Explore the vast range of titles available.

Thyroid peroxidase antibodies may increase the risk of miscarriage and preterm birth. In this controlled trial, the use of levothyroxine before conception and through birth did not improve live-birth rates among euthyroid women with such antibodies and a history of miscarriage or infertility.

To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. Observational cohort study. A total of 49 hospitals across the United Kingdom between 2011 and 2016. Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. None. Rates of thyroid dysfunction. Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

BACKGROUND Thyroid peroxidase antibodies are associated with increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate levothyroxine could reduce such adverse outcomes. METHODS We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live birth rates among euthyroid women with thyroid peroxidase antibodies and a history of miscarriage or infertility. We randomly assigned women to receive 50mcg daily of levothyroxine or placebo, commenced preconception and continued until the end of pregnancy. The primary outcome was live birth ≥34 weeks gestation. RESULTS We tested 19,585 women for thyroid peroxidase antibodies and thyroid function across 49 hospitals in the United Kingdom. A total of 952 women were randomly assigned to receive either levothyroxine (476) or placebo (476). The follow-up rate for the primary outcome was 98.7% (940/952). A pregnancy was achieved in 266/470 (56.6%) in the levothyroxine group and 274/470 (58.3%) in the placebo group. The live birth rate in the levothyroxine group was 37.4% (176/470) versus 37.9% (178/470) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, p=0.74; absolute risk difference, -0.4%; 95% CI, -6.6% to 5.8%). There were no significant differences in other pregnancy outcomes, including the rates of pregnancy loss, preterm birth, or in neonatal outcomes. Serious adverse events occurred in 6% of women in the levothyroxine group and 4% in the placebo group (p=0.14). CONCLUSION Treatment with levothyroxine in euthyroid women with thyroid peroxidase antibodies did not increase the rate of live births. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Intracellular Ca2+ signaling and Na+ homeostasis are inextricably linked via ion channels and co‐transporters, with alterations in the concentration of one ion having profound effects on the other. Evidence indicates that intracellular Na+ concentration ([Na+]i) is elevated in breast tumors, and that aberrant Ca2+ signaling regulates numerous key cancer hallmark processes. The present study therefore aimed to determine the effects of Na+ depletion on intracellular Ca2+ handling in metastatic breast cancer cell lines. The relationship between Na+ and Ca2+ was probed using fura‐2 and SBFI fluorescence imaging and replacement of extracellular Na+ with equimolar N‐methyl‐D‐glucamine (0Na+/NMDG) or choline chloride (0Na+/ChoCl). In triple‐negative MDA‐MB‐231 and MDA‐MB‐468 cells and Her2+ SKBR3 cells, but not ER+ MCF‐7 cells, 0Na+/NMDG and 0Na+/ChoCl resulted in a slow, sustained depletion in [Na+]i that was accompanied by a rapid and sustained increase in intracellular Ca2+ concentration ([Ca2+]i). Application of La3+ in nominal Ca2+‐free conditions had no effect on this response, ruling out reverse‐mode NCX activity and Ca2+ entry channels. Moreover, the Na+‐linked [Ca2+]i increase was independent of membrane potential hyperpolarization (NS‐1619), but was inhibited by pharmacological blockade of IP3 receptors (2‐APB), phospholipase C (PLC, U73122) or following depletion of endoplasmic reticulum Ca2+ stores (cyclopiazonic acid). Thus, Na+ is linked to PLC/IP3‐mediated activation of endoplasmic reticulum Ca2+ release in metastatic breast cancer cells and this may have an important role in breast tumors where [Na+]i is perturbed. Intracellular Na+ concentration is elevated in breast cancer cells, and aberrant Ca2+ signaling regulates numerous key cancer hallmark processes. Here, we found that Na+ depletion in metastatic breast cancer cell lines led to a rapid and sustained increase in intracellular Ca2+ concentration via PLC/IP3‐mediated activation of endoplasmic reticulum Ca2+ release. Our findings suggest that Na+‐dependent alteration of Ca2+ handling may have an important role in breast tumors where Na+ is perturbed.

Transition to psychosis rates within ultra-high risk (UHR) services have been declining. It may be possible to 'enrich' UHR cohorts based on the environmental characteristics seen more commonly in first-episode psychosis cohorts. This study aimed to determine whether transition rates varied according to the accumulated exposure to environmental risk factors at the individual (migrant status, asylum seeker/refugee status, indigenous population, cannabis/methamphetamine use), family (family history or parental separation), and neighborhood (population density, social deprivation, and fragmentation) level. The study included UHR people aged 15-24 who attended the PACE clinic from 2012 to 2016. Cox proportional hazards models (frequentist and Bayesian) were used to assess the association between individual and accumulated factors and transition to psychosis. UHR status and transition was determined using the CAARMS. Benjamini-Hochberg was used to correct for multiple comparisons in frequentist analyses. Of the 461 young people included, 55.5% were female and median follow-up was 307 days (IQR: 188-557) and 17.6% ( = 81) transitioned to a psychotic disorder. The proportion who transitioned increased incrementally according to the number of individual-level risk factors present (HR = 1.51, 95% CIs 1.19-1.93, < 0.001, = 0.01). The number of family- and neighborhood-level exposures did not increase transition risk ( > 0.05). Cannabis use was the only specific risk factor significantly associated with transition (HR = 1.89, 95% CIs 1.22-2.93, = 0.03, BF = 6.74). There is a dose-response relationship between exposure to individual-level psychosis-related environmental risk factors and transition risk in UHR patients. If replicated, this could be incorporated into a novel approach to identifying the highest-risk individuals within clinical services.

Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m2 intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0–1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2–25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3–22·8) in the dasatinib group and 21·2 months (20·0–23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87–1·13; p=0·90). The most common grade 3–4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3–4 pleural effusions were uncommon (ten [1%] vs three [<1%]). The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. Bristol-Myers Squibb.

IntroductionOvarian hyperstimulation syndrome (OHSS) is the most significant short-term complication of pharmacological ovarian stimulation. Symptoms range from mild abdominal discomfort to rare complications such as renal failure, thromboembolism and respiratory distress syndrome.Currently, clinical practice typically involves monitoring the patient until the condition becomes severe, at which point they are admitted to hospital, where drainage of ascitic fluid (paracentesis) may take place. Preliminary studies have indicated that earlier outpatient paracentesis may reduce the progression of OHSS and prevent hospitalisation in women.Methods and analysisThis UK, multicentre, pragmatic, two-arm, parallel-group, adaptive (group sequential with one interim analysis), open-label, superiority, confirmatory, group sequential, individually randomised controlled trial, with internal pilot will assess the clinical and cost-effectiveness and safety of outpatient paracentesis versus conservative management (usual care) for moderate or severe OHSS. 224 women from 20 National Health Service and private fertility units will be randomised (1:1) and followed up for up to 13.5 months. The primary outcome is the rate of OHSS related hospital admission of at least 24 hours within 28 days postrandomisation. The primary analysis will be an intention to treat with difference in hospitalisation rates as measure of treatment effect. Secondary outcomes include time to resolution of symptoms, patient satisfaction, adverse events and cost-effectiveness. A qualitative substudy will facilitate the feasibility of recruitment. Participant recruitment commenced in June 2022.Ethics and disseminationLondon—Southeast Research Ethics Committee approved the protocol (reference: 22/LO/0015). Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences, as well as being disseminated to trial participants and patient groups.Trial registration numberISRCTN71978064.

Background It is widely believed that small rectal tumors are more likely to have a good response to neoadjuvant treatment, which may influence the selection of patients for a ‘watch and wait’ strategy. Objective The aim of this study was to investigate whether there is a relationship between baseline tumor length on magnetic resonance imaging (MRI) and response to chemoradiotherapy. Method The 96 patients with locally advanced rectal cancer randomised (2:1–intervention:control) in the TRIGGER feasibility study where eligible. Baseline tumor length was defined as the maximal cranio-caudal length on baseline MRI (mm) and was recorded prospectively at study registration. Magnetic resonance tumor regression grade (mrTRG) assessment was performed on the post-chemoradiotherapy (CRT) MRI 4–6 weeks (no later than 10 weeks) post completion of CRT. This was routinely reported for patients in the intervention (mrTRG-directed management) arm and reported for the purposes of this study by the central radiologist in the control arm patients. Those with an mrTRG I/II response were defined as ‘good responders’ and those with an mrTRG III–V response were defined as ‘poor responders’. Results Overall, 94 patients had a post-CRT MRI performed and were included. Forty-three (46%) patients had a good response (mrTRG I/II) and 51 (54%) patients had a poor response (mrTRG III/IV). The median tumor length of good responders was 43 mm versus 50 mm ( p  < 0.001), with considerable overlap in tumor lengths between groups. Conclusion Baseline tumor length on MRI is not a clinically useful biomarker to predict mrTRG tumor response to CRT and therefore patient suitability for a deferral of surgery trial.

ObjectiveUsing a large national database of people hospitalised with COVID-19, we investigated the contribution of cardio-metabolic conditions, multi-morbidity and ethnicity on the risk of in-hospital cardiovascular complications and death.MethodsA multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 6 February 2020 and 16 March 2021. Logistic models were used to explore associations between baseline patient ethnicity, cardiometabolic conditions and multimorbidity (0, 1, 2, >2 conditions), and in-hospital cardiovascular complications (heart failure, arrhythmia, cardiac ischaemia, cardiac arrest, coagulation complications, stroke), renal injury and death.ResultsOf 65 624 patients hospitalised with COVID-19, 44 598 (68.0%) reported at least one cardiometabolic condition on admission. Cardiovascular/renal complications or death occurred in 24 609 (38.0%) patients. Baseline cardiometabolic conditions were independently associated with increased odds of in-hospital complications and this risk increased in the presence of cardiometabolic multimorbidity. For example, compared with having no cardiometabolic conditions, 1, 2 or ≥3 conditions was associated with 1.46 (95% CI 1.39 to 1.54), 2.04 (95% CI 1.93 to 2.15) and 3.10 (95% CI 2.92 to 3.29) times higher odds of any cardiovascular/renal complication, respectively. A similar pattern was observed for all-cause death. Compared with the white group, the South Asian (OR 1.19, 95% CI 1.10 to 1.29) and black (OR 1.53 to 95% CI 1.37 to 1.72) ethnic groups had higher risk of any cardiovascular/renal complication.ConclusionsIn hospitalised patients with COVID-19, cardiovascular complications or death impacts just under half of all patients, with the highest risk in those of South Asian or Black ethnicity and in patients with cardiometabolic multimorbidity.

Intracellular Ca 2+ signaling and Na + homeostasis are inextricably linked via ion channels and co‐transporters, with alterations in the concentration of one ion having profound effects on the other. Evidence indicates that intracellular Na + concentration ([Na + ] i ) is elevated in breast tumors, and that aberrant Ca 2+ signaling regulates numerous key cancer hallmark processes. The present study therefore aimed to determine the effects of Na + depletion on intracellular Ca 2+ handling in metastatic breast cancer cell lines. The relationship between Na + and Ca 2+ was probed using fura‐2 and SBFI fluorescence imaging and replacement of extracellular Na + with equimolar N‐methyl‐D‐glucamine (0Na + /NMDG) or choline chloride (0Na + /ChoCl). In triple‐negative MDA‐MB‐231 and MDA‐MB‐468 cells and Her2+ SKBR3 cells, but not ER+ MCF‐7 cells, 0Na + /NMDG and 0Na + /ChoCl resulted in a slow, sustained depletion in [Na + ] i that was accompanied by a rapid and sustained increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ). Application of La 3+ in nominal Ca 2+ ‐free conditions had no effect on this response, ruling out reverse‐mode NCX activity and Ca 2+ entry channels. Moreover, the Na + ‐linked [Ca 2+ ] i increase was independent of membrane potential hyperpolarization (NS‐1619), but was inhibited by pharmacological blockade of IP 3 receptors (2‐APB), phospholipase C (PLC, U73122) or following depletion of endoplasmic reticulum Ca 2+ stores (cyclopiazonic acid). Thus, Na + is linked to PLC/IP 3 ‐mediated activation of endoplasmic reticulum Ca 2+ release in metastatic breast cancer cells and this may have an important role in breast tumors where [Na + ] i is perturbed.