Dosage sensitivity to Pumilio1 variants in the mouse brain reflects distinct molecular mechanisms.

Different mutations in the RNA-binding protein Pumilio1 (PUM1) cause divergent phenotypes whose severity tracks with dosage: a mutation that reduces PUM1 levels by 25% causes late-onset ataxia, whereas haploinsufficiency causes developmental delay and seizures. Yet PUM1 targets are derepressed to equal degrees in both cases, and the more severe mutation does not hinder PUM1's RNA-binding ability. We therefore considered the possibility that the severe mutation might disrupt PUM1 interactions, and identified PUM1 interactors in the murine brain. We find that mild PUM1 loss derepresses PUM1-specific targets, but the severe mutation disrupts interactions with several RNA-binding proteins and the regulation of their targets. In patient-derived cell lines, restoring PUM1 levels restores these interactors and their targets to normal levels. Our results demonstrate that dosage sensitivity does not always signify a linear relationship with protein abundance but can involve distinct mechanisms. We propose that to understand the functions of RNA-binding proteins in a physiological context will require studying their interactions as well as their targets.

Proteomics, modeling, and fluorescence assays delineate cytochrome b5 residues involved in binding and stimulation of cytochrome P450 17A1 17,20-lyase.

Cytochrome b5 (b5) is known to stimulate some catalytic activities of cytochrome P450 (P450, CYP) enzymes, although mechanisms still need to be defined. The reactions most strongly enhanced by b5 are the 17,20-lyase reactions of P450 17A1 involved in steroid biosynthesis. We had previously used a fluorescently labeled human b5 variant (Alexa 488-T70C-b5) to characterize human P450 17A1-b5 interactions, but subsequent proteomic analyses indicated that lysines in b5 were also modified with Alexa 488 maleimide in addition to Cys-70, due to disulfide dimerization of the T70C mutant. A series of b5 variants were constructed with Cys replacements for the identified lysine residues and labeled with the dye. Fluorescence attenuation and the function of b5 in the steroid lyase reaction depended on the modified position. Apo-b5 (devoid of heme group) studies revealed the lack of involvement of the b5 heme in the fluorescence attenuation. A structural model of b5 with P450 17A1 was predicted using AlphaFold-Multimer algorithms/Rosetta docking, based upon the individual structures, which predicted several new contacts not previously reported, that is, interactions of b5 Glu-48:17A1 Arg-347, b5 Glu-49:17A1 Arg-449, b5 Asp-65:17A1 Arg-126, b5 Asp-65:17A1 Arg-125, and b5 Glu-61:17A1 Lys-91. Fluorescence polarization assays with two modified b5 variants yielded Kd values (for b5-P450 17A1) of 120 to 380 nM, the best estimate of binding affinity. We conclude that both monomeric and dimeric b5 can bind to P450 17A1 and stimulate activity. Results with the mutants indicate that several Lys residues in b5 are sensitive to the interaction with P450 17A1, including Lys-88 and Lys-91.

A Multipathway Phosphopeptide Standard for Rapid Phosphoproteomics Assay Development.

Recent advances in methodology have made phosphopeptide analysis a tractable problem for many proteomics researchers. There are now a wide variety of robust and accessible enrichment strategies to generate phosphoproteomes while free or inexpensive software tools for quantitation and site localization have simplified phosphoproteome analysis workflow tremendously. As a research group under the Association for Biomolecular Resource Facilities umbrella, the Proteomics Standards Research Group has worked to develop a multipathway phosphopeptide standard based on a mixture of heavy-labeled phosphopeptides designed to enable researchers to rapidly develop assays. This mixture contains 131 mass spectrometry vetted phosphopeptides specifically chosen to cover as many known biologically interesting phosphosites as possible from seven different signaling networks: AMPK signaling, death and apoptosis signaling, ErbB signaling, insulin/insulin-like growth factor-1 signaling, mTOR signaling, PI3K/AKT signaling, and stress (p38/SAPK/JNK) signaling. Here, we describe a characterization of this mixture spiked into a HeLa tryptic digest stimulated with both epidermal growth factor and insulin-like growth factor-1 to activate the MAPK and PI3K/AKT/mTOR pathways. We further demonstrate a comparison of phosphoproteomic profiling of HeLa performed independently in five labs using this phosphopeptide mixture with data-independent acquisition. Despite different experimental and instrumentation processes, we found that labs could produce reproducible, harmonized datasets by reporting measurements as ratios to the standard, while intensity measurements showed lower consistency between labs even after normalization. Our results suggest that widely available, biologically relevant phosphopeptide standards can act as a quantitative "yardstick" across laboratories and sample preparations enabling experimental designs larger than a single laboratory can perform. Raw data files are publicly available in the MassIVE dataset MSV000090564.

Racial and Ethnic Disparities in Operative Experience Among General Surgery Residents: A Multi-Institutional Study from the US ROPE Consortium.

OBJECTIVE: To determine the relationship between race/ethnicity and case volume among graduating surgical residents. BACKGROUND: Racial/ethnic minority individuals face barriers to entry and advancement in surgery; however, no large-scale investigations of the operative experience of racial/ethnic minority residents have been performed. METHODS: A multi-institutional retrospective analysis of the Accreditation Council for Graduate Medical Education case logs of categorical general surgery residents at 20 programs in the US Resident OPerative Experience Consortium database was performed. All residents graduating between 2010 and 2020 were included. The total, surgeon chief, surgeon junior, and teaching assistant case volumes were compared between racial/ethnic groups. RESULTS: The cohort included 1343 residents. There were 211 (15.7%) Asian, 65 (4.8%) Black, 73 (5.4%) Hispanic, 71 (5.3%) "Other" (Native American or Multiple Race), and 923 (68.7%) White residents. On adjusted analysis, Black residents performed 76 fewer total cases (95% CI, -109 to -43, P <0.001) and 69 fewer surgeon junior cases (-98 to -40, P <0.001) than White residents. Comparing adjusted total case volume by graduation year, both Black residents and White residents performed more cases over time; however, there was no difference in the rates of annual increase (10 versus 12 cases per year increase, respectively, P =0.769). Thus, differences in total case volume persisted over the study period. CONCLUSIONS: In this multi-institutional study, Black residents graduated with lower case volume than non-minority residents throughout the previous decade. Reduced operative learning opportunities may negatively impact professional advancement. Systemic interventions are needed to promote equitable operative experience and positive culture change.

Disparities in the Operative Experience Between Female and Male General Surgery Residents: A Multi-institutional Study From the US ROPE Consortium.

OBJECTIVE: To examine differences in resident operative experience between male and female general surgery residents. BACKGROUND: Despite increasing female representation in surgery, sex and gender disparities in residency experience continue to exist. The operative volume of male and female general surgery residents has not been compared on a multi-institutional level. METHODS: Demographic characteristics and case logs were obtained for categorical general surgery graduates between 2010 and 2020 from the US Resident OPerative Experience Consortium database. Univariable, multivariable, and linear regression analyses were performed to compare differences in operative experience between male and female residents. RESULTS: There were 1343 graduates from 20 Accreditation Council for Graduate Medical Education-accredited programs, and 476 (35%) were females. There were no differences in age, race/ethnicity, or proportion pursuing fellowship between groups. Female graduates were less likely to be high-volume residents (27% vs 36%, P < 0.01). On univariable analysis, female graduates performed fewer total cases than male graduates (1140 vs 1177, P < 0.01), largely due to a diminished surgeon junior experience (829 vs 863, P < 0.01). On adjusted multivariable analysis, female sex was negatively associated with being a high-volume resident (OR = 0.74, 95% CI: 0.56 to 0.98, P = 0.03). Over the 11-year study period, the annual total number of cases increased significantly for both groups, but female graduates (+16 cases/year) outpaced male graduates (+13 cases/year, P = 0.02). CONCLUSIONS: Female general surgery graduates performed significantly fewer cases than male graduates. Reassuringly, this gap in operative experience may be narrowing. Further interventions are warranted to promote equitable training opportunities that support and engage female residents.

Proliferative Glomerulonephritis With Hidden Monotypic IgG3κ Deposits: A Case Report.

Rare cases of immunoglobulin G (IgG)-dominant immune complex-mediated glomerulonephritis demonstrate immunoglobulin subclass restriction without light chain restriction. Some of these cases may represent proliferative glomerulonephritis with monotypic immunoglobulin deposits (PGNMID) in which monotypic immunoglobulin is obscured by coexisting polytypic immunoglobulin. However, rigorous demonstration of this possibility is lacking to date. Here, we describe a case of IgG3-restricted immune complex-mediated glomerulonephritis without light chain restriction that apparently "transformed" into IgG3κ-PGNMID in a subsequent biopsy. We demonstrate, using several ancillary techniques, including use of the newly described antibodies directed against the conformational epitope at the junctions of heavy and light chains (HLC-IF), that the first biopsy likely represents IgG3κ-PGNMID in which monotypic IgG3κ was hidden by polytypic IgM. This case underscores the need to consider PGNMID in a differential diagnosis of IgG-dominant immune complex-mediated glomerulonephritis without light chain restriction and highlights the potential utility of IgG subclass staining and HLC-IF in such cases to detect monotypic immunoglobulin that may be obscured by coexisting IgM and/or IgA deposits.

Association Between Health Insurance and Outcomes After Traumatic Brain Injury: A National ACS-TQP-PUF Database Study.

INTRODUCTION: According to the US Census Bureau, roughly 8.6% of the population lacks health care coverage. Increasing evidence suggests that insurance status plays a role in outcomes after trauma. However, its role in the setting of traumatic brain injury (TBI) remains poorly understood. METHODS: The Trauma Quality Programs Participant Use Files were queried from 2017 to 2019. All patients with isolated TBI were identified. Isolated TBI was defined as: 1) Head Abbreviated Injury Scale (AIS) > 3 and 2) AIS <3 in all other anatomical regions. Patients dead on arrival, with Head AIS = 6, or missing key data were excluded. Demographic and clinical information was compared between those with and without insurance. Multivariate regressions were used to assess associations between insurance status and TBI outcomes (inhospital mortality, discharge to facility, total ventilator days, Intensive Care Unit length of stay (ICU LOS), and hospital LOS). RESULTS: In total, 199,556 patients met inclusion criteria; 18,957 (9.5%) were uninsured. Compared to the insured, uninsured TBI patients were younger with a greater proportion of males. Uninsured patients were less severely injured and less comorbid. Uninsured patients had shorter unadjusted LOS in the ICU and hospital. Yet, uninsured patients experienced greater unadjusted inhospital mortality (12.7% versus 8.4%, P < 0.001). When controlling for covariates, lack of insurance was significantly associated with increased likelihood of mortality (OR 1.62; P < 0.001). This effect was most noticeable in patients with Head AIS = 4 (OR 1.55; P < 0.001) and Head AIS = 5 (OR 1.80; P < 0.001). Lack of insurance was also significantly associated with decreased likelihood of discharge to facility (OR 0.38), decreased ICU LOS (Coeff. -0.61), and decreased hospital LOS (Coeff. -0.82; all P < 0.001). CONCLUSIONS: This study demonstrates that insurance status is independently associated with outcome disparities after isolated TBI. Despite the Affordable Care Act (ACA) reform, lack of insurance appears significantly associated with inhospital mortality, decreased likelihood of discharge to facility, and decreased time spent in the ICU and hospital.

Hinduism.

Death is a universal experience. Regardless of one's culture, religion, race or beliefs, we will all die. Hinduism views death very uniquely. Hindus simultaneously mourn and celebrate the loss of loved ones.

Concomitant Orthopedic Injury is the Strongest Predictor of Amputation in Extremity Vascular Trauma.

BACKGROUND: Although the risk of extremity amputation related to an isolated vascular injury is low, it increases significantly with concomitant orthopedic injury. Our study aims to evaluate and quantify the impact of risk factors associated with trauma-related extremity amputation in patients with vascular injury. We sought to determine whether there are other potential predictors of amputation. METHODS: A retrospective review of patients with extremity vascular injury presenting to a single level 1 academic trauma center between January 1, 2007, and December 31, 2018, was performed. All patients diagnosed with major vascular injury to the upper or lower extremity were included. Data on patient demographics, medical comorbidities, anatomic location of vascular injury, and the presence of soft tissue or orthopedic injury were collected. The main outcome measure was major amputation of the affected extremity. Major amputation included below-the-knee amputation, above-the-knee amputation, as well as any amputation of the upper extremity at or proximal to the wrist. RESULTS: We identified 250 extremities with major vascular injury in 234 patients. Of these, 216 (86.4%) were male and 34 (13.6%) female. The mean age was 32.2 years (range 18-79 years) and mean follow-up was 6.9 (standard deviation: 3.3) years. Just over half of injuries, 130 (52.0%) involved the lower extremity. Forty extremities (29 lower and 11 upper), or 16.0%, of total injured extremities, required major amputation during the follow-up period. Concomitant orthopedic injury was present in 106 of 250 (42%) injured extremities. Using univariable logistic regression models, variables with a significant association with major amputation included older age, higher body mass index, blunt mechanism of injury, concomitant orthopedic injury, soft tissue injury, and nerve injury, and the need for fasciotomy (P < 0.05). In multivariable analyses, blunt mechanism of injury (odds ratio [OR] (confidence ratio {CI}): 6.51 (2.29, 18.46), P < 0.001) and concomitant orthopedic injury (OR [CI]: 7.23 [2.22, 23.55], P = 0.001) remained significant predictors of amputation. CONCLUSIONS: Concomitant orthopedic injury and blunt mechanism in the setting of vascular injury are associated with a higher likelihood of amputation in patients with extremity vascular injury. Further development of a vascular extremity injury protocol may be needed to enhance limb salvage. Findings may guide patient discussion regarding limb-salvage decision-making.

Polycystic Ovarian Syndrome among Young Women of a University in Central Gujarat - A Cross-sectional Study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common reproductive endocrinological disorders affecting 6%-8% of women in reproductive years. An early liberal PCOS screening appears to be a cost-effective strategy, benefiting earlier diagnosis and intervention. OBJECTIVES: The objectives are to measure the prevalence of PCOS and factors associated with PCOS among young girl students of a University in Central Gujarat. MATERIALS AND METHODS: All consenting girl medical students enrolled in MBBS curriculum during 2013-2017 were given a self-administered questionnaire (for signs and symptoms of PCOS), taking due prior permissions; during January 2018-June 2019. Using Rotterdam (2006) criteria, those who were screened for PCOS were subjected to abdominal ultrasonography (USG) and if required, laboratory investigations (random blood sugar, thyroid-stimulating hormone, and free testosterone). The proportion of young women having PCOS as per the Rotterdam and European Society for Human Reproduction and Embryology (EHSRE) Criteria are reported. RESULTS: The study enrolled 308 girl medical students. More than one-tenth of the study participants (11.7%, 36/308) had confirmed PCOS (Rotterdam Criteria). As per the EHSRE criteria, 24/36 had classic PCOS, 11/36 had ovulatory phenotype, and 01/36 had the non-hyperandrogenic phenotype PCOS. USG was required in 123/308 (39%); of which 91 consented and 16/91 (18%) had conclusive PCOS. Twenty-three girls required laboratory investigations, of which two had abnormal values suggestive of PCOS. Irregular menses and hirsutism were significantly associated with the PCOS (P < 0.05). CONCLUSION: The proportion of young medical students with PCOS was 12%. Irregular menses and hirsutism were significantly associated with PCOS.

Oral administration of TiO2 nanoparticles during early life impacts cardiac and neurobehavioral performance and metabolite profile in an age- and sex-related manner.

BACKGROUND: Nanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague-Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2-5, PND 7-10, or PND 17-20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses. RESULTS: Heart rate was found to be significantly decreased in female pups when dosed between PND 7-10 and PND 17-20. Females dosed between PND 2-5 showed decrease acoustic startle response and when dosed between PND 7-10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17-20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism. CONCLUSION: Oral administration of TiO2 NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO2 NP.

The common indoor air pollutant α-pinene is metabolised to a genotoxic metabolite α-pinene oxide.

α-Pinene caused a concentration-responsive increase in bladder hyperplasia and decrease in sperm counts in rodents following inhalation exposure. Additionally, it formed a prospective reactive metabolite, α-pinene oxide.To provide human relevant context for data generated in animal models and explore potential mechanism, we undertook studies to investigate the metabolism of α-pinene to α-pinene oxide and mutagenicity of α-pinene and α-pinene oxide.α-Pinene oxide was formed in rat and human microsomes and hepatocytes with some species differences. Based on area under the concentration versus time curves, the formation of α-pinene oxide was up to 4-fold higher in rats than in humans.While rat microsomes cleared α-pinene oxide faster than human microsomes, the clearance of α-pinene oxide in hepatocytes was similar between species.α-Pinene was not mutagenic with or without induced rat liver S9 in Salmonella typhimurium or Escherichia coli when tested up to 10 000 µg/plate while α-pinene oxide was mutagenic at ≥25 µg/plate.α-Pinene was metabolised to α-pinene oxide under the conditions of the bacterial mutation assay although the concentration was approximately 3-fold lower than the lowest α-pinene oxide concentration that was positive in the assay, potentially explaining the lack of mutagenicity observed with α-pinene.

Influence of TLR4 and TLR9 polymorphisms and haplotypes on multiple hrHPV infections and HPV16 copy number in cervical cancer and cervicitis.

Genetic polymorphism in pathogen recognition receptors tends to influence infection, disease susceptibility, and progression. We analyzed the association of TLR4 and TLR9 gene polymorphisms with multiple hrHPV infections and HPV16 copy number in cervicitis and cervical cancer. A total of 440 cervical cancer, cervicitis, and healthy individuals were studied using PCR-based assays. Student t-test, chi-square test, Welch's t-test, and Fisher's Exact test were utilized to evaluate the association of HPV infection with polymorphisms. Haploview and FAMHAP were used to analyze haplotype association with HPV infection and viral load. Study results revealed HPV45 infection as the most common one in cervical cancer after HPV16, and one-fourth HPV positive cervical cancer patients possessed multiple HPV infections. Mean HPV16 copy number of 264.4 ± 58.7 and 2.1 ± 3.3 copies/cell was detected in cervical cancer and cervicitis, respectively. TLR4 rs10759931 was protective against multiple hrHPV infections. TLR4 haplotype ACAC was associated with an increased risk of multiple hrHPV infections. TLR9 SNPs rs187084, rs352140, and rs352139 were associated with decreased risk of high HPV16 copy number. Augmentation of efforts for the multivalent HPV vaccination in India is suggested. The analyzed polymorphisms were shown to modulate hrHPV co-infections and HPV16 viral load that warrants further analysis.

Cancer Treatment Related Pain.

When discussing cancer treatment, it is important to be aware of the potential toxicities and side effects associated with these treatments.

Biodistribution, cardiac and neurobehavioral assessments, and neurotransmitter quantification in juvenile rats following oral administration of aluminum oxide nanoparticles.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10 mg/kg Al2 O3 NP (diameter: 24 nm [transmission electron microscope], hydrodynamic diameter: 148 nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

Disposition and metabolism of antibacterial agent, triclocarban, in rodents; a species and route comparison.

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85-86%; urine, 3-6%) with no apparent dose-related effect. In male rats, 29% of the administered dose was excreted in bile suggesting some of the fecal excretion is from the absorbed dose which was excreted to the intestine via bile. The tissue retention of radioactivity was low in male rats (24 h, 3.9%; 72 h, 0.1%). Disposition pattern following gavage administration of 50 mg/kg in female rats and male and female mice were similar to male rats. Plasma elimination half-life of triclocarban in rats following gavage administration was shorter (∼2 h) compared to that based on total radioactivity (≥9 h) which included all products of triclocarban. Absorption following a single dermal application of 1.5 or 3% was low (≤3%) in rodents. Hydroxylated and conjugated metabolites of triclocarban predominated in bile. In hepatocytes, clearance of triclocarban in mouse and human was similar and was faster than in rat.

Disposition and metabolism of sulfolane in Harlan Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans.

Sulfolane has been found as a ground water contaminant near refining sites. These studies investigated the in vitro hepatic clearance and in vivo disposition of [14C]sulfolane in rats and mice following a single oral administration (30, 100, or 300 mg/kg) and dermal application (100 mg/kg).[14C]Sulfolane was well-absorbed in male rats following oral administration and excreted extensively in urine (≥93%). Total radioactivity in tissues at 24 and 48 h was ∼7% and <2%. Disposition pattern was similar in female rats and male and female mice at 100 mg/kg oral dose.Dermally applied [14C]Sulfolane (covered dose site, 100 mg/kg) was poorly absorbed in male (∼16%) and female (∼19%) rats; absorption increased to 59% when the dose site was uncovered in male rats suggesting ingestion of dose via grooming of the dose site. Dermally applied [14C]sulfolane (100 mg/kg, covered dose site) was well absorbed in male (∼70%) and female (∼80%) mice.Urinary radiochemical profiles were similar between routes, species, and sexes; the main analytes present in urine were sulfolane and 3-hydroxysulfolane.Sulfolane was not cleared in hepatocytes from rodents or human suggesting sites other than liver might be involved in metabolism of sulfolane in vivo.

Impact of nonpharmacological interventions on COVID-19 transmission dynamics in India.

BACKGROUND: As of May 4, 2020, India has reported 42,836 confirmed cases and 1,389 deaths from COVID-19. India's multipronged response included nonpharmacological interventions (NPIs) like intensive case-based surveillance, expanding testing capacity, social distancing, health promotion, and progressive travel restrictions leading to a complete halt of international and domestic movements (lockdown). OBJECTIVES: We studied the impact of NPI on transmission dynamics of COVID-19 epidemic in India and estimated the minimum level of herd immunity required to halt it. METHODS: We plotted time distribution, estimated basic (R0) and time-dependent effective (Rt) reproduction numbers using software R, and calculated doubling time, the growth rate for confirmed cases from January 30 to May 4, 2020. Herd immunity was estimated using the latest Rtvalue. RESULTS: Time distribution showed a propagated epidemic with subexponential growth. Average growth rate, 21% in the beginning, reduced to 6% after an extended lockdown (May 3). Based on early transmission dynamics, R0was 2.38 (95% confidence interval [CI] =1.79-3.07). Early, unmitigated Rt= 2.51 (95% CI = 2.05-3.14) (March 15) reduced to 1.28 (95% CI = 1.22-1.32) and was 1.83 (95% CI = 1.71-1.93) at the end of lockdown Phase 1 (April 14) and 2 (May 3), respectively. Similarly, average early doubling time (4.3 days) (standard deviation [SD] = 1.86) increased to 5.4 days (SD = 1.03) and 10.9 days (SD = 2.19). Estimated minimum 621 million recoveries are required to halt COVID-19 spread if Rtremains below 2. CONCLUSION: India's early response, especially stringent lockdown, has slowed COVID-19 epidemic. Increased testing, intensive case-based surveillance and containment efforts, modulated movement restrictions while protecting the vulnerable population, and continuous monitoring of transmission dynamics should be a way forward in the absence of effective treatment, vaccine, and undetermined postinfection immunity.

Toxicokinetics and bioavailability of bisphenol AF following oral administration in rodents: A dose, species, and sex comparison.

We investigated the toxicokinetics and bioavailability of bisphenol AF (BPAF) in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following a single gavage administration of 34, 110, or 340 mg/kg. A validated analytical method was used to quantitate free (unconjugated parent) and total (unconjugated and conjugated) BPAF in plasma. BPAF was rapidly absorbed in rats with the maximum plasma concentration, Cmax, of free BPAF reached at ≤2.20 h. BPAF was cleared rapidly with a plasma elimination half-life of ≤3.35 h. Cmax and the area under the concentration versus time curve, AUC0-∞, increased proportionally to the dose. Total BPAF Cmax was reached ≤1.07 h in rats with both Cmax (≥27-fold) and AUC0-∞ (≥52-fold) much higher than corresponding free values demonstrating rapid and extensive conjugation of BPAF following oral administration. Absorption of BPAF following a 34 mg/kg gavage dose in mice was more rapid than in rats with free BPAF Cmax reached ≤0.455 h. Free BPAF was cleared rapidly in mice with an elimination half-life of ≤4.22 h. Similar to rats, total BPAF was much higher than corresponding free BPAF. There was no apparent sex-related effect in plasma toxicokinetic parameters of free or total BPAF in mice and rats. Bioavailability in rats was ~ 1% with no apparent dose-related effect. Bioavailability in mice was slightly higher than in rats (male ~ 6%, female 3%). These data demonstrate that BPAF was rapidly absorbed following gavage administration in rodents, rapidly and extensively conjugated with low bioavailability.