Chronic pelvic pain among transgender men and gender diverse adults assigned female at birth.

BACKGROUND: There are limited data on pelvic pain among transgender men and gender diverse people, and the impact of testosterone on pelvic pain is poorly understood. OBJECTIVE: Characterize the prevalence and correlates of chronic pelvic pain (CPP) among transgender men and gender diverse people and examine the association between testosterone use and CPP. MATERIALS AND METHODS: We used 2020-2022 data from The Population Research in Identity and Disparities for Equality (PRIDE) Study, an online prospective cohort study of sexual and gender minority adults in the United States, to conduct complementary cross-sectional and longitudinal analyses. Our primary outcome was self-reported CPP lasting 3 months or longer measured using the Michigan Body Map. RESULTS: Among 2579 transgender men and gender diverse people assigned female at birth included in our sample, 457 (18%) reported CPP. CPP correlates included: inflammatory bowel disease, irritable bowel syndrome (IBS), kidney stones, pelvic inflammatory disease, polycystic ovary syndrome (PCOS), uterine fibroids, current hormonal intrauterine device use, prior pregnancy, vaginal delivery, hysterectomy, and oophorectomy. Individuals with CPP reported a high prevalence of IBS (37%), PCOS (20%), uterine fibroids (9%), post-traumatic stress disorder (51%), and severe depression and anxiety symptoms (42% and 25%, respectively). Current testosterone use was associated with a 21% lower prevalence of CPP (adjusted prevalence ratio (aPR) 0.79, 95% confidence interval [CI]: 0.65-0.96). In longitudinal analyses (N = 79), 15 (19%) participants reported any CPP after initiating testosterone: eight (56%) of whom reported CPP prior to testosterone initiation, and seven (47%) who reported new-onset CPP. DISCUSSION AND CONCLUSIONS: The relationship between CPP and testosterone is complex. Although testosterone use was associated with a lower prevalence of CPP, some transgender and gender diverse individuals experienced new-onset pelvic pain after testosterone initiation. Given the significant impact that CPP can have on mental health and quality of life, future research must examine the role of testosterone in specific underlying etiologies of CPP and identify potential therapies.

Propofol-sparing and hemodynamic effects of guaifenesin in sheep.

OBJECTIVE: To evaluate the propofol-sparing and hemodynamic effects of guaifenesin administered for co-induction of anesthesia in sheep. STUDY DESIGN: Prospective, blinded, two-way crossover experimental study. ANIMALS: Thirteen healthy adult female sheep. METHODS: Anesthesia was induced without premedication with intravenous (IV) guaifenesin 5% at 100 mg kg-1 (GGE) or an equivalent volume of physiologic saline (SAL), followed by IV propofol at a controlled rate (1 mg kg-1 min-1). Heart rate (HR), respiratory rate and oscillometric noninvasive arterial blood pressure (NIBP) were recorded at baseline after co-induction administration, following endotracheal intubation and every 2 minutes thereafter for 10 minutes. Propofol doses required to achieve intubation after each co-induction treatment were compared by independent Student's t-test. Values of p < 0.05 were considered statistically significant. RESULTS: The propofol dose required (mean ± standard deviation) to achieve intubation was significantly lower (p = 0.001) in the GGE treatment (3.40 ± 0.74 mg kg-1) than in the SAL treatment (5.94 ± 1.09 mg kg-1). HR was increased after anesthetic induction compared with baseline in both treatments. HR was generally lower in the GGE treatment than in the SAL treatment. NIBP did not vary between GGE and SAL treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Guaifenesin, when administered as a co-induction agent with propofol in sheep, reduces propofol dose requirements and maintains hemodynamic variables within a clinically acceptable range.

The regulatory potential of transposable elements in maize.

Since their initial discovery in maize, transposable elements (TEs) have emerged as being integral to the evolution of maize, accounting for 80% of its genome. However, the repetitive nature of TEs has hindered our understanding of their regulatory potential. Here, we demonstrate that long- read chromatin fiber sequencing (Fiber-seq) permits the comprehensive annotation of the regulatory potential of maize TEs. We uncover that only 94 LTR retrotransposons contain the functional epigenetic architecture required for mobilization within maize leaves. This epigenetic architecture degenerates with evolutionary age, resulting in solo TE enhancers being preferentially marked by simultaneous hyper-CpG methylation and chromatin accessibility, an architecture markedly divergent from canonical enhancers. We find that TEs shape maize gene regulation by creating novel promoters within the TE itself as well as through TE-mediated gene amplification. Lastly, we uncover a pervasive epigenetic code directing TEs to specific loci, including that locus that sparked McClintock's discovery of TEs.

Resolving the chromatin impact of mosaic variants with targeted Fiber-seq.

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules-a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with ~10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of the DMPK CTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated γ-globin ( HBG1/HBG2 ) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of the HBG1 promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.

Admission Total Leukocyte Count as a Predictor of Mortality in Cardiac Intensive Care Unit Patients.

Background: Inflammation is a sequela of cardiovascular critical illness and a risk factor for mortality. Objectives: This study aimed to evaluate the association between white blood cell count (WBC) and mortality in a broad population of patients admitted to the cardiac intensive care unit (CICU). Methods: This retrospective cohort study included patients admitted to the Mayo Clinic CICU between 2007 and 2018. We analyzed WBC as a continuous variable and then categorized WBC as low (<4.0 × 103/mL), normal (≥4.0 to <11.0 × 103/mL), high (≥11.0 to <22.0 × 103/mL), or very high (≥22.0 × 103/mL). The association between WBC and in-hospital mortality was evaluated using multivariable logistic regression and random forest models. Results: We included 11,699 patients with a median age of 69.3 years (37.6% females). Median WBC was 9.6 (IQR: 7.4-12.7). Mortality was higher in the low (10.5%), high (12.0%), and very high (33.3%) WBC groups relative to the normal WBC group (5.3%). A rising WBC was incrementally associated with higher in-hospital mortality after adjustment (AICc adjusted OR: 1.03 [95% CI: 1.02-1.04] per 1 × 103 increase in WBC). After adjustment, only the high (AICc adjusted OR: 1.37 [95% CI: 1.15-1.64]) and very high (AICc adjusted OR: 1.99 [1.47-2.71]) WBC groups remained associated with increased risk of in-hospital mortality. Conclusions: Leukocytosis is associated with an increased mortality risk in a diverse cohort of CICU patients. This readily available marker of systemic inflammation may be useful for risk stratification within the increasingly complex CICU patient population.

Exploring the Effects of Instruction and Game Design on Youth Soccer Players' Skill Involvement and Cooperative Team Behaviour.

Objectives: The relationship between task constraints and player behaviors is of interest to coaches tasked with designing practice to optimize learning. This study aims to compare the skill involvements and cooperative team behavior of teams of youth soccer players engaged in a goal exaggeration and/or a prescriptive coach instruction condition compared to a free-play control condition. Methods: Twenty male soccer players aged 12-15 participated in small-sided games under four conditions: free-play, goal exaggeration, prescriptive coach instruction, and combination over four weeks. Using video footage, teams' collective skill involvements (shot, pass, dribble) and passing network characteristics (closeness, density, and betweenness) were measured for each game. Results: A Friedmans rank test identified that playing conditions resulted in significant differences in attempted dribbles (p < .001), goals scored (p < .001), network density (p = .001), closeness (p < .001) and betweenness (p = .002). Teams attempted to dribble the most in the free-play and goal-exaggeration conditions, and the most goals were scored in the goal-exaggeration and combination conditions. Additionally, teams exhibited more well-connected passing networks (i.e. higher density, higher closeness, and lower betweenness values) in the combination condition and higher network density in the explicit instruction condition. Conclusions: The results of this study indicate that coach instruction may be more associated with cooperative team behavior, whereas free-play or manipulating task constraints in the absence of instruction may be associated with players attempting more individual actions.

Natural language processing pipeline to extract prostate cancer-related information from clinical notes.

OBJECTIVES: To develop an automated pipeline for extracting prostate cancer-related information from clinical notes. MATERIALS AND METHODS: This retrospective study included 23,225 patients who underwent prostate MRI between 2017 and 2022. Cancer risk factors (family history of cancer and digital rectal exam findings), pre-MRI prostate pathology, and treatment history of prostate cancer were extracted from free-text clinical notes in English as binary or multi-class classification tasks. Any sentence containing pre-defined keywords was extracted from clinical notes within one year before the MRI. After manually creating sentence-level datasets with ground truth, Bidirectional Encoder Representations from Transformers (BERT)-based sentence-level models were fine-tuned using the extracted sentence as input and the category as output. The patient-level output was determined by compilation of multiple sentence-level outputs using tree-based models. Sentence-level classification performance was evaluated using the area under the receiver operating characteristic curve (AUC) on 15% of the sentence-level dataset (sentence-level test set). The patient-level classification performance was evaluated on the patient-level test set created by radiologists by reviewing the clinical notes of 603 patients. Accuracy and sensitivity were compared between the pipeline and radiologists. RESULTS: Sentence-level AUCs were ≥ 0.94. The pipeline showed higher patient-level sensitivity for extracting cancer risk factors (e.g., family history of prostate cancer, 96.5% vs. 77.9%, p < 0.001), but lower accuracy in classifying pre-MRI prostate pathology (92.5% vs. 95.9%, p = 0.002) and treatment history of prostate cancer (95.5% vs. 97.7%, p = 0.03) than radiologists, respectively. CONCLUSION: The proposed pipeline showed promising performance, especially for extracting cancer risk factors from patient's clinical notes. CLINICAL RELEVANCE STATEMENT: The natural language processing pipeline showed a higher sensitivity for extracting prostate cancer risk factors than radiologists and may help efficiently gather relevant text information when interpreting prostate MRI. KEY POINTS: When interpreting prostate MRI, it is necessary to extract prostate cancer-related information from clinical notes. This pipeline extracted the presence of prostate cancer risk factors with higher sensitivity than radiologists. Natural language processing may help radiologists efficiently gather relevant prostate cancer-related text information.

Cannabis use trajectories over time in relation to minority stress and gender among sexual and gender minority people.

Substance use disparities among sexual and gender minority (SGM) people are attributed to minority stress, but few studies have examined minority stress and cannabis use over time or investigated differences in cannabis use trajectories by less-studied gender subgroups. We examined if longitudinal cannabis use trajectories are related to baseline minority stressors and if gender differences persisted after accounting for minority stress. Cannabis use risk was measured annually over four years (2017-2021) within a longitudinal cohort study of SGM adults in the United States (N = 11,813). Discrimination and victimization, internalized stigma, disclosure and concealment, and safety and acceptance comprised minority stress (n = 5,673). Latent class growth curve mixture models identified five cannabis use trajectories: 'low or no risk', 'low moderate risk', 'high moderate risk', 'steep risk increase', and 'highest risk'. Participants who reported past-year discrimination and/or victimization at baseline had greater odds of membership in any cannabis risk category compared to the 'low risk' category (odds ratios [OR] 1.17-1.33). Internalized stigma was related to 'high moderate' and 'highest risk' cannabis use (ORs 1.27-1.38). After accounting for minority stress, compared to cisgender men, gender expansive people and transgender men had higher odds of 'low moderate risk' (ORs 1.61, 1.67) or 'high moderate risk' (ORs 2.09, 1.99), and transgender men had higher odds of 'highest risk' (OR 2.36) cannabis use. This study indicates minority stress is related to prospective cannabis use risk trajectories among SGM people, and transgender men and gender expansive people have greater odds of trajectories reflecting cannabis use risk.

DNA-m6A calling and integrated long-read epigenetic and genetic analysis with fibertools.

Long-read DNA sequencing has recently emerged as a powerful tool for studying both genetic and epigenetic architectures at single-molecule and single-nucleotide resolution. Long-read epigenetic studies encompass both the direct identification of native cytosine methylation as well as the identification of exogenously placed DNA N6-methyladenine (DNA-m6A). However, detecting DNA-m6A modifications using single-molecule sequencing, as well as coprocessing single-molecule genetic and epigenetic architectures, is limited by computational demands and a lack of supporting tools. Here, we introduce fibertools, a state-of-the-art toolkit that features a semisupervised convolutional neural network for fast and accurate identification of m6A-marked bases using PacBio single-molecule long-read sequencing, as well as the coprocessing of long-read genetic and epigenetic data produced using either PacBio or Oxford Nanopore sequencing platforms. We demonstrate accurate DNA-m6A identification (>90% precision and recall) along >20 kilobase long DNA molecules with a ~1,000-fold improvement in speed. In addition, we demonstrate that fibertools can readily integrate genetic and epigenetic data at single-molecule resolution, including the seamless conversion between molecular and reference coordinate systems, allowing for accurate genetic and epigenetic analyses of long-read data within structurally and somatically variable genomic regions.

Lessons Learned from the Sea Star Wasting Disease Investigation.

Marine invertebrate mass mortality events (MMEs) threaten biodiversity and have the potential to catastrophically alter ecosystem structure. A proximal question around acute MMEs is their etiologies and/or environmental drivers. Establishing a robust cause of mortality is challenging in marine habitats due to the complexity of the interactions among species and the free dispersal of microorganisms from surrounding waters to metazoan microbiomes. The 2013-2014 sea star wasting disease (SSWD) MME in the northeast Pacific Ocean highlights the difficulty in establishing responsible agents. In less than a year of scientific investigation, investigators identified a candidate agent and provided at the time convincing data of pathogenic and transmissible disease. However, later investigation failed to support the initial results, and critical retrospective analyses of experimental procedures and reinterpretation of early findings disbanded any candidate agent. Despite the circuitous path that the investigation and understanding of SSWD have taken, lessons learned from the initial investigation-improving on approaches that led to misinterpretation-have been successfully applied to the 2022 Diadema antillarum investigation. In this review, we outline the history of the initial SSWD investigation, examine how early exploration led to spurious interpretations, summarize the lessons learned, provide recommendations for future work in other systems, and examine potential links between the SSWD event and the Diadema antillarum MME.

Metaplastic neuromodulation via transcranial direct current stimulation has no effect on corticospinal excitability and neuromuscular fatigue.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool with potential for managing neuromuscular fatigue, possibly due to alterations in corticospinal excitability. However, inconsistencies in intra- and inter- individual variability responsiveness to tDCS limit its clinical use. Emerging evidence suggests harnessing homeostatic metaplasticity induced via tDCS may reduce variability and boost its outcomes, yet little is known regarding its influence on neuromuscular fatigue in healthy adults. We explored whether cathodal tDCS (ctDCS) prior to exercise combined with anodal tDCS (atDCS) could augment corticospinal excitability and attenuate neuromuscular fatigue. 15 young healthy adults (6 males, 22 ± 4 years) participated in four pseudo-randomised neuromodulation sessions: sham stimulation prior and during exercise, sham stimulation prior and atDCS during exercise, ctDCS prior and atDCS during exercise, ctDCS prior and sham stimulation during exercise. The exercise constituted an intermittent maximal voluntary contraction (MVC) of the right first dorsal interosseous (FDI) for 10 min. Neuromuscular fatigue was quantified as an attenuation in MVC force, while motor evoked potential (MEP) amplitude provided an assessment of corticospinal excitability. MEP amplitude increased during the fatiguing exercise, whilst across time, force decreased. There were no differences in MEP amplitudes or force between neuromodulation sessions. These outcomes highlight the ambiguity of harnessing metaplasticity to ameliorate neuromuscular fatigue in young healthy individuals.

Role of Ectopic Olfactory Receptors in the Regulation of the Cardiovascular-Kidney-Metabolic Axis.

Olfactory receptors (ORs) represent one of the largest yet least investigated families of G protein-coupled receptors in mammals. While initially believed to be functionally restricted to the detection and integration of odors at the olfactory epithelium, accumulating evidence points to a critical role for ectopically expressed ORs in the regulation of cellular homeostasis in extranasal tissues. This review aims to summarize the current state of knowledge on the expression and physiological functions of ectopic ORs in the cardiovascular system, kidneys, and primary metabolic organs and emphasizes how altered ectopic OR signaling in those tissues may impact cardiovascular-kidney-metabolic health.

An Adaptive Pragmatic Randomized Controlled Trial of Emergency Department Acupuncture for Acute Musculoskeletal Pain Management.

STUDY OBJECTIVE: Acute musculoskeletal pain in emergency department (ED) patients is frequently severe and challenging to treat with medications alone. The purpose of this study was to determine the feasibility, acceptability, and effectiveness of adding ED acupuncture to treat acute episodes of musculoskeletal pain in the neck, back, and extremities. METHODS: In this pragmatic 2-stage adaptive open-label randomized clinical trial, Stage 1 identified whether auricular acupuncture (AA; based on the battlefield acupuncture protocol) or peripheral acupuncture (PA; needles in head, neck, and extremities only), when added to usual care was more feasible, acceptable, and efficacious in the ED. Stage 2 assessed effectiveness of the selected acupuncture intervention(s) on pain reduction compared to usual care only (UC). Licensed acupuncturists delivered AA and PA. They saw and evaluated but did not deliver acupuncture to the UC group as an attention control. All participants received UC from blinded ED providers. Primary outcome was 1-hour change in 11-point pain numeric rating scale. RESULTS: Stage 1 interim analysis found both acupuncture styles similar, so Stage 2 continued all 3 treatment arms. Among 236 participants randomized, demographics and baseline pain were comparable across groups. When compared to UC alone, reduction in pain was 1.6 (95% confidence interval [CI]: 0.7 to 2.6) points greater for AA+UC and 1.2 (95% CI: 0.3 to 2.1) points greater for PA+UC patients. Participants in both treatment arms reported high satisfaction with acupuncture. CONCLUSION: ED acupuncture is feasible and acceptable and can reduce acute musculoskeletal pain better than UC alone.

Sexual and gender minority content in undergraduate medical education in the United States and Canada: current state and changes since 2011.

PURPOSE: To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. METHOD: Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. RESULTS: Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6-16 h, p < 0.0001). Two UME institutions (2.4%; 95% CI, 0.0%-5.8%) reported 0 h during the pre-clerkship phase; 21 institutions (24.7%; CI, 15.5%-33.9%) reported 0 h during the clerkship phase; and 1 institution (1.2%; CI, 0%-3.5%) reported 0 h across the curriculum. Median US allopathic clerkship hours were significantly different from US osteopathic clerkship hours (4 h [IQR, 1-6 h] versus 0 h [IQR, 0-0 h]; p = 0.01). Suggested strategies to increase content included more curricular material focusing on LGBTQI + health and health disparities at 55 schools (64.7%; CI, 54.6%-74.9%), more faculty willing and able to teach LGBTQI + -related content at 49 schools (57.7%; CI, 47.1%-68.2%), and more evidence-based research on LGBTQI + health and health disparities at 24 schools (28.2%; CI, 18.7%-37.8%). CONCLUSION: Compared to a 2011 study, the median reported time dedicated to LGBTQI + health-related topics in 2022 increased across US and Canadian UME institutions, but the breadth, efficacy, or quality of instruction continued to vary substantially. Despite the increased hours, this still falls short of the number of hours based on recommended LGBTQI + health competencies from the Association of American Medical Colleges. While most deans of medical education reported their institutions' coverage of LGBTQI + health as 'fair,' 'good,' or 'very good,' there continues to be a call from UME leadership to increase curricular content. This requires dedicated training for faculty and students.

Intimate partner violence is related to future alcohol use among a nationwide sample of LGBTQIA+ people: Results from The PRIDE Study.

BACKGROUND: Lesbian, gay, bisexual, transgender, queer, intersex, aromantic and asexual (LGBTQIA+) communities in the United States experience higher rates of alcohol use than the general population. While experiencing intimate partner violence (IPV) is thought to lead to increased alcohol use in LGBTQIA+ people, little research has investigated the temporal relationship between IPV and alcohol use in this population. METHODS: Data from two annual questionnaires of The Population Research in Identity and Disparities for Equality Study (The PRIDE Study) longitudinal cohort (n=3,783) were included. Overall IPV and three sub-types (physical, sexual, and emotional) - measured in 2021 using the extended Hurt, Insult, Threaten, Scream (E-HITS) screening tool - was examined as a predictor of Alcohol Use Disorders Identification Test (AUDIT) score in 2022 using multivariable linear regression to assess linear and quadratic associations. Models were adjusted for sociodemographic characteristics and history of alcohol use. RESULTS: One-quarter (24.7%) of respondents reported experiencing past-year IPV in 2021. The mean AUDIT score in 2022 was 3.52 (SD = 4.13). In adjusted models, both linear (B: 0.26, 95% CI: 0.14, 0.38) and quadratic (B: -0.03, 95% CI: -0.04, -0.01) terms for overall IPV were significantly associated with next-year AUDIT score. These patterns were mirrored in each IPV sub-type, were not attenuated when accounting for relationship characteristics, and were heterogeneous across gender identity groups. CONCLUSIONS: These results provide evidence of a temporal relationship between IPV and alcohol use in LGBTQIA+ communities, suggesting that efforts to prevent and mitigate IPV may help reduce alcohol use disparities in this population.

The Impact of Deprescribing Interventions on the Drug Burden Index and Other Outcomes: A Systematic Review.

OBJECTIVES: The Drug Burden Index (DBI) calculates a person's exposure to anticholinergic and sedative medications. We aimed to review randomized controlled trials (RCTs) of deprescribing interventions that reported the DBI as an outcome, their characteristics, effectiveness in reducing the DBI, and impact on other outcomes. DESIGN: Systematic review with meta-analysis. SETTING AND PARTICIPANTS: RCTs of deprescribing interventions where the DBI was measured as a primary or secondary outcome in humans within any setting were included. METHODS: Electronic databases, citation indexes, and gray literature were searched from April 1, 2007, to September 1, 2023. Quality was assessed using the Cochrane risk-of-bias tool. RESULTS: Of 1721 records identified, 9 met the inclusion criteria. Six interventions were delivered by pharmacists and 3 were delivered by pharmacists/nurses or pharmacists/geriatricians. All interventions required at least intermediate-level skills and involved multiple components and target groups. Studies were conducted in the community (n = 5), nursing homes (n = 2), and hospitals (n = 2). The mean or median age was ≥75 years and most participants were women in all studies. Most (n = 6) studies were underpowered. The follow-up period ranged from 3 to 12 months. Three studies reported a lower DBI in the intervention group compared with control: 1 pharmacist independent prescriber-delivered in nursing homes (adjusted rate ratio, 0.83; 95% CI, 0.74 to 0.92), 1 pharmacist/nurse practitioner-delivered in hospital (adjusted mean difference (MD), -0.28; 95% CI, -0.51 to -0.04), and 1 geriatrician/pharmacist-delivered in hospital (MD, -0.28; 95% CI, -0.52 to -0.04). Meta-analysis showed no difference in the change in DBI between control and intervention groups in the community including nursing homes (MD, -0.03; 95% CI, -0.08 to 0.01) or hospital setting (MD, -0.19; 95% CI, -0.45 to 0.06). Interventions had inconsistent effects on cognition and no effect on other reported outcomes. CONCLUSIONS AND IMPLICATIONS: RCTs of deprescribing interventions had no significant impact on reducing DBI or improving outcomes. Further suitably powered studies are required.

Does the Timing of Surgical Intervention Impact Outcomes in Necrotizing Enterocolitis?

OBJECTIVES: The optimal time for intervention in surgical necrotizing enterocolitis (sNEC) remains to be elucidated. Surgical management varies between peritoneal drain (PD), laparotomy (LAP), and PD with subsequent LAP (PD + LAP). We propose that some infants with surgical NEC benefit from late (>48 h) operative intervention to allow for resuscitation. METHODS: A retrospective comparison of clinical information in infants with sNEC from 2012 to 2022 was performed. Early intervention was defined as less than 48 hours from time of NEC diagnosis to surgical intervention. RESULTS: 118 infants were identified, 92 underwent early intervention (62 LAP; 22 PD; 8 PD + LAP) and 26 underwent late intervention (20 LAP; 2 PD; 4 PD + LAP). Infants with early intervention were diagnosed younger (DOL 8 [6, 15] vs 20 [11, 26]; P=< .05) with more pneumoperitoneum (76% vs 23%; P=< .05). The early intervention group had a higher mortality (35% vs 15%; P=< .05). When excluding infants with pneumoperitoneum, the early intervention group had a higher mortality rate (10/22 (45%), 4/26 (15%); P < .05) and had more bowel resected (29 ± 17 cm vs 9 ± 8 cm; P < .05), with the same number of patients scoring above 3 on the MD7 criteria. CONCLUSION: Infants with NEC who underwent early surgical intervention had a higher mortality and more bowel resected. While this study has a provocative finding, it is severely limited by the non-specific 48-hour cut off. However, our data suggests that a period of medical optimization may improve outcomes in infants with sNEC and thus more in-depth studies are needed.

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.