated the relationship of COVID-19 related life concerns and schizotypal traits in the winter 2021 survey. Furthermore, several of the surveys showed that excessive media consumption was associated with increased depressive and anxiety- related symptoms in people burdened by COVID-19 related life.

The ongoing uncertainties of the pandemic and the restrictions on social life have a strong impact on mental well-being and especially the expression of schizotypal traits. The negative impact is further boosted by excessive media consumption, which is especially critical for people with high schizotypal traits.


title: Single-cell mtDNA heteroplasmy in colorectal cancer

abstract: Human mitochondria can be genetically distinct within the same individual, a phenomenon known as heteroplasmy. In cancer, this phenomenon seems exacerbated, and most mitochondrial mutations seem to be heteroplasmic. How this genetic variation is arranged within and among normal and tumor cells is not well understood. To address this question, here we sequenced single-cell mitochondrial genomes from multiple normal and tumoral locations in four colorectal cancer patients. Our results suggest that single cells, both normal and tumoral, can carry various mitochondrial haplotypes. Remarkably, this intra-cell heteroplasmy can arise before tumor development and be maintained afterward in specific tumoral cell subpopulations. At least in the colorectal patients studied here, the somatic mutations in the single-cells do not seem to have a prominent role in tumorigenesis.

category: genetic and genomic medicine


title: Predictive utility of mortality by aging measures at different hierarchical levels and the response to modifiable lifestyle factors:Implications for geroprotective programs

abstract:
BackgroundAging, as a multi-dimensional process, can be measured at different hierarchical levels including biological, phenotypic, and functional levels. The aims of this study were to: 1) compare the predictive utility of mortality by three aging measures at three hierarchical levels; 2) develop a composite aging measure that integrated aging measures at different hierarchical levels; and 3) evaluate the response of these aging measures to modifiable lifestyle factors.

MethodsData from National Health and Nutrition Examination Survey 1999-2002 were used. Three aging measures included telomere length (TL, biological level), Phenotypic Age (PA, phenotypic level), and frailty index (FI, functional level). Mortality information was collected until Dec. 2015. Cox proportional hazards regression and multiple linear regression models were performed.

ResultsA total of 3249 participants (20-84 years) were included. Both accelerations (accounting for chronological age) of PA and FI were significantly associated with mortality, with HRs of 1.67 (95% confidence interval [CI] = 1.41-1.98) and 1.59 (95% CI = 1.35-1.87), respectively, while that of TL showed nonsignificant associations. We thus developed a new composite aging measure (named PC1) integrating the accelerations of PA and FI, and demonstrated its better predictive utility relative to each single aging measure. PC1, as well as the accelerations of PA and FI, were responsive to several lifestyle factors.

ConclusionThe findings, for the first time, provide a full picture of the predictive utility of mortality by three aging measures at three hierarchical levels and the response to modifiable lifestyle factors, with important implications for geroprotective programs.

category: geriatric medicine


title: Variations of the quality of care during the COVID-19 pandemic affected the mortality rate of non-COVID patients with hip fracture

abstract:
IntroductionAs COVID-19 roared through the world, governments worldwide enforced containment measures that affected various treatment pathways, including those for hip fracture (HF). This study aimed to measure process and outcome indicators related to the quality of care provided to non-COVID-19 elderly patients affected by HF in Emilia-Romagna, a region of Italy severely hit by the pandemic.

MethodsWe collected the hospital discharge records of all patients admitted to the hospitals of Emilia-Romagna with a diagnosis of HF from January to May in the years 2019/2020. We analyzed surgery rate, surgery timeliness, length of hospital stay, timely rehabilitation, and 30-day mortality for each HF patient. We evaluated monthly data (2020 vs. 2019) with the chi-square and t-test, where appropriate. Logistic regression was used to investigate the differences in 30-day mortality.

ResultsOur study included 5379 patients with HF. In April and May 2020, there was a significant increase in the proportion of HF patients that did not undergo timely surgery. In March 2020, we found a significant increase in mortality (OR = 2.22). Female sex (OR = 0.52), age [≥]90 years (OR = 4.33), surgery after 48 hours (OR = 3.08) and not receiving surgery (OR = 6.19) were significantly associated with increased mortality. After adjusting for the aforementioned factors, patients hospitalized in March 2020 still suffered higher mortality (OR = 2.21).

ConclusionsOur results show a reduction in the overall quality of care provided to non-COVID-19 elderly patients affected by HF. The mortality rate of patients with HF increased significantly in March 2020. Patients characteristics and variations in processes of care partially explained this increase. Our analysis reveals the importance of including process and outcomes indicators, for both acute and post-acute care management issues, in emergency preparedness plans, to monitor healthcare systems capacities and capabilities.

category: health systems and quality improvement


title: Differences in medication reconciliation interventions between six hospitals: a mixed method study

abstract:
BackgroundAlthough medication reconciliation (MedRec) is mandated and effective in decreasing preventable medication errors during transition of care, hospitals implement MedRec differently.

ObjectiveQuantitatively compare the number and type of MedRec interventions between hospitals upon admission and discharge, followed by a qualitative analysis on potential reasons for these differences.

MethodsThis explanatory retrospective mixed method study included patients from six hospitals and various wards in case MedRec was performed both on hospital admission and discharge. Information on pharmacy interventions to resolve unintended discrepancies and medication optimizations were collected. Based on these quantitative results, interviews and a focus group was performed to give insight in MedRec processes. Descriptive analysis was used for the quantitative-, content analysis for the qualitative part.

ResultsOn admission, patients with at least one discrepancy varied from 36-95% (mean per patient 2.2 (SD{+/-} 2.4) Upon discharge, these numbers ranged from 5-28% while optimizations reached 2% (admission) to 95% (discharge).The main themes explaining differences in numbers of interventions were patient-mix, healthcare professionals involved, location and moment of the interview plus embedding and extent of medication optimization.

ConclusionsHospitals differed greatly in the number of interventions performed during MedRec. A combination of patient-mix, healthcare professionals involved, location and timing of the interview plus embedding and extent of medication optimization resulted in the highest yield of MedRec interventions on unintended medication discrepancies and optimizations. This study supports to give direction to optimize MedRec processes in hospitals.


title: It Takes Two to Tango: Combining Conventional Culture with Molecular Diagnostics Enhances Accuracy of Streptococcus pneumoniae Detection and Pneumococcal Serogroup/Serotype determination in Carriage

abstract:
BackgroundThe specificity of molecular methods for the detection of Streptococcus pneumoniae carriage is under debate. We propose a procedure that increases the accuracy of molecular detection of live pneumococci in polymicrobial respiratory samples.

MethodsCulture and qPCR methods were applied to detect S. pneumoniae and pneumococcal serotypes in 1549 nasopharyngeal samples collected in the Netherlands (n=972) and England (n=577) from 946 toddlers and 603 adults, and in paired oropharyngeal samples collected exclusively from 319 Dutch adults. Samples with no live pneumococci isolated at primary diagnostic culture yet generating pneumococcus-specific signal in qPCRs were re-examined with a second, qPCR-guided culture. Optimal Cq cut-offs for positivity in qPCRs were determined via receiver operating characteristic (ROC) curve analysis using isolation of live pneumococci from the primary and qPCR-guided cultures as reference.

ResultsDetection of S. pneumoniae and pneumococcal serotypes with qPCRs in cultured (culture-enriched) nasopharyngeal samples exhibited near-perfect agreement with conventional culture (Cohens kappa: 0.95). Molecular methods also displayed increased sensitivity of detection for multiple serotype carriage. Among paired samples from adults, the sensitivity of S. pneumoniae detection in primary nasopharyngeal plus oropharyngeal cultures was significantly lower compared with molecular detection in both culture-enriched samples together (p<0.0001) and also in culture-enriched oropharyngeal samples alone (p<0.05).

ConclusionsThe sensitivity of S. pneumoniae carriage surveillance can be greatly improved by complementing conventional culture with qPCR and vice versa. The specificity of molecular methods for the detection of live pneumococci can be enhanced by incorporating statistical procedures based on ROC curve analysis. The procedure we propose improves detection of S. pneumoniae carriage in adults in particular and enhances specificity of serotype carriage detection.

category: infectious diseases


title: Dosing interval strategies for two-dose COVID-19 vaccination in 13 low- and middle-income countries of Europe: health impact modelling and benefit-risk analysis

abstract:
BackgroundIn settings where the COVID-19 vaccine supply is constrained, extending the intervals between the first and second doses of the COVID-19 vaccine could let more people receive their first doses earlier. Our aim is to estimate the health impact of COVID-19 vaccination alongside benefit-risk assessment of different dosing intervals for low- and middle-income countries of Europe.

MethodsWe fitted a dynamic transmission model to country-level daily reported COVID-19 mortality in 13 low- and middle-income countries in the World Health Organization European Region (Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Bulgaria, Georgia, Republic of Moldova, Russian Federation, Serbia, North Macedonia, Turkey, and Ukraine). A vaccine product with characteristics similar to the Oxford/AstraZeneca COVID-19 (AZD1222) vaccine was used in the base case scenario and was complemented by sensitivity analyses around efficacies related to other COVID-19 vaccines. Both fixed dosing intervals at 4, 8, 12, 16, and 20 weeks and dose-specific intervals that prioritise specific doses for certain age groups were tested. Optimal intervals minimise COVID-19 mortality between March 2021 and December 2022. We incorporated the emergence of variants of concern into the model, and also conducted a benefit-risk assessment to quantify the trade-off between health benefits versus adverse events following immunisation.

FindingsIn 12 of the 13 countries, optimal strategies are those that prioritise the first doses among older adults (60+ years) or adults (20-59 years). These strategies lead to dosing intervals longer than six months. In comparison, a four-week fixed dosing interval may incur 10.2% [range: 4.0% - 22.5%; n = 13 (countries)] more deaths. There is generally a negative association between dosing interval and COVID-19 mortality within the range we investigated. Assuming a shorter first dose waning duration of 120 days, as opposed to 360 days in the base case, led to shorter optimal dosing intervals of 8-12 weeks. Benefit-risk ratios were the highest for fixed dosing intervals of 8-12 weeks.

InterpretationWe infer that longer dosing intervals of over six months, which are substantially longer than the current label recommendation for most vaccine products, could reduce COVID-19 mortality in low- and middle-income countries of WHO/Europe. Certain vaccine features, such as fast waning of first doses, significantly shorten the optimal dosing intervals.

FundingWorld Health Organization


title: Altered functional connectivity relates to motor performance deficits in bipolar but not unipolar depression

abstract:
Underpinnings of psychomotor deficits in bipolar and unipolar depression remain underexplored. Here, we hypothesize that motor performance deficits in patients may be partially explained by altered functional connectivities between hand primary motor cortex and posterior cingulate cortex with supplementary motor area.

95 participants between 18-65 years of age, including bipolar depressed, unipolar depressed, and sex-, age-, and education-matched healthy controls, participated in this observational study with two separate visits about five weeks apart, during which the patients received psychopharmacological treatment. Motor performance was measured with a finger-tapping-task and related to functional connectivity from individual seeds in hand primary motor cortex and posterior cingulate cortex as well as to the default mode and sensory motor networks from resting state functional MRI data.

79 participants (45.6% females, 21 bipolar depressed, 27 unipolar depressed and 31 healthy controls) were included in the analysis. Using a finger-tapping-task, the groups differed in motor performance (ANOVA factor "group" F(2,76) = 4.122; p = 0.020) and bipolar depressed but not unipolar depressed showed performance deficits compared to controls (post-hoc-test p = 0.023 and p = 0.158 respectively). Behavioral performance correlated with functional coupling of posterior cingulate cortex - supplementary motor area, but not with coupling of primary motor cortex - supplementary motor area at cluster-wise correction level p FWEc < 0.05. Correlation differences were seen in posterior cingulate cortex - supplementary motor area (healthy controls>bipolar depressed, unipolar depressed>bipolar depressed) at second visit and in primary motor cortex - supplementary motor area (bipolar depressed>unipolar depressed) at both visits at cluster-wise correction level p FWEc<0.05. Motor performance did not relate to functional coupling of sensory motor network - anterior (visit 1 p = 0.375, visit 2 p = 0.700) or - posterior (visit 1 p = 0.903, visit 2 p = 0.772) default mode network.

Motor performance deficits were seen exclusively in bipolar depressed and related to reduced posterior cingulate cortex - supplementary motor area functional connectivity at rest. Our results shed new light on a possible disruption in the anticorrelation between these regions, which seems fundamental for the preservation of motor skills. Given that nuisance factors were controlled for in the study, it is unlikely that the main results are biased by lefthanders, medication load, seed volumes, or differences in movements during MRI scanning. If these findings are confirmed, new targeted non-invasive interventions, such as repetitive transcranial magnetic stimulation, may be more effective against psychomotor deficits in bipolar depression, when aimed at modulating the supplementary motor area.


title: Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation

abstract:
BackgroundChronic breathlessness in COPD is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness, helping to individualise therapy. Increasing evidence supports the role of expectation (i.e. placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulates any predictive model.

MethodsData from 72 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation was analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the dyspnoea-12 score.

FindingsOnly models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2).

InterpretationBrain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brains expectation pathways (either pharmacological or non-pharmacological) merits further testing in the treatment of chronic breathlessness.

FundingThis work was supported by the JABBS Foundation

Research in contextO_ST_ABSEvidence before the studyC_ST_ABSDespite considerable research we still do not know which patient characteristics predict clinical improvements in breathlessness following pulmonary rehabilitation. Recent evidence suggests that the brain processes associated with breathlessness-expectation play an important contributory role in breathlessness severity. However, this has never been examined as a predictor of pulmonary rehabilitation outcome. The ability to predict outcomes has a number of potential benefits, including identifying targets for personalised medicine and the better allocation of scare healthcare resources via parallel care pathways.

Added value of the studyThis study analysed data from a longitudinal experimental medicine study of 71 patients with COPD over a course of pulmonary rehabilitation, that used functional magnetic resonance imaging testing breathlessness-expectation mechanisms in the brain. Participants were randomised in a double-blind procedure to receive either 250mg oral D-cycloserine or a matched placebo. Using baseline variables to train machine learning models we revealed that only models containing brain markers of breathlessness-expectation successfully predicted improvements in dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine use was independently associated with breathlessness improvements. Models that only contained questionnaire and clinical measure did not predict outcome (sensitivity 0.68, specificity 0.2).

Implications of all the available evidenceThese findings are the first evidence that breathlessness-expectation related brain activity is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is a key mechanism in breathlessness perception and that the manipulation of the brains expectation pathways merits further testing as a novel therapeutic approach for breathlessness.

category: respiratory medicine


title: A cross-sectional survey of burnout in a sample of resident physicians in Sudan

abstract:
BackgroundResident physicians in Sudan suffer multiple physical and psychological stressors. Nevertheless, the prevalence of burnout among this critical population remains unknown. The purpose of this study was to estimate the prevalence of burnout and its related factors in a sample of Sudanese resident physicians.

MethodsA cross-sectional design was used to assess burnout among resident physicians at the teaching hospitals of Wad-Medani, Gezira state in Sudan. All resident physicians across nine hospitals were asked to join the study. The Arabic version of Maslach Burnout Inventory was distributed to respondents from July to October 2021.

ResultsOut of 300 resident physicians 69.3% responded. The study population had a mean age of 29.99 {+/-} 3.01 years, more than half were females (56.7%) and single (59.6%). In total, 86.1% met the criteria for burnout in at least one dimension, and 13.9 % in all three dimensions.70.7% suffer from a high level of burnout on the dimension of emotional exhaustion (EE), while 44.2% reported a high level on depersonalization (DP) and 73.1% experienced a sense of decreased professional accomplishment (PA). There were significant differences in the levels of burnout, EE and DP among different specialties. Burnout syndrome was associated with working hours per single duty; with participants working for more than 24 hours had experienced higher levels of burnout, EE and DP.

ConclusionsHigh prevalence of burnout syndrome was found in this sample of resident physicians in Sudan. Stakeholders should urgently implement effective remedies to protect the mental health of resident physicians.


title: Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review

abstract:
Polygenic risk is known to influence susceptibility to cancer. The use of data on polygenic risk, in conjunction with other predictors of future disease status, may offer significant potential for preventative care through risk-stratified screening programmes. An important element in the evaluation of screening programmes is their cost-effectiveness.

We undertook a systematic review of papers evaluating the cost-effectiveness of screening interventions informed by polygenic risk scores compared to more conventional screening modalities. We included papers reporting cost-effectiveness outcomes in the English language published as articles or uploaded onto preprint servers with no restriction on date, type of cancer or form of polygenic risk modelled. We excluded papers evaluating screening interventions that did not report cost-effectiveness outcomes or which had a focus on monogenic risk. We evaluated studies using the Quality of Health Economic Studies checklist.

Ten studies were included in the review, which investigated three cancers: prostate (n=5), colorectal (n=3) and breast (n=2). All study designs were cost-utility papers implemented as Markov models (n=6) or microsimulations (n=4). Nine of ten papers scored highly (score >75 on a 0-100) scale) when assessed using the Quality of Health Economic Studies checklist. Eight of ten studies concluded that polygenic risk informed cancer screening was likely to be more cost-effective than alternatives. However, the included studies lacked robust external data on the cost of polygenic risk stratification, did not account for how very large volumes of polygenic risk data on individuals would be collected and used, did not consider ancestry-related differences in polygenic risk, and did not fully account for downstream economic sequalae stemming from the use of polygenic risk data in these ways. These topics merit attention in future research on how polygenic risk data might contribute to cost-effective cancer screening.

FundingThis work was supported by Cancer Research UK under grant number C18281/A29019. PD and RM are members of the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_12013/1, MC_UU_12013/9). PD, EK ad RMM received support from a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SW and JCT receive funding from the Oxford NIHR Biomedical Research Centre.

RegistrationProspectively registered on PROSPERO database before searches commenced. Available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=243659

category: health economics


title: A generic method and software to estimate the transmission advantage of pathogen variants in real-time : SARS-CoV-2 as a case-study

abstract:
Recent months have demonstrated that emerging variants may set back the global COVID-19 response. The ability to rapidly assess the threat of new variants in real-time is critical for timely optimisation of control strategies.

We extend the EpiEstim R package, designed to estimate the time-varying reproduction number (Rt), to estimate in real-time the effective transmission advantage of a new variant compared to a reference variant. Our method can combine information across multiple locations and over time and was validated using an extensive simulation study, designed to mimic a variety of real-time epidemic contexts.

We estimate that the SARS-CoV-2 Alpha variant is 1.46 (95% Credible Interval 1.44-1.47) and 1.29, (95% CrI 1.29-1.30) times more transmissible than the wild type, using data from England and France respectively. We further estimate that Beta and Gamma combined are 1.25 (95% CrI 1.24-1.27) times more transmissible than the wildtype (France data). All results are in line with previous estimates from literature, but could have been obtained earlier and more easily with our off-the-shelf open-source tool.

Our tool can be used as an important first step towards quantifying the threat of new variants in real-time. Given the popularity of EpiEstim, this extension will likely be used widely to monitor the co-circulation and/or emergence of multiple variants of infectious pathogens.

Significance StatementEarly assessment of the transmissibility of new variants of an infectious pathogen is critical for anticipating their impact and designing appropriate interventions. However, this often requires complex and bespoke analyses relying on multiple data streams, including genomic data. Here we present a novel method and software to rapidly quantify the transmission advantage of new variants. Our method is fast and requires only routinely collected disease surveillance data, making it easy to use in real-time. The ongoing high level of SARS-CoV-2 circulation in a number of countries makes the emergence of new variants highly likely. Our work offers a powerful tool to help public health bodies monitor such emerging variants and rapidly detect those with increased transmissibility.


title: Analytical sensitivity and effectiveness of different SARS-CoV-2 testing options

abstract: We prepared severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) working standards and reference panels from a pool of swab fluid samples before and after inactivation by beta-propiolactone and quantified viral load in nucleic acid amplification technology (NAT) detectable RNA copies/mL using limiting dilution analysis. The following 50% lower limits of detection (LOD) were estimated by probit analysis as compared to detection limits of rapid antigen tests on 1.5 fold dilutions of the native material: Roche cobas PCR 1.8 (1.0-3.3), Hologic Aptima TMA 6.6 (4.4-9.9), DRW SAMBA 15 (7-30), Molgen LAMP 23 (13-42), Fluorecare antigen 50,000, Abbott Panbio antigen 75,000 and Roche antigen 100,000 copies/mL. One 50% Tissue Culture Infectious Dose (TCID50)/mL of culture fluid was estimated to be equivalent to approximately 1000 RNA copies/mL (2700-4300 International Units) in our working standard. When assuming this level as start of contagiousness in a log-linear ramp up viremia model with 10-fold rise of viral load per day for the B.1 (Wuhan) type we estimated relative time points of first detectability of early infection by the different SARS-CoV-2 assays from the LODs mentioned above. The four NAT assays would be able to detect early viremia 40-66 hours earlier than the 1000 copies/mL infectivity threshold, whereas the three antigen tests would become positive 41-48 hours later. Our modeling of analytical sensitivity data was found to be compatible with clinical sensitivity data of rapid antigen tests and confirms that NAT assays are more reliable than antigen assays for identifying early infected asymptomatic individuals who are potentially infectious.


title: Alkaline phosphatase variability predicts new onset heart failure, cardiovascular mortality, and all-cause mortality in patients with type-2 diabetes mellitus: a population-based study

abstract:
ObjectiveTo investigate the associations of alkaline phosphatase (ALP) variability measures with new onset heart failure, cardiovascular mortality, and all-cause mortality in type 2 diabetes mellitus patients with a populational-cohort study.

MethodThis study included patients with type 2 diabetes mellitus who presented to ambulatory, outpatient and inpatient facilities managed by the public sector in Hong Kong between January 1st, 2000 to December 31st, 2019. Comprehensive clinical and medical data including demographics, past comorbidities, medications, and laboratory examinations of complete blood, lipid/glycemic profile and their variability were collected. ALP and its variability measures were extracted. Univariable and multiple multivariable Cox regression were used to identify the associations of alkaline phosphatase variability with new onset heart failure and mortality risks. Patients were stratified into three subgroups based on the tertiles of baseline ALP level.

ResultsThe study cohort consisted of 14289 patients (52.52% males, mean age at initial drug exposure: 74.55 years old [standard deviation (SD): 12.7]). Over a mean follow up of 2513 days [interquartile range (IQR): 1151-4173]), 10182 patients suffered from all-cause mortality (incidence rate [IR]: 71.25%), 1966 patients (IR: 13.75%) died from cardiovascular causes, and 1171 patients (IR: 8.19%) developed with new onset heart failure. Higher cumulative incidences of all three outcomes were observed for the highest tertile of ALP compared to medium/low tertiles. ALP baseline and variability level predicted new onset heart failure, cardiovascular and all-cause mortality before adjusting for subclinical biomarkers (p < 0.01). Amongst the measures of ALP variability, the hazard ratio (HR) of coefficient of variation (CV) was markedly raised in particular (new onset heart failure: HR=2.73, 95% confidence interval [CI]= [1.71-4.37], p <0.0001; all-cause mortality: HR= 5.83, 95% CI= [5.01-6.79], p <0.0001; cardiovascular mortality: HR= 4.81, 95% CI= [3.36-6.88], p <0.0001).

ConclusionsRaised ALP level and variability are associated with increased risks of all-cause mortality, cardiovascular mortality and new onset heart failure amongst patients with type 2 diabetes mellitus.

category: pathology


title: Relationships among High School Student-Athletes' Mental Health, Stressors, and Social Support during the COVID-19 Pandemic in Japan

abstract:
ObjectivesThe impact of the spread of COVID-19 on the mental health and its mitigating factors of high school athletes is not fully understood. The aims of this study were 1) to describe the psychological distress and stressors experienced by high school athletes during the COVID-19 pandemic and to elucidate the relationships between them and 2) to determine the relationship between psychological distress and social support.

MethodsParticipants of this cross-sectional study were recruited from public high schools in East Japan. We conducted either an online or paper-based questionnaire survey from July 12 to 31, 2020, and used data collected from 3017 high school student athletes (valid response rate: 88.7%) for the analyses. We evaluated psychological distress (K6 [≥]10), stressors to athletes during the COVID-19 pandemic (SAC-19), and perceived social support from others. Logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for developing psychological distress.

ResultsAmong the participants, 764 (25.3%) experienced psychological distress. Among the five factors extracted from the SAC-19, self-restraint requests (OR = 1.03, 95% CI: 1.01- 1.04), pressure from the surrounding environment (OR = 1.15, 95% CI: 1.12-1.18), and difficulties in maintaining athletic activities (OR = 1.16, 95% CI: 1.12-1.21) increased the risk of psychological distress. On the other hand, participants who were satisfied with the support from family members (OR = 0.77, 95% CI: 0.67-0.90), teammates (the same grade) (OR = 0.81, 95% CI: 0.67-0.98), and coaches and instructors (OR = 0.77, 95% CI: 0.65-0.91) showed lower psychological distress.

ConclusionsDuring the COVID-19 pandemic, high school athletes experienced more psychological distress than usual. Stressors such as self-restraint requests, pressure from the surrounding environment, and difficulties in maintaining athletic activities increased the risk. On the other hand, social support from family members, teammates (the same grade), and coaches and instructors can help alleviate these stressors.

category: public and global health


title: Development and Implementation of Dried Blood Spot-based COVID-19 Serological Assays for Epidemiologic Studies

abstract: Serological surveillance studies of infectious diseases provide population-level estimates of infection and antibody prevalence, generating crucial insight into population-level immunity, risk factors leading to infection, and effectiveness of public health measures. These studies traditionally rely on detection of pathogen-specific antibodies in samples derived from venipuncture, an expensive and logistically challenging aspect of serological surveillance. During the COVID-19 pandemic, guidelines implemented to prevent the spread of SARS-CoV-2 infection made collection of venous blood logistically difficult at a time when SARS-CoV-2 serosurveillance was urgently needed. Dried blood spots (DBS) have generated interest as an alternative to venous blood for SARS-CoV-2 serological applications due to their stability, low cost, and ease of collection; DBS samples can be self-generated via fingerprick by community members and mailed at ambient temperatures. Here, we detail the development of four DBS-based SARS-CoV-2 serological methods and demonstrate their implementation in a large serological survey of community members from 12 cities in the East Bay region of the San Francisco metropolitan area using at- home DBS collection. We find that DBS perform similarly to plasma/serum in enzyme-linked immunosorbent assays and commercial SARS-CoV-2 serological assays. In addition, we show that DBS samples can reliably detect antibody responses months post-infection and track antibody kinetics after vaccination. Implementation of DBS enabled collection of valuable serological data from our study population to investigate changes in seroprevalence over an eight-month period. Our work makes a strong argument for the implementation of DBS in serological studies, not just for SARS-CoV-2, but any situation where phlebotomy is inaccessible.


title: Mendelian randomization analysis identifies blood tyrosine levels as a biomarker of non-alcoholic fatty liver disease

abstract:
Non-alcoholic fatty liver disease (NAFLD) is a complex cardiometabolic disease associated with premature mortality. The diagnosis of NAFLD is challenging and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank and a cohort of patients undergoing bariatric surgery. Our instrument for genetically-predicted NAFLD (the study exposure) included all independent genetic variants (n=7 SNPs) from a recent genome-wide association study on NAFLD. The study outcomes included 123 blood lipids, lipoproteins and metabolites measured in 24,925 individuals from 10 European cohorts. After correction for multiple testing, we identified a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites. The association between NAFLD and tyrosine levels was consistent across MR methods and robust to outliers and pleiotropy. In observational analyses performed in the Estonian Biobank (10,809 individuals including 359 patients with NAFLD), after multivariable adjustment, tyrosine levels were positively associated with the presence of NAFLD (odds ratio per 1-SD increment = 1.23 (95% confidence interval = 1.12-1.36, p = 2.19e-05). In a sample of 138 patients undergoing bariatric surgery, compared to patients without NAFLD, blood tyrosine levels were higher in those with NAFLD, but were comparable among patients with or without non-alcoholic steatohepatitis. This analysis revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting that blood tyrosine levels may represent a new biomarker of NAFLD.

Graphical abstract

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title: Modelling the interplay of SARS-CoV-2 variants in the United Kingdom.

abstract: Most COVID-19 vaccines have proved to be effective to combat the pandemic and to prevent severe disease but their distribution proceeds in a context of global vaccine shortage Their uneven distribution favors the appearance of new variants of concern, as the highly transmissible Delta variant, affecting especially non-vaccinated people. We consider that devising reliable models to analyse the spread of the different variants is crucial. These models should include the effects of vaccination as well as non-pharmaceutical measures used to contain the pandemic by modifying social behaviour. In this work, we present a stochastic geographical model that fulfills these requirements. It consists of an extended compartmental model that includes various strains and vaccination strategies, allowing to study the emergence and dynamics of the new COVID-19 variants. The models conveniently separates the parameters related to the disease from the ones related to social behavior and mobility restrictions. The geographical spread of the virus is modeled taking into account the actual population distribution in any given country of interest. Here we choose the UK as model system, taking advantage of the reliable available data, in order to fit the recurrence of the currently prevalent variants. Our computer simulations allow to describe some global features observed in the daily number of cases, as the appearance of periodic waves and the features that determine the prevalence of certain variants. They also provide useful predictions aiming to help planning future vaccination boosters. We stress that the model could be applied to any other country of interest.


title: Performance of the Reported and Intended Behavior Scale among Colombian Adolescents

abstract:
ObjectiveTo establish the Reported and Intended Behavior Scale (RIBS) psychometric performance, a mental disorder-related stigma measurement, among Colombian adolescents.

MethodsA validation study was carried out with 350 students aged between 10 and 17, 53.7% of whom were girls. The RIBS has two sub-scales -reported behaviors and intended behaviors, with four items each. Frequencies were estimated for reported behaviors, whereas internal consistency (Cronbachs alpha and McDonalds omega) and confirmatory factor analysis (CFA) were measured for intended behaviors.

ResultsThe reported behavior sub-scale ranged from 10.0 to 24.9%, whereas the intended behavior sub-scale presented a Cronbachs alpha of 0.88 (CI95% 0.86-0.90) and a McDonald omega of 0.88. For the CFA, KMO was 0.81; Bartlett chi squared, 771.1 (df=6, p=0.01); and Eigen value, 2.95 that explained 73.9% of the total variance. For the goodness-of-fit tests, chi squared was 21.9 (df=2, p=.001); RMSEA, 0.17 (CI90% 0.11-0.24); CFI, 0.97; TLI, 0.92; and SMSR, 0.03.

ConclusionsThe RIBS can measure reported behaviors, and the intended behavior sub-scale shows high internal consistency. However, the dimensionality of the intended behavior sub-scale presents modest goodness-of-fit indexes. These findings need further replications.


title: A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the delta variant in kidney transplant recipients

abstract: In immunocompetent subjects, the effectiveness of SARS-CoV-2 vaccines against the delta variant appears three- to five-fold lower than that observed against the alpha variant. Additionally, three doses of SARS-CoV-2 mRNA-based vaccines might be unable to elicit a sufficient immune response against any variant in immunocompromised kidney transplant recipients. This study describes the kinetics of the neutralizing antibody (NAbs) response against the delta strain before and after a fourth dose of a mRNA vaccine in 67 kidney transplant recipients who had experienced a weak antibody response after three doses. While only 16% of patients harbored NAbs against the delta strain prior to the fourth injection - this percentage raised to 66% afterwards. We also found that, after the fourth dose, the NAbs titer increased significantly (p=0.0001) from <7.5 (IQR : <7.5-15.1) to 47.1 (IQR <7.5-284.2). Collectively, our data indicate that a fourth dose of the mRNA-1273 vaccine in kidney transplant recipients with a weak antibody response after three previous doses improves serum neutralization against the delta variant.

category: transplantation


title: Community healthcare workers' experiences during and after COVID-19 lockdown: a qualitative study from Aotearoa New Zealand

abstract:
Shortly after the COVID-19 pandemic reached Aotearoa New Zealand, a stringent lockdown lasting seven weeks was introduced to manage community spread of the virus. This paper reports the findings of a qualitative study examining how lockdown policies impacted upon the lives of those caring for community-based patients. The study involved nationwide surveys and ethnographic interviews with 15 registered nurses (RN) employed in community settings, two community midwives, and five personal care assistants (PCAs).

During the strict lockdown levels 4 and 3, RNs and PCAs in the community showed considerable courage in answering their "call to duty" by taking on heightened care responsibilities and going "the extra mile" to help others. They faced significant risks to personal and professional relationships when they were required to take on additional and complex responsibilities for community-based patients. Despite, and sometimes due to the hypervigilant monitoring of their personal protective equipment (PPE), the need to safeguard family and community members generated considerable stress and anxiety. Many also faced personal isolation and loneliness as a result of lockdown restrictions. Although  care and  kindness became social expectations throughout Aotearoa New Zealand during the lockdown, RNs and PCAs who were already doing care work in patient homes had to do more.

This article makes five core service delivery and policy recommendations for supporting community-based nurses and PCAs in respiratory disease pandemics: acknowledging the crucial role played by community-based carers and the associated stress and anxiety endured, through championing respect and compassion; demystifying the "heroism" or "self-sacrifice" projected onto care workers to facilitate boundary setting; the timely provision of adequate protective equipment; improving remuneration with adequate provision for time off; and regular counselling, peer support groups, and education on work-life balance delivered by support workers in recognition of stressors arising from these complex and isolated working conditions.

What is known about the topicO_LINurses and personal care assistants play a pivotal role in community responses to pandemics.
C_LIO_LIThe COVID-19 pandemic has intensified many community healthcare workers clinical duties.
C_LIO_LIPandemics pose risks to healthcare workers physical and mental wellbeing.
C_LI

What this paper addsO_LICommunity healthcare workers pressured themselves to be a "good carer" or "hero" during the lockdown.
C_LIO_LICaring for patients in the community also became about caring about patients, further intensifying workload.
C_LIO_LIThe COVID-19 pandemic has negatively impacted community healthcare workers relationships, as well as their wellbeing. Impacts continued even once the virus was eliminated.
C_LIO_LINeed for recognition of this workforce distinct from other care workers.
C_LI

category: nursing


title: Persistent racial/ethnic associated disparity in anti-tumor effectiveness of immune checkpoint inhibitors despite equal access.

abstract:
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of both lung cancer and head and neck squamous cell carcinoma demonstrating clear benefit over traditional chemotherapy alone in the metastatic setting. While the overwhelming majority of ICI trial participants have been White patients, results of these trials have been broadly applied to patients of all ethnic/racial backgrounds. It has, therefore, not been well defined if response to ICIs differs between ethnic/racial populations or socio-economic groups.

We reviewed response to ICI of 208 patients with diagnoses of lung or head and neck cancers treated with ICI between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston, TX. Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority patient populations and provide equal access of care to patients regardless of means. Of the 208 patients, 175 had a diagnosis of lung cancer [non-small cell lung carcinoma (NSCLC) or small cell lung cancer (SCLC)] and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC); 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for lung cancer (31.4%) and HNSCC patients (27.3%) (p=0.894). Statistically, the ORR for Hispanic and Black patients did not differ compared to non-Hispanic White patients (H 23.7%, B 28.6%, W 35.5%; H vs. W p=0.189; B vs. W p=0.338). When considering patients treated with ICI monotherapy, the ORR for Hispanic patients dropped to 13.3% and was significantly lower than the ORR of the non-Hispanic White patients while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 34.6%, H vs. W p=0.0285; B vs. W p=0.5131). Immune related adverse events (irAEs) were the lowest in the Hispanic population occurring in only 30% of patients compared to 50% of patients exhibiting irAEs in the Black and non-Hispanic white cohorts.

ICIs demonstrate comparable anti-tumor effects in lung cancer (NSCLC + SCLC) and HNSCC during routine clinical practice regardless of race or ethnicity. The significantly lower ORR observed in our cohort for Hispanic patients, particularly when used as monotherapy, is an unexpected finding and will require additional study to identify potential biological and non-biological confounders which could contribute to reduced ICI effectiveness in this patient population.

category: oncology


title: KRAS mutations predict better response to first-line monotherapy with pembrolizumab for patients with PD-L1high metastatic Non-Small Cell Lung Cancer: a retrospective study

abstract:
PurposeThere is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PD) and immune checkpoint blockade (ICB) with pembrolizumab. Here we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (stage IV) non-small cell lung cancer (NSCLC).

MethodsAll consecutive patients molecularly assessed and diagnosed between 2016-2018 with stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. Primary study outcome was overall survival (OS).

ResultsOut of 580 stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet (n = 195), KRASMUT is a negative factor for survival (p = 0.018) with median OS 9 months vs KRASWT 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95%CI 1.124-2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1high KRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016).

ConclusionsKRAS mutations is a positive predictive factor for treatment with pembrolizumab and a negative predictive factor for platinum doublet chemotherapy as well as general OS in stage IV NSCLC.


title: KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer


title: Seven chain adaptive immune receptor repertoire analysis in rheumatoid arthritis: association to disease and clinically relevant phenotypes

abstract: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease characterized by a defective adaptive immune receptor repertoire (AIRR) that fails to distinguish self from non-self antigens. The AIRR is vast, encompassing four T cell receptor (TCR) and three B cell receptor (BCR) chains, each of which displays an extraordinary amino acid sequence variability in the antigen-binding site. How the concerted action of T and B cell clones is associated with the development and clinical evolution of immune-mediated diseases is still not known. Using a new immunosequencing technology that allows the unbiased amplification of the seven receptor chains, we conducted an in-depth quantitative analysis of the seven-receptor chain variability in RA. Compared to healthy controls, the AIRR in RA was found to be characterized by a lower BCR diversity, the depletion of highly similar BCR clones, an isotype-specific signature as well as a skewed IGL chain and gene segment usage. A predictor based on quantitative multi-chain AIRR information was able to accurately predict disease, including the elusive seronegative subset of RA patients. AIRR features of the seven immune receptor chains were also different between patients with distinct clinically relevant phenotypes. Incorporating HLA variation data, we were able to identify the TCR clones that are specifically associated with the main disease risk variants. The longitudinal analysis of the AIRR revealed that treatment with Tumor Necrosis Factor (TNF) inhibitors selectively restores the diversity of B cell clones in RA patients by reducing the frequency of clones with a similar biochemical profile. The biochemical properties of the TNFi-modulated clones were also found to differ between responders and non-responders, supporting a different antigenic reactivity in the B cell compartment of these two groups of RA patients. Our comprehensive analysis of the TCR and BCR repertoire reveals a complex T and B cell architecture in RA, and provides the basis for precision medicine strategies based on the highly informative features of the adaptive immune response.


title: Emergence and Spread of the SARS-CoV-2 Variant of Concern Delta Across Different Brazilian Regions

abstract: The SARS-CoV-2 Variant of Concern (VOC) Delta was first detected in India in October 2020. The first imported cases of the Delta variant in Brazil were identified in April 2021 in the Southern region, followed by more cases in different country regions during the following months. By early September 2021, Delta was already the dominant variant in the Southeastern (87%), Southern (73%), and Northeastern (52%) Brazilian regions. This work aimed to understand the spatiotemporal dissemination dynamics of Delta in Brazil. To this end, we employed a combination of Maximum Likelihood (ML) and Bayesian methods to reconstruct the evolutionary relationship of 2,264 of VOC Delta complete genomes (482 from this study) recovered across 21 out of 27 Brazilian federal units. Our phylogeographic analyses identified three major transmission clusters of Delta in Brazil. The clade BR-I (n = 1,560) arose in Rio de Janeiro in late April 2021 and was the major cluster behind the dissemination of the VOC Delta in the Southeastern, Northeastern, Northern, and Central-Western regions. The clade BR-II (n = 207) arose in the Parana state in late April 2021 and aggregated the largest fraction of sampled genomes from the Southern region. Lastly, the clade BR-III emerged in the Sao Paulo state in early June 2021 and remained mostly restricted to this state. In the rapid turnover of viral variants characteristic of the SARS-CoV-2 pandemic, Brazilian regions seem to occupy different stages of an increasing prevalence of the VOC Delta in their epidemic profiles. This process demands continuous genomic and epidemiological surveillance toward identifying and mitigating new introductions, limiting their dissemination, and preventing the establishment of more significant outbreaks in a population already heavily affected by the COVID-19 pandemic.


title: Development of an electronic frailty index for hospitalized geriatric patients in Sweden

abstract:
BackgroundFrailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its predictive ability for adverse outcomes in geriatric patients.

MethodsEHRs were extracted for 18,225 geriatric patients with unplanned admissions between 1/3/2020 and 17/6/2021 from nine geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modelled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression.

Results13,188 patients were included in analyses (mean age 83.1 years). A 10% increment in the eFI was associated with higher risks of in-hospital (odds ratio: 5.34; 95% confidence interval: 4.20-6.82), 30-day (hazard ratio [HR]: 3.28; 2.91-3.69), and 6-month mortality (HR: 2.70; 2.52-2.90) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the best predictive accuracy for in-hospital mortality, yielding an area under receiver operating characteristic curve of 0.813. Higher eFI also predicted a longer length of stay, but had a rather poor discrimination for 30-day readmission.

ConclusionsAn EHR-based eFI has good predictive accuracy for adverse outcomes, suggesting that it can be used in risk stratification in geriatric patients.