mRNA decapping activators Pat1 and Dhh1 regulate transcript abundance and translation to tune cellular responses to nutrient availability.

We have examined the roles of yeast mRNA decapping-activators Pat1 and Dhh1 in repressing the translation and abundance of specific mRNAs in nutrient-replete cells using ribosome profiling, RNA-Seq, CAGE analysis of capped mRNAs, RNA Polymerase II ChIP-Seq, and TMT-mass spectrometry of mutants lacking one or both factors. Although the Environmental Stress Response (ESR) is activated in dhh1Δ and pat1Δ mutants, hundreds of non-ESR transcripts are elevated in a manner indicating cumulative repression by Pat1 and Dhh1 in wild-type cells. These mRNAs show both reduced decapping and diminished transcription in the mutants, indicating that impaired mRNA turnover drives transcript derepression in cells lacking Dhh1 or Pat1. mRNA degradation stimulated by Dhh1/Pat1 is not dictated by poor translation nor enrichment for suboptimal codons. Pat1 and Dhh1 also collaborate to reduce translation and protein production from many mRNAs. Transcripts showing concerted translational repression by Pat1/Dhh1 include mRNAs involved in cell adhesion or utilization of the poor nitrogen source allantoin. Pat1/Dhh1 also repress numerous transcripts involved in respiration, catabolism of non-preferred carbon or nitrogen sources, or autophagy; and we obtained evidence for elevated respiration and autophagy in the mutants. Thus, Pat1 and Dhh1 function as post-transcriptional repressors of multiple pathways normally activated only during nutrient limitation.

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

A multicenter real-world analysis of risk factors, therapeutics, and outcomes of patients with metastatic basal cell carcinoma.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is rare and there are limited data regarding patient and tumor risk factors, optimal treatments, and disease prognosis. OBJECTIVE: To assess patient and tumor characteristics, therapeutics, and outcomes of mBCC stratified by location of metastasis. METHODS: Retrospective cohort study of 53 patients with mBCC treated at 4 large academic centers in Boston, Massachusetts; Philadelphia, Pennsylvania; and Cleveland, Ohio between January 1, 2005 and December 31, 2021. RESULTS: A total of 53 patients with mBCC were identified across 4 centers, 22 (42%) of whom had mBCC with spread limited to lymph nodes and 31 (58%) patients with distant organ spread (with or without lymph node involvement). Overall, half (n = 11) of patients with nodal metastasis achieved complete remission of disease, compared with just 1 (3%) patient with distant metastasis. The 5-year survival for nodal and distant metastatic patients was 89.3% and 61.0%, respectively. LIMITATIONS: Small sample size due to disease rarity. CONCLUSIONS AND RELEVANCE: Patients with nodal disease are more likely to have disease remission whereas patients with distant metastasis are more likely to have persistent disease and die from their disease. However, 5-year survival rates exceed 50%, even for stage IV disease.

Fetal cardiac teratoma and pericardiocentesis: A case report.

Fetal pericardial teratomas are rare. They present with pericardial effusion and hydrops. The definitive management is postnatal resection of the tumor. The exact antenatal management is not known due to its rarity. We present a case of fetal pericardial teratoma with pericardial tamponade. Pericardiocentesis performed at 31 weeks significantly relieved the venous compression, leading to resolution of hydrops and prolonging the gestational age for the definitive management.

Conversion of a Validated Melanoma Risk Stratification Tool Into a Tablet-Based Patient Questionnaire for Targeted Melanoma Screening in Primary Care Settings: A Pilot Study.

BACKGROUND: Risk stratification can identify individuals in primary care settings who are at increased risk of developing melanoma. OBJECTIVE: Converting and implementing a validated risk stratification tool as a patient self-administered tablet-based survey. METHODS: Mackie risk stratification tool was transformed into a patient questionnaire. The questionnaire was completed in academic dermatologist practices by patients and dermatologists and revised to optimize sensitivity and specificity using physician assessment as gold standard. The optimized survey was administered before routine primary care visits during 2019 to 2021. High-risk patients were referred to dermatology. The number needed to screen (NNS), sensitivity, specificity, positive predictive value, and negative predictive value to identify a melanoma were calculated. RESULTS: Of the 7,893 respondents, 5,842 (74%) and 2,051 (26%) patients were categorized as low-risk and high-risk population, respectively. The NNS to identify 1 melanoma was 64 in the high-risk population. CONCLUSION: Incorporating self-administered patient-risk stratification tools in primary care settings can identify high-risk individuals for targeted melanoma screening. Further studies are needed to optimize specificity and sensitivity in more targeted populations.

Factors Associated with Refractory Severe Hypertension in Patients with Preeclampsia.

OBJECTIVE: This study aimed to identify factors associated with refractory severe hypertension that does not resolve after an initial dose of antihypertensive medication in patients with preeclampsia. STUDY DESIGN: This was a retrospective study of all pregnant and postpartum individuals with a diagnosis of preeclampsia, superimposed preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet) syndrome, or eclampsia who delivered at 22 weeks or greater at a single academic institution from 2010 to 2020. Inclusion criteria were patients with preeclampsia who developed severe hypertension (systolic pressure ≥160 mm Hg or diastolic pressure ≥110 mm Hg) and received antihypertensive medications for acute severe hypertension. We defined refractory severe hypertension as a systolic blood pressure of ≥160 mm Hg or a diastolic blood pressure of ≥110 mm Hg that did not improve after receiving the initial treatment. To evaluate for factors associated with refractory severe hypertension, we developed multivariable modified Poisson regression using all variables with p-value <0.1 on bivariable analysis and calculated adjusted relative risks (aRRs) with 95% confidence intervals (95% CIs). RESULTS: Of 850, 386 (45.4%) had refractory severe hypertension and 464 (54.6%) responded to the initial antihypertensive medications. Factors associated with refractory severe hypertension included higher body mass index (BMI), chronic hypertension, and higher systolic pressure. Every 5 kg/m2 increase in BMI was associated with a 7% increased risk of refractory severe hypertension (aRR = 1.07; 95% CI: 1.02-1.12). Every 10 mm Hg increase in systolic blood pressure was associated with a 10% increased risk of refractory severe hypertension (aRR = 1.10; 95% CI: 1.04-1.17). Chronic hypertension was associated with a 25% increased risk of refractory severe hypertension (aRR = 1.25; 95% CI: 1.01-1.56) in the diastolic pressure model. CONCLUSION: Refractory severe hypertension was associated with elevated BMI, chronic hypertension, and higher systolic blood pressure. KEY POINTS: · Risk factors for refractory severe hypertension are not well-known.. · Almost half of the patients had refractory severe hypertension.. · Higher BMI, chronic hypertension, and higher systolic pressure were the risk factors.. · These patients would require closer follow-up and prompt response to vital signs..

Intraoperative challenges and outcomes of pediatric cataract surgery following glaucoma filtering surgery.

PURPOSE: To analyze the intraoperative challenges of cataract surgery in children, following glaucoma filtering surgery. METHODS: This was a retrospective study to analyze intra-op challenges and outcomes of pediatric cataract surgery in post-glaucoma filtration surgery eyes, between January 2007 and December 2019. RESULTS: We included 20 eyes of 16 children. The most common glaucoma surgery performed was trabeculectomy and trabeculotomy (14 eyes). The median age at the time of cataract surgery was 74.5 months. The most common cataract surgery performed was lens aspiration with posterior chamber intraocular lens implantation (LA + PCIOL) (9/20). The most common intraoperative challenge faced was difficulty in capsulorrhexis (ten eyes), followed by extension of primary posterior capsulotomy (six eyes). At the final follow up eight eyes had improvement in visual acuity, five eyes had stable visual acuity and five eyes had a drop in visual acuity. In 12/20 eyes IOL was implanted, nine eyes in-the-bag and three eyes had in ciliary sulcus. None of the IOLs in the bag had decentration of IOL. The median postoperative IOP (p = 0.12) and median number of postoperative AGM (p = 0.13) at 2 years remained stable compared to the preoperative values. The IOP remained well controlled in 4 eyes without anti-glaucoma medications and in 14 eyes with anti-glaucoma medications and none needed additional surgery for IOP control. Two eyes developed retinal detachment postoperatively. CONCLUSION: Cataract surgery in pediatric eyes with prior glaucoma surgeries, have challenges with capsulorrhexis and IOL stability. The visual outcomes were reasonably good so was the IOP control.

Betasatellite-encoded ßC1 protein regulates helper virus accumulation by interfering with the ATP hydrolysis activity of geminivirus-encoded replication initiator protein.

Geminivirus-betasatellite disease complexes are an epidemic threat to the majority of economically important crops across the world. Plant virus satellites including betasatellites are maintained by their associated helper virus. Geminivirus-betasatellites influence viral pathogenesis by substantially increasing or decreasing their helper virus accumulation. In the present study, we attempted to understand the mechanistic details of the geminivirus-betasatellite interaction. Here, we used tomato leaf curl Gujarat virus (ToLCGV) and tomato leaf curl Patna betasatellite (ToLCPaB) as a model system. This study reveals that ToLCGV can efficiently trans-replicate ToLCPaB in Nicotiana benthamiana plants, but ToLCPaB greatly reduced the accumulation of its helper virus DNA. For the first time, we have identified that the ToLCPaB-encoded ßC1 protein is able to interact with ToLCGV-encoded replication initiator protein (Rep). In addition, we demonstrate that the C-terminal region of ßC1 interacts with the C-terminus of Rep (RepC) protein. Our previous study had established that ßC1 proteins encoded by diverse betasatellites possess a novel ATP hydrolysis activity and the conserved lysine/arginine residues at positions 49 and 91 are necessary for this function. Here, we show that mutating lysine at positions 49 to alanine of ßC1 (ßC1K49A) protein did not affect its ability to interact with RepC protein. Biochemical studies performed with ATP hydrolysis activity-deficient K49A mutated ßC1 (ßC1K49A) and RepC proteins revealed that Rep-ßC1 interaction interferes with the ATP hydrolysis activity of Rep protein. Further, we demonstrate that ßC1 protein is able to interact with D227A and D289A mutated RepC proteins but not with D262A, K272A or D286A mutated RepC proteins, suggesting that the ßC1-interacting region of Rep protein encompasses its Walker-B and B' motifs. The results of docking studies supported that the ßC1-interacting region of Rep protein encompasses its motifs associated with ATP binding and ATP hydrolysis activities. Docking studies also provided evidence that the Rep-ßC1 interaction interferes with the ATP binding activity of Rep protein. Together, our findings suggest that ßC1 protein regulates helper virus accumulation by interfering with the ATP hydrolysis activity of helper virus Rep protein.

Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes.

In brief: Oocyte quality remains the most important and unsolved issue in reproduction. Our data show that multidrug resistance transporters and oocyte mitochondria are involved in determining oocyte quality in a mouse model. Abstract: Multidrug resistance transporter-1 (MDR-1) is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and by-products. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1a mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle to germinal vesicle breakdown transition, an increased percentage of symmetric divisions, chromosome misalignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more SNPs in the exomic DNA and twice the amount of mitochondrial DNA (mtDNA) SNPs compared to the wild-type ones. Ca2+ analysis revealed the inability of MDR-1 mutant oocytes to manage Ca2+ storage content and oscillations in response to several stimuli, and ATP quantification shows that mutant oocytes trend toward lower ATP levels compared to wild types. Finally, 1-year-old mutant ovaries express a lower amount of SIRT1, SIRT3, SIRT5, SIRT6 and SIRT7 compared to wild-type levels. These results together emphasize the importance of MDR-1 in mitochondrial physiology and highlight the influence of MDR-1 on oocyte quality and ovarian aging.

Extent of Follow-Up on Abnormal Cancer Screening in Multiple California Public Hospital Systems: A Retrospective Review.

BACKGROUND: Inequitable follow-up of abnormal cancer screening tests may contribute to racial/ethnic disparities in colon and breast cancer outcomes. However, few multi-site studies have examined follow-up of abnormal cancer screening tests and it is unknown if racial/ethnic disparities exist. OBJECTIVE: This report describes patterns of performance on follow-up of abnormal colon and breast cancer screening tests and explores the extent to which racial/ethnic disparities exist in public hospital systems. DESIGN: We conducted a retrospective cohort study using data from five California public hospital systems. We used multivariable robust Poisson regression analyses to examine whether patient-level factors or site predicted receipt of follow-up test. MAIN MEASURES: Using data from five public hospital systems between July 2015 and June 2017, we assessed follow-up of two screening results: (1) colonoscopy after positive fecal immunochemical tests (FIT) and (2) tissue biopsy within 21 days after a BIRADS 4/5 mammogram. KEY RESULTS: Of 4132 abnormal FITs, 1736 (42%) received a follow-up colonoscopy. Older age, Medicaid insurance, lack of insurance, English language, and site were negatively associated with follow-up colonoscopy, while Hispanic ethnicity and Asian race were positively associated with follow-up colonoscopy. Of 1702 BIRADS 4/5 mammograms, 1082 (64%) received a timely biopsy; only site was associated with timely follow-up biopsy. CONCLUSION: Despite the vulnerabilities of public-hospital-system patients, follow-up of abnormal cancer screening tests occurs at rates similar to that of patients in other healthcare settings, with colon cancer screening test follow-up occurring at lower rates than follow-up of breast cancer screening tests. Site-level factors have larger, more consistent impact on follow-up rates than patient sociodemographic traits. Resources are needed to identify health system-level factors, such as test follow-up processes or data infrastructure, that improve abnormal cancer screening test follow-up so that effective health system-level interventions can be evaluated and disseminated.

Geminiviral betasatellites: critical viral ammunition to conquer plant immunity.

Geminiviruses have mastered plant cell modulation and immune invasion to ensue prolific infection. Encoding a relatively small number of multifunctional proteins, geminiviruses rely on satellites to efficiently re-wire plant immunity, thereby fostering virulence. Among the known satellites, betasatellites have been the most extensively investigated. They contribute significantly to virulence, enhance virus accumulation, and induce disease symptoms. To date, only two betasatellite proteins, ßC1, and ßV1, have been shown to play a crucial role in virus infection. In this review, we offer an overview of plant responses to betasatellites and counter-defense strategies deployed by betasatellites to overcome those responses.

Artificial intelligence and machine learning disciplines with the potential to improve the nanotoxicology and nanomedicine fields: a comprehensive review.

The use of nanomaterials in medicine depends largely on nanotoxicological evaluation in order to ensure safe application on living organisms. Artificial intelligence (AI) and machine learning (MI) can be used to analyze and interpret large amounts of data in the field of toxicology, such as data from toxicological databases and high-content image-based screening data. Physiologically based pharmacokinetic (PBPK) models and nano-quantitative structure-activity relationship (QSAR) models can be used to predict the behavior and toxic effects of nanomaterials, respectively. PBPK and Nano-QSAR are prominent ML tool for harmful event analysis that is used to understand the mechanisms by which chemical compounds can cause toxic effects, while toxicogenomics is the study of the genetic basis of toxic responses in living organisms. Despite the potential of these methods, there are still many challenges and uncertainties that need to be addressed in the field. In this review, we provide an overview of artificial intelligence (AI) and machine learning (ML) techniques in nanomedicine and nanotoxicology to better understand the potential toxic effects of these materials at the nanoscale.

Invasion potential of the aquarium pet snail Planorbella trivolvis in India: impact of certain abiotic and biotic factors.

Planorbella trivolvis (ramshorn snail) is one of India's most extensively sold exotic aquarium pet snails. The unintentional or deliberate release of P. trivolvis may result in the colonisation and establishment as an invasive snail in freshwater ecosystems. However, the successful invasion of P. trivolvis will depend on several abiotic and biotic factors of the concerned freshwater ecosystem. We have assessed the possibility of overcoming the opposing factors in P. trivolvis invasion through laboratory-based experiments and examined the effects of household-derived pollutants on egg hatchability, adult survivability and fecundity, and temperature (15 to 35 °C) on growth, sexual maturity, and reproduction. Additionally, we have evaluated the potential of native predators as biotic resistance to invasion by prey-choice experiment. The results indicated that egg hatchability, adult survivability, and fecundity were reduced with increasing pollutant concentration. However, the same traits did not differ from a native freshwater snail, Indoplanorbis exustus. The fecundity of P. trivolvis increased with increasing body size, but no considerable differences at different temperature levels suggest a wide range of adaptation to temperature. Faster growth and the requirement of comparatively few days to attain sexual maturity were observed in the higher temperatures. The native predators, Glossiphonia weberi and Diplonychus rusticus, avoided P. trivolvis as prey over the alternative prey snails in most instances, suggesting the masking of biotic resistance against the colonisation. Our observations indicate that the chance dispersal of P. trivolvis from household or commercial aquaria may lead to a possible invasion of freshwater ecosystems under suitable conditions.

Estimating Vitamin D threshold for the Indian population: Delving into the actual disease burden.

Background: Based on the current guidelines in practice, a vast majority of the healthy Indian population is vitamin D deficient. Since the serum 25 hydroxycholecalciferol (25HCC) levels are affected by race and skin pigmentation, the normal range of vitamin D may differ in the Indians compared to the Western population. This study attempted to determine a population-specific threshold for 25 HCC levels associated with adequate bone health and calcium and phosphate homeostasis in healthy Indians. Methods: Subjects aged 20-50 years were included in the study. The exclusion criteria were obesity, chronic renal disease, liver failure, diabetes mellitus, thyroid disorders, a recent history of fracture, constant joint pain, and postmenopausal status. In addition, participants on prescribed medication such as glucocorticoids, anticonvulsants, or antifungals, as well as vitamin D and calcium supplementation, were also excluded.Blood samples were analyzed for serum calcium, phosphate, alkaline phosphatase, 25HCC, 1,25dihydroxycholecalciferol, parathyroid hormone (PTH), procollagen type-I N propeptide, and C-terminal telopeptide of type 1 collagen.Locally estimated smoothing scatter plot (LOESS) curves and Spearman correlation were utilized to study the correlation of all the biochemical parameters with 25 HCC to achieve thresholds. Results: The study consisted of 270 healthy participants, out of which 97.8% were found to have vitamin D levels below 30 ng/ml. In addition, 8.8% had raised PTH, and 1.85% had hypocalcemia. Furthermore, 1.48% had raised serum alkaline phosphatase and hypophosphatemia, respectively. A weak inverse correlation was seen between 25 HCC and PTH (rs = -0.437, p < 0.001), as well as alkaline phosphatase (rs = -0.1475, p = 0.015), while a weak positive correlation was seen with serum phosphate (rs = 0.128, p = 0.047). Conclusion: For a healthy Indian population, the reference range of 25 HCC is much lower, and the lower limit of normal is approximately 13.5 ng/ml. This study indicates that vitamin D insufficiency in this population starts at 25 HCC values of 13.5 ng/ml and deficiency at 7 ng/ml.

The new kid on the block: a dominant-negative mutation of phototropin1 enhances carotenoid content in tomato fruits.

Phototropins, the UVA-blue light photoreceptors, endow plants to detect the direction of light and optimize photosynthesis by regulating positioning of chloroplasts and stomatal gas exchange. Little is known about their functions in other developmental responses. A tomato Non-phototropic seedling1 (Nps1) mutant, bearing an Arg495His substitution in the vicinity of LOV2 domain in phototropin1, dominant-negatively blocks phototropin1 responses. The fruits of Nps1 mutant were enriched in carotenoids, particularly lycopene, compared with its parent, Ailsa Craig. On the contrary, CRISPR/CAS9-edited loss of function phototropin1 mutants displayed subdued carotenoids compared with the parent. The enrichment of carotenoids in Nps1 fruits is genetically linked with the mutation and exerted in a dominant-negative fashion. Nps1 also altered volatile profiles with high levels of lycopene-derived 6-methyl 5-hepten2-one. The transcript levels of several MEP and carotenogenesis pathway genes were upregulated in Nps1. Nps1 fruits showed altered hormonal profiles with subdued ethylene emission and reduced respiration. Proteome profiles showed a causal link between higher carotenogenesis and increased levels of protein protection machinery, which may stabilize proteins contributing to MEP and carotenogenesis pathways. The enhancement of carotenoid content by Nps1 in a dominant-negative fashion offers a potential tool for high lycopene-bearing hybrid tomatoes.

Bardet-Biedl syndrome: The pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins.

Bardet-Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin-like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin-like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.

Association of Renin Angiotensin Aldosterone System Inhibitors and Outcomes of Hospitalized Patients With COVID-19.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. SUBJECTS: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19-1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03-1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81-0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20-1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.

Characterization and Outcomes of Hospitalized Children With Coronavirus Disease 2019: A Report From a Multicenter, Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) Registry.

OBJECTIVES: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN: Retrospective study. SETTING: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

Geminivirus Betasatellite-Encoded ßC1 Protein Exhibits Novel ATP Hydrolysis Activity That Influences Its DNA-Binding Activity and Viral Pathogenesis.

Plant virus satellites are maintained by their associated helper viruses, and satellites influence viral pathogenesis. Diseases caused by geminivirus-betasatellite complexes can become epidemics and therefore have become a threat to economically important crops across the world. Here, we identified a novel molecular function of the betasatellite-encoded pathogenicity determinant ßC1. The tomato leaf curl Patna betasatellite (ToLCPaB)-encoded ßC1 protein was found to exhibit novel ATPase activity in the presence of the divalent metal ion cofactor MgCl2. Moreover, ATPase activity was confirmed to be ubiquitously displayed by ßC1 proteins encoded by diverse betasatellites. Mutational and sequence analysis showed that conserved lysine/arginine residues at positions 49/50 and 91 of ßC1 proteins are essential for their ATPase activity. Biochemical studies revealed that the DNA-binding activity of the ßC1 protein was interfered with by the binding of ATP to the protein. Mutating arginine 91 of ßC1 to alanine reduced its DNA-binding activity. The results of docking studies provided evidence for an overlap of the ATP-binding and DNA-binding regions of ßC1 and for the importance of arginine 91 for both ATP-binding and DNA-binding activities. A mutant betasatellite with a specifically ßC1-ATPase dominant negative mutation was found to induce symptoms on Nicotiana benthamiana plants similar to those induced by wild-type betasatellite infection. The ATPase function of ßC1 was found to be negatively associated with geminivirus-betasatellite DNA accumulation, despite the positive influence of this ATPase function on the accumulation of replication-associated protein (Rep) and ßC1 transcripts. IMPORTANCE Most satellites influence the pathogenesis of their helper viruses. Here, we characterized the novel molecular function of ßC1, a nonstructural pathogenicity determinant protein encoded by a betasatellite. We demonstrated the display of ATPase activity by this ßC1 protein. Additionally, we confirmed the ubiquitous display of ATPase activity by ßC1 proteins encoded by diverse betasatellites. The lysine/arginine residues conserved at positions 49 and 91 of ßC1 were found to be crucial for its ATPase function. DNA-binding activity of ßC1 was found to be reduced in the presence of ATP. Inhibition of ATPase activity of ßC1 in the presence of an excess concentration of cold ATP, GTP, CTP, or UTP suggested that the purified ßC1 can also hydrolyze other cellular nucleoside triphosphates (NTPs) besides ATP in vitro. These results established the importance of the ATPase and DNA-binding activities of the ßC1 protein in regulating geminivirus-betasatellite DNA accumulation in the infected plant cell.

Right Ventricular Ejection Fraction and Beta-Blocker Effect in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: A low right ventricular ejection fraction (RVEF) is a marker of poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Beta-blockers improve outcomes in HFrEF, but whether this effect is modified by RVEF is unknown. METHODS AND RESULTS: Of the 2798 patients in Beta-Blocker Evaluation of Survival Trial (BEST), 2008 had data on baseline RVEF (mean 35%, median 34%). Patients were categorized into an RVEF of less than 35% (n = 1012) and an RVEF of 35% or greater (n = 996). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within each RVEF subgroup and formally tested for interactions between bucindolol and RVEF. The effect of bucindolol on all-cause mortality in 2008 patients with baseline RVEF (HR 0.88, 95% CI 0.75-1.02) is consistent with that in 2798 patients in the main trial (HR 0.90, 95% CI 0.78-1.02). Bucindolol use was associated with a lower risk of all-cause mortality in patients with an RVEF of 35% or greater (HR 0.70, 95% CI 0.55-0.89), but not in those with an RVEF of less than 35% (HR 1.02, 95% CI 0.83-1.24, P for interaction = .022). Similar variations were observed for cardiovascular mortality (P for interaction = .009) and sudden cardiac death (P for interaction = .018), but not for pump failure death (P for interaction = .371) or HF hospitalization (P for interaction = .251). CONCLUSIONS: The effect of bucindolol on mortality in patients with HFrEF was modified by the baseline RVEF. If these hypothesis-generating findings can be replicated using approved beta-blockers in contemporary patients with HFrEF, then RVEF may help to risk stratify patients with HFrEF for optimization of beta-blocker therapy.