title: Post-translational modifications glycosylation and phosphorylation of the major hepatic plasma protein fetuin-A are associated with severity of CNS inflammation in children

abstract:
BackgroundFetuin-A is a liver derived plasma protein showing highest serum concentrations in utero, preterm infants and neonates. Fetuin-A is also present in cerebrospinal fluid (CSF). The origin of CSF fetuin-A, blood-derived via the blood brain barrier or synthesized intrathecally, is presently unclear. Fetuin-A prevents ectopic calcification by stabilizing calcium and phosphate as colloidal calciprotein particles mediating their transport and clearance. Thus, fetuin-A plays a suppressive role in inflammation. Fetuin-A is a negative acute-phase protein, serving as a biomarker for MS. Here we studied the association of pediatric inflammatory CNS diseases with fetuin-A glycosylation and phosphorylation.

MethodsPaired blood and CSF samples from 66 children were included in the study. Concentration measurements were performed using a commercial human fetuin-A/AHSG ELISA. Of 60 pairs, 23 pairs were analyzed by SDS-PAGE following glycosidase digestion with PNGase-F and Sialidase-AU. Phosphorylation was analyzed in 30 pairs by Phos-Tag acrylamide electrophoresis following alkaline phosphatase digestion.

Results and DiscussionMean serum and CSF fetuin-A levels were 0.30 {+/-} 0.06 mg/ml and 0.644 {+/-} 0.55 {micro}g/ml, respectively. This study showed that serum fetuin-A levels decreased in inflammation corroborating its role as a negative acute-phase protein. Blood-brain barrier disruption was associated with elevated fetuin-A in CSF. A strong positive correlation was found between the CSF fetuin-A/serum fetuin-A ratio and the CSF albumin/serum albumin ratio, suggesting predominantly transport across the blood-brain barrier rather than intrathecal fetuin-A synthesis. Sialidase digestion showed increased asialofetuin-A levels in serum and CSF samples from children with neuroinflammatory diseases. Desialylation enhanced hepatic fetuin-A clearance via the asialoglycoprotein receptor thus rapidly reducing serum levels during inflammation. Phosphorylation of fetuin-A was more abundant in serum samples than in CSF, suggesting that phosphorylation may regulate fetuin-A influx into the CNS. These results may help establish Fetuin-A as a potential biomarker for neuroinflammatory diseases.


title: Clinical prediction models for treatment outcome in newly diagnosed epilepsy: Protocol for a systematic review

abstract:
Epilepsy, characterised by a predisposition towards unprovoked seizures, is one of the most common neurological disorders globally. Whilst 60-70% of individuals diagnosed with epilepsy will gain seizure control through anti-seizure medication, the mechanisms underlying seizure persistence are unclear. Intractability can significantly degrade a patients quality of life amongst other things; the use of predictive modelling of epilepsy outcomes in deciding on treatment therefore offers a tangible benefit to the patient. Early indicators of pharmacoresistance may discourage certain treatment options, and save time in what has been indicated to be a critical stage for newly-diagnosed epilepsy. Primarily, this paper aims to evaluate existing predictive models to identify demographic, clinical, physiological (e.g. EEG), and neuroimaging (e.g. MRI) factors that may be predictive of treatment outcomes in newly-diagnosed epilepsy. Two electronic databases, MEDLINE and EMBASE, will be searched with terms related to prognosis in newly-diagnosed epilepsy, and identified studies will be included for review if they have combined at least two demographic, clinical, neuroimaging, and/or physiological factors to predict treatment outcome in people with newly-diagnosed epilepsy. Papers will be screened by two independent reviewers via titles, abstracts and then full text against the inclusion criteria for eligibility. Data will be extracted by reviewers using standardised forms, assessed for risk of bias using the PROBAST tool and synthesised narratively. If considered appropriate the authors will carry out a meta-analysis on the available data.

Prospero registration number-

category: pharmacology and therapeutics


title: Changes in English medication safety indicators throughout the COVID-19 pandemic: a federated analysis of 57 million patients' primary care records in situ using OpenSAFELY

abstract:
ObjectiveTo describe the impact of the COVID-19 pandemic on safe prescribing, using the PINCER prescribing indicators; to implement complex prescribing indicators at national scale using GP data.

DesignPopulation based cohort study, with the approval of NHS England using the OpenSAFELY platform.

SettingElectronic health record data from 56.8 million NHS patients general practice records.

ParticipantsAll NHS patients registered at a GP practice using TPP or EMIS computer systems and recorded as at risk of at least one potentially hazardous PINCER indicator between September 2019 and September 2021.

Main outcome measureMonthly trends and between-practice variation for compliance with 13 PINCER measures between September 2019 and September 2021.

ResultsThe indicators were successfully implemented across GP data in OpenSAFELY. Hazardous prescribing remained largely unchanged during the COVID-19 pandemic, with only small reductions in achievement of the PINCER indicators. There were transient delays in blood test monitoring for some medications, particularly ACE inhibitors. All indicators exhibited substantial recovery by September 2021. We identified 1,813,058 patients at risk of at least one hazardous prescribing event.

ConclusionGood performance was maintained during the COVID-19 pandemic across a diverse range of widely evaluated measures of safe prescribing.

Summary box O_TEXTBOXWHAT IS ALREADY KNOWN ON THIS TOPICO_LIPrimary care services were substantially disrupted by the COVID-19 pandemic.
C_LIO_LIDisruption to safe prescribing during the pandemic has not previously been evaluated.
C_LIO_LIPINCER is a nationally adopted programme of activities that aims to identify and correct hazardous prescribing in GP practices, by conducting manual audit on subgroups of practices.
C_LI

WHAT THIS STUDY ADDSO_LIFor the first time, we were able to successfully generate data on PINCER indicators for almost the whole population of England, in a single analysis.
C_LIO_LIOur study is the most comprehensive assessment of medication safety during the COVID-19 pandemic in England, covering 95% of the population using well-validated measures.
C_LIO_LIGood performance was maintained across many PINCER indicators throughout the pandemic.
C_LIO_LIDelays in delivering some medication-related blood test monitoring were evident though considerable recovery was made by the end of the study period.
C_LI

C_TEXTBOX

category: primary care research


title: Testing the Triple Network Model of Psychopathology in a Transdiagnostic Neurodevelopmental Cohort

abstract:
BackgroundThe triple network model of psychopathology posits that altered connectivity between the Salience (SN), Central Executive (CEN), and Default Mode Networks (DMN) may underlie neurodevelopmental conditions. However, this has yet to be tested in a transdiagnostic sample of youth.

MethodsWe investigated triple network connectivity in a sample of 175 children (60 girls) that represent a heterogeneous population who are experiencing neurodevelopmental difficulties in cognition and behavior, and 60 comparison children (33 girls) without such difficulties. Hyperactivity/impulsivity and inattention were assessed by parent-report and resting-state functional Magnetic Resonance Imaging data were acquired. Functional connectivity was calculated between independent network components and regions of interest. We then examined whether connectivity between the SN, CEN and DMN was dimensionally related to hyperactivity/impulsivity and inattention, whilst controlling for age, gender, and motion.

ResultsHyperactivity/impulsivity was associated with decreased segregation between the SN, CEN, and DMN in at-risk children, whereas it was associated with increased segregation of the CEN and DMN in comparison children. We replicated these effects in networks and regions derived from an adult parcellation of brain function and when using increasingly stringent exclusion criteria for in-scanner motion.

ConclusionsTriple network connectivity characterizes transdiagnostic neurodevelopmental difficulties with hyperactivity/impulsivity. This may arise from delayed network segregation, difficulties sustaining CEN activity to regulate behavior, and/or a heightened developmental mismatch between neural systems implicated in cognitive control relative to those implicated in reward/affect processing.

category: psychiatry and clinical psychology


title: Pre- and post-operative psychological interventions to prevent pain and fatigue after breast cancer surgery (PREVENT): a randomized controlled trial

abstract:
BackgroundBreast cancer is the most common cancer type among women worldwide with over a million new cases each year. More than 40% of these women will struggle with chronic pain and fatigue after surgery, regardless of surgical procedure. These consequences are detrimental and result in distress and disability, including work disability. Few attempts have been made to prevent chronic pain and fatigue after surgery by applying a psychological approach, despite psychological risk factors being crucial in the development of both chronic pain and fatigue. In this study, we aim to develop and test an easily implementable strategy of preventing chronic pain and fatigue after breast cancer surgery. The intervention strategy involves a pre-operative hypnosis session and a web-based post-operative Acceptance and Commitment Therapy (ACT). The hypnosis has previously been found effective in alleviating acute post-operative pain and fatigue in breast cancer patients, while ACT is well suited to cancer populations as it offers a model of healthy adaptation to difficult circumstances. Together they form an intervention strategy with both a preventive and a rehabilitative focus.

Methods/designThis randomized controlled trial aims to estimate the effects of the pre- and post-operative interventions compared to attentional control and treatment as usual (TAU) and will also include a qualitative process evaluation. Participants will be randomized to receive either a pre-operative brief hypnosis session and a post-operative web-based psychological intervention (iACT) or a pre-operative one-session mindfulness through an audio file and post-operative TAU. Self-reported questionnaire data and biomarker data will be assessed pre-surgery, post-surgery and 3 and 12 months after surgery. In addition, we will assess registry data on sick leave and prescriptions until 2-year follow-up. In the qualitative process evaluation, data will be collected from participants from both study arms (through interviews and a diary) and two different analyses performed (socio-narrative and Grounded Theory) with the objective to describe the development of chronic post-surgical pain and fatigue and the potential influence of the interventions on these processes. The study is set-up to demonstrate a minimum difference in pain of 1 point on NRS (0-10) and 3 points on FACIT-F (0-52) between the groups at 3-months follow-up by including 200 breast cancer patients in total.

DiscussionThis trial will be the first study to estimate the effect of a combined pre-operative hypnosis with a post-operative iACT to prevent pain and fatigue after breast cancer surgery. The results from our study might i) help the large group of women affected by chronic pain and fatigue after breast cancer surgery, ii) shed light on the mechanisms involved in chronic pain and fatigue development, and iii) serve as a model for other surgical procedures.

Trial registrationClinicaltrials.gov, registration number NCT04518085. Registered on January 29th, 2020.


title: Impaired visual processing in psychosis patients with a predisposition for visual hallucinations

abstract: Psychosis is frequently associated with the occurrence of visual hallucinations (VH), but their etiology remains largely unknown. While patients with psychosis show deficits on various behavioral visual and attentional tasks, previous studies have not specifically related these deficits to the presence of VH. This suggests that tasks used in these studies do not target the visual-cognitive neural mechanisms that mediate VH, which in turn limits the development of effective therapies. We therefore designed a study to target these mechanisms directly. In this case control study we asked patients with psychosis who had previously experienced VH to indicate when they recognized objects that were gradually emerging from dynamic visual noise, while scanning their brains using functional Magnetic Resonance Imaging. In a previous study, this recognition task was used to identify the neural basis of VH in patients with Parkinsons Disease. Based on this earlier work, we decided to test the following hypothesis: when compared to psychosis patients not experiencing VH and age-matched healthy controls, psychosis patients with VH show reduced occipital activity and frontal activity around the moment of recognition (known as pop-out). For all groups, neuroimaging revealed increased activity in all examined visual areas around pop-out. However, psychosis patients with VH showed reduced occipital responsiveness, especially in the inferior part of the bilateral lateral occipital complex, a region known to play a key role in object recognition. We did not observe altered frontal or prefrontal activity before pop-out in this group. A possible explanation is that the relatively sustained activation of the visual memory-related angular gyri around pop-out may have compensated for the impaired early visual processing in psychosis patients with VH. We discuss our results in terms of current theories of visual hallucinations, such as predictive coding and contextual modulation. Our study is the first to show that visual processing deficits contribute to the occurrence of VH in psychosis. These findings could be used to develop tests to identify the visual-cognitive mechanisms that mediate VH in this group.


title: Time-specific effects of a multifaceted intervention on accelerometer-measured physical activity in primary school children: A cluster-randomized controlled trial

abstract: Background It is unclear whether intervention effects on school-aged children's physical activity differ across specific periods of the week or day. This study aimed to assess the time-specific intervention effects on accelerometer-measured physical activity in primary school children. Methods This was a nested study in a cluster-randomized controlled trial conducted from September 2018 to June 2019 in China. The intervention group included 4 schools (119 children) and the control group included 4 schools (99 children) in Beijing. The obesity prevention intervention engaged schools and families to improve children's physical activity. Outcome measures included accelerometer-assessed intensity and amounts of physical activity within specific periods of a week (weekday/weekend day) or a day (in-school/out-of-school periods). Linear mixed models were used to estimate intervention effects. Subgroup analyses were also conducted to examine potential moderators including sex, age, body mass index, physical activity, and accelerometer compliance. Results The intervention lead to an increase in time engaged in moderate-to-vigorous physical activity (MVPA) within in-school periods of a day (adjusted mean difference: 0.54 minutes/hour; 95% confidence interval: 0.13, 0.94, P = 0.012) but it did not improve physical activity within out-of-school periods (P > 0.05) compared with the control group. There was no difference in the effect size across most of the moderators except for age, as younger children appeared to benefit more from the intervention in the improvement of in-school MVPA (Pinteraction = 0.035). No between-group differences were observed in physical activity within the whole weekday or weekend day (P > 0.05). Conclusion The intervention effectively increased MVPA within in-school periods but did not improve out-of-school physical activity. Findings support the tailoring of intervention components to specific periods of a day to improve school-aged children's whole pattern of physical activity.

category: public and global health


title: Factors associated with repeat childbirth among Adolescent Mothers in Soroti District, Teso sub-region, Uganda: A cross-sectional study

abstract:
The percentage of adolescent mothers aged 15 to 19 years with a repeat childbirth in Uganda (26.1%) is higher than the global estimate (18.5%). Soroti district tops Teso (a region with highest adolescent childbearing rate nationally) in adolescent childbearing. Adolescent repeat childbearing (ARC) is associated with poor health outcomes, increased risk of stillbirth, maternal and child mortality, thus a public health concern. The factors associated with, and the burden, of ARC remains unknown in Soroti district. Consequently, interventions which combat ARC in Soroti district have not been informed by empirical data. This study determined the proportion of adolescent mothers with, and factors associated with, repeat childbirth among adolescent mothers in Soroti district.

We conducted a cross-sectional study involving mixed methods of data collection. Interviewer-administered structured interviews were conducted amongst 422 adolescent mothers.

Demographic and socio-economic data of respondents, data regarding respondents family and peer related factors was collected. Chi-square was the test statistics used. Multivariate analysis was by logistic regression.

Of the 422 respondents, 31.28% (132) were married. Proportion of respondents with repeat childbirth was at 30.81% (95%CI: 26.57%-35.39%). Risk factors of ARC were (a) being married, AOR 5.74 (95%CI: 3.08-10.68), (b) incorrect knowledge of rhythm method, AOR 2.15 (95%CI: 1.21-3.82), (c) Age at first birth, AOR 0.48 (95%CI: 0.36-0.63). Protective factors of ARC included (a) not drinking alcohol, AOR 0.41(95%CI: 0.21-0.77), not being raped, AOR 0.19(95%CI: 0.06-0.55), having first childbirth from health facility, AOR 0.38 (95%CI: 0.18-0.78) and father of first baby without multiple sexual partners, AOR 0.40(95%CI: 0.22-0.72).

In conclusion, sexual partner characteristics were associated with ARC suggesting male involvement (for example in family planning) in prevention of ARC. In addition, strengthening the implementation of anti-teen marriage programs and alcohol consumption policies, and instating measures to delay age at first delivery among adolescent mothers are required. Further research is needed to validate these findings.

category: sexual and reproductive health


title: Novel visualization of the spatiotemporal relationship between ictal spiking and LFP supports the involvement of mid-range excitatory circuits during human focal seizures

abstract: The relationship between action potentials and the associated local field potential (LFP) in neural recordings is typically studied only in the temporal domain using the spike-triggered average (STA). In this study, we present a novel approach, termed the spatiotemporal spike-centered average (st-SCA), that allows for visualization of the spike-LFP relationship in both the temporal and spatial domains. In this method, a 3D spatiotemporal topography of spike-associated LFP is calculated from a 2D spatial average of the LFP centered around the time and location of individual spikes. We applied this method to 25 microelectrode array (MEA) recordings obtained from seven patients with pharmacoresistant focal epilepsy during ictal and interictal states. Five patients in this dataset had MEA implants in recruited cortex, and two had implants in unrecruited cortex. Of the five patients with arrays implanted in recruited territory, three showed STAs that resembled sine cardinal (sinc) functions, and two showed non-sinc functions. Using the st-SCA, we found that the patients who showed a sinc-function pattern in the temporal domain showed a donut-shaped ring of LFP activity in the spatial domain. This observation was corroborated by a theoretical model describing an ictal spike as measured by a macroelectrode. The model also revealed a special symmetry wherein temporal component of the st-SCA predicts the spatial component when they both approximate sinc-functions. Supporting this theoretical derivation, a radial cut of the donut-shaped st-SCA showed a spatial pattern consistent with a sinc-function. This spatial sinc-function had peaks separated by [~]2.5mm--a measurement that supports the role of mid-range excitatory connections during ictal activity. In sum these findings suggest that patients whose seizures engage mid-range connections may be identifiable by the spatiotemporal features of ictal spike-associated LFP activity.

category: neurology


title: Conceptualization of Health Literacy from A Nursing Perspective

abstract: Health as an inseparable part of human beings needs to be maintained to achieve a complete human health degree. The role of health literacy in attaining optimum health is significant. When associated with nursing, health literacy must be interpreted as a part of the role and function of nursing. However, to understand health literacy, it is necessary to study it from the aspect of scientific formation itself and a nursing perspective. This review proposes an alternative conceptualization of health literacy from a nursing perspective. This review used an integrative search through four databases: ScienceDirect, ProQuest, SAGE Journal, and Google Scholar. Search using various combinations of keywords with the help of Boolean operators, including: health literacy, nursing perspective, nursing, and conceptualization combined as MESH terms. The inclusion criteria are peer-reviewed articles in English that discuss health literacy and nursing perspective. Articles published within the last six years (2017-2022). Research such as literature reviews, dissertations, editorials, commentaries, and other expert opinions are excluded. Ten articles were considered in this literature review. We describe the conceptualization of health literacy from the nurses point of view, the predictors that influence it, the dimensions surrounding health literacy, the implication of health literacy, and how nurses will participate in supporting this health literacy. In the end, this conceptualization will be used as an illustration material to integrate the concept of health literacy into various problems that become nursing tasks.

category: nursing


title: Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis

abstract:
BackgroundIt remains unknown why [~]30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations into treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we test whether schizophrenia-associated CNVs are more prevalent in patients with treatment-resistant psychotic symptoms compared to previously published schizophrenia cases not selected for treatment-resistance.

MethodsCNVs were identified using chromosomal microarrays and exome sequencing in 509 patients with treatment-resistant psychosis (a lack of clinical response to [≥] 3 adequate antipsychotic medication trials over at least five years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared against a previous large schizophrenia cohort study.

ResultsIn total, 47 cases (9.2%) carried at least one CNV with known or possible neuropsychiatric risk. The prevalence of schizophrenia-associated CNVs (n=21; 4.1%) was significantly increased compared to a previous schizophrenia cohort study (p = 0.005322; OR = 1.93). This increase in prevalence was primarily due to duplications at 15q11.2-q13.1 and 16p11.2, which were independently associated with treatment-resistance in pairwise loci-based analysis.

ConclusionsThese findings suggest that rare schizophrenia-associated CNVs, particularly duplications of 15q11.2-q13.1 and 16p11.2, may serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.

category: genetic and genomic medicine


title: Screening for safe opening of universities under Omicron and Delta variants of COVID-19: When less is more

abstract: As new COVID-19 variants emerge, and disease and population characteristics change, screening strategies may also need to change. We develop screening guidelines for the safe opening of college campuses, considering COVID-19 infections/hospitalizations/deaths; peak daily hospitalizations; and the tests required. Our compartmental model simulates disease spread on a college campus under co-circulating variants with different disease dynamics, considering: (i) the heterogeneity in disease transmission and outcomes for faculty/staff and students based on vaccination status and level of natural immunity; and (ii) variant- and dose-dependent vaccine efficacy. Using the Spring 2022 academic semester as a case study, we study various routine screening strategies, and find that screening the faculty/staff less frequently than the students, and/or the boosted and vaccinated less frequently than the unvaccinated, may avert a higher number of infections per test, compared to universal screening of the entire population at a common frequency. We also discuss key policy issues, including the need to revisit the mitigation objective over time, effective strategies that are informed by booster coverage, and if and when screening alone can compensate for low booster coverage.

category: health policy


title: Managing COVID-19 in an Australian designated isolation facility: Implications for current and future healthcare crises

abstract: The lived experiences of healthcare workers (HCWs) and their perceptions of the pandemic can prove to be a valuable resource in the face of a seemingly persistent Novel coronavirus disease 2019 (COVID-19) to inform ongoing efforts, as well as identify components essential to a crisis preparedness plan and the issues pertinent to supporting relevant change. We employed a phenomenological approach and using purposive sampling conducted 39 semi-structured interviews with senior healthcare professionals who were employed at a designated COVID-19 facility in New South Wales (NSW), Australia during the height of the pandemic in 2020. Participants comprised administrators, heads of department and clinicians. We obtained from these HCWs (i) perspectives of their lived experience on what was done well and what could have been done differently and (ii) recommendations on actions for current and future crisis response. Four themes encapsulated insights of respondents that should inform our capacity to meet current needs, direct meaningful and in situ change, and prepare us for future crises. Observations and recommendations of respondents are informative for decision-makers tasked with mobilising an efficacious approach to the next health crisis and, in the interim, would aid the governance of a more robust workforce to effect high quality patient care in a safe environment.

category: health systems and quality improvement


title: Deep learning identified genetic variants associated with COVID-19 related mortality

abstract: Analysis of host genetic components provides insights into the susceptibility and response to viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). To reveal genetic determinants of susceptibility to COVID-19 related mortality, we train a deep learning model to identify groups of genetic variants and their interactions that contribute to the COVID-19 related mortality risk using the UK Biobank data. We refer to such groups of variants as super variants. We identify 15 super variants with various levels of significance as susceptibility loci for COVID-19 mortality. Specifically, we identify a super variant (OR=1.594, p=5.47x10-9) on Chromosome 7 that consists of the minor allele of rs76398985, rs6943608, rs2052130, 7:150989011_CT_C, rs118033050 and rs12540488. We also discover a super variant (OR=1.353, p=2.87x10-8) on Chromosome 5 that contains rs12517344, rs72733036, rs190052994, rs34723029, rs72734818, 5:9305797_GTA_G and rs180899355.

category: infectious diseases


title: Longitudinal analysis reveals elevation then sustained higher expression of autoantibodies for six months after SARS-CoV-2 infection

abstract:
High autoantibody levels are found in individuals hospitalized for COVID-19. The temporal trajectories and levels of these autoantibodies months into convalescence after SARS-CoV-2 infection are unclear. It is also unknown if the composite autoantibody signatures of convalescent SARS-CoV-2-infected individuals resemble those with diagnosed autoimmune diseases. We measured the circulating levels of 17 autoantibodies associated with autoimmune connective tissue diseases from SARS-CoV-2 hospitalized and outpatient participants, as well as from individuals with scleroderma (SSc), systemic lupus erythematosus (SLE), and uninfected pre-pandemic controls. Seven of the 17 autoantibodies measured were higher in hospitalized and/or outpatient SARS-CoV-2 individuals an average of six months after symptom onset compared with controls, with multivariate analyses revealing links between SARS-CoV-2 infection and positivity of SSB-La, Sm, Proteinase 3, Myleoperoxidase, Jo-1, and Ku reactive IgG six months post-symptom onset. Autoantibody levels from SARS-CoV-2 infected individuals were followed over time from initial symptom onset for an average of six months, and different temporal autoantibody trajectories were classified. A  negative, then positive expression pattern was found for at least one autoantibody in 18% of the outpatient and 53% of the hospitalized participants, indicating initiation and durable expression of self-reactive immune responses post-infection, particularly with severe acute illness. Analysis of individual participant autoantibody expression patterns revealed similar patterns between pre-pandemic and convalescent SARS-CoV-2 infected groups that are distinct from participants with both the SSc and SLE. As autoantibody positivity can occur years prior to autoimmune disease onset, the possibility that SARS-CoV-2-associated autoantibodies are a herald of future autoimmune disorders requires further investigation.

One Sentence SummaryAutoantibody levels rise after acute SARS-CoV-2 infection and remain elevated for at least six months after symptom onset in participants with mild or severe COVID-19.


title: Impact of COVID-19 non-pharmaceutical interventions on pneumococcal carriage prevalence and density in Vietnam

abstract: Non-pharmaceutical interventions (NPIs) implemented to contain SARS-CoV-2 have decreased invasive pneumococcal disease. We undertook an observational study to evaluate the impact of NPIs on pneumococcal carriage and density, drivers of transmission and disease, during the COVID-19 pandemic in Ho Chi Minh City, Vietnam. While NPIs did not significantly impact pneumococcal carriage, mean capsular pneumococcal density decreased by up to 91.5% (1.07 log10genome equivalents/mL, 95% Confidence Interval: 0.74-1.41) after NPI introduction compared with the pre-COVID-19 period. As higher pneumococcal density is a risk factor for disease, the observed decline provides a plausible mechanism for the reductions in invasive pneumococcal disease.


title: Covid-19 vaccine effectiveness against general SARS-CoV-2 infection from the omicron variant: A retrospective cohort study

abstract:
ObjectiveTo estimate the effectiveness of 2-dose and 3-dose mRNA vaccination (BNT162b2 and mRNA-1273) against general SARS-CoV-2 infection (asymptomatic or symptomatic) caused by the omicron variant.

DesignPropensity-score matched retrospective Cohort Study.

SettingLarge public university undergoing weekly Covid-19 testing in South Carolina, USA.

ParticipantsPopulation consists of 24,145 university students and employees undergoing weekly Covid-19 testing between January 3rd and January 31st, 2022. The analytic sample was constructed via propensity score matching on vaccination status: Unvaccinated, completion of 2-dose mRNA series within previous 5 months, and receipt of mRNA booster dose within previous 5 months. The resulting analytic sample consists of 1,944 university students and 658 university employees.

InterventionVaccination with a two dose or 3 dose regimen of the BNT162b2 or mRNA-1273 vaccine.

ResultsBooster protection against any SARS-CoV-2 infection was 66.4% among employees (95% CI: 46.1-79.0%; P<.001) and 45.4% among students (95% CI: 30.0-57.4%; P<.001). Compared to the 2-dose mRNA series, estimated increase in protection from the booster dose was 40.8% among employees (P=.024) and 37.7% among students (P=.001). We did not have enough evidence to conclude a statistically significant protective effect of the 2-dose mRNA vaccination series, nor did we have enough evidence to conclude that protection waned in the 5-month period after receipt of the 2nd or 3rd mRNA dose. Furthermore, we did not find evidence that protection varied by manufacturer.

ConclusionsCovid-19 mRNA booster doses offer moderate protection against any SARS-CoV-2 infection caused by the omicron variant and provide a substantial increase in protection relative to the 2-dose mRNA vaccination series.


title: Antibody responses to known and unknown SARS-CoV-2 infections after mRNA vaccine booster

abstract: We followed a fully-vaccinated (two mRNA vaccine doses) community cohort (n=41) without prior COVID-19 diagnosis from September 2021 through March 2022 through the Omicron wave following a booster mRNA vaccination. 19.5% of participants reported a known SARS-CoV-2 infection during the Omicron wave, which was confirmed by anti-nucleocapsid IgG. An additional 36.5% also developed anti-nucleocapsid IgG after the boost, consistent with unknown, asymptomatic SARS-CoV-2 infection during this period. Infection defined by anti-nucleocapsid IgG, whether known to participant or not, increased anti-spike IgG levels, relative to those lacking anti-nucleocapsid IgG, at 120 days post-booster.


title: Implication of DNA methylation changes at chromosome 1q21.1 in the brain pathology of Primary Progressive Multiple Sclerosis

abstract: Multiple Sclerosis (MS) is a highly heterogenous inflammatory and neurodegenerative disease of the central nervous system with unpredictable course towards progressive disability. Understanding and treating progressive forms of MS remains extremely challenging due to the limited knowledge of the underlying mechanisms. We examined the molecular changes that associate with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. We first identified and replicated hypermethylation of an intergenic region within the chromosome 1q21.1 locus in the blood of PPMS patients compared to other MS patients and healthy individuals using Illumina 450K arrays and pyrosequencing. We next revealed that methylation is under the control of genetic variation within the extended locus both in the blood and brain. Several genetic variants also affected expression of proximal genes (CHD1L, PRKAB2 and FMO5) in the brain and displayed evidence of the association with the risk of developing PPMS, suggesting a genetic-epigenetic-transcriptional interplay in PPMS pathogenesis. We next addressed the causal link between DNA methylation and gene expression using reporter systems and dCas9-TET1-induced demethylation of CpGs in the identified region, which resulted in upregulation of CHD1L and PRKAB2 genes in SH-SY5Y neuron-like cells. Independent exploration using unbiased correlation network analysis, confirmed the putative implication of CHD1L and PRKAB2 in brain processes in PPMS patients. We provide several lines of evidence suggesting distinct molecular changes in the 1q21.1 region, known to associate with brain development and disorders, associated with genetic predisposition to high methylation in PPSM patients that regulates the expression of genes within the extended locus.

category: allergy and immunology


title: Association of socioeconomic status with arterial stiffness in older African American and White Adults: The ARIC Study Cohort

abstract: Background: The contributions of traditional CVD risk factors do not fully explain the racial and socioeconomic disparities in arterial stiffness. The extent to which the association of socioeconomic status (SES) with subclinical CVD is different for older African American and White adults is unclear. Methods and Results: Cross-section associations of individual SES [education and income] with carotid femoral pulse wave velocity (cfPWV), a subclinical marker of arterial stiffness, and modification of this relationship by race were examined among 3,342 participants of the Atherosclerosis Risk in Communities (ARIC) Study (age=75plus-or-minus sign 4.9 years, 64% female, 23% African American, free of CVD in 2011-2013) using multivariable linear regression. Post-graduate education compared to less than high school, was associated with lower cfPWV (less stiffness) in African Americans (lower case Greek beta = -1.28 m/s; 95% CI, -1.97, -0.59), but not in Whites (lower case Greek beta = -0.69 m/s; 95% CI, -1.39, 0.01). Income [≥]$50K as compared to <$25K, was associated with lower cfPWV both in African Americans (lower case Greek beta = -0.82 m/s; 95% CI, -1.42, -0.22) and Whites (lower case Greek beta = -0.76 m/s; 95% CI, -1.19, -0.32). However, interaction of race with individual measures of SES on cfPWV in African American and White adults were not statistically significant (p-value for interaction >0.05). Conclusions: Higher SES was cross-sectionally associated with lower arterial stiffness in this cohort; the data did not support differences by race. Prospective studies of SES and cfPWV among a racially socioeconomically diverse cohort merit further study.

category: cardiovascular medicine


title: Use of c-peptide as a measure of cephalic phase insulin release in humans

abstract: Cephalic phase insulin release (CPIR) is a rapid pulse of insulin secreted within minutes of food-related sensory stimulation. Understanding the mechanisms underlying CPIR in humans has been hindered by its small observed effect size and high variability within and between studies. One contributing factor to these limitations may be the use of peripherally measured insulin as an indicator of secreted insulin, since a substantial portion of insulin is metabolized by the liver before delivery to peripheral circulation. Here, we investigated the use of c-peptide, which is co-secreted in equimolar amounts to insulin from pancreatic beta cells, as a proxy for insulin secretion during the cephalic phase period. Changes in insulin and c-peptide were monitored in 18 adults over two repeated sessions following oral stimulation with a sucrose-containing gelatin stimulus. We found that on average, insulin and c-peptide release followed a similar time course over the cephalic phase period, but that c-peptide showed a greater effect size. Importantly, when insulin and c-peptide concentrations were compared across sessions, we found that changes in c-peptide were significantly correlated at the 2 minute (r = 0.50, p = 0.03) and 4 minute (r = 0.65, p = 0.003) time points, as well as when individuals peak c-peptide concentrations were considered (r = 0.64, p = 0.004). In contrast, no significant correlations were observed for changes in insulin measured from the sessions (r = -0.06-0.35, p < 0.05). Herein, we detail the individual variability of insulin and c-peptide release during the cephalic phase period, and discuss why c-peptide may be a more appropriate metric to represent insulin secretion.

category: endocrinology


title: A statistical definition of epidemic waves

abstract: The timely identification of expected surges of cases during infectious disease epidemics is essential for allocating resources and preparing interventions. This study describes a simple way to evaluate whether an epidemic wave is likely to be present based on daily new case count data. The proposed measure compares two models that assume exponential or linear dynamics, respectively. Technically, the output of two regression analyses is used to approximate a Bayes factor, which quantifies the support for the exponential over the linear model and can be used for epidemic wave detection. The trajectory of the coronavirus epidemic in three countries is analyzed and discussed for illustration. The proposed measure detects epidemic waves at an early stage, which are otherwise visible only by inspecting the development of case count data retrospectively. In addition to informing public health decision making, the outlined approach may serve as a starting point for scientific discussions on epidemic waves.

category: epidemiology


title: Adherence trajectory as an on-treatment risk indicator among drug- resistant TB patients in the Philippines

abstract:
IntroductionHigh levels of treatment adherence are critical for achieving optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.

MethodsWe conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.

ResultsOf 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%) extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n=483), a moderate adherence group (n=93) and a low adherence group (n=20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90 - 6.12) and final (aOR 2.71, 95% 1.73 - 4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9 % vs. 65.4 % correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).

ConclusionsAdherence patterns are strongly predictive of patient treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns.


title: Interactions between seasonal temperature variation and temporal synchrony drive increased arbovirus co-infection incidence

abstract: Though instances of arthropod-borne (arbo)virus co-infection have been documented clinically, the overall incidence of arbovirus co-infection and its drivers are not well understood. Now that dengue, Zika, and chikungunya viruses are all in circulation across tropical and subtropical regions of the Americas, it is important to understand the environmental and biological conditions that make co-infections more likely to occur. To understand this, we developed a mathematical model of cocirculation of two arboviruses, with transmission parameters approximating dengue, Zika, and/or chikungunya viruses and co-infection possible in both humans and mosquitoes. We examined the influence of seasonal timing of arbovirus cocirculation on the extent of co-infection. By undertaking a sensitivity analysis of this model, we examined how biological factors interact with seasonality to determine arbovirus co-infection transmission and prevalence. We found that temporal synchrony of the co-infecting viruses and average temperature were the most influential drivers of co-infection incidence. For seasonal patterns typical of a tropical region, we observed non-negligible incidence irrespective of arrival time when two arboviruses arrived simultaneously. Under our default parameter settings, this corresponded to a maximum co-infection cumulative incidence of 83 per 1,000 individuals and a minimum cumulative incidence of 32 per 1,000 individuals in the year following arrival. For seasonal patterns typical of a more temperate region, co-infections only occurred if arrivals took place near the seasonal peak, and even then, did not reach 0.01 co-infections per 1,000 individuals. Our model highlights the synergistic effect of co-transmission from mosquitoes, which leads to more than double the number of co-infections than would be expected in a scenario without co-transmission. Our results show that arbovirus co-infections are unlikely to occur in appreciable numbers unless epidemics overlap in space and time and in a tropical region.


title: Alcohol Use Disorder Is Associated with Higher Risks of Adverse Brain Outcomes

abstract: Alcohol use disorder (AUD) is on the ascendancy in the US older adult population, while the association between AUD and adverse brain outcomes remains inconclusive. The objective of this work is to investigate the associations between AUD with the onset of Alzheimers disease and Parkinsons disease. In a retrospective cohort design using US insurance claim data (2007-2020), 129,182 patients with AUD were matched with 129,182 controls by age, sex, race, and clinical characteristics. After adjusting for covariates, AUD was associated with a higher risk of Alzheimers disease (female adjusted HR=1.78, 95% CI: 1.68-1.90, P<0.001; male adjusted HR=1.80, 95% CI: 1.71-1.91, P<0.001) and a higher risk of Parkinsons disease (female adjusted HR=1.49, 95% CI: 1.32-1.68 P<0.001; male adjusted HR=1.42, 95% CI: 1.32-1.52, P<0.001) in the overall sample. In separate analyses of Black, White, and Hispanic patients, those with AUD had higher risk of Alzheimers disease (adjusted HRs[≥]1.58; Ps[≤]0.001). A significantly elevated risk for Parkinsons disease was found only in the White subpopulation (female adjusted HR=1.55, 95% CI: 1.36-1.77, P<0.001; male adjusted HR=1.45, 95% CI: 1.33-1.57, P<0.001). Alcohol use disorder is associated with Alzheimers disease. Alcohol use disorder is associated with Parkinsons disease in White persons. Cognitive screening and neurological examination among older adults with severe problematic alcohol use hold the promise for early detection of Alzheimers disease and Parkinsons disease.


title: Rapid growth in disposable e-cigarette vaping among young adults in Great Britain from 2021 to 2022: a repeat cross-sectional survey

abstract: Aims: To estimate recent trends in the prevalence of disposable e-cigarette vaping in Great Britain, overall and across ages. Design: The Smoking Toolkit Study, a monthly representative cross-sectional survey. Setting: Great Britain. Participants: 29,976 adults ([≥]18 years) completed telephone interviews from January 2021 to January 2022. Measurements: Current e-cigarette vapers were asked which type of device they mainly use. We estimated age-specific time trends in the prevalence of current disposable e-cigarette use among vapers and inhaled nicotine use (vaping/smoking) among adults. Findings: From January 2021 to January 2022, there was a 14-fold increase in the percentage of vapers that used disposables, rising from 1.2% to 16.7% (prevalence ratio [PR], 14.4; 95%CI, 6.6-49.0). Growth in disposable e-cigarette vaping was most pronounced in younger adults (interaction p-value, .0.007): for example, the percentage of 18-year-old vapers using of disposables rose from 0.89% to 56.7% (PR, 64; 95%CI, 15-5790) while it rose from 1.3% to 6.2% (PR, 4.7; 95%CI, 1.7-144) among 45-year-old vapers. However, the overall percentage people currently using any inhaled nicotine, vaped or smoked, remained stable over time both among all adults (20.1% vs. 20.6%; PR, 1.03; 95%CI, 0.88-1.20) and among 18-year-olds (29.6% vs. 29.6%; PR, 1.00; 95%CI, 0.79-1.26). Conclusions: Use of disposable e-cigarettes in Great Britain grew rapidly between 2021 and 2022, especially among younger adults, but the overall prevalence of inhaled nicotine use -- smoked or vaped -- was stable over time. Most young adult vapers in Great Britain now use disposable products.


title: COVID-19 vaccine effectiveness during a prison outbreak when the Omicron was the dominant circulating variant, Zambia, December 2021

abstract: During a COVID-19 outbreak in a prison in Zambia from 14th to 19th December 2021, a case control study was done to measure vaccine effectiveness (VE) against infection and symptomatic infection, when the Omicron variant was the dominant circulating variant. Among 382 participants, 74.1% were fully vaccinated and the median time since full vaccination was 54 days. There were no hospitalizations or deaths. COVID-19 VE against any SARS-CoV-2 infection was 64.8% and VE against symptomatic SARS-CoV-2 infection was 72.9%. COVID-19 vaccination helped protect incarcerated persons against SARS-CoV-2 infection during an outbreak while Omicron was the dominant variant in Zambia.


title: The role of corticospinal and extrapyramidal pathways in motor impairment after stroke

abstract: Anisotropy of descending motor pathways has repeatedly been linked to the severity of motor impairment following stroke-related damage to the corticospinal tract (CST). Despite promising findings consistently tying anisotropy of the ipsilesional CST to motor outcome, anisotropy is not yet utilized as a biomarker for motor recovery in clinical practice as a conclusive understanding of degenerative processes in the ipsilesional CST and compensatory roles of other descending motor pathways is hindered by methodological constraints such as estimating anisotropy in voxels with multiple fiber directions, sampling biases, and confounds due to aging-related atrophy. The present study addressed these issues by combining diffusion spectrum imaging (DSI) with a novel compartmentwise analysis approach differentiating voxels with one dominant fiber direction (one-directional voxels) from voxels with multiple fiber directions. Compartmentwise anisotropy for bihemispheric CST and extrapyramidal tracts was compared between chronic stroke patients (N=25), age-matched controls (N=22), and young controls (N=24) and its associations with motor performance of the upper and lower limbs were assessed. Our results provide direct evidence for Wallerian degenration along the entire length of the ipsilesional CST reflected by decreased anisotropy in descending fibers compared to age-matched controls, while aging-related atrophy was observed more ubiquitously across compartments. Anisotropy of descending ipsilesional CST voxels showed a highly robust correlation with various aspects of upper and lower limb motor impairment, highlighting the behavioral relevance of Wallerian degeneration. Moreover, anisotropy measures of two-directional voxels within bihemispheric rubrospinal and reticulospinal tracts were linked to lower limb deficits, while anisotropy of two-directional contralesional rubrospinal voxels explained gross motor performance of the affected hand. Of note, the relevant extrapyramidal structures contained fibers crossing the midline, fibers potentially mitigating output from brain stem nuclei, and fibers transferring signals between the extrapyramidal system and the cerebellum. Thus, specific parts of extrapyramidal pathways seem to compensate for impaired gross arm and leg movements incurred through stroke-related CST lesions, while fine motor control of the paretic hand critically relies on ipsilesional CST integrity. Importantly, our findings suggest that the extrapyramidal system may serve as a compensatory structural reserve independent of post-stroke reorganization of extrapyramidal tracts. In summary, compartment-specific anisotropy of ipsilesional CST and extrapyramidal tracts explained distinct aspects of motor impairment, with both systems representing different pathophysiological mechanisms contributing to motor control post-stroke. Considering both systems in concert may help develop diffusion imaging biomarkers for specific motor functions after stroke.


title: Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

abstract:
BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels.

MethodsWe performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-{beta} 1-40 peptide (A{beta}1-40), and performed targeted metabolomic and transcriptomic profiles in SYS patients fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein.

ResultsFunctional studies show significantly decreased levels of secreted A{beta}1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients.

ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. A{beta}1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.

Key MessagesMAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here.


title: PERFORMANCE OF αSYNUCLEIN RT-QUIC IN RELATION TO NEUROPATHOLOGICAL STAGING OF LEWY BODY DISEASE

abstract: Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). Syn RT-QuIC has emerged as a promising assay to detect misfolded -synuclein in clinically or neuropathologically established patients with various synucleinopathies. In this study, Syn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFINDER study and postmortem ventricular CSF in a neuropathological cohort from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (AZSAND/BBDP). The BioFINDER cohort included 64 PD/PDD, 15 MSA, 15 PSP, 47 controls and two controls who later converted to PD/DLB. The neuropathological cohort included 101 cases with different brain disorders, including LBD and controls. In the BioFINDER cohort Syn RT-QuIC identified LBD (i.e. PD, PDD and converters) vs. controls with a sensitivity of 95% and a specificity of 83%. The two controls that converted to LBD were Syn RT-QuIC positive. Within the AZSAND/BBDP cohort, Syn RT-QuIC identified neuropathologically verified "standard LBD" (i.e. PD, PD with AD and DLB; n=25) vs. no LB pathology (n=53) with high sensitivity (100%) and specificity (94%). Only 57% were Syn RT-QuIC positive in the subgroup with "non-standard" LBD (i.e., AD with Lewy Bodies not meeting criteria for DLB or PD, and incidental LBD, n=23). Furthermore, Syn RT-QuIC reliably identified cases with LB pathology in the cortex (97% sensitivity) vs. cases with no LBs or LBs present only in the olfactory bulb (93% specificity). However, the sensitivity was low, only 50%, for cases with LB pathology restricted to the brainstem or amygdala, not affecting the allocortex or neocortex. In conclusion, Syn RT-QuIC of CSF samples is highly sensitive and specific for identifying cases with clinicopathologically-defined Lewy body disorders and shows a lower sensitivity for non-standard LBD or asymptomatic LBD or in cases with modest LB pathology not affecting the cortex.


title: Synaptic resilience is associated with maintained cognition during ageing

abstract:
INTRODUCTIONIt remains unclear why age increases risk of Alzheimers disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing.

METHODSWe examined post-mortem brain from people in mid-life (n=15), healthy ageing with either maintained cognition (n=8) or lifetime cognitive decline (n=7), and Alzheimers disease (n=13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimers brain homogenate.

RESULTSSynaptic pathology increased, and expression of genes involved in synaptic signalling decreased between mid-life, healthy ageing and Alzheimers. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signalling genes compared to people with cognitive decline.

DISCUSSIONEfficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.


title: Deep-PheWAS: a pipeline for phenotype generation and association analysis for phenome-wide association studies.

abstract:
SummaryDeep-PheWAS is a platform for phenome wide association studies that creates clinically-curated composite phenotypes, and integrates quantitative phenotypes from primary care data, longitudinal trajectories of quantitative measures, disease progression, and drug response phenotypes. Tools are provided for efficient analysis of association with any genetic input, under any genetic model, with optional sex-stratified analysis, and for developing novel phenotypes.

Availability and ImplementationThe Deep-PheWAS pipeline is freely available under GNU general public licence v3.0 at https://github.com/Richard-Packer/Deep-PheWAS.

Contactrichard.packer@leicester.ac.uk

Supplementary informationSupplementary methods and results are available at Bioinformatics online.


title: Use of Low-Dose Decitabine with or without Tyrosine Kinase Inhibitors in Advanced Phase Chronic Myelogenous Leukemia: A Systemic Review and Metaanalysis

abstract: Subject Area: Hematology Title: USE OF LOW-DOSE DECITABINE WITH OR WITHOUT TYROSINE KINASE INHIBITORS IN ADVANCED PHASE CHRONIC MYELOGENOUS LEUKEMIA: A SYSTEMIC REVIEW AND METAANALYSIS Author List: Maureen Via M. Comia, MD, FPCP, Charles Eryll S. Sy, MD, FPCP, Jomell C. Julian, MD, FPCP, FPCHTM1 1Section of Clinical Hematology, University of Santo Tomas Hospital, Espana, Manila Philippines 1008 ABSTRACT Rationale: Progression of Chronic Myelogenous Leukemia (CML) to more advanced phases can involve hypermethylation, which is correlated to resistance or intolerance to imatinib. This hypermethylation has also been found to be a negative prognostic factor independent of imatinib response and from CML phase, thus decitabine, a hypomethylating agent, can be an attractive treatment option for advanced phase CML. Objective: This systemic review and meta-analysis aims to investigate the role of low-dose decitabine among patients with advanced phase CML. Methodology: This was performed according to the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Results: Four (4) studies from 86 articles screened were eligible to be assessed in this systemic review and meta-analysis. These were phase I/II trials involving 81 advanced phase CML patients and used low-dose decitabine (5 to 20 mg/m2), with two studies using tyrosine kinase inhibitors. Outcomes of hematologic and cytogenetic response, and survival were assessed in the meta-analysis; with hematologic response being favored among advanced phase CML patients upon exposure with low-dose decitabine (p=0.05). Survival was also favored among responders to low-dose decitabine, however this was not significant. Discussion and Conclusion: Low-dose decitabine can be an effective and safe treatment option in advanced phase CML, especially in more frail patients that could not tolerate more intensive chemotherapy regimens. However, this study is limited by few studies available on this topic, thus further randomized controlled trials can be investigated to define the role of decitabine and its optimal dose among this subset of patients. Keywords: Chronic myelogenous leukemia, Decitabine, Advanced phase Conflict of Interest: The authors have no conflict of interest to declare regarding the publication of this article. Funding Source: None Corresponding Author: Maureen Via M. Comia, MD, FPCP maucomia@gmail.com +639178396329

category: hematology


title: School immunization coverage during the COVID-19 pandemic: A retrospective cohort study

abstract: Few studies have assessed the impact of the COVID-19 pandemic on immunization coverage for adolescents, and little is known about how coverage has changed throughout the pandemic. We aimed to: (1) assess the change in coverage for school-based vaccines in Alberta, Canada resulting from the pandemic; (2) determine whether coverage differed by geographic health zone and school type; and (3) ascertain whether coverage has returned to pre-pandemic levels. Using a retrospective cohort design, we used administrative health data to compare coverage for human papillomavirus (HPV) and meningococcal conjugate A, C, Y, W-135 (MenC-ACYW) vaccines in Alberta, Canada between pre-pandemic (2017-2018 school year) and pandemic (2019-2020 and 2020-2021 school years) cohorts (N=289,420). Coverage was also compared by health zone and authority type. The 2019-2020 cohort was followed over one year to assess catch-up. Compared to 2017-2018, immunization coverage for HPV was significantly lower in the 2019-2020 (absolute difference: 60.8%; 95% CI: 60.4-61.3%) and 2020-2021 cohorts (absolute difference: 59.9%; 95% CI: 59.4-60.3%). There was a smaller, significant decline in MenC-ACYW coverage comparing 2017-2018 to 2019-2020 (absolute difference: 6.1%; 95% CI: 5.6-6.5%) and 2020-2021 (absolute difference: 32.2%; 95% CI: 31.6-32.7%). Private schools had low coverage overall, while coverage fluctuated by zone. During follow-up of the 2019-2020 cohort, coverage for HPV and MenC-ACYW increased from 5.6% to 50.2%, and 80.7% to 83.0%, respectively. There was a substantial decrease in school-based immunization coverage during the COVID-19 pandemic, and coverage has not returned to pre-pandemic levels, suggesting further catch-up is needed.


title: A blueprint for biobanking in everyday clinical practice in psychiatry: The Munich Mental Health Biobank

abstract:
Translational research on complex, multifactorial mental health disorders, such as bipolar disorder, major depressive disorder, schizophrenia, and substance use disorders requires databases with large-scale, harmonized, and integrated real-world and research data.

The Munich Mental Health Biobank (MMHB) is a mental health-specific biobank that was established in 2019 to collect, store, connect, and supply such high-quality phenotypic data and biospecimens from patients and study participants, including healthy controls, recruited at the Department of Psychiatry and Psychotherapy and the Institute of Psychiatric Phenomics and Genomics, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany. Participants are asked to complete a questionnaire that assesses sociodemographic and cross-diagnostic clinical information, provide blood samples, and grant access to their existing medical records. The generated data and biosamples are available to both academic and industry researchers. In the current manuscript, we outline the workflow and infrastructure of the MMHB, describe the clinical characteristics and representativeness of the sample collected so far, and reveal future plans for expansion and application.

As of October 31, 2021, the MMHB contains a continuously growing set of data from 578 patients and 104 healthy controls (46.37% female; median age, 38.31 years). The five most common mental health diagnoses in the MMHB are recurrent depressive disorder (38.78%; ICD-10: F33), alcohol-related disorders (19.88%; ICD-10: F10), schizophrenia (19.69%; ICD-10: F20), depressive episode (15.94%; ICD-10: F32), and personality disorders (13.78%; ICD-10: F60). Compared with the average patient treated at the recruiting hospitals, MMHB participants have significantly more mental health-related contacts, less severe symptoms, and a higher level of functioning. The distribution of diagnoses is also markedly different in MMHB participants compared with individuals who did not participate in the biobank.

After establishing the necessary infrastructure and initiating recruitment, the major tasks for the next phase of the MMHB project are to improve the pace of participant enrollment, diversify the sociodemographic and diagnostic characteristics of the sample, and improve the utilization of real-world data generated in routine clinical practice.


title: Impaired functional connectivity in patients with psychosis and visual hallucinations

abstract:
Backgroundmore than one-third of patients with psychosis experience visual hallucinations, but the underlying pathomechanism remains largely unknown. Although schizophrenia is related to altered brain functional connectivity, it is unknown how this could predispose patients to experience visual hallucinations. Previous work suggested that this predisposition is caused by alterations in vision-related networks, including the Visual Network, possibly with a specific focus on the Ventral Attention Network 1. This network responds to salient stimuli from the Visual Network and operates as a switch between the internally-focused Default Mode Network and the outside-world-focused Dorsal Attention Network.

Methodsin this case control study we investigated the role of these networks in three groups: 14 participants with a psychotic disorder and visual hallucinations, 15 participants with a psychotic disorder without visual hallucinations, and 16 healthy controls. All patients underwent resting state functional Magnetic Resonance Imaging after which we determined the intra- and inter-network functional connectivity of these networks in all participants. We also used fast Eigenvector Centrality Mapping to determine the most central regions, i.e. the most functionally communicating regions, within these networks.

Resultscompared to healthy controls, patients with visual hallucinations had lower functional connectivity, both intra-network and inter-network, in all vision-related networks. This decrease was most prominent for the Ventral Attention Network and the Dorsal Attention Network for intra-network functional connectivity. Moreover, Eigenvector Centrality Mapping showed a severe decrease in functional communication within the Visual Network in the right intracalcarine sulcus, with a simultaneous increase in functional communication in the lateral part of the left middle occipital gyrus, a region involved in object recognition. The results of patients without hallucinations were generally in between patients with visual hallucinations and healthy controls.

Discussionour study shows that widespread dysconnectivity of predominantly vision-related functional networks may predispose patients with psychosis to generate visual hallucinations. These results are in line with previous models of hallucinations in psychosis which suggested that the processing deficits in the Visual Network may cause or exacerbate inadequate co-functioning and switching between the Default Mode Network and the Dorsal Attentional Network, possibly due to impaired Ventral Attention Network functioning. In combination with impaired attending of visual signals by the Dorsal Attentional Network, this may lead to inappropriate saliency processing and wrongly attributing an external origin to internally generated events and, consequently, to visual hallucinations. The often complex nature of psychotic visual hallucinations may be explained by the more central role of object processing regions.


title: Grey matter morphometric biomarkers for classifying early schizophrenia and PD psychosis: a multicentre study

abstract:
BackgroundPsychotic symptoms occur in a majority of schizophrenia patients, and in approximately 50% of all Parkinsons disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little, however, is known about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as schizophrenia and PD.

MethodsThe present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms.

ResultsSCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD as well as PDN and Con-PD, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC[~]0.80) of FEP and Con-Psy, and fair performance (AUC[~]0.72) when differentiating PDP from Con-PD. Importantly, best performance was found in partly overlapping networks including the precuneus. Finally, reduced GM volume in SCN with increased variability was linked to increased psychotic symptoms in both FEP and PDP.

ConclusionAlterations within selected SCNs seem to be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide first evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.


title: A quasi-experimental cohort study evaluating a conditional economic incentive on first-dose COVID-19 vaccination rates among older adults in South Africa

abstract: Importance: COVID-19 vaccination coverage in South Africa remains low despite increased access to vaccines. On November 1, 2021, South Africa introduced the Vooma Voucher program, which provided a small guaranteed financial incentive, a Vooma Voucher redeemable at grocery stores, for COVID-19 vaccination among older adults, a population most vulnerable to serious illness, hospitalization, and death. However, the association of financial incentives with vaccination coverage remains unclear. Objective: To evaluate the association of the conditional economic incentive program with first-dose vaccination rates among older adults (aged [≥]60 years) in South Africa. Design: A quasi-experimental cohort study using daily data on first doses administered. We ran interrupted time series (ITS) models to evaluate the Vooma Voucher program, launched on November 1, 2021, at national and provincial levels. We used data between October 1, 2021 and November 27, 2021 in models estimated at the daily level. Setting and participants: The Vooma Voucher program was a nationwide vaccination incentive program implemented for adults aged [≥]60 years from November 1, 2021 to February 28, 2022. Intervention: Individuals who received their first vaccine dose received a text message to access a ~$7 (ZAR100) voucher that was redeemable at nationwide chain of grocery stores. Main outcome: Daily first COVID-19 vaccine doses administered per 10,000 individuals aged [≥]60 years. Results: The Vooma Voucher program was associated with a of 7.15-12.01% increase in daily first-dose vaccination in November 2021 compared to late October 2021. The incentive accounted for 6,476-10,874 additional first vaccine doses from November 1-27, 2021, or 8.31-13.95% of all doses administered to those aged [≥]60 years during that period. This result is robust to the inclusion of controls for the number of active vaccine delivery sites and for the nationwide Vooma weekend initiative (November 12-14), both of which also increased vaccinations through expanded access to vaccines and demand creation activities. Conclusions/Relevance: Financial incentives for COVID-19 vaccination led to a modest increase in first dose vaccinations among older adults in South Africa. In addition to financial incentives, expanded access to vaccines may also results in higher vaccination coverage.


title: Definition of normal vertebral morphology using NHANES-II radiographs

abstract:
BackgroundA robust definition of normal is required to confidently identify vertebral abnormalities such as fractures. Between 1976 and 1980, the 2nd National Health and Nutrition Examination Survey (NHANES-II) was conducted. Justified by the prevalence of neck and back pain, approximately 10,000 lateral cervical spine and 7,000 lateral lumbar spine X-rays were collected. Demographic, anthropometric, health, and medical history data were also collected. This resource can be used for establishing normative reference data that can subsequently be used to diagnose abnormal vertebral morphology.

Purpose1) Develop normative reference data for vertebral morphology using the lateral spine radiographs from NHANES-II. 2) Document sources of variability.

Subject SampleNationwide probability sample to document health status of the United States.

MethodsThe coordinates of the four vertebral body corners were obtained using previously validated, automated technology consisting of a proprietary pipeline of neural networks and coded logic. These landmarks were used to calculate six vertebral body morphology metrics: 1) anterior/posterior vertebral body height ratio (VBHR); 2) superior/inferior endplate width ratio (EPWR); 3) forward/backward diagonal ratio (FBDR); 4) height/width ratio (HWR); 5: angle between endplates (EPA); 6) Angle between posterior wall and superior endplate (PSA). Descriptive statistics were generated and used to identify and trim outliers from the data and obtain a gaussian distribution for each metric. Descriptive statistics were tabulated using the trimmed data for use in quantifying deviation from average for each metric. The dependency of these metrics on sex, age, race, nation of origin, height, weight, and BMI was also assessed.

ResultsComputer generated lumbar landmarks were obtained for 42,980 vertebrae from lumbar radiographs and 54,093 vertebrae from cervical radiographs for subjects 25 to 74 years old. After removing outliers, means and standard deviations for the remaining 35,275 lumbar and 44,938 cervical vertebrae changed only slightly, suggesting that normal morphology and intervertebral alignment is dominant in the data. There was low variation in vertebral morphology after accounting for vertebra (L1, L2, etc.), and the R2 was high for analyses of variance. The EPWR, FBDR and PSA generally had the lowest coefficients of variation. Excluding outliers, Age, sex, race, nation of origin, height, weight, and BMI were statistically significant for most of the variables, though the F-statistic was very small compared to that for vertebral level. Excluding all variables except vertebra changed the R2 very little (e.g. for the lumbar data, VBHR R2 went from 0.804 to 0.795 and FBDR R2 went from 0.9005 to 0.9000). Reference data were generated that can be used to produce standardized metrics in units of standard deviation from average. This allows for easy identification of abnormalities resulting from vertebral fractures, atypical vertebral body morphologies, and other congenital or degenerative conditions. Standardized metrics also remove the effect of vertebra thereby enabling data for all vertebrae to be pooled in research studies.

ConclusionsThe NHANES-II collection of spine radiographs and associated data may prove to be a valuable resource that can facilitate standardized spine metrics useful for objectively identifying abnormalities. The data may be particularly valuable for identification of vertebral fractures, although X-rays taken early in life would be needed in some cases to differentiate between normal anatomic variants, fractures, and vertebral shape remodeling.

category: radiology and imaging


title: The I-SPY COVID Adaptive Platform Trial for COVID-19 Acute Respiratory Failure: Rationale, Design and Operations

abstract:
IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalized with severe COVID-19. The ISPY COVID trial was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation, and challenges of the ISPY COVID trial during the first phase of trial activity from April 2020 until December 2021.

Methods and analysisThe ISPY COVID Trial is a multi-center open label phase 2 platform trial in the United States designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID Trial network includes academic and community hospitals with significant geographic diversity across the country. Enrolled patients are randomized to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes--time to recovery and mortality. The statistical design uses a Bayesian model with "stopping" and "graduation" criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrolls to a maximum of 125 patients per arm and is compared to concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrollment and adaptation of the trial design is ongoing.

Ethics and disseminationISPY COVID operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer reviewed medical journals.

Trial registration numberClinicaltrials.gov registration number NCT04488081

Strengths and limitations of this studyO_LIThe ISPY COVID Trial was developed in early 2020 to rapidly and simultaneously evaluate therapeutics for severe COVID-19 on an adaptive open label phase 2 platform
C_LIO_LIThe ISPY COVID Adaptive Platform Trial Network is an academic-industry partnership that includes academic and community hospitals spanning a wide geographic area across the United States
C_LIO_LIOf December 2021, 11 investigational agent arms have been activated on the ISPY COVID Trial Platform
C_LIO_LIThe ISPY COVID Trial was designed to identify therapeutic agents with a large clinical effect for further testing in definitive efficacy trials--limitations to this approach include the risk of a type 2 error
C_LI

category: respiratory medicine


title: Reduced motor unit discharge rates in gastrocnemius lateralis, but not in gastrocnemius medialis or soleus, in runners with Achilles tendinopathy

abstract:
ObjectivesDeficits in muscle performance could be a consequence of a reduced ability of a motor neuron to increase the rate in which it discharges. This study aimed to investigate motor unit (MU) discharge properties of each Triceps surae muscle (TS), and TS torque steadiness during submaximal intensities in runners with Achilles tendinopathy (AT).

MethodsWe recruited runners with (n=12) and without (n=13) mid-portion AT. MU discharge rate was analysed for each of the TS muscles, using High-Density surface electromyography during 10 and 20% isometric plantar flexor contractions.

ResultsMU mean discharge rate was lower in the Gastrocnemius lateralis (GL) in AT compared to controls. In AT, GL MU mean discharge rate did not increase as torque increased from 10% peak torque, 8.24pps (95%CI: 7.08 to 9.41) to 20%, 8.52pps (7.41 to 9.63, p=0.540); however, in controls, MU discharge rate increased as torque increased from 10%, 8.39pps (7.25 to 9.53) to 20%, 10.07pps (8.89 to 11.25, p<0.001). There were no between-group difference in Gastrocnemius medialis (GM) or Soleus (SOL) MU discharge rates. We found no between-groups differences in coefficient of variation of MU discharge rate in any of the TS muscles nor in TS torque steadiness.

ConclusionOur data demonstrates that runners with AT may have a reduced neural drive to GL, failing to increase MU discharge rate to adjust for the increase in torque demand. Further research is needed to understand how interventions focusing on increasing neural drive to GL would affect muscle function in runners with AT.

category: sports medicine


title: HOXA Amplification Defines a Genetically Distinct Subset of Angiosarcomas

abstract: Angiosarcoma is a rare, devastating malignancy with few curative options for disseminated disease. We analyzed a recently published genomic data set of 48 angiosarcomas and noticed recurrent amplifications of HOXA cluster genes in 33% of patients. HOXA genes are master regulators of embryonic vascular development and adult neovascularization, which provides a molecular rationale to suspect that amplified HOXA genes act as oncogenes in angiosarcoma. HOXA amplifications typically affected multiple pro-angiogenic HOXA genes and co-occurred with amplifications of CD36 and KDR, whereas the overall mutation rate in these tumors was relatively low. HOXA amplifications were found most commonly in angiosarcomas located in the breast, and were rare in angiosarcomas arising in sun-exposed areas on the head, neck, face and scalp. Our data suggest that HOXA amplified angiosarcoma is a distinct molecular subgroup. Efforts to develop therapies targeting oncogenic HOX gene expression in AML and other sarcomas may have relevance for HOXA amplified angiosarcoma.

category: oncology


title: Comparing human and AI performance in medical machine learning: An open-source Python library for the statistical analysis of reader study data

abstract: In seeking to understand the potential effects of artificial intelligence (AI) on the practice of diagnostic medicine, many investigations involve collecting interpretations from several human experts on a common set of cases. In an effort to standardize the process of analyzing the data emerging from such studies, we have released an open-source Python library to perform applicable statistical procedures. The software implements the industry-standard Obuchowski-Rockette-Hillis (ORH) method for multi-reader multi-case (MRMC) studies. The tools can be used to compare a standalone algorithm against a panel of readers, or compare readers operating in two modalities (for example, with and without algorithmic assistance). The software supports both nonequivalence and noninferiority tests. Functions are also provided to simulate reader and model scores, useful for Monte Carlo power analysis. The code is publicly available in our Gitub repository at https://github.com/Google-Health/google-health/tree/master/analysis.

category: health informatics


title: Temporal Characterization of Longitudinal Sequelae Including Acute Pain, Physiologic Status, and Toxicity Kinetics in Head and Neck Cancer Patients Receiving Radiotherapy: A Prospective Electronic Health Record Embedded Registry Study.

abstract:
BackgroundPain is a common, debilitating symptom experienced by patients with oral cavity and oropharyngeal cancer (OC/OPC) treated with radiotherapy (RT). Managing acute pain (AP) over 6 - 7 weeks of RT remains a significant challenge, warranting further investigation. Using a modern prospective registry, the objective of this study was to characterize longitudinal AP profiles and temporal changes in vital signs (VS), radiation toxicities, and analgesic prescribing patterns during RT.

MethodsA total of 351 patients with OC (n=120) and OPC (n=228) treated with curative RT from 2013-2021 were included. Baseline cohort characteristics, weekly patient-reported pain descriptors, physician-graded toxicities (CTCAE v5), and analgesic orders during RT were extracted. Temporal changes in AP scores and VS were analyzed using linear mixed effect models. AP trajectories were reduced to single metric area under the curve calculations (AUCpain). Correlations were assessed using Spearman correlation coefficients.

ResultsMedian age was 60 years, and 70% and 42% received chemotherapy and surgery, respectively. A significant increase in pain, mucositis, dermatitis, and overall treatment toxicity severity were observed by the end of RT. AUCpain was significantly different based on gender, primary tumor site, surgery, drug use history and pre-RT pain. There was a temporal mean weight loss of 7.1% bodyweight (95%CI, 10-8.2; P<0.001), a mean arterial pressure (MAP) decline of 6.8 mmHg (95%CI, -8.8 to -4.7; P<0.001), and increased pulse rate of 11 beats/min (95%CI, 7.6-13.8; P<0.001). AP and pulse rate were positively associated over time (P<0.001) while weight and MAP were negatively associated over time (P<0.001). A temporal increase in analgesics use, mainly opioids, was detected.

ConclusionThis study characterizes longitudinal treatment-related toxicity kinetics using a prospective OC/OPC registry and demonstrates an ongoing need for optimized, timely pain control. Pain AUC metrics preserve temporal information and may be useful for developing algorithmic pain prediction and management models.


title: Assessing the feasibility of sustaining a 'Zero-COVID' policy in China in the era of highly transmissible variants

abstract: We developed a spatially structured, fully stochastic, individual-based SARS-CoV-2 transmission model to evaluate the feasibility of sustaining a 'Zero-COVID' policy in mainland China in light of currently dominant Omicron variants, China's current immunization level, and non-pharmaceutical intervention (NPI) strategies. We found that due to high transmissibility, neither Omicron BA.1 or BA.2 sublineages could be contained by China's Pre-Omicron non-pharmaceutical intervention strategies which were successful at sustaining the 'Zero-COVID' policy until March 2022. However, increased intervention intensity, such as enhanced population mobility restrictions and multi-round mass testing, could lead to containment success without the necessity of population-wide lockdown. As China's current vaccination has yet to reach high coverage in older populations, non-pharmaceutical interventions remain essential tools to maintain low levels of infection while building protective population immunity, ensuring a smooth transition out of the pandemic phase, and minimizing the overall disease burden and societal costs.


title: Escape of SARS-CoV-2 variant Omicron to mucosal immunity in vaccinated subjects.

abstract:
Omicron s escape to vaccine-induced systemic antibody responses has been shown in several studies in Omicron-infected patients and vaccine controls.

In the present study we compared mucosal antibody response to Omicron to mucosal antibody response to ancestral strain and Delta variant. This was done on nasal epithelial lining fluid (NELF) prospectively collected in 84 otherwise healthy healthcare workers who had never exhibited PCR-documented COVID-19 and had received three doses of the Pfizer-BioNTech COVID-19 mRNA vaccine. NELF was collected prior to Omicron detection in the geographical area of inclusion.

We show that NELF antibodies from vaccinated individuals were less efficient at inhibiting the binding of the Omicron Spike protein to ACE-2 compared to those of Delta or the ancestral strain.

These findings may explain the increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta in countries with a high vaccination coverage.


title: The mortality risk factor of severe community-acquired pneumonia (SCAP) patients with Sepsis: a retrospective study

abstract:
ObjectivesSepsis is one of the most common comorbidities in severe community-acquired pneumonia (SCAP) patients. We aimed to investigate the characteristics and mortality risk factors of SCAP patients hospitalized with Sepsis.

DesignA retrospective, single-centre study.

SettingThis study was conducted at a tertiary hospital in Southern China.

ParticipantsA total of 119 patients with SCAP, aged 17 years or older, were treated in the Integrated intensive care unit from 1 January 2018 to 30 December 2020.

Interventionsnone.

Outcome180-day mortality was the primary outcome.

Results119 patients were divided into the survivors (83 patients,69.75%), and the non-survivors (36 patients,30.25%). There are more pronounced inflammatory responses and respiratory problems at the beginning of the disease in non-survivors, requiring stronger respiratory and circulatory support. The CURB-65 score was a better predictor of mortality than the PSI and APACHE2 scores, AUCs of CURB-65: OR 0.744, p<0.005. For the entire treatment cycle, the non-survivors had a longer duration of persistent fever, required continuous and repeated airway intervention, and a longer duration of Vasopressor support (P<0.001). SCAP with bacterial infection as the onset, or secondary bacterial infection had a poor prognosis (P=0.018). The non-survivors had more use of different types of antimicrobials (P<0.05), because of Multidrug-resistant (MDR) organisms. And have faced more antifungal treatment failures (P=0.006). The mortality risk factors were comorbid with a duration of Vasopressors support, duration of persistent fever, age, numbers of antimicrobials for MDR organisms, CURB-65 score and duration of Neuromuscular Blocking Agents (NMBAs) (OR=1.234, OR=1.158, OR=1.084, OR=6.484, OR=3.386, OR=1.505, p<0.005, respectively).

ConclusionDynamic monitoring of the duration of patients abnormal indicators can help predict the prognosis. Age[≥]65.5 years, fever duration [≥]9.5 days, number of antimicrobials for MDR organisms [≥]2 types, longer NMBAs and Vasopressors use, and higher CURB-65 score were mortality risk factors in SCAP-Sepsis patients.

strengths and limitations of this studyWe evaluated dynamic monitoring of the duration of patients abnormal indicators can help predict the prognosis. To the best of our knowledge, a very few studies had done a dynamic monitoring of the duration of patients abnormal indicators in the field of SCAP with Sepsis. The retrospective nature of the study was a limitation, statistical data including respiratory support in later treatment, can be further quantified.

category: intensive care and critical care medicine


title: A Novel method for estimating right atrial pressure with point-of-care ultrasound (POCUS)

abstract: Current noninvasive estimation of right atrial pressure (RAP) by either bedside jugular venous pressure (JVP) exam or inferior vena cava (IVC) measurement during a formal echocardiogram offer imprecise estimates of actual RAP. We enrolled 41 patients in a prospective, blinded study to validate a novel point-of-care ultrasound method to estimate RAP. Two subjects were excluded and 39 were included in the final analysis. The ultrasound estimate of RAP (RAPU) was compared to the RAP measurement during right heart catheterization (RAPi) both as measured and corrected for the mid-AP diameter. The correlation coefficient between RAPi and corrected RAPU measurements was +0.72, regression R2 0.52, bias -0.60 mmHg (95% confidence interval [CI], -1.60 to +0.39 mmHg) with the limits of agreement -5.56 to +7.24 mmHg, and 3 mmHg accuracy of 26 (67%). Similarly, for the uncorrected RAPU measurement, the correlation coefficient was +0.75, regression R2 0.56, bias -0.49 mmHg (95% CI, -1.42 to +0.43 mmHg) with the limits of agreement -5.56 to +7.24 mmHg, and 3 mmHg accuracy of 29 (74%). This simple bedside evaluation of right atrial depth and the right jugular vein correlates with actual right atrial pressure better than traditional IVC parameters, and can accurately estimate RAP within 3mmHg in most patients.


title: Estimates of excess mortality for the five Nordic countries during the Covid-19 pandemic 2020-2021

abstract: Excess deaths during the covid-19 pandemic are of major scientific and political interest. Here we review excess all-cause death estimates from different methods for the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden), which have been much studied during the covid-19 pandemic. In the comparison of the methods, we use simple sensitivity estimates and linear interpolations of the death data to discuss uncertainties and implications for reporting ratios and infection fatality rates. We show using back-calculation of expected deaths from Nordic all-cause deaths that a recent study in Lancet, which is a clear outlier in the overviewed estimates, most likely substantially overestimates excess deaths of Finland and Denmark, and probably Sweden. The other estimates are more consistent and suggest a range of total Nordic excess deaths of approximately half of that in the Lancet study, a more uniform ability to identify covid-19-related deaths, and more similar infection fatality rates for the Nordic countries.


title: Seroprevalence of SARS-CoV-2 Antibodies among vaccinated and non-vaccinated adults in the West Bank: Results of a repeated cross-sectional study

abstract:
BackgroundSeroprevalence studies are known to provide better estimates of the proportion of people previously infected, which did not undertake diagnostic testing. Repeated cross-sectional sero-studies are encouraged in the same locations to monitor trends overtime. The aim of this study was to assess the seroprevalence among a random sample of vaccinated and non-vaccinated Palestinian adults living in the West Bank region of Palestine, irrespective of the source of antibodies, be it due to infection with COVID-19 or due to vaccination or both.

MethodsThis repeated cross-sectional study used serologic testing on a random sample of vaccinated and non-vaccinated adults, 18 years and older residing in 11 governorates of the West Bank region of Palestine. Antibodies/Blood samples were taken using Elecsys Anti-SARS-CoV-2 assay by using the Cobas Analyzer cobas e 411 (Roche) for detection of antibody seropositivity against COVID-19. Seroprevalence was estimated as the proportion of individuals who had a positive result in the total SARS-CoV-2 antibodies in the immunoassay. Sociodemographic information and medical history data was collected using a questionnaire.

ResultsAmong 1451 total participants enrolled in the study, serum samples were tested from 910 persons. Study findings from this randomly selected sample indicated a seroprevalence 75.9%, 95% CI (73.1-78.7). The seroprevalence results indicated that the prevalence of antibodies among those who reported that they were not infected and did not get vaccinated was 45.2% with 95% CI (39.9-50.5%).

The average age of participants was 37.6 years old. 49.2% were female and 50.8% were male. In relation to COVID-19, the following was found:

ConclusionOur findings revealed a drastic rise in seroprevalence of SARS-CoV-2 antibodies. This information is useful for assessing the degree of herd immunity, and provides for better understanding of the pandemic. Population-based seroprevalence studies should be conducted periodically to monitor the SARS-CoV-2 seroprevalence in Palestine and inform policymakers about the efficacy of the surveillance system.