Stroke Risk After COVID-19 Bivalent Vaccination Among US Older Adults.

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.

Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.

The emergence and evolution of intron-poor and intronless genes in intron-rich plant gene families.

Eukaryotic genes can be classified into intronless (no introns), intron-poor (three or fewer introns per gene) or intron-rich. Early eukaryotic genes were mostly intron-rich, and their alternative splicing into multiple transcripts, giving rise to different proteins, might have played pivotal roles in adaptation and evolution. Interestingly, extant plant genomes contain many gene families with one or sometimes few sub-families with genes that are intron-poor or intronless, and it remains unknown when and how these intron-poor or intronless genes have originated and evolved, and what their possible functions are. In this study, we identified 33 such gene families that contained intronless and intron-poor sub-families. Intronless genes seemed to have first emerged in early land plant evolution, while intron-poor sub-families seemed first to have appeared in green algae. In contrast to intron-rich genes, intronless genes in intron-poor sub-families occurred later, and were subject to stronger functional constraints. Based on RNA-seq analyses in Arabidopsis and rice, intronless or intron-poor genes in AP2, EF-hand_7, bZIP, FAD_binding_4, STE_STE11, CAMK_CAMKL-CHK1 and C2 gene families were more likely to play a role in response to drought and salt stress, compared with intron-rich genes in the same gene families, whereas intronless genes in the B_lectin and S_locus_glycop gene family were more likely to participate in epigenetic processes and plant development. Understanding the origin and evolutionary trajectory, as well as the potential functions, of intronless and intron-poor sub-families provides further insight into plant genome evolution and the functional divergence of genes.

[Proteomics of serum exosomes in children in the acute stage of Kawasaki disease: a prospective study]. / æ€¥æ€§æœŸå·å´Žç— æ‚£å„¿è¡€æ¸ å¤–æ³Œä½“è›‹ç™½è´¨ç»„å­¦çš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To study the biological processes and functions of serum exosomes in children in the acute stage of Kawasaki disease (KD), so as to provide new biomarkers for the early diagnosis of KD. METHODS: In this prospective study, 13 children with KD who were treated in Children's Hospital of Soochow University from June 2019 to August 2020 were enrolled as the KD group, and 13 children who were hospitalized due to bacterial infection during the same period were enrolled as the control group. Whole blood was collected on the next morning after admission, serum samples were obtained by centrifugation, and exosomes were extracted through ultracentrifugation. Serum exosomes were analyzed by label-free quantitative proteomics, and differentially expressed proteins (DEPs) were screened out for functional enrichment analysis. A protein-protein interaction (PPI) network was plotted, and unique proteins were validated by targeted proteomics. RESULTS: A total of 131 DEPs were screened out for the two groups, among which 27 proteins were detected in both groups. There were 48 unique DEPs in the KD group, among which 23 were upregulated and 25 were downregulated, and these proteins acted on "complement and coagulation cascades" and "the MAPK signaling pathway". Validation by targeted proteomics showed that FGG, SERPING1, C1R, C1QA, IGHG4, and C1QC proteins were quantifiable in the KD group. A total of 29 proteins were only expressed in the control group, among which 12 were upregulated and 17 were downregulated. Four proteins were quantifiable based on targeted proteomics, i.e., VWF, ECM1, F13A1, and TTR. A PPI network was plotted for each group. In the KD group, FGG and C1QC had close interaction with other proteins, while in the control group, VWF had close interaction with other proteins. CONCLUSIONS: The serum exosomes FGG and C1QC in children in the acute stage of KD are expected to become the biomarkers for the early diagnosis of KD. For children with unexplained fever, detection of FGG, C1QC1, and VWF may help with etiological screening.

Study towards improving artemisinin-based combination therapies.

Covering: Up to 2020 Artemisinin has made a significant contribution towards global malaria control since its initial discovery. Countless lives have been saved by this unique and miraculous molecule. In 2006, artemisinin-based combination therapies (ACTs) were recommended by the World Health Organization (WHO) as the first-line treatment for uncomplicated malaria infection and have since remained as the mainstays of the antimalarial treatment. Even so, substantial efforts to pursue better curative effects for the treatment of malaria have never ceased, particularly with regards to the circumstances surrounding the appearance of delayed clearance of malaria parasites by 3 day ACT treatments in South-East Asian countries. Strategies to further optimize artemisinin-based therapies, including synthesizing better artemisinin derivatives, developing advanced drug delivery systems, and diversifying artemisinin partner drugs, have been proposed over the past few years. Here, we provide an updated account of the continuous efforts in improving ACTs for better efficacy in curing malarial infection.

Risk of Covid-19-Related Hospitalization and More Severe Outcomes in Medicare Beneficiaries Treated with Renin-Angiotensin-Aldosterone System Inhibitors for Hypertension.

BACKGROUND: There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. OBJECTIVE: To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. DESIGN: Observational case-control study. PARTICIPANTS: Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. MAIN MEASURES: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. RESULTS: A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5-12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92-0.98; OR for ARBs 0.94, 95% CI 0.90-0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04-1.14), ARBs (OR 1.10, 95% CI 1.05-1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03-1.19). CONCLUSIONS: ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding.

Genomics-driven discovery of a new cyclodepsipeptide from the guanophilic fungus Amphichorda guana.

Two potential non-ribosomal peptide synthetases (NRPSs) were identified in the genome of a guanophilic fungus Amphichorda guana by bioinformatics analysis and gene knockout experiments. Liquid chromatography coupled with mass spectrometry (LC-MS) guided isolation led to the discovery of a new cyclodepsipeptide isaridin H (1) and seven known analogs, desmethylisaridin E (2), isaridin E (3), isariin A (4), iso-isariin B (5), iso-isariin D (6), isariin E (7), and nodupetide (8). The absolute configuration of isaridin H (1) was achieved by Marfey's method. Isaridin H (1) showed significant antifungal activity against Botrytis cinerea and Alternaria solani.

Heterologous expression of a single fungal HR-PKS leads to the formation of diverse 2-alkenyl-tetrahydropyrans in model fungi.

2-Alkenyl-tetrahydropyrans belong to a rare class of natural products that exhibit broad antifungal activities. Their structural instability and rareness in nature have restrained their discovery and drug development. In this study, the heterologous expression of a single highly reducing polyketide synthase (HR-PKS, App1) from Trichoderma applanatum in Aspergillus nidulans leads to the formation of seven 2-alkenyl-tetrahydropyran derivatives including one known compound virensol C (1) and six new compounds (2-7). However, introducing App1 into Saccharomyces cerevisiae resulted in the identification of additional two 2-alkenyl-tetrahydropyrans lacking the hydroxyl or methoxyl group at the C-2 position (8 and 9). The structures of the isolated compounds were elucidated by extensive spectroscopic analysis using NMR and HR-ESI-MS.

[Association between serum uric acid and subclinical cardiac damage in children with primary hypertension].

OBJECTIVE: To evaluate the condition of subclinical cardiac damage in children with primary hypertension and the association between serum uric acid and subclinical cardiac damage. METHODS: A retrospective analysis was performed on the medical data of 55 children who were hospitalized and diagnosed with primary hypertension in the Department of Cardiology, Children's Hospital of Soochow University from January 2015 to June 2020. Forty-five healthy children, matched for age and sex, were enrolled as the control group. The two groups were compared in terms of clinical features, laboratory examination, and parameters for left ventricular structure, systolic function, and diastolic function. The correlation of serum uric acid with the parameters for left ventricular structure, systolic function, and diastolic function in children with primary hypertension was analyzed. RESULTS: Compared with the control group, the hypertension group had significantly higher left ventricular mass (LVM), left ventricular mass index (LVMI), and relative wall thickness (RWT) (P < 0.05). Among the children with primary hypertension, 20 (36%) had left ventricular hypertrophy. The hypertension group had significantly larger left atrial diameter and aortic root diameter than the control group (P < 0.05). The hypertension group had a significantly higher ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity than the control group (P < 0.05). The correlation analysis showed that in children with primary hypertension, serum uric acid was positively correlated with LVM (r=0.534, P < 0.01), left atrial diameter (r=0.459, P < 0.01), and aortic root diameter (r=0.361, P=0.010). After adjustment for blood pressure, serum uric acid was still positively correlated with the above parameters (P < 0.05). CONCLUSIONS: Children with primary hypertension may have subclinical cardiac damage such as left ventricular hypertrophy, left ventricular diastolic dysfunction, left atrial enlargement, and proximal aortic dilation. Elevated serum uric acid is significantly associated with cardiac damage in children with primary hypertension.

Harnessing diverse transcriptional regulators for natural product discovery in fungi.

Covering: Up to March 2019 Secondary metabolites (SMs) are chemical entities produced by organisms in response to environmental stimuli and as a defense against biological warfare. The production of SMs is controlled by a hierarchical regulatory network involving core factors that orchestrate transcriptional activation of SM gene clusters. In the past few years, significant achievements have been made in the discovery of novel fungal natural products by genetic manipulations of various types of transcriptional regulators. In this review, we summarized the representative regulators for the activation of fungal secondary metabolism and focused on the strategies for the exploitation of these regulators and their application in finding novel structures.

Nitric Oxide Inhibitory Carbazole Alkaloids from the Folk Medicine Murraya tetramera C.C. Huang.

The phytochemical investigation of the leaves and stems of Murraya tetramera C.C. Huang, a traditional folk medicine used as an anti-inflammatory agent, yielded 19 simple carbazole alkaloids, two of which (1-ethoxy-3-methyl-9H-carbazol-2-ol (1) and 7-hydroxy-2,8-dimethoxy-6-methyl-9H-carbazole-1-carbaldehyde (2)) are new ones. The structures of the new compounds were determined by extensive spectroscopic analysis including NMR and HR-EI-MS experiments, as well as comparison with the reported data. Most of the isolates showed potent inhibitory effects on NO production in LPS-stimulated BV-2 microglial cells with IC50 values ranging from 5.1 to 15.1 µM.

[Value of three scoring systems in evaluating the prognosis of children with severe sepsis].

OBJECTIVE: To study the predictive value of Pediatric Age-adapted Sequential Organ Failure Assessment Score (pSOFA), Pediatric Risk of Mortality Score III (PRISM III), and Pediatric Critical Illness Score (PCIS) in children with severe sepsis. METHODS: A retrospective analysis was performed for the clinical data of 193 hospitalized children with severe sepsis. According to the final outcome, these children were divided into a survival group with 151 children and a death group with 42 children. The scores of pSOFA, PRISM III, and PCIS were determined according to the worst values of each index within 24 hours after admission. The receiver operating characteristic (ROC) curve was used to analyze the efficiency of each scoring system in predicting the risk of death due to sepsis. Smooth curve fitting was used to analyze the correlation between the three scoring systems and the threshold effect of each scoring system. Decision curve analysis (DCA) was used to evaluate the application value of each scoring system. RESULTS: The ROC analysis showed that PCIS and pSOFA had a similar predictive value (P=0.182) and that PRISM III and pSOFA had a similar predictive value (P=0.210), while PRISM III had a better predictive value than PCIS (P=0.045). PRISM III had the highest degree of fitting with prognosis, followed by pSOFA and PCIS. The DCA analysis showed that when the risk of death was 0.4 and 0.6 in children with severe sepsis and the three scoring systems were used as the basis for emergency intervention decision-making, pSOFA achieved the highest standardized net benefit, followed by PRISM III and PCIS. CONCLUSIONS: All three scoring systems have a certain value in predicting the prognosis of children with severe sepsis, and pSOFA has a better value than PRISM III and PCIS.

[Clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis].

OBJECTIVE: To study the clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis and its effect on T lymphocyte subsets. METHODS: A total of 76 children with infectious mononucleosis, who were admitted to the hospital between July 2016 and June 2017, were enrolled and randomly divided into two groups: conventional treatment and pidotimod treatment (n=38 each). The children in the conventional treatment group were given antiviral therapy with ganciclovir for injection and symptomatic treatment. Those in the pidotimod treatment group were given pidotimod oral liquid in addition to the treatment in the conventional treatment group. The course of treatment was two weeks for both groups. The two groups were compared in terms of the recovery of clinical indices and the changes in peripheral blood T lymphocyte subsets. RESULTS: Compared with the conventional treatment group, the pidotimod treatment group had significantly shorter fever clearance time, time to the disappearance of isthmopyra, time to the relief of lymph node enlargement, time to the relief of hepatosplenomegaly, and length of hospital stay (P<0.05). After treatment, the pidotimod treatment group had significant reductions in the percentages of CD3+ and CD8+ T cells and had significantly lower percentages of CD3+ and CD8+ T cells than the conventional treatment group (P<0.001). The pidotimod treatment group had significant increases in the percentage of CD4+ T cells and CD4+/CD8+ ratio after treatment, which was significantly higher than those in the conventional treatment group (P<0.001). The conventional treatment group had no significant changes in T lymphocyte subsets after treatment (P>0.05). CONCLUSIONS: Pidotimod oral liquid has a good clinical effect as the adjuvant therapy for infectious mononucleosis and can improve cellular immune function, so it holds promise for clinical application.

Role of the Clinical Features and MRI Parameters on Ki-67 Expression in Hepatocellular Carcinoma Patients: Development of a Predictive Nomogram.

PURPOSE: To develop a nomogram using clinical features and the MRI parameters for preoperatively predicting the expression of Ki-67 in patients with hepatocellular carcinoma (HCC). METHODS: One hundred and forty patients (training cohorts: n = 108; validation cohorts: n = 32) with confirmed HCC were investigated. Mann-Whitney U test, independent sample t-test, and chi-squared test were used to analyze the continuous and categorical variables. Univariate and multivariate logistic regression analyses were performed to examine the clinical variables and parameters from MRI associated with Ki-67 expression. As a result, a nomogram was developed based on these associations in patients with HCC. The performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration curves. RESULTS: In the training set, multivariable logistic regression analysis revealed that lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) levels, protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels, and tumor shape were independent predictors for Ki-67 expression (p < 0.05). These three variables and the apparent diffusion coefficient (ADC) value were used to establish a nomogram, while the ADC value was found to be a marginal significant predictor. The model demonstrated a strong ability to discriminate Ki-67 expression in both the training and validation cohorts (AUC = 0.862, 0.877). CONCLUSION: A non-invasive preoperative prediction method, which incorporates MRI variables and clinical features was developed, and showed effectiveness in evaluating Ki-67 expression in HCC patients.

Preoperative prediction of microvascular invasion classification in hepatocellular carcinoma based on clinical features and MRI parameters.

Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is a critical pathological factor and the degree of MVI influences treatment decisions and patient prognosis. The present study aimed to predict the MVI classification based on preoperative MRI features and clinical parameters. The present retrospective cohort study included 150 patients (training cohort, n=108; validation cohort, n=42) with pathologically confirmed HCC. Clinical and imaging characteristics data were collected from Shengli Oilfield Central Hospital (Dongying, China). Univariate and multivariate logistic regression analyses were conducted to assess the association of clinical variables and MRI parameters with MVI (grade M1 and M2) and the M2 classification. Nomograms were developed based on the predictive factors of MVI and the M2 classification. The discrimination capability, calibration and clinical usefulness of the nomograms were evaluated. Multivariate analysis revealed an association between the Lens culinaris agglutinin-reactive fraction of α-fetoprotein, protein induced by vitamin K absence-II and tumor margin and MVI-positive status, while peritumoral enhancement and tumor size were demonstrated to be marginal predictors, but were also included in the nomogram. However, among MVI-positive patients, only peritumoral hypointensity and tumor size were demonstrated to be risk factors for the M2 classification. The nomograms, incorporating these variables, exhibited a strong ability to discriminate between MVI-positive and MVI-negative patients with HCC in both the training and validation cohort [area under the curve (AUC), 0.877 and 0.914, respectively] and good performance in predicting the M2 classification in the training and validation cohorts (AUC, 0.720 and 0.782, respectively). Nomograms incorporating clinical parameters and preoperative MRI features demonstrated promising potential as straightforward and effective tools for predicting MVI and the M2 classification in patients with HCC. Such predictive tools could aid in the judicious selection of optimal clinical treatments.

Systematic thermal analysis of the Arabidopsis proteome: Thermal tolerance, organization, and evolution.

Understanding the thermal stability of the plant proteome in the context of the native cellular environment would aid the design of crops with high thermal tolerance, but only limited such data are available. Here, we applied quantitative mass spectrometry to profile the thermal stability of the Arabidopsis proteome and identify thermo-sensitive and thermo-resilient protein networks in Arabidopsis, providing a basis for understanding heat-induced damage. We also show that the similarities of the protein-melting curves can be used as a proxy to evaluate system-wide protein-protein interactions in non-engineered plants and enable the identification of transient interactions exhibited by metabolons in the context of the cellular environment. Finally, we report a systematic comparison of the thermal stability of paralogs in Arabidopsis to aid the investigation and understanding of gene duplication and protein evolution. Taken together, our results could have broad implications for the fields of plant thermal tolerance, plant protein assemblies, and evolution.

Risk of Severe COVID-19 in Prevalent Users of Alpha-1 Adrenergic Receptor Antagonists: A National Case-Control Study of Medicare Beneficiaries.

BACKGROUND: Alpha-1 adrenergic receptor antagonists prevent cytokine storm in mouse sepsis models. This led to the hypothesis that alpha-1 blockers may prevent severe coronavirus disease 2019 (COVID-19), which is characterized by hypercytokinemia and progressive respiratory failure. METHODS: We performed an observational case-control study in male Medicare beneficiaries aged 65 years or older, with or without benign prostatic hyperplasia (BPH), and treated with alpha-1 receptor blockers or 5-alpha reductase inhibitors. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated for outcomes of uncomplicated and severe COVID-19 hospitalization (intensive care unit admission, invasive mechanical ventilation, or death). RESULTS: There were 20,963 cases of hospitalized COVID-19 matched to 101,161 controls on calendar date and neighborhood of residence. In the primary analysis (males with BPH), there was no difference in risk of uncomplicated COVID-19 hospitalization (aOR 1.08, 95% CI 0.996-1.17) or hospitalization with severe complications (aOR 0.97, 95% CI 0.88-1.08). In the secondary analysis (males with or without BPH), the corresponding aORs were 1.02 (95% CI, 0.96-1.09) (uncomplicated) and 0.99 (95% CI, 0.91-1.07) (complicated), respectively. Subgroup and sensitivity analyses yielded similar results. Of note, there was no difference in risk of severe COVID-19 hospitalization when comparing non-selective vs selective alpha-1 blocker use (aOR 0.98, 95% CI 0.86-1.10), higher- vs lower-dose alpha-1 blocker use (aOR 0.96, 95% CI 0.86-1.08), or current vs remote alpha-1 blocker use (aOR 1.04, 95% CI 0.91-1.18). CONCLUSIONS: Prevalent use of alpha-1 receptor blockers was not associated with a protective or harmful effect on risk of uncomplicated or severe hospitalized COVID-19.

The similar eye movement dysfunction between major depressive disorder, bipolar depression and bipolar mania.

OBJECTIVE: To find eye movement characteristics in patients with affective disorders. METHOD: The demographic and clinical evaluation data of patients with major depressive disorder (MDD), bipolar disorder (BPD), and healthy control (HC) were collected. EyeLink 1000 eye tracker was used to collect eye movement data. Chi-squared test and independent sample t-test were used for demographics and clinical characteristics. The Mann-Whitney U-test was used to compare the eye movement variables among four groups, and the FDR method was used for multiple comparison correction. Pearson correlation analysis was used to analyse the relationship between clinical symptoms and eye movement variables. RESULTS: Patients with affective disorders showed smaller saccade amplitude under free-viewing task, more fixations and saccades, shorter fixation duration, longer saccade duration under fixation stability and smooth pursuit tasks (all, p < 0.05) when compared to HC, but there was no significant difference in all eye movement variables among patients in the three groups. Also, all eye movement variables under the three paradigms had no significant correlation with clinical scale scores. CONCLUSION: Patients with major depression, bipolar depression and bipolar mania share similar eye movement dysfunction under free-viewing, fixation stability and smooth pursuit tasks.

Mortality Among Parkinson's Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries.

OBJECTIVE: Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database. METHODS: This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW). RESULTS: Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients. CONCLUSIONS: Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.