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Studies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated.We conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated.Using sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P.05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity.05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer.Our study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women.

BACKGROUND: Black Americans have the highest incidence of colorectal cancer (CRC) of any racial/ethnic group in the United States. High intake of red and processed meats has been associated with an increased CRC risk in predominately White populations. However, 3 prior studies in Black populations, who have been reported to have high intakes of red and processed meats, have reported no associations. Data on a possible association between CRC risk and SFAs and MUFAs, the primary types of fat in red and processed meats, are inconclusive. OBJECTIVES: We prospectively assessed intakes of processed and unprocessed red meat, SFAs, and MUFAs in relation to CRC risk, utilizing data from the Black Women's Health Study (BWHS, 1995–2018). METHODS: Dietary data were derived from validated FFQs completed in 1995 and 2001. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. RESULTS: Among 52,695 BWHS participants aged 21–69 y at baseline and followed for ≤22 y, 564 women developed incident CRC. Unprocessed red meat intake was associated with a 33% increased CRC risk per 100 g/d (HR: 1.33; 95% CI: 1.03–1.71). Examination of CRC anatomic sites revealed that unprocessed red meat was associated with 2-times increased rectal cancer risk (HR: 2.22; 95% CI: 1.15–4.26). There was no evidence of an interaction with age (p(interaction) = 0.4), but unprocessed red meat intake was only associated with a significant increased risk of late-onset CRC (≥50 y of age, HR: 1.41; 95% CI: 1.05–1.88). Processed red meat and total SFA and MUFA intakes were not associated with CRC risk. CONCLUSIONS: Unprocessed red meat intake was associated with an increased CRC risk in the present study, the first positive evidence that red meat plays a role in the etiology of CRC in Black women. The findings suggest prevention opportunities.

Background Studies in women of European descent showed an inverse association of dietary vitamin A (retinol and carotenoids) intake with breast cancer risks, mainly in premenopausal women. Objectives We examined whether higher compared with lower levels of dietary vitamin A are associated with reduced breast cancer risks among Black women by estrogen receptor (ER) and menopausal statuses. Methods In this pooled analysis, data were from 3564 breast cancer cases and 11,843 controls (mean ages = 56.4 and 56.3 years, respectively) in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Dietary intake was assessed by FFQs. Multivariable logistic regressions were performed to estimate ORs and 95% CIs for study-specific quintiles of total vitamin A equivalents and individual carotenoids, and a pooled OR was estimated by a random-effect model. Results We observed an inverse association of total vitamin A equivalents with ER-positive breast cancer (quintiles 5 compared with 1: pooled OR: 0.82; 95% CI: 0.67-1.00; P-trend = 0.045). The association was seen among premenopausal women (pooled OR: 0.60; 95% CI: 0.43-0.83; P-trend = 0.004), but not among postmenopausal women (pooled OR: 0.99; 95% CI: 0.77-1.28; P-trend = 0.78). Additionally, there were inverse associations of dietary β-carotene (quintiles 5 compared with 1: pooled OR: 0.70; 95% CI: 0.51-0.95; P-trend = 0.08) and lutein (pooled OR: 0.63; 95% CI: 0.45-0.87; P-trend = 0.020) with ER-positive breast cancer among premenopausal women. There was no evidence for an association of total vitamin A equivalents or individual carotenoids with ER-negative breast cancer, regardless of menopausal status. Conclusions Our findings on dietary vitamin A and breast cancer risks in Black women are consistent with observations in women of European descent and advance the literature showing an inverse association for ER-positive disease.

Background Angelman syndrome (AS) patients often respond to low glycemic index therapy to manage refractory seizures. These diets significantly affect quality of life and are challenging to implement. These formulations may have benefits in AS even in the absence of biomarkers suggesting ketosis. Objectives We aimed to compare an exogenous medical food ketone formulation (KF) with placebo for the dietary management of AS. Methods This randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in an academic center from 15 November, 2018 to 6 January, 2020. Thirteen participants with molecularly confirmed AS aged 4–11 y met the criteria and completed the 16-wk study. The study consisted of four 4-wk phases: a baseline phase, a blinded KF or placebo phase, a washout phase, and the crossover phase with alternate blinded KF or placebo. Primary outcomes were safety and tolerability rated by retention in the study and adherence to the formulation. Additional secondary outcomes of safety in this nonverbal population included blood chemistry, gastrointestinal health, seizure burden, cortical irritability, cognition, mobility, sleep, and developmental staging. Results Data were compared between the baseline, KF, and placebo epochs. One participant exited the trial owing to difficulty consuming the formulation. Adverse events included an increase in cholesterol in 1 subject when consuming KF and a decrease in albumin in 1 subject when consuming placebo. Stool consistency improved with KF consumption, from 6.04 ± 1.61 at baseline and 6.35 ± 1.55 during placebo to 4.54 ± 1.19 during KF (P = 0.0027). Electroencephalograph trends showed a decrease in Δ frequency power during the KF arm and event-related potentials suggested a change in the frontal memory response. Vineland-3 showed improved fine motor skills in the KF arm. Conclusions The exogenous KF appears safe. More data are needed to determine the utility of exogenous ketones as a nutritional approach in children with AS. This trial was registered at clinicaltrials.gov as NCT03644693.

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications.

N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.

Summary Background Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care. Methods We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation). Findings Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (–0·68% change in incidence per week [95% CI −1·37 to −0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care. Interpretation Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models. Funding None.

Context Evidence-based guidelines for active surveillance (AS), a treatment option for men with low-risk prostate cancer, recommend regular follow-up at periodic intervals to monitor disease progression. However, gaps in monitoring can lead to delayed detection of cancer progression, leading to a missed window of curability. Objective We aimed to identify the extent to which real-world observational studies reported adherence to monitoring protocols among prostate cancer patients on AS. When reported, we sought to characterize definitions of adherence. Evidence acquisition We systematically reviewed observational studies assessing outcomes of prostate cancer patients on AS, published before March 22, 2019 in PubMed, Embase, and CENTRAL. Adherence definitions were considered time bound if they included prespecified time and binary if adherence was assessed but did not specify a time interval. We assessed study quality using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Evidence synthesis Forty-five studies met our inclusion criteria. Eleven studies did not report any data on adherence to AS protocols. Twenty-five studies did not explicitly measure adherence, but provided relevant data (eg, number of patients who received a repeat biopsy). Six studies reported adherence using a time-bound definition, while three studies used a binary definition. Twenty-three studies provided information on patients lost to follow-up. Conclusions Most studies reporting outcomes of patients on AS did not measure or report adherence. When reported, adherence was often not time specific. As some AS patients will benefit from maintaining a window of curability, clinical practices and future studies should track and report adherence and associated factors. Patient summary We reviewed real-world observational studies examining outcomes of prostate cancer patients on active surveillance. Most studies did not clearly define or report adherence to monitoring protocols, which is important to consider for appropriate disease management.

Introduction Zolpidem has gained popularity as a pharmaceutical therapy for insomnia, being the most prescribed hypnotic in the United States today. However, it is associated with increased mortality and morbidity. Literature regarding zolpidem use in the total knee arthroplasty (TKA) population is limited. The aim of the study was to analyze postoperative zolpidem use in the TKA population regarding medical and implant complications, falls, and readmission. Methods The study group was queried according to zolpidem use. Controls consisted of patients who underwent primary TKA without a history of hypnotic drug use. Study group patients were matched to controls in a 1:5 ratio by demographics and comorbidities. Results yielded 99,178 study participants and 495,795 controls. Primary endpoints included 90-day medical and implant complications, fall risk, and readmission. Chi-squared test was used to compare categorical variables. Multivariate logistic regression was used to calculate odds (OR) for complications, fall risk, and readmission. A P value less than 0.05 was considered statistically significant. Results Study group patients had increased odds of medical complications (OR: 1.76, 95% CI: 1.71-1.82, P Conclusion Zolpidem use following primary TKA is associated with the risk of morbidity and falls. The findings are consistent with the literature regarding zolpidem. These findings may affect discussion between orthopedic surgeons and patients in the decision-making process prior to undergoing TKA.

Pigmented villonodular synovitis (PVNS) is a condition affecting larger joints such as the hip and knee. Little is known regarding the impact of PVNS on total hip arthroplasty (THA). Therefore, the aim of this study is to determine if patients with PVNS of the hip undergoing primary THA experience greater (1) in-hospital lengths of stay (LOS); (2) complications; (3) readmission rates; and (4) costs.Patients undergoing primary THA for PVNS of the hip from the years 2005 to 2014 were identified using a nationwide claims registry. PVNS patients were matched to a control cohort in a 1:5 ratio by age, gender, and various comorbidities. The query yielded 7440 patients with (n = 1240) and without (n = 6200) PVNS of the hip undergoing primary THA. Endpoints analyzed included LOS, complications, readmission rates, and costs. Multivariate logistic regression was used to determine odds ratios (OR) of developing complications. Welch's t-tests were used to test for significance in LOS and cost between the cohorts. A P-value less than .001 was considered statistically significant.PVNS patients had approximately 8% longer in-hospital LOS (3.8 vs 3.5 days, P = .0006). PVNS patients had greater odds of (OR 1.60, P.0001) medical and (OR 1.81, P.0001) implant-related complications. Furthermore, PVNS patients were found to have higher odds (OR 1.84, P.0001) of 90-day readmissions. PVNS patients also incurred higher day of surgery ($13,119 vs $11,983, P.0001) and 90-day costs ($17,169 vs $15,097, P.0001).Without controlling for global trends in LOS, complications, readmissions, or costs between 2005 and 2014, the findings of the study suggest that PVNS of the hip is associated with worse outcomes and higher costs following primary THA. The study is useful as orthopedic surgeons can use the study to educate patients of the complications which may occur following their hip surgery.

To prospectively validate electromagnetic hand motion tracking in interventional radiology to detect differences in operator experience using simulation.Sheath task: Six attending interventional radiologists (experts) and 6 radiology trainees (trainees) placed a wire through a sheath and performed a "pin-pull" maneuver, while an electromagnetic motion detection system recorded the hand motion. Radial task: Eight experts and 12 trainees performed palpatory radial artery access task on a radial access simulator. The trainees repeated the task with the nondominant hand. The experts were classified by their most frequent radial artery access technique as having either palpatory, ultrasound, or overall limited experience. The time, path length, and number of movements were calculated. Mann-Whitney U tests were used to compare the groups, and P.05 was considered significant.Sheath task: The experts took less time, had shorter path lengths, and used fewer movements than the trainees (11.7 seconds ± 3.3 vs 19.7 seconds ± 6.5, P.01; 1.1 m ± 0.3 vs 1.4 m ± 0.4, P.01; and 19.5 movements ± 8.5 vs 31.0 movements ± 8.0, P.01, respectively). Radial task: The experts took less time, had shorter path lengths, and used fewer movements than the trainees (24.2 seconds ± 10.6 vs 33.1 seconds ± 16.9, P.01; 2.0 m ± 0.5 vs 3.0 m ± 1.9, P.001; and 36.5 movements ± 15.0 vs 54.5 movements ± 28.0, P.001, respectively). The trainees had a shorter path length for their dominant hand than their nondominant hand (3.0 m ± 1.9 vs 3.5 m ± 1.9, P.05). The expert palpatory group had a shorter path length than the ultrasound and limited experience groups (1.8 m ± 0.4 vs 2.0 m ± 0.4 and 2.3 m ± 1.2, respectively, P.05).Electromagnetic hand motion tracking can differentiate between the expert and trainee operators for simulated interventional tasks.

Antimicrobial resistance (AMR) threatens human and ecological health worldwide. Unless major changes occur across the human, animal and environmental sectors, the problem will continue to expand. An important component of AMR that deserves greater attention is the influence of emerging organic contaminants (EOCs) – ubiquitous compounds found, amongst others, in pharmaceuticals, personal care products, food, industrial and agricultural products, plastics and building materials. EOCs are widely used and can accumulate in the environment from varied sources, predominantly via waste streams. EOCs can interact with microbial communities potentially leading to the emergence and spread of AMR. Biocides and pharmaceuticals have been demonstrated to promote AMR development. Antimicrobial resistance is a multi-faceted problem that requires input from all sectors, with robust strategies and policies needed to make headway with solving the issues of this important threat.

BACKGROUND: Yogurt consumption and low-fat dairy consumption have been associated with reduced incidence of type 2 diabetes (T2D) in some studies. OBJECTIVE: We assessed the relation of yogurt and other dairy consumption to incidence of T2D in black women, a population group with a disproportionately high incidence of T2D. METHODS: The Black Women's Health Study has followed 59,000 US black women since 1995 through biennial questionnaires which update health information. Each questionnaire inquired about doctor-diagnosed diabetes in the previous 2 y. FFQs completed by participants in 1995 and 2001 provided information on yogurt and other dietary intake. HRs with 95% CIs for yogurt (nonfrozen or frozen) and other dairy consumption in relation to incident T2D (n = 8061 cases) were estimated with Cox proportional hazards regression, controlling for risk factors for T2D. RESULTS: The HR for consumption of ≥1 serving of yogurt/d relative to

Introduction Placental mitochondrial dysfunction contributes to the oxidative stress that underlies preeclampsia. Here, we assessed whether sulforaphane (SFN) could improve syncytiotrophoblast mitochondrial function after in vitro hypoxic and superoxide injury. Methods Placental cytotrophoblasts were isolated from healthy term placentae (n = 12) and incubated for 48 h in 8% O2 ± 1 μM SFN before acute (4hrs) or chronic (24hrs) hypoxic (1% O2), or superoxide (xanthine/xanthine oxidase) injury. Cytotrophoblasts were also isolated from preeclamptic placentae (n = 5) and cultured in 8% O2 ± 1 μM SFN. Mitochondrial respiration was measured using the Seahorse MitoStress XF assay. Cells were stained with mitotracker red to assess mitochondrial membrane health and mitochondrial gene expression assessed using RT-qPCR. Results SFN prevented significant reductions in syncytiotrophoblast mitochondrial maximal respiration, spare respiratory capacity, basal respiration and ATP production following acute hypoxia. Chronic hypoxia only reduced maximal and spare respiratory capacity. SFN prevented these negative changes and increased respiration overall. Alternatively, acute superoxide injury significantly increased mitochondrial maximal respiration and spare respiratory capacity. SFN treatment further increased basal respiration following superoxide injury and prevented significant decreases in ATP production and coupling efficiency. In preeclamptic placentae, SFN significantly increased mitochondrial maximal respiration, spare respiratory capacity, basal respiration and ATP production, and decreased proton leak. SFN up-regulated mRNA expression of mitochondrial complexes and corrected an up-regulation in fission gene expression observed after hypoxic-superoxide injury. Finally, preliminary results suggest SFN prevented hypoxia-induced impairment of mitochondrial membrane structure. Discussion SFN mitigated hypoxia and superoxide induced changes to syncytiotrophoblast mitochondrial function in vitro, and improved mitochondrial respiration in trophoblast cells from preeclamptic placentae.

BackgroundCOVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain.ObjectiveThe aim of this study was to investigate the sociodemographic characteristics associated with vaccine uptake in Melbourne, Australia, and to compare perinatal outcomes by vaccination status.Study designRetrospective multicenter cohort study in Melbourne following the national recommendations for mRNA COVID-19 vaccination during pregnancy in June 2021. Routinely collected data from all 12 public maternity hospitals in Melbourne were extracted on births ≥ 20 weeks’ gestation from 1st July 2021 to 31 March 2022. Maternal sociodemographic characteristics were analyzed from the total birth cohort. Perinatal outcomes were compared between vaccinated and unvaccinated women for whom weeks 20-43 of gestation fell entirely within the 9-month data collection period. The primary outcome was the rate of congenital anomaly in singleton infants ≥ 20 weeks’ gestation among women vaccinated during pregnancy. Secondary perinatal outcomes including stillbirth, preterm birth (spontaneous and iatrogenic), birthweight ≤ 3rd centile, and newborn intensive care unit admissions were examined for singleton infants ≥ 24 weeks’ gestation without congenital anomalies. We calculated the adjusted odds ratio of congenital anomalies and perinatal outcomes among vaccinated versus unvaccinated women using inverse propensity score weighting regression adjustment with multiple covariates; p< 0.05 was considered statistically significant.ResultsBirths from 32,536 women were analyzed: 17,365 (53.4%) were vaccinated and 15,171 (47.6%) were unvaccinated. Vaccinated women were significantly more likely to be older, nulliparous, non-smoking, not requiring an interpreter, of higher socioeconomic status, and vaccinated against pertussis and influenza. Vaccination status also varied by region of birth: compared with women born in Australia, women born in South and Eastern Europe, the Middle East, Africa and Oceania had lower adjusted odds of vaccination. There was no significant increase in the rate of congenital anomalies or birth weight ≤ 3rd centile in vaccinated women. Vaccinated women were significantly less like to have an infant with a major congenital anomaly compared with the unvaccinated group (2.4% vs 3.0%, aOR 0.72, 95%CI 0.56-0.94, p=0.02). This finding remained significant even when the analysis was restricted to women vaccinated before 20 weeks’ gestation. Vaccinated women had a significantly lower rate of stillbirth (0.2% vs 0.8%, aOR 0.18, 95%CI 0.09-0.37, P < 0.001. Vaccination was associated with a significant reduction in total preterm births < 37 weeks (5.1% vs 9.2%, aOR 0.60, 95% CI 0.51-0.71, p< 0.001), spontaneous preterm birth (2.4% vs 4.0%, aOR 0.73 95% CI 0.56-0.96, p=0.02) and iatrogenic preterm birth (2.7% vs 5.2%, aOR 0.52, 95%CI 0.41-0.65, p< 0.001).ConclusionsCOVID-19 Vaccine coverage was significantly influenced by known social determinants of health, which is likely to influence the strong association between COVID-19 vaccination and lower risks of stillbirth and preterm birth. We did not observe any adverse impacts of vaccination on fetal growth or development.AT A GLANCEWhy was this study conducted?⍰COVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain.⍰Most of the published literature on COVID-19 vaccination in pregnancy have methodological limitations including fixed cohort bias and time-varying exposure.⍰We conducted this multicenter study to provide robust evidence on mRNA COVID-19 vaccination and perinatal outcomes including congenital anomalies, stillbirth, and preterm birth.What are the key findings?⍰The adjusted odds of stillbirth, preterm birth, and neonatal intensive care admission were significantly reduced among infants born to COVID-19 vaccinated women compared with unvaccinated women. COVID-19 vaccination during pregnancy was not associated with an increase in congenital anomalies.⍰Our results conclusively demonstrate a significant reduction in both spontaneous and iatrogenic preterm birth for vaccinated women⍰Vaccinated women were significantly more likely to be older, nulliparous, non-smoking, not requiring an interpreter, residing in a higher socioeconomic postcode, and vaccinated against pertussis and influenza. There were also significant differences in vaccination rates by region of birth.What does this study add to what is already known?⍰Our analysis confirmed a strong relationship between the COVID-19 mRNA vaccine and lower preterm births and stillbirths⍰In addition to its impact on reducing severe COVID-19 illness, vaccination may be a proxy for other biological and social determinants of health among our pregnant population.

Infection during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The impact of maternal SARS-CoV-2 infection on infant neurodevelopment is poorly understood. The maternal immune response to infection may be mimicked in rodent models of maternal immune activation which recapitulate altered neurodevelopment and behavioural disturbances in the offspring. In these models, epigenetic mechanisms, in particular DNA methylation, are one pathway through which this risk is conferredDNA was extracted from buccal swab specimens from (n = 4) SARS-CoV-21962 hypermethylated CpG sites were identified with an unadjusted p-value of 0.05, where 1133 CpGs mapped to 959 unique protein coding genes, and 716 hypomethylated CpG sites mapped to 559 unique protein coding genes in SARS-CoV-2 exposed infants compared to non-exposed. One differentially methylated position (cg06758191), located in the gene body of AFAP1 that was hypomethylated in the SARS-CoV-2 exposed cohort was significant after correction for multiple testing (FDR-adjusted p-value0.00083). Two significant differentially methylated regions were identified; a hypomethylated intergenic region located in chromosome 6p proximal to the genes ZP57 and HLA-F (fwer0.004), and a hypomethylated region in the promoter and body of the gene GAREM2 (fwer0.036). Gene network enrichment analysis revealed differential methylation in genes corresponding to pathways relevant to neurodevelopment, including the ERBB pathway.These pilot data suggest that exposure to SARS-CoV-2

Background Universal screening has been proposed as a strategy to identify asymptomatic individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mitigate transmission. Aim To investigate the rate of positive tests among pregnant women in Melbourne, Australia. Methods We performed a cross-sectional prevalence study at three maternity hospitals (one tertiary referral hospital and two secondary maternities) in Melbourne, Australia. SARS-CoV-2 testing was offered to all pregnant women attending face-to-face antenatal visits and to those attending the hospital with symptoms of possible coronavirus disease, between 6th and 19th of May 2020. Testing was performed by multiplex-tandem polymerase chain reaction (PCR) on combined oropharyngeal and nasopharyngeal swabs. The primary outcome was the proportion of positive SARS-CoV-2 tests. Findings SARS-CoV-2 testing was performed in 350 women, of whom 19 had symptoms of possible COVID-19. The median maternal age was 32 years (IQR 28–35 years), and the median gestational age at testing was 33 weeks and four days (IQR 28 weeks to 36 weeks and two days). All 350 tests returned negative results (p = 0%, 95% CI 0–1.0%). Conclusion In a two-week period of low disease prevalence, the rate of asymptomatic coronavirus infection among pregnant women in Australia during the study period was negligible, reflecting low levels of community transmission.

Background Compared to U.S. white women, African American women are more likely to die from ductal carcinoma in situ (DCIS). Elucidation of risk factors for DCIS in African American women may provide opportunities for risk reduction. Methods We used data from three epidemiologic studies in the African American Breast Cancer Epidemiology and Risk Consortium to study risk factors for estrogen receptor (ER) positive DCIS (488 cases; 13,830 controls). Results were compared to associations observed for ER+ invasive breast cancer (n = 2,099). Results First degree family history of breast cancer was associated with increased risk of ER+ DCIS [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.31, 2.17]. Oral contraceptive use within the past 10 years (vs. never) was also associated with increased risk (OR: 1.43, 95%CI: 1.03, 1.97), as was late age at first birth (≥25 years vs., Highlights • Few studies of risk factors for ductal carcinoma in situ (DCIS) have evaluated associations for African American women. • We analyzed data from the African American African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. • Family history of breast cancer, reproductive factors, and anthropometric factors were associated with risk of ER+ DCIS. • In general, risk factor associations for ER+ DCIS were similar to those for ER+ invasive breast cancer. • Our findings support a common etiology and pathogenesis between ER+ DICS and ER+ invasive cancer in African American women.

Current inactivated polio vaccine (IPV) products are sensitive to both freezing and elevated temperatures and therefore must be shipped and stored between 2 °C and 8 °C, a requirement that imposes financial and logistical challenges for global distribution. As such, there is a critical need for a robust, thermally stable IPV to support global polio eradication and post-eradication immunization needs. Here, we present the development of air-dried thin films for temperature stabilization of IPV using the biomaterial silk fibroin. Thin-film product compositions were optimized for physical properties as well as poliovirus D-antigen recovery and were tested under accelerated and real-time stability storage conditions. Silk fibroin IPV films maintained 70% D-antigen potency after storage for nearly three years at room temperature, and greater than 50% potency for IPV-2 and IPV-3 serotypes at 45 °C for one year. The immunogenicity of silk fibroin IPV films after 2-week storage at 45 °C was assessed in Wistar rats and the stressed films generated equivalent neutralizing antibody responses to commercial vaccine for IPV-1 and IPV-2. However, the absence of IPV-3 responses warrants further investigation into the specificity of ELISA for intact IPV-3 D-antigen. By demonstrating immunogenicity post-storage, we offer the air-dried silk film format as a means to increase IPV vaccine access through innovative delivery systems such as microneedles.

Background/Objectives Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. Methods Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. Results Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2–7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. Conclusions Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.

Introduction Partial thickness rotator cuff tears (PTRCT) are a common injury reported in 13–32% of the population, yet most of the current literature focuses on full thickness rotator cuff tears. Therefore, the purpose of this study was to analyze trends among patients with PTRCT including: (1) demographics; (2) comorbidities; (3) cost of care; (4) setting of initial diagnosis; and (5) change in incidence of PTRCT or surgical approach over time. Methods A Medicare patient-population consisting of 44 million lives was retrospectively analyzed from 2007 to 2017 using International Classification of Disease, 9th Revision (ICD-9) codes. Patients were identified for PTRCT using ICD-9 code: 726.13. The query yielded a total of 44,978 patients all of which had been previously diagnosed with PTRCT. Primary trends analyzed included: demographics, comorbidities, cost of care, initial setting of diagnosis, and change in incidence of PTRCT or surgical approach over time. Results PTRCTs and surgical repair of PTRCTs were most common in patients ages 65 to 69 and least common in patients who were 85 and older. Incidence of PTRCT was greater in females (54.12%) than males (45.88%). Comorbidities found within the population included hypertension, hyperlipidemia, diabetes mellitus, tobacco use, obesity, rheumatoid arthritis, and osteoarthritis of the shoulder. The average cost per episode of care totaled $9,923.26. PTRCTs were most commonly diagnosed in patients who resided in assisted living facilities (n = 27,106), making up 60% of the patient population. Reported incidence of PTRCT has increased substantially along with the surgical repair of PTRCT. Conclusion Reported cases of PTRCT and its surgical repair have both increased substantially over time. Approximately 11.70% of patients with PTRCT undergo either open or arthroscopic procedure as a means of surgical repair. With the growing popularity of arthroscopic procedures for rotator cuff repair, further investigation should be performed to analyze trends and risk factors for PTRCT, a seemingly underrepresented orthopedic condition.

Introduction Prolific collateralization in the venous system has been associated with more severe disease. However, there is a scarcity of information on venogenesis and collateral vessel progression over time. Further, little is understood regarding the relevance of the most common preclinical model—the mouse—for studying venous collateralization. The purpose of this work was to non-invasively and quantitatively characterize collateral vein development and progression in two murine models of deep vein thrombosis using magnetic resonance imaging (MRI). Methods Venous thrombosis (VT) was induced in 12–14-week-old male C57BL/6 mice using either the inferior vena cava (IVC) ligation model (n = 5) or the electrolytic IVC model (n = 5). Magnetic Resonance Imaging (MRI) methods optimized for small venous imaging were used on days 2, 6, 14, and 21 following venous thrombosis induction to quantify collateral development and thrombus volume. Results Collateral veins ~150–200 μm in diameter could be tracked in three dimensions. Collateral pathways were influenced by pre-existing anatomy; mice with bilateral IVC branches showed a predominant superficial collateral pathway (superficial and internal epigastric veins), whereas mice with no lateral branches exhibited a strong intermediate collateral pathway (gonadal and periureteric veins) and were less likely to develop ascending lumbar collaterals. The degree of venogenesis showed a positive correlation with thrombus volume in both models (combined R2 = 0.64, p Conclusions Venous collateral pathways in C57BL/6 mice are consistent with those described in humans. Collateral pathways are influenced by pre-existing anatomy, and the degree of collateralization correlates with thrombus volume.

INTRODUCTION: The study evaluated whether sleep apnea (SA) patients undergoing total shoulder arthroplasty (TSA) are at greater odds of: 1) medical complications; 2) implant-related complications; 3) readmission rates; and 4) costs. METHODS: Complications and readmissions were assessed using logistic regression analysis. Welch's t-test was used to compare CCI and cost between cohorts. RESULTS: 33,366 patients equally distributed in both cohorts. SA increased the odds of medical [Odds-ratio (OR)]: 2.52, p

Murine models are widely used valuable tools to study deep vein thrombosis. Leading experts in venous thrombosis research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of venous thrombosis. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of venous thrombosis. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.

The COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many regions around the world. Melbourne, Australia, had one of the longest and most stringent lockdowns worldwide in 2020 while recording only rare instances of COVID-19 infection in pregnant women.This study aimed to compare the stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy.This was a retrospective, multicenter cohort study of perinatal outcomes in Melbourne before and during the COVID-19 lockdown. The lockdown period was defined as the period from March 23, 2020 to March 14, 2021. Routinely-collected maternity data on singleton pregnancies ≥24 weeks gestation without congenital anomalies were obtained from all the 12 public hospitals in Melbourne. We defined the lockdown-exposed cohort as those women for whom weeks 20 to 40 of gestation occurred during the lockdown and the unexposed control group as women from the corresponding calendar periods 12 and 24 months before. The main outcome measures were stillbirth, preterm birth, fetal growth restriction (birthweightthird centile), and iatrogenic preterm birth for fetal compromise. We performed multivariable logistic regression analysis to compare the odds of stillbirth, preterm birth, fetal growth restriction, and iatrogenic preterm birth for fetal compromise, adjusting for multiple covariates.There were 24,817 births in the exposed group and 50,017 births in the control group. There was a significantly higher risk of preterm stillbirth in the exposed group than the control group (0.26% vs 0.18%; adjusted odds ratio, 1.49; 95% confidence interval, 1.08-2.05; P=.015). There was also a significant reduction in the preterm birth of live infants37 weeks (5.68% vs 6.07%; adjusted odds ratio, 0.93; 95% confidence interval, 0.87-0.99; P=.02), which was largely mediated by a significant reduction in iatrogenic preterm birth (3.01% vs 3.27%; adjusted odds ratio, 0.91; 95% confidence interval, 0.83-0.99; P=.03), including iatrogenic preterm birth for fetal compromise (1.25% vs 1.51%; adjusted odds ratio, 0.82; 95% confidence interval, 0.71-0.93; P=.003). There were also significant reductions in special care nursery admissions during lockdown (11.53% vs 12.51%; adjusted odds ratio, 0.90; 95% confidence interval, 0.86-0.95; P.0001). There was a trend to fewer spontaneous preterm births37 weeks in the exposed group of a similar magnitude to that reported in other countries (2.69% vs 2.82%; adjusted odds ratio, 0.95; 95% confidence interval, 0.87-1.05; P=.32).Lockdown restrictions in Melbourne, Australia were associated with a significant reduction in iatrogenic preterm birth for fetal compromise and a significant increase in preterm stillbirths. This raises concerns that pandemic conditions in 2020 may have led to a failure to identify and appropriately care for pregnant women at an increased risk of antepartum stillbirth. Further research is required to understand the relationship between these 2 findings and to inform our ongoing responses to the pandemic.

Background: Intramuscular (IM) oxytocin for postpartum haemorrhage (PPH) prevention in resource-poor settings is limited by the need for cold-chain storage and skilled staff for safe injection. We compared the pharmacokinetics (PK) and safety of heat-stable oxytocin inhaled (IH) versus IM administration in women during third stage of labour (TSL). Methods: The phase 1, randomised, open-label clinical study (NCT02999100) was conducted across three centres in the UK and Australia. Participants (Group 1, women in TSL; Group 2, non-pregnant women of childbearing potential) were randomised 1:1 via validated GSK internal software: Group 1, oxytocin 240 IU (400 μg) IH or oxytocin 10 IU (17 μg) IM immediately after delivery; Group 2, intravenous (IV) oxytocin 5 IU (8·5 μg) and oxytocin 240 IU (400 μg) IH at two separate dosing sessions in a cross-over design. Primary endpoints included characterising oxytocin IH PK. The safety population included patients who received ≥1 dose; any PK sample obtained and analysed was included in the PK population. Additional investigations explored the validity of the PK concentration data. Findings: Participants were recruited between November 2016 and March 2019. In Group 1, 29 participants were randomised; 17 received IH (n=9) or IM (n=8) oxytocin. After IH and IM administration most plasma oxytocin concentrations were below quantification limits (2 pg/ml). In Group 2 (n=14), oxytocin IH concentrations remained quantifiable up to 3 hrs post dose. Adverse events were reported for: Group 1, IH n=3 (33%) and IM n=2 (25%); Group 2, n=14 (100%). No deaths were reported. Interpretation: Safety profiles of oxytocin IH and IM were similar; PK profiles could not be defined for oxytocin IH or IM in women in TSL, despite using a highly sensitive assay. Ex vivo investigations suggested oxytocin metabolism occurred in vivo and not during sample collection and processing. Trial Registration: Trial Registration Number, (ClinicalTrials.gov: NCT02999100). The study protocol can be found online (https://clinicaltrials.gov/ProvidedDocs/00/NCT02999100/Prot_000.pdf). Funding: GlaxoSmithKline (GSK 205920; NCT02999100) Declaration of Interest: KG-K, AS-C, KRP, PL, TN, JM, CG, CK and VLO have no conflicts to declare. SK, AC, RAG, SP, IS, AS, KH, MP, ME and SS are employees of and hold stocks in GSK. MPM is an inventor on the patent method and formulation for oxytocin inhalation (WO2013/016754 A1 [PCT/AU2011001430]). Ethical Approval: The study protocol was reviewed and approved by the Office for Research Ethics Committees of Northern Ireland (UK) and the Monash Health Human Research Ethics Committee (Australia) in accordance with Good Clinical Practice (GCP) guidelines.

The large-scale, high-grade Sn ores and the Cu-Sn metal association in the volcanic massive sulfide (VMS) ores in Neves Corvo are unique among VMS deposits, not only in the Iberian Pyrite Belt but also worldwide. Thus, the exceptional nature of the Neves Corvo deposit calls for unusual metallogenic processes. Previous efforts to constrain these processes have been hampered by a lack of high precision ages for the mineralization. This has led to a debate as to whether tin mineralization occurred at the same time as the associated volcanism and VMS-style mineralization, or is the result of later processes events associated with the Hercynian orogeny. We report in-situ U-Pb dating results of hydrothermal cassiterite and sulfur isotopic compositions of sulfides in the Neves Corvo deposit that place tight constraints on the timing of mineralization and on the origin of the hydrothermal ore-forming fluids. The cassiterite samples yield U-Pb ages of the Sn mineralization of 363–366 Ma; identical to the age of the host volcanic rocks. δ34S values range from −32.3‰ to +17.4‰ among the different VMS ore types and are largely consistent with microbiological reduction of seawater sulfate, but with some positive values resulting from thermochemical sulfate reduction. In contrast, the Sn-rich ores have a limited range in δ34S that clusters near 0‰, which suggests derivation from magmatic fluids. Hence, the unusually high Sn grades at the Neves Corvo deposit are interpreted to be derived from fluids exsolved from a hidden granitic source essentially synchronous with formation of the volcanic rocks and VMS mineralization.

Tourmaline often occurs in boron-rich granites and its genesis is still in dispute either formed from residual boron-rich silicate melt or from magmatic hydrothermal fluids with or without external fluid involvement. Here, we present a systematic investigation of in-situ major, trace elemental and boron isotopic variations of tourmaline from the Sanfang granite in Guangxi Province of South China, which demonstrate both the magmatic and hydrothermal origin for the formation of the tourmalines. The tourmaline occurs mainly in quartz-tourmaline nodules and tourmaline pegmatitic segregations within the Sanfang granite. Four types of tourmaline are identified: (1) isolated and disseminated tourmaline (Tur-D type) distributed in granite; (2) euhedral and subhedral tourmaline in quartz-tourmaline nodules (Tur-N type); (3) the earlier stage tourmaline (Tur-PE type) in pegmatitic segregations and (4) the later stage tourmaline (Tur-PL type) which replaced the Tur-PE type tourmaline in pegmatitic segregations. All the tourmalines belong to the alkali group representing dravite-schorl solid solution series with the former three types being schorl and the Tur-PL type being dravite. Petrography, chemical discrimination diagrams and Al occupations in the Y-site suggest that the Tur-D, Tur-N and Tur-PE type tourmalines are of magmatic origin and the Tur-PL type tourmalines are of hydrothermal fluid origin. Elemental and boron isotopic composition variations of tourmalines reflect the compositional and environmental evolution from late boron-rich magma to exsolved hydrothermal fluids. Chemical variations from the Tur-D to the Tur-N tourmalines are controlled by magma differentiation. The increase of Mg/(Mg + Fe) and Ca/(Ca + Na) ratios from the Tur-N to the Tur-PE tourmalines suggests the contamination of surrounding strata (e.g. the Sibao Group). Hydrothermal tourmalines have higher Mg/(Mg + Fe) and lower Na/(Na + Ca) ratios than the magmatic tourmalines. There is clear correlation at least in some trace elements (e.g. Sr, Pb) with major elements for all tourmalines, indicating the potential crystal chemical effects on their incorporation. Other trace element incorporation in tourmaline is largely controlled by melt and fluid composition. Hydrothermal tourmalines have high and stable V, Co and Ni contents, indicating relatively constant partition coefficient between hydrothermal tourmalines and the fluid. Hydrothermal tourmalines exhibit lower total REE contents but more pronounced positive Eu anomalies than the magmatic tourmalines. The δ11B values of all tourmalines from the Sanfang granite vary from −14.4‰ to −9.3‰, which indicate the boron in the Sanfang granite was mainly derived from partial melting of the metasedimentary source rocks. Boron isotopic variations of tourmaline are controlled by fractionation between melt-fluid and Rayleigh fractionation.

Land cover change is a pervasive force and it influences the relationship between precipitation (P) and actual evapotranspiration (AET). The study sought to determine variations in catchment scale AET attributable to land cover change over a grassland in the Eastern Cape, South Africa. Remotely sensed rainfall and AET data were used. Land cover maps for the study area were used to extract annual AET from the MOD16 ET product. The method of cumulative residuals was applied to link dynamics in AET with land cover change to enable the application of an appropriate map for retrieving AET. Rainfall and AET were subjected to the Mann- Kendall and Pettitt's tests. Grassland and built-up cover classes AET showed step changes (p

We present sediment pore fluid and sediment solid phase results obtained during IODP Expedition 340 from seven sites located within the Grenada Basin of the southern Lesser Antilles Volcanic Arc region. These sites are generally characterized as being low in organic carbon content and rich in calcium carbonate and volcanogenic material. In addition to the typical reactions related to organic matter diagenesis, pore fluid chemistry indicates that the diagenetic reactions fall within two broad categories; (1) reactions related to chemical exchange with volcanogenic material and (2) reactions related to carbonate dissolution, precipitation, or recrystallization. For locations dominated by reaction with volcanogenic material, these sites exhibit increases in dissolved Ca with coeval decreases in Mg. We interpret this behavior as being driven by sediment-water exchange reactions from the alteration of volcanic material that is dispersed throughout the sediment package, which likely result in formation of Mg-rich secondary authigenic clays. In contrast to this behavior, sediment sequences that exhibit decreases in Ca, Mg, Mn, and Sr with depth suggest that carbonate precipitation is an active diagenetic process affecting solute distributions. The distributions of pore fluid 87Sr /86Sr reflect these competitive diagenetic reactions between volcanic material and carbonate, which are inferred by the major cation distributions. From one site where we have solid phase 87Sr /86Sr (site U1396), the carbonate fraction is found to be generally consistent with the contemporaneous seawater isotope values. However, the 87Sr /86Sr of the non-carbonate fraction ranges from 0.7074 to 0.7052, and these values likely represent a mixture of local arc volcanic sources and trans-Atlantic eolian sources. Even at this site where there is clear evidence for diagenesis of volcanogenic material, carbonate diagenesis appears to buffer pore fluid 87Sr /86Sr from the larger changes that might be expected given the high abundance of tephra in these sediments. Part of this carbonate buffering, at this site as well as throughout the region, derives from the fact that the Sr concentration in the non-carbonate fraction is generally low (< 200 ppm), whereas the carbonate fraction has Sr concentrations approaching ∼1000 ppm.

Study of the origin and chemical differentiation of silicic magmas can provide important insights into crustal evolution and rare metal metallogeny. Tin mineralization always tends to form in relatively reduced, highly fractionated granite systems. Recognition of distinctions between fertile and barren magmas is of enormous benefit to mineral exploration. The Yanbei caldera complex (YCC), is a typical inland volcanic-intrusive complex that also hosts a giant porphyry-type tin ore deposit in Southeast China. To study the origin and chemical differentiation of the YCC and constrain its relationship with tin mineralization, a comprehensive petrological, whole-rock major and trace element geochemical data, along with zircon U Pb ages, trace element and Hf isotopic data of the Yanbei caldera complex (YCC) and the Xiaoji granite (XG) near the YCC are carried out. LA-ICP-MS zircon U Pb dating indicates that the generation and evolution of the YCC and the XG took place in a short time (4 M.y.) of between 142.4 and 138.4 Ma. Distinct zircon Hf isotopic compositions of the volcanic and intrusive units from the YCC suggest that they were derived from different magma sources. The volcanic rocks and the XG have consistent and low zircon Hf isotopic compositions (eHf(t) = −14.9 ~ −9.0), implying that they were almost exclusively derived from melting of Paleoproterozoic crustal rocks. But the magma source of the intrusive units (the granite porphyry, GP and the biotite granite, BG) (eHf(t) = −6.0 ~ −0.8) contains a significant mantle-derived component input. The whole-rock and zircon compositions suggest that the compositionally zoned volcano of the YCC can be interpreted in terms of the “crystal mush model”. The rhyolite has the geochemical characteristics of highly evolved magmas which undergo crystal fractionation, while the dacite displays a complementary geochemical signature implying that it represents the residual crystal mush after extraction of the rhyolitic melts. The XG displays similar chronological, compositional, and isotopic features to the rhyolite, suggesting that it is the intrusive equivalent of the rhyolite. The intrusive units (GP and BG) of the YCC are highly-evolved granites with elevated tin contents, responsible for tin mineralization. By comparison of fertile and barren systems in the YCC, we suggest that simple crystal fractionation for the high-evolved/extracted granitic melt does not necessarily lead to tin mineralization. A tin-bearing and volatile-rich melt originated under high-temperature partial melting of crustal source induced by underplating/input of a hot mantle magma is an essential precondition for some magmatic-hydrothermal tin mineralization systems.

Highlights • Gap-suppression of startle responses is regularly used as a measure for tinnitus. • We studied this phenomenon in auditory cortical evoked potentials in awake animals. • Gap-suppression of evoked potentials was also examined following noise exposure. • 120 dB SPL noise exposure, but not 105 dB, resulted in deficits in gap-suppression. • Results are discussed in the context of a potential correlate of tinnitus., Animal models of tinnitus are essential for determining the underlying mechanisms and testing pharmacotherapies. However, there is doubt over the validity of current behavioural methods for detecting tinnitus. Here, we applied a stimulus paradigm widely used in a behavioural test (gap-induced inhibition of the acoustic startle reflex GPIAS) whilst recording from the auditory cortex, and showed neural response changes that mirror those found in the behavioural tests. We implanted guinea pigs (GPs) with electrocorticographic (ECoG) arrays and recorded baseline auditory cortical responses to a startling stimulus. When a gap was inserted in otherwise continuous background noise prior to the startling stimulus, there was a clear reduction in the subsequent evoked response (termed gap-induced reductions in evoked potentials; GIREP), suggestive of a neural analogue of the GPIAS test. We then unilaterally exposed guinea pigs to narrowband noise (left ear; 8–10 kHz; 1 h) at one of two different sound levels – either 105 dB SPL or 120 dB SPL – and recorded the same responses seven-to-ten weeks following the noise exposure. Significant deficits in GIREP were observed for all areas of the auditory cortex (AC) in the 120 dB-exposed GPs, but not in the 105 dB-exposed GPs. These deficits could not simply be accounted for by changes in response amplitudes. Furthermore, in the contralateral (right) caudal AC we observed a significant increase in evoked potential amplitudes across narrowband background frequencies in both 105 dB and 120 dB-exposed GPs. Taken in the context of the large body of literature that has used the behavioural test as a demonstration of the presence of tinnitus, these results are suggestive of objective neural correlates of the presence of noise-induced tinnitus and hyperacusis.

The Palaeocene-Eocene Thermal Maximum (PETM) was a period of intense global warming that began ∼55.9 million years ago and lasted about 170,000 yrs. Various mechanisms have been proposed to cause this warming, including the emplacement of the North Atlantic Igneous Province (NAIP). Equally, many mechanisms have been invoked to explain sequestration of carbon from the ocean-atmosphere system necessary to promote the recovery to more temperate conditions. Here we propose that an important path for carbon sequestration was tied to NAIP volcanism through the precipitation of calcium carbonate (CaCO3) cements within the tephra layers. These cements formed after the deposition and burial of tephra over a wide area of the North Atlantic Ocean during the late Palaeocene and early Eocene. We find strong evidence that authigenic CaCO3 cements formed shortly after tephra deposition. Monte Carlo simulations suggest that this process may have been responsible for a quarter of the carbon sequestered during the PETM recovery phase, providing a major, but previously unconsidered sink of isotopically-light carbon, and one which may have persisted into the Eocene.

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2′-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Although widely used as a preclinical model for studying venous diseases, there is a scarcity of in vivo characterizations of the naïve murine venous system. Additionally, previous studies on naïve veins (ex vivo) have not included the influence of surrounding structures and biomechanical forces. Using MRI, we noninvasively quantified the cross-sectional area, cyclic strain, and circularity of the venous system in young and old, male and female C57BL/6 mice. We investigated the most common venous locations used to perform venous disease research: the common jugular vein, suprarenal inferior vena cava (IVC), infrarenal IVC, common iliac vein, and common femoral vein. Our results elucidate age-dependent changes in venous cross-sectional area, which varied by location. Maximum cyclic strain, a parameter of lumen expansion, showed 10% change across the cardiac cycle, approximately half the magnitude of arteries. Veins demonstrated noncircular shapes, particularly in the core vasculature. The cardiovascular stressor dobutamine had only a small impact on the venous system. Also, our data demonstrate that the peripheral veins tend to decrease in cross-sectional area and circularity with age. Conversely, the IVC tends to increase in size and circularity with age, with males exhibiting larger variability in response to dobutamine compared to females. This work provides a foundation for drawing age and sex comparisons in disease models, and represents the first in vivo characterization of the murine venous system at rest and during the application of a pharmacological exercise surrogate.

Post-collisional Cenozoic magmatic activity in NW Anatolia produced widespread volcanism across the region. In the Biga Peninsula, in the west, medium-K calc-alkaline to ultra-K rocks with orogenic geochemical signature were emplaced at similar to 43-15 Ma (Biga orogenic volcanic rocks; BOVR). Volcanic activity in the Central Sakarya region, to the east, is mainly restricted to-53-38 Ma, but also continued during the Early Miocene with small basaltic extrusives (Sakarya orogenic volcanic rocks; SOVR). This study presents a new set of geochemical data (whole rock major and trace elements and Sr-Nd-Pb isotopic compositions), obtained from the Cenozoic calc-alkaline volcanic rocks from these two regions. While there is considerable overlap in the emplacement time of volcanism in the two areas, the post-collisional volcanic rocks of these two regions differ in terms of their geochemical compositions: (1) the BOVR show an age-dependent increase in K and other large-ion lithophile elements (LILE), coupled with an increase in radiogenic Sr and Pb compositions from the Eocene to Miocene; whereas (2) the SOVR are characterized by more sodic compositions with lower K and less radiogenic Sr contents with respect to the BOVR, which were unchanged in Eocene and Miocene. We conclude that these geochemical features were principally related to the distinct modes of subduction-related mantle enrichment processes. We suggest that the Eocene to Miocene progressive enrichment in the BOVR mantle was related to successive subduction of oceanic and crustal materials in the western Aegean, while the SOVR mantle was dominantly enriched during the pre-collisional events. Magma generation in the western region was related to subduction roll-back processes associated with post-collisional extension. In the east, thermal perturbation of the mantle in response to asthenospheric upwelling due to slab break-off process was responsible for the magma generation. The time-dependent increase of K (and other LILE and radiogenic Sr) in the Cenozoic orogenic lavas from the Rhodope to Biga region emphasizes the importance of crustal imbrication and subduction in the genesis of orogenic K-rich lavas of the Alpine-Himalayan orogenic belt. Crown Copyright (C) 2017 Published by Elsevier B.V. All rights reserved.

BACKGROUND. Air pollution contains numerous carcinogens and endocrine disruptors which may be relevant for breast cancer. Previous research has predominantly been conducted in White women; however, Black women may have higher air pollution exposure due to geographic and residential factors. OBJECTIVE. We evaluated the association between air pollution and breast cancer risk in a large prospective population of Black women. METHODS. We estimated annual average ambient levels of particulate matter

Introduction Preeclampsia is a serious complication affecting 5–8% of pregnancies. Central to its pathogenesis is placental hypoxia and inflammation which leads to secretion of soluble fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread endothelial dysfunction. The molecular mechanisms regulating sFlt-1 production remain poorly understood. Recently, a binding site for the nuclear factor activated T cells (NFAT) transcription factor has been found on fms-like tyrosine kinase 1 (FLT-1) promoter. Methods We assessed whether inhibiting NFAT impacts FLT-1, sFlt-1 and cytokine expression, as well as sFlt-1 secretion in primary cytotrophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs). We investigated whether NFAT is regulated by hypoxia in primary cytotrophoblasts. We characterised the expression of NFAT1-4 in preterm preeclamptic compared to gestationally matched placentas. Results Inhibiting NFAT reduced FLT-1 and sFlt-1 splice variant e15a transcription, concordant with reduced total sFlt-1 and sFlt-1 e15a secretion from primary human cytotrophoblasts. This effect appeared tissue specific as inhibiting NFAT did not change sFlt-1 secretion from endothelial cells. Inhibiting NFAT also reduced transcription of inflammatory cytokines IL-1β and IL-10 in primary cytotrophoblasts. NFAT1 and NFAT3 mRNA expression were significantly increased under hypoxia (1% O2). Inhibiting NFAT under hypoxia significantly reduced FLT-1 and sFlt-1 e15a transcription, but did not reduce sFlt-1 secretion. NFAT mRNA and protein localisation was not different in preeclamptic compared to gestationally matched placenta. Discussion NFAT positively regulates placental FLT-1 and sFlt-1 e15a, secretion of sFlt-1 and inflammatory cytokine expression. It may be involved in the pathophysiology of preeclampsia.

High-Interstitial Fe–Cr–Mn–C–N stainless steels, CN66 (C+N=0.28+0.38 wt%) and CN71 (C+N=0.27+0.44 wt%), were produced in an induction melting furnace and cast in air atmosphere. The abrasive wear resistance of CN66 and CN71 was investigated as a function of heat treatment conditions, subsequent to casting. The wear rate of CN66 decreased from 0.107 to 0.095 mm3/m. with a heat treatment of 1200 °C solutionizing for 2 h followed by water quenching, The value of Fe2p bonding energy of CN66 shifted from 708.93 to 708.53 eV due to the heat treatment, and was caused by the dissolution of pearlite. The dissolution was also confirmed by microstructural analysis. The bonding energy of CrN, that formed as a result of heat treatment, is at 575.4 eV (Cr2p2/3). The amount of ferrite phase in CN66 and CN71 was increased with heat treatment from 3.4% to 8.9% and 1.3% to 5.7%, respectively. The enhancement of wear resistance is due to the increased amount of ferrite phase resulting from lower nitrogen content in CN66 steel as well as the dissolution of pearlite by heat treatment. The abrasive wear resistance of type 316L stainless steel comparatively is lower than any of the experimental steel developed in this study.