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Herein, we describe a rapid microwave-assisted, metal-free synthesis of substituted quinoxalinones and quinoxalines using the carbene-mediated reaction between aryldiazo esters and 1,2-diamines. The reaction can encompass a range of substituents and structural variations to afford quinoxalin-2-ones in 14–80 % yield and corresponding quinoxalines in good to excellent yields upon oxidation (67–96 %). The approach can be employed to generate symmetrical and unsymmetrical 2,3-diarylquinoxalines, bis-quinoxalines as well as novel quinoxaline-substituted diazo esters and should be a valuable addition to the heterocycle synthesis toolbox.

With the ambition to cut emissions from transport hydrogen fuelled vehicles and marine vessels are now being introduced several places in the society. To support this development there is a need for infrastructure to produce and transport gaseous and liquid hydrogen. The properties and safety challenges related to the use of hydrogen are very different from those of conventional fuels, thus safe design may require unconventional solutions. Hydrogen has extreme properties in many ways. It is buoyant when in gas phase while a liquid hydrogen spray will develop a dense plume. The reactivity is higher, flammable range wider and the ignition energy lower than for conventional fuels. Flames may be invisible, and radiation is low. When performing risk assessments for land planning purposes, bunkering assessments or passenger and crew safety these aspects must be reflected. Properties like the positive buoyancy, strong dilution for sonic releases into air, and a low reactivity and energy content for concentrations below 10% must be exploited during design to ensure acceptable risk levels. In this article a two-level risk assessment and design optimization approach is presented in which risk screening with rapid consequence calculations and frequency assessments for release, dispersion, fire and explosion can be performed during concept selection phase with indicative hazard distances estimated. Possible risks of concern are in this way identified, and design can be adjusted, or mitigation measures introduced. For final design risk assessment CFD calculations can be performed for more precise consequence estimates. The risk assessment approach is described with illustrating examples. The focus is not only to ensure safety, but to do so in a cost-efficient and practical way.

Aims Given the importance of addressing provider attitudes toward individuals with unhealthy alcohol use and the current emphasis on person-centered language to help decrease stigma and mitigate negative attitudes, the aim of this study was to evaluate the psychometric properties of a contemporary version of the Alcohol and Alcohol Problems Perception Questionnaire (AAPPQ) that uses person-centered language and addresses the spectrum of alcohol use. Methods The authors created a person-centered version of the AAPPQ (PC-AAPPQ) and conducted a cross-sectional study of its psychometric properties in academic settings in the Northeastern United States. The PC-AAPPQ was administered to 651 nursing students. Reliability analysis of the new instrument was performed using the total sample. Only surveys with complete data (n = 637) were randomly split into two datasets, one used for the exploratory factor analysis (EFA) (n = 310) and the other for confirmatory factor analysis (CFA) (n = 327). Results Compared to all the models generated from the EFA, neither the original six-factor structure nor the five-factor structure was superior to any of the other models. The results indicate that a seven-factor structure with all 30 items is the best fit for the PC-AAPPQ. Conclusions The PC-AAPPQ represents a positive effort to modernize the four-decade-old AAPPQ. This 30-item instrument, which adds one additional subscale, offers a means to assess providers' attitudes using respectful wording that avoids perpetuating negative biases and reinforces efforts to affirm the worth and dignity of the population being treated.

Do states copy or reinvent language from complex policies as they diffuse, and does this depend on legislative resources? We argue that states will more frequently reinvent more complex policies, but that states with high-resource legislatures will reinvent more than their low-resource counterparts for more complex policies. We test the theory using the bill texts from 18 policies that diffused across the 50 states from 1983 to 2014, measuring reinvention and complexity using text analysis tools. In line with expectations, we find that complex policies are reinvented more than simple policies and that high-resource legislatures reinvent bills more than low-resource legislatures on average. However, we also find that low-resource legislatures reinvent complex policies at about the same rate as high-resource legislatures. The results indicate that even legislatures with limited resources work to adapt complex policies during the diffusion process.

Objective To study the relationship between various electrodiagnostic modalities in acute facial palsy. Setting Academic tertiary care center. Patients One‐hundred and six patients who presented with traumatic or non‐traumatic acute facial paralysis (House‐Brackmann, HB, grade 6/6) between 2008 and 2017 and underwent acute electrodiagnostic testing. Intervention Electroneurography (ENoG) using nasolabial fold (NLF) or nasalis muscle (NM) methods, and volitional electromyography (EMG) in all patients. Main outcome measures Percent degeneration of ipsilateral facial nerve compound muscle action potentials (CMAP) on NLF‐ and NM‐ENoG, presence or absence of muscle unit potentials (MUPs) on EMG. Results Extent of facial nerve degeneration measured by NLF‐ and NM‐ENoG were highly correlated (r = 0.85, P, This is an original study that defines outcomes for electrodiagnostic testing in acute facial palsy and compares two methods. Electrodiagnostic testing is often used by clinicians to prognosticate outcomes for patients with acute facial palsy and determine candidacy for facial nerve decompression. This study describes one of the largest cohorts of patients to date with acute facial paralysis (House‐Brackmann 6/6) and detailed electrodiagnostic testing, consisting of two methods of electroneurography (ENoG) and electromyography (EMG).

In response to a gap in veterinary care for low-income, under-served populations, the Student Health Outreach for Wellness (SHOW) Clinic in Phoenix, AZ took a One-Health initiative to establish a pilot veterinary care program to serve the veterinary needs of the local homeless pet owners receiving human medical care at the clinic. The study examines the pilot program through the lens of the human-animal bond (HAB) and focuses specifically on the attachment dimension of the bond as measured by the Lexington Attachment to Pets Scale (LAPS). Data was collected from the homeless pet owners, and Rasch modeling was used to investigate the importance of various factors of the owner attachment to pet as described in LAPS items. The results demonstrate the perceptions of the homeless pet owners of ownership. The findings also provide psychometric evidence for revising the LAPS to better serve future research on human-animal relationships. Limitations and possible extensions of the research as related to the HAB and owner attachment to pets are discussed and enhancements proposed for the pilot program to better serve the local homeless people.

Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB. Siu and colleagues use a bespoke ctDNA assay and show predictive utility of longitudinal ctDNA analysis in a phase II clinical trial of patients receiving pembrolizumab that included multiple solid tumor types.

The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK‐2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6–12 mg/m2 i.v.) and MK‐2206 (60–135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty‐nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m2 and MK‐2206 135 mg. Treatment‐related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post‐treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK‐2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.

The development of immune checkpoint inhibitors (ICI) represents a major milestone in immune-oncology. Over the years these agents have demonstrated efficacy in an increasing array of malignancies. Despite this success however, significant challenges remain. Novel approaches to both drug development and trial design are required to incorporate the unique pharmacokinetic and pharmacodynamic properties of ICIs. Further, it has also been established that the benefit of ICIs is limited to only a subset of patients. The molecular interactions between native immune cells and tumorigenesis and progression represent an active area of biomarker research, and elucidating the mechanisms of response and resistance is crucial to develop rational trial designs for the next wave of immune-oncology (IO) clinical trials, particularly in patients with primary and/or acquired resistance. Efforts are now being made to integrate both biological and clinical information using novel multi-omic approaches which are now being developed to further elucidate the molecular signatures associated with IO treatment response and resistance and enable rational drug development and trial design processes. As such, precision IO and the ability to deliver patient-specific choices for ICI monotherapies or combination therapies has become an increasingly tangible goal. We herein describe the current landscape in ICI drug development and discuss the challenges and future directions in this exciting and evolving era in immune-oncology.

Cercospora leaf spot (CLS), caused by the fungus Cercospora beticola, is the dominant foliar disease affecting table-beet production in New York. CLS epidemics occur annually and, if uncontrolled, will rapidly lead to defoliation. In broad-acre production, season-long maintenance of healthy leaves is important to facilitate harvest by top-pulling. Fungicides are the dominant means of CLS control and applications are initiated at an action threshold of 1 CLS lesion/leaf. Regular fungicide application occurs thereafter without regard for scheduling based on weather-based risk. The current action threshold was evaluated with selected fungicides in two replicated field trials. Copper oxychloride + copper hydroxide and propiconazole significantly improved CLS control if initiated prior to infection. Pydiflumetofen + difenoconazole significantly reduced area under the disease progress stairs compared with other fungicides tested and was most efficacious when applications began at 1 CLS lesion/leaf. Six replicated field trials also evaluated the utility of scheduling fungicides on weather-based risk rather than a calendar approach. Two risk thresholds (moderate and high) integrating the accumulation of daily infection values based on temperature and relative humidity from a forecaster for CLS in sugar beet were evaluated. Applications of pydiflumetofen + difenoconazole were reduced from three to two by using the forecaster at either risk threshold compared with calendar applications without affecting CLS control. For propiconazole, the moderate risk threshold provided CLS control equivalent to calendar applications and saved one spray per season. Thus, there was substantial scope to reduce spray frequency by scheduling based on weather-based risk rather than calendar applications. The optimal risk thresholds for pydiflumetofen + difenoconazole and propiconazole were high and moderate, respectively. In these trials, periods of high risk occurred less frequently than moderate risk, increasing the reapplication intervals and, hence, represented a less conservative approach to disease management.

Bovine viral diarrhea virus continues to cost the cattle industry millions of dollars each year despite control measures. The primary reservoirs for bovine viral diarrhea virus are persistently infected animals, which are infected in utero and shed the virus throughout their lifetime. The difficulty in controlling the virus stems from a limited understanding of transplacental transmission and fetal development of immunotolerance. In this study, pregnant bovine viral diarrhea virus naïve heifers were inoculated with bovine viral diarrhea virus on day 75 of gestation and fetal spleens were collected on gestational days 82, 97, 190, and 245. Microarray analysis on splenic RNA from days 82 and 97 revealed an increase in signaling for the innate immune system and antigen presentation to T cells in day 97 persistently infected fetuses compared to controls. Reverse transcription quantitative polymerase chain reaction on select targets validated the microarray revealing a downregulation of type I interferons and lymphocyte markers in day 190 persistently infected fetuses compared to controls. Protein was visualized using western blot and tissue sections were analyzed with hematoxylin and eosin staining and immunohistochemistry. Data collected indicate that fetal immunotolerance to bovine viral diarrhea virus developed between days 97 and 190, with mass attenuation of the immune system on day 190 of gestation. Furthermore, lymphocyte transcripts were initially unchanged then downregulated, suggesting that immunotolerance to the virus stems from a blockage in lymphocyte activation and hence an inability to clear the virus. The identification of lymphocyte derived immunotolerance will aid in the development of preventative and viral control measures to implement before or during pregnancy.

STUDY QUESTIONAre intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility?SUMMARY ANSWERPatient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success.WHAT IS ALREADY KNOWNWe previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome.STUDY DESIGN, SIZE, DURATIONThis was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles.PARTICIPANTS/MATERIALS, SETTING, METHODSAMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate.MAIN RESULTS AND THE ROLE OF CHANCEAfter adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16–0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1–20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31–3.33)). However, live births did occur with TMC ≤ 1 million (5.1%).LIMITATIONS, REASONS FOR CAUTIONThis investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI.WIDER IMPLICATIONS OF THE FINDINGSMost factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI.STUDY FUNDING/COMPETING INTEREST(S)Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work.TRIAL REGISTRATION NUMBERn/a

Background We sought to develop mapping functions that use EORTC responses to approximate health utility (HU) scores for patients with head and neck cancer (HNC). Methods In total, 209 outpatients with HNC completed the EORTC QLQ-C30 & QLQ-H&N35 (EORTC), EQ-5D-5L and the HUI-3. Results of the EORTC were mapped onto both EQ-5D-5L and HUI-3 scores using ordinary least squares regression and two-part models. Results The OLS model mapping EORTC onto the EQ-5D-5L performed best (adjusted R2 = .75, 10-fold cross-validation RMSE = 0.064, MAE 0.050). The HUI-3 model mapping onto EORTC through OLS was more limited (adjusted R2 = .5746, 10-fold cross cross-validation RMSE = 0.168, MAE 0.080). The EQ-5D-5L model was able to discriminate between certain clinical indices of disease severity on subgroup analysis. Conclusion The EORTC to EQ-5D-5L mapping algorithm has good predictive validity and may enable researchers to translate EORTC scores into HU scores for head and neck patients with cancer.

Advanced adrenocortical cancer (ACC) is a rare, highly aggressive malignancy, which typically has a poor prognosis. In advanced ACC, the overall trend is toward a short PFS interval following first-line systemic therapy, highlighting a clear need for improved second-/third-line treatment strategies. We conducted a review of the literature and relevant scientific guidelines related to systemic therapy for advanced ACC. Public indexes including PubMed/MEDLINE were searched. Treatment selection in the second-line setting is based on small phase 2 trials, case reports, and pre-clinical evidence. The best data available for initial second-line therapy selection supports the use of gemcitabine and capecitabine (G + C) or streptozotocin (S), both with or without mitotane. G + C is becoming increasingly recommended based on phase 2 clinical trial data in patients of good PS, due to the inferred superior PFS and OS from non-comparative trials. Alternatively, streptozotocin was better tolerated than EDP + M in the FIRM-ACT study and remains an option when warranted. Beyond this, further treatment approaches should be tailored to individual patient characteristics, utilizing a mixture of systemic therapies, local therapies, and enrolment in clinical trials where available. Additionally, the role of molecular stratification, predictive biomarkers, and immune checkpoint inhibitors in specific individuals, such as Lynch syndrome, is evolving and may become increasingly utilized in clinical practice. Advanced ACC necessitates a multidisciplinary approach and is best managed in a specialist center. Although there is no one definitive second-line treatment strategy, there are some favorable approaches, which require further validation in larger clinical trials.

Background and aims Engaging healthcare providers (HCPs) is critical for early identification of overweight and obesity. The aim of this study is to describe the trend in clinicians’ adherence to clinical recommendations to discuss body weight status with adults with overweight and obesity. Methods and results We analyzed the data of adults aged 20 and older with overweight or obesity from the National Health and Nutrition Examination Surveys, 1999 to 2016 with a 2-year data-release cycle. The question of interest was “Has a doctor or other health professionals ever told you that you were overweight?” Adjusted biennial percentage ratio (abPR) of being notified was estimated. We observed a significant increasing trend of notification in adults with overweight [abPR = 1.04 (95% confidence interval: 1.03, 1.06), about 4% increase for every two-years] and obesity [1.01 (1.00, 1.02)]. The highest increase occurred in adults with overweight aged 20–34 [1.12 (1.08, 1.16)], however, young adults with overweight remained the group with the lowest percentage (24%, 2015–2016 survey) of notification compared to others in recent survey. Notification in adults with obesity demonstrated similar trends. In 2015–2016, among adults with obesity who visited HCPs last year, 80% of these aged 50–64 and 78% of these aged 65 and older were notified. More than 80% of adults with overweight or obesity visited HCPs at least once last year. Conclusions There was an improvement in informing patients of overweight/obesity status. However, less than a quarter of young adults with overweight were notified in recent surveys, compromising the opportunities of preventing overweight from becoming obesity in early adulthood.

Objective To compare a simultaneous vs sequential approach to residual post chemotherapy mass resections in metastatic testis cancer. Methods A retrospective review was performed of patients who underwent retroperitoneal and thoracic/cervical resection of post chemotherapy residual masses between 2002 and 2018. Group 1: “Simultaneous” (Combined Retroperitoneal and Thoracic/Cervical resections on the same date); Group 2: “Sequential” (Retroperitoneal and Thoracic/Cervical resections at separate dates). Results During the study period, 35 simultaneous and 17 sequential resections were performed. The median age at surgery was 28 years (Range 16-61). The median follow-up from last surgical procedure was 62.7 months (Range 0.4-194). Histology revealed teratoma in 38 (73.1%) patients, necrosis in 8 (15.4%) and viable tumor in 6 (11.5%). Discordant pathology findings between thoracic/cervical and abdominal resections were noted in 16 (30.8%) patients. No differences were observed between the simultaneous vs sequential groups in median operating time (585 minutes vs 545 minutes, P = .64), blood loss (1300 vs 1300 mls, P = .42), or length of stay (9 vs 11 days, P = .14). There was no difference between the 5-year (65.7% vs 68.6%) relapse-free survival between the 2 groups (P = .84) or the 5-year (88.6% vs 100%) overall and disease-specific survival (P = .25). Conclusion Simultaneous resection of retroperitoneal and thoracic/cervical post chemotherapy metastases is a feasible in some patients. It requires multidisciplinary collaboration and a longer primary procedure.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Aims To examine the delirium point prevalence studies conducted in different inpatient settings and to discuss the implication of the findings for delirium screening, assessment, prevention and management. Background Delirium-a common and distressing condition manifesting as an acute decline of attention and cognition-is frequently overlooked, misdiagnosed or treated inappropriately. This neuropsychiatric syndrome manifests as changes in attention, cognition and awareness, with resultant impact on behaviour, function and emotions. Delirium is recognised as a patient management challenge in the inpatient setting, and there is a need to understand the current point prevalence and assessment practices of delirium. Design A systematic review and meta-analysis. Methods A systematic review of published delirium prevalence studies in inpatient settings was conducted and the implications of findings for delirium screening, assessment, prevention and management identified. The random-effects meta-analysis was conducted among studies measuring delirium point prevalence. The PRISMA statement was used to report systematic review and meta-analysis. Results Nine studies were included in the review, with sample sizes ranging from 47-1867. Delirium point prevalence ranged from 9%-32%. Hypoactive delirium was the most common subtype, ranging from 23%-78%. Fifteen delirium screening tools or assessment or diagnostic methods were used. Comorbid dementia was present in up to 50% of inpatients. Conclusions Gaining a consensus on effective delirium instruments, the time windows for assessment and measurement will be crucial in driving benchmarking and quality improvement studies. Relevance to clinical practice Consistent identification of high-risk patients and treatment settings with elevated risk, accompanied by the implementation of effective preventive and management strategies, are critical to addressing delirium-a frequent and burdensome condition, that adversely affects patient outcomes.

Background Minimal qualitative data exist on the experiences of cancer patients treated with immune checkpoint inhibitors or costimulatory antibodies. Understanding the day to day experiences of patients being treated with immune checkpoint modulators, and how these relate to their health‐related quality of life, can inform future research and lead to better clinical decision‐making and care. We report here the first in depth qualitative study to consider patients' diverse and complex experiences with immune checkpoint modulators, with a focus on side effects and how these impact daily life. Methods This single‐center qualitative study was based on focus groups and semistructured interviews. Patients who were being treated or who had been treated with immune checkpoint modulators within the last year for a range of cancer diagnoses were recruited. Interpretive description informed our inductive, iterative approach to analysis. Results Eight themes were identified, characterizing the complexity of these patients' lived experiences: major categories of side effects experienced and how they impacted patient well‐being; the heterogeneous nature of side effects experienced; living with uncertainty; reframing the meaning and severity of SEs; focus on survival, hope, and being positive; acceptance and adaptation; feeling supported; and faith in medical innovation. Throughout their accounts, participants highlighted the profound impact that immune checkpoint modulators had on their daily lives. Conclusion This is the first in‐depth qualitative study into patient accounts of their experiences of treatment with immune checkpoint modulators, related side effects, and how it impacted their daily lives. This research is an integral initial step in developing an instrument that will assess treatment‐related side effects in patients treated with this form of therapy., This is the first report of patients' accounts of their experiences with ICM treatment, related SEs, and its impact on daily life. This research is an integral initial step in the development of an instrument that will measure treatment‐related SEs in patients treated with ICMs.

Members of historically underrepresented groups—women, African Americans, Latinos, and workers—are serving in American legislatures in increasing numbers. However, legislators wield substantially greater power in the lawmaking process when they hold leadership positions. Incorporation of these groups into leadership positions could indicate fuller political representation, but scholars to date have not assessed how well these groups are represented in leadership. We analyze original data describing the backgrounds of approximately 2,200 leaders in 30 states between 2003 and 2014. The data show that, on average across states, members of these groups are as well represented in state legislative leadership positions as they are in rank-and-file membership, but there is substantial variation across states and across parties. We then ask what factors might explain this variation and explore institutional characteristics, like the number of leadership positions or leader selection methods. The results show that legislative chambers with a higher number of leadership posts tend to have more women in leadership, and that selection through elections is associated with decreased African American presence in leadership. The findings have implications for minority incorporation and influence in American politics.

Objective To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population. Design Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. Setting Multicenter university-based clinical practices. Patient(s) Nine hundred couples with unexplained infertility were included. Women were 18–40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed. Intervention(s) None. Main Outcome Measure(s) The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss. Result(s) When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes. Conclusion(s) In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment. Clinical Trial Registration Number NCT 01044862.

This study examines outcome heterogeneity and potential to refine the TNM-8 cN-classification using radiologic extranodal extension (rENE) in a contemporary HPV-positive (HPV+) oropharyngeal carcinoma (OPC) cohort.All HPV+ OPC treated with definitive IMRT from 2010-2015 were included. Pre-treatment CT/MR of cN+ cases were reviewed by a head-neck radiologist for rENE. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) vs rENE-negative (rENE-). Multivariable analysis (MVA) for OS confirmed the prognostic value of rENE. Refined cN-classifications for new TNM staging proposals were evaluated against TNM-8 using established criteria.A total of 517 cN+ (rENE+: 97; rENE-: 420) and 41 cN0 cases were identified. The rENE+ proportion increased with rising N-category (N1/N2/N3: 11%/19%/84%, p 0.001). Median follow-up was 5.1 years. Compared to rENE-, rENE+ patients had a lower 5-year OS (56% vs 85%) and DFS (46% vs 83%) overall, and in N1 (OS: 57% vs 89%; DFS: 51% vs 87%) and N2 subsets (OS: 45% and 76%; DFS: 33% vs 74%) (all p 0.001). MVA confirmed the prognostic value of rENE for OS (HR = 3.86, p 0.001) and DFS (HR = 3.89, p 0.001). We proposed two new cN-classifications: Schema1 reclassified any N_rENE+ as New_N3; Schema2 reclassified N1_rENE+ as New_N2 and N2_rENE+ as New_N3. Stage incorporating either Schema1 (ranked 1st) or Schema2 (ranked 2nd) cN-categories outperformed TNM-8.This study confirms that rENE is prognostically important and facilitates understanding of known outcome heterogeneity within TNM-8 in HPV+ OPC patients. rENE is a promising parameter to refine the TNM-8 cN-classifications.

HYPOTHESIS The objective was to evaluate the effect of cochlear implant (CI) insertion technique on electrode insertion forces and intracochlear trauma. We hypothesize that robotics-assisted insertions will reduce insertion forces and intracochlear trauma compared with manual insertions. BACKGROUND Variability in CI outcomes exists across patients, implant centers, surgeons, and electrode types. While surgical techniques that reduce electrode insertion trauma are well established, insertion trauma remains one contributing factor to variability in CI outcomes. Previous work demonstrates that micromechanically controlled insertion tools reduce both maximum insertion forces and insertion variability compared with manual insertions. METHODS CI electrode insertions were performed either by hand (n = 12) or utilizing a robotics-assisted tool (n = 12) in fresh frozen, human cadaveric cochleae using electrodes from four different CI manufacturers. Electrodes array insertion forces were additionally evaluated in benchtop cochlea models. Following cadaveric insertions, samples were imaged via high resolution x-ray microscopy to evaluate electrode position and intracochlear trauma events based on a modified Eshraghi scale. RESULTS Electrode array insertions performed by robotics-assisted system showed significantly lower insertion forces and variability. Manual electrode array insertions had a significantly higher overall trauma score of 3.1 ± 2.0 compared with 0.9 ± 1.0 for robotics-assisted insertions. Robotics-assisted insertions had higher rate of basilar membrane elevations while manual insertions showed higher rates of severe trauma events. CONCLUSIONS The robotic-assisted insertion system reduced trauma events associated with CI electrode insertions in cadaveric cochleae compared with manual insertions. Surgical devices which help to precisely and more consistently insert electrodes may improve CI outcomes and hearing preservation.

Background International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment. Materials and Methods Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors. Results Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors. Conclusion This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes. Implications for Practice This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4–61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials.

Background Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. Methods Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. Results Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. Conclusions To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.

A combination of cloud-permitting model (CPM) simulations, satellite, and reanalysis data are used to test whether the diurnal cycle in surface temperature has a significant impact on the intensity of deep convection as measured by high-percentile updraft velocities, lightning, and CAPE. The land–ocean contrast in lightning activity shows that convective intensity varies between land and ocean independently from convective quantity. Thus, a mechanism that explains the land–ocean contrast must be able to do so even after controlling for precipitation variations. Motivated by the land–ocean contrast, we use idealized CPM simulations to test the impact of the diurnal cycle on high-percentile updrafts. In simulations, updrafts are somewhat enhanced due to large-scale precipitation enhancement by the diurnal cycle. To control for large-scale precipitation, we use statistical sampling techniques. After controlling for precipitation enhancement, the diurnal cycle does not affect convective intensities. To explain why sampled updrafts are not enhanced, we note that CAPE is also not increased, likely due to boundary layer quasi equilibrium (BLQE) occurring over our land area. Analysis of BLQE in terms of net positive and negative mass flux finds that boundary layer entrainment, and even more importantly downdrafts, account for most of the moist static energy (MSE) sink that is balancing surface fluxes. Using ERA-Interim data, we also find qualitative evidence for BLQE over land in the real world, as high percentiles of CAPE are not greater over land than over ocean.

The number of maritime initiatives with hydrogen as alternative fuel is increasing. While most of the early projects aim at using compressed hydrogen the use of liquid hydrogen (LH2) is more practical and is expected to become more attractive for implementation on larger vessels due to more efficient storage, bunkering and handling of the fuel. In the industry there seems to be some confusion regarding the behavior of LH2 releases, in particular whether a release into air will behave like a dense gas or a buoyant gas. The understanding of this aspect is critical to optimize design with regard to safety. This article will explain the expected behavior of LH2 releases and discuss expected hazard distances from LH2 releases relative to gaseous hydrogen releases and LNG. Some other safety concerns of LH2, like indoor releases, releases from vent masts, potential BLEVEs and RPTs are also discussed. The article explains why a higher safety standard may be required when designing hydrogen fueled vessels than for existing LNG fueled vessels.

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08–0.39 cm) and 0.07 cm (range 0.04–0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p < 0.001) and of GTV-Ns (Spearman correlation coefficient 0.55, p < 0.001). Conclusion: Contouring GTVs in patients with HNC on MRI showed that the median IOV for GTV-T and GTV-N was below 2 mm, based on observes from two separate radiation departments. However, there are still specific regions in tumours that are difficult to resolve as either malignant tissue or oedema that potentially could be improved by further training in MR-only delineation.

To determine whether successful weight loss before ovarian stimulation with intrauterine insemination (OS-IUI) affects the risk of future pregnancy complications among women with obesity and unexplained infertility after fertility treatment.Secondary analysis of the randomized controlled clinical trial Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE).Multiple academic health centers in the United States.Three hundred seventy-nine women with obesity and unexplained infertility who underwent standard infertility treatment after a lifestyle intervention.The FIT-PLESE trial evaluated whether prepregnancy lifestyle interventions (diet with weight loss medication and exercise vs. exercise alone) before OS-IUI improved the live birth rate among women with obesity and unexplained infertility. Although the primary outcome of FIT-PLESE was live birth rate, we compared the demographics and subsequent pregnancy complications of women who successfully lost some weight with those of women who did not lose any during the interventions.Obstetric complications by groups were compared using χThere was a nonsignificant trend toward a lower risk of intrauterine growth restriction (4% vs. 16%,Among women with obesity and unexplained infertility who had live births after fertility treatment, prepregnancy weight loss due to lifestyle interventions before OS-IUI was associated with a lower risk of preeclampsia.

Adverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients' reported experience of these toxicities using PRO-CTCAE.Patients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses.Of 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either 'quite a bit' or 'very much', respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild-moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions.This is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

BackgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).MethodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.ResultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).ConclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.Trial registrationThis study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .

Acute Myeloid Leukemia (AML) affects 20,000 patients in the US annually with a five-year survival rate of approximately 25%. One reason for the low survival rate is the high prevalence of clonal evolution that gives rise to heterogeneous sub-populations of leukemic cells with diverse mutation spectra, which eventually leads to disease relapse. This genetic heterogeneity drives the activation of complex signaling pathways that is reflected at the protein level. This diversity makes it difficult to treat AML with targeted therapy, requiring custom patient treatment protocols tailored to each individual’s leukemia. Toward this end, the Beat AML research program prospectively collected genomic and transcriptomic data from over 1000 AML patients and carried out ex vivo drug sensitivity assays to identify genomic signatures that could predict patient-specific drug responses. However, there are inherent weaknesses in using only genetic and transcriptomic measurements as surrogates of drug response, particularly the absence of direct information about phosphorylation-mediated signal transduction. As a member of the Clinical Proteomic Tumor Analysis Consortium, we have extended the molecular characterization of this cohort by collecting proteomic and phosphoproteomic measurements from a subset of these patient samples to evaluate the hypothesis that proteomic signatures can improve the ability to predict drug response in AML patients. In this work we describe our systematic, multi-omic approach to evaluate proteomic signatures of drug response and compare protein levels to other markers of drug response such as mutational patterns. We explore the nuances of this approach using two drugs that target key pathways activated in AML: quizartinib (FLT3) and trametinib (Ras/MEK), and show how patient-derived signatures can be interpreted biologically and validated in cell lines. In conclusion, this pilot study demonstrates strong promise for proteomics-based patient stratification to assess drug sensitivity in AML.

Eukaryotic cells use G-protein coupled receptors to sense diverse signals, ranging from chemical compounds to light. Here, we exploit the remarkable sensing capacity of G-protein coupled receptors to construct yeast-based biosensors for real-life applications. To establish proof-of-concept, we focus on cannabinoids because of their neuromodulatory and immunomodulatory activities. We construct a CB2 receptor-based biosensor, optimize it to achieve high sensitivity and dynamic range, and prove its effectiveness in three applications of increasing difficulty. First, we screen a compound library to discover agonists and antagonists. Second, we analyze 54 plants to discover a new phytocannabinoid, dugesialactone. Finally, we develop a robust portable device, analyze body-fluid samples, and confidently detect designer drugs like JWH-018. These examples demonstrate the potential of yeast-based biosensors to enable diverse applications that can be implemented by non-specialists. Taking advantage of the extensive sensing repertoire of G-protein coupled receptors, this technology can be extended to detect numerous compounds.

Multispecies biofilms are a common limitation in membrane bioreactors, causing membrane clogging, degradation, and failure. There is a poor understanding of biological fouling mechanisms in these systems due to the limited number of experimental techniques useful for probing microbial interactions at the membrane interface. Here, we develop a new experimental method, termed polymer surface dissection (PSD), to investigate multispecies assembly processes over membrane surfaces. The PSD method uses photodegradable polyethylene glycol hydrogels functionalized with bioaffinity ligands to bind and detach microscale, microbial aggregates from the membrane for microscopic observation. Subsequent exposure of the hydrogel to high resolution, patterned UV light allows for controlled release of any selected aggregate of desired size at high purity for DNA extraction. Follow-up 16S community analysis reveals aggregate composition, correlating microscopic images with the bacterial community structure. The optimized approach can isolate aggregates with microscale spatial precision and yields genomic DNA at sufficient quantity and quality for sequencing from aggregates with areas as low as 2000 μm

The in vivo function of cell-derived extracellular vesicles (EVs) is challenging to establish since cell-specific EVs are difficult to isolate and differentiate. We, therefore, created an EV reporter using truncated CD9 to display enhanced green fluorescent protein (EGFP) on the EV surface. CD9truc-EGFP expression in cells did not affect EV size and concentration but enabled co-precipitation of EV markers TSG101 and ALIX from the cell-conditioned medium by anti-GFP immunoprecipitation. We then created a transgenic mouse where CD9truc-EGFP was inserted in the inverse orientation and double-floxed, ensuring irreversible Cre recombinase-dependent EV reporter expression. We crossed the EV reporter mice with mice expressing Cre ubiquitously (CMV-Cre), in cardiomyocytes (αMHC-MerCreMer) and renal tubular epithelial cells (Pax8-Cre), respectively. The CD9truc-EGFP positive mice showed Cre-dependent EGFP expression, and plasma CD9truc-EGFP EVs were immunoprecipitated only from CD9truc-EGFP positive CD9truc-EGFPxCMV-Cre and CD9truc-EGFPxαMHC-Cre mice, but not in CD9truc-EGFPxPax8-Cre and CD9truc-EGFP negative mice. In urine samples, CD9truc-EGFP EVs were detected by immunoprecipitation only in CD9truc-EGFP positive CD9truc-EGFPxCMV-Cre and CD9truc-EGFPxPax8-Cre mice, but not CD9truc-EGFPxαMHC-Cre and CD9truc-EGFP negative mice. In conclusion, our EV reporter mouse model enables Cre-dependent EV labeling, providing a new approach to studying cell-specific EVs in vivo and gaining a unique insight into their physiological and pathophysiological function.

Pregnancy induces changes in the transcriptome of the bovine endometrium from 15 days after insemination. However, pregnancy is less likely to occur if cows had a postpartum bacterial infection of the uterus, even after the resolution of disease. We hypothesized that uterine bacterial infection alters the endometrial transcriptomic signature of pregnancy after the resolution of disease. To examine the endometrial transcriptomic signature of pregnancy, cows were inseminated 130 days after intrauterine infusion of pathogenic Escherichia coli and Trueperella pyogenes, subsequently endometrium was collected 16 days after insemination for RNA sequencing. We found 171 pregnancy regulated genes in cows 146 days after bacterial infection. When comparing our findings with previous studies that described the endometrial transcriptomic signature of pregnancy in healthy cows, 24 genes were consistently differentially expressed in pregnancy, including MX1, MX2 and STAT1. However, 12 pregnancy regulated genes were found only in the endometrium of healthy cows, including ISG15 and TRANK1. Furthermore, 28 pregnancy regulated genes were found only in the endometrium of cows following bacterial infection and these were associated with altered iNOS, TLR, and IL-7 signaling pathways. Although 94 predicted upstream regulators were conserved amongst the studies, 14 were found only in the endometrium of pregnant healthy cows, and 5 were found only in cows following bacterial infection, including AIRE, NFKBIA, and DUSP1. In conclusion, there were both consistent and discordant features of the endometrial transcriptomic signature of pregnancy 146 days after intrauterine bacterial infusion. These findings imply that there is an essential transcriptomic signature of pregnancy, but that infection induces long-term changes in the endometrium that affect the transcriptomic response to pregnancy.

BackgroundThe phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.MethodsGSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.ConclusionsGSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration numberNCT02528357.

How do working class candidates perform in primary elections? Working class candidates rarely emerge, but existing evidence suggests workers perform as well as white-collar candidates once on the ballot. However, this evidence comes from studies of general elections. It is unknown whether these findings extend to other types of elections like primaries, where candidates compete without the political and financial backing of a party. We collect and analyze novel data describing the occupational background of all candidates who competed in U.S. House primaries between 2008 and 2016. The results show that working class candidates received an average vote share 24 percentage points lower than nonworkers and are 31 percentage points less likely to win their primaries. Controlling for other candidate, contest, and district characteristics helps to attenuate the performance gap. We find mixed evidence that fundraising and prior officeholding experience moderates workers' performance, but weak or no evidence that voter bias, party affiliation, or primary type do so. The study suggests that workers struggle to compete in primaries and calls for further research explaining what prevents workers from winning public office.

Background Predicting response to treatment with exclusive enteral nutrition (EEN) in paediatric Crohn’s disease (CD) can lead to more personalised, cost-effective, and efficacious therapy. We explored the ability of pre-treatment clinical and multi-omics parameters to predict faecal calprotectin (FCal) levels at EEN completion. Methods In 37 children [median (IQR), 12.4y (10.1, 15.0)] with active CD, disease parameters, dietary intake, 19 inflammatory cytokines, and 92 plasma inflammation-related proteomic markers in plasma, diet-related bacterial metabolites and 1H NMR metabolomics in faeces, as well as the faecal, duodenal, ileal, ascending and descending colon microbiome (16S rRNA sequencing), and dietary intake were measured prior to EEN initiation. Fifteen children responded to EEN (RS) and 12 not (non-RS) using a FCal cut-off Results Disease and host immunological parameters did not predict FCal levels at EEN completion. Responders had lower fibre intake, half the concentration of butyrate, acetate, phenylacetate and higher bacterial richness, in faeces, than non-RS. A model trained with the discriminant duodenal operational taxonomic units (OTUs) demonstrated a sensitivity of 67%, specificity of 90% and positive predictive value of 80% to differentiate RS from non-RS. The predictive ability of the faecal and the microbiomes of other mucosal sites was inferior to that of the duodenum. In multicomponent prediction including all datasets and faecal microbiome, higher levels of phenylacetate and relative abundance of OTU of Bacteroides, were predictive of non-RS with a sensitivity of 73%, specificity of 81% and positive predictive value of 73%. Replacing the faecal with the duodenal microbiome in a subset of participants (n=14), produced a model with 100% accuracy to predict RS from non-RS. The single most important variable in this model was a Lachnospira OTU which was absent in all RS but highly abundant in non-RS. Conclusion We identified pre-treatment microbial signals and diet-related metabolites which may comprise targets for pre-treatment optimisation and personalised nutritional therapy in CD.