title: Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

abstract: Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWAS) into a more powerful whole. To resolve causal variants, meta-analysis studies typically apply summary statistics-based fine-mapping methods as they are applied to single-cohort studies. However, it is unclear whether heterogeneous characteristics of each cohort (e.g., ancestry, sample size, phenotyping, genotyping, or imputation) affect fine-mapping calibration and recall. Here, we first demonstrate that meta-analysis fine-mapping is substantially miscalibrated in simulations when different genotyping arrays or imputation panels are included. To mitigate these issues, we propose a summary statistics-based QC method, SLALOM, that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics based on ancestry-matched local LD structure. Having validated SLALOM performance in simulations and the GWAS Catalog, we applied it to 14 disease endpoints from the Global Biobank Meta-analysis Initiative and found that 68% of loci showed suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci were significantly depleted for having likely causal variants, such as nonsynonymous variants, as a lead variant (2.8x; Fishers exact P = 6.2 x 10-4). Compared to fine-mapping results in individual biobanks, we found limited evidence of fine-mapping improvement in the GBMI meta-analyses. Although a full solution requires complete synchronization across cohorts, our approach identifies likely spurious results in meta-analysis fine-mapping. We urge extreme caution when interpreting fine-mapping results from meta-analysis.


title: An observational study of uptake and adoption of the NHS App in England

abstract:
ObjectivesThis study aimed to evaluate patterns of uptake and adoption of the NHS App. Data metrics from the NHS App were used to assess acceptability by looking at total app downloads, registrations, appointment bookings, GP health records viewed, and prescriptions ordered. The impact of the UK COVID-19 lockdown and introduction of the COVID Pass were also explored to assess App usage and uptake.

MethodsDescriptive statistics and an interrupted time series analysis were used to look at monthly NHS App metrics at a GP practice level from January 2019-May 2021 in the population of England. Interrupted time series models were used to identify changes in level and trend among App usage and the different functionalities before and after the first COVID-19 lockdown. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used for reporting and analysis.

ResultsBetween January 2019 and May 2021, there were a total of 8,524,882 NHS App downloads and 4,449,869 registrations. There was a 4-fold increase in app downloads from April 2021 (650,558 downloads) to May 2021 (2,668,535 downloads) when the COVID Pass feature was introduced. Areas with the highest number of App registrations proportional to the GP patient population occurred in Hampshire, Southampton and Isle of Wight CCG, and the lowest in Blackburn with Darwen CCG. After the announcement of the first lockdown (March 2020), a positive and significant trend in the number of login sessions was observed at 602,124 (p=0.004)** logins a month. National NHS App appointment bookings ranged from 298 to 42,664 bookings per month during the study period. The number of GP health records viewed increased by an average of 371,656 (p=0.001)** views per month and the number of prescriptions ordered increased by an average of 19934 (p<0.001)*** prescriptions per month following the first lockdown.

ConclusionThis analysis has shown that uptake and adoption of the NHS App was positive post lockdown, and increased significantly due to the COVID Pass feature being introduced, but further research is needed to measure the extent to which it improves patient experience and influences health service access and care outcomes.

category: health informatics


title: Using Machine Learning Algorithms to predict sepsis and its stages in ICU patients

abstract: Sepsis is blood poisoning disease that occurs when body shows dysregulated host response to an infection and cause organ failure or tissue damage which may increase the mortality rate in ICU patients. As it becomes major health problem, the hospital cost for treatment of sepsis is increasing every year. Different methods have been developed to monitor sepsis electronically, but it is necessary to predict sepsis as soon as possible before clinical reports or traditional methods, because delayed in treatment can increase the risk of mortality with every single hour. For the early detection of sepsis, specifically in ICU patients, different machine learning models i.e Linear learner, Multilayer perceptron neural networks, Random Forest, lightgbm and Xgboost has trained on the data set proposed by Physio Net/ Computing in Cardiology Challenge in 2019. This study shows that Machine learning algorithms can accurately predict sepsis at the admission time of patient in ICU by using six vitals signs extracted from patient records over the age of 18 years. After comparative analysis of machine learning models, Xgboost model achieved a highest accuracy of 0.98, precision of 0.97, and recall 0.98 under the precision-recall curve on the publicly available data. Early prediction of sepsis can help clinicians to implement supportive treatments and reduce the mortality rate as well as healthcare expenses.


title: A SARS-CoV-2 negative antigen rapid diagnostic in RT-qPCR positive samples correlates with a low likelihood of infectious viruses in the nasopharynx.

abstract: SARS-CoV-2 transmission occurs even among fully vaccinated individuals; thus, prompt identification of infected patients is central to control viral circulation. Antigen rapid diagnostic tests (Ag-RDT) are highly specific, but sensitivity is variable.Discordant RT-qPCR vs Ag-RDT results are reported, raising the question of whether negative Ag-RDT in positive RT-qPCR samples could imply the absence of infectious viruses. To study the relationship between a negative Ag-RDT results with virological, molecular, and serological parameters, we selected a cross sectional and a follow-up dataset and analyzed virus culture, subgenomic RNA quantification, and sequencing to determine infectious viruses and mutations. We demonstrated that a positive SARS-CoV-2 Ag-RDT result correlates with the presence of infectious virus in nasopharyngeal samples. A decrease in sgRNA detection together with an expected increase in detectable anti-S and anti-N IgGs was verified in negative Ag-RDT / positive RT-qPCR samples. The data clearly demonstrates the less likelihood of a negative Ag-RDT sample to harbor infectious SARS-CoV-2 and consequently with a lower transmissible potential.

category: infectious diseases


title: Spatio-temporal clusters and patterns of spread of dengue, chikungunya, and Zika in Colombia

abstract:
BackgroundColombia has one of the highest burdens of arboviruses in South America. The country was in a state of hyperendemicity between 2014 and 2016, with co-circulation of several Aedes-borne viruses, including a syndemic of dengue, chikungunya, and Zika in 2015.

Methodology/Principal FindingsWe analyzed the cases of dengue, chikungunya, and Zika notified in Colombia from January 2014 to December 2018 by municipality and week. The trajectory and velocity of spread was studied using trend surface analysis, and spatio-temporal high-risk clusters for each disease in separate and for the three diseases simultaneously (multivariate) were identified using Kulldorffs scan statistics. During the study period, there were 66,628, 77,345 and 74,793 cases of dengue, chikungunya, and Zika, respectively, in Colombia. The spread patterns for chikungunya and Zika were similar, although Zikas spread was accelerated. Both chikungunya and Zika mainly spread from the regions on the Atlantic coast and the south-west to the rest of the country. We identified 21, 16, and 13 spatio-temporal clusters of dengue, chikungunya and Zika, respectively, and, from the multivariate analysis, 20 spatio-temporal clusters, among which 7 were simultaneous for the three diseases. For all disease-specific analyses and the multivariate analysis, the most-likely cluster was identified in the south-western region of Colombia, including the Valle del Cauca department.

Conclusions/SignificanceThe results further our understanding of emerging Aedes-borne diseases trajectory in Colombia and provide useful information on the identified spatio-temporal disease-specific and multivariate clusters of dengue, chikungunya, and Zika, that can be used to target interventions. To our knowledge, this is the first time that the co-occurrence of all three diseases in Colombia was explored using multivariate scan statistics.

category: epidemiology


title: A Meta-Analytic Investigation of Grey Matter Differences in Anorexia Nervosa and Autism Spectrum Disorder

abstract: Recent research reports Anorexia Nervosa (AN) to be highly dependent upon neurobiological function. Some behaviours, particularly concerning food selectivity are found in populations with both Autism Spectrum Disorder (ASD) and AN, and there is a proportionally elevated number of anorexic patients exhibiting symptoms of ASD. We performed a systematic review of structural MRI literature with the aim of identifying common structural neural correlates common to both AN and ASD. Across 46 ASD publications, a meta-analysis of volumetric differences between ASD and healthy controls revealed no consistently affected brain regions. Meta-analysis of 23 AN publications revealed increased volume within the orbitofrontal cortex and medial temporal lobe, and adult-only AN literature revealed differences within the genu of the anterior cingulate cortex. The changes are consistent with alterations in flexible reward-related learning and episodic memory reported in neuropsychological studies. There was no structural overlap between ASD and AN. Findings suggest no consistent neuroanatomical abnormality associated with ASD, and evidence is lacking to suggest that reported behavioural similarities between those with AN and ASD are due to neuroanatomical structural similarities.

category: psychiatry and clinical psychology


title: Variation in Racial and Ethnic Representation of Heart Transplant Recipients, Waitlists, and Local Census Demographics Across Transplant Centers in the US

abstract: As the uses and needs for heart transplants around the world continue to rise, its vital to investigate how the recent boom in demand comparative to availability affects racial and ethnic groups, especially in the representation in heart transplant waitlists and recipients. Here, comparisons between the racial/ethnic representation in heart transplant waitlists and recipients at heart transplant centers through the Scientific Registry for Transplant Recipients (SRTR) are drawn, comparative to the racial/ethnic representation in the location that these centers are located. Findings point towards the overrepresentation of White individuals in both waitlists and recipients, and underrepresentation in all other ethnic minorities --except African Americans-- in waitlists and recipients comparative to their demographic representation in the location of the centers. This difference in representation is largest for Hispanics/Latinos and those that the SRTR classify as "Other". Though just a snapshot of representation between 07/01/2019 and 06/30/2020, this may point to various systemic issues in the accessibility of care of minorities, especially during the COVID-19 pandemic, that need to be addressed as the general populous ages and heart transplants are increasingly relied upon as a treatment for cardiovascular conditions and failure.

category: public and global health


title: Competency for Japanese Novice Medical Laboratory Scientists: A Delphi Method

abstract:
IntroductionCompetency is used to channel abilities into successful processes and is employed in the medical field. Worldwide, many laboratory competencies are available, but little evidence-based information about the competency of novice medical laboratory scientists exists in Japan. This study aimed to clarify competencies by various expert opinions around Japan.

MethodsThe Delphi method was used to achieve an expert consensus on the competencies of novice medical laboratory scientists. We asked the participants to evaluate the importance of each item using the Likert scale and set 70% as the final consensus rate. The participants comprised medical laboratory scientists who met the following inclusion criteria: (1) qualified Japanese national medical laboratory scientists, (2) practised with >10 years of experience and (3) were heads of medical laboratory scientists in a clinical setting.

ResultsWe obtained 106 responses from 400 (26.5%) participants in round one and 95 from 106 (89.6%) participants in round two. Their professional experience mean {+/-} standard deviation was 32.4 {+/-} 6.0 years (range: 13-41). The average of each category consensus rate was >99.1%. The opinions of 95 experts converged, who agreed that competency comprised 8 categories and 54 items.

DiscussionHere, Japanese novice medical laboratory scientists required not only basic laboratory competencies but also other competencies, such as  medical safety management,  interpersonal relationships,  professional development and  ethics, and some items were characteristic of Japan. Further research is warranted to explore assessments tools through the scale development of competencies, thus helping clarify the differences between ability and correlated factors.

category: medical education


title: Reference values for amplitude-integrated EEGs in children from 1 month to 17 years of age

abstract:
AimAmplitude-integrated electroencephalography (aEEG) is used to monitor electrocortical activity in critically ill children, but reference values are lacking for patients older than 3.5 months. We aimed to derive reference values for paediatric aEEGs from neurologically healthy children.

MethodsNormal EEGs from awake children aged 1 month to 17 years (213 female, 237 male) without neurological disease or neuroactive medication were retrospectively converted into aEEGs. Two observers manually measured the upper and lower amplitude borders of the C3 - P3, C4 - P4, C3 - C4, P3 - P4, and Fp1 - Fp2 channels of the 10 - 20 system. Percentiles (10th, 25th, 50th, 75th, 90th) were calculated for each age group (< 1 year, 1 year, 2 - 5 years, 6 - 9 years, 10 - 13 years, 14 - 17 years).

ResultsAmplitude heights and curves differed between channels without sex-specific differences. During the first 2 years of life, upper and lower amplitudes of all but the Fp1 - Fp2 channel increased and then declined until 17 years. The decline of the upper Fp1 - Fp2 amplitude began at four years, while the lower amplitude declined from the first year of life.

InterpretationaEEG interpretation must account for age and electrode positions but not for sex in infants and children.

What this paper adds- aEEG amplitudes increase in the first years of life and then decline.
- aEEG amplitudes depend on electrode positions but not on sex.
- aEEG interpretation must account for age and electrode positions.

category: pediatrics


title: TUNNEL WIDENING OF ACL RECONSTRUCTION AUGMENTED BY AN PLATELET RICH OSTEOCONDUCTIVE-OSTEOINDUCTIVE ALLOGRAFT COMPOUND: A RANDOMIZED BLIND-ANALYSIS PILOT STUDY

abstract:
BackgroundThe anterior cruciate ligament (ACL) is a commonly injured ligament in the knee. Bone tunnel widening is a known phenomenon after soft-tissue ACL reconstruction and etiology and clinical relevance have not been fully elucidated. Osteoconductive compounds are biomaterials providing an appropriate scaffold for bone formation such as demineralized bone matrix. Osteoinductive materials contain growth factors stimulating bone lineage cells and bone growth. A possible application of osteoinductive/osteoconductive (OIC) material is in ACL surgery.

Questions/PurposesWe hypothesized that OIC placed in ACL bone tunnels: 1) reduces tunnel widening, 2) improves graft maturation and 3) reduces tunnel ganglion cyst formation. To test this hypothesis, this study evaluated the osteogenic effects of demineralized bone matrix (DBM) and platelet rich plasma (PRP) on tunnel widening, graft maturation, and ganglion cyst formation.

Study DesignRandomized controlled clinical trial pilot study.

MethodsA total of 26 patients electing ACL reconstruction surgery were randomized between OIC and control group. Measurements of tunnel expansion and graft-tunnel incorporation were conducted via quantitative image analysis of MRI scans performed at six months after surgery for both groups.

ResultsNo patients had adverse post-operative reactions or infections. The use of OIC significantly reduced tunnel widening (p < 0.05) and improved graft maturation (p < 0.05). Patients treated with OIC presented with a significantly lower prevalence of ganglion cyst compared to the control group (p < 0.05).

ConclusionThe use of OIC has measurable effects on the reduction of tunnel widening, improved graft maturation and decreased size of ganglion cyst after ACL reconstruction.

Clinical RelevanceThis study explored the utilization of biologics to minimize bone tunnel widening in ACL reconstruction surgery.

category: orthopedics


title: Identification of novel genetic variants in the malaria vaccine candidate PfRh5: structure-guided insights into potential function

abstract: The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRH5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.


title: Maternal Antibody Response and Transplacental Transfer Following SARS-CoV-2 Infection or Vaccination in Pregnancy

abstract:
BackgroundPregnant persons are at increased risk of severe COVID-19 and adverse obstetric outcomes. Understanding maternal antibody response and transplacental transfer after SARS-CoV-2 infection and COVID-19 vaccination is important to inform public health recommendations.

MethodsThis prospective observational cohort study included 351 birthing individuals who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. IgG and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across 1) disease severity for those with SARS-CoV-2 infection and 2) infection versus vaccination.

FindingsThere were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection category had higher maternal and cord blood IgG levels (p=0.0001, p=0.0001). Median IgG transfer ratio was 0.87-1.2. Maternal and cord blood IgG were higher after vaccination than infection (p=0.001, p=0.001). Transfer ratio was higher after 90 days in the vaccinated group (p<0.001). Modeling showed higher amplitude and half-life of maternal IgG following vaccination (p<0.0001). There were no significant differences by fetal sex.

InterpretationCOVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared to SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.


title: SARS-CoV-2 infections in infants in Haiti 2020-2021; evidence from a serological cohort

abstract: Between February 2019 and March 2021, 388 dried blood spot samples were obtained from 257 children <30 months of age who were part of a longitudinal maternal/infant cohort in Haiti. Among the children followed, 16.7% became seropositive; sampling date was the only covariate associated with the hazard of seroconversion.


title: Association of Periodic Fasting with Lower Severity of COVID-19 Outcomes in the SARS-CoV-2 Pre-Vaccine Era: An Observational Cohort from the INSPIRE Registry

abstract:
ObjectivesIntermittent fasting boosts some mechanisms of host defense against infection while modulating the inflammatory response. Lower-frequency periodic fasting is associated with greater survival and lower risk of comorbidities that exacerbate COVID-19. This study evaluated the association of periodic fasting with COVID-19 severity and, secondarily, initial diagnosis of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

DesignProspective longitudinal observational cohort study.

SettingSingle-center secondary care facility in Salt Lake City, Utah, USA with follow-up across a 24-hospital integrated healthcare system.

ParticipantsPatients enrolled in the INSPIRE registry in 2013-2020 were studied if they had SARS-CoV-2 testing in March 2020-February 2021 and either tested positive (N=205) for the primary outcome evaluation or had a positive or negative test result for evaluation of the secondary outcome (n=1,524).

InterventionsNo treatment assignments were made; individuals provided information about their personal practice and history of engaging in routine periodic fasting across their lifespan.

Main outcome measuresThe association of periodic fasting with a composite of mortality or hospitalization as the primary outcome was evaluated by Cox regression through February 2021 and multivariable adjustments considered 36 covariables in INSPIRE patients diagnosed with COVID-19. Secondary analysis evaluated the association of fasting with testing positive for SARS-CoV-2 in INSPIRE patients evaluated for COVID-19 (n=1,524).

ResultsSubjects engaging in periodic fasting (n=73, 35.6%) did so for 40.4{+/-}20.6 years (max: 81.9 years) prior to COVID-19 diagnosis. The composite outcome occurred in 11.0% of periodic fasters and 28.8% of non-fasters (p=0.013), with HR=0.61 (95% CI=0.42, 0.90) favoring fasting. Multivariable analyses confirmed this association. Other predictors of hospitalization/mortality were age, Hispanic ethnicity, prior MI, prior TIA, and renal failure, with trends for race, smoking, hyperlipidemia, coronary disease, diabetes, heart failure, and history of anxiety, but not alcohol use. In secondary analysis, COVID-19 was diagnosed in 14.3% of fasters and 13.0% of non-fasters (p=0.51).

ConclusionsRoutine periodic fasting was associated with a lower risk of hospitalization or mortality in patients with COVID-19. Fasting may be a complementary therapy to vaccination that could provide immune support and hyperinflammation control during and beyond the pandemic.

Trial registrationclinicaltrials.gov, NCT02450006 (the INSPIRE registry)

SummaryO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIDuring a period of energy restriction, fasting controls inflammation by dampening the cytokine cascade and it switches the metabolic source of energy from glucose to fats, including by increasing circulating free fatty acids such as linoleic acid.
C_LIO_LIThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domains bind linoleic acid in pockets that, when bound, reduce spike protein affinity for the angiotensin-converting enzyme 2.
C_LIO_LIRepeated fasting boosts basal levels of some parameters related to inflammation control and host defense against infections, including galectin-3, and it ameliorates insulin resistance and cardiovascular risks such that periodic fasting is associated with greater survival and lower risk of heart failure, coronary artery disease, and type 2 diabetes.
C_LI

What this study addsO_LIThis study evaluated the association of periodic fasting with severity of coronavirus disease 2019 (COVID-19) and with initial infection with SARS-CoV-2 in a population where a substantial proportion of people routinely engage in periodic dry or water-only fasting, primarily for religious purposes.
C_LIO_LIThis observational epidemiologic study found that routine low-frequency periodic fasting for an average of >40 years was associated with a lower risk of a composite of hospitalization or mortality after COVID-19 diagnosis, suggesting that fasting deserves further investigation as a complementary approach along with vaccines for reducing COVID-19 severity.
C_LIO_LIThe study also found no association of periodic fasting with the onset of SARS-CoV-2 infection.
C_LI

Trial registrationThe Intermountain INSPIRE registry (clinicaltrials.gov, NCT02450006)

TransparencyBDH affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted.

CopyrightThe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above.


title: Selective Decontamination of the Digestive Tract in Invasively Ventilated Patients in an Intensive Care Unit: A protocol for a Systematic Review and Meta-Analysis

abstract:
IntroductionThe use of Selective Decontamination of the Digestive Tract (SDD) as a preventative infection-control strategy in invasively ventilated patients in the intensive care unit (ICU) remains low despite numerous randomised controlled trials (RCTs) consistently reporting reductions in interval mortality rates and shorter durations of mechanical ventilation. The Selective Decontamination of the Digestive Tract in the Intensive Care Unit (SuDDICU) cluster cross-over RCT, that includes over 5500 participants randomised to receive a standardised commercial grade SDD interventions or standard care, will be reported in 2022 and will add substantive weight to previous RCT data assessing the effect of SDD on interval mortality compared to standard care. We will conduct an updated systematic review and prospective aggregate data meta-analysis of previous conducted and published RCTs, developed using a protocol and statistical analysis plan completed prior to the completion of the SuDDICU RCT and including the SuDDICU data to present the most current evidence available to guide clinical practice.

Methods and analysisWe will include RCTs that compare the effect on hospital mortality and other patient-centred outcomes of treatment with SDD compared to standard care in invasively ventilated adults in the ICU. We will perform a search that includes the electronic databases MEDLINE and EMBASE and clinical trial registries. Two reviewers will independently screen titles and abstracts, perform full article reviews and extract study data, with discrepancies resolved by a third reviewer. We will report study characteristics and quantify risk of bias. We will perform random effects Bayesian meta-analyses to provide pooled estimates that SDD improves outcomes, whenever it is feasible to do so. We will evaluate overall certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation framework.

ConclusionThis updated systematic review and prospective meta-analysis will provide clinicians with an expedited assessment of the totality of current evidence about the effect on mortality of using SDD in mechanically ventilated ICU patients.

category: intensive care and critical care medicine


title: Validity of reported post-acute health outcomes in children with SARS-CoV-2 infection: a systematic review

abstract:
ImportanceThere is concern that post-acute SARS-CoV-2 infection health outcomes ("post-COVID syndrome") in children could be a serious problem but at the same time there is concern about the validity of reported associations between infection and long-term outcomes.

ObjectiveTo systematically assess the validity of reported post-acute SARS-CoV-2 infection health outcomes in children.

Evidence ReviewA search on PubMed and Web of Science was conducted to identify studies published up to January 22, 2022, that reported on post-acute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of [≥]2 months since detection of infection or [≥]1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, and the risk of bias.

Findings21 studies including 81,896 children reported up to 97 symptoms with follow-up periods of 2-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16,986) and 2% to 53.3% in children without SARS-CoV-2 infection (n=64,910). Only 2 studies made a clear causal interpretation of an association of SARS-CoV-2 infection and the main outcome of "post-COVID syndrome" and provided recommendations regarding prevention measures. Two studies mentioned potential limitations in the conclusion of the main text but none of the 21 studies mentioned any limitations in the abstract nor made a clear statement for cautious interpretation. The validity of all 21 studies was seriously limited due to an overall critical risk of bias (critical risk for confounding bias [n=21]; serious or critical risk for selection bias [n=19]; serious risk for misclassification bias [n=3], for bias due to missing data [n=14] and for outcome measurement [n=12]; and critical risk for selective reporting bias [n=16]).

Conclusions and RelevanceThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on post-acute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow valid are the reported results on health outcomes in children after acute SARS-CoV-2 infection?

FindingsWe identified 21 studies with only 6 using a controlled design. Reported post-acute health-outcomes were numerous and heterogeneous. The reported proportion of children with post-COVID syndrome was up to 66.5% in children with and 53.3% in children without SARS-CoV-2 infection. All studies had seriously limited validity due to critical and serious risk of bias in multiple domains.

MeaningThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited and methodological robust evidence is urgently needed.


title: Evaluation of a throat spray with lactobacilli in COVID-19 outpatients in a randomized, double-blind, placebo-controlled trial for symptom and viral load reduction

abstract:
ObjectivesPrimary care urgently needs treatments for COVID-19 patients because current options are limited, while these patients account for more than 90% of the people infected with SARS-CoV-2.

MethodsWe evaluated a throat spray containing three Lactobacillaceae strains with broad antiviral properties in a randomized double-blind placebo-controlled trial. Seventy-eight eligible COVID-19 patients were randomized to verum (n=41) and placebo (n=37) within 96 hours of positive PCR-based SARS-CoV-2 diagnosis and per-protocol analysis was performed. Symptoms and severity were reported daily via an online diary. Combined nose-throat swabs and dried blood spots were collected at regular time points in the study.

ResultsThe daily reported symptoms were highly variable, with no added benefit for symptom resolution in the verum group. Specific monitoring of the applied lactobacilli strains showed that they were detectable via microbiome (27%) and qPCR analysis (82%) of the verum group. Their relative abundances were also negatively correlated with the acute symptom score. At the end of the trial, a trend towards lower SARS-CoV-2 viral loads was observed for the verum group (2/30, 6.7% positive) compared to the placebo group (7/27, 26% positive) (p = 0.07).

ConclusionsDespite a trend towards lower SARS-CoV-2 viral loads at the end of the trial and a negative correlation between relative abundances of the applied lactobacilli in the microbiome and acute symptoms, we did not observe a significant effect on overall symptom score for the verum group. This suggests that studies with earlier application of the spray in larger study populations are needed to further assess application potential.

category: primary care research


title: The link between autism and sex-specific neuroanatomy, and associated cognition and gene expression

abstract:
ObjectivesThe male preponderance in autism spectrum conditions (ASC) prevalence is among the most pronounced sex ratios across different neurodevelopmental conditions. Here, we aimed to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression.

MethodsUsing a novel deep learning framework trained to predict biological sex, we compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale datasets were employed at different stages of the analysis pipeline: a) Pre-training: the UK Biobank sample (>10.000 individuals); b) Transfer learning and validation: the ABIDE datasets (1,412 individuals, 5-56 years of age); c) Test and discovery: the EU-AIMS/AIMS-2-TRIALS LEAP dataset (681 individuals, 6-30 years of age) and d) Specificity: the Neuroimage and ADHD200 datasets (887 individuals, 7-26 years of age).

ResultsAcross both ABIDE and LEAP we showed that features positively predictive of neurotypical males were on average more predictive of autistic males (P=1.1e-23). Features positively predictive of neurotypical females were on average less predictive of autistic females (P=1.2e-22). These accuracy differences in autism were not observed in individuals with ADHD. In autistic females the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also with associated gene expression patterns of midgestational cell types.

ConclusionsOur results demonstrate a shift in both autistic male and female individuals neuroanatomy towards male-characteristic patterns associated with typically sex-differential, social cognitive features and related gene expression patterns. Findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.


title: Remote virtual reality assessment elucidates self-blame-related action tendencies in depression

abstract:
Darwin stated that humans have a strong and involuntary tendency to perform certain actions when a specific state of mind is induced. Such "action tendencies" are key to understanding the maladaptive impact of self-blame-related feelings in depression. For example, feeling like "hiding" and "creating a distance from oneself" in a text-based task were previously associated with recurrence risk in remitted depression. Despite their functional importance, action tendencies have not been systematically investigated in current depression, which was the aim of this pre-registered study. To this end, we developed the first virtual reality (VR) assessment of blame-related action tendencies and compared current depression (n=98) with control participants (n=40). The immersive VR-task, pre-programmed on devices sent to participants homes, used hypothetical social interactions, in which either participants (self-agency) or their friend (other-agency) were described to have acted inappropriately. Good concurrent validity was demonstrated for VR-versus the text-based task. As predicted, compared with controls, people with depression showed a maladaptive profile: Particularly in the other-agency condition, rather than feeling like verbally attacking their friend, they were prone to feeling like hiding, and punishing themselves. The depression group showed a more pronounced slowing of response times in the other-versus the self-agency condition, which may reflect a stronger ambivalence about externalising blame in depression. Interestingly, feeling like punishing oneself was associated with a history of self-harm but not suicide attempts. Current depression and self-harm history were thus linked with distinctive motivational signatures, paving the way for remote VR-based stratification and treatment.

General Scientific SummaryAs precursors of social actions, action tendencies, such as feeling like hiding when experiencing shame or guilt, provide the key link between depressive emotions and behaviour. Here, we developed a novel virtual reality task and used it in a large sample of people with depression to unveil a distinctive pattern of such action tendencies. As predicted, we found a maladaptive pattern of action tendencies in people with depression that were specifically associated with self-harm. Our findings thereby elucidate a so far unexplored key aspect of psychopathology in depression and provide important targets for the development of novel future psychological interventions tackling self-harm-related motivations and depression.


title: Predictors of HIV Testing among Youth 15-24 Years in urban Ethiopia, 2017-2018 Ethiopia Population-based HIV Impact Assessment

abstract:
IntroductionYouth (adolescents and young adults) aged 15-24 years comprise approximately 22% of Ethiopias total population and make up 0.73% of HIV cases in urban Ethiopia. However, only 63% of HIV-positive youth are aware of their HIV status. We described the HIV testing behaviors of youth 15-24 years and determined the characteristics of those who were most likely to be tested for HIV within the past year.

MethodsUsing data from the 2017-2018 Ethiopia Population-based HIV Impact Assessment, we provide survey-weighted estimates and prevalence risk ratios for engagement in HIV testing in the 12 months preceding the survey. We model the likelihood of HIV testing one year or more before the survey compared to never testing, using a multinomial logistic regression model.

ResultsAmong HIV-negative and unaware HIV-positive youth 15-24 years old (N=7,508), 21.8% [95% Confidence Interval (CI): 20.4-23.3%] reported testing for HIV in the last 12 months. Female youth [Prevalence Ratio (PR)=1.6, 95% CI: 1.4-1.8], those aged 20-24 years (PR=2.6, 95% CI:2.3-2.9), and those ever married (PR=2.8, 95% CI: 2.5-3.1) were more likely to have tested for HIV within the last year. Adjusting for select demographic characteristics, sex with a non-spousal or non-live-in partner [Relative Risk (RR)=0.3, 95% CI:0.1-0.8] among males did not increase their likelihood to test for HIV in the prior 12 months. Female youth engaged in antenatal care (RR=3.0, 95% CI: 1.7-5.3) were more likely to test for HIV in the past year.

ConclusionThe Ethiopian HIV case finding strategy may consider approaches for reaching untested youth, with a specific focus on adolescent males. This is critical towards achieving the UNAIDS HIV testing goal of 95% of all individuals living with HIV aware of their status by 2030.


title: Effects of exercise on brain health outcomes in children with overweight/obesity: the ActiveBrains randomized controlled trial

abstract:
ObjectivesTo investigate the effects of exercise on intelligence, executive functions, academic performance and brain outcomes in children with overweight/obesity. In secondary analyses, we explored potential mediators and moderators of the exercise effects.

MethodsA total of 109 children (8-11.9y) with overweight/obesity were randomized (intention-to-treat) and 90 (82.6%) completed the post-exercise evaluation and attended [≥]70% of the exercise sessions (per-protocol). Participants in the control group continued with their usual routines and received lifestyle recommendations, whereas the exercise group attended 3 sessions/week of aerobic plus resistance training during 20 weeks. Intelligence, executive functions (cognitive flexibility, inhibition, working memory) and academic performance were assessed with standardized tests; and hippocampal volume with magnetic resonance imaging (MRI).

ResultsIn per-protocol analyses, the exercise intervention improved intelligence and cognitive flexibility (medium-large effect sizes observed, 0.4-0.7 SDs). These main effects were consistent in intention-to-treat analyses and after multiple-testing correction. Moreover, we found a positive, small-magnitude (i.e., 0.2-0.3 SDs) effect of exercise on academic performance (total, mathematics and problem solving), which was partially mediated by cognitive flexibility. Inhibition, working memory, hippocampal volume, and other brain MRI outcomes studied were not affected by our exercise program. Our intervention increased cardiorespiratory fitness performance (0.4 SDs) and these changes in fitness mediated some of the effects. Effects were mostly consistent across the studied moderators, except for larger improvements for intelligence in boys compared to girls.

ConclusionExercise positively impacts intelligence and cognitive flexibility during development in children with overweight/obesity, without changes in the structural and functional brain outcomes studied.

Trial RegistrationClinicalTrials.gov Identifier: NCT02295072

SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABS- Pediatric obesity is associated not only with poorer physical health but also with poorer cognitive and brain development.
- Previous exercise interventions have mostly focused on executive functions and other dimensions of cognition, yet is largely unknown the extent to which exercise can improve intelligence during childhood, and actually, at any period of life.
- Studies integrating effects of exercise on behavioral and brain magnetic resonance outcomes in a single article are scarce.
- A in-depth study of the exercise characteristics (mode) and intensity, potential compensatory/contamination effects and role of potential mediators and moderators of the exercise effects is warranted.

What this study adds- A 20-week randomized controlled trial of exercise improved intelligence and cognitive flexibility in preadolescent children with overweight/obesity.
- Moreover, we found a positive, small-magnitude effect of exercise on academic performance, which was partially mediated by cognitive flexibility.
- Cardiorespiratory peak performance mediated some yet not all the exercise effects observed.
- The structural and functional brain outcomes studied were not affected by participation in the exercise program.

How this study might affect research, practice or policyOur investigation suggests that exercise can positively impact intelligence and cognitive flexibility during a sensitive period of brain development in childhood. This stimulus can positively affect academic performance, as shown in our study, indicating that an active lifestyle during preadolescent development may lead to more successful life trajectories. This is particularly important in children with overweight/obesity who are known to be at higher risk of poorer physical and brain health.

category: sports medicine


title: Reliability and Predictive Validity of a Gait Assessment using Inertial Measurement Units: The Importance of Standardizing Walking Surface and Footwear

abstract:
ObjectivesEvaluate procedures for analyzing raw accelerometer data (inertial measurement units) to reconstruct the gait cycle using BioKinetoGraph (BKG). We examine whether footwear and walking surface influence gait (BKG) and evaluate test-retest reliability. We also examine the association between BKG and NIH 4-meter gait, and compare BKG to other neurobehavioral measures for predicting concussion symptoms.

MethodsIn Study 1, a within-subjects design with 60 participants was used to examine the effects of footwear (shoes/no-shoes) and walking surface (tile floor/grass) on BKG data, and evaluate retest reliability. Study 2 employed a cross-sectional, cohort design of 1,008 participants to assess BKGs correlation with NIH 4-m gait, and prediction of Centers of Disease Control and Prevention (CDC) concussion symptoms relative to previously validated speed and balance measures.

Results2x2 ANOVAs illustrate footwear and walking surface effects on BKG for the power, stride, stability, and symmetry, with variable effect sizes. Retest reliability (Pearson rs) for the no shoes/ tile surface condition ranged from .72-.91 (mean = .80, 4-day average interval). BKG correlates significantly with NIH 4-m gait. Regression analyses found BKG predicts CDC concussion symptom endorsement, and outperforms (2-3 fold) BESS and NIH 4-meter gait.

ConclusionsGait assessments should be standardized for footwear and especially walking surface. When standardized (no shoes/hard surface) BKG results in strong test-retest reliability. BKG variables are strongly related to NIH 4-m gait, and are superior to standard measures of gait speed and balance when predicting concussion symptoms; offering additional information when predicting the sequalae of concussion.

Summary BoxO_ST_ABSWhat is already known on the topic?C_ST_ABSO_LISensor technology to evaluate gait has established reliability and predicts a wide range of medical outcomes. However, the influence of footwear and walking surface on gait has not been studied, nor has a sensor-based gait assessment been compared to conventional measures for predicting concussion symptoms.
C_LI

What this study adds?O_LIGait sensor data is sensitive to footwear and walking surface, but can produce good reliability when these factors are standardized. Gait sensor scores converge with other validated measures of gait, and sensor-based measures of power, stride, symmetry, and stability can outperform established gait speed and balance measures when predicting CDC concussion symptoms.
C_LI

How this study might affect research, practice, or policy?O_LIUniform standards for footwear and walking surface are needed when evaluating gait in both research and practice, and sensor-based gait measures can be reliably assessed to provide insight into the behavioral sequelae of concussion, that are superior to simple gait speed.
C_LI


title: Effectiveness of a positive deviant intervention to improve appropriate feeding practices and nutritional outcomes in West Omo Zone, Maji District: South West Region, Ethiopia: A study protocol for a cluster randomized control trial

abstract:
BackgroundNon-optimal infant and young child feeding practices (IYCFP) are linked to malnutrition and infant mortality in poor countries, notably in Ethiopia. The majority of growth stalls occur within the first two years of life; hence, there is a need to discover interventions that enhance appropriate IYCFP for improving nutritional outcomes during this critical period. Using the experience of mothers who have come up with solutions to their IYCFP problems to educate others is is a potential pathway to initiate and sustain behavioral changes in resource-limited areas. However, such interventions are not widely implemented in Ethiopia.

ObjectiveThis study aims to assess the effectiveness of a positive deviant (hearth nutrition education) intervention to improve appropriate feeding practices and nutritional outcomes in West Omo Zone, Maji District: South West region, Ethiopia.

MethodsA cluster randomized controlled trial will be conducted to compare the effect of positive deviant intervention versus routine health educationa. The intervention will be provided by positive deviant mothers who are members of the community using WHO infant and young child feeding guidelines, and "training of the trainers manual on counseling and supporting non-positive deviant mothers, infant and young child feeding" in the local language. Culturally appropriate and scientifically acceptable operational packages of information will be developed. Using preset criteria, 516 mothers will be recruited from 36 zones. The intervention arm will receive 12 demonstration (hearth) session in groups and every 15th day home visit by positive deviant mothers. Data will be entered into epi-data version 3.1 and analyzed using STATA version 13.0. All analyses will be done as intention-to-treat. We will fit mixed effects linear regression models for the continuous outcomes and mixed effects linear probability models for the binary outcomes with the study zone as random intercept to estimate study arm difference (intervention vs. routine health education) adjusted for baseline value of the outcome and additional relevant covariates.

The protocol was developed in collaboration with the West Omo Zone and Maji Woreda Health Office. Ethical approval (Ref no: IHRPG/938/2020) was obtained from Jimma University, Institute of Health Research and Postgraduate Office. This study is funded by Jimma University research and postgraduate office.

DiscussionWe expect that the trial will generate findings informing IYCFP and nutritional policies and practices in Ethiopia.

Trial registrationRegistry: PACTR202108880303760 (30/08/2021); www.pactr.org, URL : https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=16081

category: nutrition


title: Regional medical inter-institutional cooperation in medical provider network constructed using patient claims data from Japan

abstract: The aging world population requires a sustainable and high-quality healthcare system. To examine the efficiency of medical cooperation, medical provider and physician networks were constructed using patient claims data. Previous studies have shown that these networks contain information on medical cooperation. However, the usage patterns of multiple medical providers in a series of medical services have not been considered. In addition, these studies used only general network features to represent medical cooperation, but their expressive ability was low. To overcome these limitations, we analyzed the medical provider network to examine its overall contribution to the quality of healthcare provided by cooperation between medical providers in a series of medical services. This study focused on: i) the method of feature extraction from the network, ii) incorporation of the usage pattern of medical providers, and iii) expressive ability of the statistical model. Femoral neck fractures were selected as the target disease. To build the medical provider networks, we analyzed the patient claims data from a single prefecture in Japan between January 1, 2014 and December 31, 2019. We considered four types of models: a model using node strength and linear regression to a model using feature representation by node2vec and regression tree ensemble, which is a machine learning method. The results showed that a stronger medical provider reduces the duration of hospital stay. The overall contribution of the medical cooperation to the duration of hospital stay extracted from the medical provider network using node2vec is approximately 20%, which is approximately 20 times higher than the model using strength.

category: health systems and quality improvement


title: Potency and Breadth of Neutralization after 3 doses of mRNA vaccines in COVID-19 Convalescent and Naive individuals

abstract: Third doses of mRNA COVID-19 vaccines induced a significant increase in neutralizing potency and breadth in naive individuals comparable with convalescents who restored levels after the first two doses. These results suggest a limit to elicit neutralization in the number of stimuli by infection or vaccination with ancestral SARS-CoV-2 sequences


title: Interpreting Changes in Life Expectancy During Temporary Mortality Shocks

abstract: Life expectancy is the most widely used measure of mortality, largely because of its intuitive interpretation as the expected age at death of an average individual. Changes in life expectancy are also used to assess mortality trends, but mortality change is incompatible with the assumptions underpinning that intuitive interpretation of life expectancy. To provide an alternative, I return to the two main interpretations of the period life table. The first interpretation, as a synthetic-cohort life table, allows for "forward-looking" probabilistic statements regarding the individual life course. The second interpretation, as stationary population characteristics, yields standardized demographic indicators of the (past) reference period. Interpreting life table indicators such as life expectancy in the first manner is often more appealing, but only the second one makes sense during temporary mortality shocks. The absolute change in life expectancy can then be interpreted as the standardized value of the average lifespan reduction in a past death cohort.


title: Variants in Interferon Lambda are Associated with Infantile-Onset Inflammatory Bowel Disease

abstract: Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine that affect children and adults. The etiology is multifactorial with the contribution of genetic, immune, microbial, and environmental risk factors with a substantial involvement of host:microbial cross-talk in the lumen. Whether and how antiviral responses contribute to IBD pathogenesis is under intense investigation. Here, we identified two unrelated patients diagnosed with very early onset IBD (VEOIBD) with rare variants in type III Interferons (IFNs), also known as interferon lambdas (IFN{lambda}s), a group of IFNs that play key roles in the protection against enteric viruses. The first patient was found to have homozygous variants in both IFNL2 and IFNL3, the genes encoding, IFN-{lambda}2 and IFN-{lambda}3, respectively. The second patient was found to have inherited compound heterozygous variants in IFNL3, with one of the two alleles bearing the same variant as the first patient. Functional analyses revealed that the proteins coded for by these variant IFN-{lambda} genes exhibited defects in the induction of IFN signaling. More detailed assessment of the variants identified in Patient 1 demonstrated defects in their ability to bind to IFN-{lambda} receptor 1 (IFNLR1), as well as their ability to induce heterodimerization of IFNLR1 and IL10RB, which together compromise the functional receptor for IFN-{lambda} (IFNLR). These patient-encoded IFN-{lambda} variants also exhibit defects in the ability to induce robust downstream IFN-stimulated genes (ISGs) in patient-derived intestinal organoids. All in all, we demonstrate that VEOIBD is associated with variants in IFN-{lambda}s and defective induction of downstream IFN signaling.

category: gastroenterology


title: Cost-effectiveness of antigen testing for ending COVID-19 isolation

abstract:
BackgroundThe Omicron variant of SARS-CoV-2 led to a steep rise in transmissions. Recently, as public tolerance for isolation abated, CDC guidance on duration of at-home isolation of COVID-19 cases was shortened to five days if no symptoms, with no lab test requirement, despite more cautious approaches advocated by other federal experts.

MethodsWe conducted a decision tree analysis of alternative protocols for ending COVID-19 isolation, estimating net costs (direct and productivity), secondary infections, and incremental cost-effectiveness ratios. Sensitivity analyses assessed the impact of input uncertainty.

ResultsPer 100 individuals, five-day isolation had 23 predicted secondary infections and a net cost of $33,000. Symptom check on day five (CDC guidance) yielded a 23% decrease in secondary infections (to 17.8), with a net cost of $45,000. Antigen testing on day six yielded 2.9 secondary infections and $63,000 in net costs. This protocol, compared to the next best protocol of antigen testing on day five of a maximum eight-day isolation, cost an additional $1,300 per secondary infection averted. Antigen or polymerase chain reaction testing on day five were dominated (more expensive and less effective) versus antigen testing on day six. Results were qualitatively robust to uncertainty in key inputs.

ConclusionsA six-day isolation with antigen testing to confirm the absence of contagious virus appears the most effective and cost-effective de-isolation protocol to shorten at-home isolation of individuals with COVID-19.

category: health economics


title: A fast and sensitive absolute quantification assay for the detection of SARS-CoV-2 peptides using Parallel Reaction Monitoring Mass Spectrometry

abstract: The on-going SARS-CoV-2 (COVID-19) pandemic has called for an urgent need for rapid and high-throughput methods for mass testing for early detection, prevention and surveillance of the disease. Here, we tested if targeted parallel reaction monitoring (PRM) quantification using high resolution Orbitrap instruments can provide the sensitivity and speed required for a high-throughput method that could be used for clinical diagnosis. Here we report a high-throughput and sensitive PRM-MS assay that enables absolute quantification of SARS-CoV-2 nucleocapsid peptides with short turn-around times. Concatenated peptides (QconCAT) synthesized using isotopically labelled SARS-CoV-2 were used for absolute quantification. We developed a fast and high-throughput S-trap-based sample preparation method, which was then successfully utilized for testing 25 positive and 25 negative heat-inactivated nasopharyngeal swab samples for SARS-CoV-2 detection. The method was able to differentiate between negative and positive patients accurately within its limits of detection. Moreover, extrapolating from the QconCAT absolute quantification, our data show that patients with Ct values as low as 17.5 have NCAP protein amounts of around 7.5 pmol in swab samples. The present high-throughput method could potentially be utilized in specialized clinics as an alternative tool for detection of SARS-CoV-2.


title: Consent is a confounding factor in a prospective observational study of critically ill elderly patients

abstract:
During analysis of a prospective multinational observation study of critically ill patients [≥]80 years of age, the VIP2 study, we also studied the effects of differences in country consent for study inclusion. This is a post hoc analysis where the ICUs were analyzed according to requirement for study consent. Group A: ICUs in countries with no requirement for consent at admission but with deferred consent in survivors. Group B: ICUs where some form of active consent at admission was necessary either from the patient or surrogates. Patients characteristics, the severity of disease and outcome variables were compared. Totally 3098 patients were included from 21 countries. The median age was 84 years (IQR 81-87). England was not included because of changing criteria for consent during the study period. Group A (7 countries, 1220 patients), and group B (15 countries, 1878 patients) were comparable with age distribution, organ failure score, frailty score and activity of daily life. Cognition was better preserved prior to admission in group B. Group A suffered from more organ dysfunction at admission compared to group B with Sequential Organ Failure Assessment score median 8 and 5 respectively. Survival at 30-day was lower in group A, 50.8 % compared to 66.7% in group B (p<0.001). We found profound effects on outcomes according to differences in obtaining consent for this study. It seems that the most severely ill elderly patients were less often recruited to the study in group B. Hence the outcome measured as survival was higher in this group.

We therefore conclude that consent likely is an important confounding factor for outcome evaluation in international studies focusing on old patients.


title: Investigating the impact of social and environmental extremes on cholera time varying reproduction number in Nigeria

abstract: Nigeria currently reports the second highest number of cholera cases in Africa, with numerous socioeconomic and environmental risk factors. Less investigated are the role of extreme events, despite recent work showing their potential importance. To address this gap, we estimated time varying reproductive number (R) from cholera incidence in Nigeria and used a machine learning approach to evaluate its association with extreme events (conflict, flood, drought) and pre-existing vulnerabilities (poverty, sanitation, healthcare). We then created a traffic-light system for cholera outbreak risk, using three hypothetical traffic-light scenarios (Red, Amber and Green) and used this to predict R. The system highlighted potential extreme events and socioeconomic thresholds for outbreaks to occur. We found that reducing poverty and increasing access to sanitation lessened vulnerability to increased cholera risk caused by extreme events (monthly conflicts and the Palmers Drought Severity Index). The work presented here shows the need for sustainable development for disaster prevention and mitigation and to improve health and quality of life.


title: The impact of social and environmental extremes on cholera time varying reproduction number in Nigeria


title: Educational attainment, structural brain reserve, and Alzheimer's disease: a Mendelian randomization analysis

abstract:
Higher educational attainment is observationally associated with lower risk of Alzheimers disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimers disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes, and Alzheimers disease.

Summary statistics were obtained from genome-wide association studies of educational attainment (n=1,131,881), late-onset Alzheimers disease (35,274 cases, 59,163 controls), and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax=33,211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimers disease, (ii) educational attainment and imaging-derived phenotypes, (iii) imaging-derived phenotypes and Alzheimers disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the protective effect of education on Alzheimers disease risk.

Genetically-proxied educational attainment was inversely associated with Alzheimers disease (odds ratio per standard deviation increase in genetically-predicted years of schooling = 0.70, 95% confidence interval [CI]: 0.60, 0.80). There was also evidence for positive associations between genetically-predicted educational attainment and four cortical macro-structure metrics (surface area: {beta}=0.30, 95% CI: 0.20, 0.40; volume: {beta}=0.29, 95% CI: 0.20, 0.37; intrinsic curvature: {beta}=0.18, 95% CI: 0.11, 0.25; local gyrification index: {beta}=0.21, 95% CI: 0.11, 0.31), as well as inverse associations with cortical intracellular volume fraction ({beta}=-0.09, 95% CI: - 0.15, -0.03) and white matter hyperintensities volume ({beta}=-0.14, 95% CI: -0.23, -0.05).

Genetically-proxied levels of three cortical macro-structure metrics were positively associated with years of education (surface area: {beta}=0.13, 95% CI: 0.10, 0.16; volume: {beta}=0.15, 95% CI: 0.11, 0.19; intrinsic curvature: {beta}=0.12, 95% CI: 0.04, 0.19). We found no evidence of associations between genetically-predicted imaging-derived phenotypes and Alzheimers disease. The inverse association of genetically-predicted education with Alzheimers disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses.

Our results provide support for a protective causal effect of educational attainment on Alzheimers disease risk, as well as bi-directional causal associations between education and several brain macro- and micro-structure metrics. However, we did not find evidence that these structural markers affect risk of Alzheimers disease. The protective effect of education on Alzheimers disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.


title: Measuring Repositioning in Home Care for Pressure Injury Prevention and Management

abstract:
A critical best practice for prevention and management of pressure injuries is regularly repositioning individuals who are at risk of these injuries are when they are in bed. However, despite the widespread agreement of the need for regular repositioning (typically every two hours), adherence to repositioning schedules remains poor in the clinical environment and there are some indications that the situation in home environment is even worse.

Our team has recently developed a non-contact system that can continuously determine an individuals position in bed (left-side lying, right-side lying or supine) using data from a set of inexpensive load cells placed under the bed frame. A proof of principle study showed that our system was able to detect whether healthy participants were supine, left-side lying or right-side lying with 94.2% accuracy in the lab environment.

The objective of the present work was to deploy our system into the home environment to evaluate how well the system was able to detect the position of individuals sleeping in their own beds overnight by comparing to ground truth time-lapse camera images using eight machine learning classifiers. Nine participants were recruited for this study and we found our system was able to detect an individuals position in bed with 98.1% accuracy and an F1 score of 0.982 using the XGBoost classifier.

Future work will include using this system to evaluate interventions focused on improving adherence to 2-hour repositioning schedules for pressure injury prevention or management as well as incorporating this technology in a repositioning prompting system to alert caregiver when a patient has remained in the same position for too long.

category: nursing


title: Array Comparative Genomic Hybridisation and Droplet Digital PCR uncover recurrent copy number variation of the titin segmental duplication region

abstract: Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridization array, we have previously shown that a gain or loss of more than one copy of the repeated block of the nebulin triplicate region constitutes a recessive pathogenic mutation. Using targeted array-CGH, similar copy number variants can be detected in the segmental duplication region of titin. Due to the limitations of the array-CGH methodology and the repetitiveness of the region, the exact copy numbers of the blocks could not be determined. Therefore, we developed complementary custom Droplet Digital PCR assays for the titin segmental duplication region to confirm true variation. Our combined methods show that the titin segmental duplication region is subject to recurrent copy number variants, which is surprisingly common. Gains and losses were detected in samples from healthy individuals as well as in samples from patients with different muscle disorders. The copy number variation observed in our cohort is likely benign, but pathogenic copy number variants in the segmental duplication region of titin cannot be excluded. Further investigations are needed, however, this region should no longer be neglected in genetic analyses.

category: genetic and genomic medicine


title: Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases.

abstract:
BackgroundMacular diseases (MDs) are a subgroup of retinal disorders characterized by central vision loss that represent a major cause of vision impairment. Despite the identification of numerous genes associated with inherited MD (iMD) and risk factors associated with age-related MD (AMD), the extent of genetic and non-genetic factors that influence the expression of MD is still not fully explained. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease in a cost-effective manner to identify associated coding and non-coding variation, however a large portion of patients with MDs still remain genetically unexplained.

MethodsFor MD patients, we hypothesized that the missing heritability may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. We used 17,394 smMIPs to sequence the coding regions of 105 genes and non-coding or regulatory loci associated with iMD and AMD, known pseudo-exons, and the mitochondrial genome in two test cohorts that had previously been screened for variants in the entire ABCA4 gene.

ResultsSequencing of 379 probands achieved an average nucleotide coverage of 431x across all targets. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an   MD-smMIPs panel that allows a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets.

ConclusionsFurther analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients and their families. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.


title: Missorting of Plasma miRNAs in Aging and Alzheimer's Disease

abstract: Aging is the greatest risk factor for Alzheimers disease (AD)1, a pervasive cognitive disorder with unsettled etiology. The precise role of aging in AD, however, remains poorly understood. Accumulating evidence documents the dysregulation of circulating microRNAs (miRNA) separately in aging2,3 and AD4. Considering miRNAs play a role in aging and longevity5,6, we comprehensively test which aging-associated miRNA changes are observed in AD, and change in AD beyond aging in the circulating miRNA network. Here we show that plasma miRNAs in aging are downregulated and preferentially targeted to extracellular vesicle (EV) content, while in AD, miRNAs are further downregulated and of exclusive EV origin. We further show that miRNAs in AD display altered proportions of motifs relevant to their loading into EVs7,8 and secretion propensity9. Considering endosomes play a role in the genesis of EVs10,11 and are compromised early in AD12, these findings implicate endosomal pathology underlying the AD plasma miRNA profile and its potential as a mechanistic AD biomarker. Striking similarities between plasma miRNA profiles in aging and AD further suggest that the AD miRNA network profile reflects a pathological exacerbation of the aging process whereby physiological suppression of AD pathology by plasma miRNAs becomes insufficient.

category: neurology


title: Longitudinal brain age prediction and cognitive function after stroke

abstract:
BackgroundAdvanced age and poor brain health have been associated with higher risk for more severe clinical and cognitive outcomes following stroke, but more accurate models for clinical prediction are needed. Machine learning based on brain scans can be used to estimate brain age of individual patients, and the corresponding difference from chronological age, the brain age gap (BAG) has been investigated in a range of clinical conditions. Yet, the predictive value for post stroke NCD has not been established. To this end, using longitudinal data we aimed to investigate the association between BAG and post-stroke neurocognitive disorder (NCD) over time.

Methods269 stroke survivors (55.4% women, mean (SD) age = 71 (11) years) were included from the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study. MRI and clinical data were collected shortly after the acute stroke (neuropsychological data first after 3 months) and at 18- and 36 months follow-up. The brain age model was trained in an independent sample using established protocols based on machine learning and brain structural features from Freesurfer and applied to the current dataset. We used linear mixed effects (LME) models and survival analysis to assess the associations between cognitive status and longitudinal brain age.

ResultsLMEs revealed a main effect of BAG on post stroke NCD across time, confirming our main hypothesis that a younger appearing brain may protect against post stroke NCD. For patients with no NCD at baseline, survival analysis suggested that higher baseline BAG was associated with higher risk of post stroke NCD at 18 and 36 months.

ConclusionA younger appearing brain is associated with lower risk of post stroke NCD up to 36 months after a stroke, even among those showing no evidence of impairments 3 months after hospital admission. Brain age prediction based on brain scans provides a reliable assessment of brain structure and is sensitive to post stroke NCD with predictive value for cognitive decline among patients with no impairment at the initial assessment.


title: Use of therapeutic play in nursing care for school-age children: a scoping review

abstract:
BackgroundTherapeutic play is an important strategy in nursing care to relieve emotional discomfort of school-age children. The aim of this scoping review was to map the use of therapeutic play in nursing care for school-age children.

MethodsSearches in the databases: MEDLINE, CINAHL, Scopus, BDENF, LILACS and CAPES theses and dissertations portal. A total of 1,486 records were identified and 32 included in the review. Eligibility criteria: The literature on children aged 6 to 12 participating in therapeutic play sessions in nursing care in any place, in the form of original articles, theses and dissertations, in English, Spanish or Portuguese. There was no time limit.

ResultsThe focus theme has been described since 1987 in the national and international scientific literature. There is consensus on the benefits of therapeutic play in nursing care for school-age children in various situations, especially in the hospital context, with proven efficacy in research that encourages the application of this strategy in nursing practice, but there are barriers for its implementation.

ConclusionThe review identified the settings, situations, benefits, barriers and gaps regarding the use of therapeutic play in nursing care for school-age children.

ImplicationsThe positive results reported in the studies can be used to enrich discussions about the use of therapeutic play in nursing practice for school-age children and encourage awareness of the importance of this strategy. The gaps identified contribute to future research.


title: Comparison of Phase Angle Using Bioelectrical Impedance Analysis According to Device Type and Examination Posture

abstract:
BackgroundBioelectrical impedance analysis (BIA) is gaining popularity as a body composition assessment tool for patients. Although it has been studied and validated in different populations, age groups, and clinical settings, including critically ill patients, there are concerns about BIA reproducibility and reliability in different device types and postures. This study aimed to evaluate the reliability of BIA according to different devices, postures, and lead types.

MethodsCross-sectional observational data of 74 healthy volunteers (32 women and 42 men) were collected. We used two types of devices, three types of postures (standing, sitting, and lying), and two lead types (clamp lead and adhesive lead) to measure the whole-body phase angle (phA) at a single frequency of 50 kHz. The measurements were validated using the intraclass correlation coefficient (ICC) and Bland-Altman plot analysis.

ResultsAll phA measurements recorded with two types of devices, three different postures, and two types of leads were equivalent to each other (mean ICC = 0.9932, 95% confidence interval (CI) 0.9905-0.0053). The average mean difference in phA was 0.31 (95% CI 0.16- 0.46). The largest phA value was measured using BWA with an adhesive-type lead in the lying position. There were no differences between standing and sitting positions.

ConclusionThis is the first study to show the consistency and reliability of BIA in measuring phA using different devices, lead types, and postures. This could provide the confidence that BIA can be used in various clinical settings.


title: Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons

abstract: Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with pre-disposition to severe COVID-19. Here, we screened for such autoantibodies in 103 critically-ill COVID-19 patients in a tertiary intensive care unit in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFN or anti-IFN/anti-IFN{omega} IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFN IgG. Strikingly, all patients with plasma anti-IFN IgG also had anti-IFN IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for SARS-CoV-2 infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically-ill COVID-19 cohort appeared to predict herpesvirus (herpes simplex viruses types 1 and 2, HSV-1/-2; and/or cytomegalovirus, CMV) reactivations, which are linked to worse clinical outcomes. Indeed, all seven tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesvirus reactivations, and analysis revealed that these patients were substantially more likely to experience CMV reactivation than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for systemic steroid treatment (odds ratio 7.28, 95%-CI 1.14-46.31, p=0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates herpesvirus reactivations in critically-ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options.

category: infectious diseases


title: 15-month follow-up of anti-spike receptor binding domain (RBD) SARS-CoV-2 antibodies among healthcare workers in Boston, MA

abstract:
Over 15-months we found that anti-spike RBD SARS-CoV-2 antibody concentrations follow different trends with combinations and permutations of COVID-19 infection and vaccination among healthcare workers in Boston, MA. A majority of HCWs remain well above the positivity threshold for anti-spike RBD IgG antibodies for at least 9 months following vaccination regardless of infection history. Of interest, those with COVID-19 infection before vaccination had significantly higher median serum antibody concentrations in comparison to HCWs with no prior infection at each follow-up timepoint. These findings further support what is known regarding the decline in serum antibody concentrations following natural infection and vaccination, adding knowledge of serum antibodies up to 15 months post infection and 11 months post vaccination.

ImportanceBoston Medical Center (BMC) is a safety net hospital in Boston and from the initial wave of COVID-19 there has been overwhelming concern about the exposure of healthcare workers to SARS-CoV-2. We conceived a longitudinal study to assess virus exposure and trends in SARS-CoV-2 antibodies amongst healthcare workers at BMC over 15 months. We have followed HCWs through three waves of COVID-19, including the Delta variant wave from June through mid-December 2021, assessing anti-spike receptor binding domain IgG, anti-nucleocapsid IgG, and anti-spike IgM at approximately three-month intervals. Current literature largely describes antibody durability six months post vaccination. These data add to the literature by describing antibody durability and trend differences according to infection history and vaccination status. These longitudinal data contribute to a greater understanding of the ongoing COVID-19 pandemic and can help inform future research and public health decision-making regarding vaccine uptake, breakthrough infections, and overall pandemic response.


title: Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study

abstract:
ImportanceMulti-organ impairment associated with Long COVID is a significant burden to individuals, populations and health systems, presenting challenges for diagnosis and care provision. Standardised assessment across multiple organs over time is lacking, particularly in non-hospitalised individuals.

ObjectiveTo determine the prevalence of organ impairment in Long COVID patients at 6 and at 12 months after initial symptoms and to explore links to clinical presentation.

DesignThis was a prospective, longitudinal study in individuals following recovery from acute COVID-19. We assessed symptoms, health status, and multi-organ tissue characterisation and function, using consensus definitions for single and multi-organ impairment. Physiological and biochemical investigations were performed at baseline on all individuals and those with organ impairment were reassessed, including multi-organ MRI, 6 months later.

SettingTwo non-acute settings (Oxford and London).

Participants536 individuals (mean 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post-COVID-19). 331 (62%) with organ impairment or incidental findings had follow up, with reduced symptom burden from baseline (median number of symptoms: 10 and 3, at 6 and 12 months).

ExposureSARS-CoV-2 infection 6 months prior to first assessment.

Main outcomePrevalence of single and multi-organ impairment at 6 and 12 months post-COVID-19.

ResultsExtreme breathlessness (36% and 30%), cognitive dysfunction (50% and 38%) and poor health-related quality of life (EQ-5D-5L<0.7; 55% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single organ impairment. At baseline, there was fibro-inflammation in the heart (9%), pancreas (9%), kidney (15%) and liver (11%); increased volume in liver (7%), spleen (8%) and kidney (9%); decreased capacity in lungs (2%); and excessive fat deposition in the liver (25%) and pancreas (15%). Single and multi-organ impairment were present in 59% and 23% at baseline, persisting in 59% and 27% at follow-up.

Conclusion and RelevanceOrgan impairment was present in 59% of individuals at 6 months post-COVID-19, persisting in 59% of those followed up at 1 year, with implications for symptoms, quality of life and longer-term health, signalling need for prevention and integrated care of Long COVID.

Trial RegistrationClinicalTrials.gov Identifier: NCT04369807

Key pointsO_LIQuestion: What is the prevalence of organ impairment in Long COVID at 6- and 12-months post-COVID-19?
C_LIO_LIFindings: In a prospective study of 536 mainly non-hospitalised individuals, symptom burden decreased, but single organ impairment persisted in 59% at 12 months post-COVID-19.
C_LIO_LIMeaning: Organ impairment in Long COVID has implications for symptoms, quality of life and longer-term health, signalling need for prevention and integrated care of Long COVID.
C_LI


title: Mechanistic modeling-guided optimization of microneedle-based skin patch for rapid transdermal delivery of naloxone for opioid overdose treatment

abstract: Naloxone, an FDA approved opioid inhibitor, used to reverse opioid overdose complications has up till date faced challenges associated with its delivery. Limitations include the use of invasive delivery forms and the need for frequent redosing due to its short half-life. Further, the use of the non-invasive commercially available intranasal form is faced with limitations such as nasal epistaxis and inability to use the intranasal channel due to nasal trauma common in addicts from frequent drug snorting. The goal of the current study was to design a rapidly dissolving polymeric microneedle (MN) patch with delivery and pharmacokinetic properties comparable to that seen with the commercially available NAL products, eliminating their highlighted limitations. Factors such as drug loading and polymer strength influenced the fabrication of the MNs. Compared to passive permeation, a reduced lag time of about 5-15 min was observed with a significant drug flux of 15.09 {+/-} 7.68 g/cm2/h seen in the first 1 h (p<0.05) with an array of 100 needles (500 {micro}m long). Increasing the MN length and density (no. of needles/unit area) made a significant difference in the amount permeated and flux (p<0.05), with latter being more influential. Further, through a mechanistic model of drug release from the patch, integrated with pharmacokinetic modeling, we optimized the design of the patch to reproduce in-silico the clinical pharmacokinetics of NAL obtained through commercial intramuscular and intranasal devices. Model simulations and analyses revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL.

category: addiction medicine


title: Social stressors associated with age-related T lymphocyte percentages in older US adults: Evidence from the Health and Retirement Study

abstract: Exposure to stress is a well-established risk factor of poor health and accelerated aging. Immune aging, including declines in naive and increases in late memory and terminally differentiated T cells, plays an important role in immune health and tissue specific aging, and may contribute to the observed elevated risk for poor health among those who experience high psychosocial stress. However, past data have been limited in estimating the contribution of life stress to the development of accelerated immune aging and investigating mediators such as lifestyle and CMV infection, that might be useful points of intervention. The current study utilizes a national sample of 5744 US adults over the age of 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naive and terminally differentiated T cell percentages and the ratio of CD4+ to CD8+ T cells. Experiencing life trauma and chronic stress was related to a lower percentage of CD4+ naive T cells. Higher everyday discrimination, lifetime discrimination, and chronic stress were each associated with a greater percentage of terminally differentiated CD4+ T cells. Stressful life events, high lifetime discrimination, and life trauma were related to a lower percentage of CD8+ naive T cells. Stressful life events, high lifetime discrimination and chronic stress were associated with a higher percentage terminally differentiated CD8+ T cells. High lifetime discrimination and chronic stress was related to a lower CD4+:CD8+ ratio. Lifestyle factors and cytomegalovirus (CMV) seropositivity partially reduced these effects. Results identify psychosocial stress as a contributor to accelerating immune aging by decreasing naive and increasing senescent T cells.

category: allergy and immunology


title: Impact of diabetes mellitus on the stabilization and osseointegration of dental implants: a retrospective study in Greece

abstract:
IntroductionAdequate dental restoration including the use of implants is critical in healthy eating habits of diabetic patients and appropriate metabolic control.

AimTo investigate the relationship between diabetes mellitus and dental implants stabilization and osseointegration.

MethodsA retrospective study was conducted in a private dental clinic in Athens. Data collection referred to the period between January 2016 and August 2021. During this time period, all cases related to implant placement in diabetic patients at the clinic were recorded. In particular, 93 implants were recorded in 36 diabetic patients. During the same time period, 93 implant cases involving non-diabetics at the clinic were randomly taken from the clinic records to provide the comparison group. The implant stability quotient was measured immediately after implant placement and after four months.

ResultsThe mean value of the implant stability quotient immediately after implant placement was 75.97 in non-diabetics and 76.85 in diabetics (p=0.42). The mean value of the implant stability quotient after four months was 78.92 in non-diabetics and 78.44 in diabetics (p=0.58). The mean value of the implant stability quotient in non-diabetics increased statistically significantly in the first four months from 75.97 to 78.92 (p<0.001). The mean value of the implant stability quotient in diabetics increased statistically significantly in the first four months from 76.85 to 78.44 (p=0.011). No implant loss was recorded in both diabetics and non-diabetics (p=1). According to multivariate analysis, patients who did not have bio-materials placed during implantation, patients who had not undergone previous surgical procedures and patients who had implants placed in the mandible had better implant stability.

ConclusionsThe stability of the implants increased statistically significant in the first four months of implant placement. No relationship was found between diabetes mellitus and dental implants stabilization and osseointegration. However, studies with a larger sample size and longer follow-up of patients are needed to better clarify the risks and benefits of dental implants in diabetic patients.

category: dentistry and oral medicine


title: Oral health professionals and child abuse and neglect: a scoping review protocol

abstract:
IntroductionChild abuse and neglect can seriously impair social development, learning, physical, and psychological health. Oral health practitioners can recognize the orofacial manifestations of maltreatment in a dental setting, provide necessary support, and refer concern to child protection agencies to prevent further harm. There is a need to understand the responsiveness of oral health practitioners to a child protection concern. This protocol outlines the systematic processes to map evidence in the field of child protection in oral health.

Methods and analysisThis review will be guided by the PRISMA-ScR and the JBI guidelines. Primary and secondary studies, reviews, guidelines, and editorial articles written in English will be included in the review. A three-step search will be implemented. An initial search is conducted to finalised the search terms and eligbility criteria followed by a second search involving sensitive searches of databases (Scopus, MEDLINE, CINAHL, Dentistry & Oral Science Source, and Cochrane Library). A third search will involve grey literature searching for unpublished materials. Government and international health organization websites will be searched during the third search. Eligible studies will be screened based on the participants (oral health practitioners), the concept (child protection) and the context (dental setting) and data extracted by two reviewers. Outcomes from the data extraction chart will be synthesized through exploratory narratives.

Ethics and disseminationThis study involves neither human participants nor unpublished secondary data. As such, ethics approval is not required. Findings will be disseminated through publication in a peer-reviewed journals, professional networks, and conferences.

Strengths and limitations of this studyO_LIThis study will systemically identify literature from a broad range of databases and map evidence in the field of child protection in oral health.
C_LIO_LIThe review will take a rigorous approach adhering to the PRISMA-ScR and and the JBI guidelines.
C_LIO_LIMultiple reviewers will conduct screening and data extraction independently to facilitate reliability.
C_LIO_LIA limitation is that only sources in English will be reviewed.
C_LI


title: Association of assisted reproductive technology with offspring growth and adiposity from infancy to early adulthood

abstract:
ImportancePeople conceived using assisted reproductive technology (ART) make up an increasing proportion of the worlds population, and their numbers are expected to continue rising.

ObjectiveInvestigate association of ART conception with growth and adiposity outcomes from infancy to early adulthood in offspring from a large multinational multi-cohort study.

Design26 population-based cohort studies.

SettingEurope, Asia-Pacific, and North America

ParticipantsInfants, children, adolescents, and young adults born from 1984 to 2018, with mean ages at assessment of growth/adiposity outcomes ranging from 0.6 month to 27.4 years.

ExposuresConception by ART (conventional in vitro fertilisation and intracytoplasmic sperm injection) versus natural conception (NC).

Main Outcomes and MeasuresLength/height, weight, and body mass index (BMI). Each cohort was analysed separately with adjustment for maternal BMI, age, smoking, education, parity, ethnicity, and offspring sex and age. Cohort results were combined in random effects meta-analysis for thirteen age groups.

ResultsUp to 158,066 offspring (4,329 conceived by ART) were included in each age-group meta-analysis; 47.6% to 60.6% were female. Compared with NC, ART-conceived offspring were slightly shorter, lighter, and thinner from infancy to early adolescence. The differences in growth/adiposity outcomes were largest at the youngest ages and attenuated with older child age, e.g., adjusted standardised mean differences (95% confidence intervals) in offspring weight at age  <3 months,  17 to 23 months,  6 to 9 years, and  14 to 17 years were -0.27 standard deviation (SD) units (-0.39 to -0.16), -0.16SD (-0.22 to -0.09), -0.07SD (-0.10 to -0.04), and -0.02SD (-0.15 to 0.12), respectively. There was no evidence that results were driven by parental subfertility or of difference between conventional in vitro fertilisation and intracytoplasmic sperm injection however, smaller offspring size appeared to be limited to offspring conceived by fresh but not frozen embryo transfer, compared with NC. More marked but less precise differences were observed for body fat measurements. There was imprecise evidence that offspring conceived by ART may develop greater adiposity by early adulthood.

Conclusions and RelevancePeople conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

KEY POINTSO_ST_ABSQuestionC_ST_ABSIs conception by assisted reproductive technology associated with growth and adiposity from infancy to early adulthood?

FindingsIn this multi-cohort study of up to 158,066 European, Asian-Pacific, and Canadian infants, children, adolescents, and young adults, those conceived using assisted reproductive technology were on average shorter, lighter, and thinner from infancy up to early adolescence when compared with their naturally conceived peers though differences were small across all ages and reduced with older age.

MeaningParents conceiving or hoping to conceive through assisted reproductive technology and their offspring should be reassured that differences in early life growth and adiposity are small and no longer apparent by late adolescence.

category: epidemiology