title: Current therapeutic trends for tinnitus cure and control: a scoping review

abstract:
ObjectivesThe absence of high-level evidence about treatment approaches in tinnitus has eluded the clinical community from arriving at the consensus to date. This could be partially attributable to a limited number of trials. The objective of the present scoping review was to check updates in existing knowledge about tinnitus management and provide recommendations for further research and practice.

DesignScoping review with Population, Concept, and Context (PCC) framework. Review question(s) for our study were:

O_LIIs there any knowledge update from the published evidence on the treatment of tinnitus after the scoping review on tinnitus by Makar S et al. 2017?
C_LIO_LIAre there any therapies existing that do not focus on habituation but target the root cause of tinnitus?
C_LIO_LIWhich pharmacological interventions are used in the treatment of tinnitus?
C_LI

MethodsThe database of our literature search included PubMed, Joanna Briggs Evidence synthesis, Cochrane Library, Scopus, and Google Scholar. We included full-text original articles (randomized controlled trials (RCTs), systematic reviews (SLRs), or meta-analyses) published in the English language between 2010-2021. We included only studies that included interventions to treat patients without any focus on the patients habituation or natural adaptation. We excluded reviews, case studies, observational studies, and anecdotal evidence.

Patient and Public InvolvementBeing a secondary data-based analysis, our study did not directly involve any patient.

ResultsOf 20 included records, 11 SLRs and nine RCTs were found. Non-pharmacological interventions included transcranial magnetic-(TMS) (four studies) and direct current stimulation (tDCS) (three studies), vagus nerve stimulation (VNS) (one study), and hearing aid or combined amplification and sound generator (two studies); however, despite causing moderate improvement in tinnitus severity, neither of these interventions reached statistical significance. Pharmacological interventions included AM-101(two studies), anticonvulsants (one study), and antidepressants (one study) with insufficient strength to establish the efficacy of either. Also, a specific extract of the Ginkgo Biloba (EGb 761(R)) plant demonstrated a reduction in tinnitus severity (1 study). No studies included actionable insights on the quality of life (QoL) outcomes.

ConclusionsDespite the lack of actionable evidence for tDCS and rTMS like therapies, their curative potential cannot be overlooked. Hence, it is recommended to conduct large-scale trials on similar interventions. Also, aspects like patient-reported outcomes (PROs) in tinnitus.

Protocol registrationThe protocol was registered in the open science framework registry (OSF) (registration DOI:10.17605/OSF.IO/R8D39)

category: otolaryngology


title: Machine learning identifies six genetic variants and alterations in the Heart Atrial Appendage as key contributors to PD risk predictivity.

abstract: Parkinsons disease (PD) is a complex neurodegenerative disease with a range of causes and clinical presentations. Over 76 genetic loci (comprising 90 SNPs) have been associated with PD by the most recent GWAS meta-analysis. Most of these PD-associated variants are located in non-coding regions of the genome and it is difficult to understand what they are doing and how they contribute to the aetiology of PD. We hypothesised that PD-associated genetic variants modulate disease risk through tissue-specific expression quantitative trait loci (eQTL) effects. We developed and validated a machine learning approach that integrated tissue-specific eQTL data on known PD-associated genetic variants with PD case and control genotypes from the Wellcome Trust Case Control Consortium, the UK Biobank, and NeuroX. In so doing, our analysis ranked the tissue-specific transcription effects for PD-associated genetic variants and estimated their relative contributions to PD risk. We identified roles for SNPs that are connected with INPP5P, CNTN1, GBA and SNCA in PD. Ranking the variants and tissue-specific eQTL effects contributing most to the machine learning model suggested a key role in the risk of developing PD for two variants (rs7617877 and rs6808178) and eQTL associated transcriptional changes of EAF1-AS1 within the heart atrial appendage. Similarly, effects associated with eQTLs located within the brain cerebellum were also recognized to confer major PD risk. These findings warrant further mechanistic investigations to determine if these transcriptional changes could act as early contributors to PD risk and disease development.

category: genetic and genomic medicine


title: A prospective study of time-dependent exposures to childhood adversity and DNA methylation in childhood and adolescence

abstract:
BackgroundChildhood adversity influences long-term health, particularly if experienced during sensitive periods in development when physiological systems are more responsive to environmental influences. Although the underlying mechanisms remain unclear, prior studies suggest that DNA methylation (DNAm) may capture these time-dependent effects of childhood adversity. However, it remains unknown whether DNAm alterations persist into adolescence and how the timing of adversity might influence DNAm trajectories across development.

MethodsWe examined the relationship between time-dependent adversity and genome-wide DNAm measured at three waves from birth to adolescence using prospective data from the Avon Longitudinal Study of Parents and Children. We first assessed the relationship between the timing of exposure to seven types of adversity (measured 5-8 times between ages 0-11) and DNAm at age 15 using a structured life course modeling approach. We also characterized the persistence into adolescence of associations identified from age 7 DNAm, as well as the influence of adversity on DNAm trajectories from ages 0-15.

ResultsAdversity was associated with differences in age 15 DNAm at 24 loci (FDR<0.05). Most loci (19 of 24) were associated with adversity (i.e., physical/sexual abuse, one-adult households, caregiver abuse) that occurred between ages 3-5. Although no DNAm differences present at age 7 persisted into adolescence, we identified seven unique types of DNAm trajectories across development, which highlighted diverse effects of childhood adversity on DNAm.

ConclusionsOur results suggest that childhood adversity, particularly between ages 3-5, can influence the trajectories of DNAm across development, exerting both immediate and latent effects on the epigenome.


title: Neuropsychiatric disorders as risk factors and consequences of COVID-19: A Mendelian randomization study

abstract:
BackgroundMore than 170 million cases of COVID-19 have been reported worldwide. It has been proposed that psychiatric disorders may be risk factors and/or consequences of COVID-19 infection. However, observational studies could be affected by confounding bias.

MethodsWe performed bi-directional two-sample Mendelian randomization (MR) analysis to evaluate causal relationships between liability to COVID-19 (and severe/critical infection) and a wide range of neuropsychiatric disorders or traits. We employed the latest GWAS summary statistics from the COVID-19 Host Genetics Initiative. A variety of MR methods including those accounting for horizontal pleiotropy were used.

ResultsOverall we observed evidence that liability to COVID-19 or severe infection may be causally associated with higher risks of post-traumatic stress disorder (PTSD), bipolar disorder (BD) (especially BD II), schizophrenia (SCZ), attention deficit hyperactivity disorder (ADHD) and suicidal thought (ST) when compared to the general population. On the other hand, liability to a few psychiatric traits/disorders, for example ADHD, alcohol and opioid use disorders may be causally associated with higher risks of COVID-19 infection or severe disease. In genetic correlation analysis, cannabis use disorder, ADHD, and anxiety showed significant and positive genetic correlation with critical or hospitalized infection. All the above findings passed multiple testing correction at a false discovery rate (FDR)<0.05. For pneumonia, in general we observed a different pattern of associations, with bi-directional positive associations with depression- and anxiety-related phenotypes.

ConclusionsIn summary, this study provides evidence for tentative bi-directional causal associations between liability to COVID-19 (and severe infection) and a number of neuropsychiatric disorders. Further replications and prospective studies are required to verify the findings.

category: infectious diseases


title: BNT162b2 mRNA Vaccine Effectiveness Given Confirmed Exposure; Analysis of Household Members of COVID-19 Patients

abstract:
ImportanceWhile the mRNA BNT162b2 vaccine effectivness was demonstrated in general population, the question of effectiveness given confirmed exposure has yet been answered, though it has policy implications, as the need for self-quarantine when exposed and protective measures for vaccinated in high-risk areas.

ObjectiveAssessing the BNT162b2 vaccine effectiveness in preventing SARS-CoV-2 infection given high-risk exposure, through analysis of household members of confirmed cases.

DesignRetrospective cohort study. Data of household members of confirmed SARS-CoV-2 cases between 20/12/2020 and 17/03/2021 were collected.

SettingNationally centralized database of Maccabi Healthcare Services (MHS), the second largest Healthcare Maintenance Organization in Israel.

Participants2.5 million MHS members were considered, of which we included only households with two adult members, given possible lower transmission and susceptibility among children. Households with no prior confirmed infections and a confirmed index case during the study period were included.

ExposureParticipants were classified into three vaccination groups in time of the index case (the confirmed exposure)-Unvaccinated; Fully Vaccinated(7 or more days post second dose) and a reference control group of Recently Vaccinated Once(0-7 days from the first dose, presumably still unprotected).

Main Outcomes and MeasuresAssessing the probability of an additional SARS-CoV-2 infection in the household occurring within 10 days of an index case, calculated separately for the three vaccination groups. Main outcome was vaccine effectiveness given confirmed exposure. High testing rates among household members enabled us to estimate with a high degree of confidence effectiveness against asymptomatic SARS-CoV-2 infection as well.

ResultsA total of 173,569 households were included, out of which 6,351 households had an index infection (mean [SD] age, 58.9 [13.5] years; 50% were women). Vaccine effectiveness of Fully Vaccinated compared to Unvaccinated participants was 80.0% [95% CI, 73.0-85.1] and 82.0% [95% CI, 75.5-86.7] compared to those Recently Vaccinated Once.

Conclusion and RelevanceThe BNT162b2 vaccine is effective in a high-risk, real life, exposure scenario, but the protection rates afforded in these settings are lower than those previously described. Household members of COVID-19 patients and any individual with a confirmed exposure to COVID-19 are still at a considerable risk of being infected even if fully vaccinated.


title: The SARS-CoV-2 receptor-binding domain expressed in Pichia pastoris as a candidate vaccine antigen

abstract:
1.The effort to develop vaccines based on economically accessible technological platforms available by developing countries vaccine manufacturers is essential to extend the immunization to the whole world population and to achieve the desired herd immunity, necessary to end the COVID-19 pandemic. Here we report on the development of a SARS-CoV-2 receptor-binding domain (RBD) protein, expressed in yeast Pichia pastoris. The RBD was modified with addition of flexible N- and C-terminal amino acid extensions aimed to modulate the protein/protein interactions and facilitate protein purification. Fermentation with yeast extract culture medium yielded 30-40 mg/L. After purification by immobilized metal ion affinity chromatography and hydrophobic interaction chromatography, the RBD protein was characterized by mass-spectrometry, circular dichroism, and binding affinity to angiotensin-converting enzyme 2 (ACE2) receptor. The recombinant protein shows high antigenicity with convalescent human sera and also with sera from individuals vaccinated with the Pfizer-BioNTech mRNA or Sputnik V adenoviral-based vaccines. The RBD protein stimulates IFN{gamma}, IL-2, IL-6, IL-4, and TNF in mice secreting splenocytes from PBMC and lung CD3+ enriched cells. Immunogenicity studies with 50 {micro}g of the recombinant RBD formulated with alum, induce high levels of binding antibodies in mice and non-human primates, assessed by ELISA plates covered with RBD protein expressed in HEK293T cells. The mouse sera inhibited the RBD binding to ACE2 receptor in an in-vitro test and show neutralization of SARS-CoV-2 infection of Vero E6 cells. These data suggest that the RBD recombinant protein expressed in yeast P. pastoris is suitable as a vaccine candidate against COVID-19.

HighlightsO_LIThe RBD protein (C-RBD-H6 PP) is expressed with high purity in P. pastoris.
C_LIO_LIPhysico-chemical characterization confirms the right folding of the protein.
C_LIO_LIThe recombinant protein shows high antigenicity with sera from convalescents.
C_LIO_LIThe sera from animals inhibit the RBD-ACE2 binding and neutralize the virus.
C_LIO_LIThe C-RBD-H6 protein stimulates IFN{gamma}, IL-2, IL-6, IL-4, and TNF in mice.
C_LI


title: Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people

abstract:
BackgroundLong COVID, describing the long-term sequelae after SARS-CoV-2 infection, remains a poorly defined syndrome. There is uncertainty about its predisposing factors and the extent of the resultant public health burden, with estimates of prevalence and duration varying widely.

MethodsWithin rounds 3-5 of the REACT-2 study, 508,707 people in the community in England were asked about a prior history of COVID-19 and the presence and duration of 29 different symptoms. We used uni-and multivariable models to identify predictors of persistence of symptoms (12 weeks or more). We estimated the prevalence of symptom persistence at 12 weeks, and used unsupervised learning to cluster individuals by symptoms experienced.

FindingsAmong the 508,707 participants, the weighted prevalence of self-reported COVID-19 was 19.2% (95% CI: 19.1,19.3). 37.7% of 76,155 symptomatic people post COVID-19 experienced at least one symptom, while 14.8% experienced three or more symptoms, lasting 12 weeks or more. This gives a weighted population prevalence of persistent symptoms of 5.75% (5.68, 5.81) for one and 2.22% (2.1, 2.26) for three or more symptoms. Almost a third of people (8,771/28,713 [30.5%]) with at least one symptom lasting 12 weeks or more reported having had severe COVID-19 symptoms ("significant effect on my daily life") at the time of their illness, giving a weighted prevalence overall for this group of 1.72% (1.69,1.76). The prevalence of persistent symptoms was higher in women than men (OR: 1.51 [1.46,1.55]) and, conditional on reporting symptoms, risk of persistent symptoms increased linearly with age by 3.5 percentage points per decade of life. Obesity, smoking or vaping, hospitalisation, and deprivation were also associated with a higher probability of persistent symptoms, while Asian ethnicity was associated with a lower probability. Two stable clusters were identified based on symptoms that persisted for 12 weeks or more: in the largest cluster, tiredness predominated, while in the second there was a high prevalence of respiratory and related symptoms.

InterpretationA substantial proportion of people with symptomatic COVID-19 go on to have persistent symptoms for 12 weeks or more, which is age-dependent. Clinicians need to be aware of the differing manifestations of Long COVID which may require tailored therapeutic approaches. Managing the long-term sequelae of SARS-CoV-2 infection in the population will remain a major challenge for health services in the next stage of the pandemic.

FundingThe study was funded by the Department of Health and Social Care in England.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSRecent systematic reviews have documented the wide range of symptoms and reported prevalence of persistent symptoms following COVID-19. A dynamic review of Long COVID studies (NIHR Evidence) in March 2021 summarised the literature on the prevalence of persistent symptoms after acute COVID19, and reported that most studies (14) were of hospitalised patients, with higher prevalence of persistent symptoms compared with two community-based studies. There was limited evidence from community studies beyond 12 weeks. Another systematic review reported a median of over 70% of people with symptoms lasting at least 60 days. A review of risk factors for Long COVID found consistent evidence for an increased risk amongst women and those with high body mass index (BMI) but inconsistent findings on the role of age and little evidence concerning risks among different socioeconomic or ethnic groups which are often not well captured in routine healthcare records. Long COVID is increasingly recognised as heterogenous, likely underpinned by differing biological mechanisms, but there is not yet consensus on defining subtypes of the condition.

Added value of this studyThis community-based study of over half a million people was designed to be representative of the adult population of England. A random sample of adults ages 18 years and above registered with a GP were invited irrespective of previous access to services for COVID-19, providing an estimate of population prevalence that was representative of the whole population. The findings show substantial declines in symptom prevalence over the first 12 weeks following Covid-19, reported by nearly one fifth of respondents, of whom over a third remained symptomatic at 12 weeks and beyond, with little evidence for decline thereafter.

Risk factors identified for persistent symptoms (12 weeks or more) suggestive of Long COVID confirm some previous findings - an increased risk in women, obese and overweight individuals and those hospitalised for COVID-19, with strong evidence for an increasing risk with age. Additional evidence was found for an increased risk in those with lower income, smoking or vaping and healthcare or care home workers. A lower risk was found in those of Asian ethnicity.

Clustering identified two distinct groups of individuals with different symptom profiles at 12 weeks, highlighting the heterogeneity of clinical presentation. The smaller cluster had higher prevalence of respiratory and related symptoms, while for those in the larger cluster tiredness was the dominant symptom, with lower prevalence of organ-specific symptoms.

Implications of available evidenceThere is a high prevalence of persistent symptoms beyond 12 weeks after acute COVID-19, with little evidence of decline thereafter. This highlights the needs for greater support for patients, both through specialised services and, for those from low-income settings, financial support. The understanding that there are distinct clusters of persistent symptoms, the most common of which is dominated by fatigue, is important for the recognition and clinical management of the condition outside of specialised services.


title: Clinicogenomic analysis of breakthrough infections by SARS CoV2 variants after ChAdOx1 nCoV- 19 vaccination in healthcare workers

abstract:
BackgroundIndia saw a massive surge and emergence of SARS CoV2 variants. We elucidated clinical and humoral immune response and genomic analysis of vaccine breakthrough (VBT) infections after ChAdOx1 nCoV-19 vaccine in healthcare workers (HCWs).

MethodsThe study was conducted on 1858 HCWs receiving two doses of ChAdOx1 nCoV-19 vaccine. Serial blood samples were collected to measure SARS CoV2 IgG and neutralizing antibodies. 46 RT-PCR positive samples from VBT infections were subjected to whole genome sequencing (WGS).

ResultsInfection was confirmed in 219 (11.79%) HCWs of which 21.46% (47/219) were non-vaccinated, significantly more (p <0.001) than 9.52% (156/1639) vaccinated group. VBT infections were significantly higher in doctors and nurses compared to other hospital staff (p <0.001). Unvaccinated individuals had 1.57 times higher risk of infection compared to partially vaccinated (p 0.02) and 2.49 times than fully vaccinated (<0.001). Partially vaccinated were at higher risk of infection than fully vaccinated (RR 1.58,p 0.01). There were 3 (1.36%) severe cases and 1 death in unvaccinated group compared to none in the vaccinated. Non-response after 14 days of second dose was seen in 6.5% (3/46) and low antibody levels (1-4.62 S/CO) in 8.69% (4/46). Delta variant (B.1.617.2) was dominant (69.5%) and reinfection was documented in 4 (0.06%) HCWs.

ConclusionsNearly one in ten vaccinated HCWs can get infected, more so with only single dose (13.65%) than two doses (8.62%). Fully vaccinated are better protected with higher humoral immune response. Genomic analysis revealed an alarming rise of Delta variant (B.1.617.2) in VBT infections.


title: An increased ratio of SARS-CoV-2 positive to negative sense genomic and subgenomic RNAs within routine diagnostic upper respiratory tract swabs may be a marker of virion shedding

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly in the global population since its emergence in humans in late 2019. Replication of SARS-CoV-2 is characterised by transcription and replication of genomic length RNA and shorter subgenomic RNAs to produce virus proteins and ultimately progeny virions. Here we explore the pattern of both genome-length and subgenomic RNAs and positive and negative strand SARS-CoV-2 RNAs in diagnostic nasopharyngeal swabs using sensitive probe based PCR assays as well as Ampliseq panels designed to target subgenomic RNAs. We successfully developed a multiplex PCR assay to simultaneously measure the relative amount of SARS-CoV-2 full length genomic RNA as well as subgenomic N gene and subgenomic ORF7a RNA. We found that subgenomic RNAs and both positive and negative strand RNA can be readily detected in swab samples taken up to 19 and 17 days post symptom onset respectively, and are strongly correlated with the amount of genomic length RNA present within a sample. Their detection and measurement is therefore unlikely to provide anymore insight into the stage of infection and potential infectivity of an individual beyond what can already be inferred from the total viral RNA load measured by routine diagnostic SARS-CoV-2 PCRs. Using both an original commercial and two custom SARS-CoV-2 Ampliseq mini-panels, we identified that both ORF7a and N gene subgenomic RNAs were consistently the most abundant subgenomic RNAs. We were also able to identify several non-canonical subgenomic RNAs, including one which could potentially be used to translate the ORF7b protein and others which could be used to translate ORF9b and the ORF N* which has arisen from a new transcription regulatory sequence recently created by mutations after SARS-CoV-2 jumped into people. SARS-CoV-2 genomic length and subgenomic length RNAs were present in samples even if cellular RNA was degraded, further indicating that these molecules are likely protected from degradation by the membrane structures seen in SARS-CoV-2 infected cells.


title: Subgenomic and negative sense RNAs are not markers of active replication of SARS-CoV-2 in nasopharyngeal swabs


title: PERFORMANCE AND UTILITY OF AN ORAL FLUID-BASED RAPID POINT-OF-CARE TEST FOR SARS-COV-2 ANTIBODY RESPONSE FOLLOWING COVID-19 INFECTION OR VACCINATION

abstract: Analysis of anti-SARS-CoV-2 antibodies can identify recent-onset or prior COVID-19 infection or vaccine-induced humoral immunity. We have developed a rapid point-of-care test for IgG, M, or A-class immunoglobulins that recognize the S1 domain of the SARS-CoV-2 spike protein (CovAb). The test employs a lateral-flow strip design with a recombinant SARS-CoV-2 spike protein S1 domain capture antigen to detect anti-SARS-CoV-2 antibodies in oral fluid samples. Oral fluid samples are collected with a swab that captures the gingival crevicular fluid component of oral fluid that represents a plasma transudate and that is the primary source of oral fluid monomeric antibodies. The sensitivity of the CovAb test is 97.29% and the specificity is 98.13%, and the results obtained are similar to those obtained using matched fingerstick whole blood samples and in an EUA-approved commercial serology test. Oral fluid SARS-CoV-2 antibodies could be detected in subjects more than 7 months post-symptom onset. We also demonstrate the utility of the CovAb test in characterizing adaptive immune responses to vaccination in COVID-19-naive and exposed populations after first and second vaccine doses and show that significant heterogeneity in magnitude of antibody titers achieved is seen after both doses and that prior COVID-19 exposure increases the adaptive immune response to vaccination.


title: RT-LAMP has high accuracy for detecting SARS-CoV-2 in saliva and naso/oropharyngeal swabs from asymptomatic and symptomatic individuals

abstract: Previous studies have described RT-LAMP methodology for the rapid detection of SARS-CoV-2 in nasopharyngeal (NP) and oropharyngeal (OP) swab and saliva samples. This study describes the validation of an improved sample preparation method for extraction free RT-LAMP and defines the clinical performance of four different RT-LAMP assay formats for detection of SARS-CoV-2 within a multisite clinical evaluation. Direct RT-LAMP was performed on 559 swabs and 86,760 saliva samples and RNA RT-LAMP on extracted RNA from 12,619 swabs and 12,521 saliva from asymptomatic and symptomatic individuals across healthcare and community settings. For Direct RT-LAMP, overall diagnostic sensitivity (DSe) of 70.35% (95% CI 63.48-76.60%) on swabs and 84.62% (79.50-88.88%) on saliva was observed, with diagnostic specificity (DSp) of 100% (98.98-100.00%) on swabs and 100% (99.72-100.00%) on saliva when compared to RT-qPCR; analysing samples with RT-qPCR ORF1ab CT values of [≤]25 and [≤]33, DSe of 100% (96.34-100%) and 77.78% (70.99-83.62%) for swabs were observed, and 99.01% (94.61-99.97%) and 87.61% (82.69-91.54%) for saliva, respectively. For RNA RT-LAMP, overall DSe and DSp were 96.06% (92.88-98.12%) and 99.99% (99.95-100%) for swabs, and 80.65% (73.54-86.54%) and 99.99% (99.95-100%) for saliva, respectively. These findings demonstrate that RT-LAMP is applicable to a variety of use-cases, including frequent, interval-based testing of saliva with Direct RT-LAMP from asymptomatic individuals that may otherwise be missed using symptomatic testing alone.


title: A Deep Learning Model for Screening Type 2 Diabetes from Retinal Photographs

abstract:
ObjectiveWe aimed to develop and evaluate a non-invasive deep learning algorithm for screening type 2 diabetes in UK Biobank participants using retinal images.

Research Design and MethodsThe deep learning model for prediction of type 2 diabetes was trained on retinal images from 50,077 UK Biobank participants and tested on 12,185 participants. We evaluated its performance in terms of predicting traditional risk factors (TRFs) and genetic risk for diabetes. Next, we compared the performance of three models in predicting type 2 diabetes using 1) an image-only deep learning algorithm, 2) TRFs, 3) the combination of the algorithm and TRFs. Assessing net reclassification improvement (NRI) allowed quantification of the improvement afforded by adding the algorithm to the TRF model.

ResultsWhen predicting TRFs with the deep learning algorithm, the areas under the curve (AUCs) obtained with the validation set for age, sex, and HbA1c status were 0.931 (0.928-0.934), 0.933 (0.929-0.936), and 0.734 (0.715-0.752), respectively. When predicting type 2 diabetes, the AUC of the composite logistic model using non-invasive TRFs was 0.810 (0.790-0.830), and that for the deep learning model using only fundus images was 0.731 (0.707-0.756). Upon addition of TRFs to the deep learning algorithm, discriminative performance was improved to 0.844 (0.826-0.861). The addition of the algorithm to the TRFs model improved risk stratification with an overall NRI of 50.8%.

ConclusionsOur results demonstrate that this deep learning algorithm can be a useful tool for stratifying individuals at high risk of type 2 diabetes in the general population.

category: endocrinology


title: Characterizing parametric differences between the two waves of COVID-19 in India

abstract: The first case of COVID-19 in India was reported on January 30, 2020 [1]. The number of infections rose steeply and preventative measures such as lockdowns were implemented to slow down the spread of the disease. Infections peaked around mid-September the same year and the cases gradually started declining. Following the relaxation of lockdown and the appearance of mutant strains of the virus, a much severe second wave of COVID-19 emerged starting mid-February. For characterization and comparison of both the waves, a SIQR (Susceptible-Infected-Quarantined-Removed) model is used in this paper. The results indicate that a single patient can infect approximately 2.44 individuals in the population. The epidemic doubling time was calculated to be 11.8 days. It is predicted that the actual number of infected patients is grossly underestimated (by a factor of 16) by current testing methods.

category: epidemiology


title: The Emergence of SARS-CoV-2 Variant Lambda (C.37) in South America

abstract: We report the emergence of a novel lineage of SARS-CoV-2 in South America, termed C.37. It presents seven nonsynonymous mutations in the Spike gene ({Delta}247-253, G75V, T76I, L452Q, F490S, T859N) and a deletion in the ORF1a gene ({Delta}3675-3677) also found in variants of concern (VOCs) Alpha, Beta, and Gamma. Initially reported in Lima, Peru, in late December 2020, it now accounts for 97% of Peruvian public genomes in April 2021. It is expanding in Chile and Argentina, and there is evidence of onward transmission in Colombia, Ecuador, Mexico, the USA, Germany, and Israel. On June 15, 2021, the World Health Organization designated C.37 as Variant of Interest (VOI) Lambda.


title: Multi-contrast magnetic resonance imaging of visual white matter pathways in glaucoma patients

abstract:
PurposeGlaucoma is a disorder that involves visual field loss caused by retinal ganglion cell damage. Previous diffusion magnetic resonance imaging (dMRI) studies have demonstrated that retinal ganglion cell damage affects tissues in the optic tract (OT) and optic radiation (OR). However, because previous studies have used a simple diffusion tensor model to analyze dMRI data, the microstructural interpretation of white matter tissue changes remains uncertain. In this study, we used a multi-contrast MRI approach to further clarify the type of microstructural damage that occurs in glaucoma patients.

MethodsWe collected multi-shell dMRI data from 17 glaucoma patients and 30 controls using 3T MRI. Using the dMRI data, we estimated three types of tissue property metrics: intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (IsoV). Quantitative T1 (qT1) data, which may be relatively specific to myelin, were collected from all subjects.

ResultsIn the OT, all four metrics showed significant differences between the glaucoma and control groups. In the OR, only the ICVF showed significant between-group differences. ICVF was significantly correlated with qT1 in the OR of glaucoma patients, although qT1 did not show any abnormality at the group level.

ConclusionsOur results suggest that at the group level, tissue changes in the glaucoma patients OR might be explained by axonal damage, which is reflected in the intracellular diffusion signals, rather than myelin damage. The significant correlation between ICVF and qT1 suggests that myelin damage might also occur in a smaller number of severe cases.

category: ophthalmology


title: LeMeDISCO: A computational method for large-scale prediction & molecular interpretation of disease comorbidity

abstract: Often different diseases tend to co-occur (i.e., they are comorbid), which yields the question: what is the molecular basis of their coincidence? Perhaps, common proteins are comorbid disease drivers. To understand the origin of disease comorbidity and to identify the essential proteins and pathways underlying comorbid diseases, we developed LeMeDISCO (Large-Scale Molecular Interpretation of Disease Comorbidity), an algorithm that predicts disease comorbidities from shared mode of action (MOA) proteins predicted by the AI-based MEDICASCY algorithm. LeMeDISCO was applied to predict the general occurrence of comorbid diseases for 3608 distinct diseases. To illustrate LeMeDISCOs power, we elucidate the possible etiology of coronary artery disease and ovarian cancer by determining the comorbidity enriched MOA proteins and pathways and suggest hypotheses for subsequent scientific investigation. The LeMeDISCO web server is available for academic users at: http://sites.gatech.edu/cssb/LeMeDISCO.

category: health informatics


title: Trends and Variation in Data Quality on the EU Clinical Trials Register: A Cross-Sectional Study

abstract: The EU Clinical Trial Register (EUCTR) is a public facing portal containing information on trials of medicinal products conducted in the European Union (EU) and European Economic Area (EEA). Today, the registry holds information on over 30,000 trials. Given its distinct regulatory purpose, and results reporting requirements, the EUCTR should be a valuable open-source hub for trial information. Past work examining the EUCTR has suggested that data quality on the registry may be lacking. Using the full EUCTR public dataset, we examined areas in which national regulators are expected to ensure data quality including the posting of registrations, updating trial completion information, and monitoring results posting in line with EU guidelines. We identified issues across all areas examined with notable research hubs like France, Spain, and The Netherlands lacking consistent and complete data on the registry. These deficiencies complicate the utility of the EUCTR for research, transparency, and accountability efforts.

category: health policy


title: Pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: a retrospective record linkage cohort study

abstract:
BackgroundThere is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCV) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among under-vaccinated Australian children.

MethodsBirth and vaccination records, IPD notifications and hospitalisations were individually linked for children aged < five years, born between 2001 and 2012 in two Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD, (2) all-cause pneumonia and (3) pneumococcal and lobar pneumonia hospitalisation in under-vaccinated children. Under-vaccinated children received < two doses of PCV at < 12 months of age and no doses at [≥] 12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph. The main limitations of this study include the potential for differential loss to follow-up, geographical misclassification of children (based on addressed at birth only) and unmeasured confounders.

FindingsThere were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% CI 0.958-0.975, p-value <0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990-0.994, p-value<0.001) among under-vaccinated children. Subgroup analyses for children < four months old, urban, rural and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Fifty-percent coverage of PCV7 among children < five years of age prevented up to 72.5% (95% CI 51.6-84.4) of PCV7-type IPD among under-vaccinated children, while 90% coverage prevented 95.2% (95% CI 89.4-97.8).

ConclusionsIn this study we observed substantial indirect protection at low PCV coverage, challenging assumptions high vaccine coverage is required.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIPneumococcal conjugate vaccines (PCVs) reduce the burden of pneumococcal disease in vaccinated and unvaccinated populations through both direct and indirect (herd) effects.
C_LIO_LIThe indirect effects comprise a substantial component of overall vaccine impact, contributing to the cost-effectiveness of the vaccine but little is known about what factors contribute to herd protection, including vaccination coverage.
C_LIO_LIIn this study, we examined association between PCV coverage and indirect effects within in diverse populations within Australia
C_LI

What did the researchers do and find?O_LIUsing a large dataset of 1.3 million children from two states in Australia, we quantified the relationship between PCV coverage within small geographical units and indirect protection against pneumococcal disease. We also performed similar analyses for infants too young to be fully vaccinated, urban, rural and Indigenous populations.
C_LIO_LIThere were strong inverse relationships between PCV coverage and the incidence of severe invasive disease due to vaccine types and pneumonia hospitalisations among under-vaccinated children i.e. higher coverage were associated with greater reductions in disease due to indirect effects. We also found substantial indirect effects at relatively low levels of PCV coverage. We estimated that 50% and 90% coverage of 7-valent PCV (PCV7) among children under five years of age prevented almost three-quarters (72.5%, 95% CI 51.6-84.4) and almost all (95.2%, 95% CI 89.4-97.8) of PCV7-type severe invasive disease, respectively. For pneumonia, we estimated that 50% and 90% coverage was sufficient to prevent one-third (33.3%, 95% CI 27.3-38.8) and about half (51.7%, 95% CI 43.7-58.6) of all-cause pneumonia hospitalisations among under-vaccinated children.
C_LIO_LIThese trends were similar for children less than four months old, urban, rural and Indigenous populations, although these effects were smaller for rural and Indigenous populations. There was also a trend towards decreasing incidence of PCV13-type IPD among under-vaccinated children as PCV13 coverage increased.
C_LI

What do these findings mean?O_LIOur results challenge existing assumptions that high PCV coverage is required to achieve substantial indirect protection.
C_LIO_LIUnderstanding the determinants of indirect effects are particularly urgent as countries that have controlled vaccine-type pneumococcal disease consider using reducing the number of PCV doses (from three to two). Reduced dose schedules have the potential to significantly lower program costs while maintaining vaccine impact, providing indirect protection is achieved and preserved.
C_LI


title: Dermatophytic Diseases: A Review of Tinea Pedis

abstract:
Studies in skin diseases, particularly Tinea pedis are very rare in Ghana leading to low investment in dermatological services in the country and the African continent. Globally, Tinea pedis affects about 15% of the worlds population. Importantly, it is a major public health problem and socioeconomic issue. Currently, the most recommended treatment for Tinea pedis infection are polyenes, azoles, allylamines, and fluorocytosines. Although these drugs are effective, they do have adverse side effects and are limited in the clinical settings in developing countries especially Ghana.

MethodResearch papers were collected from Pubmed, Google scholar, chemical abstracts, and journal websites, reporting both in vitro and in vivo information on Tinea pedis. General information on Tinea pedis, the methods of infection, transfer, treatment options, and resistance were obtained after screening the articles. Many agents are involved in cases of Tinea pedis but are predominantly caused by Trichophyton rubrum which feeds on the keratinous layer of the topmost skin of the foot causing skin discoloration, itching, and maceration. The disease is influenced by individual lifestyle, environmental conditions, and individual factors such as age, sex, and host immunity and is prevented by the maintenance of good personal hygiene.

Tinea pedis like other tinea infections are treated with both topical and systemic agents. The classes of medications used in the treatment of Tinea pedis are polyenes, azoles, allylamines, and fluorocytosines. Tinea pedis antifungal resistance development could be partly associated with incomplete medication and misuse of antifungal medications. Additionally, patients with serious underlying health conditions such as compromised immune systems like HIV/AIDS, diabetes, radiotherapy for cancer, and transplantation could complicate resistance.

ConclusionAlthough, fungal diseases do not cause epidemics the increasing rate of fungal infections and therefore Tinea pedis has to be checked and prevented. High budgets are made in the development of medications which mostly lose their effectiveness over time due to resistance development. Good personal hygiene is very effective but the available medications must be used appropriately for effective treatment and resistance avoidance. Infection prevention and control, tracking and data sharing, good and easily accessible antifungals, vaccines, and maintenance of personal and environmental hygiene are the topmost preventive measures against resistance development.

category: dermatology


title: Gestational diabetes mellitus in women born small or premature: Systematic review and meta-analysis

abstract:
BackgroundWomen born preterm or with low birthweight (LBW) have an increased future risk of gestational diabetes mellitus (GDM) during pregnancy; however, a quantitative summary of evidence is lacking.

In this study, we aimed to investigate whether being born preterm, or with LBW or small for gestational age (SGA) are associated with GDM risk.

MethodsWe searched the MEDLINE, Embase, and CINAHL databases and study registries, including ClinicalTrials.gov and ICTRP, from launch until 29 October 2020 for observational studies examining the association between birth weight or gestational age and GDM were eligible. We pooled the odds ratios and 95% confidence intervals using the DerSimonian and Laird random-effects model.

ResultsEighteen studies were included (N = 827,382). The meta-analysis showed that being born preterm, with LBW or SGA was associated with increased risk of GDM (pooled odds ratio = 1.84; 95% confidence interval: 1.54 to 2.20; I2 = 78.3%; {tau}2 = 0.07). Given a GDM prevalence of 2.0%, 10%, and 20%, the absolute risk differences were 1.6%, 7.0%, and 11.5%, respectively. The certainty of evidence was low due to serious concerns of risk of bias and publication bias.

ConclusionWomen born prematurely, with LBW or SGA status, may be at increased risk for GDM. However, whether this should be considered in clinical decision-making depends on the prevalence of GDM.

What is already known on this subject?Approximately 10-15% of infants are born small or premature worldwide, and these children are at high risk of diseases, such as type 1 and 2 diabetes mellitus, hypertension, obesity, and kidney disease, in adulthood. A narrative review reported in 2007 that women born with LBW are at risk of gestational diabetes mellitus, but included a small number of studies. Several subsequent studies have been published since then, but there is no quantitative summary of the relevant evidence to date.

What this study adds?This is the first systematic review and meta-analysis of observational studies that provides a comprehensive summary of evidence on the association between birth size or premature birth and future GDM risk including previously unpublished data and a large sample size. LBW, preterm birth, and SGA status may be prognostic factors for GDM.


title: Tuberculostearic acid, a potential parameter for scoring system construction for Tuberculous meningitis diagnosis

abstract: This study aimed to validate the value of tuberculostearic acid (TBSA) whether it could implicate the existence of M. tuberculosis and assist for clinical diagnosis of Tuberculous Meningitis (TBM). Gas Chromatography/mass spectrometry was used to detect TBSA in the chemically pretreated cerebrospinal fluid of suspected TBM patients. In total, 140 patients were admitted for our study included 27 confirm TBM patients and 50 TBSA positive patients. Sensitivity of 0.7407 (CI 95%: 0.5372-0.8889) and specificity of 0.7345 (CI 95%: 0.6432-0.8132) were calculated. The Lancet consensus scoring system was also applied to evaluate the possibility of TBM in suspected patients, finding that TBSA positive patients showed a similar distributive grouping as the definite TBM patients. Our study implicates that the prospective use of TBSA is worth combining into a scoring system for characterizing the features of Mtb, showing a great potential of TBM diagnosis by TBSA in the future.

category: neurology


title: Feeding Activated Bifidobacterium infantis EVC001 to Very Low Birth Weight Infants is Associated with Significant Reduction in Rates of Necrotizing Enterocolitis

abstract:
ObjectivesTo assess the effects of Bifidobacterium infantis EVC001 administration on the rate of necrotizing enterocolitis (NEC) in preterm infants in a single Level IV NICU.

Study DesignThis was a retrospective observational analysis of 2 cohorts of VLBW infants (+/-B. infantis EVC001 probiotic) at OHSU from 2014 to 2020. Outcomes included NEC rates and NEC-associated mortality, including subgroup analysis of ELBW infants. Fishers exact test and log binomial models were used to determine differences between cohorts and risk reduction of NEC. Adjusted number needed to treat was calculated from the cohort coefficient of the model.

ResultsIn this analysis of 483 infants, the difference in rates of NEC between cohorts was statistically significant (11.0% vs. 2.7%, P = 0.0008). The EVC001-fed cohort had a 73% risk reduction of NEC compared to the No EVC001 cohort (adjusted risk ratio 0.270, 95% CI 0.094, 0.614, P = 0.0054) resulting in an adjusted number needed to treat of 12.4 (95% CI 10.0, 23.5) for B. infantis EVC001. There was no NEC-related mortality in the EVC001-fed cohort, yielding statistically significant differences from the No EVC001 cohort overall (0% vs. 2.7%, P = 0.0274) and the ELBW subgroup (0% vs. 5.6%, P = 0.0468).

Conclusion(s)B. infantis EVC001 feeding was associated with a significant reduction in the rate of NEC and NEC-related mortality in an observational study of 483 VLBW infants. B. infantis EVC001 supplementation may be considered safe and effective for reducing morbidity and mortality in the NICU.

category: pediatrics


title: Perceptions and acceptance of COVID-19 vaccine among pregnant and lactating women in Singapore: A cross-sectional study

abstract:
IntroductionVaccination is critical in controlling the coronavirus disease 19 (COVID-19) pandemic. However, vaccine perception and acceptance among pregnant and lactating women is unknown in Singapore. We aimed to determine the acceptance of COVID-19 vaccination among these two groups of women in Singapore, and factors associated with vaccine acceptance.

MethodsWe conducted an anonymous, online survey on the perception and acceptance of the COVID-19 vaccine in pregnant and lactating women at a tertiary hospital in Singapore from 1st March to 31st May 2021. Information on demographics and knowledge were collected, and these factors were assessed for their relationship with vaccine acceptance.

ResultsA total of 201 pregnant and 207 lactating women participated. Vaccine acceptance rates in pregnant and lactating women were 30.3% and 16.9% respectively. Pregnant women who were unsure or unwilling to take the vaccine cited concerns about safety of the vaccine during pregnancy (92.9%), while lactating women were concerned about potential long-term negative effects on the breastfeeding child (75.6%). Other factors significantly associated with vaccine acceptance included a lower monthly household income or education level, appropriate knowledge regarding vaccine mechanism and higher perceived maternal risk of COVID-19. Most pregnant (70.0%) and lactating women (83.7%) were willing to take the vaccine only when more safety data during pregnancy and breastfeeding were available.

ConclusionsCOVID-19 vaccine acceptance was low among pregnant and lactating women in Singapore. Addressing safety concerns when more data is available and education on mechanism of vaccine action will likely improve acceptance among these women.

category: public and global health


title: Ultra Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma

abstract: The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to [~]1000x median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7; novel mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells, allowing for the analysis for clinically relevant genomic variants in large cohorts of cHL patients.


title: Transmission event of SARS-CoV-2 Delta variant reveals multiple vaccine breakthrough infections

abstract:
ImportanceVaccine breakthrough by an emergent SARS-CoV-2 variant poses a great risk to global public health.

ObjectiveTo determine the SARS-CoV-2 variant responsible for 6 cases of vaccine breakthrough.

DesignNasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 by qPCR for Wuhan-Hu1 and Alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant.

SettingTransmission event occurred at events surrounding a wedding outside of Houston, TX. Two patients from India, likely transmitted the Delta variant to other guests.

ParticipantsFollowing a positive SARS-CoV-2 qPCR test at a third-party site, six fully vaccinated patients were investigated. Three males and three females ranged from 53 to 69 years old. One patient suffered from diabetes while three others were classified as overweight. No significant other comorbidities were identified. None of the patients had a history of failed vaccination.

Key PointsO_ST_ABSQuestionC_ST_ABSWhich SARS-CoV-2 variant is responsible for 6 cases of vaccine breakthrough, one interventional monoclonal antibody treatment, and one death?

FindingsViral sequencing revealed 6 vaccinated patients were infected with the Delta SARS-CoV-2 variant. With no histories of vaccine breakthrough, this suggests Delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152.

MeaningDelta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with increased transmissibility over Alpha variant and possible vaccine breakthrough.


title: Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

abstract: Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in a general population are related to ASD risk and common sleep problems like insomnia in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as parent reported sleep disturbances in children diagnosed with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection and MSSNG database, as well as 7463 individuals from two unselected populations (IMAGEN and Generation Scotland). We identified 320 and 626 rare CNVs encompassing circadian genes and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (but not duplications) were also associated with ASD. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Duplications containing circadian genes were associated with shorter sleep duration (22 minutes). Only insomnia risk genes intolerant to haploinsufficiency increased insomnia traits when duplicated. Overall, CNVs encompassing circadian and insomnia risk genes increase ASD risk despite small impacts on sleep disturbances.


title: Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis

abstract:
PurposeThe mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood. We evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability.

Patients and methodsAccording to our IPH-based protocol, 18 eligible patients with CRC-LM, who underwent complete tumor resection after neo-adjuvant treatment, with a total of 122 multi-regional tumor and perioperative liquid biopsies were analyzed via next-generation sequencing (NGS) of a custom 77-gene panel. The primary endpoints were the extent of IPH and the frequency of actionable mutations.

ResultsThe proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored actionable mutations, with an average of 3.2 oncogenic events per patient, for molecularly targeted drugs either approved or under evaluation in ongoing clinical trials or in pre-clinical studies.

ConclusionsOur proof-of-concept prospective study provides initial evidence and warrants the conduction of precision oncology trials to test the potential clinical utility of IPH-driven matched therapy.


title: Evidence of widespread endemic populations of highly multidrug-resistant  Klebsiella pneumoniae  seen concurrently through the lens of two hospital intensive care units in Vietnam

abstract:
BackgroundExtended spectrum beta-lactamases-producing (ESBL-P) and/or carbapenem-resistant (CR) Klebsiella pneumoniae have severely restricted available treatment options in healthcare settings in Vietnam. Understanding the diversity and transmission mechanisms of ESBL- and carbapenemase-encoding K. pneumoniae is important in both hospital and community settings for patient management.

MethodsWe conducted a 6-month prospective cohort study of 69 Intensive care unit (ICU) patients from two hospitals in Hanoi, Vietnam. Longitudinally collected samples from patients and the ICU environment were cultured on selective media, and 357 K. pneumoniae colonies were whole genome sequenced. We performed phylogenetic analyses, and correlated phenotypic antimicrobial susceptibility testing with genotypic features of K. pneumoniae isolates. We constructed transmission networks of patient samples, relating ICU admission times and locations with genetic similarity of infecting K. pneumoniae.

FindingsDespite being geographically and clinically separated, the two hospitals shared closely related strains carrying the same array of antimicrobial resistance genes. Many patients carried the same resistant K. pneumoniae clone from admission to discharge. 45.9% of total isolates carried both ESBL- and carbapenemase-encoding genes, with high minimum inhibitory concentrations. We found a novel co-occurrence of blaKPC-2 and blaNDM-1 in 46. 6% of samples from the globally successful ST15 lineage.

InterpretationThese results highlight the high prevalence of ESBL-positive carbapenem-resistant K. pneumoniae in Vietnamese ICUs. Through studying K. pneumoniae ST15 in detail, we illustrated how important resistance genes are coalescing in stains carried broadly by patients entering the two hospitals directly or through referral.

FundingThis study was supported by the Medical Research Council Newton Fund, United Kingdom (grant MR/N029399/1); the Ministry of Science and Technology, Vietnam (grant HNQT/SPThP/04.16); This research was funded in whole by the Wellcome Trust (grant 206194). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.


title: Characterizing Dual Combination Therapy Use in Treatment Escalation of Hypertension: Real-World Evidence from Multinational Cohorts

abstract:
BackgroundOver one billion adults have hypertension globally, of whom approximately 70% cannot achieve blood pressure control goal with monotherapy alone. Data are lacking on patterns of dual combination therapies prescribed to patients who escalate from monotherapy in routine practice.

MethodsUsing eleven electronic health record databases that cover 118 million patients across eight countries/regions, we characterized the initiation of antihypertensive dual combination therapies for patients with hypertension. In each database, we first constructed twelve exposure cohorts of patients who newly initiate dual combination therapy with one of the four most commonly used antihypertensive drug classes (angiotensin-converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB]; calcium channel blocker [CCB]; beta-blocker; and thiazide or thiazide-like diuretic) after escalating from monotherapy with one of the three alternative classes. Using these cohorts, we then described dual combination therapy utilization, stratified by age, gender, history of cardiovascular diseases (CVD), and country.

ResultsAcross data sources, we identified 980,648 patients with hypertension initiating dual combination therapy with antihypertensive agents after escalating from monotherapy: 12,541 from Australia, 6,980 from South Korea, 2,096 from Singapore, 7,008 from China, 16,663 from Taiwan, 103,994 from France, 76,082 from Italy, and 754,137 from the United States (US). Significant variations in treatment utilization existed across countries and patient subgroups. In Australia and Singapore, starting an ACEi/ARB monotherapy followed by a CCB was most common while in South Korea, China and Taiwan, starting a CCB monotherapy followed by an ACEi/ARB was most common. In Italy, France, and the US, sequential use of an ACEi/ARB monotherapy followed by a diuretic was most common. Younger patients were more likely to be prescribed ACEi/ARB followed by either a CCB or a diuretic compared with older patients. Women were more likely to be prescribed diuretics then an ACEi/ARB or a CCB compared with men. Among patients with history of CVD, ACEi/ARB followed by beta-blocker, and beta-blocker followed by ACEi/ARB were more commonly prescribed.

ConclusionThis is the largest and most comprehensive study characterizing the real-world utilization of dual combination therapies in treating hypertension. Large variation in the transition between monotherapy and dual combination therapy for hypertension was observed across countries. These results highlight the need for future research to identify which second-line dual combination therapy is most effective in practice.

category: cardiovascular medicine


title: Comparative Analysis of Major Incident Triage Tools in Children. A UK population based analysis.

abstract:
IntroductionTriage is a key principle in the effective management of major incidents. There is currently a paucity of evidence to guide the triage of children. The aim of this study was to perform a comparative analysis of nine adult and paediatric triage tools, including the novel  Sheffield Paediatric Triage Tool (SPTT), assessing their ability in identifying patients needing life-saving interventions (LSI).

MethodsA ten-year retrospective database review of TARN data for paediatric patients (<16years) was performed. Primary outcome was identification of patients receiving one or more LSIs from a previously defined list. Secondary outcomes included mortality and prediction of ISS>15. Primary analysis was conducted on patients with complete pre-hospital physiological data with planned secondary analyses using first recorded data. Performance characteristics were evaluated using sensitivity, specificity, under and over-triage.

Results15133 patients met TARN inclusion criteria. 4962 (32.8%) had complete pre-hospital physiological data and 8255 (54.5%) had complete first recorded physiological data. Male patients predominated (69.5%), sustaining blunt trauma (95.4%) with a median ISS of 9. 875 patients (17.6%) received at least one LSI.

The SPTT demonstrated the greatest sensitivity of all triage tools at identifying need for LSI (92.2%) but was associated with the highest rate of over-triage (75.0%). Both the PTT (sensitivity 34.1%) and JumpSTART (sensitivity 45.0%) performed less well at identifying LSI. By contrast, the adult MPTT-24 triage tool had the second highest sensitivity (80.8%) with tolerable rates of over-triage (70.2%).

ConclusionThe SPTT and MPTT-24 outperform existing paediatric triage tools at identifying those patients requiring LSIs. This may necessitate a change in recommended practice. Further work is needed to determine the optimum method of paediatric major incident triage, but consideration should be given to simplifying major incident triage by the use of one generic tool (the MPTT-24) for adults and children.

What this paper adds?O_ST_ABSSection 1: What is already known on this subject?C_ST_ABSTriage is a key principle in the effective management of major incidents. There is currently a paucity of evidence surrounding the use of existing paediatric major incident tools.

In the UK, two methods of paediatric major incident triage exist, the Paediatric Triage Tape and the JumpSTART method. In previous studies they have demonstrated less than 50% sensitivity at identifying children in need of life-saving interventions.

This study performed a comparative analysis on a UK paediatric trauma registry population and included a newly derived triage tool, the SPTT.

Section 2: What this study addsThe PTT and JumpSTART perform poorly (<45% sensitivity) in this paediatric trauma registry population.

The SPTT and the existing adult triage tool the MPTT-24 outperform all methods. Consideration should be given to simplifying major incident triage by the use of a single generic tool for both adults and children.

category: emergency medicine


title: Facilitators and Barriers to Compliance with COVID-19 Guidelines: A Structural Topic Modelling Analysis of Free-Text Data from 17,500 UK Adults

abstract:
BackgroundDuring the COVID-19 pandemic, the UK government has implemented a series of guidelines, rules, and restrictions to change citizens behaviour to tackle the spread of the virus, such as the promotion of face-masks and the imposition of lockdown stay-at-home orders. The success of these measures requires active co-operation on the part of citizens, but compliance has not been complete. Detailed data is required on the factors aiding or hindering compliance with these measures.

MethodsTo understand the facilitators and barriers to compliance with COVID-19 guidelines, we used structural topic modelling, a text mining technique, to extract themes from over 26,000 free-text survey responses from 17,500 UK adults, collected between 17 November and 23 December 2020.

ResultsThe main factors facilitating compliance were desires to reduce risk to ones self and ones family and friends and to, a lesser extent, the general public. Also of importance were a desire to return to normality, the availability of activities and technological means to contact family and friends, and the ability to work from home. Identified barriers were difficulties maintaining social distancing in public (due to the actions of other people or environmental constraints), the need to provide or receive support from family and friends, social isolation, missing loved one, and mental health impacts, perceiving the risks as low, social pressure to not comply, and difficulties understanding and keep abreast of changing rules. Several of the barriers and facilitators raised were related to participant characteristics. Notably, women were more likely to discuss needing to provide or receive mental health support from friends and family.

ConclusionThe results demonstrate an array of factors contribute to compliance with guidelines. Of particular policy importance, the results suggest that government communications that emphasizes the potential risks of COVID-19 and provides simple, consistent guidance on how to reduce the spread of the virus would improve compliance with preventive behaviours.


title: COVID-19 vaccine hesitancy and refusal and associated factors in an adult population in Saskatchewan, Canada: Evidence from predictive modelling

abstract:
BackgroundA high population level of vaccination is required to control the COVID-19 pandemic, but not all Canadians are convinced of the value and safety of vaccination. Understanding more about these individuals can aid in developing strategies to increase their acceptance of a COVID-19 vaccine. The objectives of this study were to describe COVID-19 vaccine acceptance, hesitancy and refusal rates and associated factors in Saskatchewan, Canada.

MethodsThis study consisted of a weighted sample of 9,252 survey responses from 7,265 Saskatchewan adults ([≥]18 years) between May 4, 2020 and April 3, 2021. The outcome variable was vaccine intention: vaccine acceptance, hesitancy, and refusal. The independent variables were layered into socio-demographic factors, risk of exposure to coronavirus, mitigating behaviours, and perceptions of COVID-19. Data were analyzed using multinomial logistic regression and a classification and regression tree.

ResultsSeventy-six percent of the respondents indicated that they had been or were willing to be vaccinated, 13% had not yet decided, and the remaining 11% said they would not be vaccinated. Factors that increased the likelihood of vaccine refusal and hesitancy were lower education level, financial instability, Indigenous status, and not being concerned about spreading the coronavirus. Perceiving COVID-19 to be more of a threat to ones community and believing that one had a higher risk of illness or death from COVID-19 decreased the likelihood of both vaccine refusal and hesitancy. Women and newcomers to Canada were more likely to be unsure about getting vaccinated. Respondents who did not plan to be vaccinated were less likely to wear face masks and practice physical distancing.

ConclusionWhile many Canadians have voluntarily and eagerly become vaccinated already, reaching sufficient coverage of the population is likely to require targeted efforts to convince those who are resistant or unsure. Identifying and overcoming any barriers to vaccination that exist within the socio-demographic groups we found were least likely to be vaccinated is a crucial component.


title: Implications of COVID-19 vaccination and public health countermeasures on SARS-CoV-2 variants of concern in Canada: evidence from a spatial hierarchical cluster analysis

abstract:
BackgroundThe influence of coronavirus disease-2019 (COVID-19) containment measures on variants of concern (VOC) has been understudied in Canada. Our objective was to identify provinces with disproportionate prevalence of VOC relative to COVID-19 mitigation efforts in provinces and territories in Canada.

MethodsWe analyzed publicly available provincial- and territorial-level data on the prevalence of VOCs in relation to mitigating factors (summarized in three measures: 1. strength of public health countermeasures: stringency index, 2. how much people moved about outside their homes: mobility index, and 3. vaccine intervention: proportion of Canadian population fully vaccinated). Using spatial agglomerative hierarchical cluster analysis (unsupervised machine learning), the provinces and territories were grouped into clusters by stringency index, mobility index and full vaccine coverage. Kruskal-Wallis test was used to determine the differences in the prevalence of VOC (Alpha, or B.1.1.7, Beta, or B.1.351, Gamma, or P.1, and Delta, or B.1.617.2 variants) between the clusters.

ResultsThree clusters of vaccine uptake and countermeasures were identified. Cluster 1 consisted of the three Canadian territories, and characterized by higher degree of vaccine deployment and lesser degree of countermeasures. Cluster 2 (located in Central Canada and Atlantic region) was typified by lesser implementation of vaccine deployment and moderate countermeasures. The third cluster was formed by provinces in the Pacific region, Central Canada, and Prairie region, with moderate vaccine deployment but stronger countermeasures. The overall and variant-specific prevalence were significantly different across the clusters.

InterpretationThis study found that implementation of COVID-19 public health measures varied across the provinces and territories. Considering the high prevalence of VOCs in Canada, completing the second dose of COVID-19 vaccine in a timely manner is crucial.


title: Testing the effects of nudging for reduced salt intake among online food delivery customers: a research protocol for a randomized controlled trial

abstract:
BackgroundChinese people on average consume almost twice as much salt as recommended by the World Health Organization. In recent years, dining out and ordering food online are increasingly popular, especially for urban residents. The aim of this study is to evaluate the effectiveness of different settings on a digital food delivery App in nudging consumers towards reduced salt options through a randomized controlled trial in China.

Methods and AnalysisThis is a randomized controlled trial with matched restaurants randomized to five parallel intervention groups plus a control group. Participating restaurants are recruited via open invitation and targeted invitation on a voluntary basis and are free to withdraw from the study at anytime. Each enrolled restaurant can select 1-3 of their most popular dishes to participate in this study. The recruitment ends at the end of June 2021. As of June 30, 285 restaurants enrolled for intervention groups and successfully completed interface set-up requirements. The primary outcome of this study is to investigate the differences in customer ordering behaviors regarding salt preference that result from changing the default settings and/or in combination with health messages before placing the order. The primary outcome will be measured by the difference between the number of regular salt orders and the number of reduced salt orders amongst the five intervention groups, and between each intervention group and the control group. We will collect order data at the end of the 2-month study period from the food delivery App. The secondary outcome is to measure if reduced the salt version of the participating dishes has less salt content than the regular version. The secondary outcome will be measured by lab testing salt content of randomly sampled dishes during the study period. In addition, we will also conduct pre- and post- intervention surveys with participating restaurants to assess their knowledge, attitude, and practice regarding salt reduction, and their perceptions on how such intervention affects their business, if at all. We will not include findings from the pre- and post-intervention interviews as an outcome but will use them to inform future restaurant- based salt reduction promotions.

DiscussionThe study will test whether changing in the choice architecture on the digital food ordering platform will promote healthier ordering behavior among consumers. Results on whether user interface modifications can promote purchases of reduced salt dishes may provide evidence to inform future sodium reduction strategies and health promotion interventions on online food ordering platforms, with the potential to apply to offline dining settings. The results may also inform current government efforts to roll out national guidelines on promoting nutrition labeling by restaurants. Despite these strengths in study design, securing the agreement of the food delivery App, recruiting individual restaurants and maintaining compliance to the interface set up through the period of the study proved to be and remains challenging.

Trial RegistrationRegistered at the Chinese Clinical Trial Registry at http://www.chictr.org.cn/searchprojen.aspx (No. ChiCTR2100047729)

Protocol versionVersion MAY112021.01

Strengths and LimitationsO_LIThis study presents an innovative and timely intervention package for promoting salt reduction for online meal ordering platform.
C_LIO_LIOur study is one of first in China and globally that tests nudging interventions on online food ordering behavior on a large-scale commercial platform and in a real-world setting.
C_LIO_LIRecruiting restaurants and ensuring their compliance remain challenging.
C_LI

category: nutrition


title: Phylogeography and transmission of M. tuberculosis in Moldova

abstract:
BackgroundThe incidence of multidrug-resistant tuberculosis (MDR-TB) remains critically high in countries of the former Soviet Union, where >20% of new cases and >50% of previously-treated cases have resistance to rifampin and isoniazid. Transmission of resistant strains, as opposed to resistance selected through inadequate treatment of drug-susceptible TB, is the main driver of incident MDR-TB in these countries.

MethodsWe conducted a prospective, genomic analysis of all culture-positive TB cases diagnosed in 2018 and 2019 in the Republic of Moldova. We used phylogenetic methods to identify putative transmission clusters; spatial and demographic data were analyzed to further describe local transmission of M. tuberculosis.

ResultsOf 2236 participants, 779 (36%) had MDR-TB, of whom 386 (50%) had never been treated previously for TB. 92% of MDR M. tuberculosis strains belonged to putative transmission clusters. Phylogenetic reconstruction identified three large clades that were comprised nearly uniformly of MDR-TB; two of these clades were of Beijing lineage and one of Ural lineage, and each had additional distinct clade-specific second-line drug resistance mutations and geographic distributions. Spatial and temporal proximity between pairs of cases within a cluster was associated with greater genomic similarity.

ConclusionsThe MDR-TB epidemic in Moldova is the result of local transmission of multiple M. tuberculosis strains, including distinct clades of highly drug-resistant M. tuberculosis with varying geographic distributions and drug resistance profiles. This study demonstrates the role of comprehensive genomic surveillance for understanding the transmission of M. tuberculosis and highlights the urgency of interventions to interrupt transmission of highly drug-resistant M. tuberculosis.


title: Importance of epidemic severity and vaccine mode of action and availability for delaying the second vaccine dose

abstract:
Following initial optimism regarding the potential for rapid vaccination, delays and shortages in vaccine supplies have occurred in many countries. Various strategies to counter this gloomy reality and speed up vaccination have been set forth, of which the most popular approach has been to delay the second vaccine dose for a longer period than originally recommended by the manufacturers. Controversy has surrounded this strategy, and overly simplistic models have been developed to shed light on this issue. Here we use three different epidemic models, all accounting for the actual COVID-19 epidemic in the Czech Republic, including the rise and eventual prevalence of the B.1.1.7 variant of SARS-CoV-2 virus and real vaccination rollout strategy, to explore when delaying the second vaccine dose from 21 days to 42 days is advantageous. Using the numbers of COVID-19-related deaths as a quantity for comparing various model scenarios, we find that vaccine mode of action at the beginning of the infection course (preventing contagion and symptom appearance), mild epidemic and sufficient vaccine supply rate call for the original inter-delay scenario of 21 days regardless of vaccine efficacy. On the contrary, for vaccine mode of action at the end of infection course (preventing severe symptoms and death), severe epidemic and low vaccine supply rate, the 42-day inter-dose period is preferable, at any plausible vaccine efficacy.

One sentence summaryWe address when delaying the second vaccine dose is advantageous, considering various epidemic severities and various vaccine actions and availabilities.


title: DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

abstract:
BackgroundDepression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability.

MethodWe investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N=8,898, mean age=49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined=2,049, mean age=79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N=423, mean age=17.1 years).

ResultWide-spread associations were found between PRS constructed using genetic risk variants for depression and DNAm in cytosine-guanine dinucleotide (CpG) probes that localised to genes involved in immune responses and neural development (NCpG=599, pBonferroni<0.05, p<6.5x10-8). The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r=0.83) and in adolescents (r=0.76). Additional analysis on the methylome-wide associations was conducted for each lead genetic risk variant. Over 40% of the independent genetic risk variants showed associations with CpG probe DNAm located in both the same (cis) and distal probes (trans) to the genetic loci (pBonferroni<0.045). Subsequent Mendelian randomisation analysis showed that DNAm and depression are mutually causal (pFDR<0.039), and there is a greater number of causal effects found from DNAm to depression (DNAm to depression: pFDR ranged from 0.045 to 2.06x10-120; depression to DNAm: pFDR ranged from 0.046 to 2.1x10-23).

ConclusionPolygenic risk scores for depression, especially those constructed from genome-wide significant genetic risk variants, showed epigenome-wide methylation association differences in the methylome associated with immune responses and brain development. We also found evidence from Mendelian randomisation evidence that DNAm may be causal to depression, as well as a causal consequence of depression.

category: psychiatry and clinical psychology


title: Men and loneliness in the Covid-19 pandemic: insights from an interview study with UK-based men

abstract:
As the SARS-COV-2 pandemic hit, the UK, like many countries, introduced severe restrictions on social contact, and injunctions of  social distancing, to reduce transmission. This led to a concern that loneliness may increase, facilitating poorer mental and physical health. Twenty qualitative interviews were conducted, with a diverse group of UK-based men, between January and March 2021, during severe restrictions. Our aim was to generate new insights into mens experience of loneliness during the pandemic, and consider the ramifications of these for continued/future restrictions, the easing of restrictions, and the future beyond the pandemic. Thematic analysis, focused on semantic themes, was employed as part of a  grounded epistemology whereby the stated perspectives of the interviewees drove the content of the study. Six themes were constructed: i) people to see and things to do (broken, changed, and new); ii) rethought and renewed recognition of what is important; iii) loneliness with a purpose; iv) loneliness as normal; v) anxiety of social contact; and vi) easier for some than others. The restrictions did cause some loneliness, particularly because of lost routines and opportunities, and the reduction in face-to-face interaction. However, a need to reduce transmission of SARS-COV-2, and a fear of catching it, became important features of participants lives that also affected loneliness and its causes. Remote forms of interaction were often utilised, and though they were imperfect, those that were dependable, were smaller than might be desired in person, and ensured a chance to speak, were constructed as more positive. The fear of Covid-19, and a loss of social skills, may mean that reducing restrictions alone will not return everyone to pre-pandemic levels of loneliness. Some believed the building of supportive local communities, and a destigmatisation of loneliness, may allow for the building of a more compassionate and less lonely society.

What is known about this topicO_LILoneliness is a public health concern, and is often a gendered experience.
C_LIO_LIPandemic related restrictions greatly reduced opportunities for social contact.
C_LIO_LIWe have a limited understanding of whether, and how, men experienced loneliness during the SARS-COV-2 pandemic.
C_LI

What this paper addsO_LIThe loss of routines, and a lack of face-to-face interaction, were the greatest challenges to loneliness, particularly among solo-living men.
C_LIO_LIRemote interaction may be better when routinised or dependable, in smaller groups, and with a structure facilitating the opportunity to speak.
C_LIO_LIAnxiety of SARS-COV-2, and identities built in relation to reducing transmission, were important influences on the causes and severity of loneliness.
C_LI


title: Human genotype-to-phenotype predictions: boosting accuracy with nonlinear models

abstract: Genotype-to-phenotype prediction is a central problem of human genetics. In recent years, it has become possible to construct complex predictive models for phenotypes, thanks to the availability of large genome data sets as well as efficient and scalable machine learning tools. In this paper, we make a three-fold contribution to this problem. First, we ask if state-of-the-art nonlinear predictive models, such as boosted decision trees, can be more efficient for phenotype prediction than conventional linear models. We find that this is indeed the case if model features include a sufficiently rich set of covariates, but probably not otherwise. Second, we ask if the conventional selection of single nucleotide polymorphisms (SNPs) by genome wide association studies (GWAS) can be replaced by a more efficient procedure, taking into account information in previously selected SNPs. We propose such a procedure, based on a sequential feature importance estimation with decision trees, and show that this approach indeed produced informative SNP sets that are much more compact than when selected with GWAS. Finally, we show that the highest prediction accuracy can ultimately be achieved by ensembling individual linear and nonlinear models. To the best of our knowledge, for some of the phenotypes that we consider (asthma, hypothyroidism), our results are a new state-of-the-art.


title: Extensive validation and prospective observation of the impact of an AI-based rapid antibiotics susceptibility prediction platform in multiple medical centers

abstract:
ImportanceNo medical artificial intelligence (AI) has been robustly validated and deployed in a clinical laboratory in real-world settings, and the clinical impact of the medical AI remains unknown.

ObjectiveTo deploy a medical AI platform for rapid antibiotics susceptibility test (AST) prediction, and evaluate its clinical impacts.

DesignA medical AI platform, XBugHunter, was extensively validated (internal validation, time-wise validation, and independent testing) with data between May 22, 2013 and June 30, 2019. The clinical impact was evaluated based on a prospective observation from February 1 to September 30, 2020 during deployment.

SettingData was collected in two tertiary medical centers in Taiwan, and the AI was deployed in a tertiary medical center.

ParticipantsFor validation, 90,064 consecutive cases were included. During the deployment, a prospective observational cohort of 1,490 consecutive cases was collected.

ExposuresAST prediction from XBugHunter

Main outcomes and MeasuresDiagnostic performance of XBugHunter was evaluated during validation. The clinical impact was evaluated in terms of the saving of inappropriate antibiotics prescription, AST turn-around-time, and mortality of bacteremia during deployment.

ResultsPredictive models consistently performed well in the extensive validations. In the deployment, XBugHunters predictive sensitivity and specificity for Staphylococcus aureus (oxacillin) were 0.95 (95% CI, 0.82-0.98) and 0.97 (95% CI, 0.94-0.99), respectively. For Acinetobacter baumannii (multiple drugs), the sensitivity was 0.95 (95% CI, 0.91-0.99) and specificity was 0.93 (95% CI, 0.88-0.98). The turn-around-time reduction on reporting AST of blood cultures was 35.72 h (standard deviation: 15.55 h). Death within 28 days occurred in 28 of 162 S. aureus bacteremia patients (17.28%) in the XBugHunter intervention group, which was lower than the 28 days mortality rate (28.06% [55/196]) in the same period of time in 2019, without XBugHunter. The relative risk reduction was 38.4% (relative risk, 0.62; 95% CI, 0.41-0.92). Regarding antibiotic prescriptions, 2723.7 defined daily dose per year of inappropriate antibiotics could be avoided for treating S. aureus by deploying XBugHunter.

Conclusions and RelevanceAmong S. aureus bacteremia patients, this study demonstrated that XBugHunter can prevent inappropriate antibiotic use, and the adjustment of antibiotic treatment can yield lower mortality.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the clinical impact of XBugHunter, a machine learning-based, antibiotic susceptibility test prediction platform?

FindingsIn the prospective observational cohort of deploying XBugHunter, the reduction of turn-around-time of reporting antibiotic susceptibility test was 35.72h. The reduction of S. aureus bacteremia mortality rate was 10.78%, and the estimated saving of inappropriate antibiotics uses was 2723.7 defined daily dose per year.

MeaningDeployment of XBugHunter provides a more rapid report of antibiotic susceptibility test, and thus reduces inappropriate antibiotics prescription and mortality of S. aureus bacteremia.


title: SARS-CoV-2 and the role of vertical transmission from infected pregnant women to their fetuses: systematic review.

abstract:
BackgroundVertical transmission of SARS-CoV-2 has been reported but does not appear to be common. This study aims to systematically review the evidence for vertical transmission of SARS-CoV-2.

MethodsThis review is part of an Open Evidence Review on the transmission dynamics of SARS-CoV-2 and the role of intrauterine mother to fetus transmission. Literature searches were performed in the WHO Covid-19 Database, LitCovid, medRxiv, and Google Scholar for SARS-CoV-2 using keywords and associated synonyms, search date up to 20 December 2020, no language restrictions.

ResultsWe included 106 studies assessing vertical transmission of SARS-CoV-2 from pregnant women to their neonates: these studies comprised 40 reviews (21 fulfilled systematic review methodology, including risk of bias assessment of included studies) and 66 primary studies including 32 case reports (of up to two cases) and 34 prospective and retrospective cohort studies, prospective and retrospective case series, observational studies (including asymptomatic screening), database studies and a quality improvement project. Almost all were conducted in a hospital setting. The 32 case reports were considered to be at high risk of bias, due to the study design; across the 34 remaining primary studies, risk of bias was low to moderate. Sixteen case reports examined vertical transmission, which was not related to maternal symptomatology. For the cohort and case series studies, the percentage of positive neonates ranged from 0% to 22% across the studies. Twenty studies reported no positive vertical transmission. Three studies that reported the highest positivity rates of 11%, 15% and 22% had specifically selected neonates with a positive test (within up to 35 days) within the study population and were therefore more selective populations. Across the cohort and case series studies there were 65/2391 (2.7%) neonates born to mothers with a diagnosis of COVID-19 tested positive for SARS-CoV-2 within 24 hours of birth. No evidence correlated maternal symptomatology to vertical transmission. Mode of delivery did not correlate with rates of vertical transmission. Of 25 studies, 7 identified SARS-CoV-2 in placental tissue; some of these did not demonstrate vertical transmission to the neonate. No study reported the results of viral culture to detect SARS-CoV-2.

ConclusionsThe results of these studies indicate that vertical transmission is possible, but is not frequent, and factors that influence when vertical transmission occurs are unknown. Further studies using standardised methods to establish viral infection are needed to establish vertical transmission rates and to assess clinical and other conditions affecting transmission.


title: Monitoring SARS-CoV-2 in sewage: toward sentinels with analytical accuracy

abstract:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemia has been one of the most difficult challenges humankind has recently faced. Wastewater-based epidemiology has emerged as a tool for surveillance and mitigation of potential viral outbreaks, circumventing biases introduced by clinical patient testing. Due to the situation urgency, protocols followed for isolating viral RNA from sewage were not adapted for such sample matrices. In parallel to their implementation for fast collection of data to sustain surveillance and mitigation decisions, molecular protocols need to be harmonized to deliver accurate, reproducible, and comparable analytical outputs. Here we studied analytical variabilities linked to viral RNA isolation methods from sewage. Three different influent wastewater volumes were used to assess the effect of filtered volumes (50, 100 or 500 mL) for capturing viral particles. Three different concentration strategies were tested by electronegative membranes, polyethersulfone membranes, and anion-exchange diethylaminoethyl cellulose columns. To compare the number of viral particles, different RNA isolation methods (column-based vs. magnetic beads) were compared. The effect of extra RNA purification steps and different RT-qPCR strategies (one step vs. two-step) were also evaluated. Results showed that the combination of 500 mL filtration volume through electronegative membranes and without multiple RNA purification steps (using column-based RNA purification) using two-step RT-qPCR avoided false negatives when basal viral load in sewage are present and yielded more consistent results during the surveillance done during the second-wave in Delft (The Hague area, The Netherlands). By paving the way for standardization of methods for the sampling, concentration and molecular detection of SARS-CoV-2 viruses from sewage, these findings can help water and health surveillance authorities to use and trust results coming from wastewater based epidemiology studies in order to anticipate SARS-CoV-2 outbreaks.

Graphical Abstract

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title: Genome-Wide Association Study of Estradiol Levels, and the Causal Effect of Estradiol on Bone Mineral Density

abstract:
ContextEstradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels.

ObjectiveIdentify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).

DesignWe performed GWAS for estradiol in males (N = 147,690) and females (N = 163,985) from UK Biobank (UKB). Estradiol was analyzed as a binary phenotype; above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization.

ResultsWe identified 14 independent loci associated (P<5x10-8) with estradiol levels in males, of which one (CYP3A7) was genome-wide and seven nominally (P<0.05) significant in females. In addition, one female specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS. For example, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7 which encode enzymes likely to be involved in estradiol elimination. The allele that tags the O blood group, at the ABO locus, was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P=1.58x10-11) and females (P=7.48x10-6).

ConclusionOur findings further support the importance of the bodys own estrogen to maintain skeletal health in males and in females.


title: Genome-wide contribution of common short-tandem repeats to Parkinson's disease genetic risk

abstract: Parkinsons disease (PD) is a complex neurodegenerative disorder with a strong genetic component, where most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (Indels). DNA repetitive elements account for >50% of the human genome, however little is known of their contribution to PD etiology. While select short tandem repeats (STRs) within candidate genes have been studied in PD, their genome-wide contribution remains unknown. Here we present the first genome-wide association study (GWAS) of STRs in PD. Through a meta-analysis of 16 imputed GWAS cohorts from the International Parkinsons Disease Genomic Consortium (IPDGC), totalling 39,087 individuals (16,642 PD cases and 22,445 controls of European ancestry) we identified 34 genome-wide significant STR loci (p < 5.34x10-6), with the strongest signal located in KANSL1 (chr17:44205351:[T]11, p=3x10-39, OR=1.31 [CI 95%=1.26-1.36]). Conditional-joint analyses suggested that 4 significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1 were independent from known PD risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTR) in RNASeq data from 13 brain regions, identified significant associations of STRs influencing the expression of multiple genes, including PD known genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here we show that STRs at known and novel candidate PD loci contribute to PD risk, and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting PD risk loci.