Citations

Abstract ZC3H18 is a multifunctional regulator of gene expression that is lost in a subset of high-grade serous ovarian cancers (HGSOC). Our prior studies have established that the loss of ZC3H18 diminishes BRCA1 levels, leading to the disruption of homologous recombination DNA repair (HR) and heightened sensitivity of HGSOC cells to PARP inhibitors. Here we show an additional facet to ZC3H18's impact, showing that its loss also induces a reprogramming of energy metabolism in HGSOC. Our findings demonstrate that the depletion of ZC3H18 results in reduced mRNA and protein levels of the NAD+-biosynthetic enzyme, NMNAT1, in HGSOC cells. Mechanistic studies uncovered that ZC3H18 occupies the NMNAT1 promoter, facilitating NMNAT1 transcription by recruiting CDK12 onto the promoter. Consistent with this mechanism, loss of ZC3H18 led to a reduction in CDK12 levels on the NMNAT1 promoter, diminishing NMNAT1 abundance and subsequently causing a decline in cellular NAD levels. These observations unveil a previously unknown role for ZC3H18 in HGSOC, shedding light on its involvement in the regulation of energy metabolism. Importantly, our findings provide valuable insights into potential therapeutic pathways that leverage the metabolic changes linked to ZC3H18 deficiency. Citation Format: Benjamin Wilson, Natalie Wilson, Xianfeng Chen, Shuwen Zhang, Chen Wang, Larry M. Karnitz, Scott H. Kaufmann, Arun Kanakkanthara. ZC3H18: A novel regulator of NAD+ metabolism in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4447.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Summary Background Stricturing Crohn's disease (CD) occurs most commonly in the terminal ileum and poses a clinical problem. Cross‐sectional imaging modalities such as intestinal ultrasound (IUS), computed tomography enterography (CTE), and magnetic resonance enterography (MRE) allow for assessment of the entire bowel wall and associated peri‐enteric findings. Radiologic definitions of strictures have been developed for CTE and MRE; their reliability and responsiveness are being evaluated in index development programs. A comprehensive assessment strategy for strictures using IUS is needed. Aims To provide a detailed summary of definitions, diagnosis and monitoring of strictures on IUS as well as technical aspects of image acquisition. Methods We searched four databases up to 6 January 2024. Two‐stage screening was done in duplicate. We assessed risk of bias using QUADAS‐2. Results There were 56 studies eligible for inclusion. Definitions for strictures on IUS are heterogeneous, but the overall accuracy for diagnosis of strictures is high. The capability of IUS for characterising inflammation versus fibrosis in strictures is not accurate enough to be used in clinical practice or trials. We summarise definitions for improvement of strictures on IUS, and discuss parameters for image acquisition and standardisation. Conclusions This systematic review is the first step for a structured program to develop a stricture IUS index for CD.

BACKGROUND AND OBJECTIVES: Although risk factors for unplanned readmission after cervical spine surgery have been widely reported, less is known about how readmission itself affects patient-reported outcome measures (PROMs). Using the Quality Outcomes Database registry of patients undergoing elective cervical spine surgery, we sought to (1) determine the impact of unplanned readmission on PROMs and (2) compare the effect of specific readmission reasons on PROMs. METHODS: An observational study was performed using a multi-institution, retrospective registry for patients undergoing cervical spine surgery. The occurrence of 90-day unplanned readmission classified into medical, surgical, pain only, and no readmissions was the exposure variable. Outcome variables included 12-month PROMs of Neck Disability Index (NDI), Numeric Rating Scale (NRS)-neck/arm pain, EuroQol-5D (EQ-5D), and patient dissatisfaction. Multivariable models predicting each PROM were built using readmission reasons controlling for demographics, clinical characteristics, and preoperative PROMs. RESULTS: Data from 13 355 patients undergoing elective cervical spine surgery (82% anterior approach and 18% posterior approach) were analyzed. Unplanned readmission within 90 days of surgery occurred in 3.8% patients, including medical (1.6%), surgical (1.8%), and pain (0.3%). Besides medical reasons, wound infection/dehiscence was the most common reason for unplanned readmission for the total cohort (0.5%), dysphagia in the anterior approach (0.6%), and wound infection/dehiscence in the posterior approach (1.5%). Based on multivariable regression, surgical readmission was significantly associated with worse 12-month NDI, NRS-neck pain, NRS-arm pain, EQ-5D, and higher odds of dissatisfaction. Pain readmissions were associated with worse 12-month NDI and NRS-neck pain scores, and worse dissatisfaction. For specific readmission reasons, pain, surgical site infection/wound dehiscence, hematoma/seroma, revision surgery, deep vein thrombosis, and pulmonary embolism were significantly associated with worsened 12-month PROMs. CONCLUSION: In patients undergoing elective cervical spine surgery, 90-day unplanned surgical and pain readmissions were associated with worse 12-month PROMs compared with patients with medical readmissions and no readmissions.

Abstract The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

OBJECTIVE When considering traumatic brachial plexus and upper extremity nerve injuries, iatrogenic nerve injuries, and nontraumatic nerve injuries, brachial plexus and upper extremity nerve injuries are commonly encountered in clinical practice. Despite this, data synthesis and comparison of available studies are difficult. This is at least in part due to the lack of standardization in reporting and a lack of a core outcome set (COS). Thus, there is a need for a COS for adult brachial plexus and upper extremity nerve injuries (COS-BPUE). The objective of this study was to develop a COS-BPUE using a modified Delphi approach. METHODS A 5-stage approach was used to develop the COS-BPUE: 1) consortium development, 2) literature review to identify potential outcome measures, 3) Delphi survey to develop consensus on outcomes for inclusion, 4) Delphi survey to develop definitions, and 5) consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. The final COS-BPUE consisted of 36 data points/outcomes covering demographic, diagnostic, patient-reported outcome, motor/sensory outcome, and complication domains. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 24 months, with the consensus optimal time points for assessment being preoperatively and 3, 6, 12, and 24 months postoperatively. CONCLUSIONS The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-BPUE should serve as a minimum set of data that should be collected in all future neurosurgical studies on adult brachial plexus and upper extremity nerve injuries. Incorporation of this COS should help improve consistency in reporting, data synthesis, and comparability, and should minimize outcome reporting bias.

Abstract VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease’s recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.