title: Making maternity and neonatal care personalised in the COVID-19 pandemic: results from the Babies Born Better Survey in the UK and the Netherlands

abstract:
Structured abstractO_ST_ABSBackgroundC_ST_ABSThe COVID-19 pandemic had a severe impact on womens birth experiences. To date, there are no studies that use both quantitative and qualitative data to compare womens birth experiences before and during the pandemic, across more than one country.

AimTo examine womens birth experiences during the COVID-19 pandemic and to compare the experiences of women who gave birth in the United Kingdom (UK) or the Netherlands (NL) either before or during the pandemic.

MethodThis study is based on analyses of quantitative and qualitative data from the online Babies Born Better survey. Responses recorded by women giving birth in the UK and the NL between June and December 2020 have been used, encompassing women who gave birth between 2017 and 2020. Quantitative data were analysed descriptively, and chi-squared tests were performed to compare women who gave birth pre- versus during pandemic and separately by country. Qualitative data was analysed by inductive thematic analysis.

FindingsRespondents in both the UK and the NL who gave birth during the pandemic were as likely, or, if they had a self-reported above average standard of life, more likely to rate their labour and birth experience positively when compared to women who gave birth pre-pandemic. This was despite the fact that those labouring in the pandemic reported less support and choice. Two potential explanatory themes emerged from the qualitative data: respondents had lower expectations during the pandemic, and they appreciated that care providers tried hard to personalise care.

ConclusionOur study implies that many women labouring during the COVID-19 pandemic experienced restrictions, but their experience was mitigated by staff actions. However, personalised care should not be maintained by the good will of care providers, but should be a priority in maternity care policy to benefit all service users equitably.

category: obstetrics and gynecology


title: Coronavirus infection in neonates: Neurodevelopmental outcomes at 18 months of age

abstract:
BackgroundAlthough most neonates with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have mild disease, the impact on neurodevelopmental outcomes is unknown. This study aimed to assess 18-month neurodevelopmental outcomes of neonates infected with SARS-CoV-2 infection.

MethodsWe conducted a prospective cohort study of neonates diagnosed with SARS-CoV-2 infection between June 2020-August 2020 through nasopharyngeal coronavirus disease 2019 (COVID-19) PCR testing. A total of 58 neonates were identified from the Kuwait national COVID-19 registry and were enrolled. Historical controls were selected from the neonatal follow-up registry and matched 2:1 based on sex and gestational age. At 18 months of age, neurodevelopmental outcomes were assessed using Bayley Scales of Infant and Toddler Development-3rd Edition (BSID-III) by two trained assessors.

ResultsA total of 40 children were diagnosed with SARS-CoV-2 infection and included in the final analysis. The median age at infection was 18 days (range: 10-26 days). Eighteen (45%) were asymptomatic, 15 (37.5%) had a sepsis-like presentation, 5 (12.5%) had respiratory distress and 2 (5%) had a multisystem inflammatory syndrome in children (MIS-C)-like presentation. At 18 months follow up, only one child had severe developmental delay, and one child had a language delay. BSID-III outcomes did not significantly differ between the SARS-CoV-2 infected group and the control group.

ConclusionsThere is no difference in neurodevelopmental outcomes in children infected with SARS-CoV-2 infection at 18 months compared to controls, although longer neurodevelopmental follow-up studies are required.

category: pediatrics


title: Clinical EEG slowing induced by electroconvulsive therapy is better described by increased frontal aperiodic activity

abstract: Electroconvulsive therapy (ECT) is one of the most efficacious interventions for treatment-resistant depression. Despite its efficacy, ECTs neural mechanism of action remains unknown. Although ECT has been associated with "slowing" in the electroencephalogram (EEG), how this change relates to clinical improvement is unresolved. Until now, increases in slow-frequency power have been assumed to indicate increases in slow oscillations, without considering the contribution of aperiodic activity, a process with a different physiological mechanism. Here we show that aperiodic activity, indexed by the aperiodic exponent, increases with ECT treatment. This increase better explains EEG "slowing" when compared to power in oscillatory peaks in the delta (1-3 Hz) range, and is correlated to clinical improvement. In accordance with computational models of excitation-inhibition balance, these increases in aperiodic exponent are linked to increasing levels of inhibitory activity, indicating that ECT might ameliorate depressive symptoms by restoring healthy levels of inhibition in frontal cortices.

category: psychiatry and clinical psychology


title: Vaccine effectiveness of CanSino (Adv5-nCoV) COVID-19 vaccine among childcare workers -- Mexico, March-December 2021

abstract:
BackgroundBeginning in March 2021, Mexico vaccinated childcare workers with a single-dose CanSino Biologics (Adv5-nCoV) COVID-19 vaccine. Although CanSino is currently approved for use in 10 Latin American, Asian, and European countries, little information is available about its vaccine effectiveness (VE).

MethodsWe evaluated CanSino VE within a childcare worker cohort that included 1,408 childcare facilities. Participants were followed during March-December 2021 and tested through SARS-CoV-2 RT-PCR or rapid antigen test if they developed any symptom compatible with COVID-19. Vaccination status was obtained through worker registries. VE was calculated as 100% x (1-hazard ratio for SARS-CoV-2 infection in fully vaccinated vs. unvaccinated participants), using an Andersen-Gill model adjusted for age, sex, state, and local viral circulation.

ResultsThe cohort included 43,925 persons who were mostly (96%) female with a median age of 32 years; 37,646 (86%) were vaccinated with CanSino. During March-December 2021, 2,250 (5%) participants had laboratory-confirmed COVID-19, of whom 25 were hospitalized and 6 died. Adjusted VE was 20% (95% CI = 10-29%) against illness, 76% (42-90%) against hospitalization, and 94% (66-99%) against death. VE against illness declined from 48% (95% CI = 33-61) after 14-60 days following full vaccination to 20% (95% CI = 9-31) after 61-120 days.

ConclusionsCanSino vaccine was effective at preventing COVID-19 illness and highly effective at preventing hospitalization and death. It will be useful to further evaluate duration of protection and assess the value of booster doses to prevent COVID-19 and severe outcomes.

SummaryWe evaluated CanSino (Adv5-nCoV) COVID-19 vaccine effectiveness during March-December 2021 using a childcare worker cohort that included 43,925 participants across Mexico. Vaccination decreased the risk of COVID-19 illness by 20%, hospitalization by 76%, and death by 94%.

category: public and global health


title: The cognitive phenotype of juvenile absence epilepsy and its heritability: an investigation of patients and unaffected siblings

abstract:
ObjectiveThe cognitive profile of juvenile absence epilepsy (JAE) remains uncharacterized. This study aimed to: (i) elucidate the neuropsychological profile of JAE; (ii) assess cognitive trait heritability, by investigating unaffected JAE siblings; (iii) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to JME.

MethodsWe investigated 123 participants with a comprehensive neuropsychological test battery: 23 JAE patients, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 JME patients. We correlated clinical measures with cognitive performance data to decode effects of age of onset and duration of epilepsy.

ResultsJAE patients performed worse than controls on tests of verbal comprehension, working memory, verbal fluency, psychomotor speed, mental flexibility, and learning. Patients and siblings were similarly impaired on measures of verbal comprehension, phonemic and semantic fluency compared to controls. Receiver operating characteristic curves indicated successful discrimination of JAE patients and siblings from controls via linguistic measures (area under the curve [≥].77, p [≤] .0001). Individuals with JME were more impaired on response inhibition than those with JAE. Across all patients, those with older age at onset had better performance on psychomotor speed and executive function tests.

ConclusionsJAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including expressive language, working memory, and executive function. JAE siblings demonstrate shared impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum.

category: neurology


title: Structured Understanding of Assessment and Plans in Clinical Documentation

abstract: Physicians record their detailed thought-processes about diagnoses and treatments as unstructured text in a section of a clinical note called the assessment and plan. This information is more clinically rich than structured billing codes assigned for an encounter but harder to reliably extract given the complexity of clinical language and documentation habits. We describe and release a dataset containing annotations of 579 admission and progress notes from the publicly available and de-identified MIMIC-III ICU dataset with over 30,000 labels identifying active problems, their assessment, and the category of associated action items (e.g. medication, lab test). We also propose deep-learning based models that approach human performance, with a F1 score of 0.88. We found that by employing weak supervision and domain specific data-augmentation, we could improve generalization across departments and reduce the number of human labeled notes without sacrificing performance.

category: health informatics


title: The effect of neoadjuvant therapy on PD-L1 expression and CD8 lymphocyte density in non-small cell lung cancer

abstract:
PD-L1 expression is the routine clinical biomarker for the selection of patients to receive immunotherapy in non-small cell lung cancer (NSCLC). However, the application and best timing of immunotherapy in the resectable setting is still under investigation. We aimed to study the effect of chemotherapy on PD-L1 expression and tumor infiltrating lymphocytes (TIL), which is to date still poorly understood. This retrospective, single-centre study cohort comprised 96 consecutive patients with NSCLC resected in 2000-2016 after neoadjuvant therapy, including paired chemo-naive specimens in 57 cases. A biologically matched control cohort of 114 primary resected cases was included. PD-L1 expression, CD8+ TIL density and tertiary lymphoid structures were assessed on whole slides and correlated with clinico-pathological characteristics and survival.

Seven/57 and 12/57 cases had lower respectively higher PD-L1 expressions after neoadjuvant therapy. Most cases (n = 38) had no changes in PD-L1 expression and the majority of these showed PD-L1 < 1% in both samples (23/38 [60.5%]). CD8+ TILs density was significantly higher after chemotherapy (p = 0.031) in paired resections. Neoadjuvant cases showed no difference in PD-L1 expression or CD8+ TILs density compared to the chemotherapy naive control cohort. In univariable analyses, higher CD8+ TILs density, higher numbers of tertiary lymphoid structures but not PD-L1 expression were significantly associated with better survival. Increased PD-L1 expression after neoadjuvant chemotherapy was visually associated with worse 5-year survival, lacking statistical significance probably due to the low number of cases. PD-L1 expression is mostly unchanged after neoadjuvant chemotherapy. However, an increase of PD-L1 expression after neoadjuvant therapy could be associated with worse survival.

category: pathology


title: Prevalence and factors associated with post-partum depression in a remote area of Cameroon: a cross-sectional study

abstract: Postpartum depression is one of the many challenges associated with childbirth. In Cameroon, the focus is more on postpartum obstetric complications resulting in underdiagnosis and misdiagnosis of this condition. The current socio-political crisis plaguing the English-speaking part of Cameroon has increased the stressors that may inherently increase the prevalence. There is no published data describing post-partum depression in a rural setting in Cameroon. We seek to determine the prevalence and factors associated with PPD in women attending the Tubah District hospital, North West Region, Cameroon. We conducted a cross-sectional hospital-based study at the Tubah District Hospital. A consecutive convenience sampling technique was used to recruit participants. Our main outcome was post-partum depression which was assessed using the Edinburgh Post-partum Depression Scale. A total of 207 post-partum women took part in this study with a mean age of 27.54 {+/-} 5.78 years. The prevalence of depression was 31.8%. Gender-based violence (OR: 4.67, P = 0.013), financial stress (OR:3.57, P = 0.002) and male baby (OR: 2.83, P < 0.001) were independent psychosocial factors associated with PPD. Independent psycho-clinical factors of post-partum depression include family history of mental health illness (OR: 4.34, P = 0.04) and previous history of depression (OR: 4.17, P = 0.02). The prevalence of post-partum depression in women attending the Tubah District Hospital, Northwest Region, Cameroon is high. The factors associated with PPD are many. Identification of risk factors, early diagnosis and proper management can prevent PPD, disabling morbidity, and suicide in mothers.


title: The impact of alternative delivery strategies for novel tuberculosis vaccines in low- and middle-income countries: a modelling study

abstract:
BackgroundTuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low- and middle-income countries (LMICs), under alternative delivery scenarios.

MethodsWe calibrated a tuberculosis model to 105 LMICs (93% of global incidence). Vaccine scenarios were implemented as Basecase: routine vaccination of 9-year-olds and a one-time vaccination campaign for ages [≥]10 with country-specific introduction between 2028-2047 and 5-year scale-up to target coverage; Accelerated Scale-up: as Basecase, but all countries introducing in 2025 with instant scale-up; and Routine Only: as Basecase, but routine vaccination only. Vaccines protected against disease for 10-years, with 50% efficacy.

FindingsThe Basecase scenario reduced tuberculosis incidence (19.5% [95% uncertainty range=18.3- 21.6%]) and mortality (20.6% [19.2-23.4%]) rates in 2050 and prevented 3.6 (3.3-3.9) million deaths before 2050, including 1.6 million in the WHO South-East Asian region. The Accelerated Scale-up scenario reduced tuberculosis incidence (25.2% [23.9-27.5%]), mortality (26.7% [25.2-29.9%]), and prevented 7.9 (7.3-8.5) million deaths. The Routine Only scenario reduced tuberculosis incidence (9.9% [9.0-11.6%]), mortality (9.9% [8.9-12.3%]), and prevented 1.1 (0.9-1.2) million deaths.

InterpretationsNovel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a campaign will be crucial for rapid impact. Accelerated introduction, similar to the pace of COVID-19 vaccines, could approximately double the lives saved before 2050. Investment is required to support vaccine development, manufacturing, prompt introduction and scale-up.

FundingWHO (2020/985800-0)


title: The effect of calcium supplementation in people under 35 years old: A systematic review and meta-analysis of randomized controlled trials

abstract:
Background and objectiveThe effect of calcium supplementation on bone mineral accretion in people under 35 years old is inconclusive. To comprehensively summarize the evidence for the effect of calcium supplementation on bone mineral accretion in young populations ([≤]35 years).

DesignThis is a systematic review and meta-analysis.

Data sourcesThe Pubmed, Embase, ProQuest and CENTRAL databases were systematically searched from database inception to April 25, 2021.

EligibilityRandomized clinical trials assessing the effects of calcium supplementation on bone mineral density (BMD) or bone mineral content (BMC) in people under 35 years old.

ResultsThis systematic review and meta-analysis identified 43 studies involving 7382 subjects. Moderate certainty of evidence showed that calcium supplementation was associated with the accretion of BMD and BMC, especially on femoral neck (SMD 0.627, 95% CI 0.338 to 0.915; SMD 0.364, 95% CI 0.134 to 0.595; respectively) and total body (SMD 0.330, 95% CI 0.163 to 0.496; SMD 0.149, 95% CI 0.006 to 0.291), also with a slight improvement effect on lumbar spine BMC (SMD 0.163, 95% CI 0.008 to 0.317), no effects on total hip BMD and BMC and lumbar spine BMD were observed. Very interestingly, subgroup analyses suggested that the improvement of bone at femoral neck was more pronounced in the peri-PBM population (20-35 years) than the pre-PBM population (<20 years).

ConclusionOur findings provided novel insights and evidence in calcium supplementation, which showed that calcium supplementation significantly improves bone mass, implying that preventive calcium supplementation before or around achieving PBM may be a shift in the window of intervention for osteoporosis.

FundingThis work was supported by Wenzhou Medical University grant [89219029].


title: The acute effects of knee extension exercises with different contraction durations on the subsequent maximal knee extension torque for athletes with different strength levels

abstract: Individuals with high fatigue resistance against a high-intensity conditioning activity (CA) may be able to avoid experiencing significant fatigue and enhance their voluntary performance. We examined whether the optimal contraction duration of dynamic knee extension exercises to maximize subsequent voluntary performance varies depending on the strength level of an individual. The study participants were 22 male American college football players. Initially, all participants performed a 10-s maximal isometric knee extension exercise and were classified as stronger individuals (n = 8) and weaker individuals (n = 8) based on their relative muscle strength. Each group then performed three types of dynamic CA with different contraction durations (6 s [6-CA], 12 s [12-CA], and 18 s [18-CA]) in random order. To observe the time-course changes in post-activation potentiation and performance enhancement, the twitch torques induced by electrical stimulation and isokinetic knee extension torques at 180{degrees}/s were recorded before and after each CA. The twitch torque increased at 10 s (29.5% {+/-} 9.3%) and 1 min (18.5% {+/-} 6.8%) after 6-CA for the stronger individuals (p < 0.05). However, no post-activation potentiation was induced in the weaker individuals in either protocol. Voluntary performance increased at 4 (7.0% {+/-} 4.5%) and 7 (8.2% {+/-} 4.3%) min after 18-CA for stronger individuals (p < 0.05). However, there was no post-activation performance enhancement in either protocol for weaker individuals. Thus, CA with a relatively long contraction duration was optimal to maximize the subsequent voluntary performance for stronger individuals. It remains unknown whether CAs performed with relatively short or long contraction durations were optimal for weaker individuals.

category: sports medicine


title: Effects of vitamin D deficiency on blood lipids and bone metabolism: a large cross- sectional study

abstract:
PurposeTo investigate the relationship between serum HDL-C and spinal bone mineral density (BMD) under different serum 25-hydroxyvitamin D (25 (OH) D) levels in adults over 40 years old and to explore its mechanism.

MethodsParticipants over the age of 40 with data on HDL-C, 25 (OH) D, spinal BMD, and other variables in NHANES 2007-2010 were included in the final analysis. A weighted multiple linear regression model was used to evaluate the association between serum HDL-C and spinal BMD in different gender, ages and serum 25 (OH) D levels.

ResultsA total of 3599 subjects aged [≥] 40 years old were included in this study. Univariate analysis of the complete correction model showed a negative correlation between serum HDL-C and spinal BMD. In the two subgroups of serum 25(OH)D, we found that the higher the serum HDL-C in the female with serum 25 (OH) D < 75nmol/L aged 40-59 years old, the lower the total spinal BMD, and a similar relationship was found in the lumbar spine (L1-L4). However, no similar relationship was found in all populations with serum 25 (OH) D [≥] 75nmol/L and males with serum 25 (OH) D < 75nmol/L.

ConclusionAmong Americans over the age of 40, the increase of serum HDL-C is related to decreased BMD of spine only in women aged 40-59 years with vitamin D insufficiency or deficiency.

Author summaryWe performed a cross-sectional study using the National Health Examination and Nutrition Survey (NHANES) data. We found that increased serum high-density lipoprotein cholesterol (HDL-C) during vitamin D deficiency is a potential risk factor for osteopenia or osteoporosis in middle-aged and elderly American women.


title: Evaluation of isotype specific salivary antibody assays for detecting previous SARS-CoV-2 infection in children and adults

abstract: Saliva is easily obtainable non-invasively and potentially suitable for detecting both current and previous SARS-CoV-2 infection. We established 6 standardised enzyme linked immunosorbent assays (ELISA) capable of detecting IgA and IgG antibodies to whole SARS-CoV-2 spike protein, to its receptor binding domain region and to nucleocapsid protein in saliva. In test accuracy (n=320), we found that spike IgG performed best (ROC AUC: 95.0%, 92.8-97.3%), followed by spike IgA (ROC AUC: 89.9%, 86.5-93.2%) for discriminating between pre-pandemic and post COVID-19 saliva samples. Using machine learning, diagnostic performance was improved when a combination of tests was used. As expected, salivary IgA was poorly correlated with serum, indicating an oral mucosal response whereas salivary IgG responses were predictive of those in serum. When deployed to 20 household outbreaks undergoing Delta and Omicron infection, antibody responses were heterogeneous but remained a reliable indicator of recent infection. Intriguingly, unvaccinated children showed evidence of exposure almost exclusively through specific IgA responses in the absence of evidence of viral infection. We have provided robust standardisation, evaluation, and field-testing of salivary antibody assays as tools for monitoring SARS-CoV-2 immune responses. Future work should focus on investigating salivary antibody responses following infection and vaccination to understand patterns of SARS-CoV-2 transmission and inform ongoing vaccination strategies.

category: infectious diseases


title: Safety and effectiveness of RBD-specific polyclonal equine F(ab')2 fragments for the treatment of hospitalized patients with severe Covid-19 disease: a retrospective cohort study.

abstract:
Passive immunotherapy has been evaluated as a therapeutic alternative for patients with COVID-19 disease. Equine polyclonal immunotherapy for COVID-19 (EPIC) showed adequate safety and potential efficacy in a clinical trial setting and obtained emergency use authorization in Argentina. We studied its utility in a real world setting with a larger population.

MethodsWe conducted a retrospective cohort study at "Hospital de Campana Escuela-Hogar" in Corrientes, Argentina, to assess safety and effectiveness of EPIC in hospitalized adults with severe COVID-19 pneumonia. Primary endpoints were 28-days all-cause mortality and safety. Mortality and improvement in modified WHO clinical scale at 14 and 21 days were secondary endpoints. Potential confounder adjustment was made by logistic regression weighted by the inverse of the probability of receiving the treatment (IPTW) and doubly robust approach.

ResultsClinical records of 395 exposed (EPIC) and 446 non-exposed (Controls) patients admitted between November 2020 and April 2021 were analyzed. Median age was 58 years and 56.8% were males. Mortality at 28 days was 15.7% (EPIC) vs. 21.5% (Control). After IPTW adjustment the OR was 0.66 (95 % CI: 0.46 - 0.96), P= 0.03. The effect was more evident in the subgroup who received two EPIC doses (complete treatment, n=379), OR: 0.58 (95% CI 0.39 to 0.85), P=0.005. Overall and serious adverse events were not significantly different between groups.

ImportanceIn this retrospective cohort study, EPIC showed adequate safety and effectiveness in the treatment of hospitalized patients with severe SARS-CoV-2 disease.


title: mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations

abstract: Two messenger RNA (mRNA)-based vaccines are widely used globally to prevent coronavirus disease 2019 (COVID-19). Both vaccine formulations contain PEGylated lipids in their composition, in the form of polyethylene glycol [PEG] 2000 dimyristoyl glycerol for mRNA-1273, and 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide for BNT162b2. It is known that some PEGylated drugs and products for human use that contain PEG, are capable of eliciting immune responses, leading to detectable PEG-specific antibodies in serum. In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). We detected an increase in the reactivity to mRNA vaccine formulations in mRNA-1273 but not BNT162b2 vaccinees sera in a prime-boost dependent manner. Furthermore, we observed the same pattern of reactivity against irrelevant lipid nanoparticles from an influenza virus mRNA formulation and found that the reactivity of such antibodies correlated well with antibody levels against high and low molecular weight PEG. Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. Overall, our data shows a differential induction of anti-PEG antibodies by mRNA-1273 and BNT162b2. The clinical relevance of PEG reactive antibodies induced by administration of the mRNA-1273 vaccine, and the potential interaction of these antibodies with other PEGylated drugs remains to be explored.

category: allergy and immunology


title: Time to Recovery from Diabetic Ketoacidosis and its Predictors among Adult Diabetic Ketoacidosis Patients in DEBRE MARKOS Referral Hospital, North West Ethiopia, 2021: Retrospective Cohort Study

abstract:
IntroductionDiabetic ketoacidosis is an acute life-threatening complication of diabetes mellitus. With appropriate treatments, diabetic ketoacidosis patients are expected to make a full recovery within 24 hours. Previous studies did not address variables such as duration of diabetic ketoacidosis symptoms, and blood glucose level. In addition, the recovery time and its predictors of diabetic ketoacidosis in adult patients are not well known in Ethiopia.

ObjectiveTo assess time to recovery from diabetic ketoacidosis and its predictors among adult diabetic ketoacidosis patients in Debre Markos referral hospital, North West Ethiopia, 2021

MethodsA retrospective cohort study was employed among 452 records of adult diabetic ketoacidosis patients who were admitted starting from January 1, 2016 to January 1, 2021 using their medical registration number. Data were entered into Epi-data version 4.6 and analyzed using Stata version 14. A Kaplan Meier survival curve was used to estimate diabetic ketoacidosis-free survival time. In addition, a generalized log-rank test was utilized to compare diabetic ketoacidosis-free survival time between different categorical explanatory variables. Cox proportional hazards model was used to identify predictors of time to diabetic ketoacidosis recovery time. Variables with a P-value < 0.25 in the bivariable analysis were entered into a multivariable Cox proportional hazards model to identify predictors of recovery time at p[≤] 0.05.

ResultThe median time to recovery from diabetic ketoacidosis for all observations was 24 hours. Severity of diabetic ketoacidosis (AHR=0.24, 95%CI=0.16-0.35), duration of diabetic ketoacidosis (AHR=0.46, 95%CI 0.33-0.64), diabetes duration (AHR=1.74, 95%CI 1.35-2.25), and random blood sugar level (AHR=0.64, 95%CI= (0.51-0.79) were significant predictors of recovery time.

Conclusion and recommendationThe median time to recovery from diabetic ketoacidosis was relatively prolonged. The hospital shall give special attention to patients with the identified predictors. Further study using a prospective design by including admission pH and admission serum potassium level is advised.

category: endocrinology


title: Whole Genome DNA and RNA Sequencing of Whole Blood Elucidates the Genetic Architecture of Gene Expression Underlying a Wide Range of Diseases

abstract: To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis-eQTL variant-gene transcript (eGene) pairs at p<5x10-8 (2,855,111 unique cis-eQTL variants and 15,982 unique eGenes) and 1,469,754 trans-eQTL variant-eGene pairs at p<1e-12 (526,056 unique trans-eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis-eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis-eGenes are enriched for immune functions (FDR <0.05). The cis-eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.

category: epidemiology


title: Association between breastfeeding, host genetic factors, and calicivirus gastroenteritis in a Nicaraguan birth cohort

abstract:
BackgroundNorovirus and sapovirus are important causes of childhood acute gastroenteritis (AGE). Breastfeeding prevents AGE generally; however, it is unknown if breastfeeding prevents AGE caused specifically by norovirus and sapovirus.

MethodsWe investigated the association between breastfeeding and norovirus or sapovirus AGE episodes in a birth cohort. Weekly data on breastfeeding and AGE episodes were captured during the first year of life. Stools were collected from children with AGE and tested by RT-qPCR for norovirus and sapovirus. Time-dependent Cox models estimated associations between weekly breastfeeding and time to first norovirus or sapovirus AGE.

FindingsFrom June 2017 to July 2018, 444 newborns were enrolled in the study. In the first year of life, 69 and 34 children experienced a norovirus and a sapovirus episode, respectively. Exclusive breastfeeding lasted a median of 2 weeks, and any breastfeeding lasted a median of 42 weeks. Breastfeeding in the last week did not prevent norovirus (HR: 1.09, 95% CI: 0.62, 1.92) or sapovirus (HR: 1.00, 95% CI: 0.82, 1.21) AGE in a given week, adjusting for household sanitation, consumption of high-risk foods, and mothers and childs histo-blood group phenotypes. Maternal secretor-positive phenotype was protective against norovirus AGE, whereas childs secretor-positive phenotype was a risk factor for norovirus AGE.

InterpretationExclusive breastfeeding in this population was short-lived, and no conclusions could be drawn about its potential to prevent norovirus or sapovirus AGE. Non-exclusive breastfeeding did not prevent norovirus or sapovirus AGE in the first year of life. However, maternal secretor-positive phenotype was associated with a reduced hazard of norovirus AGE.

WHAT IS KNOWN- Breastfeeding prevents acute gastroenteritis (AGE) in nursing infants.
- It is unknown if breastfeeding prevents AGE caused by norovirus or sapovirus, which are leading causes of childhood AGE worldwide.
- Host genetic factors can influence AGE risk, and the mediating effects of breastfeeding are unclear.

WHAT IS NEW- Exclusive breastfeeding was rare, and breastfeeding did not prevent norovirus (hazard ratio 1.09, 95% CI: 0.62, 1.92) or sapovirus (hazard ratio 1.00, 95% CI: 0.82, 1.21) AGE.
- Secretor-positive phenotype of the child and the mother may be more important than breastfeeding in determining norovirus and sapovirus AGE risk in this setting.

category: gastroenterology


title: Novel CSF biomarkers of GLUT1 deficiency syndrome: implications beyond the brain's energy deficit

abstract: We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic CSF profiles from 11 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-1-3-glucose and xylose-1-3-xylose-1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-1-3-glucose and xylose-1-3-xylose-1-3-glucose may originate from O-glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.


title: Post-operative pain management practice and associated factors among nurses working at public hospitals, in Oromia region, Ethiopia

abstract:
BackgroundManagement of postoperative pain leads to positive patient progress and shortens the duration of hospital stay. Nurses, who are the majority in almost all hospitals and spend most of their time with the patients, are expected to play big role in the postoperative pain management practice. However, there is paucity of information regarding postoperative pain management practice and its associated factors among nurses.

ObjectiveTo assess postoperative pain management practice and associated factors among nurses working at public hospitals, in Oromia Region, Ethiopia, 2020.

MethodsInstitutional based cross sectional study was employed among randomly selected 377 nurses working at public hospitals in Oromia region, Ethiopia. Data was collected by distributing structured self-administered questionnaires that adapted from different literatures. The data were entered into Epi data version 3.1 and exported to SPSS version 22 for analysis. Variables with significant association in the bivariate analyses were entered into a multivariable regression analysis to identify the independent factors associated with nurses postoperative pain management practice. Significant factors were declared at P<0.05.

ResultThe result showed that, 66% of nurses had good pain management practice. Nurses favorable attitude towards post-operative pain management [AOR: 4.698, 95% CI: (2.725-8.100)], having access to read pain management guideline [AOR: 3.112, 95% CI: (1.652-5.862)], adequate knowledge of post-operative pain management [AOR: 2.939, 95% CI: (1.652-5.227)], working at Operation Room [AOR: 2.934, 95% CI: (1.27-6.795)] and received training on pain management [AOR: 3.289, 95% CI: (1.461-7.403)] were significantly associated with the practices of postoperative pain management.

Conclusion and recommendationSixty six percent of participants (nurses) have a good level of practice of postoperative pain management. Training on post-operative pain management (POPM), access to pain management guidelines, knowledge and attitude are significant factors in post-operative pain management practice. Governmental and other bodies concerned to post-operative care quality needs to show commitment on availing infrastructures like pain management guideline and improving nurses knowledge and attitude.

category: nursing


title: Prevalence of diabetic macular edema and risk factors among diabetic patients at the University of Gondar Tertiary Eye Care and Training Center, North West Ethiopia

abstract:
BACKGROUNDDiabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes mellitus. The prevalence of DME globally is around 6.8 % and in Ethiopia range from 5.7% to 11%.Different factors are associated with DME including poor glycemic control, longer duration, hypertension, dyslipidemia

OBJECTIVETo determine the prevalence and associated factors of diabetic macular edema among diabetic patients attending University of Gondar (UOG) hospital, tertiary eye care and training center, NW Ethiopia

METHODSA hospital based cross-sectional study was conducted from March 2021 to October 2021. Socio-demographic, clinical and laboratory data of patients was gathered. The collected data was entered into epi-data 4.6 version, exported to SPSS version 20 and analyzed.

RESULTSA total of 165 diabetic patients were enrolled with mean age of 54.71 {+/-}13.66 years, 50.9% male, 85.5% urban dwellers, 79.9% type 2 DM, 49.7% on oral hypoglycemic agents and the mean duration of diabetes was 7.93 years. Cataract was the commonest ocular morbidity and 42% of patients had at least mild vision impairment. The overall prevalence of DME was 17% and 5.5% of patients had clinically significant macular edema (CSME). The presence of proteinuria was 8.04 times more likely to have DME.

CONCLUSIONThe prevalence of DME among our patients was high. The presence of proteinuria was significantly associated with DME. Screening of diabetic patients for sight threatening retinopathy early and appropriate treatment is recommended.

category: ophthalmology


title: Lens Thickness and Its Association with General and Ocular Parameters in Healthy Subjects

abstract: The crystalline lens lens thickness playing an essential role in maintaining normal visual function, but little attention is paid to the lens thickness. The purpose of this study is to document the normative values of lens thickness (LT) in healthy subjects of Southern China and to evaluate its associated factors. This was a prospective, clinic-based, observational, cross-sectional study. A total of 526 eyes from 263 healthy subjects aged between 5-84 years (mean age, 38.48 {+/-} 22.04 years) were included in the study. All subjects underwent detailed ophthalmic examination, including the measurement of ocular biometric parameters by LenStar LS900. The study focused on LT and its association with general and ocular factors. The generalized estimation equation (GEE) model was used for statistical analysis. The Mean LT was 4.01 {+/-} 0.57 mm(95% CI, 3.97 - 4.06; median, 3.94 mm; range, 3.10 - 5.36). In a univariate regression analysis, the LT was associated significantly age, body weight, body height, body mass index (BMI), systolic pressure, diastolic pressure, spherical equivalent (SE), intraocular pressure (IOP), anterior chamber depth (ACD) and axial length (AL) (all P<0.05). After adjusting the general parameters and ocular parameters, LT was associated significantly with age ({beta}, 0.0151; 95% CI, 0.0116 - 0.0186; P<0.001), gender ({beta}, 0.1233; 95% CI, 0.0553 - 0.1913; P<0.001) and ACD ({beta}, -0.5815; 95% CI, -0.8059 - -0.3571; P<0.001) using the multivariate regression model. The LT was associated with older age, female gender, and shallower ACD in healthy subjects from Southern China. The data may help understand ocular diseases concerning lens thickness.


title: Efficacy of premarital genotype screening and counselling on knowledge toward Sickle Cell disease among university students in Dodoma Tanzania: uncotrolled quasi-experimental study

abstract:
BackgroundTanzania is experiencing the increase burden of Sickle cell disease, with an estimate of 20.6% prevalence Sickle Cell carriers. However, there is no preventive measure has been put in this area by the government; a great focus has been directed in the diagnosis and management and national guideline emphasis on the care of people affected by Sickle Cell Disease.

MethodsA non-controlled quasi-experimental study was conducted from June to September 2020 among 697 randomly recruited first-years university students from the University of Dodoma. Pre and post-test knowledge information were collected through structured self-administered questionnaires. Data was analyzed using SPSS v20. Simple and multiple linear analysis model was used to test for significant association of variables at 95% CI, at p<0.05. The results were presented using tables and figures.

ResultsThe mean knowledge score at pretest was 0.009{+/-}1.014 which improved to 0.365{+/-}0.901 on the posttest, with a statistically significant difference (t=6.965, p<0.01). The results of linear regression showed that knowledge change was not statistically associated with other predictors (p>0.05)

ConclusionHealth education demonstrated to be effective towards change in knowledge on sickle cell disease among University students.


title: Predictors and barriers for the management of non-communicable diseases among older Syrian refugees amidst the COVID-19 pandemic in Lebanon: A cross-sectional analysis of a multi-wave survey

abstract:
ImportanceOlder Syrian refugees have a high burden of non-communicable diseases and economic vulnerability.

ObjectiveThis study aimed to develop and internally validate a predictive model of the inability to manage non-communicable diseases (NCDs) in older Syrian refugees, and to describe barriers to adherence to NCD medication.

DesignA nested cross-sectional study within a longitudinal study.

SettingLebanon.

PopulationSyrian refugees aged 50 years or older residing in Lebanon who self-reported having hypertension, diabetes, history of cardiovascular disease (CVD) or chronic respiratory disease (CRD).

MethodsAll households with refugees aged 50 years or older who received humanitarian assistance from a non-governmental organization were invited to participate in a study examining the impact of COVID-19 on older Syrian refugees. Data were collected through telephone surveys between September 2020 and January 2021. The study outcome was self-reported inability to manage hypertension, diabetes, CVD or CRD. Predictors of inability to manage any NCD were assessed using a logistic regression models. The model was internally validated using bootstrapping techniques, which gave an estimate of optimism. The optimism-adjusted discrimination and calibration of the model were presented using C-statistic and calibration slope (C-slope), respectively.

ResultsOut of 3,222 older Syrian refugees, 1,893 reported having at least one NCD including 43% who had hypertension, 24% diabetes, 24% history of CVD, and 11% CRD. There were 387 (20%) participants who were unable to manage at least one of their NCDs. Predictors for inability to manage NCDs were age, non-receipt of cash assistance, household water insecurity, household food insecurity, and having multiple chronic diseases. The models adjusted C-statistic was 0.65 (95%CI:0.62-0.67) and C-slope was 0.88 (95%CI:0.73-1.03). The prevalence of non-adherence to medication was 9% and the main reasons were unaffordability of medication (41%) and the belief that they no longer required the medication after feeling better (22%).

ConclusionsThis study identified that the predictors of inability to manage NCDs among older Syrian refugees in Lebanon are mainly related to financial barriers, which aids the targeting of assistance and interventions. Context-appropriate assistance is required to overcome financial barriers and enable equitable access to medication and healthcare.

Key pointsO_ST_ABSQuestionC_ST_ABSWhat are the predictors and barriers to managing NCDs as an older Syrian refugee in Lebanon?

FindingsThis nested cross-sectional study assessed the predictors and barriers to managing any NCD, which included hypertension, diabetes, history of cardiovascular disease and chronic respiratory disease. Predictors included age, no cash assistance, household water insecurity, household food insecurity and having multiple chronic diseases. Primary reasons for not taking medications were unaffordability of the medication and belief medication was no longer required.

MeaningContext-appropriate assistance is required to overcome financial barriers and enable equitable access to healthcare and medication required to manage NCDs.


title: Changing patterns in reporting and sharing of review data in systematic reviews with meta-analysis: the REPRISE project

abstract:
ObjectivesTo examine changes in completeness of reporting and frequency of sharing review materials in systematic reviews (SRs) over time; and factors associated with these changes.

MethodsWe examined a random sample of 300 SRs with meta-analysis indexed in PubMed, Science Citation Index, Social Sciences Citation Index, Scopus and Education Collection in November 2020. We compared the extent of complete reporting in these reviews against 110 SRs indexed in MEDLINE in February 2014. We examined associations between completeness of reporting and various factors (e.g. self-reported use of reporting guidelines, journals data sharing policies) by calculating risk ratios (RR) and 95% confidence intervals (CI).

ResultsAmong 300 SRs from 2020, authors of only 7% shared their review data file(s) and 1% shared analytic code. Compared to 2014 sample, reviews in 2020 were more likely to reference reporting guidelines in their manuscript (RR=2.8, 95% CI 2.1-3.8), report the full search strategy for at least one database (RR=1.3, 95% CI 1.1-1.6) and methods of data preparation for meta-analysis (RR=2.2, 95% CI 1.4-3.5). Among reviews in 2020, those for which authors mentioned using reporting guidelines reported review protocols, study screening processes and numbers of records retrieved for each database more frequently than those that did not mention reporting guidelines; however the 95% CIs for these associations included the null. Reviews published in journals that mandated either data sharing or inclusion of Data Availability Statements were more likely to share their review materials (e.g. data, code files) (RR=8.1, 95% CI 3.1-21.5).

ConclusionThere was a notable increase over time in self-reported use of a reporting guideline, but we were uncertain whether it was associated with improved reporting of SRs. Data sharing policies of journals potentially encourage sharing of review materials. Further studies are needed to explore other facilitators or barriers to complete reporting in SRs.


title: Triangulating Causality Between Childhood Obesity and Neurobehavior: Twin and Longitudinal Evidence

abstract: Childhood obesity has been linked with brain functioning and morphology. The causal directions of these relationships remain mostly untested. We filled this gap by using the Adolescent Brain Cognitive Development study cohort comprising 11,875 children aged 9-10. Cross-sectionally, body mass percentile correlated with measures of personality, psychopathology, eating behavior, cognition, cortical thickness, cortical surface area, and cortical volume. Effects were then aggregated by neurobehavioral domain for causal analyses. Direction of Causation twin modeling was used to test the direction of each relationship. Findings were validated by longitudinal analyses. Twin modeling suggested causal effects of childhood obesity on eating behavior ({beta}=.26), cognition ({beta}=.05), cortical thickness ({beta}=.15), and cortical surface area ({beta}=.07). Personality/psychopathology ({beta}=.09) and eating behavior ({beta}=.16) appeared to causally influence childhood obesity. Longitudinal evidence broadly supported these findings. Results regarding cortical volume were inconsistent. Childhood obesity had considerable causal effects on brain functioning and morphology, supporting the brain inflammation theory.


title: Clinical description, molecular delineation, and genotype-phenotype correlation in KBG syndrome: 67 new patients and review of the literature.

abstract:
BackgroundKBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been published. Both loss-of-function sequence variants and large deletions (CNVs) involving ANKRD11 have been involved in KBG, but no genotype-phenotype correlation has been reported to date. This study presents the clinical and molecular characteristics of 67 new patients with KBG syndrome and the results of the first genotype-phenotype correlation leveraging data on 273 patients previously published.

Methods67 patients with KBG syndrome were recruited through a Spanish collaborative effort and were assessed using a custom phenotypic questionnaire. The frequency of all features was calculated. Manifestations present in >50% of the patients and a "severity score" were used to perform a genotype-phenotype correlation in the 340 KBG patients.

ResultsNeurodevelopmental delay (95%), comorbidites (82.8%), macrodontia (80.9%), triangular face (71%), characteristic ears (76%), nose (75.9%) and eyebrows (67.3%) were the most prevalent features in the 67 patients. The genotype-phenotype correlation yielded significant associations with the triangular face (71.1% in patients with sequence variants vs 45.2% in CNVs, p=0.015), short stature (62.5% variants in exon 9 vs. 27.8% outside; p=0.009) and macrodontia (with larger deletions, p=0.028), ID/ADHD/ASD (70.4% in c.1903_1907del vs. 89.4%; p=0.012) and a higher phenotypic score in patients with sequence variants compared with CNVs (p=0.005).

ConclusionsWe present a detailed phenotypic description of KBG syndrome in the largest series of patients reported to date, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 aberrations, and propose updated clinical diagnostic criteria based on our findings.

category: genetic and genomic medicine


title: Admissions to a large tertiary care hospital and Omicron BA.1 and BA.2 SARS-CoV-2 PCR positivity: primary, contributing, or incidental COVID-19

abstract: SARS-CoV-2 Omicron variants BA.1 and BA.2 seem to show reduced clinical severity. We classified 172 COVID-19 Omicron patient admissions. 66.2% of patients were admitted with primary or admission-contributing COVID-19. We therefore must be careful to base healthcare and public health decisions on the total number of hospitalized COVID-19 patients alone.


title: A protocol for a prospective observational cross sectional study as part of a service evaluation to identify whether living with frailty is a risk factor of digital exclusion from video consultations.

abstract:
Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

O_TBL View this table:
org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

O_TBL View this table:
org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL

category: geriatric medicine


title: A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations


title: Gut microbiota composition correlates with disease severity in myelodysplastic syndrome

abstract: The myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders of hematopoietic progenitor cells related to ineffective hematopoiesis and an increased risk of transformation to acute myelogenous leukemia. MDS is divided into categories, namely lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB). The International Prognostic Classification System (IPSS) ranks the patients as very low, low, intermediate, high, and very high based on disease evolution and survival rates. Evidence points to toll-like receptor (TLR) abnormal signaling as an underlying mechanism of this disease, providing a link between MDS and immune dysfunction. Notably, microbial signals, such as lipopolysaccharide from gram-negative bacteria can activate or suppress TLRs. Therefore, we hypothesized that MDS patients present gut microbiota alterations associated with disease subtypes and prognosis. We sequenced the 16S rRNA gene from fecal samples of 30 MDS patients and 16 healthy elderly controls to test this hypothesis. We observed a negative correlation between Prevotella spp. and Akkermansia spp. in MDS patients compared with the control group. High-risk patients presented a significant increase in the genus Prevotella spp. in relation to the other risk categories. There was a significant reduction in the abundance of the genus Akkermansia spp. in high-risk patients compared with low- and intermediate-risk. There was a significant decrease in the genus Ruminococcus spp. in MDS-EB patients compared with controls. Our findings show a new association between gut dysbiosis and higher-risk MDS, with a predominance of gram-negative bacteria in the gut of these patients.

category: hematology


title: Characterization of SARS-CoV-2 vaccine waning in Mexico

abstract: 1.We use survival analysis to analyze the decay in the protection induced by eight vaccines using data from 44, 006 patients from the IMSS public health system in Mexico, including only previously vaccinated, confirmed SARS-CoV-2 positive with a PCR test. We analyze three groupings: all data, complete vs. incomplete dose and less than 60 years or older. We found that a Weibull distribution fits very well the complete dose data. Only three vaccines still had 30% of their initial strength after 32 weeks. In two-dose vaccines, we found that the average protection time of a complete dose increases 2 to 3 times compared to that of an incomplete dose.


title: The ETKA study - Impact of early therapy termination on treated phonemes in conversational speech tasks in children aged 5 to 6 years with phonologically delayed development: protocol for a multicenter randomized controlled trial

abstract:
BackgroundChildren with speech and language disorders frequently display speech sound disorders, the treatment of which improves childrens ability to communicate. However, there is a significant gap between those therapy capacities needed and those provided in Austria. In addition, as the effect of early therapy termination has not yet been systematically evaluated, the aim of this project is to investigate the influence of an early therapy termination on phonological processes in children aged 5 to 6 years with phonologically delayed development.

Methods/DesignForty 5- to 6-year-old children, currently participating in speech therapies in the Upper Austrian region will participate in this multicenter randomized controlled trial. The participants will be randomly allocated to either the intervention group (early therapy termination) or the control group (uninterrupted ongoing therapy) by envelop randomization. Phoneme accuracy in spontaneous speech determined during 15 minutes of conversational sampling and phoneme accuracy for single-word production determined with the PLAKKS assessment will be used to assess therapy efficacy. The results from both groups will be compared regarding the correct use of the target phoneme/consonant cluster in conversational speech situation.

DiscussionThis study will explore the effect of early therapy termination on speech sound disorders in 5- to 6-yearold children. If an early termination exhibits non-inferiority to the current ongoing therapy, therapy resources could be used more effectively. Subsequently, earlier therapy starts for more children could be facilitated and negative consequences of delayed therapies could be counteracted.

Ethics and disseminationThe study was approved by an institutional review board (ID: A-2019-035). Dissemination will be achieved through peer-review conferences and journals.

Trial registrationThe study is registered at ClinicalTrials.gov (Identifier: NCT03972891, Registered 4 June 2019, https://www.clinicaltrials.gov/ct2/show/NCT03972891).

category: pediatrics


title: Familial risk of psychosis in obsessive-compulsive disorder: Impact on clinical characteristics, comorbidity and treatment response

abstract:
BackgroundFamily studies in obsessive-compulsive disorder (OCD) indicate higher rates of psychosis among their first-degree relatives (FDRs). However, the etiological and clinical relationships between the two disorders remain unclear. We compared the clinical characteristics & pharmacological treatment response in OCD patients with a family history of psychosis (OCD-FHP), with a family history of OCD (OCD-FHO) and those with sporadic (OCD-S).

MethodsA total of 226 patients who met DSM-IV criteria for OCD (OCD-FHP=59, OCD-FHO=112, OCD-S=55) were included for analysis. All patients were evaluated using the Mini International Neuropsychiatric Interview (MINI 6.0.0), Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Family Interview for Genetic Studies (FIGS). Treatment response was characterized over naturalistic follow-up.

ResultsThe three groups did not differ across any demographic or clinical variables other than treatment response. Patients in the OCD-FHP risk were found to have received a greater number of trials with serotonin reuptake inhibitors (SRI) (p<0.001) and were more likely to have failed [≥] 2 trials of SRIs.

ConclusionsWe observed that having a relative with psychosis may predispose to treatment resistance in OCD. Further research on the influence of genetic liability to psychosis on treatment response in OCD may offer novel translational leads.

category: psychiatry and clinical psychology


title: When do persuasive messages on vaccine safety steer COVID-19 vaccine acceptance and recommendations? Behavioral insights from a randomised controlled experiment in Malaysia.

abstract:
IntroductionVaccine safety is a primary concern among vaccine hesitant individuals. We examined how seven persuasive messages with different frames, all focusing on vaccine safety, influenced Malaysians to accept the COVID-19 vaccine, and recommend it to individuals with different health and age profiles; i.e. healthy adults, elderly, and people with pre-existing health conditions.

MethodsA randomized controlled experiment was conducted among 5,784 Malaysians who were randomly allocated into 14 experimental arms. They were exposed to one or two messages that promoted COVID-19 vaccination. Interventional messages were applied alone or in combination and compared against a control message. Outcome measures were assessed as intent to both take the vaccine and recommend it to healthy adults, elderly, and people with pre-existing health conditions, before and after message exposure. Changes in intent after message exposure were modeled and we estimate the average marginal effects with respect to changes in the predicted probability of selecting a positive intent for all four outcomes.

ResultsThe average baseline proportion of participants with positive intents in each arm to take, and recommend the vaccine to healthy adults, elderly, and people with pre-existing health conditions was 61.6%, 84.9%, 72.7% and 51.4% respectively. We found that persuasive communication via several of the experimented messages improved recommendation intent to people with pre-existing health conditions, with improvements ranging between 4 to 8 percentage points. In contrast, none of the messages neither significantly improved vaccination intentions, nor recommendations to healthy adults and the elderly. Instead, we found evidence suggestive of backfiring among this group with messages using negative frames, risky choice frames, and priming descriptive norms.

ConclusionPersuasive messages aimed at influencing vaccination decisions should incorporate a combination of factors linked to hesitancy. Messages intended to promote recommendation of novel health interventions to people with pre-existing health conditions should incorporate safety dimensions.

Clinical Trials registration numberNCT05244356

Key Messages1. What is already known?O_LIPersuasive messages have been shown to influence COVID-19 vaccination intentions, but evidence from Low- and Middle-income countries are limited.
C_LIO_LIThere are limited studies investigating the effect of persuasive messages in influencing decisions to recommend the COVID-19 vaccine, with only a single study to date which investigated effects directed at recommending the COVID-19 vaccine to a friend, but without considering the individuals health and age profile.
C_LI

2. What are the new findings?O_LIPersuasive messages that focused on vaccine safety did not positively influence Malaysian adults to take the COVID-19 vaccine or recommend it to healthy adults and the elderly, while messages framed as descriptive norms, negative attribute, and risky choices, significantly backfired for some of these outcomes.
C_LIO_LISeveral persuasive messages focusing on vaccine safety significantly improved intent to recommend the COVID-19 vaccine to people with pre-existing health conditions.
C_LI

3. What do the new findings imply?O_LIInstead of only addressing safety, persuasive messages aimed at nudging vaccination should incorporate multiple behavioral determinants linked to vaccine acceptance.
C_LIO_LIPersuasive messages that are intended to promote uptake of novel health interventions should incorporate safety dimensions as a form of assurance for others to recommend it to people with pre-existing health conditions, given that they may be perceived as more susceptible to hazards from adverse events.
C_LI

category: public and global health


title: Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada

abstract:
BackgroundAs of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine [≥]84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant.

MethodsWe used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged [≥]60 years who were tested for SARS-CoV-2 between December 30, 2021 and March 2, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death).

ResultsWe included 9,957 Omicron cases and 46,849 test-negative controls. The marginal effectiveness of a fourth dose [≥]7 days after vaccination versus a third dose received [≥]84 days prior was 40% (95% Confidence Interval[CI], 34-45%) against infection, 63% (95%CI, 51-71%) against symptomatic infection, and 54% (95%CI, 31-70%) against severe outcomes. VE (compared to an unvaccinated group) increased with each additional dose, and for a fourth dose was 65% (95%CI, 60-70%), 87% (95%CI, 81-91%), and 92% (95%CI, 87-95%), against infection, symptomatic infection, and severe outcomes, respectively.

ConclusionsOur findings suggest that compared to a third dose received [≥]84 days ago, a fourth dose recommendation for LTC residents improved protection against infection, symptomatic infection, and severe outcomes caused by Omicron. Compared to unvaccinated individuals, fourth doses provide strong protection against symptomatic infection and severe outcomes but the duration of protection remains unknown.


title: A Model to Predict In-hospital Mortality in Elderly Patients with Community-acquired Pneumonia: a Retrospective Study

abstract:
ObjectivesTo develop and validate a predictive model for evaluating in-hospital mortality risk in elderly patients with community-acquired pneumonia.

SettingTwo tertiary care hospitals with 2000 beds and 1000 beds respectively in Beijing, China.

ParticipantsElderly patients (age [≥] 65 years) with community-acquired pneumonia admitted to the Department of Internal Medicine of the two hospitals from January 2010 to December 2019 or from January 2019 to December 2019 respectively.

DesignIt was a retrospective study. After dividing the data set into training and validation sets, we created a mortality model that included patient demographics, hospitalization time, hospital outcome, and various clinical conditions associated with hospitalization. We then applied the model to the validation set.

Main outcome measuresIn-hospital mortality.

ResultsThe training cohort included 2,466 patients admitted to the one hospital, while the validation cohort included 424 patients at the other hospital. The overall in-hospital mortality rate was 15.6%. In the multivariable model, age, respiratory failure, heart failure, and malignant tumors were associated with mortality. The model had excellent discrimination with AUC values of 0.877 and 0.930 in the training and validation cohorts, respectively.

ConclusionsThe predictive model to evaluate in-hospital mortality in elderly patients with community-acquired pneumonia, which was established based on administrative data, provides a simple tool for physicians to assess the prognosis of elderly patients with community-acquired pneumonia in Beijing.

Strengths and limitations of this studyO_LIThe clinical data collected were obtained from a large retrospective cohort over a 10-year period, resulting in good reliability.
C_LIO_LIThe model based on administrative data can help healthcare workers determine the prognosis and outcomes of elderly patients of CAP, especially in resource limited regions in China.
C_LIO_LIOur main outcome was in-hospital mortality, not 30-day mortality or longer.
C_LIO_LIAll included cases were collected from inpatient, outpatient and emergency patients were not included.
C_LIO_LIThe model was only verified in two hospitals in Beijing and further verification should be conducted in other areas and different levels of hospitals.
C_LI

category: respiratory medicine


title: Acute kidney injury in patients with non-valvular atrial fibrillation treated with rivaroxaban or warfarin: a population-based study from the United Kingdom

abstract: Acute kidney injury (AKI) has been associated with use of oral anticoagulants (OACs) in patients with non-valvular atrial fibrillation (NVAF). We aimed to compare AKI risk among users of rivaroxaban vs. warfarin. We identified two cohorts of NVAF patients who initiated rivaroxaban (15/20 mg/day, N=6436) or warfarin (N=7129) excluding those without estimated glomerular filtration rate values recorded in the year before OAC initiation and those with a history of end-stage renal disease or AKI. We used two methods to define AKI during follow-up (mean 2.5 years): coded entries (method A), and the Aberdeen AKI phenotyping algorithm (method B), using recorded renal function laboratory values during the study period to identify a sudden renal deterioration event. Cox regression was used to calculate hazard ratios (HRs) for AKI with rivaroxaban vs. warfarin use, adjusted for confounders. The number of identified incident AKI cases was 249 (method) A and 723 (method B). Of the latter, 104 (14.4%) were also identified by method A. After adjusting for age, sex, baseline renal function and comorbidity, HRs (95% CIs) for AKI were 1.20 (0.93-1.55; p=0.16) using method A, and 0.80 (0.68-0.93; p<0.01) using method B. Estimates stratified by baseline level of chronic kidney disease were largely consistent with the main estimates. In conclusion, our results support a beneficial effect of rivaroxaban over warfarin in terms of AKI occurrence in patients with NVAF. More research into how best to define AKI using primary care records would be valuable for future studies.

category: nephrology


title: Interplay between mosaic chromosomal alterations and polygenic risk score increases risk of non-small cell lung cancer

abstract: We investigated autosomal mosaic chromosomal alterations (mCAs) in 10,248 non-small cell lung cancer (NSCLC) cases and 9,298 cancer-free controls of Chinese ancestry. Mosaic loss and copy-neutral loss of heterozygosity were associated with an increased risk of NSCLC, while mosaic gain was associated with a decreased risk of NSCLC, especially those spanning telomeres. The increased cell fraction of mCAs was also correlated with an increasing NSCLC risk in the affected individuals. Both multiplicative and additive interactions were observed between polygenic risk score (PRS) and the presence of mosaic loss, where carriers of mosaic loss events with cell fractions [≥]5% among the high genetic risk group had the greatest risk for developing NSCLC. These findings suggest that mCA events may act as a new endogenous indicator for risk of NSCLC and have the potential to be jointly used with PRS to optimize risk stratification of NSCLC.


title: Clonal diversity determines persistence of SARS-CoV-2 epitope-specific T cell response

abstract: T cells play a pivotal role in reducing disease severity during SARS-CoV-2 infection and formation of long-term immune memory. We studied 50 COVID-19 convalescent patients and found that T cell response was induced more frequently and persisted longer than circulating antibodies. To identify epitopes that give rise to long-lived T cell memory, we performed ex vivo T cell expansion, MHC-tetramer cell-sorting, and high-throughput sequencing. We identified 756 clonotypes specific to nine known CD8+ T cell receptor (TCR) epitopes. Some epitopes were recognized by highly similar public clonotypes with restricted variable and joining segment usage. Receptors for other epitopes were extremely diverse, suggesting alternative modes of recognition. We also tracked persistence of epitope-specific response and individual clonotypes for a median of eight months after infection. The number of recognized epitopes per patient and quantity of epitope-specific clonotypes decreased over time, but the studied epitopes were characterized by uneven decline in the number of specific T cells. Epitopes with more clonally diverse TCR repertoires induced more pronounced and durable responses. In contrast, the abundance of specific clonotypes in peripheral circulation had no influence on their persistence. Our study demonstrates the durability of SARS-CoV-2-specific CD8+ memory, and offers important implications for vaccine design.


title: Why were Twitter Users Obsessed with Vitamin D during the first year of the pandemic?

abstract: The aim of this study was to explore how the relationship between vitamin D and COVID-19 has been represented on the social media site Twitter. NCapture was used to collect textual Tweets on a weekly basis for three months during the pandemic. In total, 21,140 Tweets containing the keywords "vitamin D" and "COVID" were collected and imported to NVivo12. An inductive thematic analysis was carried out on the Tweets collected on the first (12/2/2021) and last week (21/5/2021) of the recording period to identify themes and subthemes. Quality control of the coding was conducted on a sample of the dataset (20%). Data were also compared to the "ground truth" to explore the accuracy of media outputs. The four main themes identified were "association of vitamin D with COVID-19", "politically informed views", "vitamin D deficiency" and "vitamin D sources". When compared to the ground truth, the majority of information relating to the key findings was  incorrect for all of the findings. This study contributes to the area of research by highlighting the extent of the issue social media sites face with health-related misinformation. In the context of COVID-19, it is important that sites such as Twitter improve their existing misinformation policies, as misinformation can be detrimental in disease prevention.

category: nutrition


title: A year in the public life of COVID-19 and Vitamin D: Representation in UK news media and implications for health communications.

abstract:
ObjectivesTo investigate how the relationship between vitamin D and COVID-19 has been presented in traditional media sources (UK newspapers) and assess the level of misinformation associated with this issue by comparing newspaper article content to the evidence-based guidelines.

DesignQualitative study

SettingData were collected over the first year of the pandemic (February 2019-20), from the five most widely read UK based newspapers by searching the Nexis database using keywords "vitamin D" and "COVID". An inductive thematic analysis was carried out on the data to identify themes and subthemes. Quality control of the coding was conducted on a sample of the dataset (20%). Data were also compared to the "ground truth" identified as the NICE report titled "COVID-19 rapid guideline: vitamin D" to explore the accuracy of media outputs.

ResultsThe four main themes identified were  association of vitamin D with COVID-19,  politically informed views,  vitamin D deficiency and  vitamin D sources. When compared to the ground truth, most of the information from newspaper articles relating to the key findings was  correct for each of the findings, except for COVID-19 infection.

ConclusionsAlthough most of the information included in newspaper articles concerning the relationship of vitamin D with COVID-19 was  correct, this study highlighted that there was still a notable amount of  incorrect information published. In the context of COVID-19, it is imperative that media outputs are accurate and inform the public and front-line health professionals as correct information is a key factor in disease prevention. Future research should focus on the accuracy of media outputs to further investigate health misinformation as an issue in traditional media and how that may affect public health. Attempts should be made to improve journalistic integrity through more rigorous and standardised regulations enforced across all media outlets so that public knowledge on current events is based on evidence rather than conjecture.

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title: Life-course exposure to air pollution and biological ageing in the Lothian Birth Cohort 1936

abstract:
BackgroundExposure to ambient air pollution is associated with a range of diseases. Biomarkers derived from DNA methylation (DNAm) indicate a potential pathway to human health differences, connecting disease pathogenesis and biological ageing. However, little is known about sensitive periods during the life course where air pollution might have a stronger impact on DNAm, or whether effects accumulate over time.

ObjectivesWe examined associations between air pollution exposure across the life course and DNAm-based biomarkers of ageing.

MethodsData were derived from the Lothian Birth Cohort 1936. Participants residential history was linked to annual levels of PM2.5, SO2, NO2, and O3 around 1935, 1950, 1970, 1980, 1990, and 2001; pollutant concentrations were estimated using the EMEP4UK atmospheric chemistry transport model. Blood samples were obtained between ages of 70 and 80 years, and Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, DNAmGrimAge, and DNAm telomere length (DNAmTL) were computed. We applied the structured life-course modelling approach: least angle regression identified best-fit life-course models for a composite measure of air pollution (air quality index [AQI]), and mixed-effects regression estimated selected models for AQI and single pollutants.

ResultsWe included 525 individuals with 1782 observations. In the total sample, increased air pollution around 1970 was associated with higher epigenetic age (AQI: b=0.622 year, 95%CI: 0.151, 1.094) measured with Horvath DNAmAge in late adulthood. We found shorter DNAmTL among males with higher air pollution around 1980 (AQI: b=-0.035 kilobase, 95%CI: -0.057, -0.014) and among females with higher exposure around 1935 (AQI: b=-0.036 kilobase, 95%CI: -0.059, -0.013). Findings passed false discovery rate correction for DNAmTL, and were more consistent for the pollutants PM2.5, SO2 and NO2.

DiscussionWe tested the life-course relationship between air pollution and DNAm-based biomarkers. Air pollution in utero and in young-to-mid adulthood is linked to accelerated epigenetic ageing and telomere-associated ageing in later life.

category: occupational and environmental health


title: Effect of SARS-CoV-2 digital droplet RT-PCR assay sensitivity on COVID-19 wastewater based epidemiology

abstract:
We developed and implemented a framework for examining how molecular assay sensitivity for a viral RNA genome target affects its utility for wastewater-based epidemiology. We applied this framework to digital droplet RT-PCR measurements of SARS-CoV-2 and Pepper Mild Mottle Virus genes made using 10 replicate wells, and determined how using fewer wells affected assay sensitivity and its performance for wastewater-based epidemiology applications. We used a computational, downsampling approach. When percent of positive droplets was between 0.024% and 0.5% (as was the case for SARS-CoV-2 genes during the Delta surge), measurements obtained with 3 or more wells were similar to those obtained using 10. When percent of positive droplets was less than 0.024%, then 6 or more wells were needed to obtain similar results as those obtained using 10 wells. When COVID-19 incidence is low, as it was before the Delta surge and SARS-CoV-2 gene concentrations are <104 cp/g, using 6 wells will yield a detectable concentration 90% of the time. Overall, results support an adaptive approach where assay sensitivity is increased by running 6 or more wells during periods of low SARS-CoV-2 gene concentrations, and 3 or more wells during periods of high SARS-CoV-2 gene concentrations.

SynopsisAdaptive approaches developed with assay sensitivity in consideration may reduce cost and increase sensitivity for wastewater-based epidemiology.

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category: infectious diseases


title: Household transmission of SARS-CoV-2 from adult index cases living with and without HIV in South Africa, 2020-2021: a case-ascertained, prospective observational household transmission study

abstract:
BackgroundIn South Africa 19% of the adult population aged 15-49 years are living with HIV (LWH). Few data on the influence of HIV on SARS-CoV-2 household transmission are available.

MethodsWe performed a case-ascertained, prospective household transmission study of symptomatic index SARS-CoV-2 cases LWH and HIV-uninfected adults and their contacts in South Africa. Households were followed up thrice weekly for 6 weeks to collect nasal swabs for SARS-CoV-2 testing. We estimated household cumulative infection risk (HCIR), duration of SARS-CoV-2 positivity (at cycle threshold value<30 as proxy for high viral load), and assessed associated factors.

ResultsWe recruited 131 index cases and 457 household contacts. HCIR was 59% (220/373); not differing by index HIV status (60% [50/83] in cases LWH vs 58% [173/293] in HIV-uninfected cases, OR 1.0, 95%CI 0.4-2.3). HCIR increased with index case age (35-59 years: aOR 3.4 95%CI 1.5-7.8 and [≥]60 years: aOR 3.1, 95%CI 1.0-10.1) compared to 18-34 years, and contacts age, 13-17 years (aOR 7.1, 95%CI 1.5-33.9) and 18-34 years (aOR 4.4, 95%CI 1.0-18.4) compared to <5 years. Mean positivity duration at high viral load was 7 days (range 2-28), with longer positivity in cases LWH (aHR 0.3, 95%CI 0.1-0.7).

ConclusionsHIV-infection was not associated with higher HCIR, but cases LWH had longer positivity duration at high viral load. Adults aged >35 years were more likely to transmit, and individuals aged 13-34 to acquire SARS-CoV-2 in the household. Health services must maintain HIV testing with initiation of antiretroviral therapy for those HIV-infected.

SummaryIn this case-ascertained, prospective household transmission study, household cumulative infection risk was 59% from symptomatic SARS-CoV-2 index cases, not differing based on index HIV status. Index cases living with HIV were positive for SARS-CoV-2 for longer at higher viral loads.


title: Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: a retrospective cohort study

abstract:
BackgroundDe novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI).

MethodsThis study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI who underwent patient-parent trio-based WES.

ResultsA likely molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Exome-wide evaluation of rare, non-synonymous DNVs affecting coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were identified in IEI genes (NLRP3 and RELA) and potentially novel candidate genes, including PSMB10, DDX1, KMT2C and FBXW11. The FBXW11 canonical splice site DNV, in a patient with autoinflammatory disease, was shown to lead to defective RNA splicing, increased NF-{kappa}B p65 signalling, and elevated IL-1{beta} production in primary immune cells.

ConclusionsThis retrospective cohort study advocates the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we have provided functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease.

FundingThis research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.


title: Three-dose mRNA-1273 vaccination schedule: sufficient antibody response in majority of immunocompromised hematology patients

abstract:
ImportanceIn patients with hematologic malignancies, the immunogenicity of the standard 2-dose mRNA-1273 coronavirus disease 19 (COVID-19) vaccination schedule is often insufficient due to underlying disease and current or recent therapy.

ObjectiveTo determine whether a 3rd mRNA-1273 vaccination raises antibody concentrations in immunocompromised hematology patients to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule.

DesignProspective observational cohort study.

SettingFour academic hospitals in the Netherlands.

Participants584 evaluable immunocompromised hematology patients, all grouped in predefined cohorts spanning the spectrum of hematologic malignancies.

ExposureOne additional vaccination with mRNA-1273 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule.

Main Outcomes and MeasuresSerum IgG antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after each vaccination, and pseudovirus neutralization of wildtype, delta and omicron variants in a subgroup of patients.

ResultsIn immunocompromised hematology patients, a 3rd mRNA-1273 vaccination led to median S1 IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1 IgG concentration after the 3rd vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid malignancies or multiple myeloma, and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1 IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients on or shortly after rituximab therapy, CD19-directed chimeric antigen receptor T cell therapy recipients, and chronic lymphocytic leukemia patients on ibrutinib were less or unresponsive to the 3rd vaccination. In the 27 patients who received cell therapy between the 2nd and 3rd vaccination, S1 antibodies were preserved, but a 3rd mRNA-1273 vaccination did not significantly enhance S1 IgG concentrations except for multiple myeloma patients receiving autologous HCT. A 3rd vaccination significantly improved neutralization capacity per antibody.

Conclusions and RelevanceThe primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation.

Trial RegistrationEudraCT 2021-001072-41

Key pointsO_ST_ABSQuestionC_ST_ABSCan a 3rd mRNA-1273 vaccination improve COVID-19 antibody concentrations in immunocompromised hematology patients to levels similar to healthy adults after the standard 2-dose mRNA-1273 schedule?

FindingsIn this prospective observational cohort study that included 584 immunocompromised hematology patients, a 3rd mRNA-1273 vaccination significantly improved SARS-CoV-2 antibody concentrations to levels not significantly different from those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Pseudovirus neutralization capacity per antibody of wild type virus and variants of concern also significantly improved.

MeaningThe primary COVID-19 vaccination schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination.


title: Urinary tract infections in children: building a causal model-based decision support tool for diagnosis with domain knowledge and prospective data

abstract:
BackgroundDiagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support.

MethodsWe prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods.

ResultsWe summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting E.coli culture results, with a mean AUROC of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios.

ConclusionCausal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.


title: Permissive Omicron breakthrough infections in individuals with binding or neutralizing antibodies to ancestral SARS-CoV-2

abstract:
BackgroundBreakthrough infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) has occurred in populations with high vaccination rates. These infections are due to sequence variation in the spike protein leading to a reduction in protection afforded by the current vaccines, which are based on the original Wuhan-Hu-1 strain, or by natural infection with pre-Omicron strains.

MethodsIn a longitudinal cohort study, pre-breakthrough infection sera for Omicron breakthroughs (n=12) were analyzed. Assays utilized include a laboratory-developed solid phase binding assay to recombinant spike protein, a commercial assay to the S1 domain of the spike protein calibrated to the World Health Organization (WHO) standard, and a commercial solid-phase surrogate neutralizing activity (SNA) assay. All assays employed spike protein preparations based on sequences from the Wuhan-Hu-1 strain. Participant demographics and clinical characteristics were captured.

ResultsPre-breakthrough binding antibody (bAB) titers ranged from 1:800-1:51,200 for the laboratory-developed binding assay, which correlated well and agreed quantitatively with the commercial spike S1 domain WHO calibrated assay. SNA was detected in 10/12 (83%) samples.

ConclusionsNeither high bAB nor SNA were markers of protection from Omicron infection/re-infection. Laboratory tests with antigen targets based on Wuhan-Hu-1 may not accurately reflect the degree of immune protection from variants with significant spike protein differences. Omicron breakthrough infections are likely due to high sequence variation of the spike protein and reflect incomplete immune protection from previous infection with strains that preceded Omicron or with vaccinations based on the original Wuhan-Hu-1 strain.


title: Safety and feasibility of an FES-Cycling based neuromuscular evaluation method in mechanically ventilated patients

abstract:
PurposeFES-Cycling can be used to assess neuromuscular performance, however the safety and feasibility of this evaluation method has never been investigated.

Materials and methodsan observational prospective study was carried out. The FES-Cycling equipment was set in the evaluation mode. For safety determination, hemodynamic parameters and peripheral oxygen saturation were measured before and immediately after the evaluation protocol, as well as venous oxygen saturation and blood lactate. The creatine phosphokinase level (CPK) was measured before and 24, 48 and 72 hours after the test. The time spent to carry out the entire evaluation protocol and the number of patients with visible muscle contraction were recorded to assess feasibility.

ResultsHeart rate, systolic and diastolic blood pressure did not change after protocol evaluation, as well as peripheral and venous oxygen saturation (p > 0.05). Moreover, blood lactate did not change (p > 0.05). CPK did not change up to 72 hours after the test (p > 0.05). The time for evaluation was 11.3 (SD = 1.1) minutes. Furthermore, 75% of the patients presented very visible muscle contraction, 25% of the patients presented barely visible and no patients presented non-visible muscle contraction.

ConclusionsFES-Cycling based neuromuscular evaluation method is safe and feasible.

category: intensive care and critical care medicine


title: Re-contacting biobank participants: lessons from a pilot study within FinnGen

abstract:
BackgroundBiobank studies are well suited to identify novel disease risk factors. However, these studies often offer limited insights into participants lifestyle, behavioral, or cognitive characteristics, among others. FinnGen is a nation-wide biobank project in Finland and one of the largest in the world that has successfully linked genetic and register-based information for 259,578 individuals (N=500,000 by 2023); however, it lacks cognitive, behavioral, and lifestyle measurements.

MethodsWe conducted a pilot study to evaluate the feasibility of obtaining cognitive, behavioral, and lifestyle information by re-contacting 5,995 participants from three FinnGen-participating Biobanks. We created an online portal to allow participants to securely log-in, provide consent, and access the study survey tools.

ResultsThe overall participation rate was 18.6% (23.1% among individuals aged 18-69). A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Re-contacting participants via an online healthcare portal yielded lower participation than re-contacting via physical letter. The completion rate of questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92.

ConclusionsIn summary, this pilot suggests that re-contacting FinnGen participants with the goal to collect a wide range of cognitive, behavioral and lifestyle information without additional engagement, results in a low participation rate, but with reliable data. We suggest that such information be collected at enrollment, if possible, rather than via post-hoc re-contacting.