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The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Abstract Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021–22 and 2022–23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021–22 and 12 out of 18 models in 2022–23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021–22 and the 5th most accurate in the 2022–23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

BackgroundInfants experiencing bronchiolitis are at increased risk for asthma, but few studies have identified modifiable risk factors. We assessed whether early life air pollution influenced child asthma and wheeze at age 4-6 years among children with a history of bronchiolitis in the first postnatal year.MethodsChildren with caregiver-reported physician-diagnosed bronchiolitis were drawn from ECHO-PATHWAYS, a pooled longitudinal cohort from six US cities. We estimated their air pollution exposure from age 1 to 3 years from validated spatiotemporal models of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ). Caregivers reported children's current wheeze and asthma at age 4-6 years. We used modified Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI), adjusting for child, maternal, and home environmental factors. We assessed effect modification by child sex and maternal history of asthma with interaction models.ResultsA total of 224 children had caregiver-reported bronchiolitis. Median (interquartile range) 2-year pollutant concentrations were 9.3 (7.8-9.9) µg/m 3 PM 2.5 , 8.5 (6.4-9.9) ppb NO 2 , and 26.6 (25.6-27.7) ppb O 3 . RRs (CI) for current wheeze per 2-ppb higher O 3 were 1.3 (1.0-1.7) and 1.4 (1.1-1.8) for asthma. NO 2 was inversely associated with wheeze and asthma whereas associations with PM 2.5 were null. We observed interactions between NO 2 and PM 2.5 and maternal history of asthma, with lower risks observed among children with a maternal history of asthma.ConclusionOur results are consistent with the hypothesis that exposure to modest postnatal O 3 concentrations increases the risk of asthma and wheeze among the vulnerable subpopulation of infants experiencing bronchiolitis.

Extracorporeal life support (ECLS) serves as a rescue therapy for patients with congenital diaphragmatic hernia (CDH) and severe cardiopulmonary failure, and only half of these patients survive to discharge. This costly intervention has a significant complication risk and is reserved for patients with the most severe disease physiology refractory to maximal cardiopulmonary support. Some contraindications to ECLS do exist such as coagulopathy, lethal chromosomal or congenital anomaly, very preterm birth, or very low birth weight, but many of these limits are being evaluated through further research. Consensus guidelines from the past decade vary in recommendations for ECLS use in patients with CDH but this therapy appears to have a survival benefit in the most severe subset of patients. Improved outcomes have been observed for patients treated at high-volume centers. This review details the evolving literature surrounding management paradigms for timing of CDH repair for patients receiving preoperative ECLS. Most recent data support early repair following cannulation to avoid non-repair which is uniformly fatal in this population. Longer ECLS runs are associated with decreased survival, and patient physiology should guide ECLS weaning and eventual decannulation rather than limiting patients to arbitrary run lengths. Standardization of care across centers is a major focus to limit unnecessary costs and improve short-term and long-term outcomes for these complex patients.

Abstract Background and aim Studies suggest prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may influence wheezing or asthma in preschool-aged children. However, the impact of prenatal PAH exposure on asthma and wheeze in middle childhood remain unclear. We investigated these associations in socio-demographically diverse participants from the ECHO PATHWAYS multi-cohort consortium. Methods We included 1,081 birth parent–child dyads across five U.S. cities. Maternal urinary mono-hydroxylated PAH metabolite concentrations (OH-PAH) were measured during mid-pregnancy. Asthma at age 8–9 years and wheezing trajectory across childhood were characterized by caregiver reported asthma diagnosis and asthma/wheeze symptoms. We used logistic and multinomial regression to estimate odds ratios of asthma and childhood wheezing trajectories associated with five individual OH-PAHs, adjusting for urine specific gravity, various maternal and child characteristics, study site, prenatal and postnatal smoke exposure, and birth year and season in single metabolite and mutually adjusted models. We used multiplicative interaction terms to evaluate effect modification by child sex and explored OH-PAH mixture effects through Weighted Quantile Sum regression. Results The prevalence of asthma in the study population was 10%. We found limited evidence of adverse associations between pregnancy OH-PAH concentrations and asthma or wheezing trajectories. We observed adverse associations between 1/9-hydroxyphenanthrene and asthma and persistent wheeze among girls, and evidence of inverse associations with asthma for 1-hydroxynathpthalene, which was stronger among boys, though tests for effect modification by child sex were not statistically significant. Conclusions In a large, multi-site cohort, we did not find strong evidence of an association between prenatal exposure to PAHs and child asthma at age 8–9 years, though some adverse associations were observed among girls.

The animal gut acts as a potent reservoir for spreading and maintaining conjugative plasmids that confer antimicrobial resistance (AMR), fitness, and virulence attributes. Interventions that inhibit the continued emergence and expansion of AMR and virulent strains in agricultural and clinical environments are greatly desired. This study aims to determine the presence and efficacy of short-chain fatty acids (SCFA) inhibitory effects on the conjugal transfer of AMR plasmids. In vitro broth conjugations were conducted between donor Escherichia coli strains carrying AMP plasmids and the plasmid-less Escherichia coli HS-4 recipient strain. Conjugations were supplemented with ddH2O or SCFAs at 1, 0.1, 0.01, or 0.001 molar final concentration. The addition of SCFAs completely inhibited plasmid transfer at 1 and 0.1 molar and significantly (p

Abstract Background The vast majority of patients with ROS1 positive non‐small cell lung cancer (NSCLC) derive clinical benefit from currently approved ROS1 therapies, including crizotinib and entrectinib. However, a small proportion of patients treated with ROS1 inhibitors fail to derive any clinical benefit and demonstrate rapid disease progression. The biological mechanisms underpinning intrinsic resistance remain poorly understood for oncogene‐driven cancers. Methods We generated a patient‐derived cell line, CUTO33, from a ROS1 therapy naive patient with CD74‐ROS1+ NSCLC, who ultimately did not respond to a ROS1 inhibitor. We evaluated a panel of ROS1+ patient‐derived NSCLC cell lines and used cell‐based assays to determine the mechanism of intrinsic resistance to ROS1 therapy. Results The CUTO33 cell line expressed the CD74‐ROS1 gene fusion at the RNA and protein level. The ROS1 fusion protein was phosphorylated at baseline consistent with the known intrinsic activity of this oncogene. ROS1 phosphorylation could be inhibited using a wide array of ROS1 inhibitors, however these inhibitors did not block cell proliferation, confirming intrinsic resistance in this model and consistent with the patient's lack of response to a ROS1 inhibitor. CUTO33 expressed high levels of AXL, which has been associated with drug resistance. Combination of an AXL inhibitor or AXL knockdown with a ROS1 inhibitor partially reversed resistance. Conclusions In summary, we demonstrate that AXL overexpression is a mechanism of intrinsic resistance to ROS1 inhibitors.

Let X be a smooth fan and denote its set of endpoints by E(X). Let E be one of the following spaces: the natural numbers, the irrational numbers, or the product of the Cantor set with the natural numbers. We prove that there is a smooth fan X such that E(X) is homeomorphic to E and for every homeomorphism h : X → X , the restriction of h to E(X) is the identity. On the other hand, we also prove that if X is any smooth fan such that E(X) is homeomorphic to complete Erdős space, then X is necessarily homeomorphic to the Lelek fan; this adds to a 1989 result by Włodzimierz Charatonik.

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value

Abstract Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approval by the FDA, tianeptine has been distributed online and at small retail locations. The term “gas station drugs” refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as “Zaza” and “Tianna Red.” It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.

Abstract Background More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. Methods We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP’s main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10–9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10–8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10–8). GRN (rs5848, P = 4.21 × 10–8) and PURG (rs117523305, P = 1.73 × 10–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10–8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10–9) and PTPRD (rs145989094, P = 8.34 × 10–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10–8) and PTPRD (rs145989094, P = 3.85 × 10–8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Correction for “An open challenge to advance probabilistic forecasting for dengue epidemics,” by Michael A. Johansson, Karyn M. Apfeldorf, Scott Dobson, Jason Devita, Anna L. Buczak, Benjamin Baugher, Linda J. Moniz, Thomas Bagley, Steven M. Babin, Erhan Guven, Teresa K. Yamana, Jeffrey Shaman, Terry Moschou, Nick Lothian, Aaron Lane, Grant Osborne, Gao Jiang, Logan C. Brooks, David C. Farrow, Sangwon Hyun, Ryan J. Tibshirani, Roni Rosenfeld, Justin Lessler, Nicholas G. Reich, Derek A. T. Cummings, Stephen A. Lauer, Sean M. Moore, Hannah E. Clapham, Rachel Lowe, Trevor C. Bailey, Markel García-Díez, Marilia Sá Carvalho, Xavier Rodó, Tridip Sardar, Richard Paul, Evan L. Ray, Krzysztof Sakrejda, Alexandria C. Brown, Xi Meng, Osonde Osoba, Raffaele Vardavas, David Manheim, Melinda Moore, Dhananjai M. Rao, Travis C. Porco, Sarah Ackley, Fengchen Liu, Lee Worden, Matteo Convertino, Yang Liu, Abraham Reddy, Eloy Ortiz, Jorge Rivero, Humberto Brito, Alicia Juarrero, Leah R. Johnson, Robert B. Gramacy, Jeremy M. Cohen, Erin A. Mordecai, Courtney C. Murdock, Jason R. Rohr, Sadie J. Ryan, Anna M. Stewart-Ibarra, Daniel P. Weikel, Antarpreet Jutla, Rakibul Khan, Marissa Poultney, Rita R. Colwell, Brenda Rivera-García, Christopher M. Barker, Jesse E. Bell, Matthew Biggerstaff, David Swerdlow, Luis Mier-y-Teran-Romero, Brett M. Forshey, Juli Trtanj, Jason Asher, Matt Clay, Harold S. Margolis, Andrew M. Hebbeler, Dylan George, and Jean-Paul Chretien, which was first published November 11, 2019; 10.1073/pnas.1909865116 (Proc. Natl. Acad. Sci. U.S.A. 116, 24268–24274). The authors note that the following statement should be added to the Acknowledgments: “E.A.M. was supported by NIH Grant R35GM133439.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue.

Abstract Background ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI‐resistant ROS1+ lung cancers. Methods Utilizing a primary, patient‐derived TPM3‐ROS1 cell line (CUTO28), we derived an entrectinib‐resistant line (CUTO28‐ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74‐ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK‐2 entrectinib trial to determine the prevalence of MET amplification. Results CUTO28‐ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28‐ER cells. CUTO28‐ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74‐ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib‐resistant ROS1+ NSCLC STARTRK‐2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. Conclusions Treatment with ROS1‐selective inhibitors may lead to MET‐mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1‐selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET‐driven resistance.

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.

Process-Driven Math is a fully audio method of mathematics instruction and assessment that was created at Auburn University at Montgomery, Alabama, to meet the needs of one particular student, Logan. He was blind, mobility impaired, and he could not speak above a whisper. Logan was not able to use traditional low vision tools like braille and Nemeth code because he lacked the sensitivity in his fingers required to read the raised dots. Logan's need for tools that would enable him to perform the rigorous algebraic manipulations that are common in mathematics courses led to the development of Process-Driven Math. With this method, he was able to succeed in both college algebra and pre-calculus with trigonometry. These tools may help other visually impaired students who are not succeeding in mathematics because they lack access to, or knowledge of, the Nemeth code. Within many algebraic problems, there are processes (algorithms) that must be performed to simplify expressions and solve for variables. Process-Driven Math frees up working memory during the delivery of the mathematic content to the student, and during the student's subsequent manipulation of the equation while working toward a solution. As a result, the student who cannot use or access Nemeth code can better focus on the required algorithms because the cognitive load on working memory is greatly reduced. When using this method, a person who functions as the student's reader and scribe systematically reveals the algebraic expression in layers. The process is highly interactive and places control over the flow of information into the hands of the student.

IntroductionGut microbes like segmented filamentous bacteria (SFB) play a key role in gut maturation during early life, as demonstrated in humans and mice. Our previous study demonstrated oral inoculation of ileum-spores containing SFB to chickens after hatch increases early SFB gut colonization, which increases immune maturation and resistance to bacteria, like Salmonella, as tested in vitro; however, more studies are needed for treatment optimization and in vivo testing. The objectives of this study were to (1) test a treatment that includes both spores and filamentous SFB, (2) validate antimicrobial ability of the treatment in layer hens in vivo, and (3) elucidate its molecular mechanism.MethodsOne-day-old specific pathogen-free layers (n = 12 per group) were orally treated with either PBS (CON) or SFB-based treatment (SFB). At 4 days post-inoculation (DPI), both CON and SFB groups were orally challenged with Salmonella Typhimurium. Total Enterobacteriaceae and Salmonella were examined by plating and enumeration in feces at 7,10 and 14 dpi; and in the ileum, cecum, and spleen at 16 dpi in euthanized birds. The presence and levels of SFB were determined from ilea scrapings via microscopy and qPCR, respectively. Relative gene expression of host-derived antimicrobial peptides and cytokines in the distal ileum was determined by RT-qPCR.ResultsAt 10 and 14 dpi, a significant decrease in total Enterobacteriaceae was observed in the feces of the SFB group. At necropsy, the level of SFB was significantly higher in the SFB group than in the CON group, while a significant decrease in total Enterobacteriaceae and Salmonella was observed in the ceca of the SFB group. RT-qPCR revealed increased expression of β-defensin 14, and cytokines IL-10 and IFNγ.DiscussionThe introduction of SFB at hatch as a prophylactic treatment may benefit commercial partners as well as consumers by reducing the incidence of Enterobacteriaceae in food animals. Reduction of these bacteria in animals would, in turn, increase animal health, productivity, and safety for consumers. Studies to optimize the treatment for poultry industry applications are ongoing in our lab.

Summary: Failure of inherently protective cellular processes and misfolded protein-associated stress contribute to the progressive loss of dopamine (DA) neurons characteristic of Parkinson’s disease (PD). A disease-modifying role for the microbiome has recently emerged in PD, representing an impetus to employ the soil-dwelling nematode, Caenorhabditis elegans, as a preclinical model to correlate changes in gene expression with neurodegeneration in transgenic animals grown on distinct bacterial food sources. Even under tightly controlled conditions, hundreds of differentially expressed genes and a robust neuroprotective response were discerned between clonal C. elegans strains overexpressing human alpha-synuclein in the DA neurons fed either one of only two subspecies of Escherichia coli. Moreover, this neuroprotection persisted in a transgenerational manner. Genetic analysis revealed a requirement for the double-stranded RNA (dsRNA)-mediated gene silencing machinery in conferring neuroprotection. In delineating the contribution of individual genes, evidence emerged for endopeptidase activity and heme-associated pathway(s) as mechanistic components for modulating dopaminergic neuroprotection.