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Objectives Physicians must leverage several factors when making antibiotic therapy decisions, including route of administration and duration of therapy. Oral administration provides several potential advantages including increased accessibility, prevention of hospitalizations and earlier discharges. Sulopenem—a broad-spectrum, synthetic penem β-lactam agent—uniquely possesses both oral and IV formulations along with noted stability among antimicrobial-resistant subsets. This study evaluated the in vitro activity of sulopenem and comparator agents against contemporary Enterobacterales and anaerobic clinical isolates predominantly from patients with bloodstream, intra-abdominal and urinary tract infections. Methods A contemporary collection of 1647 Enterobacterales and 559 anaerobic isolates was assembled from medical centres in Europe and the USA. Isolates were susceptibility tested using the CLSI reference methods: broth microdilution for Enterobacterales and agar dilution for anaerobes. Results Sulopenem demonstrated potent in vitro antimicrobial activity (MIC50/90, 0.03/0.25 mg/L) against Enterobacterales isolates regardless of infection type, inhibiting 99.2% of isolates at ≤1 mg/L. This activity was conserved against resistant phenotypes including ESBL-phenotype Escherichia coli (MIC50/90, 0.03/0.06 mg/L) and ESBL-phenotype Klebsiella pneumoniae (MIC50/90, 0.06/1 mg/L). Sulopenem maintained activity against ciprofloxacin-, nitrofurantoin- and trimethoprim/sulfamethoxazole-non-susceptible subsets (MIC50/90, 0.03–0.06/0.12–0.5 mg/L). Against anaerobic isolates, sulopenem (98.9% inhibited at ≤4 mg/L) and meropenem [98.4% susceptible (CLSI)] were the most active compounds tested. Conclusions The potent in vitro activity of sulopenem against this large collection of recent Enterobacterales and anaerobic clinical isolates from multiple infection types supports its further clinical evaluation in the treatment of intra-abdominal and urinary tract infections.

Converting two-dimensional measurement units presents challenges for K-8 preservice teachers (PSTs) (e.g., 9 ft2 = __ yd2). Place value deficiency, lack of understanding of metric system measurement units, misconceptions about relationships between measurement units, and uncertain knowledge of ratios have been identified as causes of student error in one-dimensional analysis (e.g., Livy Vale, 2011; Morris, 2001; Southwell Penglase, 2005). However, PSTs’ strategies for solving two-dimensional measurement unit conversion problems (MUCPs) and possible interventions for improvement are rarely investigated in research. The purpose of this study is to design and test a set of tasks that may help students develop correct conceptions and skills for solving MUCPs with the emphasis on two-dimensional problems. The research question is: What is the potential impact of designed task-based interventions on K-8 preservice teachers’ knowledge and ability to solve MUCPs? Data participants are 40 K-8 PSTs enrolled in a Foundations of Data and Geometry course. PSTs completed four MUCPs each in a pre-test and a post-test. Analysis of PSTs’ results from both control and treatment groups show an improvement in the treatment group.

The purpose of this study was to determine K-8 preservice teacher (PST) candidates’ statistical thinking when selecting the best center representation for the given data. Forty-four PSTs enrolled in a Statistics and Probability for K-8 Teachers course in a university located in the southeastern region of the United States were asked to complete a 2007 National Assessment of Educational Progress test item. All 44 PSTs’ data were qualitatively analyzed for correctness and statistical thinking strategies used. Findings were that most PSTs either incorrectly selected the mean, rather than median, as the best measure of center for the given data or did not use appropriate statistical reasoning when explaining their answers. Future research includes modifying the explanation component so PSTs must better explain their statistical thinking for their choice of best measure of center using the context of the problem. Future research could also include implementing a pre- and post-test design with the post-test item embedded in the final exam. This design will provide additional understanding of how much knowledge PSTs bring to the course versus how much they learn in the course and provide incentive for giving thoughtful consideration for their answers.

Supplementary File Article: Mode of Delivery and Asthma in Childhood and Adolescence: Findings from the Millennium Cohort Study. Methods: Study Population and Ethical Approval. Methods: Exposure: Mode of Delivery. Methods: Description of Potential Confounders. Data Analysis S1: Description of Sensitivity Analyses Results S1: Sensitivity Analyses. Table S1: Association between Mode of Delivery and Wheezing in the last 12 months at ages 7 and 11 years among Millennium Cohort Study Participants. Table S2: Association between Mode of Delivery and Asthma at ages 7, 11 and 14 years among Millennium Cohort Study Participants (excluding preterm births). Table S3: Association between any Caesarean section and Persistent and Adolescent asthma among Millennium Cohort Participants. Table S4: Association between Mode of Delivery and Asthma at ages 7, 11 and 14 years among Millennium Cohort Study Participants (only including participants at age 14). Table S5: Association between Mode of Delivery and Asthma at ages 7, 11 and 14 years among Millennium Cohort Study Participants. Table S6: Comparison of Maternal and Child Characteristics at Baseline and at age 14 years among Millennium Cohort Study Participants. Table S7: Association between Mode of Delivery and Loss to Follow-up at age 14 years and Asthma at age 7 years and Loss to Follow-up at age 14 years among Millennium Cohort Study Participants. Figure S1: Directed acyclic graph identifying potential confounders of a mode of delivery-asthma relationship.

We investigated the effects of garlic extract on the peripheral blood immune cells in mice treated with the extract for twenty days. The study was carried out on ten male ICR mice. The mice were divided into two groups. The control group received a distilled water and garlic extract group in which the mice received garlic extract at a dose of 500 mg/kg. b.w, for twenty days. Blood samples were collected on day ten and day twenty post inoculation (p.i) for differential leucocytic count (WBCs count and Lymphocytes %) and flowcytometric analysis. In comparison to the control group, garlic extract treatment induced a significant increase in WBCs count and lymphocytes percentage on day 10 and day 20 p.i. Furthermore, garlic extract administration to the experimental mice caused significant increase in the expression percentage of CD4, CD8 and γ-δ T cells when analyzed by flowcytometry on day 10 and increased dramatically on day 20 p.i. The WBCs count and lymphocytes percentage as well as the percentage of the expressed cells increased on day 20 more than their levels on day 10 p.i with a fixed dose of garlic extract. In conclusion, inoculation of garlic extract induced an increase in the immune responses of the cellular immunity in the peripheral blood circulation of mice. Scholars Middle East Publishers

Purpose: Coronary physiological assessment is now routinely applied in the catheter laboratory to guide percutaneous coronary intervention (PCI). Currently most physiological assessment is performed in a binary manner to determine whether a vessel requires intervention. Although studies have reported the high diagnostic efficiency of physiological assessment in minimizing the number of vessels requiring treatment, it is widely recognized that interrogation of individual stenosis in the presence of tandem lesions or diffuse disease under hyperemic conditions makes PCI planning complex and less practical. The aim of this study was to perform assessment of severity of coronary lesions of a pressure guide wire with continuous instantaneous wave-free ratio (iFR) co-registration measurement compared coronary angiography and quantitative coronary analysis (QCA) aiming to minimize the procedure, decrease number and length of stents used. Methodology: This non randomized controlled trial was conducted at Cardiology Department, Benha University, National Heart Institute (NHI) from February 2020 to September 2022. The study included a group of 30 patients presented with diffuse coronary artery disease and undergoing elective PCI. Findings: The study found out that the distribution of risk factors among studied groups was HTN representing 54%, regarding DM 60%, concerning dyslipidemia 64% and smokers represented 57%. The median of expected length of stent using QCA assessment was 40.2 mm with standard deviation (SD) (8mm) higher than detected actually deployed by iFR co-registration. The mean length of stents used by IFR co-registration was 20.2 mm stents (SD: 11.2 mm) and P-value was 0.0000. Also, all patients needed stent via QCA while only 86% actually need stent application via iFR co-registration assessment, leading to a fewer stents placed per patient. The difference was statistically significant p

The initial peak incidence of Hodgkin lymphoma (HL) occurs during reproductive years.Synthesise published literature on the relationship between HL and maternal and perinatal outcomes.Systematic search of PubMed/Medline, Cochrane Library, Scopus, Embase and Science Direct from inception to June 2022, supplemented by hand-searching reference lists.Two reviewers independently reviewed titles, abstracts and full-text articles. Published studies containing original data were eligible.Two reviewers independently extracted data and appraised study quality. Outcomes for pregnant women with a previous/current diagnosis of HL were compared separately with women never diagnosed with HL. Where data permitted, meta-analyses of odds ratios and proportions were performed. Certainty of evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.Of the 5527 studies identified, 33 met the inclusion criteria. In the groups with HL before pregnancy and HL during pregnancy, adjusted odds ratios were not statistically significant for congenital malformation (aOR 1.7, 95% CI 0.9-3.1, and aOR 1.84, 95% CI 0.81-4.15, respectively), preterm birth (PTB) (aOR 0.99, 95% CI 0.65-1.51, and aOR 6.74, 95% CI 0.52-88.03, respectively) and miscarriage (aOR 0.78, 95% CI 0.55-1.10, and aOR 0.38, 95% CI 0.05-2.72, respectively). The aORs for all other outcomes were not statistically significant, except for blood transfusion (aOR 1.38, 95% CI 1.05-1.82) and venous thromboembolism (VTE) (aOR 7.93, 95% CI 2.97-21.22) in the group for HL during pregnancy. The proportion of anaemia was also increased in this group (69%, 95% CI 57%-80% vs 4%, 95% CI 4%-5%, respectively). The GRADE certainty of findings ranged from low to very low.Rates of most adverse pregnancy outcomes among women with a previous/current HL diagnosis are not increased significantly compared with the general pregnant population. Women with HL diagnosed during pregnancy may have a higher PTB rate and increased likelihood of VTE, anaemia and blood transfusion; however, small study numbers and the low to very low GRADE certainty of findings preclude firm conclusions.

Over 200 interstitial lung diseases, from ultra rare to relatively common, are recognised. Most interstitial lung diseases are characterised by inflammation or fibrosis within the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. Outcomes vary considerably for each of the different interstitial lung diseases. In some conditions, spontaneous reversibility or stabilisation can occur, but unfortunately in many people with interstitial lung disease, especially in those manifesting progressive pulmonary fibrosis, respiratory failure and death are a sad reality. Over the past 3 years, the field of interstitial lung disease has had important advances, with the approval of drugs to treat systemic sclerosis-associated interstitial lung disease, interstitial lung disease-associated pulmonary hypertension, and different forms of progressive pulmonary fibrosis. This Seminar provides an update on epidemiology, pathogenesis, presentation, diagnosis, disease course, and management of the interstitial lung diseases that are most frequently encountered in clinical practice. Furthermore, we describe how developments have led to a shift in the classification and treatment of interstitial lung diseases that exhibit progressive pulmonary fibrosis and summarise the latest practice-changing guidelines. We conclude with an outline of controversies, uncertainties, and future directions.

Objective: To develop and validate (both internally and externally) a prediction model examining a combination of risk factors in order to predict postpartum haemorrhage (PPH) in a general obstetric Irish population of singleton pregnancies. Study design: We used data from the National Maternal and Newborn Clinical Management System (MN-CMS), including all singleton deliveries at Cork University Maternity Hospital (CUMH), Ireland during 2019. We defined PPH as an estimated blood loss of = 1000 ml following the birth of the baby. Multivariable logistic regression with backward stepwise selection was used to develop the prediction model. Candidate predictors included maternal age, maternal body mass index, parity, previous caesarean section, assisted fertility, gestational age, fetal macrosomia, mode of delivery and history of PPH. Discrimination was assessed using the area under the receiver operating characteristic curve (ROC) C-statistic. We used bootstrapping for internal validation to assess overfitting, and conducted a temporal external validation using data from all singleton deliveries at CUMH during 2020. Results: Out of 6,077 women, 5,807 with complete data were included in the analyses, and there were 270 (4.65%) cases of PPH. Four variables were considered the best combined predictors of PPH, including parity (specifically nulliparous), macrosomia, mode of delivery (specifically operative vaginal delivery, emergency caesarean section and prelabour caesarean section), and history of PPH. These predictors were used to develop a nomogram to provide individualised risk assessment for PPH. The original apparent C-statistic was 0.751 (95% CI: 0.721, 0.779) suggesting good discriminative performance. There was minimal optimism adjustment to the C-statistic after bootstrapping, indicating good internal performance (optimism adjusted C-statistic: 0.748). Results of external validation were comparable with the development model suggesting good reproducibility. Conclusions: Four routinely collected variables (parity, fetal macrosomia, mode of delivery and history of PPH) were identified when predicting PPH in a general obstetric Irish population of singleton pregnancies. Use of our nomogram could potentially assist with individualised risk assessment of PPH and inform clinical decision-making allowing those at highest risk of PPH be actively managed.

RATIONALE: Genetic studies of Idiopathic Pulmonary Fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. OBJECTIVE: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. METHODS: We performed gene burden analysis of whole exome data, tested single variants for disease association, conducted KIF15 functional studies, and examined human lung single cell RNA sequencing data. MEASUREMENT AND MAIN RESULTS: Gene burden analysis of 1,725 cases and 23,509 controls identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT, RTEL1, PARN). KIF15 was implicated in autosomal dominant models of rare deleterious variants (OR 4.9 [95%CI 2.7, 8.8] P=2.55x10-7) and rare protein-truncating variants (OR 7.6 [3.3, 17.1], P=8.12x10-7). Meta-analysis of the discovery and replication cohorts, including 2,966 cases and 29,817 controls, confirm the involvement of KIF15, plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405, OR 1.6 [1.4, 1.9], P=5.63x10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells, and shows diminished expression in replicating epithelial cells of IPF patients. CONCLUSIONS: Both rare deleterious variants and common variants in KIF15 link a non-telomerase pathway of cell proliferation with IPF susceptibility.

Although most of the poor outcomes with cutaneous squamous cell carcinoma (CSCC) occur in high-stage tumors, 26% of nodal metastases and 8% of disease-specific deaths develop in Brigham and Women's Hospital (BWH) T2a tumors.To determine risk factors associated with poor outcomes (nodal metastasis, distant metastases, and disease-specific deaths) in BWH T2a CSCC.A 17-year retrospective multi-institutional cohort study of primary CSCC BWH T2a tumors. A predictive model based on tumor characteristics was developed to identify those at higher risk of poor outcomes.Presence of 1 major criterion (primary tumor diameter ≥40 mm, invasion depth beyond subcutaneous fat, poor differentiation, or large-caliber perineural invasion) and ≥ 1 minor criterion (invasion depth in subcutaneous fat, moderate differentiation, small-caliber perineural invasion, or lymphovascular invasion) was most predictive of developing poor outcomes (area under the curve, 0.53; C-statistic, 0.60). This model has a sensitivity of 7.7%, specificity of 97.4%, and a positive and negative predictive value of 33.3% and 86.1%, respectively. The 5-year cumulative incidence of poor outcomes in these tumors is 8.0% (95% CI, 5.1-13.7) compared to 2.8% (95% CI, 1.9-4.1) in other T2a tumors (sub-hazard ratio, 3.0; 95% CI, 1.5-5.8).Multi-institutional cohort study was not externally validated.BWH T2a-high CSCCs have an 8% chance of developing poor outcomes.

BackgroundConsiderable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.MethodsWe co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).FindingsWe identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).InterpretationWe have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

This study aimed to describe Aboriginal and Torres Strait Islander women's views of self-collection introduced in the renewed National Cervical Screening Program.A total of 79 Aboriginal and/or Torres Strait Islander women (50 screened in previous five years, 29 under-screened) from five clinics across three Australian states/territories participated. Topics discussed were perceptions of self-collection, the instruction card and suggestions for implementing self-collection. We employed yarning (a qualitative method), which established relationships and trust between participants and researchers to facilitate culturally safe conversations. Transcripts were analysed thematically.Most women were unaware of self-collection before the yarn but found it to be an acceptable way to participate in cervical screening. Women perceived self-collection would be convenient, provide a sense of control over the screening experience, and maintain privacy and comfort. The instructions were perceived to be simple and easy to follow. Women had concerns about collecting the sample correctly and the accuracy of the sample (compared to clinician-collected samples).Self-collection is acceptable to Aboriginal and Torres Strait Islander women.Given the inequitable burden of cervical cancer experienced by Aboriginal and Torres Strait Islander women, self-collection is likely to significantly improve participation and ultimately improve cervical cancer outcomes.

Autophagic flux assay.

Subcellular fractionation.

Emerging evidence suggests that Sigma1 (SIGMAR1, also known as sigma-1 receptor) is a unique ligand-regulated integral membrane scaffolding protein that contributes to cellular protein and lipid homeostasis. Previously, we demonstrated that some small-molecule modulators of Sigma1 alter endoplasmic reticulum (ER)–associated protein homeostasis pathways in cancer cells, including the unfolded protein response and autophagy. Programmed death-ligand 1 (PD-L1) is a type I integral membrane glycoprotein that is cotranslationally inserted into the ER and is processed and transported through the secretory pathway. Once at the surface of cancer cells, PD-L1 acts as a T-cell inhibitory checkpoint molecule and suppresses antitumor immunity. Here, we demonstrate that in Sigma1-expressing triple-negative breast and androgen-independent prostate cancer cells, PD-L1 protein levels were suppressed by RNAi knockdown of Sigma1 and by small-molecule inhibition of Sigma1. Sigma1-mediated action was confirmed by pharmacologic competition between Sigma1-selective inhibitor and activator ligands. When administered alone, the Sigma1 inhibitor decreased cell surface PD-L1 expression and suppressed functional interaction of PD-1 and PD-L1 in a coculture of T cells and cancer cells. Conversely, the Sigma1 activator increased PD-L1 cell surface expression, demonstrating the ability to positively and negatively modulate Sigma1 associated PD-L1 processing. We discovered that the Sigma1 inhibitor induced degradation of PD-L1 via autophagy, by a mechanism distinct from bulk macroautophagy or general ER stress–associated autophagy. Finally, the Sigma1 inhibitor suppressed IFNγ-induced PD-L1. Our data demonstrate that small-molecule Sigma1 modulators can be used to regulate PD-L1 in cancer cells and trigger its degradation by selective autophagy.Implications: Sigma1 modulators sequester and eliminate PD-L1 by autophagy, thus preventing functional PD-L1 expression at the cell surface. This posits Sigma1 modulators as novel therapeutic agents in PD-L1/PD-1 blockade strategies that regulate the tumor immune microenvironment.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/2/243/F1.large.jpg. Mol Cancer Res; 16(2); 243–55. ©2017 AACR.

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Isopycnic fractionation.

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Multiple Sigma1 shRNA and absence of general protein level changes - evidence of selective actions.

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ATG5 and ATG7 shRNA.

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Cycloheximide (CHX) pulse-chase.

Genome-wide rare variant studies of IPF patients of non-European ancestry have been understudied. Here, we evaluate the enrichment of rare genetic variants of 241 unrelated non-European cases, representing individuals of Latino, African, South Asian, East Asian, and Other Admixed ancestry. Gene burden analysis of deleterious rare (protein-truncating and missense) variants demonstrate an excess of TERT rare damaging variants (OR 67.1, 95% CI [23.1, 195.0], P = 9.4 x 10-14) in non-European subjects. Analysis by ancestry demonstrated an excess of rare, damaging TERT variants in the Latino subgroup (OR 80.9, 95% CI [17.3, 383.8], P = 2.6 x 10-8). Although the non-European group did not show enrichment of PARN, RTEL1, and KIF15 rare deleterious variants, these groups all showed a trend in the same direction as the European ancestry group. For TERT and KIF15, the inclusion of IPF patients of non-European ancestry led to a higher odds ratios and increased evidence in favor of rare deleterious variant contributions, thus demonstrating the increased power of multi-ethnic studies over single-ethnicity studies. To our knowledge, this is the first study that confirms the involvement of rare deleterious TERT variants for IPF patients of Latino and non-European ancestry. To better understand the genetic underpinnings of IPF patients of all ancestries, additional work will be needed to broaden patient recruitment to normalize imbalances.

Professional organizations have provided recommendations for mathematics teaching and learning; however, few studies have investigated the practical integration of those recommendations into mathematics teacher education programs. In this study, we examine how the reported “big ideas” of courses in secondary mathematics teacher education programs emphasized the content and teaching practices necessary for future mathematics teachers, as recommended by policy documents. As part of a larger study, we conducted a series of interviews in secondary mathematics teacher education programs at four universities (names are descriptive pseudonyms): Great Lakes University (GLU), Midwestern Research University (MRU), Midwestern Urban University (MUU), and Southeastern Research University (SRU). We selected the institutions and programs based on their Carnegie Classification, the types of communities in which they were situated, the average number of graduates from a program, the departmental homes of their secondary mathematics education programs, and the demographics of their student populations. The analysis of data collected from 12 courses across four universities revealed specific ways in which big ideas in secondary mathematics teacher education programs emphasized areas related to mathematics learning, teaching, and issues of equity and access.

The COVID-19 pandemic identified an urgent need to re-evaluate the provision of spirometry for clinical monitoring. Home spirometry offers the opportunity for real-time disease evaluation without risk of nosocomial infection. To determine the utility of home spirometry in interstitial lung disease (ILD), interim data from the ongoing INJUSTIS study was evaluated. High correlation was observed between home and hospital spirometry at baseline(r=0.89) and three-months(r=0.82). Over 90% of home spirometry values were within Bland-Altman agreement limits at both time points, although frequently underestimated hospital values. Home spirometry is feasible in people with fibrotic ILD.

Background The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison to people with chronic obstructive pulmonary disease (COPD), remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program, and to determine whether pulmonary rehabilitation is associated with survival in IPF. Research question Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are non-completion of and/or non-response to pulmonary rehabilitation associated with one-year all-cause mortality in IPF? Study design and methods Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred to pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over one-year following pulmonary rehabilitation discharge. Cox proportional-hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality. Results Similar pulmonary rehabilitation completion rates (IPF: 69%; COPD: 63%; p=0.24) and improvements in exercise response were observed in both groups with no significant mean (95% confidence interval (CI)) between-group differences in incremental shuttle walk (ISW) change (2 (-18 to 22) meters). Pulmonary rehabilitation non-completion (hazard ratio (HR) (95%CI) 5.62 (2.24 to 14.08)) and non-response (HR (95%CI) 3.91 (1.54 to 9.93)) were independently associated with increased one-year all-cause mortality in IPF. Interpretation Compared with a matched group of patients with COPD, this real-word study demonstrates that patients with IPF have similar completion rates and magnitude of response to pulmonary rehabilitation. In IPF, non-completion of and non-response to pulmonary rehabilitation were associated with increased all-cause mortality. These data reinforce the benefits of pulmonary rehabilitation in patients with IPF.

Purpose To examine the association between mode of delivery (in particular caesarean section) and behavioural outcomes in offspring at six time-points between age 3 and 17 years. Methods Similar to previous work examining the association between mode of delivery and behavioural outcomes in offspring at age 7, we used maternal-reported data from the Millennium Cohort Study. Data on mode of delivery were collected when children were 9 months and categorised as spontaneous vaginal delivery, assisted vaginal delivery, induced vaginal delivery, emergency caesarean section, planned caesarean section and caesarean section after induction of labor. Data on behavioural outcomes were collected at ages 3, 5, 7, 11, 14 and 17 years using the Strengths and Difficulties Questionnaire (SDQ). Crude and adjusted logistic regression examined mode of delivery–behavioural difficulties relationship, using validated SDQ cut-off points (total SDQ ≥ 17, emotional ≥ 5, conduct ≥ 4, hyperactivity ≥ 7, peer problems ≥ 4 and prosocial behaviour ≤ 4). Multilevel models with linear splines examined the association between mode of delivery and repeated measures of SDQ. Results There were 18,213 singleton mother–child pairs included at baseline, 13,600 at age 3; 13,831 at age 5; 12,687 at age 7; 11,055 at age 11; 10,745 at age 14 and 8839 at age 17. Adjusted logistic regression suggested few associations between mode of delivery and behavioural outcomes at ages 3, 5, 11, 14 and 17 years using validated SDQ cut-off points. After correction for multiple testing, only the protective association between planned caesarean section-Conduct difficulties at age 5 years (OR 0.63, 95% CI 0.46, 0.85) and positive association between caesarean section after induction-Emotional difficulties at age 11 years (OR 1.57, 95% CI 1.19, 2.07) remained statistically significant. Multilevel modelling suggested mean SDQ scores were similar in each mode of delivery group at each time point. Conclusions Results of this study indicate that mode of delivery is unlikely to have a major impact on behavioural outcomes.

Mental health has long been a challenge on college and university campuses. Though it has historically taken a back seat to physical health, college administrators recently identified mental health as a key area for additional support. With the COVID-19 pandemic bringing mental health into the conversation across the country, there is no more critical and opportune time for colleges and universities to prioritize mental health. Many public and private universities alike have begun to do this, but how can they ensure that the services and resources they are providing and promoting get used and that students, faculty, and staff reap the benefits of these efforts? This commentary describes a set of universal steps the authors recommend based on their experience working with colleges and universities across New York State to increase uptake and usage of services.

Background and objective A proportion of patients with fibrotic hypersensitivity pneumonitis (fHP) follow a progressive disease course despite immunosuppressive treatment. Little is known about predictors of mortality in fHP. We aimed to investigate the impact of short-term lung function changes in fHP on mortality. Methods Baseline demographics for 145 consecutive patients with a multi-disciplinary team diagnosis of fHP, as well as baseline and 1-year follow-up of lung function, baseline echocardiographic findings, bronchoalveolar lavage (BAL) cellularity and all-cause mortality were recorded. Changes in forced vital capacity (FVC) ≥ 5% and ≥10%, and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 10% and ≥15% at 1 year were calculated. Cox proportional hazards analysis was performed to test for associations with mortality. Results Baseline lung function severity, age, presence of honeycombing on computed tomography (CT) and echocardiographic pulmonary arterial systolic pressure (PASP) ≥ 40 mm Hg were associated with early mortality, while BAL lymphocytosis was associated with improved survival. A decline in FVC ≥ 5% (hazard ratio [HR]: 3.10, 95% CI: 2.00–4.81, p

This table provide supplemental information on the results of ChIP-seq and gene expression analyses of primary and spinal metastatic tumors in MAP mice.

Specificity of ARV7 and ARv567es antibodies.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and ARv567es as well as full-length AR. Treatment of mice xenografted with ARV-driven CRPC tumors with a drug-like small-molecule Sigma1 inhibitor significantly inhibited tumor growth associated with elimination of AR and ARV7 in responsive tumors. Together, our data show that Sigma1 modulators can be used to suppress AR/ARV–driven prostate cancer cells via regulation of pharmacologically responsive Sigma1-AR/ARV interactions, both in vitro and in vivo. Cancer Res; 77(9); 2439–52. ©2017 AACR.

Nuclear hormone receptors that are not eliminated by small molecule Sigma1 inhibitor (IPAG).