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Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly effective combination strategy in MAPK-dependent cancer, such as KRAS mutant tumors. [ABSTRACT FROM AUTHOR]

Decitabine, a cancer therapeutic that inhibits DNA methyl-ation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells. Pretreatment with decitabine decreased the cytotoxic activity of MEK inhibitors in KRAS-mutant ovarian cancer cells, with reciprocal downregulation of DNMT1 and MEK/ERK phosphorylation. In parallel with these responses, decitabine also upregulated the proapoptotic BCL-2 family member BNIP3, which is known to be regulated by MEK and ERK, and heightened the activity of proapoptotic small-molecule navitoclax, a BCL-2 family inhibitor. In a xenograft model of KRAS-mutant ovarian cancer, combining decitabine and navitoclax heightened antitumor activity beyond administration of either compound alone. Our results define the RAS/MEK/DNMT1 pathway as a determinant of sensitivity to DNA methyltransferase inhibition, specifically implicating KRAS status as a biomarker of drug response in ovarian cancer. [ABSTRACT FROM AUTHOR]

Pathogen transmission by mosquitoes is tightly linked to blood feeding which, in turn, is required for egg development. Studies of these processes would greatly benefit from genetic methods, such as the binary Gal4/UAS system. The latter has been well established for model organisms, but its availability is limited for mosquitoes. The objective of this study was to develop the blood-meal-activated, gut-specific Gal4/UAS system for the yellow-fever mosquito Aedes aegypti and utilize it to investigate the regulation of gut-specific gene expression. A 1.1-kb, 5 ′ upstream region of the carboxypeptidase A ( CP ) gene was used to genetically engineer the CP-Gal4 driver mosquito line. The CP-Gal4 specifically activated the Enhanced Green Fluorescent Protein (EGFP) reporter only after blood feeding in the gut of the CP-Gal4 > UAS-EGFP female Ae. aegypti . We used this system to study the regulation of CP gene expression. In vitro treatments with either amino acids (AAs) or insulin stimulated expression of the CP-Gal4 > UAS-EGFP transgene; no effect was observed with 20-hydroxyecdysone (20E) treatments. The transgene activation by AAs and insulin was blocked by rapamycin, the inhibitor of the Target-of-Rapamycin (TOR) kinase. RNA interference (RNAi) silence of the insulin receptor (IR) reduced the expression of the CP-Gal4 > UAS-EGFP transgene. Thus, in vitro and in vivo experiments have revealed that insulin and TOR pathways control expression of the digestive enzyme CP. In contrast, 20E, the major regulator of post-blood-meal vitellogenic events in female mosquitoes, has no role in regulating the expression of this gene. This novel CP-Gal4/UAS system permits functional testing of midgut-specific genes that are involved in blood digestion and interaction with pathogens in Ae. aegypti mosquitoes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate diagnostic trends in pediatric and adult patients presenting for multidisciplinary subspecialty evaluation of dizziness and imbalance across the lifespan., Study Design: Retrospective chart review., Setting: Single pediatric and single adult academic tertiary care hospital., Methods: Retrospective review of electronic health record for patients presenting to an adult or pediatric multidisciplinary vestibular clinic from 2017 to 2020, including clinical data, physical therapy evaluation, and audiovestibular testing., Results: A total of 1934 patients aged 1 to 95 were evaluated. Most patients were female (n = 1188, 61%); the largest cohort was in the fifth decade of life (n = 321, 17%). Seventy-six percent of patients (n = 1470) were assigned a pathologic diagnosis. Central causes of dizziness were most common in children and young adults, comprising 38% to 54% of all diagnoses in ages 1 to 30. The proportion of peripheral vestibular disorders increased with age, peaking at 32% in ages 61 to 70. Vestibular migraine was the most common pathologic diagnosis in ages 6 to 20 (n = 110, 39%) and 31 and 50 (n = 69, 17%) regardless of gender, but was more prevalent in females (21% vs 14%; P < .0001). The prevalence of benign paroxysmal positional vertigo (BPPV) increased throughout the lifespan, peaking at age 71 to 80. Meniere's disease (MD) did not occur within the first decade of life, but increased thereafter, peaking at ages 51 to 60., Conclusion: Multidisciplinary vestibular evaluation resulted in a diagnosis for the majority of patients. Vestibular diagnoses vary across the lifespan however among most age groups, central disorders, including migraine disorders, outnumber peripheral vestibulopathies. The prevalence of peripheral vestibular disorders such as BPPV and MD increased with age., Level of Evidence: Level IV., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: To develop machine learning (ML) models predicting unplanned readmission and reoperation among patients undergoing free flap reconstruction for head and neck (HN) surgery., Methods: Data were extracted from the 2012-2019 NSQIP database. eXtreme Gradient Boosting (XGBoost) was used to develop ML models predicting 30-day readmission and reoperation based on demographic and perioperative factors. Models were validated using 2019 data and evaluated., Results: Four-hundred and sixty-six (10.7%) of 4333 included patients were readmitted within 30 days of initial surgery. The ML model demonstrated 82% accuracy, 63% sensitivity, 85% specificity, and AUC of 0.78. Nine-hundred and four (18.3%) of 4931 patients underwent reoperation within 30 days of index surgery. The ML model demonstrated 62% accuracy, 51% sensitivity, 64% specificity, and AUC of 0.58., Conclusion: XGBoost was used to predict 30-day readmission and reoperation for HN free flap patients. Findings may be used to assist clinicians and patients in shared decision-making and improve data collection in future database iterations., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Competing Interests: The authors declare no conflicts of interest.

Competing Interests: The author declares no conflicts of interest.

The priority review voucher was established to incentivize research and development of treatments for traditionally underfunded diseases and was extended to medical countermeasures from 2016 to 2023, despite limited evidence of an association between the voucher program and increased product development. To determine whether the voucher program has incentivized initiation of new medical countermeasures in clinical trials, we created three cohorts of material threats: (i) COVID-19, (ii) opioid pharmaceutical-based agents, and (iii) all others. Using the Citeline Trialtrove database, we determined the number of medical countermeasures initiated in clinical trials from 2009-2016 and 2017-2023. Eligibility of COVID-19 products for the voucher was confirmed with the issuance of a voucher for remdesivir in October 2020, so we compared January 2020-October 2020 to November 2020-July 2023. We fit two Poisson models-before and after voucher creation-within each cohort. Among COVID-19 medical countermeasures, there was a decrease in the proportion of drugs initiated before (4.5%; 95% CI, 1.0 to 8.3%) vs. after voucher eligibility (-5.1%; 95% CI, -6.1 to -4.0%) (P = 0.01). Among opioid pharmaceutical-based agents medical countermeasures, the rate of new drugs initiated did not change from 2009-2016 (8.1%, 95% CI, -4.4 to 22.6%) to 2017-2023 (5.6%; 95% CI, -3.2 to 15.2%) (P = 0.82). Among all other medical countermeasures, the rate of new drugs initiated also did not change from 2009-2016 (6.6%; 95% CI, -5.6 to 20.8%) to 2017-2023 (-14.8%; 95% CI, -29.2 to 2.0%) (P = 0.15). The priority review voucher program was not associated with stimulating new clinical testing of investigational medical countermeasures., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Importance: Endometrial cancer and precancer are common gynecologic problems for many women. A majority of these patients require surgery as the mainstay of treatment. Many of these patients often have concurrent pelvic floor disorders. Despite the prevalence and shared risk, fewer than 3% of women undergo concomitant surgery for PFDs at the time of surgery for endometrial cancer or endometrial intraepithelial neoplasia/hyperplasia., Objective: This study aimed to evaluate postoperative morbidity of concomitant pelvic organ prolapse (POP) and/or urinary incontinence (UI) procedures at the time of hysterectomy for endometrial cancer (EC) or endometrial intraepithelial neoplasia/endometrial hyperplasia (EIN/EH)., Methods: This retrospective analysis of women undergoing hysterectomy for EC or EIN/EH between 2017 and 2022 used the American College of Surgeons National Surgical Quality Improvement Program database. The primary outcome was any major complication within 30 days of surgery. Comparisons were made between 2 cohorts: hysterectomy with concomitant pelvic organ prolapse/urinary incontinence procedures (POPUI) versus hysterectomy without concomitant POP or UI procedures (HYSTAlone). A subgroup analysis was performed in patients with EC. A propensity score matching cohort was also created., Results: A total of 23,144 patients underwent hysterectomy for EC or EIN/EH: 1.9% (n = 432) had POP and/or UI procedures. Patients with POPUI were older, were predominantly White, had higher parity, and had lower body mass index with lower American Society of Anesthesiologists class. Patients with POPUI were less likely to have EC (65.7% vs 78.3%, P < 0.0001) and more likely to have their hysterectomy performed by a general obstetrician- gynecologists or urogynecologists. Major complications were low and not significantly different between POPUI and HYSTAlone (3.7% vs 3.6%, P = 0.094). A subgroup analysis of EC alone found that the HYSTAlone subset did not have more advanced cancers, yet the surgeon was more likely a gynecologic oncologist (87.1% vs 68.0%, P < 0.0001). There were no statistically significant differences between the 2 cohorts for the primary and secondary outcomes using propensity score matching analysis., Conclusions: Concomitant prolapse and/or incontinence procedures were uncommon and did not increase the rate of 30-day major complications for women undergoing hysterectomy for EC/EH., (Copyright © 2024 American Urogynecologic Society. All rights reserved.)

Introduction/objective: The KidneyIntelX is a multiplex, bioprognostic, immunoassay consisting of 3 plasma biomarkers and clinical variables that uses machine learning to predict a patient's risk for a progressive decline in kidney function over 5 years. We report the 1-year pre- and post-test clinical impact on care management, eGFR slope, and A1C along with engagement of population health clinical pharmacists and patient coordinators to promote a program of sustainable kidney, metabolic, and cardiac health., Methods: The KidneyIntelX in vitro prognostic test was previously validated for patients with type 2 diabetes and diabetic kidney disease (DKD) to predict kidney function decline within 5 years was introduced into the RWE study (NCT04802395) across the Health System as part of a population health chronic disease management program from [November 2020 to April 2023]. Pre- and post-test patients with a minimum of 12 months of follow-up post KidneyIntelX were assessed across all aspects of the program., Results: A total of 5348 patients with DKD had a KidneyIntelX assay. The median age was 68 years old, 52% were female, 27% self-identified as Black, and 89% had hypertension. The median baseline eGFR was 62 ml/min/1.73 m 2 , urine albumin-creatinine ratio was 54 mg/g, and A1C was 7.3%. The KidneyIntelX risk level was low in 49%, intermediate in 40%, and high in 11% of cases. New prescriptions for SGLT2i, GLP-1 RA, or referral to a specialist were noted in 19%, 33%, and 43% among low-, intermediate-, and high-risk patients, respectively. The median A1C decreased from 8.2% pre-test to 7.5% post-test in the high-risk group ( P  < .001). UACR levels in the intermediate-risk patients with albuminuria were reduced by 20%, and in a subgroup treated with new scripts for SGLT2i, UACR levels were lowered by approximately 50%. The median eGFR slope improved from -7.08 ml/min/1.73 m 2 /year to -4.27 ml/min/1.73 m 2 /year in high-risk patients ( P  = .0003), -2.65 to -1.04 in intermediate risk, and -3.26 ml/min/1.73 m 2 /year to +0.45 ml/min/1.73 m 2 /year in patients with low-risk ( P  < .001)., Conclusions: Deployment and risk stratification by KidneyIntelX was associated with an escalation in action taken to optimize cardio-kidney-metabolic health including medications and specialist referrals. Glycemic control and kidney function trajectories improved post-KidneyIntelX testing, with the greatest improvements observed in those scored as high-risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJD, TM, FF, and RT are employees of Renalytix; SC, GN, MK, and AZ are consultants for Renalytix, All remaining authors have nothing to disclose.

Study Objective: Investigate outcomes for patients undergoing minimally invasive hysterectomies (MIHs) performed for endometrial cancer at ambulatory surgery centers (ASCs)., Design: Our study aimed to explore the feasibility and discharge outcomes for MIHs for endometrial cancer in an ASC setting by using same-day discharge data., Setting: The prevalence of MIH for endometrial cancer between 2016 and 2019 was estimated from the Nationwide Ambulatory Surgery Sample., Patients: Patients who underwent MIHs for endometrial cancer at an ASC were included., Interventions: N/A MEASUREMENTS MAIN RESULTS: Weighted estimates of prevalence and association between discharge status and sociodemographic factors were explored. Same-day discharge was defined as discharge on the day of surgery, and delayed discharge was defined as discharge after the day of surgery. An estimated 95 041 MIHs for endometrial cancer were performed at ASCs between 2016 and 2019. Notably, 91.9% (n = 87 372) resulted in same-day discharge, 1.2% (n = 1121) had delayed discharge, and 6.9% (n = 6548) had missing discharge information; 78.7% procedures (n = 68 812) were performed at public hospitals. The proportion of delayed discharges were lower in private, not-for profit ASCs (0.8%, p = .03) than public hospitals. Patients who had delayed discharges on average were older (69.7 vs 62.4 years, p <.001), more likely to have comorbid conditions including diabetes (adjusted odds ratio [aOR] 1.48, 95% confidence interval [CI] 1.25-1.75) and overweight or obese body mass indices (aOR 1.18, 95% CI 1.01-1.39), and more likely to have public insurance (aOR 1.78, 95% CI 1.40-2.25)., Conclusion: MIHs for endometrial cancer are feasible in an ASC. Optimal candidates for receipt of MIHs for endometrial cancer at an ASC are patients who are younger and have less comorbidities, lower body mass index, and private insurance., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Trastuzumab is a humanised, monoclonal antibody that interferes with the human epidermal growth factor receptor 2 (HER2)/neu receptor and binds selectively to the HERB2 protein. It has been shown to prolong survival of patients with HER2-positive advanced uterine serous carcinoma.We report the case of a woman in her 70s with HER2-positive metastatic papillary serous endometrial adenocarcinoma, who experienced severe thrombocytopenia related to trastuzumab administration. One week after the first dose of carboplatin/paclitaxel/trastuzumab combination chemotherapy, the patient was admitted to the hospital with vaginal bleeding, melena, petechiae and platelet counts of 0×10 9 /L. The patient was suspected to have a severe trastuzumab-induced thrombocytopenia. A rapid and complete recovery was observed after multiple platelet transfusions, high-dose IV corticosteroids and immunoglobulin.Among the 13 reported cases of trastuzumab-induced thrombocytopenia, this is the first case reported in the literature occurring in a patient with a gynecologic malignancy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We describe provider documented counseling patterns and perception regarding HPV vaccination among patients with a history of cervical dysplasia., Methods: All patients ages 21-45 who underwent colposcopy at a single academic medical center from 2018 to 2020were sent a self-administered survey through the electronic medical record patient portal to assess their attitudes regarding human papillomavirus (HPV) vaccination. Demographic information, HPV vaccination history, and documented obstetrics and gynecology provider counseling at the time of colposcopy were examined., Results: Of 1465patients, 434 (29.6 %) reported or had documented receipt of at least one dose of the human papillomavirus vaccine. The remainder reported they were not vaccinated or had no documentation of vaccination. Proportion of vaccinated patients was higher among White compared to Black and Asian patients (P = 0.02). On multivariate analysis, private insurance (aOR 2.2, 95 % CI 1.4-3.7) was associated with vaccinated status while Asian race (aOR 0.4, 95 % CI 0.2-0.7) and hypertension (aOR 0.2, 95 % CI 0.08-0.7) were less likely to be associated with vaccination status. Among patients with unvaccinated or unknown vaccination status, 112 (10.8 %) received documented counseling regardingcatch-up human papillomavirus vaccination at a gynecologic visit. Patients seen by a sub-specialist obstetrics and gynecologic provider were more likely to have documented provider counseling regarding vaccination compared to those seen by a generalist obstetric/gynecologist provider (26 % vs 9.8 %, p < 0.001). Patients cited lack of physician discussion (53.7 %) and the belief that they were too old to receive the HPV vaccine (48.8 %) as the main reasons for remaining unvaccinated., Conclusion: HPV vaccination and the rate of obstetric and gynecologic provider counseling regarding HPV vaccination among patients undergoing colposcopy remains low. When surveyed, many patients with a history of colposcopy cited provider recommendation as afactor in their decision to undergo adjuvant HPV vaccination, demonstrating the importance of provider counseling in thisgroup., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Shared decision-making (SDM) helps patients weigh risks and benefits of screening approaches. Little is known about SDM visits between patients and healthcare providers in the context of lung cancer screening. This study explored the extent that patients were informed by their provider of the benefits and harms of lung cancer screening and expressed certainty about their screening choice. We conducted a survey with 75 patients from an academic medical center in the Southeastern U.S. Survey items included knowledge of benefits and harms of screening, patients' value elicitation during SDM visits, and decisional certainty. Patient and provider characteristics were collected through electronic medical records or self-report. Descriptive statistics, Kruskal-Wallis tests, and Pearson correlations between screening knowledge, value elicitation, and decisional conflict were calculated. The sample was predominately non-Hispanic White (73.3%) with no more than high school education (53.4%) and referred by their primary care provider for screening (78.7%). Patients reported that providers almost always discussed benefits of screening (81.3%), but infrequently discussed potential harms (44.0%). On average, patients had low knowledge about screening (score = 3.71 out of 8) and benefits/harms. Decisional conflict was low (score = - 3.12) and weakly related to knowledge (R= - 0.25) or value elicitation (R= - 0.27). Black patients experienced higher decisional conflict than White patients (score = - 2.21 vs - 3.44). Despite knowledge scores being generally low, study patients experienced low decisional conflict regarding their decision to undergo lung cancer screening. Additional work is needed to optimize the quality and consistency of information presented to patients considering screening., (© 2022. The Author(s) under exclusive licence to American Association for Cancer Education.)

Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1-2) GEP-NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1-3 GEP-NET, we calculated baseline TGR (TGR 0 ) from radiological images of metastases acquired prior to first-line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1-3 tumors combined was 5% (range = 0.1%-52%) and median TGR 0 was 4.8%/month (m) (range = 0%-45.9%/m). TGR 0 correlated with pretreatment Ki67 across G1-3 pooled and within G3 GEP-NET. Patients with higher TGR 0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p = .03) and shorter overall survival (median, 4.1 years vs. not reached; p = .003). Independent of therapies given, higher TGR 0 GEP-NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p = .02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p = .04) upon serial biopsy. Importantly, TGR 0 , but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP-NETs, future clinical trials may benefit from stratification for TGR 0 , particularly in G1-2 tumors, in which TGR 0 does not correlate with Ki67. TGR 0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR 0 in larger and more homogeneously treated cohorts, and to ascertain if post-treatment TGR has value in previously treated patients starting a new line of therapy., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Background: Cytomegalovirus (CMV) infection leads to effector memory CD8 + T cell expansion and is associated with immune dysfunction in older adults. However, the molecular alterations of CMV-specific CD8 + T cells in CMV infected healthy young and middle-aged adults has not been fully characterized., Results: We compared CD8 + T cells specific for a CMV epitope (pp65 495-503 , NLV) and an influenza A virus (IAV) epitope (M1 58-66 , GIL) from the same young and middle-aged healthy adults with serum positive for anti-CMV IgG. Compared to the IAV-specific CD8 + T cells, CMV-specific CD8 + T cells contained more differentiated effector memory (T EM and T EMRA ) cells. Isolated CMV-specific central memory (T CM ) but not naïve (T N ) cells had a significant reduced activation-induced expansion in vitro compared to their IAV-specific counterparts. Furthermore, we found that CD70 expression was reduced in CMV-specific CD28 + CD8 + T CM and that CD70 + T CM had better expansion in vitro than did CD70 - T CM . Mechanistically, we showed that CD70 directly enhanced MAPK phosphorylation and CMV-specific CD8 + T CM cells had a reduced MAPK signaling upon activation. Lastly, we showed that age did not exacerbate reduced CD70 expression in CMV- specific CD8 + T CM cells., Conclusion: Our findings showed that CMV infection causes mild expansion of CMV-NLV-specific CD8 + T cells, reduced CD70 expression and signaling, and proliferation of CMV-NLV-specific CD8 + T CM cells in young and middle-aged healthy adults and revealed an age-independent and CMV infection-specific impact on CD8 + memory T cells., (© 2022. The Author(s).)

Objective: Endocervical curettage (ECC) during colposcopy is recommended in certain circumstances; however, diagnostic use remains unclear. We evaluate the utility of ECC among patients with non-fully visualized squamocolumnar junction (SCJ) and certain patient socioeconomic factors., Methods: Retrospective chart analysis was completed for patients aged older than 21 years who underwent a colposcopy at 2 study sites between 2012 and 2021. Demographics and histopathologic results were analyzed., Results: A total of 1,516 colposcopies were reviewed; 73.8% (n = 1,119) had an ECC with colposcopy. Of those, 92.1% (n = 1,031) had benign ECC whereas 13.9% (n = 156) had a positive ECC at time of colposcopy. Most patients with benign ECC had benign/low-grade squamous intraepithelial lesion pathology on colposcopy biopsy (82.3%; n = 914; p < .001), and most patients with high-grade squamous intraepithelial lesion (HSIL) on ECC had HSIL on colposcopy biopsy (63.4%; n = 52; p < .001) However, when looking at patients with high-grade pathology on colposcopy biopsy, it was seen that most had benign or low-grade squamous intraepithelial lesion on ECC (79.5%; n = 205; p < .001). Most patients with adequately visualized SCJ on colposcopy were noted to have HSIL on biopsy and negative ECC (73%; n = 81; p < .001). This result was similar in patients with non-fully visualized SCJ, although not statistically significant. When stratified by socioeconomic status, most patients with high-grade lesions had a benign ECC., Conclusions: Endocervical curettage has been described to increase the identification of high-grade lesions at time of colposcopy. This descriptive study shows that many high-grade lesions at time of excisional procedure had a benign ECC on colposcopy, with no demonstrated clear additional utility in high-risk groups., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2022, ASCCP.)

Nanofibrils play a pivotal role in spider silk and are responsible for many of the impressive properties of this unique natural material. However, little is known about the internal structure of these protein fibrils. We carry out polarized Raman and polarized Fourier-transform infrared spectroscopies on native spider silk nanofibrils and determine the concentrations of six distinct protein secondary structures, including β-sheets, and two types of helical structures, for which we also determine orientation distributions. Our advancements in peak assignments are in full agreement with the published silk vibrational spectroscopy literature. We further corroborate our findings with X-ray diffraction and magic-angle spinning nuclear magnetic resonance experiments. Based on the latter and on polypeptide Raman spectra, we assess the role of key amino acids in different secondary structures. For the recluse spider we develop a highly detailed structural model, featuring seven levels of structural hierarchy. The approaches we develop are directly applicable to other proteinaceous materials., (© 2022. The Author(s).)

Objective: The aim of the study was to define the incidence, prognosis, and treatment patterns associated with synchronous lower genital tract squamous cell carcinoma (LGTSCC) among women diagnosed with any LGTSCC., Materials and Methods: Surveillance, Epidemiology, and End Results (SEER) database patients diagnosed with synchronous cervical, vaginal, vulvar, and/or anal SCC from 2000 to 2016 were included. Incidence and mortality were evaluated using Kaplan-Meier curves. Multivariable Cox proportional hazards regression was used to identify treatment patterns, risk factors, and mortality associated with LGTSCC., Results: Among 15,424 women with LGTSCC, 138 had synchronous LGTSCC (0.89%). Vulvar and vaginal SCC was the most common combination (49.3%), and cervical with anal SCC was the least common (1.4%). Only one patient had 3 or more primary LGTSCC. Synchronous LGTSCC was independently associated with higher mortality compared with single-site LGTSCC (adjusted hazards ratio [aHR] = 1.67; p < .001). Synchronous LGTSCC was significantly associated with older age (63 vs. 58 years, p < .001) and lower stage (adjusted odds ratio [aOR] = 0.38; p < .001) and grade of disease (aOR = 0.32; p < .001). Patients with synchronous LGTSCC were more likely to receive radiation (aOR = 1.74; p = .005) and were more likely to receive adjuvant radiation after primary surgical resection compared with single-site LGTSCC (aOR = 1.88; p = .007). Receipt of any treatment including radiation (aHR = 0.85; p < .001), chemotherapy (aHR = 0.50; p < .001), and surgery (aHR = 0.70; p < .001) was independently associated with decreased mortality hazard., Conclusions: Synchronous LGTSCC is rare but is associated with increased mortality and higher rates of adjuvant radiation compared with single-site LGTSCC despite lower stage and grade at diagnosis. More research is needed to define optimal therapy for these patients., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2022, ASCCP.)

Nanoparticulate albumin bound paclitaxel (nab-paclitaxel, nab-PTX) is among the most widely prescribed nanomedicines in clinical use, yet it remains unclear how nanoformulation affects nab-PTX behaviour in the tumour microenvironment. Here, we quantified the biodistribution of the albumin carrier and its chemotherapeutic payload in optically cleared tumours of genetically engineered mouse models, and compared the behaviour of nab-PTX with other clinically relevant nanoparticles. We found that nab-PTX uptake is profoundly and distinctly affected by cancer-cell autonomous RAS signalling, and RAS/RAF/MEK/ERK inhibition blocked its selective delivery and efficacy. In contrast, a targeted screen revealed that IGF1R kinase inhibitors enhance uptake and efficacy of nab-PTX by mimicking glucose deprivation and promoting macropinocytosis via AMPK, a nutrient sensor in cells. This study thus shows how nanoparticulate albumin bound drug efficacy can be therapeutically improved by reprogramming nutrient signalling and enhancing macropinocytosis in cancer cells., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Post-stroke optogenetic stimulation has been shown to enhance neurovascular coupling and functional recovery. Neuronal nitric oxide synthase (nNOS) has been implicated as a key regulator of the neurovascular response in acute stroke; however, its role in subacute recovery remains unclear. We investigated the expression of nNOS in stroke mice undergoing optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN). We also examined the effects of nNOS inhibition on functional recovery using a pharmacological inhibitor targeting nNOS. Optogenetically stimulated stroke mice demonstrated significant improvement on the horizontal rotating beam task at post-stroke days 10 and 14. nNOS mRNA and protein expression was significantly and selectively decreased in the contralesional primary motor cortex (cM1) of cLCN-stimulated mice. The nNOS expression in cM1 was negatively correlated with improved recovery. nNOS inhibitor (ARL 17477)-treated stroke mice exhibited a significant functional improvement in speed at post-stroke day 10, when compared to stroke mice receiving vehicle (saline) only. Our results show that optogenetic stimulation of cLCN and systemic nNOS inhibition both produce functional benefits after stroke, and suggest that nNOS may play a maladaptive role in post-stroke recovery.

Standardized classroom experiments provide evidence about how well scientific results reproduce when nearly identical methods are used. We use a sample of around 20,000 observations to test reproducibility of behaviour in trading and ultimatum bargaining. Double-auction results are highly reproducible and are close to equilibrium predictions about prices and quantities from economic theory. Our sample also shows robust correlations between individual surplus and trading order, and autocorrelation of successive price changes, which test different theories of price dynamics. In ultimatum bargaining, the large dataset provides sufficient power to identify that equal-split offers are accepted more often and more quickly than slightly unequal offers. Our results imply a general consistency of results across a variety of different countries and cultures in two of the most commonly used designs in experimental economics.

We study popular attitudes in Germany, Spain, the Philippines, and the United States toward three controversial markets-prostitution, surrogacy, and global kidney exchange (GKE). Of those markets, only prostitution is banned in the United States and the Philippines, and only prostitution is allowed in Germany and Spain. Unlike prostitution, majorities support legalization of surrogacy and GKE in all four countries. So, there is not a simple relation between public support for markets, or bans, and their legal and regulatory status. Because both markets and bans on markets require social support to work well, this sheds light on the prospects for effective regulation of controversial markets., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Microtubules (MTs) mediate mitosis, directional signaling, and are therapeutic targets in cancer. Yet in vivo analysis of cancer cell MT behavior within the tumor microenvironment remains challenging. Here we developed an imaging pipeline using plus-end tip tracking and intravital microscopy to quantify MT dynamics in live xenograft tumor models. Among analyzed features, cancer cells in vivo displayed higher coherent orientation of MT dynamics along their cell major axes compared with 2D in vitro cultures, and distinct from 3D collagen gel cultures. This in vivo MT phenotype was reproduced in vitro when cells were co-cultured with IL4-polarized MΦ. MΦ depletion, MT disruption, targeted kinase inhibition, and altered MΦ polarization via IL10R blockade all reduced MT coherence and/or tumor cell elongation. We show that MT coherence is a defining feature for in vivo tumor cell dynamics and migration, modulated by local signaling from pro-tumor macrophages.

Interpreting how multicellular interactions in the tumor affect resistance pathways to BRAF and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via receptor tyrosine kinases (RTKs) including AXL, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process frequently involves vasodilation and an increase in vascular permeability. Numerous players referred to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. An increased level of angiogenesis is associated with decreased survival in breast cancer patients. Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective treatments for breast cancer progression, thereby enhancing patients' survival. Disrupting the initiation and progression of this process by targeting angiogenic factors such as vascular endothelial growth factor (Vegf)-one of the most potent member of the VEGF family- or by targeting transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators, have been considered potential treatment options for several types of cancers. The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its role in the progression of malignancy in breast cancer, as well as to highlight the undergoing research in the development of angiogenesis-targeting therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The G AL4 T echnique for R eal-time a nd C lonal E xpression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide., (Copyright © 2019 Olson et al.)

Intact tropical forests, free from substantial anthropogenic influence, store and sequester large amounts of atmospheric carbon but are currently neglected in international climate policy. We show that between 2000 and 2013, direct clearance of intact tropical forest areas accounted for 3.2% of gross carbon emissions from all deforestation across the pantropics. However, full carbon accounting requires the consideration of forgone carbon sequestration, selective logging, edge effects, and defaunation. When these factors were considered, the net carbon impact resulting from intact tropical forest loss between 2000 and 2013 increased by a factor of 6 (626%), from 0.34 (0.37 to 0.21) to 2.12 (2.85 to 1.00) petagrams of carbon (equivalent to approximately 2 years of global land use change emissions). The climate mitigation value of conserving the 549 million ha of tropical forest that remains intact is therefore significant but will soon dwindle if their rate of loss continues to accelerate., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.

Resting heart rate (RHR) is independently associated with cardiovascular disease (CVD) risk. We determined whether RHR, measured in mid-life, is also associated with cognitive decline. We studied 13,720 middle-aged white and black ARIC participants without a history of stroke or atrial fibrillation. RHR was obtained from a 12-lead resting electrocardiogram at the baseline visit (1990 to 1992) and categorized into groups as <60 (reference), 60 to 69, 70 to 79 and ≥80 beats/min. Cognitive scores were obtained at baseline and at up to 2 additional visits (1996 to 1998 and 2011 to 2013). The primary outcome was a global composite cognitive score (Z-score) derived from 3 tests: delayed word recall, digit symbol substitution, and word fluency. The associations of RHR with cognitive decline and incident dementia were examined using linear mixed-effects and Cox hazard models, respectively, adjusting for sociodemographics, CVD risk factors, and AV-nodal blockade use. Multiple imputation methods were used to account for attrition over follow-up. Participants had mean ± SD age of 58 ± 6 years; 56% were women, 24% black. Average RHR was 66 ± 10 beats/min. Over a mean follow-up of 20 years, those with RHR ≥80 beats/min had greater global cognitive decline (average adjusted Z-score difference -0.12 [95% confidence interval -0.21, -0.03]) and increased risk for incident dementia (hazard ratio 1.28 (1.04, 1.57), compared with those with RHR <60 beats/min. In conclusion, elevated RHR is independently associated with greater cognitive decline and incident dementia over 20 years. Further studies are needed to determine whether the associations are causal or secondary to another underlying process, and whether modification of RHR can affect cognitive decline., (Copyright © 2018. Published by Elsevier Inc.)

Training accurate classifiers requires many labels, but each label provides only limited information (one bit for binary classification). In this work, we propose BabbleLabble, a framework for training classifiers in which an annotator provides a natural language explanation for each labeling decision. A semantic parser converts these explanations into programmatic labeling functions that generate noisy labels for an arbitrary amount of unlabeled data, which is used to train a classifier. On three relation extraction tasks, we find that users are able to train classifiers with comparable F1 scores from 5-100× faster by providing explanations instead of just labels. Furthermore, given the inherent imperfection of labeling functions, we find that a simple rule-based semantic parser suffices.

Using machine learning to analyze data often results in developer exhaust - code, logs, or metadata that do not define the learning algorithm but are byproducts of the data analytics pipeline. We study how the rich information present in developer exhaust can be used to approximately solve otherwise complex tasks. Specifically, we focus on using log data associated with training deep learning models to perform model search by predicting performance metrics for untrained models. Instead of designing a different model for each performance metric, we present two preliminary methods that rely only on information present in logs to predict these characteristics for different architectures. We introduce (i) a nearest neighbor approach with a hand-crafted edit distance metric to compare model architectures and (ii) a more generalizable, end-to-end approach that trains an LSTM using model architectures and associated logs to predict performance metrics of interest. We perform model search optimizing for best validation accuracy, degree of overfitting, and best validation accuracy given a constraint on training time. Our approaches can predict validation accuracy within 1.37% error on average, while the baseline achieves 4.13% by using the performance of a trained model with the closest number of layers. When choosing the best performing model given constraints on training time, our approaches select the top-3 models that overlap with the true top- 3 models 82% of the time, while the baseline only achieves this 54% of the time. Our preliminary experiments hold promise for how developer exhaust can help learn models that can approximate various complex tasks efficiently.

We report the case of a 62-year-old black man who was on a maintenance immunosuppressive regimen that included mycophenolate mofetil and cyclosporine following renal transplantation 9 years prior. He presented to the dermatology department for evaluation of a pigmented longitudinal streak on the left third finger adjacent to the lateral nail fold that had been present for several months. He noted that the streak was increasing in size, and his fingertip had recently become tender. The pigmented band was biopsied, and histopathology showed atypia of the epidermis consistent with pigmented squamous cell carcinoma (pSCC). Although subungual melanoma is the most concerning cause for longitudinal melanonychia, there are a number of other potential causes, including fungal infection, trauma, benign melanocytic lesions, or other cutaneous malignancies. Pigmented squamous cell carcinoma is another potential cause of longitudinal melanonychia and should be included in the differential diagnosis, particularly in individuals with skin of color or those who are immunosuppressed. This article highlights features of the clinical presentation of pSCC presenting as longitudinal melanonychia that mimicked the clinical appearance of subungual malignant melanoma in a renal transplant recipient. A review of pSCC and its associated risk factors also is provided.

As the terrestrial human footprint continues to expand, the amount of native forest that is free from significant damaging human activities is in precipitous decline. There is emerging evidence that the remaining intact forest supports an exceptional confluence of globally significant environmental values relative to degraded forests, including imperilled biodiversity, carbon sequestration and storage, water provision, indigenous culture and the maintenance of human health. Here we argue that maintaining and, where possible, restoring the integrity of dwindling intact forests is an urgent priority for current global efforts to halt the ongoing biodiversity crisis, slow rapid climate change and achieve sustainability goals. Retaining the integrity of intact forest ecosystems should be a central component of proactive global and national environmental strategies, alongside current efforts aimed at halting deforestation and promoting reforestation.

Background: Sacral chordomas are rare, slow growing, locally aggressive tumors. Unfortunately, aggressive surgical resection is often associated with increased neurological morbidity., Methods: This technical note focuses on the utilization of partial sacrectomy for the resection of complex spinal chordomas., Results: The case presented documents the potential range of postoperative morbidity seen in patients undergoing partial sacrectomy for chordomas. Despite iatrogenic morbidity and tumor recurrence, with the cooperation of medical and surgical spine specialists, majority of patients can achieve good long-term outcomes., Conclusions: Sacral chordomas are rare lesions and pose a therapeutic challenge for spinal surgeons and oncologists. En-bloc surgical resection (e.g., partial sacrectomy) is the treatment of choice for these lesions, and the cooperation between subspecialists can lead to good neurologic outcomes, particularly if gross total resection is achieved., Competing Interests: There are no conflicts of interest.

Background: During the postpartum visit, health care providers address issues with short- and long-term implications for maternal and child health. Women with Medicaid insurance are less likely to return for a postpartum visit compared with women with private insurance. Behavioral economics acknowledges that people do not make exclusively rational choices, rather immediate gratification, cognitive and psychological biases, and social norms influence decision making. Drawing on insights from decision science, behavioral economists have examined how these biases can be modulated through carefully designed interventions. We have developed a Web-based tool, Healthy Beyond Pregnancy, that incorporates empirically derived concepts of behavioral economics to improve adherence rates to the postpartum visit., Objectives: The primary objectives of this pilot study were to (1) refine and assess the usability of Healthy Beyond Pregnancy and (2) assess the feasibility of a randomized controlled trial (RCT) of the intervention., Methods: We used a multistep process and multidisciplinary team of maternal-fetal medicine physicians, a behavioral economist, and researchers with expertise in behavioral interventions to design Healthy Beyond Pregnancy. We assessed the usability of the program with the Post-Study System Usability Questionnaire (PSSUQ), a validated 7-point scale, and semistructured interviews with postpartum women. We then conducted a feasibility trial to determine the proportion of eligible women who were willing to participate in an RCT of Healthy Beyond Pregnancy and the proportion of women willing to complete the Web-based program. Exploratory outcomes of the pilot trial included attendance at the postpartum visit, uptake of long-acting reversible contraception, and uptake of any contraception., Results: The median PSSUQ score for Healthy Beyond Pregnancy was 6.5 (interquartile range: 6.1-7) demonstrating high usability. Semistructured interviews (n=10) provided in-depth comments about users' experience and further improved the program. A total of 34 postpartum women with Medicaid insurance were approached for the pilot trial, and 30 (88%) were consented and randomized. All women randomized to Healthy Beyond Pregnancy completed the Web-based program, had text-enabled cell phones, and were willing to receive text messages from the study team. Women in the Healthy Beyond Pregnancy arm were more likely to return for a postpartum visit compared with women in the control arm with 85% of women in Healthy Beyond Pregnancy returning versus 53% in the control arm (odds ratio in the Healthy Beyond Pregnancy group: 5.3; 95% CI 0.9-32.0; P=.06)., Conclusions: We have developed a highly usable and acceptable Web-based program designed to increase attendance at the postpartum visit. Our pilot trial demonstrates that women are willing and able to participate in a randomized trial of a Web-based program and text messaging system., Trial Registration: Clinicaltrials.gov NCT03296774; https://clinicaltrials.gov/ct2/show/NCT03296774 (Archived by WebCite at http://www.webcitation.org/6tpgXFzyk)., (©Katherine Park Himes, Heidi Donovan, Stephanie Wang, Carrie Weaver, Jillian Rae Grove, Francesca Lucia Facco. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 10.10.2017.)

Unlabelled: Kinase inhibitor resistance often involves upregulation of poorly understood "bypass" signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance., Significance: Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action., Competing Interests: of Potential Conflicts of Interest: No potential conflicts of interest were disclosed., (©2016 American Association for Cancer Research.)

We study the effect of financial resources on decision-making. Low-income U.S. households are randomly assigned to receive an online survey before or after payday. The survey collects measures of cognitive function and administers risk and intertemporal choice tasks. The study design generates variation in cash, checking and savings balances, and expenditures. Before-payday participants behave as if they are more present-biased when making intertemporal choices about monetary rewards but not when making intertemporal choices about non-monetary real-effort tasks. Nor do we find before-after differences in risk-taking, the quality of decision-making, the performance in cognitive function tasks, or in heuristic judgments., Competing Interests: The authors declare that they have no relevant or material financial interests that relate to the research described in this paper.

Alcohol use has become far too prevalent in our society. Alcohol kills 6.5 times more youth than all other illicit drugs combined. In combination with traumatic and hemorrhagic injuries, alcohol results in a much higher mortality rate. Alcohol, alone and in high dosages, also causes great damage to the body, often leading to death as well. Thus, it is of utmost importance that research is conducted to help explain the pathological mechanism of high fatalities and injuries associated with alcohol use. In order to simulate this complex situation in vitro, a rat hepatoma cell line (H-II-4-E) was exposed to various concentrations of ethanol as well as the condition of hypoxia. Hypoxia mimics the primary level of tissue damage caused by hemorrhage after impact in a car accident. In this way, we tested the hypothesis that the presence of ethanol in combination with hypoxia causes greater cellular damage compared to conditions of ethanol or hypoxia alone. Ethanol, alone and in high concentrations, was found to greatly affect cell function as shown by decreased cellular ATP levels, increased LDH release, and a downregulated expression of CYP2E1 gene. By adding the condition of hypoxia to low concentrations of ethanol, cellular damage increased dramatically as well. Decreased gene expression and protein levels of CYP2E1 correlated with increased hepatocyte injury and thus, this enzyme may significantly contribute to the severity of cellular damage. These results provide useful information for future research on the effects of ethanol in combination with hemorrhage on cells in vitro, simulating the condition of driving while intoxicated and binge drinking.