Association of Baseline Magnetic Resonance Imaging Prostate Imaging Reporting and Data System Score With Prostate Cancer Active Surveillance Early Biopsy Reclassification: Data From the Michigan Urological Surgery Improvement Collaborative (MUSIC).

PURPOSE: The purpose of our study was to evaluate the association of baseline MRI Prostate Imaging Reporting and Data System (PI-RADS) score with biopsy reclassification in a multicenter active surveillance (AS) cohort. MATERIALS AND METHODS: We identified men in the Michigan Urological Surgery Improvement Collaborative registry (46 hospital-based/academic/private practice urology groups) with National Comprehensive Cancer Network (NCCN) low-risk and favorable intermediate-risk prostate cancer who underwent MRI within 6 months before or after initial biopsy and enrolled in AS from June 2016 to January 2021. The primary objective was to determine the association of baseline MRI PI-RADS score (≥4 lesion) with reclassification to high-grade prostate cancer (≥grade group 3) on surveillance biopsy. Multivariable Cox proportional hazards regression models were constructed and adjusted for pathologic, MRI, and clinical/biopsy factors, with landmark time of 6 months from diagnostic biopsy. We included an interaction term between PI-RADS score and NCCN group in the Cox model. RESULTS: A total of 1491 men were included with median age 64 years (IQR: 59-69) with median follow-up 11.0 months (IQR: 6.0-23.0) after landmark. Baseline PI-RADS ≥ 4 lesion was associated with an increased hazard of biopsy reclassification (HR: 2.3 [95% CI: 1.6-3.2], P < .001), along with grade group 2 vs 1 (HR: 2.5 [95% CI: 1.7-3.7], P < .001), and increasing age (per 10 years; HR: 1.8 [95% CI: 1.4-2.4], P < .001). The interaction between NCCN risk group with MRI findings was not significant (P = .7). CONCLUSIONS: In this multicenter cohort study of real-world data, baseline MRI PI-RADS score was significantly associated with early biopsy reclassification in men undergoing AS with NCCN low- or favorable intermediate-risk prostate cancer.

Comparison of three antepartum risk assessment tools to predict significant postpartum hemorrhage in livebirths.

BACKGROUND: To adequately predict significant postpartum hemorrhage (PPH) at hospital admission, we evaluated and compared the accuracy of three risk assessment tools: 1. California Maternal Quality Care Collaborative (CMQCC), 2. American College of Obstetrics and Gynecology Safe Motherhood Initiative (ACOG SMI) and 3. Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN). STUDY DESIGN AND METHODS: This is a retrospective cohort study of people who delivered liveborn infants from January 2018 to June 2021 at our center. Patients with comorbidities necessitating higher hemoglobin values, those who refused blood transfusions, and missing pertinent data were excluded. Significant PPH was defined as a blood transfusion within 48 hours following delivery. Diagnostic statistics were calculated for each tool. RESULTS: Of the 11,679 included pregnancies, 232 (1.9%) people had significant PPH. Amongst those diagnosed as high-risk by the CMQCC tool, 67/1485 (4.5%) had significant PPH; 62/1672 (3.7%) by the ACOG SMI tool, and 85/1864 (4.6%) by the AWHONN tool had significant PPH. All tools have low sensitivity and high negative predictive values. The area under the receiver operating characteristics curve of the three tools is moderately poor (CMQCC: 0.58, ACOG SMI: 0.55, AWHONN:0.61). DISCUSSION: Upon admission to labor and delivery, all three studied tools are poor predictors of significant PPH. The development and validation of better PPH risk stratification tools are required with the inclusion of additional important variables.

Gene therapy in sickle cell disease: Attitudes and informational needs of patients and caregivers.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder that results in serious morbidity and early mortality. Novel therapies for SCD, most notably genetic therapies (GTs) and HLA-mismatched donor hematopoietic cell transplantation, are in clinical trials. While potentially curative, these interventions are some of the most intensive treatments for SCD and are associated with serious and life-altering side effects, which may manifest several years after treatment. Little is known about knowledge, beliefs, and attitudes of individuals with SCD, or their caregivers, toward existing and these emerging therapies. METHODS: Patients with SCD at least 13 years of age (n = 66) and caregivers (n = 38) were surveyed about knowledge, attitudes, and beliefs surrounding treatments for SCD. RESULTS: Only 4.8% felt "extremely knowledgeable" about GT for SCD while the majority (63.4%) reported little knowledge. Overall, health literacy was low among respondents. Most respondents had a neutral attitude regarding the safety of GT for SCD, and whether it was a good treatment for the disorder (56.7% and 58.6%, respectively). Only a few respondents endorsed the idea that GT was "unsafe" or "not a good treatment" (5.8% and 4.8%, respectively). There was an association between increasing knowledge about GT and agreement that it is safe (p = .012) and a good treatment for SCD (p = .031). CONCLUSIONS: Given that very few patients with SCD feel knowledgeable about GT and a majority have neutral feelings about the safety and utility of this new approach, culturally appropriate patient-centered education is urgently needed as these treatments get regulatory approval and proceed to the clinic.

Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters.

miR-17 approximately 92, miR-106b approximately 25, and miR-106a approximately 363 belong to a family of highly conserved miRNA clusters. Amplification and overexpression of miR-1792 is observed in human cancers, and its oncogenic properties have been confirmed in a mouse model of B cell lymphoma. Here we show that mice deficient for miR-17 approximately 92 die shortly after birth with lung hypoplasia and a ventricular septal defect. The miR-17 approximately 92 cluster is also essential for B cell development. Absence of miR-17 approximately 92 leads to increased levels of the proapoptotic protein Bim and inhibits B cell development at the pro-B to pre-B transition. Furthermore, while ablation of miR-106b approximately 25 or miR-106a approximately 363 has no obvious phenotypic consequences, compound mutant embryos lacking both miR-106b approximately 25 and miR-17 approximately 92 die at midgestation. These results provide key insights into the physiologic functions of this family of microRNAs and suggest a link between the oncogenic properties of miR-17 approximately 92 and its functions during B lymphopoiesis and lung development.

Distribution of emergency medicine programs by location and reproductive rights: A cross-sectional study of the 2023 Match.

INTRODUCTION: The 2023 Match saw over 500 unfilled positions in emergency medicine (EM). Geographic location is the third most important factor for all United States (US) EM-bound senior medical students when selecting programs to rank and can be affected by political climate. Given the perceived importance of geography on program selection and recent changes to reproductive rights in the US, we sought to evaluate the impact of geography and reproductive rights on unmatched positions among EM programs. METHODS: This was a cross-sectional study assessing Match rates in EM by program US state, region, and degree of reproductive rights. We included all EM programs participating in the 2023 Match year. Our primary outcome was to determine the unfilled programs and positions rate per US state. Secondary outcomes included Match rates by region and by degree of reproductive rights. RESULTS: We found notable differences in unfilled programs by US state, with the highest percentage of unfilled programs and positions in Arkansas (100%, 56.3%), Nevada (100%, 35.5%), Kansas (100%, 40.0%), Ohio (81.3%, 33.3%), and Michigan (80.0%, (36.8%). Among regions, the highest percentage of unfilled programs (62.5%) and residency positions (26.0%) was East North Central (IL, IN, MI, OH, WI). US states with limited reproductive rights had the highest percent (52.9%) of programs with unmatched positions and the highest percent (20.5%) of unfilled positions. CONCLUSION: We identified notable differences in unmatched positions by US state and region, as well as the highest rate of unmatched positions in US states with more limited reproductive rights.

Divergence of Arctic shrub growth associated with sea ice decline.

Arctic sea ice extent (SIE) is declining at an accelerating rate with a wide range of ecological consequences. However, determining sea ice effects on tundra vegetation remains a challenge. In this study, we examined the universality or lack thereof in tundra shrub growth responses to changes in SIE and summer climate across the Pan-Arctic, taking advantage of 23 tundra shrub-ring chronologies from 19 widely distributed sites (56°N to 83°N). We show a clear divergence in shrub growth responses to SIE that began in the mid-1990s, with 39% of the chronologies showing declines and 57% showing increases in radial growth (decreasers and increasers, respectively). Structural equation models revealed that declining SIE was associated with rising air temperature and precipitation for increasers and with increasingly dry conditions for decreasers. Decreasers tended to be from areas of the Arctic with lower summer precipitation and their growth decline was related to decreases in the standardized precipitation evapotranspiration index. Our findings suggest that moisture limitation, associated with declining SIE, might inhibit the positive effects of warming on shrub growth over a considerable part of the terrestrial Arctic, thereby complicating predictions of vegetation change and future tundra productivity.

Retrospective review of GCT cutoff value based on pre-pregnancy BMI class in patients with GDM.

OBJECTIVES: To determine the optimal glucose challenge test (GCT) cutoff value for the screening of gestational diabetes mellitus (GDM) based on pre-pregnancy BMI. METHODS: An-IRB approved retrospective cohort analysis of singleton pregnancies at a large tertiary healthcare center from January 2004 to December 2020 was performed. The first GCT value completed between 20 and 32 weeks was used. Using a receiver operator curve (ROC), we sought to determine the optimal GCT cutoff value for each BMI category that would predict the development of GDM. Youden Index was used to determine optimal cut-point of GCT values for each BMI class. RESULTS: A total of 23,550 patients with a GCT value were identified. Of those, 1,676 (7.1%) were diagnosed with GDM. 513 (30.6%) with normal BMI, 449 (26.8%) overweight, 347 (20.7%) class I obese, 210 (12.5%) class II obese, and 157 (9.4%) class III obese patients were diagnosed with GDM. Gestational diabetes was predicted at GCT cutoff value of 130 mg/dL with an area under the curve (AUC) of 0.92 (BMI <25), 131 mg/dL with an AUC of 0.92 (overweight BMI), 131 mg/dL with an AUC of 0.89 (class I BMI), 133 mg/dL with an AUC of 0.88 (class II BMI), and 131 mg/dL with an AUC of 0.88 (class III BMI). CONCLUSIONS: AUC ranged from 0.88 to 0.92 with 93% or greater sensitivity for GCT cutoff value across each of the BMI categories. The findings support a GCT cutoff value of 130 mg/dL for GDM screening regardless of BMI.

Systematic review: emotion dysregulation and challenging behavior interventions for children and adolescents on the autism spectrum with graded key evidence-based strategy recommendations.

Challenging behavior, such as aggression, is highly prevalent in children and adolescents on the autism spectrum and can have a devastating impact. Previous reviews of challenging behavior interventions did not include interventions targeting emotion dysregulation, a common cause of challenging behavior. We reviewed emotion dysregulation and challenging behavior interventions for preschoolers to adolescents to determine which evidence-based strategies have the most empirical support for reducing/preventing emotion dysregulation/challenging behavior. We reviewed 95 studies, including 29 group and 66 single case designs. We excluded non-behavioral/psychosocial interventions and those targeting internalizing symptoms only. We applied a coding system to identify discrete strategies based on autism practice guidelines with the addition of strategies common in childhood mental health disorders, and an evidence grading system. Strategies with the highest quality evidence (multiple randomized controlled trials with low bias risk) were Parent-Implemented Intervention, Emotion Regulation Training, Reinforcement, Visual Supports, Cognitive Behavioral/Instructional Strategies and Antecedent-Based Interventions. Regarding outcomes, most studies included challenging behavior measures, while few included emotion dysregulation measures. This review highlights the importance of teaching emotion regulation skills explicitly, positively reinforcing replacement/alternative behaviors, using visuals and metacognition, addressing stressors proactively, and involving parents. It also calls for more rigorously designed studies and for including emotion dysregulation as an outcome/mediator in future trials.

Acquisition and retention of lung ultrasound skills by respiratory therapists: A curriculum for respiratory therapists.

Purpose: Lung point-of-care ultrasound (POCUS) is a versatile bedside tool. The utility of POCUS has grown during the coronavirus disease 2019 pandemic, as it allows clinicians to obtain real-time images without requiring transport of the patient outside the intensive care unit. As respiratory therapists (RTs) are involved in caring for those with respiratory failure, there is a good rationale for their adoption of lung ultrasound. However, no training standards have been defined. Our objective was to develop and implement a training programme for RTs to achieve and sustain competence in lung ultrasound. Methods: This was a single-centre, prospective, single-cohort observational study. A total of 10 RTs completed our curriculum and were tasked with independently completing and interpreting 10 initial lung ultrasound exams and 3 subsequent exams after a 6-week interim period. All exams were blindly overread by a local expert in lung ultrasound. Results: After completing the curriculum, RTs were able to acquire and accurately interpret their images over 85% of the time. They were more successful in the upper lung zone image acquisition and interpretation compared with the lower lung zones. After 6 weeks, the RTs' lung POCUS skills remained stable, and their lower lung zone image interpretation improved. The RTs reported that their confidence improved throughout the study. Conclusion: The RTs in our study have demonstrated competence in acquisition and interpretation of upper lung zone images. They have also reported confidence in acquiring and interpreting upper lung zone images. More experience appears to be required to gain competence and confidence in lower lung zone ultrasound. Next steps would be to repeat the present study with a higher number of RTs completing at least 20 lung POCUS studies.

When does early palliative care influence aggressive care at the end of life?

BACKGROUND: Early palliative care improves patient quality of life and influences cancer care. The time frame of early has not been established. Eight quality measures reflect aggressive care at the end of life. We retrospectively reviewed patients who died with cancer between January 1, 2018, through December 31, 2019, and compared the timing of palliative care consultation, advance directives (AD), and home palliative care with aggressive care at the end of life (ACEOL). METHODS: Patients without ACEOL indicators were compared to patients with one or more than one indicator of ACEOL. The proportion of patients who received palliative care, completed AD, and the timing of palliative care and AD (less than 30 days, 30-90 days, and greater than 90 days prior to death) was compared for patients who had ACEOL versus those who did not. Chi-square analysis was used for categorical data, one-way ANOVA for continuous variables, and odds ratio (OR) with confidence intervals (CI) was reported as a measure of effect size. A p value ≤ 0.05 was considered significant. RESULTS: 1727 patients died, 46% were female, and the mean age was 69 (SD 11.91). Seventy-one percent had a palliative care consult, 26% completed AD, and 888 (51.4%) had at least one indicator of ACEOL. The most common indicator of ACEOL was new chemotherapy within 30 days of death, in 571 of 888 (64%) of patients experiencing ACEOL. ADs completed at any time reduced ACEOL (OR 0.80, 95%CI 0.64-0.99). Palliative care initiated at 30 days was associated with a greater risk of ACEOL (OR 5.32, 95% CI 3.94-7.18) and initiated between 30 and 90 days (OR 1.39, 95% CI 1.07-1.80) compared to no palliative care but was associated with reduced chemotherapy as an indicator of ACEOL when > 90 days (OR 0.46, 95% CI 0.38-0.57) before death. DISCUSSION: Completed ADs were associated with reduced chemotherapy in the last 30 days of life and reduced ICU admissions. This may reflect goals of care and end-of-life discussions and transition of care to comfort measures. Palliative care paradoxically when initiated within 90 days before death was associated with greater ACEOL compared to no palliative care. This may be due to consultation late in the course of illness with a focus on crisis management in patients frequently utilizing the health care system. There is an associated reduction in the use of chemotherapy in the last 30 days of life if palliative care is consulted 90 days prior to death. CONCLUSIONS: An initial palliative care consult greater than 90 days before death and ADs completed at any time during the disease trajectory was associated only with reduced chemotherapy in the last 30 days of life compared with no palliative care among the 7 ACEOL indicators. ADs were associated with reduced ICU admissions. Most palliative care consults occurred within 90 days of death and a palliative care consult within 90 days of death is not an optimal utilization of services.

An Educational Module to Teach Interprofessional Learner Feedback Skills for Trauma Simulation Events.

BACKGROUND: Peer feedback, or feedback given by a learner to another learner, is an important active learning strategy. Hierarchy and stereotypes may affect interprofessional (IP) learner-to-learner feedback. The aim was to assess the efficacy of an educational module for IP learners in delivering effective feedback during trauma simulations. METHODS: Multiple simulation events designed to improve teamwork and leadership skills during trauma simulations included IP learners (residents and nurses). Participants completed a pre-course educational module on IP peer feedback. The Trauma Team Competence Assessment-24 tool structured feedback. Learners completed pre/post-assessments utilizing IP Collaborative Competencies Attainment Survey (ICCAS). RESULTS: Twenty-five learners participated in the trauma simulations (13 general surgery and 5 emergency residents, 3 medical students, 4 nurses). The majority of learners had either not received any previous training in how to effectively deliver peer feedback (40%) or had engaged in self-directed learning only (24%). Most learners (64%) had delivered peer feedback less than ten times. Learner knowledge and confidence in delivering feedback to fellow IP learners improved after simulations. All learners felt the feedback received was useful to their daily practice (68% agree, 32% strongly agree). All participants agreed that the simulation achieved each of the ICCAS competencies. CONCLUSIONS: Formal education on IP peer feedback is rare. This pilot work demonstrates educational modules with a foundation in validated tools can be effective in improving learner knowledge and confidence in the process. Engaging in IP peer feedback may also serve to flatten hierarchies that can challenge effective interprofessional teamwork.

Reproductive safety of aripiprazole: data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Aripiprazole has become one of the most commonly prescribed psychotropics, making a more comprehensive understanding of its reproductive safety profile a priority. The goal of the current analysis was to determine the risk of major malformations in infants exposed during the first trimester of pregnancy to aripiprazole compared to infants whose mothers had psychiatric diagnoses but did not use an atypical antipsychotic during pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Medical records are assessed to confirm presence or absence of major malformations. Pregnant women ages 18-45 with psychiatric diagnoses are enrolled. As of April 2020, N = 848 women who had delivered infants were eligible for analyses. A total of 158 women with first trimester exposure to aripiprazole were compared to 690 controls. For 163 infants born to women in the exposed group, seven major malformations were confirmed (4.29%), compared to fourteen of the 690 unexposed infants (1.99%). The unadjusted odds ratio for major malformations between aripiprazole-exposed and unexposed infants was 2.21 (95% confidence interval [CI] = (0.88, 5.57) The adjusted odds ratio for major malformations was 1.35 (95% confidence interval [CI] = (0.43, 4.20). After adjustment for confounding variables, the risk of major malformations after first trimester exposure to aripiprazole was not significant compared to controls. While these results are reassuring, they are limited by relatively small numbers of participants. Future analyses with larger numbers are expected to provide more of a complete and precise reproductive safety profile regarding aripiprazole use during pregnancy. Trial registration: clinicaltrials.gov NCT01246765.

Analysis of Gender Diversity Within Hand Surgery Fellowship Programs.

PURPOSE: To define and compare gender diversity among faculty and trainees within hand surgery fellowship programs. METHODS: We determined the gender of each program director for all orthopedic residency and fellowship programs. Specific to hand fellowship programs, we determined the gender of the fellowship director and all faculty members for all plastic surgery and orthopedic hand fellowship programs. Lists of prior hand surgery fellows from 2014 to 2019 were obtained from official program websites or program coordinators. The gender distribution of the hand fellowship program directors and faculty was compared to the prior fellows. RESULTS: Hand surgery fellowship programs had the second highest percentage of female fellowship directors (13%) behind orthopedic oncology (27%). Within hand surgery, 614 total faculty positions were identified, and 15% were female. Of the 89 hand surgery programs evaluated, 36 (60%) had at least 1 female faculty member. For the 849 prior fellows identified, 213 (25%) were female, and 79% of programs had at least 1 female fellow. Hand programs led by a female director did not have a higher percentage of prior female fellows compared to programs led by a male director (26% vs 25%). Programs with a female fellowship director were as likely to have had at least 1 prior female fellow compared to programs with a male fellowship director. CONCLUSIONS: For orthopedic subspecialties, hand surgery fellowship programs had the second highest percentage of female fellowship directors (13%). While mentorship plays an important role in surgical education, hand fellowship programs with female faculty did not appear to attract more female fellows or faculty. CLINICAL RELEVANCE: Hand fellowship programs should recognize that the presence of female faculty may not be a primary factor in fellowship selection for female applicants, and further study into recruiting qualified female candidates should be encouraged.

Technology, Social Media, and Telemedicine Utilization for Rural Hand and Upper-Extremity Patients.

PURPOSE: To define technology and social media use among rural upper-extremity patients. In addition, we aimed to assess how patients use social media in relation to health care and their willingness to participate in telemedicine programs. METHODS: An anonymous multiple-choice written survey was administered to 550 upper-extremity patients at 4 rural outreach clinics. Demographic information was obtained, as was social media use, habits and interests. We compared both users and nonusers of social media to define demographic differences between these groups. RESULTS: A total of 412 patients completed surveys and were included in our analysis (75%); 225 reported using social media (55%). Of the respondents, 67% had a high school education or less and 60% reported an income of less than $50,000/y with an unemployment rate of 58%. In addition, 28% reported not owning a smartphone and 20% lacked home Internet access. Multivariable regression demonstrated that age, female sex, and home Internet access were all independently associated with increased social media use. Facebook was the most frequently used social media platform. Moreover, 42% were interested in telemedicine and social media users were significantly more likely to be interested in telemedicine programs compared with non-social media users. CONCLUSIONS: Within a population of rural and economically disadvantaged upper-extremity patients, 55% currently use social media; 32% used these platforms to research health conditions. Whereas younger female patients with home Internet access were more likely to use social media, older patients were more likely to use these platforms to research health conditions. CLINICAL RELEVANCE: As more health information moves on-line and as telemedicine programs continue to evolve, some rural upper-extremity patients may still have technological barriers in the form of smartphone and computer ownership as well as a lack of home Internet access.

A Pilot Study of a Parent-Mediated, Web-Based Motor Skill Intervention for Children With Down Syndrome: Project SKIP.

To inform the development of scalable and sustainable fundamental motor skill interventions for children with Down syndrome, this study examined the feasibility and preliminary effectiveness of Project Skill Intervention Implemented by Parents (Project SKIP), a web-based, parent-mediated intervention intended to improve ball skills among children with Down syndrome. Twenty-four families enrolled in the study (including 13 boys and 11 girls; Mage = 4.92). Fourteen children were assigned to an experimental group and participated in the 6-week intervention, and 10 children served as the inactive comparison group. The Test of Gross Motor Development-3 was administered preintervention and postintervention. In addition, parents of children in the experimental group completed a postintervention survey to assess their perceptions of Project SKIP. Following the intervention, there was a significant improvement in ball skills (p = .023, d = 0.86) for children in the experimental group, whereas the comparison group did not show significant improvement. Moreover, parents perceived Project SKIP to be feasible and effective; all parents reported being satisfied with their overall experience in the program, and 11 parents indicated that their child's fundamental motor skills were positively influenced by the intervention. Engagement was high, with the majority of parents (n = 8, 57%) interacting with Project SKIP content three to four times a week.

Let Their Voices Be Seen.

STUDY OBJECTIVE: The mutual distrust, in part caused by misunderstanding and bias, between sickle cell disease (SCD) patients and their emergency department (ED) providers has been widely documented in the SCD literature. This study seeks to illustrate the perceptions and experiences of adult sickle cell patients who have had at least 1 ED experience in the last 2 years. METHODS: Qsource, a nonprofit health care consultancy based in Tennessee, used photovoice, a qualitative research method, to facilitate the representation of patients' experiences in living with SCD. Photovoice has participants document their experiences through photography and then, as a group, discuss and analyze the emotional state behind the photographs. Eight participants with SCD took 25 photographs during 4 weeks. Then, in a 2-hour critical dialogue, participants identified recurring themes through consensus. RESULTS: Participants identified 6 themes that emerged from their discussion: unpredictability of SCD, fickleness of time, coping with pain, proximity to death, avoidance of the ED, and need for improved communication. They expressed their wish to be active participants in their care, and many described a fear of death, which is exacerbated by a lack of control in the ED setting. CONCLUSION: Factors such as poor patient experience and misunderstanding may contribute to delays in seeking care for SCD patients. This may, in turn, escalate pain crises and increase the likelihood of hospital admission. We believe that photovoice may be a new means to educate ED providers on SCD patient perceptions, ultimately resulting in better ED care.

Genomic basis of recombination suppression in the hybrid between Caenorhabditis briggsae and C. nigoni.

DNA recombination is required for effective segregation and diversification of genomes and for the successful completion of meiosis. Recent studies in various species hybrids have demonstrated a genetic link between DNA recombination and speciation. Consistent with this, we observed a striking suppression of recombination in the hybrids between two nematodes, the hermaphroditic Caenorhabditis briggsae and the gonochoristic C. nigoni. To unravel the molecular basis underlying the recombination suppression in their hybrids, we generated a C. nigoni genome with chromosome-level contiguity and produced an improved C. briggsae genome with resolved gaps up to 2.8 Mb. The genome alignment reveals not only high sequence divergences but also pervasive intra- and inter-chromosomal sequence re-arrangements between the two species, which are plausible culprits for the observed suppression. Comparison of recombination boundary sequences suggests that recombination in the hybrid requires extensive sequence homology, which is rarely seen between the two genomes. The new genomes and genomic libraries form invaluable resources for studying genome evolution, hybrid incompatibilities and sex evolution for this pair of model species.

Infant acid suppression use is associated with the development of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an esophageal allergic inflammatory disorder often presenting with infant/toddler gastroesophageal reflux symptoms refractory to treatment, including acid suppression trials with histamine H2 antagonists and proton pump inhibitors. We propose to evaluate the impact of infant acid suppressant exposure in EoE. Geisinger's pediatric EoE cases were matched to controls (1:5 EoE case control ratio) using age, race, sex, and ages at other diagnoses of asthma, eczema, and environmental allergies, totaling 526 EoE cases and 2,630 controls. Comparisons between EoE cases and matched controls were tested with regard to rates of acid suppression use with H2 antagonists and PPIs during infancy. Our analyses found the use of acid suppression in infancy was positively associated with EoE: PPI (5.7% EoE cases vs. 1.6% controls; P < 0.0001), H2 antagonists (8.8% EoE cases vs. 4.5% controls; P < 0.0001). Additionally, analysis of EoE cases using acid suppression during infancy indicated a likelihood for the diagnosis with EoE at an earlier age. Early acid suppression use in infants is significantly associated with the diagnosis of EoE in childhood in this well-matched retrospective cohort study. The potential link warrants additional investigation. Our study further reinforces the evidence-based stewardship of acid suppressant use, especially in our most vulnerable populations.

Whole-genome and targeted sequencing of drug-resistant Mycobacterium tuberculosis on the iSeq100 and MiSeq: A performance, ease-of-use, and cost evaluation.

BACKGROUND: Accurate, comprehensive, and timely detection of drug-resistant tuberculosis (TB) is essential to inform patient treatment and enable public health surveillance. This is crucial for effective control of TB globally. Whole-genome sequencing (WGS) and targeted next-generation sequencing (NGS) approaches have potential as rapid in vitro diagnostics (IVDs), but the complexity of workflows, interpretation of results, high costs, and vulnerability of instrumentation have been barriers to broad uptake outside of reference laboratories, especially in low- and middle-income countries. A new, solid-state, tabletop sequencing instrument, Illumina iSeq100, has the potential to decentralize NGS for individual patient care. METHODS AND FINDINGS: In this study, we evaluated WGS and targeted NGS for TB on both the new iSeq100 and the widely used MiSeq (both manufactured by Illumina) and compared sequencing performance, costs, and usability. We utilized DNA libraries produced from Mycobacterium tuberculosis clinical isolates for the evaluation. We conducted WGS on three strains and observed equivalent uniform genome coverage with both platforms and found the depth of coverage obtained was consistent with the expected data output. Utilizing the standardized, cloud-based ReSeqTB bioinformatics pipeline for variant analysis, we found the two platforms to have 94.0% (CI 93.1%-94.8%) agreement, in comparison to 97.6% (CI 97%-98.1%) agreement for the same libraries on two MiSeq instruments. For the targeted NGS approach, 46 M. tuberculosis-specific amplicon libraries had 99.6% (CI 98.0%-99.9%) agreement between the iSeq100 and MiSeq data sets in drug resistance-associated SNPs. The upfront capital costs are almost 5-fold lower for the iSeq100 ($19,900 USD) platform in comparison to the MiSeq ($99,000 USD); however, because of difference in the batching capabilities, the price per sample for WGS was higher on the iSeq100. For WGS of M. tuberculosis at the minimum depth of coverage of 30x, the cost per sample on the iSeq100 was $69.44 USD versus $28.21 USD on the MiSeq, assuming a 2 × 150 bp run on a v3 kit. In terms of ease of use, the sequencing workflow of iSeq100 has been optimized to only require 27 minutes total of hands-on time pre- and post-run, and the maintenance is simplified by a single-use cartridge-based fluidic system. As these are the first sequencing attempts on the iSeq100 for M. tuberculosis, the sequencing pool loading concentration still needs optimization, which will affect sequencing error and depth of coverage. Additionally, the costs are based on current equipment and reagent costs, which are subject to change. CONCLUSIONS: The iSeq100 instrument is capable of running existing TB WGS and targeted NGS library preparations with comparable accuracy to the MiSeq. The iSeq100 has reduced sequencing workflow hands-on time and is able to deliver sequencing results in <24 hours. Reduced capital and maintenance costs and lower-throughput capabilities also give the iSeq100 an advantage over MiSeq in settings of individualized care but not in high-throughput settings such as reference laboratories, where sample batching can be optimized to minimize cost at the expense of workflow complexity and time.

Specific down-regulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-Chromosome introgression.

Hybrid incompatibility (HI) prevents gene flow between species, thus lying at the heart of speciation genetics. One of the most common HIs is male sterility. Two superficially contradictory observations exist for hybrid male sterility. First, an introgression on the X Chromosome is more likely to produce male sterility than on autosome (so-called large-X theory); second, spermatogenesis genes are enriched on the autosomes but depleted on the X Chromosome (demasculinization of X Chromosome). Analysis of gene expression in Drosophila hybrids suggests a genetic interaction between the X Chromosome and autosomes that is essential for male fertility. However, the prevalence of such an interaction and its underlying mechanism remain largely unknown. Here we examine the interaction in nematode species by contrasting the expression of both coding genes and transposable elements (TEs) between hybrid sterile males and its parental nematode males. We use two lines of hybrid sterile males, each carrying an independent introgression fragment from Caenorhabditis briggsae X Chromosome in an otherwise Caenorhabditis nigoni background, which demonstrate similar defects in spermatogenesis. We observe a similar pattern of down-regulated genes that are specific for spermatogenesis between the two hybrids. Importantly, the down-regulated genes caused by the X Chromosome introgressions show a significant enrichment on the autosomes, supporting an epistatic interaction between the X Chromosome and autosomes. We investigate the underlying mechanism of the interaction by measuring small RNAs and find that a subset of 22G RNAs specifically targeting the down-regulated spermatogenesis genes is significantly up-regulated in hybrids, suggesting that perturbation of small RNA-mediated regulation may contribute to the X-autosome interaction.