tbuckley/cabot-search huggingface dataset:
Survival outcomes and risk group validation from SWOG S0925, a randomized phase II study of androgen deprivation (AD) +/- cixutumumab, in new metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Risa Liang Wong, Mai T. Duong, Catherine Tangen, Neeraj Agarwal, Heather H. Cheng, Nicholas J. Vogelzang, Maha H. A. Hussain, Ian Murchie Thompson, David I. Quinn, Evan Y. Yu
Journal: Journal of Clinical Oncology (2020)

106 Background: Cixutumumab, a monoclonal antibody targeting insulin-like growth factor I receptor, did not improve rate of undetectable PSA at 28 weeks when combined with AD in the randomized phase II SWOG S0925 trial for patients with new mHSPC. We now present mature radiographic progression-free survival (rPFS) and overall survival (OS) analyses, along with pre-specified secondary and exploratory endpoints. Methods: We used Kaplan-Meier curves to analyze OS, rPFS, and castration resistance-free survival by treatment arm, disease volume (as per CHAARTED), and risk (as per LATITUDE). We explored differences in survival by treatment arm via covariate-adjusted Cox proportional hazard models adjusted for disease volume and risk. Results: The trial enrolled 210 patients, 105 per treatment arm. Median follow-up was 5.3 years. No difference was seen between treatment arms in OS (HR 1.01 [0.70-1.45]; p=0.97), rPFS (HR 1.17 [0.85-1.60]; p=0.35), or castration resistance-free survival (HR 1.02 [0.75-1.41]; p=0.88). At baseline, 105/198 (53.0%) patients had high risk and 119/210 (56.7%) had high volume disease. 17.3% of high volume patients were classified as low risk and 15.9% of low volume patients were classified as high risk; together, 16.7% of patients had discordant classification of high or low category for risk and volume. Adjusting for risk or volume yielded no differences in OS between arms. Inferior survival was observed in high risk (HR 1.89 [1.29-2.80]; p=0.001) and high volume (HR 2.75 [1.84-4.10]; p&lt;0.0001) disease. Disease volume was a better fit to survival data than risk (AIC 878.3 vs. 889.2). Compared to patients achieving undetectable PSA at 28 weeks, inferior survival was observed in patients whose PSA was &gt;0.2 to ≤4.0 ng/mL (HR 3.72 [1.99-6.95]; p&lt;0.0001) or &gt;4.0 ng/mL (HR 7.13 [4.24-11.9]; p&lt;0.0001). Conclusions: In new mHSPC, adding cixutumumab to AD did not improve survival measures. Baseline risk and disease volume carried prognostic value for this distinct trial population, though disease volume was a better predictor of survival. PSA treatment response was a strong intermediate endpoint for survival. Clinical trial information: NCT01120236.
How Significant Is Severe Hypoglycemia in Older Adults With Diabetes?
Authors: Lisa Chow, Elizabeth R. Seaquist
Journal: Diabetes Care (2020)

Severe hypoglycemia is a devastating event in the lives of people with diabetes treated with insulin and/or insulin secretogogues. Severe hypoglycemia is defined as an episode in which the person with diabetes requires the assistance of another to increase blood glucose, usually by administration of glucagon or contacting a medical professional. These occurrences are not rare. More than 10% of adult patients in the T1D Exchange registry reported at least one episode of severe hypoglycemia over the past 12 months (1). These events elicit profound fear in patients with diabetes. By depriving the brain of glucose, severe hypoglycemia acutely alters brain function, resulting in neuroglycopenic symptoms, seizures, or even death. The impact extends beyond the acute event. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that patients with type 2 diabetes who experience severe hypoglycemia were at higher risk for a major macrovascular event or death over the subsequent 12 months (2). As the population ages, there remains a critical need to understand the significance and impact of severe hypoglycemia in older patients with diabetes.

In this issue of Diabetes Care , complementary articles provide new insights into the consequences of severe hypoglycemia in older adults. Lacy et al. (3) report that severe hypoglycemia is associated with reduced cognitive function in older adults with type 1 diabetes, and Standl et al. (4) confirm the bidirectional nature of the association between severe hypoglycemia and cardiovascular (CV) events in adults with type 2 diabetes. Both investigations …
Contribution of extragonadal steroids to the androgen receptor activity and to the castration-resistance development in recurrent prostate cancers after primary therapy.
Authors: Frederic Pouliot, Mélanie Rouleau, Bertrand Neveu, Paul Toren, Fannie Morin, Lauriane Vélot, Keyue Ding, Patrick Caron, Louis Lacombe, Eric Levesque, Laurence Klotz, Chantal Guillemette
Journal: Journal of Clinical Oncology (2020)

148 Background: Beyond testosterone, several steroids contribute to the activation of the androgen receptor (AR) pathway, but their relative contributions in castrated prostate cancer (PCa) patients remain unknown. Methods: Serum levels of nine steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (n=219) and from the PCA24 cohort (n=116). For each steroid, standard curves for dose-dependent prostate-specific antigen promoter activation were built in castration-sensitive (LAPC4) and resistant (VCaP) PCa models. Standard curves were used to determine the AR activation potency for each steroid measurement from patients. Results: In LAPC4 and VCaP cells, testosterone, dihydrotestosterone and androstenedione induced AR transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol, androsterone stimulated AR only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total AR transcriptional activity found in castrated patients. The total AR transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR=2.17; 95% CI: 1.12-4.23; p=0.02) in multivariate analysis using the castration-sensitive model (LAPC4). AR transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR=1.89; 95% CI: 1.04-3.44; p=0.036). Conclusions: Extragonadal steroids contribute significantly to the AR axis activation at testosterone castration levels in recurrent non-metastatic PCa and these sustain the development of castration resistance after primary local treatment.
Keep an eye on adenosine: Its role in retinal inflammation
Authors: Ana Raquel Santiago, Maria H. Madeira, Raquel Boia, Inês Dinis Aires, Ana Catarina Rodrigues-Neves, Paulo Fernando Santos, António Francisco Ambrósio
Journal: Pharmacology & Therapeutics (2020)

Adenosine is an endogenous purine nucleoside ubiquitously distributed throughout the body that interacts with G protein-coupled receptors, classified in four subtypes: A1R, A2AR, A2BR and A3R. Among the plethora of functions of adenosine, it has been increasingly recognized as a key mediator of the immune response. Neuroinflammation is a feature of chronic neurodegenerative diseases and contributes to the pathophysiology of several retinal degenerative diseases. Animal models of retinal diseases are helping to elucidate the regulatory roles of adenosine receptors in the development and progression of those diseases. Mounting evidence demonstrates that the adenosinergic system is altered in the retina during pathological conditions, compromising retinal physiology. This review focuses on the roles played by adenosine and the elements of the adenosinergic system (receptors, enzymes, transporters) in the neuroinflammatory processes occurring in the retina. An improved understanding of the molecular and cellular mechanisms of the signalling pathways mediated by adenosine underlying the onset and progression of retinal diseases will pave the way towards the identification of new therapeutic approaches.
Transition from intravenous epoprostenol to selexipag in pulmonary arterial hypertension: a word of caution
Authors: Kenichi Yanaka, Alicia Guillien, Thibaud Soumagne, Justin Benet, Nicolas Piliero, François Picard, Christophe Pison, Olivier Sitbon, Hélène Bouvaist, Bruno Degano
Journal: European Respiratory Journal (2020)

<b>Even for patients who are very stable while receiving <i>i.v.</i> epoprostenol over a long period of time, any transition to selexipag warrants careful long-term clinical and haemodynamic follow-up because worsening is likely to occur</b>http://bit.ly/32wR9eX
Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1
Authors: Xin Liu, Yunwei Wei, Xue Bai, Mingqi Li, Huimin Li, Lei Wang, Shuqian Zhang, Xia Li, Tong Zhao, Yang Liu, Rui Geng, Hao Cui, Hui Chen, Ranchen Xu, Heng Liu, Yong Zhang, Baofeng Yang
Journal: Acta Pharmaceutica Sinica B (2020)

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and represent the major cause of postsurgical morbidity. Enterolysis at repeat surgeries induces adhesion reformation that is more difficult to prevent than primary adhesion. Here we studied the preventive effects of different approaches of berberine treatment for primary adhesion, and its effects on adhesion reformation compared to Interceed. We found the primary adhesion was remarkably prevented by berberine through intraperitoneal injection 30 min before abrasive surgery (pre-berberine) or direct addition into injured cecum immediately after the surgery (inter-berberine). Rats with adhesion reformation had a more deteriorative collagen accumulation and tissue injury in abrasive sites than rats with primary adhesion. The dysregulated TIMP-1/MMP balance was observed in patients after surgery, as well as adhesion tissues from primary adhesion or adhesion reformation rats. Inter-berberine treatment had a better effect for adhesion reformation prevention than Interceed. Berberine promoted the activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core, which was reversed by TIMP-1 overexpression in fibroblasts. In conclusion, this study suggests berberine as a reasonable approach for preventing primary adhesion formation and adhesion reformation.
Design of self-polymerized insulin loaded poly(n-butylcyanoacrylate) nanoparticles for tunable oral delivery
Authors: Hongbo Cheng, Xin Zhang, Lu Qin, Yingnan Huo, Zhixiang Cui, Chang Liu, Yujiao Sun, Jian Guan, Shirui Mao
Journal: Journal of Controlled Release (2020)
Factors Associated With County-Level Variation in Premature Mortality Due to Noncommunicable Chronic Disease in the United States, 1999-2017
Authors: Suhang Song, Michael G. Trisolini, Kenneth A. LaBresh, Sidney C. Smith, Yinzi Jin, Zhi-Jie Zheng
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Progress against premature death due to noncommunicable chronic disease (NCD) has stagnated. In the United States, county-level variation in NCD premature mortality has widened, which has impeded progress toward mortality reduction for the World Health Organization (WHO) 25 × 25 target. <h3>Objectives</h3> To estimate variations in county-level NCD premature mortality, to investigate factors associated with mortality, and to present the progress toward achieving the WHO 25 × 25 target by analyzing the trends in mortality. <h3>Design, Setting, and Participants</h3> This cross-sectional study focused on NCD premature mortality and its factors from 3109 counties using US mortality data for cause of death from the Centers for Disease Control and Prevention WONDER databases and county-level characteristics data from multiple databases. Data were collected from January 1, 1999, through December 31, 2017, and analyzed from April 1 through October 28, 2019. <h3>Exposures</h3> County-level factors, including demographic composition, socioeconomic features, health care environment, and population health status. <h3>Main Outcomes and Measures</h3> Variations in county-level, age-adjusted NCD mortality in the US residents aged 25 to 64 years and associations between mortality and the 4 sets of county-level factors. <h3>Results</h3> A total of 6 794 434 deaths due to NCD were recorded during the study period (50.58% women; 16.49% aged 65 years or older). Mortality decreased by 4.30 (95% CI, −4.54 to −4.08) deaths per 100 000 person-years annually from 1999 to 2010 (<i>P</i> &lt; .001) and decreased annually at a rate of 0.90 (95% CI, −1.13 to −0.73) deaths per 100 000 person-years annually from 2010 to 2017 (<i>P</i> &lt; .001). Mortality in the county with the highest mortality was 10.40 times as high as that in the county with the lowest mortality (615.40 vs 59.20 per 100 000 population) in 2017. Geographic inequality was decomposed by between-state and within-state differences, and within-state differences accounted for most inequality (57.10% in 2017). County-level factors were associated with 71.83% variation in NCD mortality. Association with intercounty mortality was 19.51% for demographic features, 23.34% for socioeconomic composition, 16.40% for health care environment, and 40.75% for health-status characteristics. <h3>Conclusions and Relevance</h3> Given the stagnated trend of decline and increasing variations in NCD premature mortality, these findings suggest that the WHO 25 × 25 target appears to be unattainable, which may be related to broad failure by United Nations members to follow through on commitments of reducing socioeconomic inequalities. The increasing inequalities in mortality are alarming and warrant expanded multisectoral efforts to ameliorate socioeconomic disparities.
Sarcomatoid urothelial carcinoma (SUC): A single-institution experience of oncologic outcomes and recurrence patterns.
Authors: Leonidas Nikolaos Diamantopoulos, Rishi Robert Sekar, Ali Raza Khaki, Brian Winters, Funda Vakar-Lopez, Maria S. Tretiakova, John L. Gore, George R. Schade, Sarah P. Psutka, Andrew Caleb Hsieh, John Kyung Lee, Todd Yezefski, Michael Thomas Schweizer, Heather H. Cheng, Evan Y. Yu, Daniel W. Lin, Robert B. Montgomery, Petros Grivas, Jonathan L. Wright
Journal: Journal of Clinical Oncology (2020)

465 Background: SUC is a rare histology with aggressive behavior. We evaluated outcomes and recurrence patterns of patients (pts) with SUC, in comparison with conventional urothelial carcinoma (CUC). Methods: We retrospectively assessed our radical cystectomy (RC) database to identify pts with cT2-4 SUC (any %) or CUC, at RC or transurethral resection specimens. Clinicopathologic/treatment data were captured and compared with t and χ 2 tests, as appropriate. Overall survival (OS; diagnosis to death) and recurrence-free survival (RFS; RC to recurrence or death) were estimated (KM method). Significant factors in univariable (UVA) Cox regression for OS were included in multivariable analysis (MVA). Results: We identified 38 consecutive pts with cT2-4 SUC and 287 with CUC (2003-2018); 17 (45%) and 162 (56%) received neoadjuvant chemotherapy (NAC). The primary non-mesenchymal component was urothelial in all SUC cases. SUC had higher rates of pT3/4 (66% vs. 35%, p &lt; .001) but comparable rates of pN+ disease (26% vs. 20%, p = .38). Complete response (ypT0N0) after NAC was lower for SUC (6% vs. 35%, p = .02). Median follow-up was 73.6 months (95%CI 62.6 – 84.7). Median RFS and OS was inferior among pts with SUC (9.4 vs 109.8 months, p &lt; .001, 19.7 vs. 130.4 months, p &lt; .001 respectively). On MVA, SUC was independently associated with worse OS ( Table). Of 17 (45%) pts with SUC who recurred post-RC, 5 presented with abdomino-pelvic cystic masses, with an average time to recurrence &lt; 5 months. Conclusions: SUC was associated with high rates of extravesical spread at RC and worse NAC response, RFS and OS, vs. CUC. Development of abdomino-pelvic fluid collections should raise suspicion of recurrence among pts with this histology. [Table: see text]
In acute pain in prehospital settings, opioid and nonopioid analgesics do not differ for pain at 15 or 60 min
Authors: Evan S. Schwarz, Hawnwan P. Moy
Journal: Annals of Internal Medicine (2020)

Source Citation Sobieraj DM, Baker WL, Martinez BK, et al. Comparative effectiveness of analgesics to reduce acute pain in the prehospital setting. AHRQ Publication No. 19-EHC021-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2019. 31509367
Associations of Assisted Reproductive Technology and Twin Pregnancy With Risk of Congenital Heart Defects
Authors: Shi Wu Wen, Qun Miao, Monica Taljaard, Jane Lougheed, Laura Gaudet, Michael Davies, Andrea Lanes, Art Leader, Daniel J. Corsi, Ann E. Sprague, Mark Walker
Journal: JAMA Pediatrics (2020)

The extent to which assisted reproductive technology is associated with increased risk of congenital heart defects independent of its known association with twinning remains uncertain.To assess the extent to which assisted pregnancy is associated with increased risk of congenital heart defects independent of its known association with twinning.This retrospective cohort study linked records of congenital heart defect diagnoses with assisted reproductive technology cycles in 507 390 singleton or twin pregnancies (10 149 assisted pregnancies and 497 241 nonassisted pregnancies), including singleton and twin early pregnancy losses, stillbirths, and live births (follow-up to 1 year of age) in Ontario, Canada, between April 1, 2012, and October 31, 2015. Statistical analysis was performed from January 1, 2017, to September 9, 2019.Assisted reproductive technology and its 2 subtypes: intracytoplasmic sperm injection and in vitro fertilization without intracytoplasmic sperm injection.The main outcome was congenital heart defects (prevalence and relative risk measured as odds ratios [ORs]). Mediation analysis was performed to assess the extent to which the association between assisted reproductive technology and congenital heart defects was mediated by twinning.Of 507 390 mother-infant pairs with singleton or twin pregnancies evaluated, the prevalence of congenital heart defects in assisted pregnancies (223 [2.2%]) was higher than that in nonassisted pregnancies (6057 [1.2%]; crude OR, 1.82; 95% CI, 1.59-2.09). The strength of the association between assisted pregnancy and congenital heart defects decreased after adjusting for several risk factors simultaneously (adjusted OR, 1.70; 95% CI, 1.48-1.95). Further mediation analysis indicated that most of the association between assisted pregnancy and congenital heart defects was mediated by twinning (adjusted OR, 1.68; 95% CI, 1.44-1.92), and the natural direct association of assisted pregnancy with congenital heart defects among singleton pregnancies was 1.09 (95% CI, 0.93-1.25). Mediation of twinning accounted for 87.3% of the association.Our study results suggest that the association between assisted reproductive technology and congenital heart defects may be mediated by twinning.
Evidence of SARS-CoV-2 Infection in Returning Travelers from Wuhan, China
Authors: Sebastian Hoehl, Holger Rabenau, Annemarie Berger, Marhild Kortenbusch, Jindrich Cinatl, Denisa Bojkova, Pia Behrens, Boris Böddinghaus, Udo Götsch, Frank Naujoks, Peter Neumann, Joscha Schork, Petra Tiarks-Jungk, Antoni Walczok, Markus Eickmann, Maria J.G.T. Vehreschild, Gerrit Kann, Timo Wolf, René Gottschalk, Sandra Ciesek
Journal: New England Journal of Medicine (2020)

Coronavirus in Travelers Returning from China A group of 126 German nationals was evacuated from Wuhan to Frankfurt after screening for symptoms of Covid-19 and was to undergo a 14-day quarantine a...
Prenatal and Early Childhood Triclosan Exposure and Allergic Outcomes in a Prospective Pregnancy and Birth Cohort
Authors: Medina Jackson-Browne, Melissa Eliot, Adam Spanier, George Papandonatos, Aimin Chen, Antonia Calafat, Kimberly Yolton, Bruce Lanphear, Joseph Braun
Journal: Journal of Allergy and Clinical Immunology (2020)
Suicidal thoughts (ideation) among elite athletics (track and field) athletes: associations with sports participation, psychological resourcefulness and having been a victim of sexual and/or physical abuse
Authors: Toomas Timpka, Armin Spreco, Orjan Dahlstrom, Jenny Jacobsson, Jan Kowalski, Victor Bargoria, Margo Mountjoy, Carl Göran Svedin
Journal: British Journal of Sports Medicine (2020)

Objective To examine associations between suicidal ideation and sexual and physical abuse among active and recently retired elite athletics (track and field) athletes. Methods The study population consisted of all athletes (n=402) selected for a Swedish Athletics team between 2011 and 2017. Data on suicidal ideation, suicidal events (estimated through the 1 year non-sports injury prevalence), lifetime abuse experiences, sociodemographics, sense of coherence and coping strategies were collected using a cross-sectional survey. The data were analysed using binary logistic regression with suicidal ideation and non-sports injury as outcomes. Results 192 athletes (47.8%) returned data. The prevalence of suicidal ideation was 15.6% (men 17.4%; women 14.2%) and the non-sports injury prevalence was 8.0% (men 11.6%; women 5.7%). Among women, suicidal ideation was associated with having been sexually abused (OR 5.94, 95% CI 1.42 to 24.90; p=0.015) and lower sense of coherence (OR 0.90, 95% CI 0.85 to 0.96; p=0.001) (Nagelkerke R 2 =0.33). Among men, suicidal ideation was only associated with use of behavioural disengagement for coping (OR 1.51, 95% CI 1.18 to 1.95; p=0.001) ( R 2 =0.25). Among women, non-sports injury prevalence was associated with having been sexually abused (OR 8.61, 95% CI 1.34 to 55.1; p=0.023) and participating in an endurance event (OR 7.37, 95% CI 1.11 to 48.9; p=0.039 ( R 2 =0.23), while among men, having immigrant parents (OR 5.67, 95% CI 1.31 to 24.5; p=0.020) ( R 2 =0.11) was associated with injury outside sports. Conclusions About one out of six international athletics athletes reported having experienced suicidal ideation. World Athletics and National Olympic Committees need to include suicide prevention in their athlete protection programmes.