Unique anticodon loop conformation with the flipped-out wobble nucleotide in the crystal structure of unbound tRNAVal.

During protein synthesis on ribosome, tRNA recognizes its cognate codon of mRNA through base-pairing with the anticodon. The 5'-end nucleotide of the anticodon is capable of wobble base-pairing, offering a molecular basis for codon degeneracy. The wobble nucleotide is often targeted for post-transcriptional modification, which affects the specificity and fidelity of the decoding process. Flipping-out of a wobble nucleotide in the anticodon loop has been proposed to be necessary for modifying enzymes to access the target nucleotide, which has been captured in selective structures of protein-bound complexes. Meanwhile, all other structures of free or ribosome-bound tRNA display anticodon bases arranged in stacked conformation. We report the X-ray crystal structure of unbound tRNAVal1 to a 2.04 Å resolution showing two different conformational states of wobble uridine in the anticodon loop, one stacked on the neighboring base and the other swiveled out toward solvent. In addition, the structure reveals a rare magnesium ion coordination to the nitrogen atom of a nucleobase, which has been sampled very rarely among known structures of nucleic acids.

PRMT7 ablation in cardiomyocytes causes cardiac hypertrophy and fibrosis through ß-catenin dysregulation.

Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/ß-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited the cardiac hypertrophy and fibrosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-deficient hearts revealed the alteration in gene expression profile related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of ß-catenin. PRMT7 deficiency decreases symmetric dimethylation of ß-catenin. Mechanistic studies reveal that methylation of arginine residue 93 in ß-catenin decreases the activity of ß-catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of ß-catenin activity.

Parallel Analysis of Pre- and Postoperative Circulating Tumor DNA and Matched Tumor Tissues in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Cohort Study.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for early tumor detection and minimal residual disease (MRD) assessment in early-stage cancer, but quantifying minute amounts of ctDNA is challenging and well-designed studies on ctDNA in early-stage cancer are still lacking. Here, we adapted a sensitive next-generation sequencing (NGS) technology and performed parallel analysis of pre- and postoperative ctDNA and matched tumor tissues in a prospective cohort of patients with resectable pancreatic ductal adenocarcinoma (PDAC). METHODS: In total, 70 consecutive patients undergoing curative resection for resectable PDAC were enrolled. We performed integrated digital error suppression-enhanced cancer personalized profiling by deep sequencing NGS of triple-matched samples (pre/postoperative plasma cell-free DNA [cfDNA], tumor tissue, and genomic DNA) targeting 77 genes. RESULTS: Preoperative ctDNA was detected in 37.7% of the evaluable patients, with a median variant allele frequency of 0.09%. Twelve additional oncogenic mutations were detected exclusively in preoperative ctDNA but not in tissue. When quantitative concentrations of ctDNA were estimated in haploid genome equivalents per milliliter (hGE/mL), the risk of early recurrence was high in patients with postoperative ctDNA >1 hGE/mL. cfDNA variants from 24.5% of patients had features compatible with clonal hematopoiesis. CONCLUSIONS: An optimized NGS approach might add value beyond tissue analysis through the highly sensitive detection of minute amounts of ctDNA in resectable PDAC. Postoperative ctDNA concentration could be a tool for MRD assessment. Moreover, parallel analyses of matched tissues and leukocytes might be required to accurately detect clinically relevant ctDNA.

Interspecies differences in clinical characteristics and risk factors for third-generation cephalosporin resistance between Escherichia coli and Klebsiella pneumoniae bloodstream infection in patients with liver cirrhosis.

This retrospective study aimed to clarify the interspecies differences in the clinical characteristics and risk factors of bloodstream infection (BSI) due to third-generation cephalosporin-resistant (3GC-R) Escherichia coli (EC) and Klebsiella pneumoniae (KP) in patients with liver cirrhosis (LC). KP BSI had more comorbidities and higher treatment failure rate than EC BSI. Non-alcoholic LC was a risk factor for treatment failure in EC, whereas it was not associated with KP. Risk factors for BSI due to 3GC-R strain were nosocomial infection in EC, and ß-lactam/fluoroquinolone treatment ≤ 30 days in KP. These results could help predict outcomes of BSI and improve clinical practice.

Kv4.1, a Key Ion Channel For Low Frequency Firing of Dentate Granule Cells, Is Crucial for Pattern Separation.

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.1 as a key player. Immunofluorescence analysis showed that Kv4.1 was preferentially expressed in the DG, and its expression level determined by Western blot analysis was higher at 8-week than 3-week-old mice, suggesting a developmental regulation of Kv4.1 expression. With respect to firing frequency, GCs are categorized into two distinctive groups: low-frequency (LF) and high-frequency (HF) firing GCs. Input resistance (Rin) of most LF-GCs is lower than 200 MΩ, suggesting that LF-GCs are fully mature GCs. Kv4.1 channel inhibition by intracellular perfusion of Kv4.1 antibody increased firing rates and gain of the input-output relationship selectively in LF-GCs with no significant effect on resting membrane potential and Rin, but had no effect in HF-GCs. Importantly, mature GCs from mice depleted of Kv4.1 transcripts in the DG showed increased firing frequency, and these mice showed an impairment in contextual discrimination task. Our findings suggest that Kv4.1 expression occurring at late stage of GC maturation is essential for low excitability of DG networks and thereby contributes to pattern separation.SIGNIFICANCE STATEMENT The sparse activity of dentate granule cells (GCs), which is essential for pattern separation, is supported by high inhibitory inputs and low intrinsic excitability of GCs. Low excitability of GCs is thought to be attributable to a high K+ conductance at resting membrane potentials, but this study identifies Kv4.1, a depolarization-activated K+ channel, as a key ion channel that regulates firing of GCs without affecting resting membrane potentials. Kv4.1 expression is developmentally regulated and Kv4.1 currents are detected only in mature GCs that show low-frequency firing, but not in less mature high-frequency firing GCs. Furthermore, mice depleted of Kv4.1 transcripts in the dentate gyrus show impaired pattern separation, suggesting that Kv4.1 is crucial for sparse coding and pattern separation.

Clinical Application of the Standard Q COVID-19 Ag Test for the Detection of SARS-CoV-2 Infection.

We evaluated the Standard Q COVID-19 Ag test for the diagnosis of coronavirus disease 2019 (COVID-19) compared to the reverse transcription-polymerase chain reaction (RT-PCR) test. We applied both tests to patients who were about to be hospitalized, had visited an emergency room, or had been admitted due to COVID-19 confirmed by RT-PCR. Two nasopharyngeal swabs were obtained; one was tested by RT-PCR and the other by the Standard Q COVID-19 Ag test. A total of 118 pairs of tests from 98 patients were performed between January 5 and 11, 2021. The overall sensitivity and specificity for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the Standard Q COVID-19 Ag test compared to RT-PCR were 17.5% (95% confidence interval [CI], 8.8-32.0%) and 100% (95% CI, 95.3-100.0%). Analysis of the results using RT-PCR cycle thresholds of ≤ 30 or ≤ 25 increased the sensitivity to 26.9% (95% CI, 13.7-46.1%), and 41.1% (95% CI, 21.6-64.0%), respectively.

Intracellular Zn2+ Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells.

Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca2+] allowed LTP-IE because of Ca2+-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction. High-frequency MF inputs, however, could induce LTP-IE at high dendritic [Ca2+] of the window. We show that MF input-induced Zn2+ signaling inhibits postsynaptic PTP, and thus enables MF inputs to induce LTP-IE at a wide range of [Ca2+]i values. Extracellular chelation of Zn2+ or genetic deletion of vesicular zinc transporter abrogated the privilege of MF inputs for LTP-IE induction. Moreover, the incompetence of somatic stimulation was rescued by the inhibition of PTP or a supplement of extracellular zinc, indicating that MF input-induced increase in dendritic [Zn2+] facilitates the induction of LTP-IE by inhibiting PTP. Consistently, high-frequency MF stimulation induced immediate and delayed elevations of [Zn2+] at proximal and distal dendrites, respectively. These results indicate that MF inputs are uniquely linked to the regulation of direct cortical inputs owing to synaptic Zn2+ signaling.SIGNIFICANCE STATEMENT Zn2+ has been mostly implicated in pathological processes, and the physiological roles of synaptically released Zn2+ in intracellular signaling are little known. We show here that Zn2+ released from hippocampal mossy fiber (MF) terminals enters postsynaptic CA3 pyramidal cells, and plays a facilitating role in MF input-induced heterosynaptic potentiation of perforant path (PP) synaptic inputs through long-term potentiation of intrinsic excitability (LTP-IE). We show that the window of cytosolic [Ca2+] that induces LTP-IE is normally very narrow because of the Ca2+-dependent coactivation of antagonistic signaling pairs, whereby non-MF inputs become ineffective in inducing excitability change. The MF-induced Zn2+ signaling, however, biases toward facilitating the induction of LTP-IE. The present study elucidates why MF inputs are more privileged for the regulation of PP synapses.

Long non-coding RNA ChRO1 facilitates ATRX/DAXX-dependent H3.3 deposition for transcription-associated heterochromatin reorganization.

Constitutive heterochromatin undergoes a dynamic clustering and spatial reorganization during myogenic differentiation. However the detailed mechanisms and its role in cell differentiation remain largely elusive. Here, we report the identification of a muscle-specific long non-coding RNA, ChRO1, involved in constitutive heterochromatin reorganization. ChRO1 is induced during terminal differentiation of myoblasts, and is specifically localized to the chromocenters in myotubes. ChRO1 is required for efficient cell differentiation, with global impacts on gene expression. It influences DNA methylation and chromatin compaction at peri/centromeric regions. Inhibition of ChRO1 leads to defects in the spatial fusion of chromocenters, and mislocalization of H4K20 trimethylation, Suv420H2, HP1, MeCP2 and cohesin. In particular, ChRO1 specifically associates with ATRX/DAXX/H3.3 complex at chromocenters to promote H3.3 incorporation and transcriptional induction of satellite repeats, which is essential for chromocenter clustering. Thus, our results unveil a mechanism involving a lncRNA that plays a role in large-scale heterochromatin reorganization and cell differentiation.

Determinants of clinical outcomes in patients with mixed mitral valve disease.

BACKGROUND: Although significant stenosis and regurgitation can be observed on a single heart valve, studies on the outcome predictors for mixed valve disease are limited. The purpose of the current study was to investigate the fate and determinants of clinical outcomes in patients with mixed single mitral valve disease who have concomitant mitral stenosis (MS) and mitral regurgitation (MR). METHODS: We retrospectively reviewed 82 consecutive patients with rheumatic heart disease who had both significant MS (MVA ≤ 1.5 cm2 ) and at least moderate MR, excluding patients with significant aortic valve stenosis or regurgitation. The primary endpoint was a composite of all-cause mortality during follow-up, mitral valve replacement, heart failure admission, and stroke. RESULTS: There were 37 events (45.1%), 5 all-cause deaths (6.0%), and 32 mitral valve replacements (39.0%). In a multivariable Cox regression analysis, a transmitral mean pressure gradient (TMPG) over 6 mm Hg was the only independent echocardiographic predictor for events (hazard ratio 3.69, 95% confidential interval 1.31-10.44, P = .014), after adjusting for sex, age, symptoms, and the severity of MS and MR. The estimated 6-year event-free survival rate was significantly lower in patients with TMPG ≥ 6 mm Hg than in those with TMPG < 6 mm Hg (76.3% vs 22.9%, log-rank P < .001). CONCLUSION: Transmitral mean pressure gradient, which reflects the hemodynamic burden of the mitral valve lesion, appears to be the most important echocardiographic predictor of clinical outcomes in patients with mixed mitral valve disease.

PRMT7 deficiency enhances adipogenesis through modulation of C/EBP-ß.

Obesity that is critically correlated with the initiation and development of metabolic syndrome and cardiovascular diseases has increased worldwide. Adipogenesis is coordinated through multi-steps involving adipogenic commitment, mitotic clonal expansion (MCE) and differentiation. Recently, protein arginine methyltransferase 4 (PRMT4) and PRMT5 have been implicated in modulation of adipogenesis via regulation of C/EBP-ß activity or PPAR-γ2 expression. In the current study, we demonstrate a suppressive role of PRMT7 in adipogenesis. PRMT7-depleted preadipocytes or PRMT7-/- mouse embryonic fibroblasts (MEFs) displayed increased adipogenesis while PRMT7 overexpression attenuated it. PRMT7 depletion in preadipocytes promoted MCE, an initial step of adipogenesis. Furthermore, we found that PRMT7 interacted with and methylated a key adipogenic factor C/EBP-ß upon adipogenic induction and modulated the accumulation of C/EBP-ß at its target sites in the PPAR-γ2 promoter. Taken together, our data suggest that PRMT7 suppresses adipogenesis through modulation of C/EBP-ß activity.

Factors influencing changing bowel habits in patients undergoing sphincter-saving surgery for rectal cancer.

A research survey research was conducted to identify factors affecting changes in bowel habits of rectal cancer patients undergoing sphincter-saving surgery and to provide basic information useful in nursing interventions supporting treatment for rectal cancer patients. The subjects were rectal cancer patients who had undergone sphincter-saving surgery over 2 years ago. The final analysis included 107 patients who had made outpatient visits to the colorectal surgery from 12th to 31st May, 2014. Collected data were processed with SPSS Version 21.0. Changes in bowel habits in the subjects were observed: frequent bowel movement in 74 patients (69.2%) and faecal incontinence in 48 (44.9%). Most of the patients used self-care to improve their bowel function including dietary modification (78.5%), regular exercise (72.0%) and pelvic floor exercise (34.6%). Frequent defecation was associated with adjuvant chemoradiation therapy (P < 0.001) and faecal incontinence was associated with age of ≥65 years (P = 0.019) and a group who underwent adjuvant radiation therapy (P < 0.001). It is necessary to give sufficient information about possible postoperative changes in bowel habits to patients with the risk factors before surgery.

Vitamin D ameliorates age-induced nonalcoholic fatty liver disease by increasing the mitochondrial contact site and cristae organizing system (MICOS) 60 level.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Despite intensive research, considerable information on NAFLD development remains elusive. In this study, we examined the effects of vitamin D on age-induced NAFLD, especially in connection with mitochondrial abnormalities. We observed the prevention of NAFLD in 22-month-old C57BL/6 mice fed a vitamin D3-supplemented (20,000 IU/kg) diet compared with mice fed a control (1000 IU/kg) diet. We evaluated whether vitamin D3 supplementation enhanced mitochondrial functions. We found that the level of mitochondrial contact site and cristae organizing system (MICOS) 60 (Mic60) level was reduced in aged mice, and this reduction was specifically restored by vitamin D3. In addition, depletion of Immt, the human gene encoding the Mic60 protein, induced changes in gene expression patterns that led to fat accumulation in both HepG2 and primary hepatocytes, and these alterations were effectively prevented by vitamin D3. In addition, silencing of the vitamin D receptor (VDR) decreased the Mic60 levels, which were recovered by vitamin D treatment. To assess whether VDR directly regulates Mic60 levels, we performed chromatin immunoprecipitation and reporter gene analysis. We discovered that VDR directly binds to the Immt 5' promoter region spanning positions -3157 to -2323 and thereby upregulates Mic60. Our study provides the first demonstration that a reduction in Mic60 levels due to aging may be one of the mechanisms underlying the development of aging-associated NAFLD. In addition, vitamin D3 could positively regulate Mic60 expression, and this may be one of the important mechanisms by which vitamin D could ameliorate age-induced NAFLD.

Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss.

Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases. However, the molecular mechanisms underlying neuromuscular dysfunction are currently unclear. Recent studies have proposed important roles of Protein arginine methyltransferase 1 (Prmt1) in muscle stem cell function and muscle maintenance. In the current study, we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1 (mnKO) using Hb9-Cre. mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality. Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury. The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation, cell death, oxidative stress, and mitochondria. Consistently, mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor neurons. Furthermore, Prmt1 inhibition in motor neurons elicited mitochondrial dysfunction. Our findings demonstrate that Prmt1 ablation in motor neurons causes age-related motor neuron degeneration attributing to muscle loss. Thus, Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging.

Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions, such as neurodegenerative diseases and diabetes; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here, we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farnesol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/Zfp746), a transcriptional repressor of PGC-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS expression in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.

Structural and functional characterization of TrmM in m6 A modification of bacterial tRNA.

N6 -methyladenosine (m6 A), widely distributed in both coding and noncoding RNAs, regulates the epigenetic signals and RNA metabolism in eukaryotes. Although this posttranscriptional modification is frequently observed in messenger and ribosomal RNA, it is relatively rare in transfer RNA. In Escherichia coli, TrmM encoded by yfiC is the tRNA-specific N6 methyltransferase, which modifies the A37 residue of tRNAVal (cmo5 UAC) using S-adenosyl-l-methionine as a methyl donor. However, the structure-function relationship of this enzyme is not completely understood. In this report, we determined two x-ray crystal structures of Mycoplasma capricolum TrmM with and without S-adenosyl-l-homocysteine, which is a reaction product. We also demonstrated the cellular and in vitro activities of this enzyme in the m6 A modification of tRNA and the requirement of a divalent metal ion for its function, which is unprecedented in other RNA N6 methyltransferases, including the E. coli TrmM. Our results reveal that the dimeric form of M. capricolum TrmM is important for efficient tRNA binding and catalysis, thereby offering insights into the distinct substrate specificity of the monomeric E. coli homolog.

Performance of STANDARD™ M10 SARS-CoV-2 Assay for the Diagnosis of COVID-19 from a Nasopharyngeal Swab.

The STANDARD™ M10 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) assay (M10 assay) (SD Biosensor Inc., Suwon, Korea) is a rapid, fully-automated, cartridge-type molecular diagnostic assay that detects SARS-CoV-2 RNA using primers and probes for each target gene (ORF1ab gene, E gene). This study evaluated its performance by assessing its concordance with the approved SARS-CoV-2 real-time PCR assay. Tests were performed on 80 nasopharyngeal samples. The sensitivity and specificity of the M10 assay were 100%. The M10 assay effectively diagnosed SARS-CoV-2 infection, and it was comparable to the approved SARS-CoV-2 real-time PCR assay. It is a viable point-of-care test due to its short turnaround time.

SARS-CoV-2 shedding dynamics and transmission in immunosuppressed patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have been emerging. However, knowledge of temporal and spatial dynamics of SARS-CoV-2 is limited. This study characterized SARS-CoV-2 evolution in immunosuppressed patients with long-term SARS-CoV-2 shedding for 73-250 days, without specific treatment. We conducted whole-genome sequencing of 27 serial samples, including 26 serial samples collected from various anatomic sites of two patients and the first positive sample from patient 2's mother. We analysed the intrahost temporal dynamics and genomic diversity of the viral population within different sample types. Intrahost variants emerging during infection showed diversity between individual hosts. Remarkably, N501Y, P681R, and E484K, key substitutions within spike protein, emerged in vivo during infection and became the dominant population. P681R, which had not yet been detected in the publicly available genome in Korea, appeared within patient 1 during infection. Mutually exclusive substitutions at residues R346 (R346S and R346I) and E484 (E484K and E484A) of spike protein and continuous turnover of these substitutions occurred. Unique genetic changes were observed in urine samples. A household transmission from patient 2 to his mother, at least 38 days after the diagnosis, was characterized. Viruses may differently mutate and adjust to the host selective pressure, which could enable the virus to replicate efficiently for fitness in each host. Intrahost variants could be candidate variants likely to spread to the population eventually. Our findings may provide new insights into the dynamics of SARS-CoV-2 in response to interactions between the virus and host.

Prognostic value of left atrial volume index in patients with rheumatic mitral stenosis.

BACKGROUND: The significance of left atrial volume index (LAVI) for predicting outcomes in patients with mitral stenosis (MS) has been unclear, even though rheumatic MS is known to be associated with left atrium enlargement and functional deterioration. HYPOTHESIS: The current study aimed to investigate the prognostic value of LAVI, based on the severity in patients with rheumatic MS. METHODS: We retrospectively reviewed 611 patients with pure rheumatic MS. The prognostic value of LAVI and the effect of MS severity on the prognostic value of LAVI for events were evaluated. The events were defined as a composite end-point that included all-cause death, heart failure admission, mitral valve replacement, percutaneous mitral valvuloplasty, and stroke. RESULTS: There were 236 (38.6%) overall events during a median follow-up of 8 months. The optimal LAVI cutoff for the prognostic threshold was 57 ml/m2 . The MS severity had a significant effect on the prognostic value of LAVI. A LAVI >57 ml/m2 was a prognostic value for events in progressive MS (hazard ratio [HR]: 2.40, 95% confidence interval [CI]: 1.41-5.40, p = .004) and in patients with severe MS (HR: 1.70, 95% CI: 1.06-2.74, p = .029), but it was not prognostic in patients with very severe MS (HR: 1.02, 95% CI: 0.56-1.84, p = .955). CONCLUSIONS: The prognostic value of LAVI varies and is dependent on the MS severity. A LAVI >57 mL/m2 was independently associated with poor outcomes in patients with progressive MS, while this association was minimized in patients with severe MS.

Sex Differences in Mitral Annular Calcification and the Clinical Implications.

Background: Heterogeneous mechanisms may contribute to the occurrence of mitral annular calcification (MAC), however, little is known about the sex differences in MAC and the clinical implications of these differences. This study aimed to investigate clinical and imaging differences of MAC according to sex. Methods: In total, 537 patients (221 men) with MAC were identified by transthoracic echocardiography at a single center from January 2012 to June 2016. Moderate-to-severe MAC was defined as calcification extent ≥120° of the mitral annulus. Significant functional mitral stenosis (MS) was defined as a transmitral mean diastolic pressure gradient ≥5 mmHg. Results: Women more frequently had moderate-to-severe MAC and concomitant mitral regurgitation than men; however, significant functional MS was comparable between sexes. In the logistic regression analysis, old age, uncontrolled hypertension, end-stage renal disease (ESRD), and obstructive hypertrophic cardiomyopathy were significantly associated with moderate-to-severe MAC in women, whereas ESRD and moderate-to-severe aortic stenosis were in men. In the Cox regression analysis, significant functional MS was associated with all-cause death in both sexes, although an independent association was found in only women. Conclusion: Women had more extended MAC than men. Significant functional MS was independently associated with unfavorable clinical outcomes in patients with MAC, which was more pronounced in women than in men.

Are coveralls required as personal protective equipment during the management of COVID-19 patients?

OBJECTIVES: Few studies have investigated the contamination of personal protective equipment (PPE) during the management of patients with severe-to-critical coronavirus disease (COVID-19). This study aimed to determine the necessity of coveralls and foot covers for body protection during the management of COVID-19 patients. METHODS: PPE samples were collected from the coveralls of physicians exiting a room after the management of a patient with severe-to-critical COVID-19 within 14 days after the patient's symptom onset. The surface of coveralls was categorized into coverall-only parts (frontal surface of the head, anterior neck, dorsal surface of the foot cover, and back and hip) and gown-covered parts (the anterior side of the forearm and the abdomen). Sampling of the high-contact surfaces in the patient's environment was performed. We attempted to identify significant differences in contamination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between the coverall-only and gown-covered parts. RESULTS: A total of 105 swabs from PPEs and 28 swabs from patient rooms were collected. Of the PPE swabs, only three (2.8%) swabs from the gown-covered parts were contaminated with SARS-CoV-2. However, 23 of the 28 sites (82.1%) from patient rooms were contaminated. There was a significant difference in the contamination of PPE between the coverall-only and gown-covered parts (0.0 vs 10.0%, p = 0.022). CONCLUSIONS: Coverall contamination rarely occurred while managing severe-to-critical COVID-19 patients housed in negative pressure rooms in the early stages of the illness. Long-sleeved gowns may be used in the management of COVID-19 patients.