title: No impact of sex on surgical site infections in abdominal surgery: A multi-center study

abstract:
ObjectiveMale sex is controversially discussed as a risk factor for surgical site infections (SSI). The aim of the present study was to evaluate the impact of sex on SSI in abdominal surgery under elimination of relevant confounders.

MethodsClinicopathological data of 6603 patients undergoing abdominal surgery from a multi-center prospective database of four Swiss hospitals including patients between 2015 and 2018 were assessed. Patients were stratified according to postoperative SSI and risk factors for SSI were assessed using univariate and multivariate analysis.

ResultsIn 649 of 6603 patients SSI was reported (9.8%). SSI was significantly associated with reoperation (22.7% vs. 3.4%, p <0.001), higher mortality rate (4.6% vs. 0.9%, p <0.001) and higher rate of length of hospital stay over the 75th percentile (57.0 % vs. 17.9 %, p <0.001). In univariate analysis male sex was a significant risk factor for SSI (p = 0.01). In multivariate analysis including multiple confounders   such as comorbidities and perioperative factors there was no association between male sex and risk of SSI (odds ratio (OR) 1.1 [CI 0.8 - 1.4]). Independent risk factors for SSI in multivariate analysis were BMI [≥] 30 kg/m2 (OR 1.8 [CI 1.3 - 2.3]), duration of surgery > 75th percentile (OR 2.3 [1.8 - 2.9]), high contamination level (OR 1.3 [1.0 - 1.6]), laparotomy (OR 1.3 [1.0 - 1.7]), pervious laparotomy (OR 1.4 [1.1 - 1.7]), blood transfusion (OR 1.7 [1.2 - 2.4]), cancer (OR 1.3 [1.0-1.8], malnutrition (OR 2.5 [1.8 - 3.4]).

ConclusionUnder elimination of relevant confounders there is no significant correlation between sex and risk of SSI after abdominal surgery.

category: surgery


title: Efficacy of bladder training in adults with overactive bladder: A systematic review protocol

abstract:
IntroductionThe aim of this systematic review will be to investigate and update whether bladder training can promote improvement of symptoms of overactive bladder syndrome with or without urgency urinary incontinence in adults.

MethodsWe will perform a systematic review according to the Cochrane methodology of randomized controlled trials. An overall search strategy will be developed and adapted for each database. A bibliographic search will be conducted in eight databases - PubMed, PEDro, SciELO, LILACS, Cochrane Library, Web of Science, EMBASE, CINAHL, by manual searching. The MeSH terms will be "Bladder Training", "Bladder Drill", "Bladder Re-education", "Bladder Retraining", "Bladder Discipline", "Overactive Bladder", "Bladder, Overactive", "Overactive Urinary Bladder", "Urinary Bladder", "Overactive, Urinary Bladder", "Bladder, Urinary", "Urinary Bladder Disease", "Bladder Disease", "Bladder Detrusor Muscle" and "Detrusor Muscle, Bladder". Meta-analysis, if plausible, will be performed by the software Review Manager 5.4. Primary outcomes: symptoms of overactive bladder syndrome (urinary urgency with daytime voiding frequency, nocturia with or without urgency urinary incontinence), and cure/improvement assessed by instruments. Secondary outcomes: quality of life, functional assessment, validated scale/questionnaire and adverse events. Quality assessment will be performed by Cochrane instrument and quality of evidence will be assessed by GRADE.

DiscussionThis study is a review of randomized controlled studies to analyze the efficacy of bladder training in improving the symptoms of adults with overactive bladder syndrome. The study design of randomized controlled trials for a higher level of scientific evidence was chosen. The aim is to obtain results that allow further studies and evidence that this intervention generates beneficial effects in the sample studied.

Trial registration

Systematic review registrationPROSPERO CRD42022301522.

category: urology


title: Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and signs of neurodegeneration: a prospective cross-sectional study

abstract:
ImportanceGrowing evidence suggests that coronavirus disease 2019 (COVID-19) is associated with neurological sequelae. However, the underlying pathophysiological mechanisms resulting in central nervous system (CNS) derogation remain unclear.

ObjectiveTo identify severity-dependent immune mechanisms in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and their association with brain imaging alterations.

DesignProspective cross-sectional cohort study.

SettingThis study was performed from August 2020 to April 2021. Participants were enrolled in the outpatient clinics, hospital wards and intensive care units (ICU) of two clinical sites in Basel and Zurich, Switzerland.

ParticipantsAge >18 years and a positive SARS-CoV-2 test result were inclusion criteria. Potentially matching individuals were identified (n=310), of which 269 declined to participate and 1 did not match inclusion criteria. Paired CSF and plasma samples, as well as brain images, were acquired. The COVID-19 cohort (n=40; mean [SD] age, 54 [20] years; 17 women (42%)) was prospectively assorted by neurological symptom severity (classes I, II and III). Age/sex-matched inflammatory (n=25) and healthy (n=25) CSF and plasma control samples were obtained. For volumetric brain analysis, a healthy age/sex-matched control cohort (n=36) was established.

ExposuresLumbar puncture, blood sampling and cranial MRI and/or CT.

Main outcomes and measuresProteomics, standard parameters and antibody profiling of paired CSF and plasma samples in COVID-19 patients and controls. Brain imaging and gray matter volumetric analysis in association with biomarker profiles. Follow-up after 10-months.

ResultsCOVID-19 patients displayed a plasma cytokine storm but a non-inflammatory CSF profile. Class III patients displayed signs of blood-brain barrier (BBB) impairment and a polyclonal B cell response targeting self- and non-self antigens. Decreased regional brain volumes were present in COVID-19 patients and associated with specific CSF and plasma parameters.

Conclusion and relevanceNeuro-COVID class III patients had a strong, peripheral immune response resulting in (1) BBB impairment (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Our data point towards several potentially actionable targets that may be addressed to prevent COVID-19-related neurological sequelae.

Trial registrationThe trial (NCT04472013) was registered on clinicaltrials.gov.

Key pointsO_ST_ABSQuestionC_ST_ABSDoes a severity-dependent pattern of immune mechanisms exist in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and are these associated with clinical and brain imaging findings?

FindingsNeuro-COVID patients display a robust class III-specific peripheral immune response resulting in (1) blood-brain barrier (BBB) impairment, (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Integration of MRIs, brain volumetry and proteomics identified biomarkers associated with regional brain volume loss in severe Neuro-COVID.

MeaningWe provide a multidimensional framework of mechanisms associated with severe Neuro-COVID and present possible targets to prevent COVID-19-related neurological sequelae.

category: neurology


title: Impact and cost-effectiveness of frequent HIV re-testing among key populations in Viet Nam: a modeling study

abstract:
BackgroundHIV testing and counseling is a key component of HIV prevention and the entry point into the treatment cascade, which improves for individual clinical outcomes and reduces onward HIV transmission. Current guidelines recommend at least annual testing for key populations. More frequent testing could provide health benefits, but these additional services increase the program the cost-effectiveness is not well-evaluated.

MethodsWe used a compartmental mathematical model to simulate the health and economic impact of HIV testing one to four times per year for men who have sex with men, people who inject drugs, and female sex workers in Viet Nam. Model outcomes included costs, HIV infections, HIV-related deaths, and disability-adjusted life years (DALYs) associated with each scenario. We used an opportunity cost-based cost-effectiveness threshold of US $2,255 per DALY averted, discounted costs and health benefits at 3% annually, and used a time horizon from 2021 to 2030 to calculate incremental cost-effectiveness ratios (ICERs).

ResultsCompared to the baseline scenario, more frequent HIV testing was estimated to incrementally avert 10.2%, 5.2%, 3.0%, and 1.6% discounted infections for one-, two-, three-, and four-tests per year, respectively. ICERs associated with each scenario ranged from $464, $1,190, $1,762, and $2,727 per DALY averted for one-, two-, three-, and four-tests per year, respectively.

ConclusionsIncreased HIV testing frequency for key populations was projected to avert HIV incidence, mortality, and disability in Viet Nam and was cost-effective. Settings with a similar context should consider strategies on how to optimize retesting among key populations.

category: hiv aids


title: Treatment Outline and Clinical Outcome of Hospitalized COVID-19 Patients: Experiences from a Combined Military Hospital of Bangladesh

abstract:
BackgroundGlobal knowledge of treatment and outcomes of COVID-19 has been evolving since the onset of the pandemic.

Materials and MethodsThe objective of this cross-sectional study was to explore treatment and outcome of COVID-19 patients admitted in a Combined Military Hospital of Bangladesh. Data were collected from treatment records of patients of the CMH Bogura during the period of June 2020 to August 2020. Total 219 RT-PCR positive admitted patients were included as study population.

ResultAmong 219 patients, 78.6% were male and 21.5% were female, mean age of patients was 34.3 {+/-} 12.2. About14.6% patients had one or more comorbidities. Most (83.1%) of the admitted patients were diagnosed as mild cases. Antimicrobials were used in 98.8% cases, and frequent use of doxycycline (80.4%) and ivermectine (77.2%) was found. Anticoagulant and steroid therapy were used in 42.0% and 15.5% patients respectively. O2 therapy was required in 6.0% cases and intensive care unit (ICU) support was needed in 2.3% cases.Duration of hospital stay was 12.1{+/-} 4.4 days and 100% of patients were discharged from hospital. There was no single mortality during the study period.

ConclusionHigh prevalence of antimicrobials use was observed among the hospitalized COVID-19 patients in this single center study.Supportive care was effective with no incidence of mortality.

category: infectious diseases


title: Impact of Delta and Vaccination on SARS-CoV-2 transmission risk: Lessons for Emerging Breakthrough infections

abstract: With the continuous emergence of SARS-CoV-2 variants of concern and implementation of mass-scale interventions like vaccination, understanding factors affecting disease transmission has critical implications for control efforts. Here we used a simple adapted N95 mask sampling method to demonstrate the impact of circulating SARS-CoV-2 variants and vaccination on 92 COVID-19 patients to expel virus into the air translating to a transmission risk. Between July and September 2021, when the Delta was the dominant circulating strain in Mumbai, we noted a two-fold increase in the proportion of people expelling virus (95%), about an eighty-fold increase in median viral load and a three-fold increase in high emitter type (41%; people expelling >1000 viral copy numbers in 30 minutes) compared to initial strains of 2020. Eight percent of these patients continued to be high emitters even after eight days of symptom onset, suggesting a probable increased transmission risk for Delta strain even at this stage. There was no significant difference in expelling pattern between partial, full and un-vaccinated individuals suggesting similar transmission risk. We noted significantly more infections among vaccinated study patients and their household members than unvaccinated, probably due to increased duration from vaccination and/or increased risk behaviour upon vaccination due to lower perceived threat. This study provides biological evidence for possible continued transmission of the Delta strain even with vaccination, emphasizing the need to continue COVID-19 appropriate behaviour. The study also indicates that the mask method may be useful for screening future vaccine candidates, therapeutics or interventions for their ability to block transmission.


title: Comparison of the reactogenicity and immunogenicity of a reduced and standard booster dose of the mRNA COVID-19 vaccine in healthy adults after two doses of inactivated vaccine.

abstract:
The coronavirus disease 2019 (COVID-19) pandemic has been a serious healthcare problem worldwide since December 2019. The third dose of heterologous vaccine was recently approved by World Health Organization. The present study compared the reactogenicity and immunogenicity of the reduced and standard third booster dose of the BNT162b2 and mRNA-1273 vaccine in adults who previously received the two-dose CoronaVac vaccine. Results showed that headache, joint pain, and diarrhea were more frequent in the 15 g-than the 30 g-BNT162b2 groups, whereas joint pain and chilling were more frequent in the 100 g-than the 50 g-mRNA-1273 groups. No significant differences in immunogenicity were detected. These findings demonstrate that the reduced dose of the mRNA vaccines elicited antibody responses against the SARS-CoV-2 delta and omicron variants that were comparable to the standard dose. The reduced dose could be used to increase vaccine coverage in situations of limited global vaccine supply.

HighlightsO_LIThe 15 g- and 30 g-BNT162b2, and 50 g- and 100 g-mRNA-1273 booster doses were compared
C_LIO_LIBooster vaccination with the mRNA vaccine elicits high Ig and IgG anti-RBD in CoronaVac-vaccinated adults
C_LIO_LINo differences were observed in antibody responses after the reduced or standard booster dose of the mRNA vaccine in CoronaVac-vaccinated adults
C_LIO_LINeutralizing antibodies against the delta and omicron variants were significantly higher after the booster dose
C_LIO_LINeutralizing antibody titers were lower against the omicron variant than the delta variant in all vaccinated adults
C_LI

category: allergy and immunology


title: When Diagnosis Is Made By Playing Shuffled Cards: A Non-Invasive, Real-Time, Adaptive Method to Functionally Evaluate Coronary Artery Based on Coronary Angiography

abstract:
AimsThe great value concealed in the sequence of coronary angiography frames is not discovered in the world. We discovered and demonstrated the "Sequence Value" concealed in the coronary angiography and proposed DZL (Disarranged Zone Learning) to realize the sequence value in functional evaluation of coronary artery disease. Furthermore, we automated the DZL using a deep learning model to release huge medical resources.

Methods and ResultsWe gave a novel definition of TIMI flow grade using the term temporal and spatial coupling tightness (TSCT) of the antegrade contrast agent. We used the TSCT to model the myocardial ischemia in a functional perspective and used the PCI conduction after CAG as the outcome event of myocardial ischemia. We proposed a novel method (Disarranged Zone Learning) to measure TSCT and we designed an experiment to validate its effectiveness. We further automated the novel method using an unsupervised deep learning model. The prediction accuracy of the model was applied as a proxy of myocardial ischemia. We further proposed Difference DZL to quantify the functional capability of any specific vessel segment. DZL overall AUC reaches 0.92. DZL automation reveals an AUC of 0.84 (95%CI, 0.81-0.87).

ConclusionWe unprecedentedly discovered the "Sequence Value" concealed in coronary angiography. We then proposed a novel method termed DZL to functionally evaluate the coronary artery in a non-invasive, real-time and adaptive manner.

DisclosureThe Authors declare that there is no conflict of interest.

category: cardiovascular medicine


title: Non-occupational physical activity and risk of 22 cardiovascular disease, cancer, and mortality outcomes: a dose-response meta-analysis of large prospective studies

abstract:
ObjectiveTo estimate dose-response associations between non-occupational physical activity and multiple chronic disease outcomes in the general adult population.

Eligibility criteriaProspective cohort studies with (a) general population samples >10,000 adults, (b) [≥]3 exposure categories, and (c) risk measures and confidence intervals for all-cause mortality, total cardiovascular disease, coronary heart disease, stroke, heart failure, total cancer, and site-specific cancers (head and neck, myeloid leukemia, myeloma, gastric cardia, lung, liver, endometrium, colon, breast, bladder, rectum, esophagus, prostate, kidney).

Information sourcesPubMed, Scopus, Web of Science, and reference lists of published studies, searched in February 2019.

Data extraction and synthesisIndependent extraction and double-checking of study characteristics, exposure, and outcome assessment by two reviewers for each paper. Primary exposure was non-occupational physical activity volume, harmonized to physical activity energy expenditure in marginal MET-hours per week (mMET-h/week). The current minimum recommendations for physical activity (150 min/week of moderate-to-vigorous physical activity) equate to 8.75 mMET-h/week. Outcomes were risks of mortality, cardiovascular diseases, and cancers. We used restricted cubic splines in random-effects meta-analyses. Potential population impact was quantified using impact fractions.

Results196 articles were included, covering 94 cohorts. The evidence base was largest for all-cause mortality (50 independent results; 163,415,543 person-years; 811,616 events), and incidence of cardiovascular disease (37 independent results; 28,884,209 person-years; 74,757 events) and cancer (31 independent results; 35,500,867 person-years; 185,870 events). In general, inverse non-linear associations were observed, steeper between 0 and 8.75 mMET-h/week, with smaller marginal reductions in risk above this level to 17.5 mMET-h/week, beyond which additional reductions were small and uncertain. Associations were stronger for all-cause and cardiovascular disease mortality than for cancer mortality. If all insufficiently active individuals had met the recommended physical activity level, 15.7% (95%CI: 13.1 to 18.2%) of all premature deaths would have been averted.

ConclusionsInverse non-linear dose-response associations suggest substantial protection against a range of chronic disease outcomes from small increases in non-occupational physical activity in inactive adults.

Review registrationPROSPERO CRD42018095481.

category: epidemiology


title: Persisting decreases in state and trait anxiety post-psilocybin: A naturalistic, observational study among retreat attendees

abstract: Anxiety disorders are the most common type of psychiatric disorders among Western countries. Evidence-based treatment modalities including pharmacological and cognitive-behavioral therapy result in relatively low response rates (average range: 51 - 58%). Historical and recent research suggests psychedelic drugs may be efficacious in alleviating anxiety-related symptoms among healthy and clinical populations. The main aim of the present study was investigation of the effects of psilocybin-containing truffles, when taken in a supportive group setting, on ratings of state and trait anxiety across self-reported healthy volunteers. Attendees of psilocybin ceremonies were asked to complete a test battery at three separate occasions: before the ceremony (baseline), the morning after, and one week after the ceremony. The test battery included questionnaires assessing state and trait anxiety (State-Trait Anxiety Inventory), mindfulness capacities (Five Facet Mindfulness Questionnaire), and personality (Big Five Inventory). Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire and the Ego Dissolution Inventory. The total amount of psilocybin-containing truffles consumed by each participant was recorded, and a sample of the truffles was analyzed to determine psilocin concentrations. Fifty-two attendees (males= 25; females= 25; others= 2) completed parts of the baseline assessment, 46 (males= 21; females= 24; others= 1) completed assessments the morning after the ceremony, and 23 (males= 10; females= 13) completed assessments at the one-week follow-up. Average psilocin consumption across individuals was 27.1 mg. We observed medium to large reductions in anxiety measures (both state and trait) compared to baseline which persisted over a one-week period post-ceremony. At one week post-ceremony, the non-judging facet of the mindfulness scale was increased, while the personality trait neuroticism decreased, when compared to baseline. Additionally, we found neuroticism and ratings of ego dissolution to be the strongest predictors of reductions in trait and state anxiety, respectively. In sum, results indicate rapid and persisting (up to one week) anxiolytic effects in psilocybin retreat attendees, which are related to the acute experience of ego dissolution, as well as lasting changes in trait neuroticism. To understand whether these effects extend to wider populations suffering from heightened anxiety, and the mechanisms involved, further experimental research is needed.

category: pharmacology and therapeutics


title: Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome

abstract:
BackgroundHigh-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a [~]40-fold increased risk for schizophrenia, and a [~]30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown.

MethodsHere, we report the first in vivo quantitative neuroimaging study in 3q29Del individuals (N=24) and healthy controls (N=1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del participants and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships.

Results3q29Del participants had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link.

ConclusionsAbnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease.

category: psychiatry and clinical psychology


title: Prevalence of Chronic Diseases, Depression, and Stress among U.S. Child Care Professionals during the COVID-19 Pandemic

abstract:
ImportanceThere is no published national research reporting child care professionals physical health, depression, or stress during the COVID-19 pandemic. Given their central role in supporting childrens development, child care professionals overall physical and mental health is important.

ObjectivesTo evaluate the prevalence of chronic diseases, depression, and stress levels during the COVID-19 pandemic among U.S. child care professionals.

DesignIn this large-scale national survey, data were collected through an online survey from May 22, 2020 to June 8, 2020. We analyzed the association of sociodemographic characteristics with four physical health conditions (asthma, heart disease, diabetes, and obesity), depression, and stress weighted to national representativeness. Sociodemographic characteristics included race, ethnicity, age, gender, medical insurance status, and child care type.

SettingCenter- and home-based child care.

ParticipantsChild care professionals (n = 81,682) from all U.S. states and the District of Columbia.

ResultsMean age was 42.1 years (standard deviation = 14.1); 96.0% (n = 78,725) were female, 2.5% (n = 2,033) were male, and 0.3% (n = 225) were non-binary. For physical health conditions, 14.3% (n = 11,717) reported moderate to severe asthma, 6.5% (n = 5,317) diabetes, 4.9% (n = 3,971) heart disease, and 19.8% (n = 16,207) being obese. Regarding mental health, 45.7% (n = 37,376) screened positive for depression and 66.5% (n = 54,381) reported moderate to high stress levels. Race, ethnicity, and gender disparities were evidenced for physical health conditions of child care professionals, but not for mental health during the pandemic.

Conclusions and RelevanceOur findings highlight that child care professionals depression rates during the pandemic were much higher than before the pandemic, and depression, stress and asthma rates were higher than U.S. adult depression rates during the pandemic. Given the essential work child care professionals provide during the pandemic, policy makers and public health officials should consider what can be done to support the physical and mental health of child care professionals.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of chronic diseases, depression, and stress among U.S. child care professionals during the COVID-19 pandemic?

FindingsIn this survey of 81,682 U.S. child care professionals, 14.3% reported moderate to severe asthma, 6.5% diabetes, 4.9% heart disease, 19.8% being obese, 45.7% screening positive for depression, and 66.5% moderate to high stress levels.

MeaningDuring the pandemic, child care professionals reported depression rates much higher than before the pandemic, and asthma, stress, and depression much greater than U.S. adult estimates, highlighting a need for effective supports for the wellbeing of this essential workforce.

category: public and global health


title: Development of a vocal biomarker for fatigue monitoring in people with COVID-19

abstract:
ObjectiveTo develop a vocal biomarker for fatigue monitoring in people with COVID-19.

DesignProspective cohort study.

SettingPredi-COVID data between May 2020 and May 2021.

ParticipantsA total of 1772 voice recordings was used to train an AI-based algorithm to predict fatigue, stratified by gender and smartphones operating system (Android/iOS). The recordings were collected from 296 participants tracked for two weeks following SARS-CoV-2 infection.

primary and secondary outcome measuresFour machine learning algorithms (Logistic regression, k-nearest neighbors, support vector machine, and soft voting classifier) were used to train and derive the fatigue vocal biomarker. A t-test was used to evaluate the distribution of the vocal biomarker between the two classes (Fatigue and No fatigue).

ResultsThe final study population included 56% of women and had a mean ({+/-}SD) age of 40 ({+/-}13) years. Women were more likely to report fatigue (P<.001). We developed four models for Android female, Android male, iOS female, and iOS male users with a weighted AUC of 79%, 85%, 86%, 82%, and a mean Brier Score of 0.15, 0.12, 0.17, 0.12, respectively. The vocal biomarker derived from the prediction models successfully discriminated COVID-19 participants with and without fatigue (t-test P<.001).

ConclusionsThis study demonstrates the feasibility of identifying and remotely monitoring fatigue thanks to voice. Vocal biomarkers, digitally integrated into telemedicine technologies, are expected to improve the monitoring of people with COVID-19 or Long-COVID.


title: Recurrent SARS-CoV-2 Mutations in Immunodeficient Patients

abstract:
Long-term SARS-CoV-2 infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COG-UK dataset. The spike gene receptor binding domain (RBD) and N-terminal domains (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, - T30I was determined to be the most recurrent frequently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation.

There is an apparent selective pressure for mutations which aid intra-host transmission or persistence which are often different to mutations which aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted.


title: Collecting mortality data via mobile phone surveys: a non-inferiority randomized trial in Malawi

abstract:
IntroductionDespite the urgent need for timely mortality data in low-income and lower-middle-income countries, mobile phone surveys rarely include questions about recent deaths. There are concerns that such questions might a) be too sensitive, b) prompt negative/adverse reactions among respondents, c) take too long to ask and/or d) generate unreliable data. We assessed the feasibility of mortality data collection during mobile phone surveys.

MethodsWe conducted a non-inferiority trial among a random sample of mobile phone users in Malawi. Participants were allocated 3:1 to an interview about recent deaths in their family (treatment group) or about their economic activity (control group). In the treatment group, half of the respondents completed a short mortality questionnaire, focused on information necessary to calculate recent mortality rates, whereas the other half completed an extended questionnaire that also included questions about symptoms and healthcare use. The primary trial outcome was the cooperation rate. Secondary outcomes included the completion rate, self-reports of negative feelings and stated intentions to participate in future interviews. We also documented the amount of time required to collect mortality data, and we explored the quality of death reports.

ResultsThe difference in cooperation rates between treatment and control groups was 0.9 percentage points (95% CI = -2.3, 4.1), which satisfied the non-inferiority criterion. Similarly, the mortality questionnaire was non-inferior to the control questionnaire on all secondary outcomes. Collecting mortality data required approximately 2 to 4 additional minutes per reported death, depending on the inclusion of questions about symptoms and healthcare use. More than half of recent deaths elicited during mobile phone interviews had not been reported to the national civil registration system.

ConclusionIncluding mortality-related questions in mobile phone surveys appears acceptable and feasible. It might help strengthen the surveillance of mortality trends in low-income and lower-middle-income countries with limited civil registration systems.

KEY QUESTIONSO_ST_ABSWhat is already known?C_ST_ABSO_LIIn many low-income and lower-middle-income countries, civil registration systems only record a fraction of all deaths. The excess mortality associated with health crises is thus not known in near real-time.
C_LIO_LIMobile phone surveys are increasingly common in low-income and lower-middle-income countries. They could help fill mortality-related data gaps, but there are concerns that asking questions about recent deaths over the phone might be too sensitive, might take too long, and/or might generate unreliable data.
C_LI

What are the new findings?O_LIIn a randomized trial conducted with mobile phone users in Malawi, asking questions about recent deaths was not less acceptable than asking questions about economic activity and household livelihoods.
C_LIO_LIFew participants reported experiencing negative feelings during the interview, and these feelings were temporary.
C_LIO_LIMore than half of the deaths reported during mobile phone interviews had not been previously registered with the national civil registration system.
C_LI

What do the new findings imply?O_LIIncluding questions about recent deaths in mobile phone surveys appears feasible and acceptable.
C_LIO_LIIt might help strengthen the surveillance of mortality trends in low-income and lower-middle-income countries with limited civil registration systems.
C_LI


title: Gaussian-Enveloped Tones (GET): a vocoder that can simulate pulsatile stimulation in cochlear implants

abstract: Acoustic simulations of cochlear implants allow comprehensive evaluation of not only perceptual performance under impoverished listening conditions but also relative contributions of classical spectral and temporal cues to speech recognition. Conventional simulations use continuous sinusoidal or noise carriers, lacking the vital pulsatile characteristics in a typical cochlear-implant processing strategy. The present study employed Gaussian-enveloped tones (GETs) as a discrete carrier to simulate the electric pulse train in modern cochlear implants. Two types of GET vocoders were implemented and evaluated in normal-hearing listeners to compare their performance to actual cochlear-implant performance. In the first implementation, GETs with different durations were used to simulate electric current interaction across channels that produced vowel and consonant recognition similar to the actual cochlear-implant result. In the second implementation, a direct mapping from electric pulses to GETs was developed to simulate a widely-used clinical n-of-m strategy in cochlear implants. The GET processing simulated the actual implant speech in noise perception in terms of the overall trend, the absolute mean scores, and their standard deviations. The present results demonstrated that the pulsatile GET vocoders simulate the cochlear implant performance more accurately than the conventional sinusoid or noise vocoders.

category: otolaryngology


title: Investigating automatic speech emotion recognition for children with autism spectrum disorder in interactive intervention sessions with the social robot Kaspar

abstract: In this contribution, we present the analyses of vocalisation data recorded in the first observation round of the European Commissions Erasmus Plus project "EMBOA, Affective loop in Socially Assistive Robotics as an intervention tool for children with autism". In total, the project partners recorded data in 112 robot-supported intervention sessions for children with autism spectrum disorder. Audio data were recorded using the internal and lapel microphone of the H4n Pro Recorder. To analyse the data, we first utilise a child voice activity detection (VAD) system in order to extract child vocalisations from the raw audio data. For each child, session, and microphone, we provide the total time child vocalisations were detected. Next, we compare the results of two different implementations for valence- and arousal-based speech emotion recognition, thereby processing (1) the child vocalisations detected by the VAD and (2) the total recorded audio material. We provide average valence and arousal values for each session and condition. Finally, we discuss challenges and limitations of child voice detection and audio-based emotion recognition in robot-supported intervention settings.

category: health informatics


title: Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis

abstract:
BackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19.

MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).

FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0{middle dot}87; 95% CI 0{middle dot}77-0{middle dot}98; p=0{middle dot}026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes.

InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.

FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).


title: Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

abstract:
Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as "COVID toes", remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

SummaryNET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains.


title: Genomic epidemiology offers high resolution estimates of serial intervals for COVID-19

abstract: Estimating key aspects of transmission is crucial in infectious disease control. Serial intervals - the time between symptom onset in an infector and infectee - are fundamental, and help to define rates of transmission, estimates of reproductive numbers, and vaccination levels needed to prevent transmission. However, estimating the serial interval requires knowledge of individuals contacts and exposures (who infected whom), which is typically obtained through resource-intensive contact tracing efforts. We develop an alternate framework that uses virus sequences to inform who infected whom and thereby estimate serial intervals. The advantages are many-fold: virus sequences are often routinely collected to support epidemiological investigations and to monitor viral evolution. The genomic approach offers high resolution and cluster-specific estimates of the serial interval that are comparable with those obtained from contact tracing data. Our approach does not require contact tracing data, and can be used in large populations and over a range of time periods. We apply our techniques to SARS-CoV-2 sequence data from the first two waves of COVID-19 in Victoria, Australia. We find that serial interval estimates vary between clusters, supporting the need to monitor this key parameter and use updated estimates in onward applications. Compared to an early published serial interval estimate, using cluster-specific serial intervals can cause estimates of the effective reproduction number Rt to vary by a factor of up to 2-3. We also find that serial intervals estimated in settings such as schools and meat processing/packing plants tend to be shorter than those estimated in healthcare facilities.


title: Comprehensive characterization of Candida isolates in a given geographical area for the determination of prevalence and drug sensitivity.

abstract:
PurposeAn alarming increase in Candidiasis infections has been observed worldwide and in India. This increase is attributed to increase in immune-compromised individuals and an increase in plethora of species causing the disease. The emergence of drug resistance of isolates has further worsened the situation.

Materials & MethodsCandida isolates causing infections were obtained from patients and evaluated for their macroscopic and microscopic characteristics by colony morphology and staining procedures. The patients demography was also analyzed to identify any correlation between the isolates. Doubling time was determined to analyze growth characteristics of these isolates. Isolates were also characterized biochemically for their ability to assimilate carbon and nitrogen sources and for fermentative capabilities. Additionally, drug sensitivity profiles of these isolates were analyzed towards Azoles.

ResultsDemographic analysis of the isolates suggested that all age groups were affected by Candida via both albicans and non-albican species. The infections were not gender biased but majority isolates were obtained from urine samples suggesting Candida as an important species causing urine-genital infections. Macroscopic and microscopic analysis showed cream colored circular colonies with smooth surface and entire margins with cells in single and budding stage. The doubling time ranged between 40 mins to 180 mins with 81 mins being the average. Biochemical characterization showed sucrose to be the most metabolizable sugar with maximum fermentative capacity with glucose. Surprisingly, very low nitrogen assimilation capacity was observed with all the nitrogen sources tested (nitrate, urea and glycine). Drug sensitivity towards Azoles suggested almost 50% and 90% isolates were resistant to Fluconazole and Itraconazole respectively, the most common Azoles used against fungal infections in the current scenario.

ConclusionsThe results obtained from the study suggested differential characteristics of the isolates towards various parameters thereby indicating the relevance of isolate characterization, for appropriate control and prevention of the disease.

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title: Using Twitter Data for Cohort Studies of Drug Safety in Pregnancy: A Proof-of-Concept with Beta-Blockers

abstract:
BackgroundDespite that medication is taken during more than 90% of pregnancies, the fetal risk for most medications is unknown, and the majority of medications have no data regarding safety in pregnancy.

ObjectiveUsing beta-blockers as a proof-of-concept, the primary objective of this study was to assess the utility of Twitter data for a cohort study design--in particular, whether we could identify (1) Twitter users who have posted tweets reporting that they took a beta-blocker during pregnancy and (2) their associated pregnancy outcomes.

MethodsWe searched for mentions of beta-blockers in 2.75 billion tweets posted by 415,690 users who announced their pregnancy on Twitter. We manually reviewed the matching tweets to first determine if the user actually took the beta-blocker mentioned in the tweet. Then, to help determine if the beta-blocker was taken during pregnancy, we used the timestamp of the tweet reporting intake and drew upon an automated natural language processing (NLP) tool that estimates the date of the users prenatal time period. For users who posted tweets indicating that they took or may have taken the beta-blocker during pregnancy, we drew upon additional NLP tools to help identify tweets that report their adverse pregnancy outcomes, including miscarriage, stillbirth, preterm birth, low birth weight, birth defects, and neonatal intensive care unit admission.

ResultsWe retrieved 5114 tweets, posted by 2339 users, that mention a beta-blocker, and manually identified 2332 (45.6%) tweets, posted by 1195 (51.1%) of the users, that self-report taking the beta-blocker. We were able to estimate the date of the prenatal time period for 356 pregnancies among 334 (27.9%) of these 1195 users. Among these 356 pregnancies, we identified 257 (72.2%) during which the beta-blocker was or may have been taken. We manually verified an adverse pregnancy outcome--preterm birth, neonatal intensive care unit admission, low birth weight, birth defects, or miscarriage--for 38 (14.8%) of these 257 pregnancies.

ConclusionsOur ability to detect pregnancy outcomes for Twitter users who posted tweets reporting that they took or may have taken a beta-blocker during pregnancy suggests that Twitter can be a complementary resource for cohort studies of drug safety in pregnancy.


title: Utilization of Pharmacy Value-Added Services and Its Association with Waiting Time for Medication Collection in Public Health Institutions across Malaysia

abstract:
BackgroundPharmacy value-added services (PVAS) have long been offered in public health institutions across Malaysia as an alternative to conventional counter services for prescription refills, with the aim to reduce the waiting time.

ObjectiveTo assess the utilization of the PVAS in individual health institutions, and its association with the achievement of the key performance indicator (KPI) set for the pharmacy waiting time.

MethodThis was a cross-sectional study based on the data contributed by 142 hospitals and 648 health clinics throughout 2018. The availability and uptake of the PVAS were summarized as percentages. The impacts of the PVAS uptake and the other institution-related factors on the KPI achievement were further explored using the logistic regression analysis.

ResultsApproximately 2.9 million (17.1%) of the refill prescriptions were dispensed via the PVAS. The appointment-and-pickup services (42.7%) and the Integrated Drug Dispensing System (23.7%) emerged as the most commonly used types of PVAS. A higher PVAS uptake was associated with a better KPI achievement (OR=0.91, 95% CI: 0.84-0.98). In contrast, adding a new type of PVAS to the existing services yielded an opposite outcome (OR=1.48, 95% CI: 1.15-1.89). Both the prescription load and location of health institutions were also found have influenced the KPI achievement.

ConclusionThe PVAS are generally well accepted in Malaysia and showed to have reduced the pharmacy waiting time. However, strategies to optimize the PVAS uptake are warranted.

category: health systems and quality improvement


title: Pegylated-interferon-{lambda} treatment-induced peripheral interferon stimulated genes are associated with SARS-CoV-2 viral load decline despite delayed T cell response in older individuals

abstract: Interferons (IFNs) are antiviral cytokines induced very early after SARS-CoV-2 infection and are crucial for viral clearance, shaping immunity, and preventing the development of severe COVID-19. We previously demonstrated that a single injection of peginterferon-lambda1 (PEG-IFN-{lambda}) accelerated viral clearance in COVID-19 patients. To determine if the rapid viral decline was mediated by enhanced immunity, we assessed in vivo responses to PEG-IFN-{lambda} by single cell RNA sequencing and measured SARS-CoV-2-specific T cell and antibody responses between placebo and PEG-IFN-{lambda}-treated patients. PEG-IFN-{lambda} treatment induced interferon stimulated genes in peripheral immune cells expressing IFNLR1, with plasmacytoid dendritic cells having the greatest response, followed by B cells. PEG-IFN-{lambda} did not significantly affect SARS-CoV-2-specific antibody levels in plasma or the magnitude or functionality of virus-specific T cells. However, we identified a delayed T cell response in older adults, suggesting that PEG-IFN-{lambda} can overcome the delay in adaptive immunity to accelerate viral clearance in patients most at risk for severe disease. Taken together, PEG-IFN-{lambda} offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral SARS-CoV-2 adaptive immunity


title: Vaccine effectiveness and duration of protection against symptomatic and severe Covid-19 during the first year of vaccination in France

abstract:
BackgroundSARS-CoV-2 continues to spread despite fast vaccine rollout, which could be attributed to waning immunity or to a reduced protection against some variants. A thorough characterization of vaccine protection and its duration in time is needed to inform vaccination policies and enhance public trust.

MethodsWe matched three national databases with exhaustive information on screening, vaccination and hospitalizations in France over the year 2021. We performed a two-step analysis to estimate vaccine effectiveness against severe forms of Covid-19 in people aged 50 years or over, combining: (i) a test-negative case-control design to assess vaccine effectiveness against symptomatic infections; and (ii) a survival analysis to assess the additional protection against severe outcomes (hospitalizations and inpatient deaths) in infected individuals.

ResultsWe found a high vaccine effectiveness in people aged 50 years or more, reaching 82% against symptomatic infections and 94% against severe outcomes, after a full vaccination scheme.

Vaccine effectiveness against symptomatic infections strongly decreased over time, dropping to 53% after six months, but remained high against severe forms (90% after six months). The booster dose allowed restoring high protection levels. Vaccine protection and its evolution in time, showed little difference against the variants that circulated prior to December 2021 in France, including the Delta variant.

ConclusionThough vaccine immunity decreases over time, vaccination remains crucial to provide individual protection against severe diseases. This decline can be reversed by the injection of a booster dose.


title: Electronic Nicotine Delivery Systems (ENDS) use during a five-year period is not associated with self-reported chronic obstructive pulmonary disease (COPD) after adjustment of cigarette smoking history: A longitudinal analysis of PATH data.

abstract:
BackgroundUnderstanding the relationship between electronic nicotine delivery systems (ENDS) use and chronic obstructive pulmonary disease (COPD) and other respiratory conditions is critical. However, previous studies have not adequately controlled for history of cigarette smoking.

Research QuestionTo examine the prospective association between ENDS use and self-reported incident COPD after adjusting for cigarette smoking history.

Study Design and MethodsUsing waves 1-5 of the US Population Assessment of Tobacco and Health (PATH) study, we examined the association between ENDS use and self-reported incident COPD among adults aged 40+ using discrete time survival models. Current ENDS use was measured as a time-varying covariate, lagged by one wave, defined as established daily or some days use. We controlled for baseline demographics (age, sex, race/ethnicity, education), health characteristics (asthma, obesity, exposure to second-hand smoke), and smoking history (smoking status and cigarette pack-years).

ResultsIncident COPD was self-reported by 925 respondents during the five-year follow-up period. Prior to adjusting for other covariates, time-varying ENDS use appeared to nearly double the risk of incident COPD (HR 1.98, 95% CI 1.44-2.74). However, ENDS use was no longer significantly associated with COPD (aHR 1.10, 95% CI 0.78-1.57) after adjusting for current cigarette smoking and cigarette pack-years. The risk of self-reported incident COPD increased with cigarette pack-years and was higher for respondents who were older, female, less educated, and had baseline asthma or obesity.

InterpretationENDS use did not significantly increase the risk of self-reported incident COPD over a five-year period once current smoking status and cigarette pack-years were taken into account. Cigarette pack-years, on the other hand, remained associated with a net increase in the risk of self-reported incident COPD. These findings highlight the importance of using prospective longitudinal data and properly controlling for cigarette smoking history to assess the independent health effects of ENDS.


title: Variation in hospital cost trajectories at the end of life by age, multimorbidity and cancer type

abstract:
BackgroundApproximately thirty thousand people in Scotland are diagnosed with cancer annually, of whom a third live less than one year. The timing, nature and value of hospital-based healthcare for patients with advanced cancer are not well understood. The aim of this study was to describe patterns of hospital-based healthcare use and associated costs in the last year of life for patients with a cancer diagnosis.

MethodsWe undertook a Scottish population-wide administrative data linkage study of hospital-based healthcare use for individuals with a cancer diagnosis aged 60 years and over on their date of death, who died between 2012 and 2017. Hospital admissions, length of stay (LOS), number and nature of outpatient and day case appointments were analysed for all cancer types. Generalised linear models were used to adjust costs for age, gender, socioeconomic deprivation status, rural-urban (RU) status and comorbidity.

ResultsThe study included 85,732 decedents with a cancer diagnosis, for whom 64,553 (75.3%) cancer was the primary cause of death. Mean age at death was 80.01 (SD 8.15) years. The mean number of inpatient stays in the last year of life was 5.88 (SD 5.68), with a mean LOS of 7 days. Mean total inpatient, outpatient and daycase costs per patient were {pound}10261, {pound}1275 and {pound}977 respectively. Admission rates rose sharply in the last month of life. One year adjusted and unadjusted costs decreased with increasing age. A higher comorbidity burden was associated with higher costs and major cost differences between cancer types were also observed.

ConclusionsPeople in Scotland in their last year of life with cancer are high users of secondary care. Hospitalisation accounts for a high proportion of costs, particularly in the last month of life. Further research is needed to examine triggers for unplanned hospitalisation and to identify modifiable reasons for variation in hospital use among different cancer cohorts.

category: health economics


title: Are Dutch General Practitioners willing to prescribe mifepristone and misoprostol?: a mixed-methods study

abstract:
BackgroundThe World Health Organization (WHO) indicates that General Practitioners (GPs) can effectively and safely provide mifepristone and misoprostol for medical termination of pregnancy (TOP). Dutch GPs are permitted to treat miscarriages with mifepristone and misoprostol, but in practice only guide spontaneous miscarriages. Current Dutch abortion law forbids GPs to prescribe these medications for medical TOP. Medical TOP is limited to the specialized settings of abortion clinics and hospitals. A shift to primary care is debated in the House of Representative, following the example of France and Ireland. It would improve reproductive health care and choices for women. Little is known about GPs willingness to provide medical TOP and miscarriage management.

AimThis study aimed to gain insight into Dutch GPs willingness and anticipated obstacles to prescribing mifepristone and misoprostol for medical TOP and miscarriages.

Design and SettingThis is a mixed-method study among Dutch GPs.

MethodA questionnaire provided quantitative data that was analysed using descriptive methods. Thematic analyses were performed on qualitative data collected by in-depth interviews.

ResultsThe questionnaire was sent to 575 GPs, the response rate was 22.1%. Of the responders, 84.3% were willing to prescribe mifepristone and misoprostol and 58.3% were willing to provide both medical TOP and miscarriage management. 57.5% indicated a need for training. The main barriers influencing GPs willingness were lack of experience, knowledge, time and a restrictive abortion law.

ConclusionOver 80% of the respondents were willing to prescribe mifepristone and misoprostol for medical TOP or miscarriages. Training, (online) education and a revision of the abortion law are recommended.

How this fits inMedical TOP in the Netherlands can only be provided in abortion clinics and hospitals. GPs may prescribe these same medications for miscarriage management, but in practice only guide spontaneous miscarriages. To improve access to woman-centred care, it is important to allow GPs by law to provide medical TOP. Our study is the first to assess Dutch GPs willingness to provide mifepristone and misoprostol and aims to understand enablers and barriers that give insight into the feasibility of a shift in care. Our results illustrate the need to revise laws and to provide training and education in the similar procedure of medical TOP and miscarriage management.

category: primary care research


title: Differences in Genetic Correlations between Posttraumatic Stress Disorder and Alcohol Use Disorder-Related Phenotypes Compared to Alcohol Consumption-Related Phenotypes

abstract:
BackgroundPosttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-AUD comorbidity also contribute to PTSD-alcohol consumption.

MethodsWe used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD (both the diagnosis and re-experiencing symptoms) and a range of alcohol consumption-related and AUD-related phenotypes (e.g., drinks per week, max drinks, consumption, AUD).

ResultsIn EAs, there were positive genetic correlations between PTSD phenotypes and AUD-related phenotypes (i.e., Alcohol Use Disorders Identification Test (AUDIT) problem score, maximum alcohol intake, AUD, and alcohol dependence) (rGs: .132-.533, all FDR adjusted p<.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (i.e., drinks per week, AUDIT consumption score, AUDIT total score, and a combination of consumption and problems) were negatively associated or non-significant (rGs: -.417- -.042, FDR adjusted p: <.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for AUD--related: -.275 -.266, FDR adjusted p: NS, alcohol consumption-related: .145-.699, FDR adjusted p: NS).

ConclusionsThese findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and consume large quantities of alcohol are not the same as those that lead someone to develop PTSD-AUD.

category: genetic and genomic medicine


title: Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research.

abstract:
IntroductionA major challenge to enabling precision health at a global scale is the bias between those who enroll in state sponsored genomic research and those suffering from chronic disease. More than 30 million people have been genotyped by direct-to-consumer (DTC) companies such as 23andMe, Ancestry DNA, and MyHeritage, providing a potential mechanism for democratizing access to medical interventions and thus catalyzing improvements in patient outcomes as the cost of data acquisition drops. However, much of these data are sequestered in the initial provider network, without the ability for the scientific community to either access or validate. Here, we present a novel geno-pheno platform that integrates heterogeneous data sources and applies learnings to common chronic disease conditions including Type 2 diabetes (T2D) and hypertension.

MethodsWe collected genotyped data from a novel DTC platform where participants upload their genotype data files, and were invited to answer general health questionnaires regarding cardiometabolic traits over a period of 6 months. Quality control, imputation and genome-wide association studies were performed on this dataset, and polygenic risk scores were built in a case-control setting using the BASIL algorithm.

ResultsWe collected data on N=4,550 (389 cases / 4,161 controls) who reported being affected or previously affected for T2D; and N=4,528 (1,027 cases / 3,501 controls) for hypertension. We identified 164 out of 272 variants showing identical effect direction to previously reported genome-significant findings in Europeans. Performance metric of the PRS models was AUC=0.68, which is comparable to previously published PRS models obtained with larger datasets including clinical biomarkers.

DiscussionDTC platforms have the potential of inverting research models of genome sequencing and phenotypic data acquisition. Quality control (QC) mechanisms proved to successfully enable traditional GWAS and PRS analyses. The direct participation of individuals has shown the potential to generate rich datasets enabling the creation of PRS cardiometabolic models. More importantly, federated learning of PRS from reuse of DTC data provides a mechanism for scaling precision health care delivery beyond the small number of countries who can afford to finance these efforts directly.

ConclusionsThe genetics of T2D and hypertension have been studied extensively in controlled datasets, and various polygenic risk scores (PRS) have been developed. We developed predictive tools for both phenotypes trained with heterogeneous genotypic and phenotypic data generated outside of the clinical environment and show that our methods can recapitulate prior findings with fidelity. From these observations, we conclude that it is possible to leverage DTC genetic repositories to identify individuals at risk of debilitating diseases based on their unique genetic landscape so that informed, timely clinical interventions can be incorporated.


title: Ultrarare missense and frameshift variants in the TECTA gene may involve tectorial membrane in familial Meniere disease

abstract:
BackgroundMenieres disease (MD) is an inner ear disease defined by episodes of vertigo associated with sensorineural hearing loss initially affecting low- to medium frequencies, tinnitus, and aural fullness. Familial aggregation has been reported in 9-10% of MD patients showing, mostly, an autosomal dominant inheritance pattern with incomplete penetrance. However, familial MD is a genetically heterogeneous disorder and other inheritance patterns have been recently proposed, such as recessive and digenic inheritance involving rare variants in OTOG and MYO7A genes, respectively. In this study, a familial MD cohort was recruited to identify new candidate genes.

MethodsExome sequencing was performed in 99 individuals (from 77 families) diagnosed with MD according to the diagnostic criteria defined by the Barany Society. Candidate variants were classified based on the ACMG/AMP guidelines, and their effects were evaluated by protein modeling. Standard audiometric evaluations were retrieved, and a case report was made of each family to assess the genotype-phenotype correlations.

ResultsThe TECTA gene, which encodes -tectorin, was highlighted as a candidate for four multicase MD families carrying rare missense heterozygous variants and a short deletion in this gene. Variants in -tectorin were also found in two additional families with one MD patient and relatives with partial syndromes carrying a missense heterozygous variant and a short deletion. According to the predicted protein model, these variants could affect the stability of -tectorin.

ConclusionsSeveral MD families were identified carrying rare variants and deletions in the TECTA gene, which encodes one of the main proteins of the tectorial membrane (TM). The TM is an extracellular matrix localized over the sensory epithelium mediating the mechanical stimulation of cochlear hair cells, a critical role in the process of hearing. Modifications on the TM stability and the micromechanics involved in the sound-evoked motion of stereocilia might be involved in familial MD.


title: Mathematical Analysis of a Zika Model with reservoirs and Human Movement

abstract: A mathematical model for Zika virus is proposed describing the spread of the disease in three interacting populations, namely, human, vector (mosquitoes) and non-human primate (monkeys) inhabiting forests area. Human movement between rural and forest areas has been also considered. It is assumed that Zika virus spreads within non-human primate population, which in turn acts as a reservoir of infection, and then transmitted to the human population through infected mosquitoes. The proposed model incorporates vertical transmission and direct transmission in all populations. The proposed model has been first normalized. The normalized model has been then fully analyzed both qualitatively and quantitatively to investigate the role of the interaction between forest mosquitoes and primates on the ZIKV transmission dynamics. The mathematical analysis includes positivity and boundedness of solutions, derivation of the basic reproduction number R0 using the next generation matrix method, sensitivity analysis, existence and stability analysis of all equilibria and bifurcation analysis. Finally, numerical simulations have been carried out to illustrate the obtained theoretical results and to demonstrate the effect of some model parameters in the disease transmission dynamics. The results show that the interaction between forest mosquitoes and primates has a significant impact on the ZIKV transmission dynamics among human population through the fraction of susceptible moving to forest areas. Furthermore, the results highlight that the transmission probabilities are as important as the ratios of population size between vector population and human or primate populations in the disease transmission dynamics.


title: Exploring the experiences of loneliness in adults with mental health problems: a co-produced participatory qualitative interview study

abstract:
BackgroundMany mental health conditions are associated with loneliness, which is both a potential trigger and an exacerbating factor in mental health conditions. Richer evidence about how people with mental health problems experience loneliness, and about what exacerbates or alleviates it, is needed to underpin research on strategies to help with loneliness in this context.

MethodsOur aim was to explore experiences of loneliness, as well as what contributes to or helps address it, among a diverse sample of adults living with mental health problems in the UK. We recruited purposively via online networks and community organisations. Qualitative semi-structured interviews were conducted with 59 consenting participants by video call or telephone. Researchers with relevant lived experience were involved at all stages, including design, data collection, analysis and writing up of results.

FindingsAnalysis led to identification of four overarching themes: 1. What the word "lonely" meant to participants, 2. Contributory factors to ongoing loneliness, 3. Connections between loneliness & mental health, 4. Ways of reducing loneliness. Central aspects of loneliness were lack of meaningful connections with others and lack of a sense of belonging to valued groups and communities. Some drivers of loneliness, such as losses and transitions, were universal, but specific links were made between living with mental health problems and being lonely. These included direct effects of psychiatric symptoms, the need to withdraw to cope with mental health problems, and impacts of stigma and poverty.

ConclusionsThe multiplicity of contributors to loneliness that we identified, and of potential strategies for reducing it, suggest that a variety of approaches are relevant to reducing loneliness among people with mental health problems, including peer support and supported self-help, psychological and social interventions, and strategies to facilitate change at community and societal levels. The views and experiences of adults living with mental health problems are a rich source for understanding why loneliness is a frequent experience in this context and what may address it. Co-produced approaches to developing and testing interventions have potential to draw on this experiential knowledge in formulating effective approaches to loneliness.


title: Exploring the experiences of loneliness in adults with mental health problems: a participatory qualitative interview study


title: Optimal vaccination with time-varying based on immunity barrier in Hunan Province, China

abstract: The current outbreak of novel coronavirus disease 2019 (COVID-19) is already causing a serious disease burden worldwide, this paper analyzed data of a delta variant Covid-19 outbreak in Hunan, China, and proposed an optimal dose-wise dynamical vaccinating process based on local contact pattern and vaccine coverage that minimize the accumulative cases in a certain future time interval. The optimized result requires an immediate vaccination to that none vaccinated at age group 30 to 39, which is coherent to the prevailing strategies. The dose-wise optimal vaccinating process can be directive for countries or regions where vaccines are not abundant. We recommend that vaccination should be further intensified to increase the coverage of booster shots, thus effectively reducing the spread of COVID-19.


title: Development and validation of a modified Cambridge Multimorbidity Score for use with internationally recognized electronic health record clinical terms (SNOMED CT)

abstract:
BackgroundPeople with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. This study aims to develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms which are routinely used in electronic health records across the world (SNOMED CT).

Methods and FindingsWe curated new variables describing 37 health conditions and modelled the associations between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n=300,000). We then developed two simplified models - a 20-condition model as per the original Cambridge Multimorbidity Score, and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n=150,000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n=150,000).

Our final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration.

ConclusionsThis modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms which can be applied internationally across multiple healthcare settings.


title: Multiple sclerosis cortical lesion detection with deep learning at ultra-high-field MRI

abstract:
Manually segmenting multiple sclerosis (MS) cortical lesions (CL) is extremely time-consuming, and past studies have shown only moderate inter-rater reliability. To accelerate this task, we developed a deep learning-based framework (CLAIMS: Cortical Lesion Artificial Intelligence-based assessment in Multiple Sclerosis) for the automated detection and classification of MS CL with 7T MRI.

Two 7T datasets, acquired at different sites, were considered. The first consisted of 60 scans that include 0.5mm isotropic MP2RAGE acquired 4 times (MP2RAGEx4), 0.7mm MP2RAGE, 0.5mm T2*-weighted GRE, and 0.5mm T2*-weighted EPI. The second dataset consisted of 20 scans including only 0.75x0.75x0.9 mm MP2RAGE. CLAIMS was first evaluated using 6-fold cross-validation with single and multi-contrast 0.5mm MRI input. Second, performance of the model was tested on 0.7mm MP2RAGE images after training with either 0.5mm MP2RAGEx4, 0.7mm MP2RAGE, or alternating the two. Third, its generalizability was evaluated on the second external dataset and compared with a state-of-the-art technique based on partial volume estimation and topological constraints (MSLAST). CLAIMS trained only with MP2RAGEx4 achieved comparable results to the multi-contrast model, reaching a CL true positive rate of 74% with a false positive rate of 30%. Detection rate was excellent for leukocortical and subpial lesions (83%, and 70%, respectively), whereas it reached 53% for intracortical lesions. The correlation between disability measures and CL count was similar for manual and CLAIMS lesion counts. Applying a domain-scanner adaptation approach and testing CLAIMS on the second dataset, the performance was superior to MSLAST when considering a minimum lesion volume of 6L (lesion-wise detection rate of 71% vs 48%).

The proposed framework outperforms previous state-of-the-art methods for automated CL detection across scanners and protocols. In the future, CLAIMS may be useful to support clinical decisions at 7T MRI, especially in the field of diagnosis and differential diagnosis of multiple sclerosis patients.


title: Low Haemoglobin Levels are Associated with Reduced Psychomotor and Language Abilities in Young Ugandan Children.

abstract: Children living in Sub-Saharan Africa are vulnerable to developmental delay, particularly in the critical first five years due to various adverse exposures including disease and nutritional deficiencies. Anaemia and iron deficiency (ID) are highly prevalent in pregnant mothers and young children and are implicated in abnormal brain development. However, available evidence on the association between anaemia, ID and neurodevelopment in Sub-Saharan Africa is limited. Using data from the Entebbe Mother and Baby Study prospective birth cohort, we examined the effect of maternal and child haemoglobin (Hb) levels and child iron status on developmental scores in 933 and 530 pre-school Ugandan children respectively. Associations between Hb levels, iron status and developmental scores were assessed using regression analyses adjusting for potential confounders. Lower maternal and child Hb levels were associated with reduced psychomotor scores at 15 months, while only lower Hb levels in infancy were associated with reduced language scores. We found no evidence that anaemia or ID was associated with cognitive or motor scores at five years. This study emphasizes the importance of managing anaemia in pregnancy and infancy and highlights the need for further studies on the effects of anaemia and ID in children living in Sub-Saharan Africa.

category: nutrition


title: Altered brain reward response to monetary incentives in fibromyalgia: A replication study

abstract: Dysregulated brain reward systems have been observed in chronic pain. Using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in patients with fibromyalgia. The current study aimed to replicate these results in a separate cohort of patients with fibromyalgia recruited at a new location using a similar study design. Twenty patients with fibromyalgia and 20 healthy controls were included in the replication study. Group fMRI analyses revealed a solid and consistent trend of main findings similar to the previous results. Specifically, in the replication cohort of patients with fibromyalgia, medial prefrontal cortex (MPFC) activity was reduced during gain anticipation and increased during no-loss (non-punishment) outcomes, as compared to controls. Similar to the Martucci et al. results, again in the replication cohort, nucleus accumbens activity during gain anticipation did not differ in patients compared to controls. The same behavioral, correlational, and exploratory analyses that were conducted in the Martucci et al. study were conducted in the present replication study, with prior results largely replicated here. Thus, the present replication study results solidify observations of altered cortico-striatal processing to monetary rewards in chronic pain, which underscore relevance of altered brain reward circuits, particularly as related to the MPFC in patients with fibromyalgia.

category: pain medicine


title: A predictive model for hospitalization and survival to COVID-19 in a retrospective population-based study

abstract: The severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is highly transmissible and has been responsible for a pandemic associated with a high number of deaths. The clinical management of patients and the optimal use of resources are two important factors in reducing this mortality, especially in scenarios of high incidence. To this end, it is necessary to develop tools that allow early triage of patients with the minimal use of diagnostic tests and based on readily accessible data, such as electronic medical records. This work proposes the use of a machine learning model that allows the prediction of mortality and risk of hospitalization using simple demographic characteristics and comorbidities, using a COVID-19 dataset of 86867 patients. In addition, we developed a new method designed to deal with data imbalance problems. The model was able to predict with high accuracy (89-93%, ROC-AUC = 0.94) the patients final status (expired/discharged) and with medium accuracy the risk of hospitalization (71-73%, ROC-AUC = 0.75). These models were obtained by assembling and using easily obtainable clinical characteristics (2 demographic characteristics and 19 predictors of comorbidities). The most relevant features of these models were the following patient characteristics: age, sex, number of comorbidities, osteoarthritis, obesity, depression, and renal failure.


title: Evidence of co-infection during Delta and Omicron variants of concern co-circulation, weeks 49-2021 to 02-2022, France

abstract: We report evidence of Delta/Omicron SARS-CoV-2 co-infections during the fifth wave of COVID-19 pandemics in France for 7 immunocompetent and epidemiologically unrelated patients. These co-infections were detected by PCR assays targeting SARS-CoV-2 S-gene mutations K417N and L452R and confirmed by whole genome sequencing which allowed the proportion estimation of each subpopulation. For 2 patients, the analyses of longitudinal samples collected 7 to 11 days apart showed that Delta or Omicron can outcompete the other variant during dual infection.


title: Vaccine Breakthrough Infection with the SARS-CoV-2 Delta or Omicron (BA.1) Variant Leads to Distinct Profiles of Neutralizing Antibody Responses

abstract: There is increasing evidence that the risk of SARS-CoV-2 infection among vaccinated individuals is variant-specific, suggesting that protective immunity against SARS-CoV-2 may differ by variant. We enrolled vaccinated (n = 39) and unvaccinated (n = 11) individuals with acute, symptomatic SARS-CoV-2 Delta or Omicron infection and performed SARS-CoV-2 viral load quantification, whole-genome sequencing, and variant-specific antibody characterization at the time of acute illness and convalescence. Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses. Increases in antibody titers and neutralizing activity occurred at convalescence in a variant-specific manner. Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals. For individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, whereas infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2.


title: SARS-CoV-2 IgG seroprevalence in the Okinawa Main Island and remote islands in Okinawa, Japan, 2020-2021.

abstract: We estimated the seroprevalence of anti-SARS-COV-2 IgG in different island groups in Okinawa and described its changes over time. A cross-sectional sero-survey was repeated in three distinct periods between July 2020 and February 2021. A total of 2683 serum samples were collected from six referral medical centers, each covering a separate region in Okinawa. Patients who visited the emergency department for any reason and underwent blood collection were eligible for the study. Samples were analyzed using an FDA-authorized two-step enzyme-linked immunosorbent assay (ELISA) protocol. The case detection ratio was computed by dividing the seroprevalence by the attack rate obtained from publicly available surveillance data. In the main island, the seroprevalence was 0.0% (0/392, 95% CI: 0.0-0.9), 0.6% (8/1448, 0.2-1.1), and 1.4% (8/582, 0.6-2.7) at the 1st, 2nd, and 3rd sero-survey, respectively. In the remote islands, the seroprevalence was 0.0% (0/144, 95% CI: 0.0-2.5) and 1.6% (2/123, 0.2-5.8) at the 2nd and 3rd survey, respectively. The overall case detection ratios at the 3rd survey were 2.7 (95% CI: 1.3-5.3) in the main island and 2.8 (0.7-11.1) in the remote islands. The highest age-specific case detection ratio was observed in people aged 20-29 years (8.3, 95% CI: 3.3-21.4) in the main island and in those aged 50-59 years (14.1, 2.1-92.7) in the remote islands. The low seroprevalence at the latest survey suggested that a large-scale epidemic had not yet occurred in Okinawa by February 2021. The case detection ratios imply that the cumulative number of incident cases in Okinawa should be 2-3 times higher than that reported by routine surveillance. The ratio was particularly high in young people probably due to a frequent asymptomatic/mild COVID-19 disease in this age group. To accurately measure the scale of the COVID-19 epidemic, it is crucially important to conduct a sero-survey targeting the young.


title: Examining the Impact of ICU Population Interaction Structure on Modeled Colonization Dynamics of Staphylococcus aureus

abstract:
BackgroundComplex transmission models of healthcare-associated infections provide insight for hospital epidemiology and infection control efforts; however, many are difficult to implement and come at high computational costs. Structuring more simplified models to incorporate the heterogeneity of the intensive care unit (ICU) patient-provider interactions, we explore how methicillin-resistant Staphylococcus aureus (MRSA) dynamics and acquisitions may be better represented and approximated.

MethodsUsing a stochastic compartmental model of an 18-bed ICU, we compared the rates of MRSA acquisition across three ICU population interaction structures: a model with nurses and physicians as a single staff type (SST), a model with separate staff types for nurses and physicians (Nurse-MD model), and a Metapopulation model where each nurse was assigned a group of patients. The proportion of time spent with the assigned patient group ({gamma}) within the Metapopulation model was also varied.

ResultsThe SST, Nurse-MD, and Metapopulation models had a mean of 40.6, 32.2 and 19.6 annual MRSA acquisitions respectively. All models were sensitive to the same parameters in the same direction, although the Metapopulation model was less sensitive. The number of acquisitions varied non-linearly by values of{gamma} , with values below 0.40 resembling the Nurse-MD model, while values above that converged toward the metapopulation structure.

DiscussionComplex population interactions of a modeled hospital ICU has considerable impact on model results, with the SST model having more than double the acquisition rate of the more structured metapopulation model. While the direction of parameter sensitivity remained the same, the magnitude of these differences varied, producing different colonization rates across relatively similar populations. The non-linearity of the models response to differing values of a parameter gamma ({gamma}) suggests only a narrow space of relatively dispersed nursing assignments where simple model approximations are appropriate.

ConclusionSimplifying assumptions around how a hospital population is modeled, especially assuming random mixing, may overestimate infection rates and the impact of interventions. In many, if not most cases, more complex models that represent population mixing with higher granularity are justified.

Author SummarySome models of healthcare-associated infection assume random mixing between healthcare workers and patients - that is, all healthcare workers care for all patients in the model at equal frequency. This paper explores the impact of that assumption, creating a model of an 18-bed intensive care unit that compares a model with random mixing with one that segments patients into distinct groups with a single nurse assigned to them while a dedicated critical care physician continues to see all patients. Higher rates of segmentation result in lower rates of predicted acquisitions of methicillin-resistant Staphylococcus aureus, as well as more modest predicted impacts of interventions - represented by changes in parameter values. These findings suggest that the simpler random mixing models that are used for analytical tractability or computational speed may not be appropriate approximations in settings where healthcare workers are not uniformly distributed among patients due to scheduling, patient complexity or cohorting, the built environment, or hospital policy, and that balancing the computational costs with the trend toward more complex models in hospital epidemiology is justified.


title: Self-Care, Health Literacy and Their Associations Amongst Patients with Chronic Kidney Disease (CKD) in Primary Care

abstract:
AimThe study objective was to determine the levels of self-care (including domains of behaviour, motivation, self-efficacy) and health literacy, and study their associations amongst patients with chronic kidney disease (CKD) in primary care setting in Singapore.

MethodA cross-sectional, questionnaire-based study was conducted in one public-sector primary care clinic. Participants aged 21 to 80 years with hypertension were recruited from the clinic CKD register with 5,500 patients. Self-care profile (including behaviour, motivation and self-efficacy) were measured using Hypertension Self-Care Profile (HTN-SCP, range 0-240, domain range 0-80). Health literacy was measured using Short-Form Health Literacy Scale (HLS-SF12, range 0-50, limited literacy [≤]33).

ResultsA total of 347 out of 354 randomly selected patients consented to participate in the study. Two hundred and eighty-nine fully-completed responses were analysed. The mean self-care (HTN-SCP) score was 182.7 (SD 23.2), while mean scores were 55.3 (SD 8.6), 63.3 (SD 8.7), 64.0 (SD 9.3), for behaviour, self-efficacy and motivation domains respectively. The mean health literacy score was 36.1 (SD 7.7), and 31.1% of participants had limited health literacy. Limited health literacy was associated with self-efficacy (OR= -7.2, 95%CI=-9.1 to -5.2, p<0.001), motivation (OR= -6.1, 95%CI=-8.3 to -3.9, p<0.001) and behaviour (OR= -4.5, 95%CI=-6.6 to -2.4, p<0.001). Self-care was not associated with age, CKD status, household income and education but was associated with gender and limited health literacy. In the final regression model only limited health literacy was associated with self-care scores (Adjusted beta -17.4, p<0.001).

ConclusionOne-third of the patients with CKD in primary care had limited health literacy. Self-care was not associated with age, gender, CKD status, household income or education. Limited health literacy was associated with self-care, with strongest association with self-efficacy, followed by motivation and behaviour. More targeted approach can be adopted to improve self-care and health literacy amongst patients with CKD.


title: A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development

abstract:
Somatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.

Short summaryA germline homozygous recessive loss-of-function mutation p.T453M in RAF1 causes a neonatal lethal progeroid syndrome. In vitro and in vivo tests demonstrate that Thr543 is necessary for RAF1s protein stability, to transduce signaling to the MAPK pathway and to respond to stress-induced apoptosis.


title: NOVEL RT-qPCR ASSAYS ENABLE RAPID DETECTION AND DIFFERENTIATION BETWEEN SARS-COV-2 OMICRON (BA.1) AND BA.2 VARIANTS

abstract: In this report, we describe the development and initial validation of novel SARS-COV-2 Omicron-specific reactions that enable the identification of Omicron (BA.1) and BA.2 variants. Mutations that are either shared by both BA.1 and BA.2, or are exclusive for BA.1 or for BA.2 were identified by bioinformatic analysis, and corresponding probe-based quantitative PCR reactions were developed to identify them. We show that multiplex combinations of these reactions provide a single-reaction identification of the sample as BA.1, BA.2, or as non-Omicron SARS-COV-2. All four reactions described herein have a sensitivity of less than ten copies per reaction, and are amendable for multiplexing. The results of this study suggest that the new assays may be useful for testing both clinical and environmental samples to differentiate between these two variants.


title: Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo controlled randomized trial in healthcare workers

abstract:
ObjectiveTo assess the effect of hydroxychloroquine (HCQ), Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC), and their combination as pre-exposure prophylaxis on the risk of symptomatic COVID-19.

MethodsEPICOS is a double-blind, placebo-controlled randomized trial conducted in 51 hospitals in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo and TDF/FTC placebo plus HCQ placebo. The primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19 infection. We compared group-specific 14-week risks via differences and ratios with 95% confidence intervals (CI).

ResultsOf 1002 individuals screened, 926 (92.4%) were eligible; 64.2% recruited in Spain, 22.3% in Bolivia, and 13.6% in Venezuela. Median age was 38 years (range 18 - 68), 62.5% were female, 62.3% worked at inpatient care, and comorbidities were rare. Compared with the placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00, 1.98) for TDF+HCQ, 0.34 (0.00, 2.06) for TDF, and 0.49 (0.00, 2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21, 1.00) for TDF+HCQ, 0.81 (0.44, 1.49) for TDF, and 0.73 (0.41, 1.38) for HCQ. Adverse events were generally mild.

ConclusionA beneficial effect of TDF/FTC and HCQ, alone or in combination, as pre-exposure prophylaxis for COVID-19 cannot be ruled out but effect estimates are imprecise because the target sample size was not met. These findings support launching randomized trials of TDF/FTC for the early treatment of COVID-19.


title: Identifying risk factors associated with death among patients with MDR-TB in KwaZulu-Natal, South Africa: an illustration using Weibull parametric model.

abstract:
BackgroundThis study aim was to identify the risk factors associated with multidrug-resistant tuberculosis (MDR-TB) disease. The Weibull model has shown to perform better than the Cox proportional models with respect to the accuracy and efficient of the estimates. Therefore, a Weibull parametric model was employed to identify predictors of death in patients with MDR-TB and the efficiency of the models using current dataset.

MethodsPatients diagnosed with MDR-TB were studied in four decentralised sites located in rural areas and one centralised hospital in KwaZulu-Natal, South Africa from July 2008 to July 2012. Patients were followed from the date of MDR-TB diagnosis until death or the last follow-up date.

ResultsA total of 1 542 patients were included in the analyses: 812 and 730 from the centralised hospital and decentralised sites, respectively. Of the 1 542 enrolled, 15.9% patients died. We found that the hazard of death was significantly higher among patients treated in decentralised sites (aHR) = 1.84, 95% CI = 1.38 - 2.75; SE = 0.81 than that of those who were treated in the centralised hospital. However, the results from the Cox PH model showed an insignificant hazard of death between the decentralised sites and the centralised hospital (aHR = 1.46, 95% CI = 0.69 - 2.36; SE = 0.92). Patients who are between 31 - 40 years of age had increased hazard of death compared to those between 18 - 30 years (aHR = 1.52, 95% CI = 1.04 - 2.23). The hazard of death in female patients was 24% higher compared to male patients (aHR = 1.24, 95% CI = 0.93 - 1.63). Furthermore, patients with previous MDR-TB episodes had an increased hazard of death (aHR = 1.79, 95% CI = 0.23 - 0.62) compared to those with no previous MDR-TB episodes. The hazard of death in HIV negative patients was low compared to those who were HIV positive (aHR = 0.95, 95% CI = 0.57 - 0.77).

ConclusionMore health facilities are needed especially in decentralised places and that can help the 2030 World Health Organisation strategy to reduce or end TB infection.