title: Toward a preventive approach to prolonged grief disorder in palliative care: Insecure attachment moderates the impact of perceived support on the severity of symptoms

abstract:
ObjectiveThis study aimed to investigate the relationships between the perceived support at the time of assistance, insecure attachment (i.e., avoidance and anxious attachment factors), and the prolonged grief symptoms in family caregivers of palliative care patients deceased for at least one year. We also investigated the moderating role of insecure attachment in the relationship between perceived support and intensity of prolonged grief symptoms.

MethodA sample of 157 participants completed the Prolonged Grief Scale (PG-13) and the Attachment Style Questionnaire (ASQ).

ResultsCorrelational analysis indicated that prolonged grief symptoms were positively correlated with the Avoidance attachment factor but not with the Anxious one. The perceived support was negatively related to both the Avoidance and the Anxious attachment factors. Lastly, the two insecure attachment factors were moderately and positively correlated with each other. Results of moderation analysis showed that the high Avoidance attachment moderated the effect of the perceived family and social support on the intensity of prolonged grief symptoms among family caregivers of patients assisted in palliative home care. Results also showed that the Anxious attachment factor had a significant effect on prolonged grief symptoms, even though the interaction with the perceived support was not significant.

ConclusionsOverall, these results underline that a high level of avoidance attachment may moderate the relationship between the perceived support and intensity of grief symptoms and thereby increasing the risk of developing a mental disorder. Intervention to prevent prolonged grief disorder among family caregivers should take into account these findings.

category: palliative medicine


title: Large scale brain network dynamics in very preterm children and relationship with socio-emotional outcomes

abstract: Children born very preterm (VPT; < 32 completed weeks of gestation) are at high risk of neurodevelopmental and neurobehavioral difficulties associated with atypical brain maturation. The analysis of large-scale brain network dynamics during rest allows to investigate brain functional connectivity and their association with behavioural outcomes. Of interest, prematurity has been associated with atypical socio-emotional development with significant implications for the forming of peer relationships, adaptive functioning, academic achievement and mental health. In this study, we extracted dynamic functional connectivity by using the innovation-driven co-activation patterns (iCAPs) framework in preterm and full-term children aged 6 to 9 to explore changes in spatial organisation, laterality and temporal dynamics of spontaneous large-scale brain activity. Multivariate pattern analysis was used to explore potential biomarkers for socio-emotional difficulties in preterm children. Results show a spatial organisation of 13 networks retrieved comparable to full-term controls. Dynamic features and lateralisation of network brain activity were also comparable across groups for all large-scale brain networks. Despite apparent similarities in terms of dynamical functional connectivity parameters, multivariate pattern analysis unveiled group differences in their associations with socio-emotional abilities. While a pattern of decreased engagement in certain brain networks were associated with better socio-emotional abilities in full-term controls; in the VPT group, better socio-emotional abilities were associated with coordination of activity across different networks, i.e., coupling duration between different pairs of networks. It is possible that group differences reflect reduced degree of maturation of functional architecture in the VPT group for socio-emotional abilities.

category: pediatrics


title: A 16-Month Longitudinal Investigation of Risk and Protective Factors for Mental Health Outcomes Throughout Three National Lockdowns and a Mass Vaccination Campaign: Evidence from a Weighted Israeli Sample During COVID-19

abstract:
BackgroundThe COVID-19 pandemic is an ongoing global crisis, with a multitude of factors that affect mental health worldwide. Here, we explore potential predictors for the emergence and maintenance of depression, anxiety, and posttraumatic stress symptoms (PTSS) in the general population in Israel.

MethodsAcross the span of 16 months, 2,478 people completed a repeated self-report survey which inquired psychiatric symptoms and pandemic related stress factors (PRSF). PRSF were divided into four clusters of environmental stressors: financial, health-related, fatigue and sense of protection by authorities. We applied mixed-effects linear models to assess how each stressor contributes to depression, anxiety and PTSS at each time point, alongside a longitudinal exploration among participants who completed at least two consecutive surveys (n=400).

ResultsFatigue was the strongest predictor for depression, anxiety and PTSS at all time points (standardized {beta} between 0.28-0.60, p<.0001), and predicted deterioration overtime ({beta} between 0.22-0.36, p<.0001). Financial concerns associated with depression and anxiety at all time points ({beta} between 0.13- 0.26, p<.01), and with their deterioration overtime ({beta} between 0.16-0.18, p<.0001), while health related concerns were uniquely associated with anxiety and PTSS at all time points ({beta} between 0.14-0.29, p<.01) and their deterioration ({beta} between 0.11-0.16, p<.001), but not with depression. Improvement in sense of protection overtime associated with decrease in depression and anxiety ({beta} between -0.09 to -0.16, p<.01).

ConclusionsOur findings accentuate the multitude of risk factors for psychiatric morbidity during COVID-19, and the dynamics in their association with different aspects of psychopathology at various time points.

category: psychiatry and clinical psychology


title: Clinical and Computational Speech Measures are Associated with Social Cognition in Schizophrenia Spectrum Disorders

abstract: In this study, we compared three domains of social cognition (emotion processing, mentalization, and attribution bias) to clinical and computational language measures in 63 participants with schizophrenia spectrum disorders. Based on the active inference model for discourse, we hypothesized that emotion processing and mentalization, but not attribution bias, would be related to language disturbances. Clinical ratings for speech disturbance assessed disorganized and underproductive dimensions. Computational features included speech graph metrics, use of modal verbs, use of first-person pronouns, cosine similarity of adjacent utterances, and measures of sentiment; these were represented by four principal components characterizing content-rich speech, insular speech, local coherence, and affirmative speech. We found that higher clinical ratings for disorganized speech predicted greater impairments in both emotion processing and mentalization, and that these relationships remained significant when accounting for demographic variables, overall psychosis symptoms, and verbal ability. Similarly, computational features reflecting insular speech also consistently predicted greater impairment in emotion processing. There were notable trends for underproductive speech and decreased content-rich speech predicting mentalization ability. Exploratory longitudinal analyses in a small subset of participants (n=17) found that improvements in both emotion processing and mentalization were predicted by improvements in disorganized speech. Attribution bias did not demonstrate strong relationships with language measures. Altogether, our findings are consistent with the active inference model of discourse and suggest greater emphasis on treatments that target social cognitive and language systems.


title: Who Does What to Whom? Graph Representations of Action-Predication in Speech Relate to Psychopathological Dimensions of Psychosis

abstract: Graphical representations of speech generate powerful computational measures related to psychosis. Previous studies have mostly relied on structural relations between words as the basis of graph formation, i.e. connecting each word to the next in a sequence of words. Here, we introduced a method of graph formation grounded in semantic relationships by identifying elements that act upon each other (action relation) and contents of those actions (predication relation). Speech from picture description and open-ended narrative tasks were collected from a cross-diagnostic group of healthy volunteers and people with psychotic as well as non-psychotic disorders. Recordings were transcribed and underwent automated language processing, including semantic role labeling to identify action and predication relations. Structural and semantic graph features were computed using static and dynamic (moving-window) techniques. Compared to structural graphs, semantic graphs were more highly correlated with dimensional psychosis symptoms. Dynamic features also outperformed static features, and samples from picture descriptions were more informative than narrative responses for psychosis diagnoses and symptom dimensions. Overall, semantic graphs capture unique and clinically meaningful information about psychosis and related symptom dimensions. These features, particularly when derived from semi-structured tasks using dynamic measurement, are meaningful additions to the repertoire of computational linguistic methods in psychiatry.


title: Modifications to student quarantine policies in K-12 schools implementing multiple COVID-19 prevention strategies restores in-person education without increasing SARS-CoV-2 transmission risk, January-March 2021

abstract:
ObjectiveTo determine whether modified K-12 student quarantine policies that allow some students to continue in-person education during their quarantine period increase schoolwide SARS-CoV-2 transmission risk following the increase in cases in winter 2020-2021.

MethodsWe conducted a prospective cohort study of COVID-19 cases and exposures among students and staff (n=65,621) in 103 Missouri public schools. Participants were offered free, saliva-based RT-PCR testing. An adjusted Cox regression model compared hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy.

ResultsFrom January-March 2021, a projected 23 (1%) school-based transmission events occurred among 1,636 school close contacts. There was no difference in the adjusted hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy (hazard ratio=1.00; 95% confidence interval: 0.97-1.03).

DiscussionSchool-based SARS-CoV-2 transmission was rare in 103 K-12 schools implementing multiple COVID-19 prevention strategies. Modified student quarantine policies were not associated with increased school incidence of COVID-19. Modifications to student quarantine policies may be a useful strategy for K-12 schools to safely reduce disruptions to in-person education during times of increased COVID-19 community incidence.

category: public and global health


title: 'It all ends too soon' - Exploring stroke survivors and physiotherapists perspectives on stroke rehabilitation and the role of technology for promoting access to rehabilitation in the community

abstract:
INTRODUCTIONMany stroke survivors do not receive the optimal levels of personalised therapy needed to support their recovery. Rehabilitation technology could offer a means to provide personalised guidance to stroke survivors struggling to access rehabilitation through other means.

AIMSThe aim of this study was to explore stroke survivor and therapist experiences of stroke rehabilitation post discharge into the community and their thoughts about the potential use of markerless, 3D motion capture technology which could support rehabilitation, to contribute towards a better understanding of how technology can support stroke rehabilitation.

METHODSFocus groups and interviews were conducted with stroke survivors and therapists and the transcripts analysed using thematic analysis.

RESULTSSix themes were identified across the data: access and continuity of care for stroke survivors in the community, stroke survivor confusion and lack of education impacting service navigation and ability to access rehabilitation services, stroke survivor access to non-NHS/private facilities, impact of Covid on stroke services, potential use of technology to support post-stroke rehabilitation in the community and, stroke survivors willingness to try new technology.

CONCLUSIONSStroke survivors and therapists identified problems with stroke survivors accessing rehabilitation services but were positive about the potential for technology to support stroke rehabilitation.

category: rehabilitation medicine and physical therapy


title: Medical students' crisis-induced stress and the association with social support

abstract:
BackgroundMedical schools are challenged to guard student wellbeing due to the potential negative impact of the COVID-19 outbreak on top of the already high prevalence of mental distress. Whereas social support is generally associated with less crisis-induced stress, it is unknown whether this applies to medical students during the COVID-19 outbreak.

ObjectivesThe impact of the COVID-19 outbreak on perceived stress of medical students was assessed by comparing their perceived stress levels during the outbreak to both their own baseline and the previous cohorts pre-COVID-19 stress levels. Then, the association between social support and COVID-19 induced stress was assessed.

MethodsDutch Year-1 medical students of cohort 2019 (n=99) completed the 14-item Perceived Stress Scale (PSS-14) at two time points: baseline (pre-COVID-19) and final measurement (COVID-19). Social support - emotional-informational support and club membership - was assessed during the final measurement. PSS and social support scores were compared to similar measurements of cohort 2018 (n=196). Students baseline stress levels, gender and study performance were controlled for when comparing two cohorts.

ResultsStress levels did not differ statistically significant between both pre-COVID-19 measurements of cohort 2018 and baseline cohort 2019. During the COVID-19 outbreak, cohort 2019 showed significantly higher stress levels compared to baseline (paired t-test: t=6.07, p<.001) and compared to cohort 2018 (linear regression: B=4.186, p<.001). Only during the COVID-19 outbreak, higher levels of social support - i.e. emotional-informational support (B=-0.75, p<.001) and club membership (B=-3.68, p<.01) - were associated with lower levels of stress.

ConclusionsDuring the COVID-19 outbreak, the perceived stress of medical students was higher - especially for students with lower levels of social support. Our results suggest that medical schools should optimize social support to minimize crisis-induced stress.

category: medical education


title: Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study of the ISARIC cohort

abstract:
BackgroundAcute kidney injury (AKI) is one of the most common and significant problems in patients with COVID-19. However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional KDIGO definition can fail to identify patients for whom hospitalization coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesized that an extended KDIGO definition, adapted from the International Society of Nephrology 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI with similarly poor outcomes as previously reported in this population.

Methods and FindingsAll individuals in the ISARIC cohort admitted to hospital with SARS-CoV-2 infection from February 15th, 2020, to February 1st, 2021, were included in the study. Data was collected and analysed for the duration of a patients admission. Incidence, staging and timing of AKI were evaluated using a traditional and extended KDIGO (eKDIGO) definition which incorporated a commensurate decrease in serum creatinine. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristic and outcomes - intensive care unit (ICU) admission, invasive mechanical ventilation and in-hospital death - were compared for all three groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. 75,670 patients from 54 countries were included in the final analysis cohort. Median length of admission was 12 days (IQR 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7 vs 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% vs 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% vs 23%) invasive ventilation (45% vs 15%) and increased mortality (38% vs 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted OR: 1.78, 95% confidence interval: 1.71-1.8, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% vs 50% death and 35% vs 70% ICU admission) but significantly higher when compared to patients with no AKI (25% vs 19% death and 35% vs 23% ICU admission) (all p values < 5x10-5). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis.

ConclusionsThe use of an extended KDIGO definition to diagnose AKI in this population resulted in a significantly higher incidence rate compared to traditional KDIGO criteria. These additional cases of AKI appear to be occurring in the community or early in the hospital admission and are associated with worse outcomes than those without AKI.

Author SummaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIPrevious studies have shown that acute kidney injury (AKI) is a common problem among hospitalized patients with COVID-19.
C_LIO_LIThe current biochemical criteria used to diagnose AKI may be insufficient to capture AKI that develops in the community and is recovering by the time a patient presents to hospital.
C_LIO_LIThe use of an extended definition, that can identify AKI both during its development and recovery phase, may allow us to identify more patients with AKI. These patients may benefit from early management strategies to improve long term outcomes.
C_LI

What did the researchers do and find?O_LIIn this study, we examined AKI incidence, severity and outcomes among a large international cohort of patients with COVID-19 using both a traditional and extended definition of AKI.
C_LIO_LIWe found that using the extended definition identified almost twice as many cases of AKI than the traditional definition (31.7 vs 16.8%).
C_LIO_LIThese additional cases of AKI were generally less severe and occurred earlier in the hospital admission. Nevertheless, they were associated with worse outcomes, including ICU admission and in-hospital death (adjusted odds ratio: 1.78, 95% confidence interval: 1.71-1.8, p-value < 0.001) than those with no AKI.
C_LI

What do these findings mean?O_LIThe current definition of AKI fails to identify a large group of patients with AKI that appears to develop in the community or early in the hospital admission.
C_LIO_LIGiven the finding that these cases of AKI are associated with worse admission outcomes than those without AKI, identifying and managing them in a timely manner is enormously important.
C_LI

category: nephrology


title: Projected impact on blood pressure, chronic kidney disease burden and healthcare costs of achieving the Australian sodium reduction targets: a modelling study

abstract:
BackgroundExcess sodium intake increases blood pressure and risk of vascular complications. Most studies have focused on heart disease and stroke, but the impact on chronic kidney disease (CKD) is less well-characterised. The aim of this study was to estimate the impact of sodium intake on CKD burden in Australia.

MethodsA dynamic epidemiological model was developed to estimate the potential impact on CKD if the Australian Suggested Dietary Target (SDT) and the National Preventive Health Strategy 2021-2030 (NPHS) sodium target were achieved. Outcomes were estimated between 2019 (base year) and 2030, and lifetime.

FindingsAchieving the SDT and NPHS target could lower overall mean systolic blood pressure by 2.1 mmHg and 1.7 mmHg respectively. Compared to current sodium intake levels, attaining the SDT could prevent 59,220 (95% UI, 53,140 - 65,500) incident CKD cases and 568 (95% UI, 479 - 652) CKD deaths by 2030. Over the lifetime, this is projected to generate 199,488 (95% UI, 180,910 - 218,340) HALYs and AU$ 644 million in CKD health expenditure savings. Similarly, if achieved, the NPHS is estimated to prevent 49,890 (95% UI, 44,377 - 55,569) incident CKD cases and 511 (95% UI, 426 - 590) CKD deaths by 2030. Over the lifetime, this could produce 170,425 (95% UI, 155,017 - 186,559) HALYs and AU$ 514 million in CKD health expenditure savings.

ConclusionAchieving the national sodium reduction targets could deliver substantial health and economic benefits for people with CKD in Australia. Robust government action is required in order to achieve the projected outcomes of these policy targets.


title: Epidemiology and medical costs of orthopedic conditions in a tertiary hospital in Kenya; A five-year analysis of admission data.

abstract:
BackgroundOrthopedic services are a key component of the surgical healthcare system. Scaling up these services would not only reduce the musculoskeletal diseases burden but also the overall disease burden significantly. As such quality intelligence on epidemiology and costs of orthopedic services should be accurately represented for guiding effective policy formulation and implementation.

AimThe aim of the study was to provide a snapshot of the pattern of orthopedic admissions, care and associated medical costs in Kenya.

MethodsA retrospective study was conducted reviewing case files of patients admitted to the orthopedic department from 1st January 2015 to 30st November 2019.

ResultsThere were 4320 distinct musculoskeletal admission diagnoses among the 3527 admissions. The study shows that trauma accounts for 53.04% of all admissions while joint replacement, shoulder and knee, limb deformities, infection, removal of hardware, ankle and foot and tumour procedures accounts for 15.01%, 8.87%, 7.29%, 6.44%, 3.94% and 3.23% respectively. Joint replacement is the leading diagnosis among patients in the 61 to 75 years age group and fragility fractures and posttraumatic arthritis featured prominently as the key reasons for joint reconstruction. The proportion of admissions with health insurance (60.82%) was exceptionally high compared to the national average (19.59%). However, current financing mechanism provide inadequate social protection against cost of orthopedic surgery.

ConclusionThe case volume and mix highlight the growing importance of trauma, fragility fractures and degenerative joint diseases in orthopedic care in developing country set up. Overall, the observed model of care and associated outcome and costs provide a blueprint for orthopedic system development.

category: orthopedics


title: Dystonia-Parkinsonism Gene Variants in Individuals with Parkinsonism and Brain Scans without Evidence for Dopaminergic Deficit (SWEDD)

abstract:
ObjectiveTo investigate the genetic etiology of dystonia-parkinsonism among individuals with parkinsonism who have dopamine transporter (DAT) SPECT scans without evidence of dopaminergic deficits (SWEDD).

MethodsData for this case-control study were from the Parkinsons Progression Markers Initiative (PPMI) cohort, a multisite observational study. The sample analyzed included participants with whole genome sequencing (WGS) who were diagnosed as Parkinsons disease (PD, n=421), SWEDD (n=64) or healthy controls (HC, n=196). WGS data were analyzed to identify rare pathogenic variants in 30 dystonia-parkinsonism genes. Rare variants were prioritized for those present in individuals with SWEDD, but not in HC, reported pathogenicity in the literature and genetic databases, and with data from programs analyzing variant conservation and effect on protein function. For each SWEDD case with predicted or reported pathogenic variant(s), demographic, clinical, and imaging data were reviewed.

ResultsEight of the 64 SWEDD participants (12.5%) had a pathogenic variant in one or more dystonia-parkinsonism genes, including PRKRA, SGCE, GLB1, ADCY5, SLC6A3, and GCDH. Notably, one case had a heterozygous variant in SGCE, p.R263H, which is predicted pathogenic but currently classified as a variant of uncertain significance due to insufficient evidence.

ConclusionsPathogenic variants in parkinsonism-dystonia genes occurred in more than 10% of SWEDD cases in the PPMI cohort, supporting the importance of considering dystonia disorders in the differential diagnosis of PD, particularly in the case of participants with normal DAT SPECT scans. Analysis of genetic variants in parkinsonism-dystonia genes in SWEDD cases can provide information which will improve clinical diagnosis and management.

KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSIndividuals with parkinsonism with scans without evidence of dopamine deficiency (SWEDD) constitute up to 16% of subjects with early parkinsonism referred for inclusion in multicenter observational studies and randomized clinical trials; however, the majority of these individuals do not have Parkinsons disease. Dystonic disorders are high on the list of differential diagnoses for individuals with parkinsonism and SWEDD, and an increasing number of studies support genetic etiologies for dystonic disorders. What proportion of individuals with parkinsonism and SWEDD referred for research studies might carry pathogenic variants in dystonia-parkinsonism related genes is not known.

What this study addsThis study identified predicted or reported pathogenic variants in dystonia-parkinsonism related genes in more than 10% of SWEDD cases in the PPMI cohort, supporting the utility of evaluating dystonia-parkinsonism related genetic etiology in SWEDD cases.

How this study might affect research, practice, or policyThis study supports the importance of genetic analyses in SWEDD cases which could improve clinical diagnosis and patient management.

category: genetic and genomic medicine


title: Estimating diagnostic noise in panel-based genomic analysis

abstract:
BackgroundGene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panels vary in size, which affects the sensitivity and specificity of the test. We sought to investigate the background rate of candidate diagnostic variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases.

MethodsWe used the Genotype-2-Phenotype database with the Variant Effect Predictor plugin to identify rare non-synonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated five clinically curated gene panels: developmental disorders (DD; 1708 genes), heritable eye disease (536 genes), skin disorders (293 genes), cancer syndromes (91 genes) and cardiac conditions (49 genes). We further tested the DD panel in 9,860 proband-parent trios from the Deciphering Developmental Disorders (DDD) study.

ResultsAs expected, bigger gene panels resulted in more variants being prioritised, varying from an average of [~]0.3 per person in the smallest panels, to [~]3.5 variants per person using the largest panel. The number of individuals with prioritised variants varied linearly with coding sequence length for monoallelic disease genes ([~]300 individuals per 1000 base pairs) and quadratically for biallelic disease genes, with some notable outliers. Based on cancer registry data from UK Biobank, there was no detectable difference between cases and controls in the number of individuals with prioritised variants using the cancer panel, presumably due to the predominance of sporadic disease. However, we observed a marked increase in the number of prioritised variants in the DD panel in the DDD study ([~]5 variants per proband). Phasing of compound heterozygotes in biallelic genes resulted in a modest reduction in the number of prioritised variants.

ConclusionsAlthough large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they will frequently prioritise false positive candidate variants potentially requiring additional clinical follow-up. Most individuals will have at least one rare nonsynonymous variant in panels containing >500 monogenic disease genes. Extreme caution should therefore be applied when interpreting potentially pathogenic variants found in the absence of relevant phenotypes.


title: De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders

abstract: Variant interpretation remains a major challenge in medical genetics. We developed Meta-Domain HotSpot (MDHS) to identify mutational hotspots across homologous protein domains. We applied MDHS to a dataset of 45,221 de novo mutations (DNMs) from 31,058 patients with neurodevelopmental disorders (NDDs) and identified three significantly enriched missense DNM hotspots in the ion transport protein domain family (PF00520). The 37 unique missense DNMs that drive enrichment affect 25 genes, 19 of which were previously associated with NDDs. 3D protein structure modelling supports function-altering effects of these mutations. Hotspot genes have a unique expression pattern in tissue, and we used this pattern alongside in silico predictors and population constraint information to identify candidate NDD-associated genes. We also propose a lenient version of our method, which identifies 32 hotspot positions across 16 different protein domains. These positions are enriched for likely pathogenic variation in clinical databases and DNMs in other genetic disorders.


title: A Systematic Review of Human Challenge Trials, Designs, and Safety

abstract:
BackgroundThere exists no prior systematic review of human challenge trials (HCTs) that focuses on participant safety. Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective.

MethodsA systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 10/7/2021.

ResultsOf 2,838 articles screened, 276 were reviewed in full. 15,046 challenged participants were described in 308 studies that met inclusion criteria. 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies which reported on SAEs, 0.2% of participants experienced at least one challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. 80% of studies published after 2010 were registered in a trials database.

ConclusionsHCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. From the available data, most HCTs do not lead to a high number of severe symptoms or SAEs. This study was preregistered on PROSPERO as CRD42021247218.

category: infectious diseases


title: Genomic Epidemiology of SARS-CoV-2 in Seychelles, 2020-2021

abstract: Seychelles, an archipelago of 155 islands in the Indian Ocean, had confirmed 24,788 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the 31st December 2021. The first SARS-CoV-2 cases in Seychelles were reported on the 14th of March 2020, but cases remained low until January 2021, when a surge of SARS-CoV-2 cases was observed on the islands. Here, we investigated the potential drivers of the surge by genomic analysis 1,056 SARS-CoV-2 positive samples collected in Seychelles between 14th March 2020 and 31st December 2021. The Seychelles genomes were classified into 32 Pango lineages, 1,042 of which fell within four variants of concern i.e., Alpha, Beta, Delta and Omicron. Sporadic cases of SARS-CoV-2 detected in Seychelles in 2020 were mainly of lineage B.1 (European origin) but this lineage was rapidly replaced by Beta variant starting January 2021, and which was also subsequently replaced by the Delta variant in May 2021 that dominated till November 2021 when Omicron cases were identified. Using ancestral state reconstruction approach, we estimated at least 78 independent SARS-CoV-2 introduction events into Seychelles during the study period. Majority of viral introductions into Seychelles occurred in 2021, despite substantial COVID-19 restrictions in place during this period. We conclude that the surge of SARS-CoV-2 cases in Seychelles in January 2021 was primarily due to the introduction of more transmissible SARS-CoV-2 variants into the islands.


title: Evaluation of the Panbio™ COVID-19 Antigen Rapid Diagnostic Test in subjects infected with Omicron using different specimens

abstract: Community testing is a crucial tool for the early identification of SARS-CoV-2 infection and transmission control. The emergence of the highly mutated Omicron variant (B.1.1.259) raised concerns about its primary site of replication, impacting sample collection, and its detectability by rapid antigens tests. We tested the Antigen Rapid Diagnostic Test (Ag-RDT) performance using nasal, oral, and saliva specimens for COVID-19 diagnosis in 192 symptomatic individuals, using RT-qPCR from nasopharyngeal samples as control. Variant of Concern (VOC) investigation was determined by the 4Plex SARS-CoV-2 screening kit. SARS-CoV-2 positivity rate was 66.2%, with 99% of the positive samples showing an amplification profile consistent with that of the Omicron variant. Nasal Ag-RDT showed higher sensitivity (89%) than oral (12.6%) and saliva (22.1%) Ag-RDTs. Our data showed the good performance of the Ag-RDT in a pandemic scenario dominated by the Omicron VOC. Furthermore, our data also demonstrated that nasal specimens perform better than oral and saliva ones for Omicron Ag-RDT detection.


title: Electrocardiography-Based Prediction of Sudden Cardiac Death in Heart Failure Patients: Application of Artificial Intelligence

abstract:
BackgroundAlthough predicting sudden cardiac death (SCD) in patients with heart failure (HF) is critical, the current predictive model is suboptimal. Electrocardiography-based artificial intelligence (ECG-AI) algorithms may better stratify risk. We assessed whether the ECG-AI index established here could better predict SCD in HF and whether the ECG-AI index and conventional predictors of SCD can improve SCD stratification.

MethodsIn a prospective observational study, four tertiary care hospitals in metropolitan Tokyo that enrolled 2,559 patients hospitalized with HF who were successfully discharged after acute decompensation. ECG data collected during the index hospitalization were extracted from the hospitals electronic medical record systems. The ECG-AI index is the output from an AI model that was trained to predict the risk of SCD based on ECG input. The association between ECG-AI index and SCD was evaluated with adjustment for left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, and competing risk of non-SCD. The outcome measure was a composite of SCD and implantable cardioverter-defibrillator activation. The ECG-AI index was established using a derivation (hospital A) and validation cohort (hospital B), and its ability was evaluated in a test cohort (hospitals C and D).

ResultsThe ECG-AI index plus classical predictive guidelines (i.e., LVEF [≤] 35%, NYHA class II-III) significantly improved the discriminative value of SCD (area under the receiver operating characteristic curve, 0.66 vs. 0.59; p=0.017; Delongs test) with good calibration (p=0.11; Hosmer-Lemeshow test) and improved net reclassification (36%; 95% confidence interval, 9%-64%; p=0.009). The Fine-Gray model considering the competing risk of non-SCD demonstrated that the ECG-AI index was independently associated with SCD (adjusted sub-distributional hazard ratio, 1.25; 95% confidence interval, 1.04-1.49; p=0.015). An increased proportional risk of SCD vs. non-SCD with increasing ECG-AI index was also observed (low, 16.7%; intermediate, 18.5%; high, 28.7% risk; p for trend = 0.023). Similar findings were observed in patients aged [≤]75 years with a non-ischemic etiology and an LVEF >35%.

ConclusionsAmong patients with HF, ECG-based AI significantly improved the SCD risk stratification compared to the conventional indication for implantable cardioverter-defibrillators inclusive of LVEF and NYHA class.

category: cardiovascular medicine


title: The motivational control of human action, its neural bases and functional impact in OCD

abstract: Establishing the motivational influences on human behaviour is essential for understanding choice and decision-making in health and disease. Here we used tests of value-based decision-making that manipulated both predicted and experienced reward values to reveal the role these processes play in human action selection, their neural bases and functional significance in people with OCD. We found clear evidence that both predicted and experienced values influence choice and decision-making in humans and for a circuit involving orbitofrontal cortex (OFC) and caudate nucleus in these aspects of action control. To establish the functional significance of this circuit in value-based processes we assessed their influence in healthy participants and a matched cohort of people diagnosed with obsessive-compulsive disorder (OCD). We found that choice between actions in people with OCD was insensitive to changes in either predicted or experienced values and that these behavioural impairments corresponded to aberrant activity in the OFC, the caudate nucleus and their connectivity.


title: Targeted memory reactivation during REM sleep in patients with social anxiety disorder

abstract:
BackgroundSocial anxiety disorder (SAD) is an anxiety disorder characterized by a significant amount of fear when confronted to social situations and can cause considerable distress in daily life. Exposure therapy, which is based on fear extinction, is a popular and effective treatment for SAD, although it does not often lead to full remission. Here, we aimed at improving exposure therapy outcome. Specifically, based on previous research showing that rapid eye movement (REM) sleep promotes the consolidation of extinction memory, we used targeted memory reactivation (TMR) during REM sleep to enhance extinction learning.

Methods48 subjects (32 women and 16 men, mean age of 24.41 {+/-} 4.91) with moderate or severe SAD according to DSM-5 participated in our study, and were randomly assigned to one of two matched groups: control or TMR group. All patients had two successive exposure therapy sessions in a virtual reality (VR) environment, where they were asked to give a public talk in front of a virtual jury. At the end of each session, and only in the TMR group (N=24), a sound was paired to the positive feedback phase of exposure therapy (i.e. approval of their performance), and which represents the extinction memory to be strengthened during REM sleep. All participants slept at home with a wearable headband device which automatically identified sleep stages online and administered the sound several times during REM sleep. Anxiety level was assessed using measures of sympathetic (electrodermal activity component : non-specific skin conductance responses, ns-SCRs) and parasympathetic (heart rate variability component : root mean square of successive differences between normal heartbeats, RMSSD) activity, and subjective measures (Subjective Units of Distress Scale, SUDS), during the preparation phase of their virtual talks before (T1) and after (T2) one full-nights sleep with auditory stimulation and after one week of auditory stimulation at home (T3). Participants also filled in a dream diary one week prior and one week after the day of exposure therapy.

ResultsSubjective anxiety was reduced during the second and third anticipatory preparation phase of exposure, compared to the first one, for both groups (p < 0.001). RMSSD levels were lower in the TMR group compared to the control group (p=.037) during the preparation phase after 8 nights of stimulation at home (T3). No significant result between groups was observed for SUDS and the ns-SCRs at T3. Importantly, the longer REM sleep and the more stimulations the TMR group (but not the control group) had at home, the less anxious (increased RMSSD) these participants were. Finally, fear in dreams correlated positively with measures of stress (ns-SCRs and SUDS) in this group.

ConclusionsTMR during REM sleep did not modulate the beneficial effect of exposure therapy on anxiety-related distress (SUDS). Yet, our results support that REM sleep can contribute to extinction processes and substantiate strong links between emotional experiences in dreams and waking stress levels in these patients.


title: Parental income gradients in child and adolescent mortality: Norwegian trends over half a century

abstract:
BackgroundChild mortality declined rapidly the last century in many high-income countries. However, little is known about the socioeconomic differences in this decline, and whether these vary across causes of death.

MethodsWe use register data including all Norwegian births between 1968 to 2010 (2.1 million), and analyse how all-cause and cause-specific child (0-5) and adolescent mortality (6-21) vary with relative parental income the year before the birth

ResultsChild all-cause mortality decreased with increasing parental relative income within all birth cohorts. Among children aged 0-5, the socioeconomic gradient for all-cause, accidental deaths, sudden infant death syndrome and perinatal factors declined over the periode, while there was no systematic decline related to congenital malformations. Among children 6-21, the gradient did not weaken similarly, although there were indications of declines in the socioeconomic gradient related to all-cause deaths, accidents, and suicides. While the absolute differences in mortality declined over time, the relative differences remained stable.

ConclusionThere has been a large reduction in child mortality in all socioeconomic groups across 50 years for all-cause and most cause-specific mortality groups. However, children of parents in the lowest part of the income distribution still have an elevated mortality, and the relative differences have not always been declining.


title: The tryptophan catabolite or kynurenine pathway in Alzheimer's disease: a systematic review and meta-analysis.

abstract:
BackgroundAlzheimers disease (AD), characterized by gradual brain dysfunction and memory loss, is one of the major elderly health issues worldwide. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway.

ObjectivesTo delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients.

MethodsWe employed PubMed, Google Scholar, Web of Science, and SciFinder to obtain the relevant articles through a search process lasting the entire February 2022. We found 19 eligible articles which involved 738 patients and 665 healthy controls.

ResultsOur result revealed a significant difference (p = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = -0.520, 95% CI: -0.738; -0.302, p < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS, brain and cerebrospinal fluid, CSF) kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid (XA) in the CNS and blood.

ConclusionsAD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD.

category: neurology


title: The outcome of Gynecologic Cancer Patients With The Covid-19 Infection: A Systematic Review And Meta-Analysis

abstract:
ObjectiveCancer is a comorbidity that leads to progressive worsening of Covid-19 with increased mortality. This is a systematic review and meta-analysis to yield evidence of adverse outcomes of Covid-19 in gynecologic cancer.

MethodsSearches through PubMed, Google Scholar, ScienceDirect, and medRxiv to find articles on the outcome of gynecologic cancer with Covid-19 (24 July 2021-19 February 2022). Newcastle-Ottawa Scale tool is used to evaluate the quality of included studies. Pooled odds ratio (OR), 95% confidence interval (CI), random-effects model were presented. This study was registered to PROSPERO (CRD42021256557).

ResultsWe accepted 51 studies (1991 gynecologic cancer with Covid-19). Covid-19 infection was lower in gynecologic cancer vs hematologic cancer (OR 0.71, CI 0.56-0.90, p 0.005). Severe Covid and death were lower in gynecologic cancer vs lung and hematologic cancer (OR 0.36, CI 0.16-0.80, p 0.01), (OR 0.52, CI 0.44-0.62, p <0.0001), (OR 0.26, CI 0.10-0.67 p 0.005), (OR 0.63, CI 0.47-0.83, p 0.001) respectively. Increased Covid death is seen in gynecologic cancer vs breast, non-covid cancer, and non-cancer covid (OR 1.50, CI 1.20-1.88, p 0.0004), (OR 11.83, CI 8.20-17.07, p <0.0001), (OR 2.98, CI 2.23-3.98, p <0.0001) respectively.

ConclusionGynecologic cancer has higher Covid-19 adverse outcomes compared to non-cancer, breast cancer, non-metastatic, and Covid-19 negative population. Gynecologic cancer has fewer Covid-19 adverse outcomes compared to other cancer types, lung cancer, and hematologic cancer. These findings may aid health policies and services during the ongoing global pandemic.

category: oncology


title: The Outcome of Gynecologic Cancer Patients With Covid-19 Infection: A Systematic Review And Meta-Analysis


title: Retinal Microvasculature Alteration in Patients with Rheumatoid Arthritis

abstract:
BackgroundRheumatoid arthritis (RA) is an autoimmune disease that usually causes synovial inflammation, cartilage and bone deformity, and is associated with the production of rheumatoid factor (RF) and anti-citrullinated protein antibody (1-3). The ocular, cardiovascular and other systemic complications of this disease are of significant concern (4-6). In particular, the eye is susceptible to inflammation or autoimmune disorders and shows ocular manifestations that may be early clinical symptoms of systemic vasculitis in some rheumatic disease cases (7-8). This study used optical coherence tomography angiography (OCTA) to evaluate retinal and conjunctival microvascular alterations in RA patients.

MethodsTwelve patients (24 eyes) with a history of at least 5 years of rheumatoid arthritis (RA) were identified from their medical records and compared with 12 normal controls (24 eyes). The microvasculature of each eye was measured quantitatively using OCTA images. The images were manually segmented into representations of two physiologic layers: the superficial retinal layer (SRL) and the deep retinal layer (DRL). The microvascular (SMIR, DMIR), macrovascular (SMAR, DMAR) and total microvascular (STMI, DTMI) density were quantified and calculated in each layer. Simultaneously, macular retinal area was segmented into different regions based on the hemisphere segmentation (SR, SL, IL, and IR), early treatment of diabetic retinopathy study (ETDRS; R, S, L, and I) and central wheel division methods (C1-C6). Microvasculature measurements were used to compare microvascular densities between RA and normal controls and to explore the correlation between microvascular alteration and disease.

ResultsCompared with the control group, superficial and deep retinal layer microvascular density was decreased in the RA group. The STMI (p<0.0001), DTMI (p<0.0001), SMIR (p<0.0001), and DMIR (p<0.0001), were lower in RA than in controls, while the SMAR (p=0.207), and DMAR (p=0.828), density was statistically similar between groups. A significant difference was found in both superficial and deep layers in S (p<0.0001), SL (p<0.0001 and p<0.0004 respectively), SR (p<0.0001 and p=0.008 respectively), IL (p<0.0001) and C1 (p<0.0001 and p<0.004 respectively), C2 (p<0.0001 and p=0.0002 respectively), C4 (p=0.02 and p=0.007 respectively) regions, and additionally in the L (p<0.0001), I (p=0.004), C3 (p<0.0001) and C5 (p=0.002), regions in the superficial layer. Similarly, the temporal conjunctival vessel density was found to be lower in RA patients than in controls (t=2.030; P=0.048). In RA group, a statistically positive correlation was indicated between conjunctival microvascular and STMI densities (correlation coefficient 0.712, p=0.02).

ConclusionRA is complicated by several severe ocular symptoms and causes superficial and deep microvascular density alteration. This finding could precede diagnosis of the underlying RA and may be a useful factor in early diagnosis and the avoidance of long-term sequelae in systemic rheumatic diseases.

category: ophthalmology


title: Traumatic Experience and Self-Control in Old Age

abstract:
The behavioral economics literature suggests that exposure to traumatic events shifts preference features like risk aversion and time preference. Drawing on this literature, this study explored the relationship between early life exposure to traumatic events and self-control at older ages. The data were obtained from the Health and Retirement Study, which offers retrospective data on trauma exposure and a measure of self-control. The results showed that the experience of serious physical attacks or assaults was associated with a 3.1% reduction in self-control, above and beyond the influence of demographic characteristics and childhood socioeconomic disadvantages. The mean number of years elapsed since the physical attack was about 30, conditional on exposure, indicating that traumatic experiences early in life exert a lasting influence on self-control. Our findings were consistent with evidence that experiences of natural disasters and armed conflicts increased impatience among survivors.

JEL classification codeD12, D14, D91

category: health economics


title: An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?

abstract:
BackgroundsEvidence from several meta-analyses are still controversial about the effects of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes.

PurposeUmbrella review of systematic reviews/meta-analysis to provide comprehensive assessment of the effect of ACEIs/ARBs on COVID-19 related outcomes by summarising the currently available evidence.

Data SourceMedline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1st February 2021.

Study SelectionSystematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19 related clinical outcomes

Data ExtractionTwo reviewers independently extracted the data and assessed studies risk of bias using AMSTAR 2 Critical Appraisal Tool.

Data SynthesisPooled estimates were combined using the random-effects meta-analyses model including several sub-group analyses. Overall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR=0.80, 95%CI=0.75-0.86; I2=51.9%), death/ICU admission as composite outcome (OR=0.86, 95%CI=0.80-0.92; I2=43.9%), severe COVID-19 (OR=0.86, 95%CI=0.78-0.95; I2=68%), and hospitalisation (OR=1.23, 95%CI=1.04-1.46; I2= 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR=0.63, 95%CI=0.47-0.84) and were of moderate quality (OR=0.74, 95%CI=0.63-0.85).

LimitationsThe effect of unmeasured confounding could not be ruled out. Only 21.3% (n=10) of the studies were of  moderate quality.

ConclusionCollective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19.

RegistrationThe study protocol was registered in PROSPERO (CRD42021233398).

Funding SourceNone


title: Heritability of cardiovascular health across three generations in South Africa: the Birth to Twenty-Plus cohort

abstract:
ObjectivesCardiovascular disease is increasing in many low-middle income countries, including those in Africa. To inform strategies for the prevention of cardiovascular disease in South Africa, we sought to determine the broad heritability of phenotypic markers of cardiovascular risk across three generations.

DesignA cross-sectional study conducted in a longitudinal family cohort.

SettingResearch unit within a tertiary hospital in a historically disadvantaged, large urban township of South Africa.

Participants195 individuals from 65 biological families with all three generations including third generation children aged 4-10 years were recruited from the longest running intergenerational cohort study in Africa, the Birth to Twenty Plus cohort. All adults (grandparents and parents) were female, while children were male or female.

Primary and secondary outcome measuresThe primary outcome was heritability of blood pressure (BP, brachial and central pressures). Secondary outcomes were heritability of arterial stiffness (pulse wave velocity), carotid intima media thickness (cIMT), and left ventricular mass indexed to body surface area (LVMI).

ResultsWhile no significant intergenerational relationships of BP or arterial stiffness were found, there were significant relationships in LVMI across all three generations (p<0.04), and in cIMT between grandparents and parents (p=0.0166). Heritability estimates were 23-44% for cIMT and 21-39% for LVMI.

ConclusionsStructural indicators of vascular health, which are strong markers of future clinical cardiovascular outcomes transmit between generations within African families. Identification of these markers in parents may be useful to trigger assessments of preventable risk factors for cardiovascular disease in offspring.

StrengthsO_LIIntergenerational transmission was evaluated for a range of indicators of cardiovascular health within urban African families
C_LIO_LIThe sample included biological family members from three generations
C_LIO_LIHeritability estimates were compared for three commonly used statistical methods.
C_LI

LimitationsO_LIThe sample size is a limitation with the random family statistical method used to increase the numbers of comparisons available.
C_LIO_LIOnly maternal family members were included.
C_LI


title: More severe pneumonitis in children predicts the need for admission and elevation of some but not all markers of severe Covid-19.

abstract:
Unlike most other viral pneumonitis, SARS-CoV-2 often causes hyperferritinemia, elevations in D-dimer, lactate dehydrogenase (LDH), transaminases, troponin, CRP, and other inflammatory markers. We questioned (1) if the severity of pneumonitis observed on lung ultrasound was associated with hospitalization and (2) could lung ultrasound be used to stratify which children needed blood tests?

MethodsWe did a retrospective cross-sectional review of children aged between 14 days and 21 years of age being evaluated for Covid-19 in our pediatric emergency department from 30/November/2019 to 14/August/2021 who had had a point-of-care lung ultrasound. Lung ultrasounds were categorized using a 6-point ordinal scale. We used logistic regression to estimate the adjusted effect of lung ultrasound on hospital admission. We performed ordinary least square regression for the association between lung ultrasound severity and laboratory abnormalities. We adjusted these using propensity score derived inverse probability weighting to account for the non-random decision to obtain laboratory investigations.

ResultsWe identified 500 point-of-care lung ultrasounds of which 427 could be assigned a severity category. Increasing lung ultrasound severity was associated with increased hospital admission OR 1.36(95% CI 1.08, 1.72.) Ferritin, LDH, transaminases, and D-dimer, but not CRP or troponin were significantly associated with more than moderately severe lung ultrasounds. D-Dimer, CRP, and troponin were sometimes elevated even when lung ultrasound was normal.

ConclusionSeverity of pneumonitis was associated with hospital admission. Ferritin, LDH, transaminases, and D-dimer were increased in more than moderately severe pneumonitis but lung ultrasound did not predict elevation of other markers.

category: emergency medicine


title: Risk factors of chronic liver disease among adult patients in tertiary hospitals, Northern Ethiopia: An unmatched case-control study

abstract:
IntroductionChronic liver disease imposed substantial health and economic burden causing 1.75 million deaths and increased hospital admission rates. However, it is a neglected health issue in resource-limited countries like Ethiopia, with the paucity of data on the determinants of chronic liver disease. Besides, available studies considered single or limited factors. Thus, the aim of this study was to assess the determinant factors of chronic liver disease among patients who were attending at the gastroenterology units.

MethodsAn unmatched case-control study was conducted on 281 (94 cases and 187 controls) systematically selected subjects at tertiary hospitals in Northern Ethiopia from November 2018 to June 2019. Data were collected using an interviewer-administered questionnaire and checklists, entered to Epi data version 4.4.2, and analyzed using SPSS version 25. Bi-variable and multivariate analyses were done using binary logistic regression. Variables with p< 0.25 in the bi-variable analysis were fitted to the final model. An adjusted odds ratio with 95% CI was used to declare significance and associations.

ResultsAn overall 281 (94 cases and 187 controls) patients attending at the gastroenterology units had been included with a response rate of 100%. Being chronic alcohol consumer (AOR=2.8; 95% CI: 1.1-7.0), having a history of herbal medication use (AOR=14; 95% CI: 5.2-42), history of injectable drug use (AOR=8.7; 95% CI: 3-24.8), and hepatitis B infection (AOR=12; 95% CI: 3.0-49) were found to have an independent association with chronic liver disease.

ConclusionAlcohol consumption, history of herbal medication use, hepatitis B infection, and history of parenteral medication use were found to be determinant factors of chronic liver disease. Strengthening viral hepatitis screening activities, interventions focused on behavioral change, and linking traditional healers to the healthcare system is crucial.

What is known about the subject?Chronic liver disease (CLD) causes substantial health and economic burden where more than 1 million deaths occurred due to CLD complications annually. Studies reported that CLD causes 1.8-10% of all deaths and responsible for increased hospital admission rates. From 1980 to 2010, chronic liver disease-related deaths doubled in sub-Saharan African countries. Despite measures have been designed and on implementation to decrease this burden, the access to these interventions is limited, and the number of patients increased dramatically.

What does this study add?O_LIDifferent behavioral, socio-cultural, and clinical factors had a statistically significant association with chronic liver disease.
C_LIO_LIAlcohol consumption, history of herbal medication use, hepatitis B infection (HBV+), and history of parenteral medication use were found to be determinant factors of chronic liver disease (CLD).
C_LI

Strength and limitations of the studyO_LIDespite this study presented important findings that could input for the scientific world in the area of CLD, the study had its own limitations.
C_LIO_LISince almost all participants did not have documented medical checkups, it was challenging to extract previous history of chronic viral hepatitis. Hence, the effect of this pertinent variable was left unevaluated in this study.
C_LI

category: gastroenterology


title: Developing and piloting a preterm birth registry prioritizing social determinants of health and patient-reported data

abstract: Biomedical factors and social determinants of health (SDH) affect preterm birth (PTB). Given the complexity of PTB and the increasing rates in the United States, public datasets involving multicomponent variables--from biomedical to structural--can motivate novel interventions to address PTB in the US. The primary aim of this study was to develop a PTB registry based on multi-modal data collection tools that prioritize biomedical and SDH data and identify PTB phenotype (i.e. spontaneous labor, preterm premature rupture of membrane, or medically indicated). The secondary aim of this study was to execute a pilot study to assess feasibility. This study aimed to describe recruitment practices, assess data accessibility and concordance, and to provide an example of how the registry can be used to generate hypothesis and analyze data. We designed the registry through a conceptual model provided by the Dahlgren and Whitehead model of SDH using validated questionnaires and literature on PTB. The registry included a survey, interview, and medical and birth certificate abstraction. To pilot the registry, we recruited 92 participants who delivered preterm, were admitted for risk of preterm delivery, or delivered at term at an urban public hospital. Enrollment was most effective in-person and in the postpartum period. Consent to different parts of the registry was similar regardless of when participants were recruited. There was also a range of data concordance depending on the data source and chosen variable. The registrys PTB phenotype algorithm identified the correct PTB phenotype 100% of the time. The example analysis demonstrated six unique SDH domains. Participants who delivered preterm reported an average of 11 total stressors and 19.7 protective items and 66% had a significant medical or obstetric comorbidity. Results of this study demonstrate that a PTB registry is feasible and could help advance research to prevent PTB.

category: obstetrics and gynecology


title: Unified Predictive Model for Endometriosis: Merging Clinical, Self-reporting and Genetic Information

abstract: Endometriosis is a condition characterized by implants of endometrial tissues into extrauterine sites, mostly within the pelvic peritoneum. The prevalence of endometriosis is under-diagnosed, and estimated to account for 5-10% of all women of reproductive age. The goal of this study is to develop a model for endometriosis based on the UK-biobank (UKBB). We partitioned the data into those diagnosed with endometriosis (5,924; ICD-10: N80) and a control group (142,576). We included over 1000 variables from UKBB covering personal information about female health, lifestyle, self-reported data, genetic variants, and medical history prior to endometriosis diagnosis. We applied machine learning algorithms to train an endometriosis prediction model. The optimal prediction was achieved with the gradient boosting algorithms of CatBoost for the data-combined model, with an area under the ROC curve (roc-AUC) of 0.78. We discovered that, prior to being diagnosed with endometriosis, women had significantly more ICD-10 diagnoses than the average unaffected woman. Informative features, ranked by SHAP values included irritable bowel syndrome (IBS) and the length of the menstrual cycle. We conclude that the rich population-based retrospective data from the UKBB is valuable for developing predictive models despite the limitations of missing data and noisy medical input. The informative features of the model may improve clinical utility for endometriosis diagnosis.


title: Targeting phenotypic plasticity prevents metastasis and the development of chemotherapy-resistant disease

abstract:
Cancer cells invoke phenotypic plasticity programs to drive disease progression and evade chemotherapeutic insults, yet until now there have been no validated clinical therapies targeting this process. Here, we identify a phenotypic plasticity signature associated with poor survival in basal/triple-negative breast cancer, in which androgen signalling is prominent. We establish that anti-androgen therapies block cancer stem cell function and prevent chemotherapy-induced emergence of new cancer stem cells. In particular, the anti-androgen agent seviteronel synergizes with chemotherapy to improve chemotherapeutic inhibition of primary and metastatic tumour growth and prevent the emergence of chemotherapy-resistant disease. We validate cytoplasmic AR expression as a clinical phenotypic plasticity biomarker that predicts poor survival and poor response to chemotherapy, and positive response to seviteronel plus chemotherapy. This new targeted combination therapy validates modulating phenotypic plasticity as an effective strategy to prevent and treat chemotherapy-resistant cancers with transformative clinical potential.

STATEMENT OF SIGNIFICANCEThere are currently no curative therapies for patients with chemotherapy-resistant cancer. We demonstrate that modulating phenotypic plasticity prevents the emergence of chemotherapy-resistant disease in triple-negative breast cancer. This represents the first known validated clinical therapy leveraging phenotypic plasticity. Moreover, we identify a highly effective anti-androgen drug and a biomarker to select and treat patients best-suited to this new therapy. A clinical trial is underway (NCT04947189).

SUMMARY SENTENCEBlocking phenotypic plasticity is an effective targeted therapeutic strategy to treat cance


title: Womens Seclusion during Menstruation and Childrens Health in Nepal

abstract:
ObjectivesThere is limited empirical evidence from low-income countries on the effects of womens seclusion during menstruation on childrens health. We documented the association between mothers extreme seclusion during menstruation and childrens health in Nepal.

MethodsUsing nationally representative data from the 2019 Multiple Indicator Cluster Survey, we examined the relationship between mothers exposure to extreme forms of seclusion during menstruation and anthropometric measures of nutritional status and health outcomes among children ages 5-59 months (n=6,301). We analyzed the data in a regression framework, controlling for potential confounders, including province fixed effects. We assessed extreme seclusion during menstruation based on womens exposure to chhaupadi, a practice in which women are forced to stay away from home--in separate huts or animal sheds--during menstruation and childbirth.

ResultsMothers exposure to extreme seclusion during menstruation was associated with 0.18 standard deviation lower height-for-age z-scores (HAZ) (p=0.046) and 0.20 standard deviation lower weight-for-age z-scores (WAZ) (p=0.007) among children. Analysis by the place of seclusion showed that the negative association was stronger when women stayed in animal sheds--0.28 SD for HAZ (p=0.007) and 0.32 SD for WAZ (p<0.001)--than when they stayed in separate huts. Extreme seclusion was associated with higher incidence of acute respiratory symptoms but not with incidence of diarrhea, irrespective of the place of seclusion.

ConclusionsWomens extreme seclusion during menstruation in Nepal has profound implications on the physical health of their children. Additional research is needed to ascertain potential mechanisms.


title: Regional importation and asymmetric within-country spread of SARS-CoV-2 variants of concern in the Netherlands

abstract: Variants of concern (VOCs) of SARS-CoV-2 have caused resurging waves of infections worldwide. In the Netherlands, Alpha, Beta, Gamma and Delta variants circulated widely between September 2020 and August 2021. To understand how various control measures had impacted the spread of these VOCs, we analyzed 39,844 SARS-CoV-2 genomes collected under the Dutch national surveillance program. We found that all four VOCs were introduced before targeted flight restrictions were imposed on countries where the VOCs first emerged. Importantly, foreign introductions, predominantly from other European countries, continued during these restrictions. Our findings show that flight restrictions had limited effectiveness in deterring VOC introductions due to the strength of regional land travel importation risks. We also found that the Alpha and Delta variants largely circulated more populous regions with international connections after their respective introduction before asymmetric bidirectional transmissions occurred with the rest of the country and the variant dominated infections in the Netherlands. As countries consider scaling down SARS-CoV-2 surveillance efforts in the post-crisis phase of the pandemic, our results highlight that robust surveillance in regions of early spread is important for providing timely information for variant detection and outbreak control.

category: epidemiology


title: Should the governance of individual treatment attempts (''Individuelle Heilversuche	'') include praxis evaluation? Results from qualitative stakeholder interviews.

abstract:
IntroductionIndividual treatment attempts (ITAs) are a German concept for the treatment of individual patients by physicians with nonstandard therapeutic approaches. ITAs span from nonstandard off-label drug uses to first-in-human uses of newly developed drugs/ interventions. Due to the lack of evidence, ITAs come with a high amount of uncertainty regarding the risk-benefit ratio. At present, no prospective review and no systematic retrospective evaluation of ITAs are required in Germany; therefore, no opportunity exists for the basic evaluation of the frequency, type, or outcomes of ITAs. Our objective was to explore stakeholders attitudes toward the retrospective evaluation (monitoring) or prospective evaluation (review) of ITAs.

MethodsWe conducted a qualitative interview study among relevant stakeholder groups. We used the SWOT framework to represent the stakeholders attitudes. We applied content analysis to the recorded and transcribed interviews in MAXQDA.

ResultsTwenty interviewees participated in the study. The interviewees pointed to several arguments in favor of the retrospective evaluation of ITAs, such as the knowledge gain about and setting and circumstances of ITAs. At the same time, the interviewees expressed concerns regarding the validity and practical relevance of the evaluation results. The viewpoints on review addressed several contextual factors (e.g., different medical disciplines) that should be acknowledged when judging the necessity of a review.

ConclusionOne main conclusion is that the current situation with a complete lack of evaluation insufficiently reflects safety concerns. German health policy decision makers should be more explicit about where and why some sort of evaluation is needed or not needed. Another conclusion is that there is no one-size-fits-all model for evaluating ITAs. Both prospective and retrospective evaluations should be piloted in areas of ITAs with particularly high risks and conflicts of interest, such as in the application of very experimental therapies (e.g., bench-to-bedside applications) outside clinical trials.

category: health systems and quality improvement


title: Rett syndrome severity estimation with the BioStamp nPoint using interactions between heart rate variability and body movement

abstract: Rett syndrome, a rare genetic neurodevelopmental disorder in humans, does not have an effective cure. However, multiple therapies and medications exist to treat symptoms and improve patients quality of life. As research continues to discover and evaluate new medications for Rett syndrome patients, there remains a lack of objective physiological and motor activity-based (physio-motor) biomarkers that enable the measurement of the effect of these medications on the change in patients Rett syndrome severity. In our work, using a commercially available wearable chest patch, we recorded simultaneous electrocardiogram and three-axis acceleration from 20 patients suffering from Rett syndrome along with the corresponding Clinical Global Impression - Severity score, which measures the overall disease severity on a 7-point Likert scale. We derived physio-motor features from these recordings that captured heart rate variability, activity metrics, and the interactions between heart rate and activity. Further, we developed machine learning (ML) models to classify high-severity Rett patients from low-severity Rett patients using the derived physio-motor features. For the best-trained model, we obtained a pooled area under the receiver operating curve equal to 0.92 via a leave-one-out-patient cross-validation approach. Finally, we computed the feature popularity scores for all the trained ML models and identified physio-motor biomarkers for Rett syndrome.

category: health informatics


title: Insulin sensitivity in mesolimbic pathways predicts and improves with weight loss in older dieters

abstract: Central insulin is critically involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain, but how this relates to effective weight management is unclear, especially in the elderly, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, fifty overweight, pre-diabetic elderly participated in a double-blind, placebo-controlled pharmacological longitudinal fMRI study before and after randomization to a 3-month caloric restriction or active waiting group. Our data show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and whole-body insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.

category: endocrinology


title: Associations between maternal complications during pregnancy and childhood asthma: a retrospective cohort study in southern China

abstract:
BackgroundThe associations between maternal complications during pregnancy and childhood asthma have rarely been investigated in low and middle-income countries. We aimed to investigate the associations among the southern Chinese population, and to determine whether the associations were mediated through preterm birth, cesarean delivery, low birth weight and non-breasting feeding in the first 6 months or modified by childs lifestyles (smoking, body mass index(BMI), and sleep duration).

MethodsWe conducted a retrospective cohort study of 208,190 children in Guangzhou, China. Information on maternal gestational hypertension, gestational diabetes, gestational anemia, and hepatitis B during pregnancy was extracted from medical records. Ever diagnosis of asthma of the children was obtained by questionnaire. We used binomial logistic regression models to estimate the adjusted odds ratios (aORs) and 95% confidential interval (CI) for childhood asthma. We conducted mediation analyses to estimate the indirect effects of gestational complications on childhood asthma mediated through preterm birth, cesarean delivery, low birth weight, and non-breastfeeding in the first 6 months.

FindingsThe overall prevalence of ever diagnosed asthma was 1.3%. Gestational hypertension, gestational diabetes, gestational anemia, or hepatitis B during pregnancy was positively associated with ever diagnosed childhood asthma, with the aOR of 1.66(95%CI 1.31-2.10), 1.68(95%CI 1.40-2.02), 1.69(95%CI 1.49-1.91) and 1.54(95%CI 1.13-2.08), respectively. A stronger association was observed for 2 or more gestational complications (aOR= 2.34, 95%CI 1.71-3.23) than 1 gestational complication (aOR=1.80, 95%CI 1.62-1.99). The associations between maternal complications and childhood asthma did not differ by childs smoking, BMI, or sleep duration, except that the aOR for maternal gestational hypertension was significantly higher in children who were active smoker (aOR=5.68, 95%CI 2.09-15.42) than those who were non-smoker (aOR=1.56, 95%CI 1.21-2.00). A small proportion of the associations were mediated through preterm birth, cesarean delivery, low birth weight, and non-breastfeeding in the first 6 months.

InterpretationGestational hypertension, diabetes, anemia, or hepatitis B during pregnancy was significantly associated with childhood asthma in the southern Chinese population, and the associations were partially explained by the mediation effects of cesarean delivery, preterm birth, low birthweight and non-breastfeeding in the first 6 months.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIEarly stage of life is a sensitive period for the development of respiratory health, but there is rarely study investigated the associations between maternal complications during pregnancy and childhood asthma in low and middle income countries.
C_LIO_LIBirth outcomes, breastdfeeding and childrens lifestyles are associated with athma, but it remain unclear whether the effects of maternal complications during the pregnancy on childhood asthma could be moderated by lifestyles of children or mediated through birth outcomes and breastfeeding.
C_LI

What did the researchers do and find?O_LIIn this large cohort study of more than 220,000 participants, we found gestational hypertension, diabetes, anemia, or hepatitis B during pregnancy was significantly associated with childhood ever diagnosed asthma.
C_LIO_LIA stronger association was observed for 2 or more gestational complications than 1 gestational complication.
C_LIO_LIThe associations between maternal complications and childhood asthma did not differ by childs smoking, body mass index, or sleep duration, but a small proportion of the associations were mediated through preterm birth, cesarean delivery, low birth weight, and non-breastfeeding in the first 6 months.
C_LI

What do these findings mean?O_LIThe findings suggest that interventions to address childhood asthma should consider potential associations with maternal complications.
C_LIO_LITo avoid cesarean delivery, preterm birth, low birthweight and non-breastfeeding in the first 6 months may reduce the effects of maternal complication during pregnancy on childhood asthma.
C_LI


title: Early detection of SARS-CoV-2 variants using traveler-based genomic surveillance at four US airports, September 2021- January 2022

abstract: We enrolled arriving international air travelers in SARS-CoV-2 genomic surveillance, using molecular testing of pooled nasal swabs, and sequencing positive samples for viral lineage. Traveler-based genomic surveillance provided early warning variant detection; we reported the first U.S. Omicron BA.2 and first BA.3 in North America, weeks before next reported detection.


title: Health behaviours prior to pregnancy and fertility outcomes: Triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa)

abstract:
IntroductionCurrent advice to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range, and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding.

MethodsThis study uses data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. First, we analysed associations between health behaviours prior to pregnancy (alcohol and caffeine consumption, body-mass index (BMI) and smoking) and multiple indicators of fertility (including number of children, time to conception, and miscarriage) (n=83,128 women, 67,555 men), adjusting for birthyear, education and attention deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility outcomes (n=27,216 women, 26,131 men). Finally, we performed summary-level MR for available outcomes (n=91,462-1,232,091) and conducted multi-variable MR to control for education and ADHD liability.

ResultsIn observational analysis, higher BMI and smoking (and to a lesser extent caffeine) were predominantly associated with reduced fertility outcomes. Unexpectedly, higher alcohol consumption was associated with predominantly improved fertility outcomes. There was little evidence from individual-level MR analyses, except smoking and higher BMI were associated with younger age at first birth in women (mean difference in years, per SD increase in genetic score; smoking: -2.65 (95%CI: -3.57, -1.73); BMI: -0.11 (95%CI: -0.16, -0.08)) and men (smoking: -2.82 (95%CI: -4.07, -1.58); BMI: -0.17 (95%CI: -0.23, -0.11)). These results were replicated in the summary-level MR analysis, however effects attenuated after adjusting for education and ADHD liability.

ConclusionsMost observational evidence for associations between health behaviours and fertility was not supported by MR analyses, suggesting possible residual confounding. Evidence from MR analyses supported an effect of smoking and higher BMI on younger age of first birth, but multivariable MR suggested this might be explained by underlying liability to ADHD and low educational attainment.


title: Directional anchor genes refine polygenic informed treatment selection in schizophrenia and bipolar disorder

abstract: Genetically informed drug development and repurposing is an attractive prospect for improving outcomes in patients with psychiatric illness; however, the effectiveness of these endeavours can be confounded by heterogeneity. In this study, we propose a novel approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritise individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, we call pharmagenic enrichment scores (PES), identify individuals with a higher burden of genetic risk, localised in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed, including antioxidants, vitamins, antiarrhythmics, and lipid modifying agents. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS and distinct correlations with measured biochemical traits. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

category: psychiatry and clinical psychology


title: Altered Brain Responses to Noxious Dentoalveolar Stimuli in High-Impact Temporomandibular Disorder Pain Patients

abstract: High-impact temporomandibular disorder (TMD) pain may involve brain mechanisms related to central sensitization. We investigated brain responses to stimulation of trigeminal sites not typically associated with TMD pain by applying noxious dentoalveolar pressure to high- and low-impact TMD pain cases and pain-free controls during functional magnetic resonance imaging (fMRI). Fifty female participants were recruited and assigned to one of three groups based on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and Graded Chronic Pain Scale: controls (n=17), low-impact (n=17) and high-impact TMD (n=16). Multimodal whole-brain MRI was acquired following the Human Connectome Project protocol, including stimulus-evoked fMRI scans during which painful dentoalveolar pressure was applied to the buccal gingiva of participants. Group analyses were performed using non-parametric permutation tests for parcellated cortical and subcortical neuroimaging data. There were no significant between-group differences for brain activations/deactivations evoked by the noxious dentoalveolar pressure. For individual group mean activations/deactivations, a gradient in the number of parcels surviving thresholding was found according to the TMD pain grade, with the highest number seen in the high-impact group. Among the brain regions activated in chronic TMD pain groups were those previously implicated in sensory-discriminative and motivational-affective pain processing. These results suggest that dentoalveolar pressure pain evokes abnormal brain responses to sensory processing of noxious stimuli in high-impact TMD pain participants, which supports the presence of maladaptive brain plasticity in chronic TMD pain.

category: pain medicine


title: DNAmFitAge: Biological Age Indicator Incorporating Physical Fitness

abstract: Physical fitness is a well-known correlate of health and the aging process. DNA methylation (DNAm) data lend themselves for estimating chronological and biological age through epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance physical fitness parameters in their construction. Here, we develop blood DNAm biomarkers for fitness parameters gait speed (walking speed), hand grip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max). We then use these DNAm biomarkers to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness with epigenetic mortality risk estimators. Adjusting DNAmFitAge for chronological age generates a novel measure of epigenetic age acceleration, FitAgeAcceleration, which is informative for physical activity level (p=1.2E-12), mortality risk (p=5.9E-13), coronary heart disease risk (p=0.0051), comorbidities (p=9.0E-9), and disease-free status (p=1.1E-6) across several large validation datasets. These newly constructed DNAm biomarkers and DNAmFitAge provide researchers and physicians a new method to incorporate physical fitness into epigenetic clocks and emphasizes the effect of lifestyle on the aging process.


title: In the pursuit of longevity: anti-aging substances, nanotechnological preparations, and emerging approaches

abstract:
ObjectivesTo summarize information on anti-aging substances and nanotechnology formulations against aging and to unveil emerging anti-aging approaches like gene therapy, stem cells, monoclonal antibodies, and future trends.

MethodsA systematic literature search was conducted through May 10, 2021. Eligibility criteria were articles in English relevant to the aim of this review.

ResultsAnti-aging substances like coenzyme Q10, curcumin, ginsenoside Rg1, bioidentical hormones, and geroprotectants, can help to slow the aging process. Nano-delivery of anti-aging substances are novel approaches able to delay aging. Cryogenic sleep, therapeutic hypothermia, and caloric restriction are promising interventions that may one day grant humans biological immortality.

DiscussionThe ability to target basic maturation mechanisms, such as responses to oxidative damage, inflammation, irritation, and senescence associated with multiple concurrent deficits, is the most important feature. Nanocarriers to transport bioactive compounds have been shown to improve their stability, increase intestinal absorption, and prolong their circulation time.

category: geriatric medicine


title: Towards Formal Computable Representation of Clinical Trial Eligibility Criteria for Alzheimer's Disease

abstract: Ambiguity and misunderstanding of free-text clinical trial eligibility can affect the accuracy of translating trial investigators mental model of the study population to the correct cohort identification queries. In this pilot study, to eliminate the ambiguity when parsing eligibility criteria, we built ontology-based representations to standardize clinical trial eligibility criteria. We analyzed 10 Alzheimers disease (AD) trials eligibility criteria and categorized them into general query patterns using an annotation schema borrowed from the literature on constructing knowledge graphs. Then, for each pattern, we built the corresponding ontological representations, linked them to real-word electronic health record (EHR) data, and constructed cohort identification queries using the neo4j graph database. Our evaluation results of these cohort queries verified the accuracy of our ontology representation; and interestingly, we found that graph-queries achieved better runtime performance for complex study traits. These results indicated that our approach is feasible and potentially beneficial; nevertheless, more systematic and comprehensive investigations are warranted.


title: Long-term symptoms after SARS-CoV-2 infection in a cohort of hospital employees: duration and predictive factors

abstract:
ObjectiveTo evaluate the frequency, duration and patterns of long-term coronavirus disease 2019 (COVID-19) symptoms and to analyze risk factors for long-lasting COVID-19 sequelae among hospital employees (HEs).

DesignRetrospective observational cohort study.

SettingThree medical centers in Cologne, Germany.

ParticipantsWe included HEs who had a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test between March 2020 and May 2021.

MethodsWe conducted a survey in mid-2021 with all HEs tested SARS-CoV-2 PCR positive during the study period and asked about the presence and duration of 24 different COVID-19 related symptoms. Chronological development and patterns of symptom complexes, probability of symptom persistence and possible risk factors for protracted COVID-19 course were analyzed.

ResultsOf 221 included HEs, a number of 104 HEs (47.1%) reported at least one persisting symptom for more than 90 days after initial SARS-CoV-2 detection. A symptom duration over 28 days was associated with multiple symptom complexes. The most common was the interrelated occurrence of shortness of breath, memory disorder, concentration disorders and fatigue. Each one cycle higher initial Ct value significantly increased the chances of overcoming symptoms (odds ratio [OR] = 1.05; p = 0.019). The occurrence of breathlessness within the first ten days (OR = 7.89; p = 0.008), an initial Ct value under 30 (OR = 3.36; p = 0.022) and a definitely nosocomial SARS-CoV-2 transmission (OR = 3.05; p = 0.049) showed a statistically significant association with increased odds of illness duration over 90 days.

ConclusionAbout half of the HEs suffered from long lasting symptoms over 90 days after almost entirely mild acute COVID-19. Different symptom complexes could be shown and predictive factors for long-term symptoms were identified. Predictive factors at the onset of the infection could possibly be used for early treatment to prevent development of long-term symptoms after COVID-19 in future.


title: Generalized and specific whole-brain white matter abnormalities in human cocaine and heroin use disorders

abstract:
Neuroimaging studies in substance use disorder have shown widespread impairments in white matter (WM) microstructure suggesting demyelination and axonal damage. However, substantially fewer studies explored generalized vs. acute/specific drug effects on WM. Our study assessed whole-brain WM integrity in three subgroups of addicted individuals, encompassing cocaine (CUD) and heroin (HUD) use disorder, compared to healthy controls (CTL).

Diffusion MRI was acquired in 58 CTL, 28 current cocaine users/CUD+, 32 abstinent cocaine users/CUD-, and 30 individuals with HUD (positive urine for cocaine in CUD+ and opiates used for treatment in HUD). Tract-Based Spatial Statistics allowed voxelwise analyses of diffusion metrics [fractional anisotropy/FA, mean diffusivity/MD, radial diffusivity/RD, and axial diffusivity/AD]. Permutation statistics (p-corrected<.05) were used for between-group t-tests.

Compared to CTL, all drug-addicted individuals showed widespread FA reductions, and increased MD, RD, and AD (19-57% of WM skeleton, p<.05). The HUD showed the most impairments, followed by the CUD+, with only minor FA reductions in CUD- (<.2% of skeleton, p=.05). Longer periods of regular use were associated with decreased FA and AD, and higher subjective craving was associated with increased MD, RD, and AD, across all drug-addicted individuals (p<.05).

These findings demonstrate extensive WM impairments in drug-addicted individuals characterized by decreased anisotropy and increased diffusivity, thought to reflect demyelination and lower axonal packing. Extensive abnormalities in both groups with positive urine status (CUD+ and HUD), and correlations with craving, suggest greater WM impairments with recency of use. Results in CUD-, and correlations with regular use, further imply cumulative and/or persistent WM damage.

category: addiction medicine


title: Palliative care in the treatment of women with breast cancer: a scoping review protocol

abstract:
IntroductionPalliative care is an approach that improves patients quality of life and their families when they face problems inherent to a life-threatening illness. In the current scenario where breast cancer ranks first among the most common types of cancer in women, research has revealed little control by these patients over the symptoms of the disease and its treatment, resulting in poor quality of life, which should be the focus of attention of palliative care. Thus, the purpose of this study is to map and synthesize the available evidence on palliative care in treating breast cancer women.

MethodsThis scoping review protocol was elaborated following the methodological recommendations proposed by the Joanna Briggs Institute (JBI) and the PRISMA Extension for Scoping Reviews (PRISMA-ScR) checklist. All study designs, experimental studies, observational studies, qualitative studies, mixed studies, and reviews reporting the palliative care for breast cancer women, will be considered. The following electronic databases will be searched: MEDLINE (via PubMed), Embase, Cochrane Library, Web of Science, Scopus, JBI Evidence Synthesis, Epistemonikos, CINAHL (via EBSCO), LILACS, and the electronic repository SciELO. In addition, The British Library, Google Scholar, Preprints for Health Sciences [medRXiv], Open Grey, Who Library Database, ProQuest Global Dissertations and Theses, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform will be searched. No language or date restriction will be applied in the search strategy. Two investigators will independently select studies and perform data extraction and critical appraisal using the using JBI design-specific tolos. A narrative synthesis of the evidence will be carried out and will be grouped and presented in tables and graphic models. Also, a similarity analysis will be performed using IRaMuTeQ software version 0.7 alpha 2, leading to textual categories and themes.

Expected ResultsThe findings of this review will help to identify the gaps for the design of future primary research on women with breast cancer in palliative care. Ultimately, will position care services, managers, and health professionals in the knowledge of the phenomenon, so that they can implement the best evidence-based palliative care practices and improve the quality of care provided to breast cancer patients.

Open Science Framework Registrationosf.io/5bwq7

category: palliative medicine