Heavy-element production in a compact object merger observed by JWST.

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs)1, sources of high-frequency gravitational waves (GWs)2 and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process)3. Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers4-6 and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs. 7-12). We obtained James Webb Space Telescope (JWST) mid-infrared imaging and spectroscopy 29 and 61 days after the burst. The spectroscopy shows an emission line at 2.15 microns, which we interpret as tellurium (atomic mass A = 130) and a very red source, emitting most of its light in the mid-infrared owing to the production of lanthanides. These observations demonstrate that nucleosynthesis in GRBs can create r-process elements across a broad atomic mass range and play a central role in heavy-element nucleosynthesis across the Universe.

Adult Kawasaki disease: a rare and challenging diagnosis-a case report.

Background: Kawasaki disease (KD) is an acute systemic vasculitis which predominantly occurs in childhood but rarely in adulthood. Diagnosis relies on the presence of typical clinical features; however, patients may present atypically, increasing the challenge of timely diagnosis for physicians. Case summary: We report a case of a 40-year-old male presenting with persistent fever, rash, and unilateral neck swelling. Initial investigations were suggestive of necrotizing lymphadenitis, with a presumed infective aetiology. However, extensive microbiology and immunological investigations remained negative. Cardiac injury was evident with elevated troponin T and NT-proBNP; however, left ventricular systolic function was normal. After 4 days, clinical features consistent with KD were noted and the results of a lymph node biopsy supported this diagnosis. Despite timely treatment with intravenous immunoglobulins (IVIG) and high-dose aspirin, follow-up computed tomography (CT) coronary angiography demonstrated two sequential aneurysms (max 6 mm) in the right coronary artery, plus one small subtle aneurysm in the proximal left anterior descending artery (4 mm). Discussion: Diagnosis of adult KD remains challenging, as symptoms often present sequentially over time rather than simultaneously and many of the clinical features necessary for diagnosis share commonality with other infectious disease processes.

A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer.

One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0-5.3), P < 0.001; median 7.1 versus 22.3 months for high- versus low-intermediate risk) and with partial response (HR = 3.3 (1.7-6.4), P < 0.001; median 8.8 versus 28.6 months). The model also identified high-risk patients in an external validation cohort from the randomized phase 3 OAK study of ICI versus chemo in NSCLC (OS HR = 3.73 (1.83-7.60), P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials.

The adult outcome of childhood quasi-autism arising following extreme institutional deprivation.

BACKGROUND: Rutter and colleagues' seminal observation that extended early life exposure to extreme institutional deprivation can result in what he termed quasi-autism (QA), informed both our understanding of the effects of adversity on development and the nature of autism. Here we provide the first detailed analysis of the adult outcomes of the group of institutionally deprived-then-adopted children identified as displaying QA. METHODS: Twenty-six adult adoptees identified with QA in childhood (Childhood QA+) were compared to 75 adoptees who experienced extended institutional deprivation (>6 months) but no QA (Childhood QA-), and 116 adoptees exposed to Low/No institutional deprivation. The outcomes were child-to-adult developmental trajectories of neuro-developmental symptoms (autism, attention-deficit/hyperactivity disorder (ADHD), disinhibited social engagement (DSE) and cognitive impairment), adult functioning, life satisfaction and mental health. RESULTS: Childhood QA+ was associated with elevated and persistent trajectories of broad-based autism-related difficulties, ADHD and DSE symptoms and low IQ, as well as adult mental health difficulties and functional impairment, including high rates of low educational attainment and unemployment. Life satisfaction and self-esteem were unaffected. Autism-related communication problems, in particular, predicted negative adult outcomes. Childhood QA+ was still associated with poor outcomes even when ADHD, DSE and IQ were controlled. CONCLUSIONS: Early and time-limited institutional deprivation has a critical impact on adult functioning, in part via its association with an early established and persistent variant of autism, especially related to communication difficulties. Apparent similarities and differences to non-deprivation related autism are discussed.

Effect of psychotherapy for adult depression on self-esteem: A systematic review and meta-analysis.

BACKGROUND: There is emerging evidence to suggest that Cognitive Behavioral Therapy for depression may have a secondary effect on self-esteem, but less is known about non-CBT based interventions. To examine this, we had two main aims; (1) to meta-analyze psychotherapy effects on (i) depression and (ii) self-esteem, and (2) to investigate the relationship between reductions in depression symptoms and improvements in self-esteem. DESIGN: A systematic review and meta-analysis. METHODS: Following the PRISMA guidelines, we conducted a meta-analysis of randomized control trials of psychotherapy for adult depression, which included a self-esteem outcome at post-treatment. Nineteen studies with a total of 3423 participants met the inclusion criteria. For each comparison between psychotherapy and a control condition, we calculated Hedges' g both for depression and self-esteem and pooled them in two separate meta-analyses. Furthermore, meta-regression was used to explore the association between the effect of psychotherapy for depression and its effect on self-esteem. RESULTS: The effects on depression were large and significant (Hedges' g = -0.95; [95 % CI: -1.27, -0.63]). We found evidence of smaller, albeit still moderate, effects on self-esteem (Hedges'g = 0.63; [95 % CI:0.32, 0.93]), with sustained effects at 6-12 months (Hedges'g = 0.70; [95 % CI: -0.03, 1.43]). We also found a strong inverse association between the effects of psychotherapy for depression and self-esteem (ß = -0.60, p < 0.001). LIMITATIONS: Heterogeneity was very high (I2 = 97 %), and out of 19 trials, only 6 trials were rated as having a low risk of bias. CONCLUSIONS: The results suggest that psychotherapy for depression may improve self-esteem to a moderate degree.

Colchicine-regeneration of an old drug.

Immunomodulation by colchicine is a well-established therapy for targeting inflammatory pathways in gout, pericarditis and Behchet's disease. In more recent times, evidence has emerged demonstrating a potential role for colchicine in several cardiac conditions. This article aims to summarise the evidence behind the established guidelines for use of low-dose colchicine in pericarditis and examine the evolving evidence for its use in cardiovascular disease and most recently COVID-19.

Morphological characteristics of lesions with thin cap fibroatheroma-a substudy from the COMBINE (OCT-FFR) trial.

AIMS: To study if any qualitative or quantitative optical coherence tomography (OCT) variables in combination with thin cap fibroatheroma (TCFA) patients could improve the identification of lesions at risk for future major adverse cardiac events (MACEs). METHODS AND RESULTS: From the combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non- culprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT-FFR) trial database (NCT02989740), we performed a detailed assessment OCT qualitative and quantitative variables in TCFA carrying diabetes mellitus (DM) patients with vs. without MACE during follow-up. MACEs were defined as a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, and hospitalization for unstable angina. From the 390 fractional flow reserve (FFR)-negative DM patients, 98 (25.2%) had ≥1 OCT-detected TCFA, of which 13 (13.3%) had MACE and 85 (86.7%) were event-free (non-MACE). The baseline characteristics were similar between both groups; however, a smaller minimal lumen area (MLA) and lower mean FFR value were observed in MACE group (1.80 vs. 2.50 mm2, P = 0.01, and 0.85 vs. 0.89, P = 0.02, respectively). Prevalence of healed plaque (HP) was higher in the MACE group (53.85 vs. 21.18%, P = 0.01). TCFA were predominantly located proximal to the MLA. TCFA area was smaller in the MACE group, while no difference was observed regarding the lesion area. CONCLUSION: Within TCFA carrying patients, a smaller MLA, lower FFR values, and TCFA location adjacent to a HP were associated with future MACE. Carpet-like measured lesion area surface was similar, while the TCFA area was smaller in the MACE arm, and predominantly located proximal to the MLA.

Long-term outcomes of patients with normal fractional flow reserve and thin-cap fibroatheroma.

BACKGROUND: The long-term prognostic implications of fractional flow reserve (FFR)-negative lesions hosting vulnerable plaques remain unsettled. AIMS: The aim of this study was to evaluate the association of non-ischaemic lesions hosting optical coherence tomography (OCT)-detected thin-cap fibroatheromas (TCFA) with first and recurrent cardiovascular events during follow-up up to 5 years in a diabetes mellitus (DM) patient population. METHODS: COMBINE OCT-FFR is a prospective, international, double-blind, natural history study. Patients with DM and with ≥1 FFR-negative lesion were classified into 2 groups based on the presence or absence of ≥1 TCFA lesion. The primary endpoint (PE) is a composite of cardiac mortality, target vessel-related myocardial infarction (TV-MI), clinically driven target lesion revascularisation (TLR), or unstable angina (UA) requiring hospitalisation during follow-up up to 5 years. RESULTS: Among 390 DM patients (age 67.5±9 years; 37% female) with ≥1 FFR-negative lesion, 292 (74.9%) were TCFA-negative while 98 (25.1%) were TCFA-positive. The PE occurred more frequently in TCFA-positive than in TCFA-negative patients (21.4% vs 8.2%, hazard ratio [HR] 2.89, 95% confidence interval [CI]: 1.61-5.20; p<0.001; 6.42 vs 2.46 events per 100 patient-years, rate ratio [RR] 2.61, 95% CI: 1.38-4.90; p=0.002). Furthermore, when TV-MI, TLR, and UA were treated as recurrent components of the PE, TCFA-positive patients experienced a higher risk of recurrent events (HR 2.89, 95% CI; 1.74-4.80; p<0.001; 13.45 vs 2.87 events per 100 patient-years, RR 4.69, 95% CI: 2.86-7.83; p<0.001). A multivariable analysis identified the presence of TCFA as an independent predictor of the PE (HR 2.76, 95% CI: 1.53-4.97; p<0.001). CONCLUSIONS: OCT-detected TCFA-positive lesions, although not ischaemia-generating, are associated with an increased risk of adverse events during long-term follow-up. CLINICALTRIALS: gov: NCT02989740.

Understanding the prospective associations between neuro-developmental problems, bullying victimization, and mental health: Lessons from a longitudinal study of institutional deprivation.

Studies suggest that children who have experienced neglect are at risk for bullying which in turn increases the risk for poor mental health. Here we extend this research by examining whether this risk extends to the neglect associated with severe institutional deprivation and then testing the extent to which these effects are mediated by prior deprivation-related neuro-developmental problems such as symptoms of inattention, hyperactivity and autism. Data were collected at ages 6, 11, 15, and young adulthood (22-25 years) from 165 adoptees who experienced up to 43 months of deprivation in Romanian Orphanages in 1980s and 52 non-deprived UK adoptees (N = 217; 50.23% females). Deprivation was associated with elevated levels of bullying and neuro-developmental symptoms at ages 6 through 15 and young adult depression and anxiety. Paths from deprivation to poor adult mental health were mediated via cross-lagged effects from earlier neuro-developmental problems to later bullying. Findings evidence how deep-seated neuro-developmental impacts of institutional deprivation can cascade across development to impact social functioning and mental health. These results elucidate cascade timing and the association between early deprivation and later bullying victimization across childhood and adolescence.

Thin-Cap Fibroatheroma Rather Than Any Lipid Plaques Increases the Risk of Cardiovascular Events in Diabetic Patients: Insights From the COMBINE OCT-FFR Trial.

BACKGROUND: Autopsy studies have established that thin-cap fibroatheromas (TCFAs) are the most frequent cause of fatal coronary events. In living patients, optical coherence tomography (OCT) has sufficient resolution to accurately differentiate TCFA from thick-cap fibroatheroma (ThCFA) and not lipid rich plaque (non-LRP). However, the impact of OCT-detected plaque phenotype of nonischemic lesions on future adverse events remains unknown. Therefore, we studied the natural history of OCT-detected TCFA, ThCFA, and non-LRP in patients enrolled in the prospective multicenter COMBINE FFR-OCT trial (Combined Optical Coherence Tomography Morphologic and Fractional Flow Reserve Hemodynamic Assessment of Non-Culprit Lesions to Better Predict Adverse Event Outcomes in Diabetes Mellitus Patients). METHODS: In the COMBINE FFR-OCT trial, patients with diabetes and ≥1 lesion with a fractional flow reserve >0.80 underwent OCT evaluation and were clinically followed for 18 months. A composite primary end point of cardiac death, target vessel-related myocardial infarction, target-lesion revascularization, and hospitalization for unstable angina was evaluated in relation to OCT-based plaque morphology. RESULTS: A total of 390 patients (age 67.5±9 years; 63% male) with ≥1 nonischemic lesions underwent OCT evaluation: 284 (73%) had ≥1 LRP and 106 (27%) non-LRP lesions. Among LRP patients, 98 (34.5%) had ≥1 TCFA. The primary end point occurred in 7% of LRP patients compared with 1.9% of non-LRP patients (7.0% versus 1.9%; hazard ratio [HR], 3.9 [95% CI, 0.9-16.5]; P=0.068; log rank-P=0.049). However, within LRP patients, TCFA patients had a much higher risk for primary end point compared with ThCFA (13.3% versus 3.8%; HR, 3.8 [95% CI, 1.5-9.5]; P<0.01), and to non-LRP patients (13.3% versus 1.9%; HR, 7.7 [95% CI, 1.7-33.9]; P<0.01), whereas ThCFA patients had risk similar to non-LRP patients (3.8% versus 1.9%; HR, 2.0 [95% CI, 0.42-9.7]; P=0.38). Multivariable analyses identified TCFA as the strongest independent predictor of primary end point (HR, 6.79 [95% CI, 1.50-30.72]; P=0.013). CONCLUSIONS: Among diabetes patients with fractional flow reserve-negative lesions, patients carrying TCFA lesions represent only one-third of LRP patients and are associated with a high risk of future events while patients carrying LRP-ThCFA and non-LRP lesions portend benign outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02989740.

Severe deprivation in early childhood leads to permanent growth stunting: Longitudinal analysis of height trajectories from childhood-to-adulthood.

BACKGROUND: Childhood institutional deprivation is associated with growth stunting in childhood but long-term effects in adulthood remain uncertain. OBJECTIVE: To examine the impact of global institutional deprivation experienced in early childhood on subsequent growth with a special focus on final adult height and puberty timing. PARTICIPANTS & SETTING: The study was originally set in the UK, though some adoptive families lived abroad by the time of the adult follow up. 165 individuals adopted by UK families before 43 months of age from Romanian orphanages after the fall of the Ceaușescu regime in the early 1990's were compared to 51 non-deprived UK adoptees, adopted before the age of 6 months. METHODS: The English and Romanian Adoptees (ERA) study is a 20-year longitudinal natural experiment on the effects of institutional deprivation on development. Key growth milestones were extracted from growth curve modelling of height data collected at ages 4, 6, 11, 15 and 23 years using a Bayesian approach to fit the JPA2 model. RESULTS: Deprivation effects on height were present at the take-off point of accelerating adolescent growth and persisted into adulthood - the largest effects being for individuals who experienced over six months of deprivation. Deprivation was associated with earlier take-off and achievement of peak height velocity of adolescent growth acceleration - an effect driven largely by females' data and correlated with parent ratings of pubertal development. CONCLUSIONS: Early deprivation appears to reset tempo of growth early in development leading to permanent growth stunting in adulthood and accelerated onset of puberty, specifically in females.

Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial.

AIMS: The aim of this study was to understand the impact of optical coherence tomography (OCT)-detected thin-cap fibroatheroma (TCFA) on clinical outcomes of diabetes mellitus (DM) patients with fractional flow reserve (FFR)-negative lesions. METHODS AND RESULTS: COMBINE OCT-FFR study was a prospective, double-blind, international, natural history study. After FFR assessment, and revascularization of FFR-positive lesions, patients with ≥1 FFR-negative lesions (target lesions) were classified in two groups based on the presence or absence of ≥1 TCFA lesion. The primary endpoint compared FFR-negative TCFA-positive patients with FFR-negative TCFA-negative patients for a composite of cardiac mortality, target vessel myocardial infarction, clinically driven target lesion revascularization or unstable angina requiring hospitalization at 18 months. Among 550 patients enrolled, 390 (81%) patients had ≥1 FFR-negative lesions. Among FFR-negative patients, 98 (25%) were TCFA positive and 292 (75%) were TCFA negative. The incidence of the primary endpoint was 13.3% and 3.1% in TCFA-positive vs. TCFA-negative groups, respectively (hazard ratio 4.65; 95% confidence interval, 1.99-10.89; P < 0.001). The Cox regression multivariable analysis identified TCFA as the strongest predictor of major adverse clinical events (MACE) (hazard ratio 5.12; 95% confidence interval 2.12-12.34; P < 0.001). CONCLUSIONS: Among DM patients with ≥1 FFR-negative lesions, TCFA-positive patients represented 25% of this population and were associated with a five-fold higher rate of MACE despite the absence of ischaemia. This discrepancy between the impact of vulnerable plaque and ischaemia on future adverse events may represent a paradigm shift for coronary artery disease risk stratification in DM patients.

Racial differences in the treatment and outcomes for prostate cancer in Massachusetts.

BACKGROUND: Massachusetts is a northeastern state with universally mandated health insurance since 2006. Although Black men have generally worse prostate cancer outcomes, emerging data suggest that they may experience equivalent outcomes within a fully insured system. In this setting, the authors analyzed treatments and outcomes of non-Hispanic White and Black men in Massachusetts. METHODS: White and Black men who were 20 years old or older and had been diagnosed with localized intermediate- or high-risk nonmetastatic prostate cancer in 2004-2015 were identified in the Massachusetts Cancer Registry. Adjusted logistic regression models were used to assess predictors of definitive therapy. Adjusted and unadjusted survival models compared cancer-specific mortality. Interaction terms were then used to assess whether the effect of race varied between counties. RESULTS: A total of 20,856 men were identified. Of these, 19,287 (92.5%) were White. There were significant county-level differences in the odds of receiving definitive therapy and survival. Survival was worse for those with high-risk cancer (adjusted hazard ratio [HR], 1.50; 95% CI, 1.4-1.60) and those with public insurance (adjusted HR for Medicaid, 1.69; 95% CI, 1.38-2.07; adjusted HR for Medicare, 1.2; 95% CI, 1.14-1.35). Black men were less likely to receive definitive therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.83) but had a 17% lower cancer-specific mortality (adjusted HR, 0.83; 95% CI, 0.7-0.99). CONCLUSIONS: Despite lower odds of definitive treatment, Black men experience decreased cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population. LAY SUMMARY: There is a growing body of evidence showing that the excess risk of death among Black men with prostate cancer may be caused by disparities in access to care, with few or no disparities seen in universally insured health systems such as the Veterans Affairs and US Military Health System. Therefore, the authors sought to assess racial disparities in prostate cancer in Massachusetts, which was the earliest US state to mandate universal insurance coverage (in 2006). Despite lower odds of definitive treatment, Black men with prostate cancer experience reduced cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population.

Clinical guidance for navigating the QTc-prolonging and arrhythmogenic potential of pharmacotherapy during the COVID-19 pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), has rapidly spread since December 2019 to become the focus of healthcare systems worldwide. Its highly contagious nature and significant mortality has led to its prioritization as a public health issue. The race to prevent and treat this disease has led to "off-label" prescribing of medications such as hydroxychloroquine, azithromycin, and Kaletra (lopinavir/ritonavir). Currently, there is no robust clinical evidence for the use of these drugs in the treatment of COVID-19, with most, if not all of these medications associated with the potential for QT interval prolongation, torsades de pointes, and resultant drug-induced sudden cardiac death. The aim of this document is to help healthcare providers mitigate the potential deleterious effects of drug-induced QTc prolongation.

Opioid Requirement following Arthroscopic Knee Surgery: Are There Predictive Factors Associated with Long-Term Use.

The purpose of this study is to identify patterns of postoperative narcotic use and determine the impact of psychosocial and perioperative factors on postoperative opioid consumption following arthroscopic knee surgery. Fifty consecutive patients undergoing arthroscopic knee surgery were prospectively enrolled. Patients were contacted via telephone at 1 week postoperatively to report their pain level and opioid consumption. The patient was contacted again at 2 weeks, 4 weeks, and 90 days as necessary until opioid cessation, at which time the patient's plan for unused pills was inquired. Opioid consumption was compared using t-tests and one-way analysis of variance for demographic and surgical factors. Linear regression was used to determine whether the Pain Catastrophizing Scale (PCS), Resilience Scale (RS-11), International Knee Documentation Committee questionnaire, or patient-reported pain at 1 week predicted higher opioid consumption. The average morphine equivalent dose of opioid consumption was 142 mg. Sixty-four percent consumed less than 100 mg, and 68% discontinued opioid use by 1 week postoperatively. Seventy-four percent reported surplus pills, and 49% of those patients plans for pill disposal. Factors associated with higher consumption included undergoing a major procedure, having a regional anesthesia block, and higher area deprivation index score (p < 0.05). Higher PCS scores and reported average pain level at 1 week were predictive of higher opioid consumption (p < 0.05). In conclusion, a majority of patients undergoing outpatient knee surgery did not require the entirety of their narcotic prescription. The majority of patients consumed less than 100 mg of morphine equivalents and discontinued opioid use by 1 week postoperatively. Ligament reconstruction, living in an area with a higher index of deprivation, and higher score on the PCS were associated with greater opioid consumption. Overall, patient knowledge regarding opioid disposal was poor, and patients would likely benefit from additional education prior to surgery.

Wait Times in Musculoskeletal Patients: What Contributes to Patient Satisfaction.

INTRODUCTION: The purpose of this study was to determine how wait time duration is associated with patient satisfaction and how appointment characteristics relate to wait time duration and patient satisfaction in the orthopedic surgery clinic. METHODS: Two hundred sixty-four patients visiting one of 3 ambulatory orthopedic surgery clinics were asked to estimate their wait time and to rate their satisfaction with the visit. The associations between appointment characteristics, wait time, and satisfaction were analyzed using t tests, 1-way analysis of variance, and Pearson correlation coefficients. RESULTS: Wait times were significantly different based on visit type, appointment time, whether an X-ray was required, and whether a trainee was involved (P < .001). Patients with wait times less than 30 minutes had higher satisfaction scores (P < .001). Satisfaction ratings were significantly different based on the surgeon's management recommendation (P = .0211), but were not significantly different based on sex, age, office location, visit type, appointment time subsection, or time spent with the physician (P > .05). CONCLUSION: Wait times negatively correlated with satisfaction. New patient visits, appointment times in the later third of the day, appointments requiring an X-ray, and appointments involving a trainee had significantly longer wait times. Care should be taken to inform patients with visits involving these characteristics that they may experience longer than average wait times.

Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin.

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne®Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.

Effectiveness of a school-based intervention in Guatemala to increase knowledge of sexual and reproductive health.

OBJECTIVES: Adolescent pregnancy in Guatemala is a multifactorial issue contributing to maternal and child mortality as well as negative social and economic outcomes. While multiple organizations have identified this as an important area for improvement, little has been published on methods for reducing rates of adolescent pregnancy in resource-limited settings. We characterized the effects of a brief intervention on the knowledge and attitudes towards sexual health of high schoolers in a rural Guatemalan community. METHODS: We created a condensed, 2-h sexual education course, which was taught to over 500 high school students in San Juan Sacatepequez, Guatemala. Students completed pre- and post-intervention surveys assessing their knowledge about pregnancy prevention and attitudes toward contraception use. Chi-square tests were used to assess the difference between the pre- and post-intervention responses as well as the responses between male and female participants. RESULTS: Analysis of the survey results revealed significant improvements in all questions assessing knowledge regarding pregnancy prevention (p<0.01). Our pre-intervention survey revealed that male participants possessed greater knowledge regarding pregnancy prevention (p<0.01). Following the intervention, several areas of initial difference between male and female students' knowledge disappeared, including knowledge of what a contraceptive is, awareness that one sexual relation is sufficient for pregnancy, and recognition that condoms can prevent sexually transmitted infections. CONCLUSIONS: This study demonstrates that brief, school-based sexual health courses are low-resource, feasible interventions to significantly increase knowledge about contraception and sexual health in resource-limited settings and improve the disparities in knowledge between male and female participants.

A dorsal-ventral gradient of Wnt3a/ß-catenin signals controls mouse hindgut extension and colon formation.

Despite the importance of Wnt signaling for adult intestinal stem cell homeostasis and colorectal cancer, relatively little is known about its role in colon formation during embryogenesis. The development of the colon starts with the formation and extension of the hindgut. We show that Wnt3a is expressed in the caudal embryo in a dorsal-ventral (DV) gradient across all three germ layers, including the hindgut. Using genetic and lineage-tracing approaches, we describe novel dorsal and ventral hindgut domains, and show that ventrolateral hindgut cells populate the majority of the colonic epithelium. A Wnt3a-ß-catenin-Sp5/8 pathway, which is active in the dorsal hindgut endoderm, is required for hindgut extension and colon formation. Interestingly, the absence of Wnt activity in the ventral hindgut is crucial for proper hindgut morphogenesis, as ectopic stabilization of ß-catenin in the ventral hindgut via gain- or loss-of-function mutations in Ctnnb1 or Apc, respectively, leads to severe colonic hyperplasia. Thus, the DV Wnt gradient is required to coordinate growth between dorsal and ventral hindgut domains to regulate the extension of the hindgut that leads to colon formation.