Nevin Manimala

Neuron. 2022 Jan 11:S0896-6273(21)01036-9. doi: 10.1016/j.neuron.2021.12.019. Online ahead of print.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.

PMID:35045337 | DOI:10.1016/j.neuron.2021.12.019

Am Heart J. 2022 Jan 16:S0002-8703(22)00006-0. doi: 10.1016/j.ahj.2022.01.006. Online ahead of print.

ABSTRACT

BACKGROUND: Typical late gadolinium enhancement (LGE) patterns in dilated cardiomyopathy (DCM) include intramyocardial and subepicardial distribution. However, the ischemic pattern of LGE (subendocardial and transmural) has also been reported in DCM without coronary artery disease (CAD), but its correlates and prognostic significance are still not known. On these bases, this study sought to describe the prevalence and prognostic significance of the ischemic LGE pattern in DCM.

METHODS: 611 DCM patients with available cardiac magnetic resonance were retrospectively analyzed. A composite of all-cause-death, major ventricular arrhythmias (MVAs), heart transplantation (HTx) or ventricular assist device (VAD) implantation was the primary outcome of the study. Secondary outcomes were a composite of sudden cardiac death or MVAs and a composite of death for refractory heart failure, HTx or VAD implantation.

RESULTS: Ischemic LGE was found in 7% of DCM patients without significant CAD or history of myocardial infarction, most commonly inferior/inferolateral/anterolateral. Compared to patients with non-ischemic LGE, those with ischemic LGE had higher prevalence of hypertension and atrial fibrillation or flutter. Ischemic LGE was associated with worse long-term outcomes compared to non-ischemic LGE (36% vs 23% risk of primary outcome events at 5 years respectively, p = 0.006), and remained an independent predictor of primary outcome after adjustment for clinically and statistically significant variables (adjusted hazard ratio 2.059 [1.055 – 4.015], p = 0.034 with respect to non-ischemic LGE).

CONCLUSIONS: The ischemic pattern of LGE is not uncommon among DCM patients without CAD and is independently associated with worse long-term outcomes.

PMID:35045326 | DOI:10.1016/j.ahj.2022.01.006

J Clin Epidemiol. 2022 Jan 16:S0895-4356(22)00012-9. doi: 10.1016/j.jclinepi.2022.01.010. Online ahead of print.

ABSTRACT

OBJECTIVES: Interrupted Time Series (ITS) are a type of non-randomised design commonly used to evaluate public health policy interventions, and the impact of exposures, at the population level. Meta-analysis may be used to combine results from ITS across studies (in the context of systematic reviews) or across sites within the same study. We aimed to examine the statistical approaches, methods, and completeness of reporting in reviews that meta-analyse results from ITS.

STUDY DESIGN AND SETTINGS: Eight electronic databases were searched to identify reviews (published 2000-2019) that meta-analysed at least two ITS. Characteristics of the included reviews, the statistical methods used to analyse the ITS and meta-analyse their results, effect measures, and risk of bias assessment tools were extracted.

RESULTS: Of the 4213 identified records, 54 reviews were included. Nearly all reviews (94%) used two-stage meta-analysis, most commonly fitting a random effects model (69%). Among the 41 reviews that re-analysed the ITS, linear regression (39%) and ARIMA (20%) were most commonly used; 38% adjusted for autocorrelation. The most common effect measure meta-analysed was an immediate level-change (46/54). Reporting of the statistical methods and ITS characteristics was often incomplete.

CONCLUSION: Improvement is needed in the conduct and reporting of reviews that meta-analyse results from ITS.

PMID:35045318 | DOI:10.1016/j.jclinepi.2022.01.010

J Clin Epidemiol. 2022 Jan 16:S0895-4356(22)00013-0. doi: 10.1016/j.jclinepi.2022.01.008. Online ahead of print.

ABSTRACT

OBJECTIVES: Among ID studies seeking to make causal inferences and pooling individual-level longitudinal data from multiple infectious disease cohorts, we sought to assess what methods are being used, how those methods are being reported, and whether these factors have changed over time.

STUDY DESIGN AND SETTING: Systematic review of longitudinal observational infectious disease studies pooling individual-level patient data from 2+ studies published in English in 2009. 2014, or 2019. This systematic review protocol is registered with PROSPERO (CRD42020204104).

RESULTS: Our search yielded 1,462 unique articles. Of these, 16 were included in the final review. Our analysis showed a lack of causal inference methods and of clear reporting on methods and the required assumptions.

CONCLUSION: There are many approaches to causal inference which may help facilitate accurate inference in the presence of unmeasured and time-varying confounding. In observational ID studies leveraging pooled, longitudinal IPD, the absence of these causal inference methods and gaps in the reporting of key methodological considerations suggests there is ample opportunity to enhance the rigor and reporting of research in this field. Interdisciplinary collaborations between substantive and methodological experts would strengthen future work.

PMID:35045316 | DOI:10.1016/j.jclinepi.2022.01.008

Cell Rep. 2022 Jan 18;38(3):110251. doi: 10.1016/j.celrep.2021.110251.

ABSTRACT

The hypothalamus regulates many innate behaviors, but its development remains poorly understood. Here, we used single-cell RNA sequencing (RNA-seq) and hybridization chain reaction (HCR) to profile multiple stages of early hypothalamic development in the chick. Hypothalamic neuroepithelial cells are initially induced from prethalamic-like cells. Two distinct hypothalamic progenitor populations then emerge and give rise to tuberal and mammillary/paraventricular hypothalamic cells. At later stages, the regional organization of the chick and mouse hypothalamus is highly similar. We identify selective markers for major subdivisions of the developing chick hypothalamus and many previously uncharacterized candidate regulators of hypothalamic induction, regionalization, and neurogenesis. As proof of concept for the power of the dataset, we demonstrate that prethalamus-derived follistatin inhibits hypothalamic induction. This study clarifies the organization of the nascent hypothalamus and identifies molecular mechanisms that may control its induction and subsequent development.

PMID:35045288 | DOI:10.1016/j.celrep.2021.110251

J Phys Chem Lett. 2022 Jan 19:864-871. doi: 10.1021/acs.jpclett.1c03374. Online ahead of print.

ABSTRACT

We present measurements of the product-channel branching ratios of the reactions (i) HD⁺ + HD forming H₂D⁺ + D (38.1(30)%) and HD₂⁺ + H (61.9(30)%), (ii) HD⁺ + D₂ forming HD₂⁺ + D (61.4(35)%) and D₃⁺ + H (38.6(35)%), and (iii) D₂⁺ + HD forming HD₂⁺+ D (60.5(20)%) and D₃⁺ + H (39.5(20)%) at collision energies E_coll near zero, i.e., below k_B × 1 K. These branching ratios are compared with branching ratios predicted using three simple models: a combinatorial model (M1), a model (M2) describing the reactions as H-, H⁺-, D-, and D⁺-transfer processes, and a statistical model (M3) that relates the reaction rate coefficients to the translational and rovibrational state densities of the H_nD_3-n⁺ + H/D (n = 0, 1, 2 or 3) product channels. The experimental data are incompatible with the predictions of models M1 and M2 and reveal that the branching ratios exhibit clear correlations with the product state densities.

PMID:35045261 | DOI:10.1021/acs.jpclett.1c03374

Microsc Res Tech. 2022 Jan 19. doi: 10.1002/jemt.24059. Online ahead of print.

ABSTRACT

We introduce a study of image analysis of kefir biofilms associated with Acai extract prepared by fermentation of fresh kefir grains natural. Atomic force microscopy data were studied, aiming to understand how the concentration of acai berry (Euterpe oleracea Mart.) influences the surface morphology as well as the texture complexity, evaluated by the fractal dimension. The results showed that the superficial morphology was affected by the increase of Acai concentration in the biofilms, as well as the fractal dimension. It has also been observed that the surface of the biofilm presented saturation when concentration changes from 40 to 60 ml. On the other hand, it was observed that the intermediate sample produced with 20 ml of acai berry seems to be the best point for biofilms production that can serve as a skin dressing since other studies related to mechanical properties and in vitro and in vivo tests can confirm this applicability. Thus, the characterization of the surface morphology of kefir biofilms by the evaluation of surface statistical parameters and fractal geometry may provide promising results regarding the applicability of these films.

PMID:35045209 | DOI:10.1002/jemt.24059

Health Rep. 2021 Dec 15;32(12):13-26. doi: 10.25318/82-003-x202101200002-eng.

ABSTRACT

BACKGROUND: Reliance on the use of opioids to manage pain has increased over time, as have opioid-related morbidity and deaths. In 2018, 12.7% of Canadians reported having used opioid pain relief medications (OPRMs) in the previous year. Among these people, 9.6% had engaged in problematic use that could cause harm to their health. Though socioeconomic characteristics associated with opioid-related harms have previously been reported, population-level evidence based on administrative health data lacks important behavioural and psychosocial information. This analysis extends previous research by using modelling to report factors related to the problematic use of OPRMs for the household population aged 15 and older in Canada.

DATA AND METHODS: This analysis uses responses to the 2018 Canadian Community Health Survey to identify factors that are significantly associated, after adjustment using multivariate logistic regression models, with elevated odds of problematic use of OPRMs.

RESULTS: The fully adjusted model confirmed that being male, being younger (ages 20 to 24), having fair or poor mental health, having unmet needs for help with mental or emotional health or substance problems, being a smoker, or being unattached and living with others were significantly related to problematic OPRM use.

INTERPRETATION: Subjective perceptions significantly related to problematic OPRM use, independent of socioeconomic circumstances, were examined in this study. While previous research based on administrative health data has contributed much to knowledge about factors associated with opioid harms, modelled results revealed that self-reported experiential factors also warrant consideration as they are significantly associated with problematic use. Having fair or poor mental health, having unmet perceived needs for help, and being unattached in terms of household arrangement relationship were related to problematic use of OPRMs, even after adjustment for socioeconomic and other health covariates. This study suggests risk profiles that could be used to inform health care providers, and strategies to support safe pain management.

PMID:35044740 | DOI:10.25318/82-003-x202101200002-eng

Health Rep. 2021 Dec 15;32(12):3-12. doi: 10.25318/82-003-x202101200001-eng.

ABSTRACT

BACKGROUND: The National Standard of Canada for Psychological Health and Safety in the Workplace (the Standard) identifies 13 psychosocial factors affecting psychological health and safety in the workplace that employers should measure and monitor with the goal of addressing areas for improvement. The present study sought to determine the suitability of the Public Service Employee Survey as a tool for the assessment of these psychosocial factors in public service employees. It also aimed to explore-in a preliminary manner-predictors of job satisfaction in these employees.

DATA AND METHODS: Data from the 2017 and 2019 Public Service Employee Survey (PSES) were analyzed. Specifically, exploratory structural modelling and tests of measurement invariance were used to identify a measurement model reflecting the psychosocial factors outlined in the Standard and to evaluate the equivalence of this model across both PSES administrations.

RESULTS: The analyses uncovered 10 of the 13 psychosocial factors, as well as 2 closely related factors-diversity and inclusion-and supported the full invariance of the resulting measurement model across both PSES administrations. Lastly, preliminary results pointed to recognition and reward (encompassing leader reward behaviours) and involvement and influence (touching on participative decision making, innovation and initiative) as predictors of job satisfaction in both samples of public service employees.

INTERPRETATION: The present study identified the PSES as a tool for the assessment-in public service employees-of the majority of the psychosocial factors outlined in the Standard as well as two additional factors of particular importance to the federal government, diversity and inclusion. Future research to address current limitations is discussed, as are preliminary implications for practice.

PMID:35044739 | DOI:10.25318/82-003-x202101200001-eng

Pol Arch Intern Med. 2022 Jan 19. doi: 10.20452/pamw.16195. Online ahead of print.

ABSTRACT

INTRODUCTION: Ovarian cancer is the most lethal gynecologic malignancy, and early detection of ovarian cancer is important for prognosis. Human epididymal secretory protein 4 (HE4) elevation has been studied as a crucial biomarker for ovarian cancer. There are currently many organic pollutants in the environment, including polycyclic aromatic hydrocarbons (PAHs).

OBJECTIVES: The purpose of our study was to determine relationships among PAH exposure, HE4 levels and ovarian cancer.

PATIENTS AND METHODS: Our study enrolled 799 participants over the age of 20 from U.S. National Health and Nutrition Examination Survey (NHANES) datasets (2001 and 2002) with complete data for multivariable analysis consisting of urinary PAH metabolites. A multivariable linear regression model was used to investigate the associations between PAH metabolites and HE4 in ovarian cancer.

RESULTS: Multivariable linear regression analysis showed that except for 2-hydroxyphenanthrene, PAH metabolites correlated positively with In(HE4) after adjustment for relevant covariates (all P < 0.05). Higher quartiles of PHA metabolites tended to be associated with higher HE4 levels, with statistical significance in quartile-based analysis. A dose-dependent relationship between PAH metabolites and HE4 was found (all P-trends < 0.05).

CONCLUSIONS: Exposure to PAH was found to be associated with elevated HE4 levels and a higher risk of ovarian cancer, and epidemiological evidence revealed the influential impact. This result will alert gynecologists and public health experts to pay more attention to the potential role of PAH metabolites in the tumorigenesis of ovarian cancer.

PMID:35044732 | DOI:10.20452/pamw.16195