Involvement of IL-17 A/IL-17 Receptor A with Neutrophil Recruitment and the Severity of Coronary Arteritis in Kawasaki Disease.

PURPOSE: To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA). METHODS: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected. RESULTS: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra+/+ littermates, and absent IL-17RA upregulation at aortic roots. CONCLUSION: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.

Effects of Decentration of Implantable Collamer Lens V4c on Visual Quality With the OPD-Scan III Aberrometer.

PURPOSE: This study aimed to analyze the relationship between visual quality and implantable collamer lenses (ICL) decentration. DESIGN: Prospective treatment evaluation clinical study METHODS: This prospective study included 119 eyes with ICL implantation. Refractive parameters and ocular aberrations were examined pre- and postoperatively. ICL decentration and higher-order aberrations (HOAs) were evaluated using the OPD-Scan III aberrometer. RESULTS: At the 1-month follow-up, the mean values for decentration were 0.38 ± 0.19 mm (0.02-0.78). Regarding the position of decentration in right and left eyes, 22.8% and 17.7% were located in the superior nasal section, 0% and 6.5% in the inferior nasal section, 50.9% and 53.2% in the superior temporal section, and 26.3% and 22.6% in the inferior temporal section, respectively. The root mean square values of whole-eye total HOAs, coma, and trefoil had significantly increased. Decentration had a significant negative correlation with variation in the pre- and postoperative trefoils of the whole eye. CONCLUSIONS: ICL decentration had a slightly negative correlation with trefoil and slightly affected visual quality.

Long non-coding RNA FKSG29 regulates oxidative stress and endothelial dysfunction in obstructive sleep apnea.

Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling.

Prenatal High-Fat Diet Combined with Microplastic Exposure Induces Liver Injury via Oxidative Stress in Male Pups.

Prenatal high-fat diet (HFD) or exposure to microplastics can affect the accumulation of liver fat in offspring. We sought to determine the effects of maternal HFD intake and microplastic exposure on fatty liver injury through oxidative stress in pups. Pregnant female Sprague-Dawley rats were randomly divided into maternal HFD (experimental group) or normal control diet (NCD; control group) groups with or without microplastic exposure. As a result, the following groups were established: HFD-L (HFD + microplastics, 5 µm, 100 µg/L), HFD-H (HFD + microplastics, 5 µm, 1000 µg/L), NCD-L (NCD + microplastics, 5 µm, 100 µg/L), and NCD-H (NCD + microplastics, 5 µm, 1000 µg/L). The pups were sacrificed on postnatal day 7 (PD7). Liver histology revealed increased hepatic lipid accumulation in pups in the HFD-L and HFD-H groups compared to those in the HFD, NCD-L, NCD-H, and NCD groups on PD7. Similarly, liver TUNEL staining and cellular apoptosis were found to increase in pups in the HFD-L and HFD-H groups compared to those in the HFD, NCD-L, NCD-H, and NCD groups. The expression levels of malondialdehyde, a lipid peroxidation marker, were high in the HFD, HFD-L, and HFD-H groups; however, the highest expression was observed in the HFD-H group (p < 0.05). The levels of glutathione peroxidase, an antioxidant enzyme, decreased in the HFD, HFD-L, and HFD-H groups (p < 0.05). Overall, oxidative stress with cellular apoptosis plays a vital role in liver injury in offspring after maternal intake of HFD and exposure to microplastic; such findings may shed light on future therapeutic strategies.

Effect of long-term rotation on astigmatism following EVO-toric intraocular collamer lens implantation.

Objective: To evaluate the effect of long-term rotation on astigmatism following Evolution-toric intraocular collamer lens (EVO-TICL) implantation. Methods: Forty eyes of 22 patients were enrolled in this prospective study. Visual acuity, refractive parameters, and axial position of the EVO-TICL by OPD-Scan III aberrometer were measured preoperatively, 1 month and 3 years postoperatively. Results: Last visit, the safety index was 1.32 ± 0.15 and the efficacy index was 1.01 ± 0.23. The best-fitting curve of the attempted versus achieved correction was y = 0.9751x + 0.001. The mean spherical equivalent (SE) decreased from -8.94 ± 2.72D preoperatively to 0.06 ± 0.24D and - 0.36 ± 0.46D 1 month and 3 years postoperatively, respectively. The mean target and surgical induced astigmatism were 1.55 ± 0.61D and 1.67 ± 0.94D 3 years postoperatively. The average expected axis of the TICL was-1.15 ± 9.07 (-21-19°). One month and 3 years postoperatively, the average actual axis was -0.70 ± 9.86 (-20-20°) and - 0.35 ± 11.72 (-25-30°), respectively. The absolute rotation of the TICL was 3.70 ± 4.42 (0-22°) and 6.00 ± 6.70 (0-32°) 1 month and 3 years postoperatively, respectively (p < 0.001). The expected astigmatism was -0.10 ± 0.12D, and the mean actual astigmatism was -0.21 ± 0.30D and - 0.44 ± 0.45D 1 month and 3 years postoperatively, respectively. The mean absolute rotation without postoperative astigmatism was 3.73 ± 2.69 (0-9°) and 1.67 ± 1.66 (0-5°) for low (<2D) and high (≥2D) astigmatic TICL, respectively (p < 0.05). Conclusion: EVO-TICL implantation is safe and effective, with good predictability and stability. OPD-Scan is a fast device to detect the axial position of the TICL without mydriasis, and the axial position is relatively stable in the long term postoperatively. A slight rotation of low-astigmatic TICL may not cause postoperative astigmatism, whereas rotation of the high-astigmatic TICL may cause it.

Risk of herpes zoster following mRNA COVID-19 vaccine administration.

BACKGROUND: Adverse events following mRNA COVID-19 vaccines, including herpes zoster (HZ), have been reported. We conducted a cohort study to evaluate the association between mRNA COVID-19 vaccination and subsequent HZ at Kaiser Permanente Southern California (KPSC). RESEARCH DESIGN AND METHODS: The vaccinated cohort consisted of KPSC members who received their first dose of mRNA COVID-19 vaccine (mRNA-1273 and BNT162b2) during 12/2020-05/2021 and were matched to unvaccinated individuals on age and sex. Incident HZ cases occurring within 90 days of follow-up were identified by diagnosis codes and antiviral medications. Cox proportional hazards models estimated adjusted hazard ratios (aHR), comparing HZ incidence between the vaccinated and unvaccinated cohorts. RESULTS: Cohort included 1,052,362 mRNA-1273 recipients, 1,055,461 BNT162b2 recipients, and 1,020,334 comparators. Compared to unvaccinated individuals, aHR for HZ up to 90 days after the second dose of mRNA-1273 and BNT162b2 was 1.14 (1.05-1.24) and 1.12 (1.03-1.22), respectively. In those aged ≥50 years not vaccinated with zoster vaccine, aHR was also increased after the second dose of mRNA-1273 (1.18 [1.06-1.33]) and BNT162b2 (1.15 [1.02-1.29]) vaccine vs. unvaccinated individuals. CONCLUSIONS: Our findings suggest a potential increased risk of HZ after a second dose of mRNA vaccines, potentially driven by the increased risk in individuals aged ≥50 years without history of zoster vaccination.

Medical outcomes of children with neurodevelopmental disorders after SARS-CoV-2 vaccination: A six-month follow-up study.

INTRODUCTION: The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines have been approved for children and adolescents for protecting against SARS-CoV-2 infection. This longitudinal study aimed to compare adverse outcomes after SARS-CoV-2 vaccination in children with neurodevelopmental disorders (ND) (e.g., attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], communication disorders, intellectual disability, and tic disorders) and healthy control children. METHODS: A total of 1335 children who received the SARS-CoV-2 vaccination (762 children with ND and 573 healthy controls) were recruited. All subjects were followed-up for 180 days, and outcome events were defined as outpatient department (OPD) or emergency department (ER) visits during follow-up. Multivariate Cox proportional hazards regression models were used to identify the potential differences in outcomes between the propensity score-matched ND group (n = 311) and the control group (n = 311), and to explore the factors associated with outcomes among all children with ND (n = 762). RESULTS: Compared with the control group, children with ND exhibited a higher likelihood of subsequent OPD or ER visits and paediatric neurology OPD visits after the first dose of vaccination. However, we found that only a small proportion of the children visited the OPD or ER because of adverse vaccination-related effects. Among all children with ND, those with communication disorders showed a higher likelihood of any OPD or ER visit. Paediatric neurology OPD visits were associated with communication disorders, intellectual disability, and methylphenidate and aripiprazole prescriptions. ADHD and ASD were not associated with adverse outcomes. CONCLUSIONS: No specific ND diagnosis or medication use clearly increased the risk of adverse effects of SARS-CoV-2 vaccination. Children with ND can be reassured that the SARS-CoV-2 vaccination is a safe regimen to protect themselves.

Design, structure-activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin-based sulfamates as steroid sulfatase inhibitors.

Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin-based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM-1min-1 on human placenta STS, respectively.

Autophagy impairment in patients with obstructive sleep apnea modulates intermittent hypoxia-induced oxidative stress and cell apoptosis via hypermethylation of the ATG5 gene promoter region.

BACKGROUND: Autophagy is a catabolic process that recycles damaged organelles and acts as a pro-survival mechanism, but little is known about autophagy dysfunction and epigenetic regulation in patients with obstructive sleep apnea (OSA). METHODS: Protein/gene expressions and DNA methylation levels of the autophagy-related genes (ATG) were examined in blood leukocytes from 64 patients with treatment-naïve OSA and 24 subjects with primary snoring (PS). RESULTS: LC3B protein expression of blood monocytes, and ATG5 protein expression of blood neutrophils were decreased in OSA patients versus PS subjects, while p62 protein expression of cytotoxic T cell was increased, particularly in those with nocturia. ATG5, ULK1, and BECN1 gene expressions of peripheral blood mononuclear cells were decreased in OSA patients versus PS subjects. LC3B gene promoter regions were hypermethylated in OSA patients, particularly in those with excessive daytime sleepiness, while ATG5 gene promoter regions were hypermethylated in those with morning headache or memory impairment. LC3B protein expression of blood monocytes and DNA methylation levels of the LC3B gene promoter region were negatively and positively correlated with apnea hyponea index, respectively. In vitro intermittent hypoxia with re-oxygenation exposure to human THP-1/HUVEC cell lines resulted in LC3B/ATG5/ULK1/BECN1 down-regulations and p62 up-regulation along with increased apoptosis and oxidative stress, while rapamycin and umbilical cord-mesenchymal stem cell treatment reversed these abnormalities through de-methylation of the ATG5 gene promoter. CONCLUSIONS: Impaired autophagy activity in OSA patients was regulated by aberrant DNA methylation, correlated with clinical phenotypes, and contributed to increased cell apoptosis and oxidative stress. Autophagy enhancers may be novel therapeutics for OSA-related neurocognitive dysfunction.

Assessment of vascular and endothelial function in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile vasculitis. Patients with previous KD have increased risk of coronary arterial aneurysms (CAA) and early-onset arteriosclerosis. Endothelial dysfunction is the earliest manifestation of arteriosclerosis. We aimed to explore the endothelial function and clinical characteristics of patients with previous KD. METHODS: In this case-control study, we investigated childhood KD patients, with and without CAA, and a group of healthy controls. We obtained the anthropometric measurements, metabolic markers, vascular ultrasonography evaluating arterial stiffness and flow-mediated dilatation (FMD), and clinical information obtained by reviewing the patients' charts. Continuous variables were compared using non-parametric analyses and categorical variables, using the chi-square or Fisher's exact tests. RESULTS: Seventy KD patients (median current age, 12.95 years; median follow-up duration, 10.88 years) and 14 healthy controls were recruited. FMD was significantly lower in the CAA group (n = 15) than the control group (FMDs: 5.59% [interquartile range, 3.99-6.86%] vs. 7.49% [5.96-9.42%], p = 0.049; diastolic FMD: 6.48% [4.14-7.32%] vs. 7.87% [6.19-9.98%], p = 0.042). The CAA group had a higher percentage of impaired FMD and the significantly largest coronary segments of the three groups. Other parameters including metabolic markers, carotid intima-media thickness, and arterial stiffness were not statistically different. CONCLUSION: KD patients, especially those with CAAs, may have impaired endothelial function. FMD may be a good indicator of endothelial dysfunction for use in long-term follow-up of KD patients.

Na2Ti3O7@RF@Ag Heterostructures as Efficient Substrates for SERS and Photocatalytic Applications.

A multi-step procedure was effectively employed to synthesize innovative three-dimensional (3D) heterostructures encompassing sodium titanate (Na2Ti3O7) nanowire cores, an intermediate resorcinol-formaldehyde (RF) layer, and outer silver (Ag) nanoparticle sheaths, referred to as Na2Ti3O7@RF@Ag heterostructures. Initially, a one-step hydrothermal technique facilitated the direct growth of single-crystal Na2Ti3O7 nanowires onto a flexible Ti foil. Subsequently, a two-step wet chemical process facilitated the sequential deposition of an RF layer and Ag nanoparticles onto the Na2Ti3O7 nanowires at a low reaction temperature. Optimal concentrations of silver nitrate and L-ascorbic acid can lead to the cultivation of Na2Ti3O7@RF@Ag heterostructures exhibiting heightened surface-enhanced Raman scattering (SERS), which is particularly beneficial for the detection of rhodamine B (RhB) molecules. This phenomenon can be ascribed to the distinctive geometry of the Na2Ti3O7@RF@Ag heterostructures, which offer an increased number of hot spots and surface-active sites, thereby showcasing notable SERS enhancement, commendable reproducibility, and enduring stability over the long term. Furthermore, the Na2Ti3O7@RF@Ag heterostructures demonstrate remarkable follow-up as first-order chemical kinetic and recyclable photocatalysts for the photodecomposition of an RhB solution under UV light irradiation. This result can be attributed to the enhanced inhibition of electron-hole pair recombination and increased surface-active sites.

Maternal Metformin Treatment Reprograms Maternal High-Fat Diet-Induced Hepatic Steatosis in Offspring Associated with Placental Glucose Transporter Modifications.

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.

Effects of Maternal Gut Microbiota-Targeted Therapy on the Programming of Nonalcoholic Fatty Liver Disease in Dams and Fetuses, Related to a Prenatal High-Fat Diet.

Metabolic disorders can start in utero. Maternal transmission of metabolic phenotypes may increase the risks of adverse metabolic outcomes, such as nonalcoholic fatty liver disease (NAFLD); effective intervention is essential to prevent this. The gut microbiome plays a crucial role in fat storage, energy metabolism, and NAFLD. We investigated the therapeutic use of probiotic Lactobacillus reuteri and postbiotic butyrate gestation in the prevention of perinatal high-fat diet-induced programmed hepatic steatosis in the offspring of pregnant Sprague-Dawley rats who received regular chow or a high-fat (HF) diet 8 weeks before mating. L. reuteri or sodium butyrate was administered via oral gavage to the gestated rats until their sacrifice on day 21 of gestation. Both treatments improved liver steatosis in pregnant dams; L. reuteri had a superior effect. L. reuteri ameliorated obesity and altered the metabolic profiles of obese gravid dams. Maternal L. reuteri therapy prevented maternal HF diet-induced fetal liver steatosis, and reformed placental remodeling and oxidative injury. Probiotic therapy can restore lipid dysmetabolism in the fetal liver, modulate nutrient-sensing molecules in the placenta, and mediate the short-chain fatty acid signaling cascade. The therapeutic effects of maternal L. reuteri on maternal NAFLD and NAFLD reprogramming in offspring should be validated for further clinical translation.

The Design, Structure-Activity, and kinetic studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates as Steroid sulfatase inhibitors.

Steroid sulfatase inhibitors block the local production of estrogenic steroids and are attractive agents for the treatment of estrogen-dependent cancers. Inspiration of coumarin-based inhibitors, we synthesized thirty-two 5-oxa-1,2,3,4-tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates, focusing on the substitution derivatives on the adjacent phenyl ring and evaluated their abilities to block STS from human placenta and MCF-7 cells. SAR analysis revealed that the incorporation of chlorine at either meta and/or para position of the adjacent phenyl ring of the tricyclic skeleton enhanced STS inhibition. Di-substitutions at the adjacent phenyl ring were superior to mono and tri-substitutions. Further kinetic analysis of these compounds revealed that chloride-bearing compounds, such as 19m, 19v, and 19w, had KI of 0.02 to 0.11 nM and kinact/KI ratios of 8.8-17.5 nM-1min-1, a parameter indicated for the efficiency of irreversible inhibition. We also used the docking model to illustrate the difference in STS inhibitory potency of compounds. Finally, the safety and anti-cancer activity of selected compounds 19m, 19v, and 19w were also studied, showing the results of low cytotoxicity on NHDF cell line and being more potent than irosustat on ZR-75-1 cell, which was a hormone-dependent cancer cell line with high STS expression.

Association Between Daytime vs Overnight Digit Replantation and Surgical Outcomes.

Importance: Recent evidence suggests that select delayed replantation may not adversely affect digit survival; however, whether surgical timing (overnight or daytime) is associated with digit replantation outcomes is unknown. Objective: To assess whether digit survival, complication rate, and duration of surgery are associated with time of replantation. Design, Setting, and Participants: This retrospective case series study included all replantations performed at a single tertiary referral academic center between January 1, 2000, and August 1, 2021. Data were analyzed between October 2, 2021, and January 1, 2022. Four daytime surgery intervals were selected based on literature review. Daytime replantations started within the intervals whereas overnight replantations began outside the intervals. For each case, the procedure difficulty score and the attending surgeon expertise score were calculated. Logistic and linear regressions adjusting for confounders including procedure difficulty score and expertise score were used to assess surgical timing and outcomes. Participants were adults (aged ≥18 years) undergoing digit replantations between January 2000 and August 2021 with at least 1-month follow-up. Replantation was defined as the reattachment of a completely amputated digit that necessitated anastomosis of both artery and vein. Exposures: Daytime or overnight digit replantation. Main Outcomes and Measures: Viable replanted digit at 1-month follow-up, number of complications, and duration of surgery. Results: A total of 98 patients (mean [SD] age, 39.5 [15.3] years; 136 [93%] men) and 147 digits met inclusion criteria. Overall success rate was 55%. Between 4 pm and 7 am, overnight replantations were associated with 0.4 fewer complications (ß, -0.4; 95% CI, -0.8 to -0.1) and 90.7 minutes shorter operative time (ß, -90.7; 95% CI, -173.6 to -7.7). A 1-point increase in surgeon expertise score was associated with 1.7 times increased odds of replantation success for all intervals (adjusted odds ratio, 1.7; 95% CI, 1.2 to 2.4; P = .002). There were no differences in digit survival by surgical time. Conclusions and Relevance: In this case series study of digit replantations, time of operation was not associated with replantation success. Overnight replantation was associated with fewer complications and shorter duration of surgery compared with daytime surgery. Results of this study suggest that overnight replantations may be performed with outcomes comparable to daytime replantations at a tertiary care academic center.

Sodium butyrate modulates blood pressure and gut microbiota in maternal tryptophan-free diet-induced hypertension rat offspring.

Maternal nutrition, gut microbiome composition, and metabolites derived from gut microbiota are closely related to the development of hypertension in offspring. A plethora of metabolites generated from diverse tryptophan metabolic pathways show both beneficial and harmful effects. Butyrate, one of the short-chain fatty acids (SCFAs), has shown vasodilation effects. We examined whether sodium butyrate administration in pregnancy and lactation can prevent hypertension induced by a maternal tryptophan-free diet in adult progeny and explored the protective mechanisms. Pregnant Sprague-Dawley rats received normal chow (CN), tryptophan-free diet (TF), sodium butyrate 400 mg/kg/d in drinking water (CNSB), or TF diet plus sodium butyrate (TFSB) in pregnancy and lactation. Male offspring were sacrificed at the age of 16 weeks (n=8 per group). Compared with normal chow, offspring exposed to the maternal tryptophan-free diet had markedly increased blood pressure, associated with activation of the renin-angiotensin system (RAS). Treatment with sodium butyrate rescued maternal TF-exposed offspring from hypertension. The protective effect of sodium butyrate is related to alterations to microbiome composition, increased renal expression of SCFA receptor G protein-coupled receptor 41 (GPR41) and GPR109A, and restoration of RAS balance. In summary, these results suggest that sodium butyrate protects against maternal TF-induced offspring hypertension, likely by modulating gut microbiota, its derived metabolites, and the RAS.

Risk of Severe Coronavirus Disease 2019 Disease in Individuals With Down Syndrome: A Matched Cohort Study From a Large, Integrated Health Care System.

BACKGROUND: Down syndrome (DS) is associated with an increased risk of infections attributed to immune defects. Whether individuals with DS are at an increased risk of severe coronavirus disease 2019 (COVID-19) remains unclear. METHODS: In a matched cohort study, we evaluated the risk of COVID-19 infection and severe COVID-19 disease in individuals with DS and their matched counterparts in a pre-COVID-19 vaccination period at Kaiser Permanente Southern California. Multivariable Cox proportion hazard regression was used to investigate associations between DS and risk of COVID-19 infection and severe COVID-19 disease. RESULTS: Our cohort included 2541 individuals with DS and 10 164 without DS matched on age, sex, and race/ethnicity (51.6% female, 53.3% Hispanic, median age 25 years [interquartile range, 14-38]). Although the rate of COVID-19 infection in individuals with DS was 32% lower than their matched counterparts (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], .56-.83), the rate of severe COVID-19 disease was 6-fold higher (aHR, 6.14; 95% CI, 1.87-20.16). CONCLUSIONS: Although the risk of COVID-19 infection is lower, the risk of severe disease is higher in individuals with DS compared with their matched counterparts. Better infection monitoring, early treatment, and promotion of vaccine for COVID-19 are warranted for DS populations.

Investigation of the Gender Distribution of National Institutes of Health Grants Across Six Surgical Specialties From 2015 to 2020: Toward Promoting Equity in Academic Surgery.

INTRODUCTION: There is a paucity of literature evaluating research-funding differences between male and female surgeons. Our study aims to evaluate possible disparities in the National Institutes of Health (NIH) grant awards by surgeon gender, type of medical degree (MD/DO), and advanced degrees among six surgery specialties: general surgeons, neurosurgeons, urologists, obstetricians/gynecologists, plastic, and orthopedic surgeons, from 2015 to 2020. METHODS: A retrospective cohort study was performed investigating the number of NIH grants received by male and female surgeon-scientists overall and within each listed specialty, 2015-2020. As a surrogate for grants submitted, the proportion of active surgeon-scientists per specialty was used. A priori level of significance was defined as P < 0.05. RESULTS: After adjusting for confounders, male surgeons had a higher mean number of NIH grants and higher grant funding than female surgeons (P < 0.001 for both). Type of medical degree (MD/DO) was not significantly associated with NIH funding. An advanced degree was associated with NIH funding among neurosurgeons only (P < 0.05). Differences in the proportion of active surgeon-scientists and proportion of NIH grants received by male and female surgeon-scientists were found only in the fields of orthopedic surgery (5.8% female surgeons and received 20.7% of grants, P = 0.003) and plastic surgery (17.2% female surgeons and received 33.3% of grants, P = 0.01). CONCLUSIONS: Male surgeons received most of the total surgical NIH grants. However, funding for female surgeons in orthopedic and plastic surgery outpaces that of their male counterparts when compared to gender proportions in their respective field. Future studies should further investigate the effects of additional applicant demographics on securing NIH grant funding.