title: COVID-19 mortality in the United States: It's been two Americas from the start

abstract:
During the summer of 2021, a narrative of "two Americas" emerged: one with high demand for the COVID-19 vaccine and the second with widespread vaccine hesitancy and opposition to masks and vaccines.

We analyzed "excess mortality" rates (the difference between total deaths and what would have been expected based on earlier time periods) prepared by the CDC for the United States from January 3, 2020 to September 26, 2021.

Between Jan. 3, 2020 and Sept. 26, 2021, there were 895,693 excess deaths associated with COVID-19, 26% more than reported as such. The proportion of deaths estimated by the excess mortality method that were reported as COVID-19 was highest in Northeast (92%) and lowest in the West (72%) and South (76%).

Of the estimated deaths, 43% occurred between Oct. 4, 2020 and Feb. 27, 2021. Before May 31, 2020, approximately 56% of deaths were in the Northeast, where 17% of the population resides. Subsequently, 48% of deaths were in the South, which makes up 38% of the population. Since May 31, 2020, the South experienced COVID-19 mortality 26% higher than the national rate, whereas the Northeasts rate was 42% lower.

If each region had the same mortality rate as the Northeast, more than 316,234 COVID-19 deaths between May 31, 2020 and Sept. 26, 2021 were "avoidable." More than half (63%) of the avoidable deaths occurred between May 31, 2020 and February, 2021, and more than half (60%) were in the South.

Regional differences in COVID-19 mortality have been strong throughout the pandemic. The South has had higher mortality rates than the rest of the U.S. since May 31, 2020, and experienced 62% of the avoidable deaths. A comprehensive COVID-19 policy, including population-based restrictions as well as vaccines, is needed to control the pandemic.

category: public and global health


title: Reproducible in vivo detection of locus coeruleus pathology in Parkinson's disease

abstract:
BackgroundPatients with Parkinsons disease undergo a loss of melanized neurons in substantia nigra pars compacta and locus coeruleus. There are very few in vivo studies of locus coeruleus pathology in Parkinsons disease with magnetic resonance imaging. Existing studies have used varying methodologies, and reproducibility has not been established for any approach.

ObjectivesWe used neuromelanin-sensitive magnetic resonance imaging to examine the reproducibility of locus coeruleus and substantia nigra pars compacta degeneration in discovery and validation cohorts.

MethodsTwo cohorts, discovery and validation, recruited from the Emory Movement Disorders Clinic were scanned on two different magnetic resonance imaging scanners. In cohort 1, imaging data from 19 controls and 22 Parkinsons disease patients were acquired with a Siemens Trio 3 Tesla scanner using a 2D gradient echo sequence with magnetization transfer preparation pulse. Cohort 2 consisted of 33 controls and 39 Parkinsons disease patients were scanned on a Siemens Prisma 3 Tesla scanner with a similar imaging protocol. Nigral and locus coeruleus volumes were segmented in both cohorts.

ResultsNigral volume (Cohort 1: p=0.0148; Cohort 2: p=0.0011) and locus coeruleus volume (Cohort 1: p=0.0412; Cohort 2: p=0.0056) were significantly reduced in the Parkinsons disease group as compared to controls in both cohorts.

InterpretationSubstantia nigra pars compacta volume and locus coeruleus volume were significantly reduced in Parkinsons disease compared to controls in both cohorts. This imaging approach robustly detects Parkinsons disease effects on these structures suggesting its use as a potential diagnostic biomarker of Parkinsons disease.

category: neurology


title: Challenges and Opportunities Experienced by Performing Artists during COVID-19 Lockdown: Scoping Review

abstract: This scoping review synthesises published literature on the experiences of professional and amateur performing artists during COVID-19 and their perceptions of the challenges and opportunities faced. Six electronic databases were searched for published English-language articles containing primary data on this topic; twenty-one studies were reviewed. Themes included loss of work, financial impact, concerns about the future, psychological wellbeing, social connections, continuing creative pursuits, and inequalities. Participants reported both detrimental psychological effects of lockdown such as anxiety and sleep problems and positive effects including reduced stress and enjoyment of having more free time. Most continued creative pursuits throughout lockdown, most commonly shifting to online platforms. However, many barriers to creative pursuits were reported, including lack of technological expertise or equipment. Concerns were raised about inequality, in particular racial disparities in the financial impact of the pandemic and additional pressures faced by performers with disabilities; with insufficient funds to afford the equipment needed to shift to remote performing; and with additional caring responsibilities. It is important that performing artists have access to peer support; that education on digital technologies is incorporated into future performing arts education; and that inequities are addressed to ensure the needs of diverse communities are met.

category: occupational and environmental health


title: A community-based Advanced Nurse Practitioner-led integrated oncology care model for adults receiving oral anticancer medication-protocol for a pilot study

abstract:
Oncology has been undergoing a profound transition in the last ten years or more with the increased usage in oral anti-cancer medication (OAM). Approximately 25% of all anti-cancer medication is now designed for oral use and this is likely to increase prospectively. Oral anti-cancer medications have the potential to alleviate capacity issues in cancer treating units as patients receive their treatment at home. There remains however a requirement for safe and efficient assessment and monitoring but this does not necessarily require them to repeatedly attend a hospital day unit. Therefore the opportunity exists to transition this cohort to a community-based setting to be assessed by a specialist such as an Advanced Nurse Practitioner (ANP) in nurse-led clinics. Having an OAM assessment closer to their home would be more convenient to the patient. Furthermore, this could help alleviate hospital capacity issues which were brought into sharp focus with the onset of the COVID-19 pandemic and the use of nurse-led clinics are promoted in the aims of the current healthcare system reform process in Ireland.

Within the context of the Irish healthcare system reform and the COVID-19 pandemic this protocol will outline a collaboration between an Oncology Department in Letterkenny University Hospital in Ireland and the National University of Ireland, Galway aimed to develop and pilot a community-based Advanced Nurse Practitioner-led integrated oncology care model for adults receiving OAM. Phase 1 of this two-phase study commenced in September 2020 and comprised a scoping review, a benchmarking exercise and a qualitative analysis of relevant stakeholders. This protocol paper presents a pilot to be undertaken in phase 2 as OAM care is transitioned to an ANP-led community-based model, which is a radical shift for oncology care in Ireland. The pilot outlined will provide data that will identify potential refinements to the model and address specific uncertainties about a definitive trial.

category: oncology


title: Olfactory loss is an early and reliable marker for COVID-19

abstract: Detection of early and reliable symptoms is important in relation to limiting the spread of an infectious disease. For COVID-19, the most prevalent symptom is either losing or experiencing reduced olfactory functions. Anecdotal evidence suggests that olfactory dysfunction is also one of the earlier symptoms of COVID-19 but objective measures supporting this notion are currently missing. To determine whether olfactory dysfunction is an early sign of COVID-19, we assessed available longitudinal data from a web-based interface enabling individuals to test their sense of smell by rating the intensity of selected household odors. Individuals continuously used the interface to assess their olfactory functions and at each login, in addition to odor ratings, recorded their symptoms and result from potential COVID-19 test. A total of 205 COVID-19 positive individuals and 156 pseudo-randomly matched control individuals lacking positive test provided longitudinal data which enabled us to assess olfactory functions in relation to their test results date. We found that odor intensity ratings started to decline in the COVID-19 group as early as 6 days prior to test result date. Symptoms such as sore throat, aches, and runny nose appear around the same point in time; however, with a lower predictability of a COVID-19 diagnose. Our results suggest that olfactory dysfunction is an early symptom but does not appear before other related COVID-19 symptoms. Olfactory dysfunction is, however, more predictive of an COVID-19 diagnose than other early symptoms.

category: otolaryngology


title: Association of Physical Activity Volume and Intensity with Incident Cardiovascular Disease: a UK Biobank Study

abstract:
BackgroundAlthough the cardiovascular disease (CVD) benefits of both overall volume and intensity of physical activity (PA) are known, the role of PA intensity, over and above volume, is poorly understood. We aimed to investigate the interplay between PA volume and intensity in relation to incident CVD.

MethodsData were from 88,412 UK Biobank participants without prevalent CVD (58% women) who wore an accelerometer on their dominant wrist for 7 days, from which we estimated total physical activity energy expenditure (PAEE) using population-specific validation. Cox proportional hazards regressions modelled associations between PAEE (kJ/kg/day)] and PA intensity [%MVPA; the fraction of PAEE accumulated from moderate-to-vigorous-intensity PA] with incident CVD, adjusted for potential confounders.

ResultsThere were 4,068 CVD events during 584,568 person-years of follow-up (median 6.8 years). Higher PAEE and higher %MVPA (adjusted for PAEE) were associated with lower rates of incident CVD. In interaction analyses, CVD rates were 17% (95%CI: 8-26%) lower when MVPA accounted for 20% rather than 10% of 15 kJ/kg/d PAEE; equivalent to the difference between a 12-min stroll into a brisk 7-min walk. CVD rates did not differ significantly between values of PAEE when the %MVPA was fixed at 10%. However, the combination of higher PAEE and %MVPA was associated with lower CVD rates. Rates were 24% (10-35%) lower for 20 kJ/kg/d PAEE with 20% from MVPA, and 49% (23-66%) lower for 30 kJ/kg/d with 40% from MVPA (compared to 15 kJ/kg/d PAEE with 10% MVPA).

ConclusionsReductions in CVD risk may be achievable through higher levels of PA volume and intensity, with the role of moderately intense PA appearing particularly important for future CVD risk. Our findings support multiple approaches or strategies to PA participation, some of which may be more practical or appealing to different individuals.

category: sports medicine


title: CoviVac vaccination induces production of neutralizing antibodies against Delta and Omicron variants of SARS-CoV-2

abstract: Vaccines are proven to be an effective tool in prophylaxis of severe COVID-19, but emerging mutated SARS-CoV-2 variants constantly challenge vaccines protectivity. We have evaluated the ability of the sera from individuals vaccinated with two variants of inactivated vaccine CoviVac and COVID-19 convalescents (May-December 2020) to neutralize SARS-CoV-2 variants Delta and Omicron. Four groups of serum samples (CoviVac vaccinees; COVID-19 convalescents; mice immunized with CoviVac preparations based on prototype B.1.1 strain and Delta variant) were evaluated in virus neutralization test against SARS-CoV-2 heterologous B.1.1 virus, Delta and Omicron variants. CoviVac preparations based on B.1.1 and Delta induced neutralizing antibodies against SARS-CoV-2 B.1.1 and two variants of concern. We observed a decrease in neutralization capacity in the sera from CoviVac (based on B.1.1 strain) vaccinees: 57.1% samples had detectable neutralizing antibodies against Delta and 61.9% against Omicron variants. Sera samples of all (100%) mice immunized with a candidate vaccine based on the SARS-CoV-2 Delta variant strain had neutralizing antibodies against all tested strains.

category: infectious diseases


title: An evaluation of global Chikungunya clinical management guidelines - a systematic review

abstract:
BackgroundChikungunya virus (CHIKV) has expanded its geographical reach in recent decades and is an emerging global health threat. CHIKV can cause significant morbidity and lead to chronic, debilitating arthritis in up to 40% of infected individuals, impacting on livelihoods. Prevention, early identification, and clinical management are key for improving outcomes. This review aims to evaluate the availability of inclusive, evidence-based clinical management guidelines for CHIKV in a global context.

MethodsSix databases were searched systematically from inception to 14th October 2021 and complemented with a grey literature search until 16th September 2021. We included CMGs providing supportive care and treatment recommendations. Two reviewers independently screened records, extracted data and assessed quality using the AGREE II tool. Findings are presented in a narrative synthesis.

ResultsTwenty-eight CMGs were included; most were of low-quality (median score 2 out of 7 (range 1-7)). None were produced specifically in a low-income country and 54% (15/28) were produced more than five years ago. There were variations in the CMGs guidance on the management of different at-risk populations, long-term sequelae, and the prevention of disease transmission in community and hospital settings. In the acute phase, 54% (15/28) recommended hospitalisation for severe cases, however only 39% (11/28) provided clinical management guidance for severe disease. Further, 46% (13/28) advocated for steroids in the chronic phase, yet 18% (5/28) advised against its use.

ConclusionThere was a lack of high-quality CMGs that provided supportive care and treatment guidance; this scarcity may impact patient care and outcomes. It is essential that existing guidelines are updated and adapted to provide detailed evidence-based treatment guidelines for different at-risk populations. This study also highlights a need for more research into the management of the acute and chronic phases of CHIKV infection to inform evidence-based care.

Systematic review registration: PROSPERO CRD42020167361

What was known beforeO_LICHIKV is endemic across most of the southern hemisphere, with risk of expansion into new regions driven by global travel, trade, and climate change.
C_LIO_LIInfection can result in severe illness with long-term sequelae, particularly in vulnerable groups. Chronic sequelae of CHIKV infection is a cause of significant debilitating morbidity affecting individual functionality and quality of life with wider health system and socio-economic impact.
C_LIO_LIThere is no effective vaccine or targeted treatment against Chikungunya and supportive care is the mainstay of treatment.
C_LIO_LIEven with a limited evidence base, clinical management guidelines (CMGs) are key tools for standardising best available evidence-based care, and reduce inappropriate use of treatments, to reduce morbidity and improve patient outcomes.
C_LI

What this study addsO_LIThis review highlights a global scarcity of CMGs for chikungunya providing detailed guidance on optimal supportive care and treatment for different at-risk populations and settings.
C_LIO_LIThere was limited guidance available on care for severe cases, and available guidance was heterogenous and discordant (e.g., on use of analgesia, corticosteroids, and monitoring).
C_LIO_LIThe limited availability of up-to-date CMGs and heterogenous recommendations identified is a concern, which may impact on equity in access to best available evidence-based care and patient outcomes.
C_LIO_LIFurther research into access to and implementation of CMGs in different settings is needed, to ensure equitable access to best available care.
C_LIO_LIThis study also highlights a need for further investment into research into supportive care and treatment for different at-risk populations, and new evidence incorporated into guidelines to reduce morbidity and improve long term outcomes for the people affected by and at risk of Chikungunya.
C_LI


title: A passive OneHealth surveillance system to track canine rabies in urban India

abstract: Robust and widely implementable "OneHealth" surveillance systems are required to detect and control the spread of zoonotic infectious diseases. Using technological tools coupled with a rapid field response and rapid diagnostics can help in surveillance of deadly diseases such as rabies, even in densely populated urban areas. Here, we describe the use of an animal rescue system (Hawk Data Pro) that was adapted as a passive surveillance tool for rabies in a large metropolis in India. We used a webline and helpline that reported injured or sick animals to an animal rescue facility to determine possible rabies cases in street animals in Pune city in western India. Suspected rabid animals were tested using lateral flow assays and this information was used to direct awareness materials on rabies as well as in conducting mass dog vaccinations in areas that reported multiple cases. Over a [~]4 year period, we received over 90,700 calls or reports, of which 1162 calls were for suspected rabies cases in dogs, and 6 for other animals (cats, goats and cattle). Of these, 749 dogs and 4 other animals tested positive for rabies. Most of the cases were reported from the densely human populated central Pune region. In response, [~]21,000 people were provided with educational materials on post-bite management, and [~]23,000 dogs were vaccinated. We show that the adoption of the Hawk Data Pro system as a passive surveillance tool allowed us to document an ongoing outbreak of rabies in a large metropolis in India. Such systems can be modified or adapted to other areas as well to meet the surveillance and reporting requirements of the WHOs Zeroby30 strategy to eliminate rabies globally.


title: A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2

abstract:
PurposeNSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) region. Recent descriptions delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occures somatically in leukemia and has a gain-of-function (GoF) effect.

MethodsWe describe two unrelated individuals carrying c.3295G>A, p.Glu1099Lys as heterozygous de novo germline variants identified by exome sequencing of blood DNA and subsequently confirmed in two ectodermal tissues. We use omics data from the Cancer Cell Line Encyclopedia to analyze the GoF effect.

ResultsClinically these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands and organomegaly. We confirmed increased K36me2 methylation in lines with either NSD2 GoF variants or duplications. Cells with GoF variants showed increased DNA promoter methylation and dysregulated RNA expression, influencing cellular modules involved in white blood cell activation, cell growth and organ development.

ConclusionNSD2 GoF caused by the missense variant p.Glu1099Lys leads to a novel syndromic phenotype distinct from both the previously described LoF phenotypes. Other variants causing NSD2 hyperactivation or overexpression may cause a similar phenotype. This syndrome should be distinguished from the recently named Rauch-Steindl syndrome caused by NSD2 haploinsufficiency.

category: genetic and genomic medicine


title: Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates

abstract:
ImportanceAlthough observational studies demonstrate that higher levels of vascular risk factors are associated with an increased risk of dementia, these associations might be explained by confounding or other biases. Mendelian randomization (MR) uses genetic instruments to test causal relationships in observational data.

ObjectiveTo determine if genetically predicted modifiable risk factors (type 2 diabetes mellitus, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, and circulating glucose) are associated with dementia by meta-analysing published MR studies. Secondary objectives were to identify heterogeneity in effect estimates across primary MR studies and to compare meta-analysis results with observational studies.

Data sourcesMR studies identified by systematic search of Web of Science, OVID and Scopus.

Study selectionPrimary MR studies investigating the modifiable risk factors of interest. Only one study from each cohort per risk factor was included. A quality assessment tool was developed to primarily assess the three assumptions of MR for each MR study.

Data extraction and synthesisData were extracted on study characteristics, exposure and outcome, effect estimates per unit increase, and measures of variation. Effect estimates were pooled to generate an overall estimate, I2 and Cochrane Q values using fixed-effect model.

Main outcomes and measuresOdds ratio (OR) of developing dementia per standardized unit increase in the risk factor of interest.

ResultsWe screened 5211 studies and included 12 primary MR studies after applying inclusion and exclusion criteria. Higher genetically predicted body mass index was associated with a higher odds of dementia (OR 1.03 [1.01, 1.05] per 5 kg/m2 increase, one study, p = 0.00285). Overall estimates from MR studies showed a smaller number of associations than those from meta-analyses of observational studies.

Conclusion and relevanceGenetically predicted body mass index was associated with an increase in risk of dementia.

Key pointsO_ST_ABSQuestionC_ST_ABSAre genetically predicted modifiable risk factors associated with dementia?

FindingsGenetically predicted higher body mass index was associated with a higher odds of dementia. No evidence was found to support an association between genetically predicted type 2 diabetes mellitus, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, plasma glucose and dementia risk.

MeaningMany modifiable risk factors associated with dementia in observational studies may not play a causative role.


title: Demographic and socioeconomic factors predict maternal postpartum rehospitalization: a retrospective nuMoM2b dataset study

abstract: The advent of artificial intelligence/machine learning (AI/ML) in medicine has opened opportunities for harnessing the power of ML to predict patient outcomes based on diverse data contained in the electronic medical records (EMR). Taken by themselves singular features represented by such diverse data are often not clearly predictive but combined in an ML modeling framework such so-called weak learners have the power to yield highly predictive models of health outcomes. We hypothesized that sociodemographic and basic, easily obtainable health characteristics of pregnant mothers strongly predict the risk of rehospitalization. Using the nuMoM2b dataset from NICHD and reproducible, open access AI/ML techniques we tested and validated this hypothesis. Among a large (n=10,038) and geographically diverse cohort of nulliparous women with singleton gestations, the present findings show that while some of these characteristics highlight the known disparities in health outcomes (race/ethnicity), most of them are modifiable through social policies and health counseling. These include access to and support during education, comprehensive health insurance, alleviating coming out of poverty, smoking, and unhealthy lifestyle habits. Across the four ML models deployed, the results are mutually reinforcing yielding a clear cohesive picture. This solution can be used to develop a prospective risk prediction for this important health outcome in pregnant mothers. The strengths of the presented solution are its focus on preventable maternal morbidities and risk factors, demonstration of the impact on adversely affected populations, and reproducible step-by-step executable, documented open-access code with relatively low computational requirements. This enables easy adoption and further development on this and other similar datasets to study the contributions and predictive power of various factors to maternal morbidities.

category: obstetrics and gynecology


title: An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposis sarcoma under ART

abstract: HIV-associated Kaposis sarcoma (KS), which is caused by Kaposis sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally persists in individuals with durable HIV viral suppression and CD4 T cell recovery under anti-retroviral therapy (ART). The underlying mechanisms associated with this persistence are unclear. Suppression of viral infections can be mediated by CD8 T cells that detect infected cells via their T cell receptor and the CD8 co-receptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether persistent KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 ("CD8dim T cells") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial perturbations (PGC-1, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS persistence under ART. CD8 co-receptor down-modulation may be symptomatic of ongoing disease.

category: hiv aids


title: Effectiveness of the third dose of BNT162b2 vaccine on neutralizing Omicron variant in the Japanese population

abstract:
IntroductionThe vaccine against SARS-CoV-2 provides humoral immunity to fight COVID-19; however, the acquired immunity gradually declines. Booster vaccination restores reduced humoral immunity; however, its effect on newly emerging variants, such as the Omicron variant, is a concern. As the waves of COVID-19 cases and vaccine programs differ between countries, it is necessary to know the domestic effect of the booster.

MethodsSerum samples were obtained from healthcare workers (20-69 years old) in the Pfizer BNT162b2 vaccine program at the Toyama University Hospital 6 months after the second dose (6mA2D, n = 648) and 2 weeks after the third dose (2wA3D, n = 565). The anti-SARS-CoV-2 antibody level was measured, and neutralization against the wild-type and variants (Delta and Omicron) was evaluated using pseudotyped viruses. Data on booster-related events were collected using questionnaires.

ResultsThe median anti-SARS-CoV-2 antibody was >30.9-fold elevated after the booster (6mA2D, 710.0 U/mL [interquartile range (IQR): 443.0-1068.0 U/mL]; 2wA3D, 21927 U/mL [IQR: 15321.0->25000.0 U/mL]). Median neutralizing activity using 100-fold sera against wild-type-, Delta-, and Omicron-derived variants was elevated from 84.6%, 36.2%, and 31.2% at 6mA2D to >99.9%, 99.1%, and 94.6% at 2wA3D, respectively. The anti-SARS-CoV-2 antibody levels were significantly elevated in individuals with fever [≥]37.5 {degrees}C, general fatigue, and myalgia, local swelling, and local hardness.

ConclusionThe booster effect, especially against the Omicron variant, was observed in the Japanese population. These findings contribute to the precise understanding of the efficacy and side effects of the booster and the promotion of vaccine campaigns.


title: Comparative Effects of Weight Loss and Incretin-Based Therapies on Endothelial Vasodilatory and Fibrinolytic Function

abstract:
BackgroundGlucagon-like peptide-1 receptor (GLP1R) agonists decrease cardiovascular events in patients with type 2 diabetes, and cause weight loss regardless of diabetes status. The contribution of weight loss to the cardiovascular benefits of GLP1R agonists is unknown.

MethodsObese pre-diabetic individuals were randomized to 14 weeks of the GLP1R agonist liraglutide, hypocaloric diet-mediated weight loss, or the dipeptidyl peptidase 4 inhibitor sitagliptin as an incretin-based drug comparator. Treatment with drug was double blind and placebo-controlled. Weight, metabolic and hemodynamic measures, endothelium-dependent vasodilation and fibrinolytic function were measured at baseline and after 2 and 14 weeks of treatment.

ResultsLiraglutide and diet reduced weight, fasting blood glucose, and insulin resistance at 14 weeks, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilatory function as measured by flow-mediated dilation (FMD). Because baseline endothelial function was normal in the overall cohort, post-hoc subgroup analyses were conducted in participants stratified by FMD below or above the median for gender. All three treatments improved FMD at 2 weeks in individuals with baseline endothelial dysfunction and sitagliptin and diet also improved endothelium-dependent vasodilation at 14 weeks. Liraglutide and diet reduced plasminogen activator inhibitor-1 (PAI-1) at 14 weeks. GLP1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1 in the overall group. Exendin (9-39) attenuated the increase in FMD in the sitagliptin-treated group at two weeks.

ConclusionsLiraglutide and diet cause weight loss, improve insulin resistance and reduce PAI-1 at 14 weeks. The effect on PAI-1 is GLP1R-independent. In individuals with low baseline FMD, sitagliptin and diet improve FMD at two and 14 weeks, while liraglutide improves FMD at two weeks.

Clinical Trial RegistrationNCT03101930 https://clinicaltrials.gov/ct2/show/NCT03101930

category: cardiovascular medicine


title: Autonomic dysfunction is associated with the development of arterial stiffness: The Whitehall II cohort

abstract:
Background and aimTo examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness.

MethodsAutonomic nervous function was assessed of 4,901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997-2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007-2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2).

ResultsA decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results.

ConclusionPeople who experience a steeper decline of autonomic nervous function have higher levels of arterial stiffness. However, the association was weaker at higher ages.

category: epidemiology


title: Bibliometric study of preclinical, clinical, and public health systematic reviews and meta-analyses in Ethiopia: systematically mapping publication outputs, authors collaboration networks, trending research topics, and influential articles

abstract:
IntroductionThe publication rate of systematic reviews (SRs) and meta-analyses (MA) has been substantially growing in Ethiopia. However, there is no robust study that systematically characterized these SRs and MA. The objective of this study was to map authors collaboration networks and identify trending research topics and most cited SRs and MA in Ethiopia.

MethodsSRs and MA published up to December 31, 2021, were searched in PubMed, PsycInfo, EMBASE, and Web of Science databases. We included all SRs and MA based on preclinical, clinical, and public health primary studies associated with the Ethiopian population irrespective of the place of publication and authors affiliation. Full record and cited references meta-data of SRs and MA were extracted from the Web of Science Core Collection database. VOSviewer software was used to perform bibliometric analysis and create, visualize, and explore network maps of authors collaboration, keyword and term occurrences, journals and (co-)citations using the full or binary counting method. The relevance of an item and strength of link between items was measured by their weight (frequencies) and total link strength (TLS) respectively.

ResultsIn total, 422 SRs and MA were included in our analysis that published by nearly 14 research groups (1,066 authors participated) who affiliated with institutions from 33 countries. The largest number of SRs and MA were published by authors affiliated with institutions in Amhara region. These SRs and MA were published in 160 journals, which most of them published in PLOS ONE and BioMed Central journals. Strong collaboration was observed among authors affiliated with institutions in Ethiopia, the Netherlands, Australia, and Canada. The trending research topics were maternal and child health, infectious disease (except HIV/AIDS), depression and substance use, nutritional problems, HIV/AIDS, hepatitis, and cardiometabolic diseases and risk factors. The most cited SR was published on domestic violence against women in 2015.

ConclusionsIn this study, for the first time, we provided a comprehensive summary of active author collaboration networks, trending research topics, and influential SRs and MA to gain a deeper understanding of SRs and MA researches outputs in Ethiopia. We believe our study informs researchers, higher institutions, and policymakers about trends and gaps in preclinical, clinical, and public health studies. National and international authors collaboration should encourage and stakeholders fund researchers to increase the output of primary studies, publication rate of SRs and MA, and broaden research areas to less explored topics.


title: Protection by vaccines and previous infection against the Omicron variant of SARS-CoV-2

abstract:
The Omicron variant of the SARS-CoV-2 virus carries mutations, which enable it to evade immunity conferred by vaccines and previous infections. We used a Cox proportional hazards model and a logistic regression model on individual-level data on all laboratory-confirmed SARS-CoV-2 infections in the Czech Republic to estimate the relative risk of infection, hospitalization, including severe states, for Delta and Omicron variants, adjusting for sex, age, previous infection, vaccine type and vaccination status. A recent (<2 months) two-dose vaccination reached VE 43% (95% CI: 42-44) against infection by Omicron compared to 73% (95% CI: 72-74) against Delta. A recent booster increased VE to 56% (95% CI: 55-56) against Omicron infection compared to 90% (95% CI: 90-91) for Delta. The VE against Omicron hospitalization of a recent two-dose vaccination was 45% (95% CI: 29-57), with a recent booster 87% (95% CI: 84-88). The VE against the need for oxygen therapy due to Omicron was 57% (95% CI: 32-72) for recent vaccination, 90% (95% CI: 87-92) for a recent booster. Post-infection protection against Omicron hospitalization declined from 68% (95% CI: 68-69) at <6 months to 13% (95% CI: 11-14) at >6 months after a previous infection. A recent combination of a previous infection and vaccination was more protective then either alone with a slight benefit from a vaccination preceding an infection. Once infected, the OR for Omicron relative to Delta was 0.36 (95% CI: 0.34-0.38) for hospitalization, 0.24 (95% CI: 0.22-0.26) for oxygen therapy, and 0.24 (95% CI: 0.21-0.28) for ICU admission.

Significance StatementA nation-wide study shows that the protection of a previous infection or vaccination is lower against Omicron compared to Delta variant of SARS-CoV-2 and further declines with time. A booster dose or a combination of post-infection immunity with a vaccine conferred significant benefit to individuals in the Omicron wave in the Czech Republic, which further strengthens the importance of vaccination as an effective public health measure.


title: The impact of COVID passport mandates on the number of cases of and hospitalizations with COVID-19 in the UK: a difference-in-differences analysis

abstract:
BackgroundMandatory COVID-19 certification was introduced at different times in the four countries of the UK. We aimed to study the effect of this intervention on the incidence of cases and hospital admissions.

MethodsThe main outcome was the weekly averaged incidence of COVID-19 confirmed cases and hospital admissions. We performed Negative Binomial Segmented Regression (NBSR) and Autoregressive Integrated Moving Average (ARIMA) analyses for the four countries (England, Northern Ireland, Scotland and Wales), and fitted Difference-in-Differences (DiD) models to compare the latter three to England, where COVID-19 certification was imposed the latest.

FindingsNBSR methods suggested COVID-19 certification led to a decrease in the incidence of cases in Northern Ireland, but not in hospitalizations. In Wales, they also caused a decrease in the incidence of cases but not in hospital admissions. In Scotland, we observed a decrease in both cases and admissions. ARIMA models confirmed these results. The DiD model showed that the intervention decreased the incidence of COVID compared to England in all countries except Wales, in October. Then, the incidence rate of cases already had a decreasing tendency, as well as in England, hence a particular impact of Covid Passport was less obvious. In Wales, the model coefficients were 2.2 (95% CI -6.24,10.70) for cases and -0.144 (95% CI -0.248, -0.039) for admissions in October and -7.75 (95% CI -13.1, -2.46) for cases and -0.169 (95% CI-0.308, -0.031) for admissions in November. In Northern Ireland, -10.1 (95% CI -18.4, -1.79) for cases and -0.269 (95% CI -0.385, -0.153) for admissions. In Scotland they were 7.91 (95% CI 4.46,11.4) for cases and -0.097 (95% CI - 0.219,0.024) for admissions.

InterpretationThe introduction of mandatory certificates decreased cases in all countries except in England. Differences on concomitant measures, on vaccination uptake or Omicron variant prevalence could explain this discrepancy.


title: Trajectories of Perceived Negative Impact in Parents of Individuals with Autism Spectrum Disorders from 9 to 25 years of age

abstract: Caregivers raising a child with autism experience increased parental burden, though many have positive experiences as well. Perceived negative impact, a form of parental burden, is the degree to which a caregiver reports negative financial, social, and emotional experiences associated with having a child with a disability. This longitudinal study defined parental perceived negative impact trajectory classes across time, determined predictors, and explored the relationship between functional adult outcomes and impact class. Participants (n = 209) were comprised of caregivers whose child received an ASD diagnosis or had developmental delay. Latent class growth modeling defined three trajectory classes (e.g., low [n = 68, 32.54%], medium [n = 98, 46.89%], and high [n = 43, 20.57%]). Regressions revealed the low impact trajectory class had more caregivers who were racial minorities, less educated, and more socially supported. Membership in the high negative impact class was associated with increased childhood hyperactivity, irritability, autism symptomology, and poor adaptive skills. The low negative impact trajectory class was associated with young adults achieving more functional outcomes. Overall negative impact declined over time all for all classes, though never completely subsided. Possible implications for clinical practices are discussed

category: psychiatry and clinical psychology


title: Epigenetic aging and perceived psychological stress in old age

abstract:
Adverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results.

DNAmAA was estimated from five epigenetic clocks (7-CpG, Horvaths, Hannums, PhenoAge and GrimAge DNAmAA). Cohens Perceived Stress Scale (PSS) was used as marker of psychological stress.

We analyzed data from 1,100 Berlin Aging Study II (BASE-II) participants assessed as part of the GendAge study (mean age = 75.6 years, SD = 3.8 years, 52.1% women).

In a first step, we replicated well-established associations of perceived stress with morbidity, frailty, and symptoms of depression in the BASE-II cohort studied here. In a second step, we did not find any statistically significant association of perceived stress with any of the five epigenetic clocks in multiple linear regression analyses that adjusted for covariates.

Although the body of literature suggests an association between higher DNAmAA and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people. We discuss possible reasons for the lack of associations and highlight directions for future research.


title: The effect of self-management online modules plus nurse-led support on pain and quality of life among young adults with irritable bowel syndrome: A randomized controlled trial

abstract:
BackgroundIrritable bowel syndrome (IBS) is a chronic pain condition that needs life-long self-management. However, the effect of self-management among young adults with IBS is limited.

ObjectivesThis study aimed to examine the effect of a nurse-led self-management program on IBS related pain and symptoms, and quality of life (QOL) among young adults with IBS.

Theoretical frameworkThe Individual and Family Self-Management Theory (IFSMT).

DesignA randomized controlled trial with data collected at baseline, 6- and 12-week follow up.

Settings and participantsEighty young adults with IBS recruited from two campuses of a public university and two gastrointestinal clinics were randomly assigned into a Self- Management Online education and learning Modules group (SMOM, n = 41) or a Nurse-Led SMOM group (NL + SMOM, n = 39). Twenty-one healthy controls (HCs) were also recruited from these two campuses.

MethodsAll the IBS participants received the SMOM after baseline data collection. Participants in the NL + SMOM received additional three nurse-led one-to-one consultations at baseline, 6- and 12-week follow up. Self-reported pain, symptoms, IBS-related QOL, self- efficacy for managing chronic disease, and coping were measured at baseline, and 6- and 12- week follow up among the IBS participants. The HCs completed data collection of pain and symptoms at baseline and 12-week follow up. The intervention effects across study time points and the comparisons between the two interventional groups were analyzed using linear mixed models. A longitudinal mediation analysis was also conducted to explore the mediation effects of self-management mechanisms of the interventions.

ResultsBoth the SMOM and NL + SMOM groups showed significant interventional effects on decreasing pain intensity and pain interference and increasing IBS-QOL among young adults with IBS at the 12-week follow up (all p < 0.05). The NL + SMOM also had significant effect on reducing anxiety and greater improvement in IBS-QOL compared with the SMOM at the 12- week follow up (both p < 0.05). Increased self-efficacy mediated the intervention effect of the NL + SMOM on reducing pain interference and improving IBS-QOL, while the effect of the SMOM was mediated through decreased an inefficient coping strategy-catastrophizing.

ConclusionsGuided by the IFSMT, this study showed that both the pain self-management online education and nurse-led interventions were effective for alleviating pain and improving QOL among young adults with IBS by targeting the self-management process. The nurse-led program had a better outcome than the online education alone in improving IBS-QOL. Registration number: NCT03332537

What is already known about the topicO_LIIrritable bowel syndrome (IBS) is a chronic condition warranting lifelong self- management.
C_LIO_LIUnrelieved abdominal pain is associated with increased healthcare expenditures and decreased quality of life (QOL) in young adults with IBS.
C_LIO_LISelf-management interventions have moderate effect on attenuating IBS related pain and symptoms.
C_LI

What this paper addsO_LIBoth the IBS Self-Management Online education and learning Modules (SMOM) and Nurse-Led SMOM (NL + SMOM) developed in this study were efficient in reducing pain intensity and pain interference and ameliorating IBS-QOL among young adults with IBS.
C_LIO_LIThe NL + SMOM had a greater interventional effect on improving IBS-QOL compared with the SMOM alone.
C_LIO_LIThe NL + SMOM had an indirect effect on pain and QOL by increasing self-efficacy, while the indirect effect of SMOM on pain and QOL was derived by decreasing inefficient coping (e.g., catastrophizing).
C_LI

category: nursing


title: Detection of SARS-CoV-2 in air and on surfaces in rooms of infected nursing home residents

abstract:
There is an ongoing debate on airborne transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) as a risk factor for infection. In this study, the level of SARS-CoV-2 in air and on surfaces of SARS-CoV-2 infected nursing home residents was assessed to gain insight in potential transmission routes.

During outbreaks, air samples were collected using three different active and one passive air sampling technique in rooms of infected patients. Oropharyngeal swabs (OPS) of the residents and dry surface swabs were collected. Additionally, longitudinal passive air samples were collected during a period of 4 months in common areas of the wards. Presence of SARS-CoV-2 RNA was determined using RT-qPCR, targeting the RdRp- and E-genes. OPS, samples of two active air samplers and surface swabs with Ct value [≤]35 were tested for the presence of infectious virus by cell culture. In total, 360 air and 319 surface samples from patient rooms and common areas were collected. In rooms of 10 residents with detected SARS-CoV-2 RNA in OPS, SARS-CoV-2 RNA was detected in 93 of 184 collected environmental samples (50.5%) (lowest Ct 29,5), substantially more than in the rooms of residents with negative OPS on the day of environmental sampling (n=2) (3.6%). SARS-CoV-2 RNA was most frequently present in the larger particle size fractions (>4 m 60% (6/10); 1-4 m 50% (5/10); <1 m 20% (2/10)) (Fischer exact test p=0.076). The highest proportion of RNA-positive air samples on room level was found with a filtration-based sampler 80% (8/10) and the cyclone-based sampler 70% (7/10), and impingement-based sampler 50% (5/10). SARS-CoV-2 RNA was detected in ten out of twelve (83%) passive air samples in patient rooms. Both high-touch and low-touch surfaces contained SARS-CoV-2 genome in rooms of residents with positive OPS (high 38% (21/55); low 50% (22/44)). In one active air sample, infectious virus in vitro was detected.

In conclusion, SARS-CoV-2 is frequently detected in air and on surfaces in the immediate surroundings of room-isolated COVID-19 patients, providing evidence of environmental contamination. The environmental contamination of SARS-CoV-2 and infectious aerosols confirm the potential for transmission via air up to several meters.


title: Assessment of burden and segregation profiles of CNVs in patients with epilepsy

abstract:
1ObjectiveMicrodeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance.

MethodsWe analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole genome (WGS) or exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (> 1Mb) deletions and duplications and for deletions overlapping different genes set.

ResultsLarge deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found an enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot.

InterpretationWe could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo hit on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.


title: Prevalence of central obesity and its associated risk factors among adults in Southeast Ethiopia: a community-based cross-sectional study

abstract:
BackgroundObesity and overweight are known are public health scourge challenges affecting populations across the world. These conditions have been associated with a wide range of chronic diseases including type 2 diabetes mellitus, cardiovascular disease, and cancers. In Ethiopia, literature regarding the burden of central (abdominal) obesity is scarce. This study aimed to fill this gap by assessing the prevalence and risk factors associated with central obesity among adults in Ethiopia.

MethodsFrom May to July 2021, a community-based cross-sectional survey was conducted on a sample of 694 adults aged [≥]18 years in administrative towns of Bale zone, Southeast Ethiopia. Multi-stage sampling followed by systematic random sampling was employed to identify study participants. Waist and hip circumferences were measured using standard protocols. The World Health Organization STEPS wise tool was used to assess risk factors associated with central obesity. Bi-variable and multi-variable binary logistic regression were used to identify factors associated with central obesity. Adjusted odds ratios (AOR) and their corresponding 95% confidence intervals (CI) were reported to estimate the strength of associations.

ResultsThe overall prevalence of central obesity using waist circumference was 39.01% (15.44% for men and 53.12% for women). Multi-variable binary logistic regression analysis revealed that female sex (AOR=12.93, 95% CI: 6.74-24.79), Age groups: 30-39 years old (AOR=2.8, 95% CI: 1.59-4.94), 40-49 years (AOR=7.66, 95% CI: 3.87-15.15), 50-59 years (AOR=4.65, 95% CI: 2.19-9.89), [≥]60 years (AOR=12.67, 95% CI: 5.46-29.39), occupational status like: housewives (AOR=5.21, 95% CI: 1.85-14.62), self-employed workers (AOR=4.63, 95% CI: 1.62-13.24), government/private/non-government employees (AOR=4.68, 95% CI: 1.47-14.88) and skipping breakfast (AOR=0.46, 95% CI: 0.23-0.9) were significantly associated with central obesity.

ConclusionsAbdominal obesity has become an epidemic in towns of southeast Ethiopia, and the prevalence is higher among women. Female sex, older age group, being employed, not skipping breakfast were significantly associated with central obesity.


title: Psychosocial factors associated with mental health and quality of life during the COVID-19 pandemic among low-income urban dwellers in Peninsular Malaysia

abstract:
Background and aimsThe mental well-being among low-income urban populations is arguably challenged more than any other population amid the COVID-19 pandemic. This study investigates factors associated with depression and anxiety symptoms, and quality of life among Malaysias multi-ethnic urban lower-income communities.

MethodsThis is a community-based house-to-house survey conducted from September to November 2020 at the Petaling district in Selangor, Malaysia. Five hundred and four households were identified using random sampling, and heads of eligible households were recruited. Inclusion criteria were age [≥] 18 years with monthly household income [≤]RM6960 (estimated USD 1600) without acute psychiatric illness. The PHQ-9, GAD-7 and EQ-5D were used for depression, anxiety, and quality of life. Multivariable logistic regression was performed for the final analysis.

ResultsA total of 432 (85.7%) respondents with a mean age of 43.1 years completed the survey. Mild to severe depression was detected in 29.6%, mild to severe anxiety in 14.7%, and problematic quality of life in 27.8% of respondents. Factors associated with mild to severe depression were younger age, chronic health conditions, past stressful events, lack of communication gadgets and lack of assets or commercial property. While respiratory diseases, marital status, workplace issues, financial constraints, absence of investments, substance use and lack of rental income were associated with mild to severe anxiety. Not attributing poverty to structural issues, help-seeking from professionals, and self-stigma were barriers, while resiliency facilitated good psychological health. Problematic quality of life was associated with depression, older age, unemployment, cash shortage, hypertension, diabetes, stressful life events and low health literacy.

ConclusionsA higher proportion had reported mild to severe anxiety and depression symptoms in the sampled urban poor population than previous pre-pandemic reports. The psychosocial determinants should inform policy and direct future research within this underserved population.


title: Presence of Symptoms 6 Weeks After COVID-19 Among Vaccinated and Unvaccinated U.S. Healthcare Personnel

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSAlthough COVID-19 vaccines protect against infection and severe disease, the role of vaccination in preventing prolonged symptoms in those with subsequent infection is unclear.

ObjectiveTo determine differences in symptoms stratified by prior vaccination reported by healthcare personnel (HCP) 6 weeks after onset of COVID-19, and whether there were differences in timing of return to work.

DesignNested cohort study within a multicenter vaccine effectiveness study. HCP with COVID-19 between December 2020 and August 2021 were followed up 6 weeks after illness onset.

SettingHealth systems in 12 U.S. states.

ParticipantsHCP participating in a vaccine effectiveness study were eligible for inclusion if they had confirmed COVID-19 with either verified mRNA vaccination (symptom onset [≥]14 days after two doses) or no prior COVID-19 vaccination. Among 681 eligible participants, 419 (61%) completed a follow-up survey approximately 6 weeks after illness onset.

ExposuresTwo doses of a COVID-19 mRNA vaccine compared with no COVID-19 vaccine.

Main outcomes and measuresPresence of symptoms 6 weeks after onset of COVID-19 illness and days to return to work after COVID-19 illness.

ResultsAmong 419 HCP with confirmed COVID-19, 298 (71%) reported one or more COVID-like symptoms 6 weeks after illness onset, with a lower prevalence among vaccinated participants (60.6%) compared with unvaccinated participants (60.6% vs. 79.1%; aRR 0.70, 95% CI 0.58-0.84). Vaccinated HCP returned to work a median 2.0 days (95% CI 1.0-3.0) sooner than unvaccinated HCP (aHR 1.37; 95% CI, 1.04-1.79).

ConclusionsA history of two doses of COVID-19 mRNA vaccine among HCP with COVID-19 illness was associated with decreased risk of COVID-like symptoms at 6 weeks and earlier to return to work. Vaccination is associated with improved recovery from COVID-19, in addition to preventing symptomatic infection.

KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes vaccination lead to improved recovery of symptoms and return to work following COVID-19?

FindingsIn this nested cohort study of healthcare personnel, participants with COVID-19 who had received two doses of a COVID-19 mRNA vaccine were less likely to report symptoms 6 weeks after illness onset than participants with COVID-19 who were unvaccinated. Return to work was sooner if previously vaccinated.

MeaningVaccination is associated with improved recovery from COVID-19, in addition to prevention of infection and disease.


title: Female gender, depressive symptoms, manual job, and higher physical disability predict long term low back pain persistence

abstract:
BackgroundLow Back Pain (LBP) is a long-term health condition with distinct clinical courses. The characterization of these courses together with the identification of prognostic factors of a persistent disabling LBP course has the potential to enable a better identification of patients in high-risk and ultimately allow the development of personalized interventions to change their long-term prognosis. This study aimed to assess the course of chronic LBP (CLBP) over 5 years in a large population-based study, its cumulative impact on disability and health-related quality of life (HRQoL) and the indicators for persistent CLBP course.

Material and methodsActive CLBP participants were identified from a representative sample of 10.661 adults randomly recruited from the dwelling population of EpiDoC. Pain, disability and HRQoL were assessed at three time-points. According to their pain symptoms over time, participants were classified as having a persistent or relapsing pain course. A General Linear Model was used to compare mean differences between and within groups. The relation between baseline variables and persistent CLBP was modulated through logistic regression.

ResultsAmong the 1.201 adults with active CLBP at baseline, 634 completed the three time-points of data collection (52.8%) and 400 (63.1%) were classified as having a persistent course. Statistically significant interactions were found between the group and time on disability (F (2.126)= 23.78, p<0.001) and HRQoL (F (2.125)= 82.78, p<0.001). In the adjusted model, the persistent course was associated with the disability level (OR: 1.84, CI95% 1.4 to 2.4), presence of depressive symptoms (OR: 1.96, CI95% 1.2 to 3.2), female gender (OR: 1.9, CI95% 1.26-2.87), and having a manual job (OR: 1.46, CI95% 1.02 to 2.1).

ConclusionIn the long-term, CLBP patients have distinct clinical courses. Being female, presenting depressive symptoms, having a manual job and a higher disability at baseline predict a CLBP persistent outcome.


title: Pathway-based Rare Variant Burden Analysis Identifies a Role for the Complement System in an Extreme Phenotype of Sepsis with Coagulopathy

abstract: Extreme disease phenotypes have the potential to provide key pathophysiologic insights, but the study of these conditions is challenging due to their rarity and the limited statistical power of existing methods. Herein, we apply a novel pathway-based approach to investigate the role of rare genomic variants in infectious purpura fulminans (PF)1,2, an extreme phenotype of sepsis with hyperinflammation and coagulopathy for which the role of inherited risk factors is currently unknown. Using whole exome sequencing, we found a significantly increased burden of rare, putatively function-altering coding variants in the complement system in patients with PF compared to unselected patients with sepsis (p-value = 0.01). Functional characterization of a subset of PF-associated variants in integrin complement receptors 3 and 4 (CR3 and CR4) revealed that they exhibit a pro-inflammatory phenotype. Our results suggest that rare inherited defects in the complement system predispose individuals to the maladaptive hyperinflammatory response that characterizes severe sepsis.


title: Multivariate Genomic Architecture of Cortical Thickness and Surface Area at Multiple Levels of Analysis

abstract: Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA). We model this multivariate system of genetic relationships by applying Genomic Structural Equation Modeling (Genomic SEM) to parsimoniously define five genomic brain factors for both CT and SA. We reify these factors by demonstrating the generalizability of the model in a semi-independent sample and show that the factors align with biologically and functionally relevant parcellations of the cortex. We apply Stratified Genomic SEM to identify specific categories of genes (e.g., neuronal cell types) that are disproportionately associated with pleiotropy across specific subclusters of brain regions, as indexed by the genomic factors. Finally, we examine genetic associations with psychiatric and cognitive correlates, finding that SA is associated with both broad aspects of cognitive function and specific risk pathways for psychiatric disorders. These analyses provide key insights into the multivariate genomic architecture of two critical features of the cerebral cortex.


title: Public Health Impact of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) in the first year of rollout in the United States

abstract:
BackgroundAs the body of evidence on COVID-19 and post-vaccination outcomes continues to expand, this analysis sought to evaluate the public health impact of the Pfizer-BioNTech COVID-19 Vaccine, BNT162b2, during the first year of its rollout in the US.

MethodsA combined Markov decision tree model compared clinical and economic outcomes of the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) versus no vaccination in individuals aged [≥]12 years. Age-stratified epidemiological, clinical, economic, and humanistic parameters were derived from existing data and published literature. Scenario analysis explored the impact of using lower and upper bounds of parameters on the results. The health benefits were estimated as the number of COVID-19 symptomatic cases, hospitalizations and deaths averted, and Quality Adjusted Life Years (QALYs) saved. The economic benefits were estimated as the amount of healthcare and societal cost savings associated with the vaccine-preventable health outcomes.

ResultsIt was estimated that, in 2021, the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) contributed to averting almost 9 million symptomatic cases, close to 700,000 hospitalizations, and over 110,000 deaths, resulting in an estimated $30.4 billion direct healthcare cost savings, $43.7 billion indirect cost savings related to productivity loss, as well as discounted gains of 1.1 million QALYs. Scenario analyses showed that these results were robust; the use of alternative plausible ranges of parameters did not change the interpretation of the findings.

ConclusionsThe Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) contributed to generate substantial public health impact and vaccine-preventable cost savings in the first year of its rollout in the US. The vaccine was estimated to prevent millions of COVID-19 symptomatic cases and thousands of hospitalizations and deaths, and these averted outcomes translated into cost-savings in the billions of US dollars and thousands of QALYs saved. As only direct impacts of vaccination were considered, these estimates may be conservative.

KEY SUMMARY POINTSO_ST_ABSWhy carry out this study?C_ST_ABSO_LIAssessing the population-level health and economic impact of the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) is important for policy makers and payers who support decision-making and investment in vaccination.
C_LIO_LIThese analyses may be relevant to the public, especially those who remain hesitant to COVID-19 vaccination.
C_LI

What was learned from the study?O_LIThis study showed that Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) was an effective strategy that contributed to generating substantial public health impact and economic gains in the US in 2021
C_LIO_LIThe vaccine was estimated to prevent millions of COVID-19 symptomatic cases and thousands of hospitalizations and deaths, and these averted outcomes translated into cost-savings in the billions of US dollars and millions of QALYs saved
C_LIO_LIThe study highlights the importance of continuing widespread uptake of the Pfizer-BioNTech COVID-19 Vaccine (BNT162b2) to prevent COVID-19 related disease and generate substantial benefits from a broad, patient-centric, societal perspective
C_LI

category: health policy


title: Clinical and Virologic Factors associated with Outcomes of COVID-19 before and after Vaccination among Veterans: Retrospective Analysis from Six New England States

abstract:
BackgroundA region-wide analysis of COVID-19 outcomes in New England has not been done. We aimed to characterize clinical, demographic, and vaccination status affecting COVID-19 clinical outcomes and describe viral epidemiology.

MethodsClinical variables of Veterans with COVID-19 in Veterans Administration healthcare systems in six New England states from April 8, 2020, to September 2, 2021 were correlated with outcomes of 30-day mortality, non-psychiatric hospitalization, intensive care unit admission (ICU-care), and post-vaccination infection. We sequenced 754 whole viral genomes and 197 partial genomes.

ResultsOf 4,170 Veterans with COVID-19, 81% were White, 8% women, mean age was 60.1 {+/-}17.7 years, and 2,399 became fully vaccinated. Overall, 19% Veterans needed hospitalization, 2.8% required ICU-care, and 3.7% died. Veterans with post-vaccination COVID-19 were older, with higher rates of tobacco/drug use, CKD, and malignancy, and 0.38% died. Among the unvaccinated, ICU-care and mortality correlated with age, while hospitalization correlated with age, male sex, black race, drug use, chronic heart disease, COPD, CKD, and chronic liver disease. Age, CKD, and alcohol use correlated with hospitalization in vaccinated patients.

Most New England Veterans (>97%) were infected with B.1 sub-lineages with the D614G mutation in 2020 and early 2021. B.1.617.2 lineage (71%) predominated after July 2021, including the post-vaccination infections.

ConclusionIn New England Veterans with mean age of 60 years, age and CKD significantly correlated with hospitalization regardless of vaccination-status. Age correlated with mortality and ICU-care among the unvaccinated. The Delta variant of SARS-CoV-2 (B.1.617.2) dominated post-vaccination infections.


title: Diabetes-related excess mortality in Mexico: a comparative analysis of national death registries between 2017-2019 and 2020

abstract:
BACKGROUNDExcess all-cause mortality rates in Mexico in 2020 during the COVID-19 pandemic were among the highest globally. Recent reports suggest that diabetes-related deaths were also higher, but the contribution of diabetes as a cause of excess mortality in Mexico during 2020 compared to prior years has not yet been characterized.

METHODSWe conducted a retrospective, state-level study using national death registries from Mexican adults [≥]20 years for the 2017-2020 period. Diabetes-related deaths were classified using ICD-10 codes that listed diabetes as the primary cause of death, excluding certificates which listed COVID-19 as a cause of death. Excess mortality was estimated as the increase in diabetes-related mortality in 2020 compared to average rates in 2017-2019. Analyses were stratified by diabetes type, diabetes-related complication, and in-hospital vs. out-of-hospital death. We evaluated the geographic distribution of diabetes-related excess mortality and its socio-demographic and epidemiologic correlates using spatial analyses and negative binomial regression models.

RESULTSWe identified 148,437 diabetes-related deaths in 2020 (177/100,000 inhabitants), 41.6% higher than the average for 2017-2019, with the excess occurring after the onset of the COVID-19 pandemic. In-hospital diabetes-related deaths decreased by 17.8% in 2020 compared to 2017-2019, whereas out-of-hospital deaths increased by 89.4%. Most deaths were attributable to type 2 diabetes and type 1 diabetes (129.7 and 4.0/100,000 population). Diabetes-related emergencies as contributing causes of death also increased in 2020 compared to 2017-2019 for hyperglycemic hyperosmolar state (128%), and ketoacidosis (116%). Diabetes-related excess mortality clustered in southern Mexico and was highest in states with higher social lag, higher rates of COVID-19 hospitalization, and higher prevalence of HbA1c [≥]7.5%.

INTERPRETATIONDiabetes-related mortality increased among Mexican adults by 41.6% in 2020 after the onset of the pandemic compared to 2017-2019, largely attributable to type 2 diabetes. Excess diabetes-related deaths occurred disproportionately out-of-hospital, clustered in southern Mexico, and were associated with higher state-level marginalization, rates of COVID-19 hospitalizations, and higher prevalence of suboptimal glycemic control. Urgent policies to mitigate mortality due to diabetes in Mexico are needed, particularly given the ongoing challenges in caring for people with diabetes posed by the COVID-19 pandemic.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and Google Scholar for research articles published up to February 15, 2022, using the terms [("diabetes-related mortality" OR ("excess mortality" AND "diabetes"))]. No language restriction was applied. This search revealed few international studies evaluating nationwide diabetes-related mortality in general. In Mexico, only one unpublished study evaluated diabetes-related mortality up to 2019. We identified no studies which evaluated diabetes-related excess mortality in Mexico or elsewhere during 2020 or which explored correlates of diabetes-related excess mortality in 2020.

Added value of this studyThis is the first report and characterization of an excess in diabetes-related mortality in Mexico during 2020 compared to recent years. Diabetes as a primary cause of death in Mexico was higher in 2020 compared to 2017-2019, particularly for people living with type 2 diabetes, starting in March 2020 with the onset of the COVID-19 pandemic. Compared to the 2017-2019 period, most of these excess deaths occurred out of hospital, with a concurrent decrease in in-hospital diabetes-related mortality. Hyperosmolar hyperglycemic state and ketoacidosis as primary causes of diabetes-related deaths also increased in 2020 compared to prior years. Our study also identified substantial geographic variation in diabetes-related excess mortality in Mexico, with southern, poorer States bearing a disproportionate burden. Finally, we report that diabetes-related excess mortality was associated with higher marginalization, suboptimal glycemic control, and higher rates of COVID-19 hospitalization, which were clustered in southern Mexico.

Implications of the available evidenceReadily treatable, high morbidity diabetes-related conditions were likely untreated due to the constraints of the health care system during the COVID-19 pandemic, leading to diabetes-related excess mortality. This is a problem for Mexico, but it is likely to be generalizable to other countries and other conditions, as seen even in high-income countries. Given the ongoing challenges posed by the COVID-19 pandemic on healthcare systems, policies that can strengthen care for diabetes and other chronic conditions are urgently needed to mitigate the dramatic rise in diabetes-related mortality occurring in the out-of-hospital setting and its disproportionate burden on populations with high levels of marginalization.

category: endocrinology


title: A real-world evaluation of the implementation of NLP technology in abstract screening of a systematic review

abstract: The laborious and time-consuming nature of systematic review production hinders the dissemination of up-to-date evidence synthesis. Well-performing natural language processing (NLP) tools for systematic reviews have been developed, showing promise to improve efficiency. However, the feasibility and value of these technologies have not been comprehensively demonstrated in a real-world review. We developed an NLP-assisted abstract screening tool that provides text inclusion recommendations, keyword highlights, and visual context cues. We evaluated this tool in a living systematic review on SARS-CoV-2 seroprevalence, conducting a quality improvement assessment of screening with and without the tool. We evaluated changes to abstract screening speed, screening accuracy, characteristics of included texts, and user satisfaction. The tool improved efficiency, reducing screening time per abstract by 45.9% and decreasing inter-reviewer conflict rates. The tool conserved precision of article inclusion (positive predictive value; 0.92 with tool vs 0.88 without) and recall (sensitivity; 0.90 vs 0.81). The summary statistics of included studies were similar with and without the tool. Users were satisfied with the tool (mean satisfaction score of 4.2/5). We evaluated an abstract screening process where one human reviewer was replaced with the tools votes, finding that this maintained recall (0.92 one-person, one-tool vs 0.90 two tool-assisted humans) and precision (0.91 vs 0.92) while reducing screening time by 70%. Implementing an NLP tool in this living systematic review improved efficiency, maintained accuracy, and was well-received by researchers, demonstrating the real-world effectiveness of NLP in expediting evidence synthesis.


title: Protection of Omicron sub-lineage infection against reinfection with another Omicron sub-lineage

abstract:
BACKGROUNDThe SARS-CoV-2 Omicron (B.1.1.529) variant has two main sub-lineages, BA.1 and BA.2 with significant genetic distance between them. This study investigated protection of infection with one sub-lineage against reinfection with the other sub-lineage in Qatar during a large BA.1 and BA.2 Omicron wave, from December 19, 2021 to February 21, 2022.

METHODSTwo national matched, retrospective cohort studies were conducted to estimate effectiveness of BA.1 infection against reinfection with BA.2 (N=20,197; BA.1-against-BA.2 study), and effectiveness of BA.2 infection against reinfection with BA.1 (N=100,925; BA.2-against-BA.1 study). Associations were estimated using Cox proportional-hazards regression models.

RESULTSIn the BA.1-against-BA.2 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.01-0.07%) for the BA.1-infected cohort and at 0.62% (95% CI: 0.51-0.75%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.1 infection against reinfection with BA.2 was estimated at 94.9% (95% CI: 88.4-97.8%). In the BA.2-against-BA.1 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.02-0.04%) for the BA.2-infected cohort and at 0.17% (95% CI: 0.15-0.21%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.2 infection against reinfection with BA.1 was estimated at 85.6% (95% CI: 77.4-90.9%).

CONCLUSIONSInfection with an Omicron sub-lineage appears to induce strong, but not full protection against reinfection with the other sub-lineage, for at least several weeks after the initial infection.


title: Risk of COVID-19 related deaths for SARS-CoV-2 Omicron (B.1.1.529) compared with Delta (B.1.617.2)

abstract:
ObjectiveTo assess the risk of death involving COVID-19 following infection from Omicron (B.1.1.539/BA.1) relative to Delta (B.1.617.2).

DesignRetrospective cohort study.

SettingEngland, UK, 1 December 2021 to 25 January 2022.

Participants1,035,163 people aged 18-100 years who tested positive for SARS-CoV-2 in the national surveillance programme, and had an infection identified as either Omicron- or Delta compatible.

Main outcome measuresDeath involving COVID-19 as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause-specific Cox proportional hazard regression models were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, Index of Multiple Deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Additionally, we tested for interactions between variant and sex, age, vaccination status and comorbidities.

ResultsThe risk of death involving COVID-19 was 67% lower for Omicron compared to Delta and the reduction in the risk of death involving COVID-19 for Omicron compared to Delta was more pronounced in males than in females and in people under 70 years old than in people aged 70 years or over. Regardless of age, reduction of the risk of death from Omicron relative to Delta more was more pronounced in people who had received a booster than in those having received only two doses.

ConclusionsOur results support early work showing the relative reduction in severity of Omicron compared to Delta in terms of hospitalisation and extends this research to assess COVID-19 mortality. Our work also highlights the importance of the vaccination booster campaign, where the reduction in risk of death involving COVID-19 is most pronounced in individuals who had received a booster.

What is already known on this topicThe Omicron variant, which refers to the whole lineage (BA.1, BA.2, BA.3) had already been shown to be more transmissible than the Delta variant, but there is emerging evidence suggests that the risk of hospitalisation and risk of death within 28 days after a SARS-COV-2 test is lower. However, with a highly transmissible infection and high levels of population testing, definition of death within 28 days is more likely to be susceptible to misclassification bias due to asymptomatic or co-incidental infection. There is no study so far comparing the risk of COVID-19 death as identified from death certification records, with the cause of death assessed by the physician who attended the patient in the last illness.

What this study addsUsing data from a large cohort of COVID-19 infections that occurred in December 2021, we examined the difference in the risk COVID-19 death, as identified from death certification records, between the Delta and Omicron BA.1 variant. Our study shows that risk of death involving COVID-19 was reduced by 67% following infection with the Omicron BA.1 variant relative to the Delta variant after adjusting for a wide range of potential confounders, including vaccination status and comorbidities. Importantly, we found that the relative risk of COVID-19 mortality following Omicron versus Delta infection varied by age and sex, with lower relative risk in younger individuals and for males than females. The reduction in risk of death involving COVID-19 was also most pronounced in individuals who had received a booster.


title: A mixture model to estimate SARS-CoV-2 seroprevalence in Chennai, India

abstract:
BackgroundSerological assays used to estimate SARS-CoV-2 seroprevalence rely on manufacturer cut-offs established based on more severe early cases who tended to be older.

MethodsWe conducted a household-based serosurvey of 4,677 individuals from 2,619 households in Chennai, India from January to May, 2021. Samples were tested for SARS-CoV-2 IgG antibodies to the spike (S) and nucelocapsid (N) proteins. We calculated seroprevalence using manufacturer cut-offs and using a mixture model in which individuals were assigned a probability of being seropositive based on their measured IgG, accounting for heterogeneous antibody response across individuals.

ResultsThe SARS-CoV-2 seroprevalence to anti-S and anti-N IgG was 62.0% (95% confidence interval [CI], 60.6 to 63.4) and 13.5% (95% CI, 12.6 to 14.5), respectively applying the manufacturers cut-offs, with low inter-assay agreement (Cohens kappa 0.15). With the mixture model, estimated anti-S IgG and anti-N IgG seroprevalence was 64.9% (95% Credible Interval [CrI], 63.8 to 66.0) and 51.5% (95% CrI, 50.2 to 52.9) respectively, with high inter-assay agreement (Cohens kappa 0.66). Age and socioeconomic factors showed inconsistent relationships with anti-S IgG and anti-N IgG seropositivity using manufacturers cut-offs, but the mixture model reconciled these differences. In the mixture model, age was not associated with seropositivity, and improved household ventilation was associated with lower seropositivity odds.

ConclusionsWith global vaccine scale-up, the utility of the more stable anti-S IgG assay may be limited due to the inclusion of the S protein in several vaccines. SARS-CoV-2 seroprevalence estimates using alternative targets must consider heterogeneity in seroresponse to ensure seroprevalence is not underestimated and correlates not misinterpreted.


title: Psychological Distress and Metabolomic Markers: A Systematic Review

abstract:
Psychological distress is a multifactorial construct that refers to non-specific symptoms of depression, anxiety, posttraumatic stress disorder (PTSD), or stress more generally. A systematic review of metabolomic markers associated with distress has the potential to reveal underlying molecular mechanisms linking distress to adverse health outcomes. The current systematic review extends prior reviews of clinical depressive disorders by synthesizing 39 existing studies that examined metabolomic markers for PTSD, anxiety disorders, and subclinical psychological distress in biological specimens. Most studies were based on small sets of pre-selected candidate metabolites, with few metabolites overlapping between studies. Vast heterogeneity was observed in study design and inconsistent patterns of association emerged between distress and metabolites. To gain a more robust understanding of distress and its metabolomic signatures, future research should include 1) large, population-based samples and longitudinal assessments, 2) replication and validation in diverse populations, 3) and agnostic metabolomic strategies profiling hundreds of targeted and nontargeted metabolites. Addressing these research priorities will improve the scope and reproducibility of future metabolomic studies of psychological distress.

HighlightsO_LILiterature on metabolomic markers of distress beyond clinical depression is scarce
C_LIO_LIMost existing studies were candidate based and had little overlap of targets
C_LIO_LIVast heterogeneity exists in methods and patterns of findings from studies reviewed
C_LIO_LICritical gaps in sample selection, study design, and methods need to be addressed
C_LI


title: Health Provider and Sexual and Gender Minority Service User Perspectives on Provision of Mental Health Services During the Early Phase of the COVID-19 Pandemic in British Columbia, Canada

abstract: While the COVID-19 pandemic impacted everyone, social determinants of health and structural inequities have had compounding effects that shaped the experiences of some sub-populations during the pandemic. Stigmatization, discrimination, and exclusion contribute to a disproportionately high burden of mental health concerns among sexual minority (i.e., lesbian, gay, bisexual, queer, and other sexually-diverse) and gender minority people. Pre-pandemic, these health inequities are exacerbated by barriers to adequate mental health services including cost, waitlists, and experiences of sexual and gender minority stigma when accessing providers. During the COVID-19 pandemic, these barriers were further complicated by drastic changes in service delivery and access during the pandemic--i.e., a shift to online/virtual provision of care to reduce risk of COVID-19 transmission. To better understand the experiences of sexual and gender minority people accessing mental health services during the first three to nine months of the COVID-19 pandemic, we conducted semi-structured interviews with a purposive sample of 15 health care providers and administrators (summer 2020) and 14 sexual and gender minority individuals interested in accessing mental health services (fall 2020) in British Columbia, Canada. We used interpretive description to inductively analyze interview data. Triangulating between the provider and service user datasets, we examined changes in mental health and coping during the COVID-19 pandemic. We recorded increases in isolation and lack of identity affirmation; inequities in accessing mental health services during the pandemic, perceived opportunities for mental health support, and avenues for reducing mental health inequities through system-level changes that deserve particular attention during the pandemic.


title: Current status and future opportunities in modeling Multiple Sclerosis clinical characteristics

abstract:
Development of effective treatments requires understanding of disease mechanisms. For diseases of the central nervous system (CNS), like Multiple sclerosis (MS), human pathology studies and animal models tend to identify candidate disease mechanisms. However, these studies cannot easily link identified processes to clinical outcomes, such as MS severity, required for causality assessment of candidate mechanisms. Technological advances now allow generation of thousands of biomarkers in living human subjects, derived from genes, transcripts, medical images and proteins or metabolites in biological fluids. These biomarkers can be assembled into computational models of clinical value, provided such models are generalizable. Reproducibility of models increases with technical rigor of study design, such as blinding, implementing controls, using large cohorts that encompass entire spectrum of disease phenotypes and, most importantly, validating models in independent cohort(s).

To facilitate growth of this important research area, we performed a meta-analysis of publications that model MS clinical outcomes (n=302), extracting effect sizes, while also scoring technical quality of study design using pre-defined criteria. Finally, we generated a Shiny-App-based website that allows dynamic exploration of data using selective filtering.

On average, published studies fulfilled only one out of seven criteria of study design rigor. Only 15.2% of studies used any validation strategy, and only 8% used the gold standard of independent cohort validation. Many studies also used small cohorts, e.g., for MRI and blood biomarker predictors the median sample size was below 100 subjects. We observed inverse relationships between reported effect sizes and the numbers of study design criteria fulfilled, expanding analogous reports from non-MS fields, that studies that fail to limit bias over-estimate effect sizes.

In conclusion, the presented meta-analysis represents a useful tool for researchers, reviewers, and funders to improve design of future modeling studies in MS and to easily compare new studies with published literature. We expect that this will accelerate research in this important area, leading to development of robust models with proven clinical value.


title: Oral health and its association with self-rated health in Colombian community-dwelling older adults

abstract:
ObjectiveDetermine the association between different parameters of oral health and the self-rated health (SRH) in Colombian community-dwelling older adults.

MethodsThis is a secondary analysis of the SABE-Colombia study performed in 2015. The dependent variable was defined as the SRH status assessed by the question "Compared with other people your age: Do you consider your health status to be: better, equal or worse?" The oral health parameters were edentulism, the GOHAI score and the use of dental prosthesis. Three multivariable logistic regression was performed compared better vs. worse, better vs. equal and equal vs. worse health status, adjusted by socio-demographic variables, comorbidities, and geriatric syndromes.

ResultsAfter the exclusion of missing data, 18180 persons were included in the final analysis. 10.6, 37.6 and 51.6% persons reported worse, equal and better SRH, respectively. The worse SRH group had a higher proportion of > 80 years old persons, dependence, cognitive impairment, and depressive symptoms. The presence of edentulism and a low score of GOHAI were more frequent in the worse SHR group. After the multivariable logistic regression, all parameters of oral health status were associated with a worse SRH.

ConclusionIn our study, the oral health parameters were associated with self-rated health status. This result supports the inclusion of oral health in comprehensive geriatric assessment.

category: geriatric medicine


title: Inflammatory and immune markers in HIV-infected older adults on long-term antiretroviral therapy: persistent elevation of sCD14 and of proinflammatory effector memory T cells

abstract: HIV-positive patients whose viral loads are successfully controlled by active antiretroviral therapy (ART) show no clinical signs of AIDS. However, their lifespan is shorter compared to individuals with no HIV infection and they prematurely exhibit a multitude of chronic diseases typically associated with advanced age. It was hypothesized that immune system aging may correlate with, and provide useful biomarkers for, this premature loss of healthspan in HIV+ subjects. Here, we tested whether the immune correlates of aging, including cell numbers and phenotypes, inflammatory status and control of human cytomegalovirus (hCMV) in HIV-positive subjects on long-term successful ART (HIV+) may reveal increased "immunological age" compared to healthy, age-matched cohort (HC) in participants between 50 and 69 years of age. Specifically, we expected that younger HIV+ subjects may immunologically resemble older individuals without HIV. We found no evidence to support this hypothesis. While T cells from HIV+ participants displayed different expression of several differentiation and/or inhibitory/exhaustion markers in different T cell subpopulations, aging by a decade did not pronounce these changes. Similarly, while the HIV+ participants exhibited higher T cell responses and elevated inflammatory marker levels in plasma, indicative of chronic inflammation, this trait was not age-sensitive. We did find differences in immune control of hCMV, and, more importantly, a sustained elevation of sCD14 and of proinflammatory CD4 and CD8 T cell responses across age groups, pointing towards uncontrolled inflammation as a factor in reduced healthspan in successfully treated older HIV+ patients.


title: Joint modeling of survival and backwards recurrence outcomes: an analysis of factors associated with fertility treatment

abstract: The increase in methods focused on various types of survival outcomes has allowed practitioners to analyze data that are difficult or expensive to prospectively observe. Still, there are populations that are challenging to study. For example, obtaining a representative sample of couples attempting to become pregnant is difficult due to the dynamic nature of the population. This has led to an increase in the use of cross-sectional designs yielding backwards recurrent survival outcomes. In this paper, we consider the analysis of a survival outcome where subjects are observed if they are at-risk for a separate dependent survival outcome. The motivation for this problem is to determine which factors are associated with time-to-fertility-treatment (TTFT) among women currently attempting pregnancy in a cross-sectional sample. We propose appending a marginal accelerated failure time (AFT) model on TTFT with a conditional model on time-to-pregnancy (TTP) given TTFT to account for their dependence and avoid biases. We address challenges that arise due to the censoring of TTFT and the resulting increased computational complexity. The performance is validated via comprehensive simulation studies. We apply our approach to data from the National Survey of Family Growth to estimate the association insurance type has on TTFT, and estimate the impact of fertility treatment on TTP.


title: Examining the Association between the Gastrointestinal Microbiota and Gulf War Illness: A Prospective Cohort Study

abstract: Gulf War Illness (GWI) affects 25-35% of the 1991 Gulf War Veteran population. Patients with GWI experience pain, fatigue, cognitive impairments, gastrointestinal dysfunction, skin disorders, and respiratory issues. In longitudinal studies, many patients with GWI have shown little to no improvement in symptoms since diagnosis. The gut microbiome and diet play an important role in human health and disease, and preliminary studies suggest it may play a role in GWI. To examine the relationship between the gut microbiota, diet, and GWI, we conducted an eight-week prospective cohort study collecting stool samples, medications, health history, and dietary data. Sixty-nine participants were enrolled into the study, 36 of which met the case definition for GWI. The gut microbiota of participants, determined by 16S rRNA sequencing of stool samples, was stable over the duration of the study and showed no within person (alpha diversity) differences. Between group analyses (beta diversity) identified statistically significant different between those with and without GWI. Several taxonomic lineages were identified as differentially abundant between those with and without GWI (n=9) including a greater abundance of Lachnospiraceae and Ruminococcaceae in those without GWI. Additionally, there were taxonomic differences between those with high and low HEI scores including a greater abundance of Ruminococcaceae in those with higher HEI scores. This longitudinal cohort study of GWVs found that participants with GWI had significantly different microbiomes from those without GWI. Further studies are needed to determine the role these differences may play in the development and treatment of GWI.

category: gastroenterology


title: Elevated fecal mitochondrial DNA from symptomatic norovirus infections suggests potential health relevance of human mitochondrial DNA in fecal source tracking

abstract: An end goal of fecal source tracking (FST) is to provide information on risk of transmission of waterborne illnesses associated with fecal contamination. Ideally, concentrations of FST markers in ambient waters would reflect exposure risk. Human mtDNA is an FST marker that is exclusively human in origin and may be elevated in feces of individuals experiencing gastrointestinal inflammation. In this study, we examined whether human mtDNA is elevated in fecal samples from individuals with symptomatic norovirus infections using samples from the US, Mozambique, and Bangladesh. We quantified hCYTB484 (human mtDNA) and HF183/BacR287 (human-associated Bacteroides) FST markers using droplet digital PCR. We observed the greatest difference in concentrations of hCYTB484 when comparing samples from individuals with symptomatic norovirus infections versus individuals without norovirus infections or diarrhea symptoms: log10 increase of 1.42 in US samples (3,820% increase, p-value = 0.062), 0.49 in Mozambique (308% increase, p-value = 0.061), and 0.86 in Bangladesh (648% increase, p-value = 0.035). We did not observe any trends in concentrations of HF183/BacR287 in the same samples. These results suggest concentrations of fecal mtDNA increase during symptomatic norovirus infection and that mtDNA in environmental samples may represent an unambiguously human source-tracking marker that correlates with enteric pathogen exposure risk.

category: public and global health


title: A three gene signature predicts response to selinexor in multiple myeloma

abstract: Selinexor is the first selective inhibitor of nuclear export (SINE) to be approved for treatment of relapsed or refractory multiple myeloma (MM). There are currently no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aim to characterize transcriptomic correlates of response to selinexor-based therapy, and present a novel, three-gene expression signature that predicts selinexor response in MM. We analyzed RNA sequencing of CD138+ tumor cells from bone marrow of 100 MM patients who participated in the BOSTON study and identified three genes upregulated in responders. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM, and additionally in an external cohort of 35 patients treated in a real world setting outside of clinical trials. We also found that the signature tracked with response in a cohort of 57 patients with recurrent glioblastoma treated with selinexor. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. This signature has important clinical relevance as it could identify cancer patients that are most likely to benefit from treatment with selinexor-based therapy.