Anaerobic Soil Disinfestation and Vermicompost to Manage Bottom Rot in Organic Lettuce.

Rhizoctonia solani Kühn (teleomorph: Thanatephorus cucumeris [Frank] Donk) is an aggressive soilborne pathogen with a wide host range that survives saprophytically between crops, presenting a challenge for organic vegetable farmers who lack effective management tools. A 2-year field experiment was conducted at two organic farms to compare anaerobic soil disinfestation (ASD) and worm-cured compost (vermicompost) to manage bottom rot caused by R. solani subspecies AG1-IB in field-grown organic lettuce (Lactuca sativa). At each farm, four replicate plots of seven treatments were arranged in a randomized complete block design. Randomization was restricted by grouping treatments to evaluate ASD, and treatments to evaluate vermicompost in starter plugs. ASD experiment treatments were three different ASD carbon sources that are commonly used and widely available to local farmers in Vermont: compost, cover crop residues, and poultry manure fertilizer, as well as a tarped control. Vermicompost experimental treatments were vermicompost compared with two types of controls: a commercial biocontrol product (RootShield PLUS + G), and unamended (untarped control). This study demonstrated that the ASD method is achievable in a field setting on Vermont farms. However, neither ASD nor vermicompost produced significant disease suppression or resulted in higher marketable yields than standard growing practices. Given the laborious nature of ASD, it is likely more appropriate in a greenhouse setting with high-value crops that could especially benefit from being grown in plastic tarped beds (e.g., tomatoes and strawberries). This study is the first known attempt of field-implemented ASD for soil pathogen control in the northeastern United States.

Readability of Spanish-Language Online Patient Educational Materials for Peripheral Artery Disease Do Not Meet Recommended Standards and Represent a Literacy Barrier to Care.

BACKGROUND: Online resources are a valuable source of information for patients and have been reported to improve engagement and adherence to medical care. However, readability of online patient educational materials (OPEMs) is crucial for them to serve their intended purpose. The American Medical Association (AMA) recommends that OPEM be written at or below the sixth grade reading level. To avoid disparities in access to comprehensible health information on peripheral artery disease (PAD), it is imperative that the readability of PAD OPEM is appropriate for both English-speaking and Spanish-speaking patients. The aim of this study is to evaluate the readability of PAD OPEM in Spanish and compare to English-language OPEM. METHODS: We conducted a Google search in English and Spanish using "peripheral arterial disease" and "enfermedad arterial periferica", respectively, and the top 25 patient-accessible articles were collected for each. Articles were categorized by source type: hospital, professional society, or other. Readability of English-language OPEM was measured using the Flesch Reading Ease Readability Formula, Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog, Linsear Write Formula, and the Simple Measure of Gobbledygook Index. Readability of Spanish OPEM was measured using the Fernández-Huerta Index and Índice Flesch-Szigriszt Scale. Readability of the articles was compared to the AMA recommendation, between English- and Spanish-language, and across sources using statistical tests appropriate to the data. RESULTS: OPEM from professional societies represented the fewest number of English- (n = 7, 28%) and Spanish-language (n = 6, 24%) articles. Most English-speaking (n = 18, 72%) and Spanish-language (n = 20, 80%) OPEM were considered difficult as measured by the Flesch Reading Ease Readability Formula and Fernández-Huerta Index, respectively, but did not significantly differ between languages (P = 0.59). There were no significant differences in the average readability of all readability measurements across sources (hospital, professional society, or other). All the average readability grade levels for English-speaking and Spanish-language OPEM was significantly higher than the sixth grade reading level (P < 0.01). Only 3 (6%) OPEM met the AMA recommended reading level and there was no significant difference between English-language and Spanish-language OPEM (P = 1.0). CONCLUSIONS: Nearly all Spanish-language and English-language PAD OPEM assessed were written at a reading grade level higher than recommended by the AMA. There was no significant difference in the readability of materials from hospitals or professional societies. To prevent further widening of health disparities related to literacy, health content creators, particularly hospitals and professional societies, should prioritize, develop, and ensure that English-language and Spanish-language patient education materials are written at a level appropriate for the public.

Review of Intra-Articular Use of Antibiotics and Antiseptic Irrigation and Their Systematic Association with Chondrolysis.

Introduction: Intra-articular antibiotics have been proposed as a treatment for septic arthritis to allow for high local concentrations without subjecting a patient to the toxicity/side effects of systemic therapy. However, there is concern for chondrotoxicity with intra-articular use of these solutions in high concentrations. The purpose of this systematic review was to evaluate the intra-articular use of antibiotics and antiseptic solutions, and to determine their association with chondrolysis following in vitro or in vivo administration. Methods: A systematic review was conducted following PRISMA guidelines through PubMed, Clinical Key, OVID, and Google Scholar. Studies in English were included if they evaluated for chondrotoxicity following antibiotic exposure. Results: The initial search resulted in 228 studies, with 36 studies meeting criteria. These 36 studies included manuscripts that studied 24 different agents. Overall, 7 of the 24 (29%) agents were non-chondrotoxic: minocycline, tetracycline, chloramphenicol, teicoplanin, pefloxacin, linezolid, polymyxin-bacitracin. Eight (33%) agents had inconsistent results: doxycycline, ceftriaxone, gentamicin, vancomycin, ciprofloxacin, ofloxacin, chlorhexidine, and povidone iodine. Chondrotoxicity was evident with 9 (38%) agents, all of which were also dose-dependent chondrotoxic based on reported estimated half maximal inhibitory concentrations (est. IC50): amikacin (est. IC50 = 0.31-2.74 mg/mL), neomycin (0.82), cefazolin (1.67-3.95), ceftazidime (3.16-3.59), ampicillin-sulbactam (8.64 - >25), penicillin (11.61), amoxicillin (14.01), imipenem (>25), and tobramycin (>25). Additionally, chondroprotective effects of doxycycline and minocycline were reported. Conclusions: This systematic review identified agents that may be used in the treatment of septic arthritis. Nine agents should be avoided due to their dose-dependent chondrotoxic effects. Further studies are needed to clarify the safety of these medications for human intra-articular use.

Rhizoctonia solani AG1-IB, AG1-IC, and AG4-HGII cause bottom rot of field lettuce in Vermont.

Members of Rhizoctonia solani (teleomorph: Thanatephorus cucumeris) species complex cause bottom rot on lettuce (Latuca sativa) and yield losses up to 70% (Subbarao et al. 2017). Severe symptoms include necrosis, stem rot, and/or discoloration especially on the leaf midrib. In Vermont, vegetable farms are small (0.5-30 acres) and grow lettuce concurrently with other vegetable crops in the same field but the AG(s) that causes the disease in Vermont has not been determined. Isolates (n = 157) were collected from 31 fields with reported history of bottom rot between July 10 and October 8, 2019, across Addison, Caledonia, Chittenden, Franklin, Lamoille, and Orleans counties. Isolates were collected from lettuce tissue or potato (Solanum tuberosum), a common rotation crop, or uncropped soil baited using radish (Raphanus sativus). Pieces of tissue (5-10 mm) were cut from the leading margin of lesions, surface disinfested with 0.1% NaClO for 1 min followed by 2 rinses with sterile water, blotted dry, and plated onto acidified 2% water agar (0.085% lactic acid, pH 4.8). After incubation for 48 to 72 h, mycelia resembling Rhizoctonia were examined for morphological characteristics including hyphal branching at ca. 90o angles, a septum near the branching point, multiple nuclei per cell, and lack of both clamp connections and conidia (Sneh et al. 1991). Colonies were white to dark brown, and some produced small sclerotia. Koch's postulates were performed by inoculating nine 8-week-old (9 leaf pairs) romaine lettuce plants (Johnny's Seeds, Winslow, ME, cv. Monte Carlo) per isolate. Isolates were grown on 2% potato dextrose agar for 1 week, from which a 5-mm agar plug was placed on the adaxial leaf surface at the base of a petiole. Plants were enclosed in a plastic bag to maintain high humidity and grown under a 16-hour photoperiod at 24 °C. Disease severity was rated 4 days after inoculation (0: healthy, 1: isolated lesions, 2: lesions across multiple petioles, and 3: systemic disease). Putative AG were determined by Sanger sequencing of the internal transcribed spacer (ITS) region using the ITS1F and ITS4B primer pair (758 bp) (Gardes and Bruns 1993). Contigs were assembled using CAP3 software (Huang and Madan 1999). Taxonomy was assigned to each OTU via the NCBI BLASTn database with criteria as 0.0 E and nucleotide match of at least 97%. Of the 10 isolates sequenced with sufficient coverage (735 to 784 bp alignment length) and definitive resolution (96.7 to 99.9% identity), 5 were putative AG 1-IB (Genbank Accession HG934430.1), 2 AG 1-IC (Genbank Accession AF354058.1), 2 AG 3 (Genbank Accession AF354064.1), and 1 AG 4-HGII (Genbank Accession AF354074.1). Fasta files and metadata are archived at 10.6084/m9.figshare.20301324, 10.6084/m9.figshare.20301375. Putative AG 1-IB was highly virulent on lettuce plants whether it originated from potato (mean 2.6) or lettuce (mean 1.3 to 3). AG 4-HGII and AG 1-IC isolated from lettuce and radish, respectively, were moderately severe (mean 1.4 to 2.2) on lettuce with identical symptoms. The two potato isolates (AG3) were not pathogenic on lettuce. Similarly, higher incidence of AG 1-IB is reported on lettuce in Quebec (Wallon et al. 2021), Ohio (Herr 1993), and Germany (Grosch et al. 2004). Because AG vary in their host range (Sneh et al. 1991), knowing the AG will inform management decisions such as crop rotation and weed control. This is the first report of the causal agent of bottom rot of lettuce or any AG of R. solani in Vermont.

Quantifying the Bioavailable Energy in an Ancient Hydrothermal Vent on Mars and a Modern Earth-Based Analog.

Putative alkaline hydrothermal systems on Noachian Mars were potentially habitable environments for microorganisms. However, the types of reactions that could have fueled microbial life in such systems and the amount of energy available from them have not been quantitatively constrained. In this study, we use thermodynamic modeling to calculate which catabolic reactions could have supported ancient life in a saponite-precipitating hydrothermal vent system in the Eridania basin on Mars. To further evaluate what this could mean for microbial life, we evaluated the energy potential of an analog site in Iceland, the Strytan Hydrothermal Field. Results show that, of the 84 relevant redox reactions that were considered, the highest energy-yielding reactions in the Eridania hydrothermal system were dominated by methane formation. By contrast, Gibbs energy calculations carried out for Strytan indicate that the most energetically favorable reactions are CO2 and O2 reduction coupled to H2 oxidation. In particular, our calculations indicate that an ancient hydrothermal system within the Eridania basin could have been a habitable environment for methanogens using NH4+ as an electron acceptor. Differences in Gibbs energies between the two systems were largely determined by oxygen-its presence on Earth and absence on Mars. However, Strytan can serve as a useful analog for Eridania when studying methane-producing reactions that do not involve O2.

Quantification of cytosol and membrane proteins in rumen epithelium of sheep with low or high CH4 emission phenotype.

BACKGROUND: Ruminant livestock are a major contributor to Australian agricultural sector carbon emissions. Variation in methane (CH4) produced from enteric microbial fermentation of feed in the reticulo-rumen of sheep differs with different digestive functions. METHOD: We isolated rumen epithelium enzymatically to extract membrane and cytosol proteins from sheep with high (H) and low (L) CH4 emission. Protein abundance was quantified using SWATH-mass spectrometry. RESULTS: The research found differences related to the metabolism of glucose, lactate and processes of cell defence against microbes in sheep from each phenotype. Enzymes in the methylglyoxal pathway, a side path of glycolysis, resulting in D-lactate production, differed in abundance. In the H CH4 rumen epithelium the enzyme hydroxyacylglutathione hydrolase (HAGH) was 2.56 fold higher in abundance, whereas in the L CH4 epithelium lactate dehydrogenase D (LDHD) was 1.93 fold higher. Malic enzyme 1 which converts D-lactate to pyruvate via the tricarboxylic cycle was 1.57 fold higher in the L CH4 phenotype. Other proteins that are known to regulate cell defence against microbes had differential abundance in the epithelium of each phenotype. CONCLUSION: Differences in the abundance of enzymes involved in the metabolism of glucose were associated with H and L CH4 phenotype sheep. Potentially this represents an opportunity to use protein markers in the rumen epithelium to select low CH4 emitting sheep.

Readability assessment of online peripheral artery disease education materials.

OBJECTIVE: Online resources can be a valuable source of information for patients and have been shown to result in more inquiry during medical office visits, following physician medical recommendation more closely, and making self-directed lifestyle changes. The accessibility to these resources is limited by the readability level of the article and the literacy level of the population. Peripheral artery disease (PAD) is estimated to affect between 8 and 12 million people in the United States with greater disease severity among under insured or uninsured populations. As PAD continues to increase in prevalence, it is imperative that patients have access to comprehensible patient-centered health information. This study aims to evaluate the readability of online PAD patient education materials. METHODS: The search engine Google was used to collect the first 25 patient-accessible online articles pertaining to the search term "peripheral artery disease." Articles were then categorized by source type: hospital, professional society, or other. Readability was measured using the following tests: Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog, Linsear Write Formula, and the SMOG Index. Statistical analyses were performed using Statistical Analysis Software, with P values less than .05 being statistically significant. RESULTS: Twenty-five articles were categorized by source and statistically analyzed. The average readability of PAD patient education materials was 10.8 and significantly above the American Medical Association, National Institutes of Health, and US Department of Health and Human Services recommended reading level of sixth grade. Readability scores among source categories were not significantly different. CONCLUSIONS: Commonly available online PAD resources are written at a grade level above that currently recommended by medical societies. Hospitals, professional societies, and other stakeholders in PAD patient education should take into consideration the readability of their materials to make medicine more accessible. Readable articles may combat the historic and structural racism often found in our health care system that marginalizes those with lower health literacy. It is imperative to develop patient education at an appropriate level to enrich patient autonomy.

Hospital admissions in infants with Down syndrome: a record-linked population-based cohort study in Wales.

BACKGROUND: Despite recent advances, mortality in children with Down syndrome remains five times higher than in the general population. This study aims to describe the burden, patterns and causes of hospital admissions in infants with Down syndrome, and compare this with infants without Down syndrome in a population-based cohort. METHODS: This study used data from the Wales Electronic Cohort for Children, a cohort of all children born in Wales between 1990 and 2012. The cohort was generated from routine administrative data, linked to create an anonymised data set within the Secure Anonymised Information Linkage databank. This analysis is based on all infants born between January 2003 and January 2012 who were followed to their first birthday, a move out of Wales, death, or until 31 October 2012 (end of follow-up). Infants with Down syndrome were identified using the Congenital Anomaly Register and Information Service in Wales. Multivariable Cox regression was used to compare the time to first hospital admission. Admission codes were used to identify the commonest indications for hospitalisation and to determine the presence of other congenital anomalies. RESULTS: We included 324 060 children, 356 of whom had Down syndrome. Of infants with Down syndrome, 80.3% had at least one hospital inpatient admission during the first year of life, compared with 32.9% of infants without Down syndrome. These first admissions were earlier [median of 6 days interquartile range (IQR) (3, 72) compared with 45 days [IQR 6, 166)] and longer [median of 4 days (IQR 1, 15) compared with 1 day (IQR 0, 3)] than in infants without Down syndrome. The most common causes of admissions were congenital abnormalities, respiratory diseases, conditions originating in the perinatal period and infectious diseases. The presence of other congenital abnormalities increased hospitalisations in all infants, but more so in infants with Down syndrome who spent a median of 21 days in hospital (IQR 11, 47) during their first year of life. CONCLUSION: Infants with Down syndrome are at high risk for early, more frequent and longer hospital admissions. Congenital heart disease and respiratory infections remain a major burden in this population. More research is needed to understand how to better manage these conditions particularly in the first month of life when most admissions occur.

Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

CHARACTERISATION OF RADIOPHOTOLUMINESCENCE DOSIMETRY SYSTEM FOR INDIVIDUAL MONITORING.

Performance evaluation is typically assessed as part of the approval procedure to verify that a dosimetry system fulfils specified national or international type-test requirements under representative exposure conditions that are expected to mimic workplace fields from the radiological activities being monitored. The International Atomic Energy Agency Radiation Safety Technical Services Laboratory has recently implemented an integrated radiophotoluminescence (RPL) personal dosimetry system developed by Chiyoda Technol Corporation. This paper reports on the successful verification of dosimetric performance properties of the RPL dosimetry system to IEC 62387:2020, in which the badges were exposed to a range of radiation energies and angles of incidence as well as other influence parameters. Characteristics under test included the coefficient of variation, non-linearity of response due to dose dependence as well as the energy and angular response to photon and beta radiation.

Identifying children with Cystic Fibrosis in population-scale routinely collected data in Wales: A Retrospective Review.

INTRODUCTION: The challenges in identifying a cohort of people with a rare condition can be addressed by routinely collected, population-scale electronic health record (EHR) data, which provide large volumes of data at a national level. This paper describes the challenges of accurately identifying a cohort of children with Cystic Fibrosis (CF) using EHR and their validation against the UK CF Registry. OBJECTIVES: To establish a proof of principle and provide insight into the merits of linked data in CF research; to identify the benefits of access to multiple data sources, in particular the UK CF Registry data, and to demonstrate the opportunity it represents as a resource for future CF research. METHODS: Three EHR data sources were used to identify children with CF born in Wales between 1st January 1998 and 31st August 2015 within the Secure Anonymised Information Linkage (SAIL) Databank. The UK CF Registry was later acquired by SAIL and linked to the EHR cohort to validate the cases and explore the reasons for misclassifications. RESULTS: We identified 352 children with CF in the three EHR data sources. This was greater than expected based on historical incidence rates in Wales. Subsequent validation using the UK CF Registry found that 257 (73%) of these were true cases. Approximately 98.7% (156/158) of individuals identified as CF cases in all three EHR data sources were confirmed as true cases; but this was only the case for 19.8% (20/101) of all those identified in just a single data source. CONCLUSION: Identifying health conditions in EHR data can be challenging, so data quality assurance and validation is important or the merit of the research is undermined. This retrospective review identifies some of the challenges in identifying CF cases and demonstrates the benefits of linking cases across multiple data sources to improve quality.

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

High-profile studies frequently and repetitively present data on the same patients, particularly in immunotherapy studies.

BACKGROUND: Traditionally, study results have been presented as abstracts at major scientific meetings at the conclusion of the analysis. Recently, presentations of studies in progress and updates to previously presented data have been allowed at major meetings. The frequency and implications of a single study being presented multiple times, particularly in high profile oral presentations, have not been fully evaluated. METHODS: To identify studies presented multiple times, abstracts from an approximately 1-year period from international conferences for three major societies devoted largely or in part to lung cancer research were assessed (ASCO 2015, World Lung 2015, ESMO 2015 and ASCO 2016). Abstracts were selected in a two-step process. The first step was for subject matter based on keywords: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or immunotherapy. Searches differed slightly based on individual website functionality, with ASCO searched by track, World Lung by session and ESMO by individual abstract. In a second step, abstracts for which clinical outcome data was presented from a trial with an identifiable National Clinical Trial (NCT) number were selected. Immunotherapy abstracts that did not include the treatment of NSCLC or SCLC were excluded in the second step. RESULTS: A total of 851 abstracts were identified that were related to NSCLC, SCLC or immunotherapy. Of these, 357 referred to a clinical trial. In total, 110 of 357 (31%) described clinical trials that were presented multiple times (mean 2.75, range 2-7), and in 44 (12%), this occurred at the same conference. Of the 113 oral presentations, 75 (66%) presented data from clinical trials, either as posters or oral presentations. Further, 35 of the 113 (31%) oral presentations presented data from clinical trials that had generated other oral presentations. Of the 16 unique clinical trials leading to multiple oral presentations, a variety of issues led to the duplicate presentations, including different cohorts of the same trial, biomarker analysis, analysis by one study variable, or simply updated data. Moreover, 107 of the 357 (30%) clinical trial abstracts pertained to immunotherapy, including 4 of the 16 clinical trials generating multiple oral presentations. Of the 16 trials generating multiple oral presentations, 11 (69%) lead to a full-length publication by July 2017, including all of those pertaining to immunotherapy. CONCLUSIONS: There is a pattern of multiple presentations of clinical trials, particularly in oral presentations, at major meetings. In most cases, data presented in subsequent oral presentations related entirely to patients whose data was presented in the previous oral presentation.

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center.

We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti-PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288-94. ©2018 AACR.

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

BACKGROUND: Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. METHODS: The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. RESULTS: In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. CONCLUSIONS: Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.

Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy - a cohort linkage study.

OBJECTIVE: To examine the effect of maternal exposure to asthma medications on the risk of congenital anomalies. DESIGN: Meta-analysis of aggregated data from three cohort studies. SETTING: Linkage between healthcare databases and EUROCAT congenital anomaly registries. POPULATION: 519 242 pregnancies in Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010). METHODS: Exposure defined as having at least one prescription for asthma medications issued (Wales) or dispensed (Norway, Denmark) from 91 days before to 91 days after the pregnancy start date. Odds ratios (ORs) were estimated separately for each register and combined in meta-analyses. MAIN OUTCOME MEASURES: ORs for all congenital anomalies and specific congenital anomalies. RESULTS: Overall exposure prevalence was 3.76%. For exposure to asthma medication in general, the adjusted OR (adjOR) for a major congenital anomaly was 1.21 (99% CI 1.09-1.34) after adjustment for maternal age and socioeconomic position. The OR of anal atresia was significantly increased in pregnancies exposed to inhaled corticosteroids (3.40; 99% CI 1.15-10.04). For severe congenital heart defects, an increased OR (1.97; 1.12-3.49) was associated with exposure to combination treatment with inhaled corticosteroids and long-acting beta-2-agonists. Associations with renal dysplasia were driven by exposure to short-acting beta-2-agonists (2.37; 1.20-4.67). CONCLUSION: The increased risk of congenital anomalies for women taking asthma medication is small with little confounding by maternal age or socioeconomic status. The study confirmed the association of inhaled corticosteroids with anal atresia found in earlier research and found potential new associations with combination treatment. The potential new associations should be interpreted with caution due to the large number of comparisons undertaken. TWEETABLE ABSTRACT: This cohort study found a small increased risk of congenital anomalies for women taking asthma medication.

Prevention of neural tube defects in the UK: a missed opportunity.

OBJECTIVE: In 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in the UK from 1998 as it had been in the USA. DESIGN: Estimates of NTD prevalence, the preventive effect of folic acid and the proportion of women taking folic acid supplements before pregnancy were used to predict the number of NTD pregnancies that would have been prevented if folic acid fortification had been implemented. SETTING: Eight congenital anomaly registers in England and Wales. MAIN OUTCOME MEASURES: The prevalence of pregnancies with an NTD in the UK and the number of these pregnancies that would have been prevented if folic acid fortification had been implemented. RESULTS: From 1991 to 2012, the prevalence of NTD pregnancies was 1.28 (95% CI 1.24 to 1.31) per 1000 total births (19% live births, 81% terminations and 0.5% stillbirths and fetal deaths ≥20 weeks' gestation). If the USA levels of folic acid fortification from 1998 onwards had been adopted in the UK, an estimated 2014 fewer NTD pregnancies would have occurred. CONCLUSIONS: Failure to implement folic acid fortification in the UK has caused, and continues to cause, avoidable terminations of pregnancy, stillbirths, neonatal deaths and permanent serious disability in surviving children.

Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel.

The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.