Association between Liver Function Markers and Menstrual Cycle Irregularity in Korean Female Population.

Background: The liver plays an important role in gonadal steroid hormone metabolism, which can affect reproductive health, including the menstrual cycle. However, evidence from large population-based studies is limited. Therefore, this study aimed to investigate the association between liver function markers and menstrual cycle irregularities in premenopausal Korean women using nationwide data. Methods: This study analyzed Data from the Korea National Health and Nutrition Examination Survey 2010-2011. We investigated 3,045 premenopausal women aged 19-59 years. Liver function markers including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase, and fatty liver index were analyzed. Multivariable logistic regression analysis was performed to investigate the association between liver function markers and menstrual cycle irregularity while adjusting for confounding factors. Values were presented as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analysis was also performed. Results: Baseline characteristic analysis showed that approximately 14.4% of the study population experienced menstrual cycle irregularity. The mean age was 34.5±0.7 years. The highest quartile of serum ALT and AST levels showed significantly higher ORs for menstrual cycle irregularity (adjusted OR, 1.83; 95% CI, 1.26-2.64 and adjusted OR, 1.67; 95% CI, 1.17-2.39, respectively). A similar result was observed in the subgroup analysis. Conclusion: Liver function markers were positively associated with menstrual cycle irregularities. In clinical settings, women of reproductive age with relatively decreased liver function should be considered for regular followup of their reproductive health status.

Control of OPC proliferation and repopulation by the intellectual disability gene PAK1 under homeostatic and demyelinating conditions.

Appropriate proliferation and repopulation of oligodendrocyte progenitor cells (OPCs) determine successful (re)myelination in homeostatic and demyelinating brains. Activating mutations in p21-activated kinase 1 (PAK1) cause intellectual disability, neurodevelopmental abnormality, and white matter anomaly in children. It remains unclear if and how PAK1 regulates oligodendroglial development. Here, we report that PAK1 controls proliferation and regeneration of OPCs. Unlike differentiating oligodendrocytes, OPCs display high PAK1 activity which maintains them in a proliferative state by modulating PDGFRa-mediated mitogenic signaling. PAK1-deficient or kinase-inhibited OPCs reduce their proliferation capacity and population expansion. Mice carrying OPC-specific PAK1 deletion or kinase inhibition are populated with fewer OPCs in the homeostatic and demyelinated CNS than control mice. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.

Cost-effectiveness of mask mandates on subways to prevent SARS-CoV-2 transmission in the United States.

BACKGROUND: Community-based mask wearing has been shown to reduce the transmission of SARS-CoV-2. However, few studies have conducted an economic evaluation of mask mandates, specifically in public transportation settings. This study evaluated the cost-effectiveness of implementing mask mandates for subway passengers in the United States by evaluating its potential to reduce COVID-19 transmission during subway travel. MATERIALS AND METHODS: We assessed the health impacts and costs of subway mask mandates compared to mask recommendations based on the number of infections that would occur during subway travel in the U.S. Using a combined box and Wells-Riley infection model, we estimated monthly infections, hospitalizations, and deaths averted under a mask mandate scenario as compared to a mask recommendation scenario. The analysis included costs of implementing mask mandates and COVID-19 treatment from a limited societal perspective. The cost-effectiveness (net cost per averted death) of mandates was estimated for three different periods based on dominant SARS-CoV-2 variants: Alpha, Beta, and Gamma (November 2020 to February 2021); Delta (July to October 2021); and early Omicron (January to March 2022). RESULTS: Compared with mask recommendations only, mask mandates were cost-effective across all periods, with costs per averted death less than a threshold of $11.4 million (ranging from cost-saving to $3 million per averted death). Additionally, mask mandates were more cost-effective during the early Omicron period than the other two periods and were cost saving in January 2022. Our findings showed that mandates remained cost-effective when accounting for uncertainties in input parameters (e.g., even if mandates only resulted in small increases in mask usage by subway ridership). CONCLUSIONS: The findings highlight the economic value of mask mandates on subways, particularly during high virus transmissibility periods, during the COVID-19 pandemic. This study may inform stakeholders on mask mandate decisions during future outbreaks of novel viral respiratory diseases.

Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia.

Ischemic stroke (IS), characterized by high mortality rate, occurs owing to diminished or blocked blood flow to the brain. Hyperglycemia (HG) is a major contributor to the risk of IS. HG induces augmented oxidative stress and Blood-Brain Barrier breakdown, which increases the influx of blood-derived myeloid cells into the brain parenchyma. In cerebral ischemia, infiltrating monocytes undergo differentiation into pro-inflammatory or anti-inflammatory macrophages, having a large effect on outcomes of ischemic stroke. In addition, interleukin-4 (IL-4) and interleukin-13 (IL-13) engage in post-ischemia repair by polarizing the infiltrating monocytes into an anti-inflammatory phenotype. In this study, we aimed to determine the effect of phenotypic polarization of monocyte-derived macrophages on the prognosis of IS with HG (HG-IS). We first established a hyperglycemic mouse model using streptozotocin (150 mg/kg) and induced transient middle cerebral artery occlusion. We observed that blood-brain barrier permeability increased in HG-IS mice, as per two-photon live imaging and Evans blue staining. We also confirmed the increased infiltration of monocyte-derived macrophages and the downregulation of anti-inflammatory macrophages related to tissue remodeling after inflammation in HG-IS mice through immunohistochemistry, western blotting, and flow cytometry. We observed phenotypic changes in monocyte-derived macrophages, alleviated infarct volume, and improved motor function in HG-IS mice treated with IL-4 and IL-13. These findings suggest that the modulation of phenotypic changes in monocyte-derived macrophages following IS in hyperglycemic mice may influence ischemic recovery.

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3-p62-ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalized with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery.

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles.

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the 'good' or 'bad' aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis-localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell-specific genetic tools are critically important to tease out the potential roles of cell type-dependent Serpina3n in CNS diseases/injuries.

Association between Combustible Cigarettes and Noncombustible Nicotine or Tobacco Products and Generalized Anxiety Disorder Based on Data from the 8th Korea National Health and Nutrition Examination Survey 2021.

Background: Despite the increasing prevalence of anxiety disorders in Korea, there have been no nationwide studies on the association between tobacco status and generalized anxiety disorder (GAD). Furthermore, despite the increasing number of people using noncombustible nicotine or tobacco products (NNTPs), the association between NNTP use and GAD remains unclear. Therefore, this study investigated the association between tobacco use and GAD. Methods: This nationwide study used data from the 8th Korea National Health and Nutrition Examination Survey (2021) and included 5,454 adults aged ≥19 years who self-reported on the tobacco use and mental health sections. Multivariable logistic regression analysis was performed to investigate the odds ratios (ORs) of GAD (Generalized Anxiety Disorder-7 score ≥10) according to tobacco status among Korean adults. The severity of anxiety was assessed using the Generalized Anxiety Disorder-7 scale. Results: Compared to never tobacco users, the ORs of GAD for combustible cigarette smokers and NNTP users were 2.74 (95% confidence interval [CI], 1.66-4.50) and 2.11 (95% CI, 1.16-3.83), respectively. The OR of GAD for former tobacco users was 1.63 (95% CI, 0.98-2.72). Conclusion: Tobacco use (combustible cigarettes and NNTP) was positively associated with GAD. However, in former tobacco users, there was no significant association with GAD when compared with never tobacco users. Given the OR of GAD among tobacco users, it is crucial to pay attention to screening for GAD and implement appropriate early interventions.

Dispensable regulation of brain development and myelination by Serpina3n.

Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory glycoprotein expressed primarily in the liver and brain under homeostatic conditions and dysregulated in various CNS pathologies. Yet its cellular expression profile and physiological significance in postnatal development remain elusive. Here, we showed that Serpina3n protein is expressed predominantly in oligodendroglial lineage cells in the postnatal CNS and that oligodendrocytes (OLs) responded to oxidative injury by upregulating Serpina3n production and secretion. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells did not affect motor and cognitive functions in mice. Serpina3n depletion in Olig2-expressing cells did not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affect the population of other glial cells and neurons in vivo. In vitro primary cell culture showed that Serpina3n-sufficient and -deficient oligodendroglial progenitor cells (OPCs) differentiated into myelin gene-expressing OLs comparatively. Together, these data suggest that Serpina3n plays a minor role, if any, in regulating brain neural cell development and myelination under homeostatic conditions and raise interests in pursuing its functional significance in CNS diseases and injuries.

Lessons Learned from Translating Genome Sequencing to Clinical Routine: Understanding the Accuracy of a Diagnostic Pipeline.

The potential of genome sequencing (GS), which allows detection of almost all types of genetic variation across nearly the entire genome of an individual, greatly expands the possibility for diagnosing genetic disorders. The opportunities provided with this single test are enticing to researchers and clinicians worldwide for human genetic research as well as clinical application. Multiple studies have highlighted the advantages of GS for genetic variant discovery, emphasizing its added value for routine clinical use. We have implemented GS as first-line genetic testing for patients with rare diseases. Here, we report on our experiences in establishing GS as a reliable diagnostic method for almost all types of genetic disorders, from validating diagnostic accuracy of sequencing pipelines to clinical implementation in routine practice.