Faculty Bibliography

OBJECTIVE:The Diabetes in Children, Adolescents, and Young Adults (DiCAYA) network seeks to create a nationwide electronic health record (EHR)-based diabetes surveillance system. This study aimed to develop a DiCAYA-wide EHR-based computable phenotype (CP) to identify prevalent cases of diabetes. RESEARCH DESIGN AND METHODS/METHODS:We conducted network-wide chart reviews of 2,134 youth (aged <18 years) and 2,466 young adults (aged 18 to <45 years) among people with possible diabetes. Within this population, we compared the performance of three alternative CPs, using diabetes diagnoses determined by chart review as the gold standard. CPs were evaluated based on their accuracy in identifying diabetes and its subtype. RESULTS:The final DiCAYA CP requires at least one diabetes diagnosis code from clinical encounters. Subsequently, diabetes type classification was based on the ratio of type 1 diabetes (T1D) or type 2 diabetes (T2D) diagnosis codes in the EHR. For both youth and young adults, the sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) in finding diabetes cases were >90%, except for the specificity and NPV in young adults, which were slightly lower at 83.8% and 80.6%, respectively. The final DiCAYA CP achieved >90% sensitivity, specificity, PPV, and NPV in classifying T1D, and demonstrated lower but robust performance in identifying T2D, consistently maintaining >80% across metrics. CONCLUSIONS:The DiCAYA CP effectively identifies overall diabetes and T1D in youth and young adults, though T2D misclassification in youth highlights areas for refinement. The simplicity of the DiCAYA CP enables broad deployment across diverse EHR systems for diabetes surveillance.

OBJECTIVE:Assess postintervention and dose effects of a child obesity prevention program, delivered from pregnancy through the age of 3 years, on child weight outcomes at the ages of 4 and 5 years among low-income Hispanic families. METHODS:As postintervention follow-up of the Starting Early Program (StEP) randomized controlled trial, StEP enrolled pregnant people in the third trimester to standard care control or the StEP intervention, which provided 15 nutrition and parenting support sessions. We analyzed differences in weight-for-age z scores (WFAz) and obesity status by group within intervention group analyses of program dose and moderation by adverse social drivers of health (SDoH). RESULTS:Weight data were available for 312 and 264 children aged 4 and 5 years, respectively. Mean WFAz (0.59 [1.08] vs 0.52 [1.16], P = .55; 0.60 [1.07] vs 0.58 [1.22], P = .86) and proportion with obesity (15.2% vs 15.6%, P = .90; 16.2% vs 19.5%, P = .47) were not different by intervention status at the ages of 4 and 5 years. The mean (SD) number of sessions attended was 8.7 (4.2) with the highest tertile attending 11 sessions or more. Lower WFAz and obesity prevalence were found for families with top tertile attendance. In moderation analysis, impacts on weight in children aged 5 years were greater for families with low social support compared high social support. CONCLUSION/CONCLUSIONS:Participation in StEP was not associated with postintervention differences in child weight. Higher attendance was associated with lower obesity prevalence, while treatment effects were greater for families with low social support. This highlights the need to evaluate program dose on long-term outcomes, especially for those with adverse SDoH.

Ultrasound (US) is a valuable tool in the evaluation of arthritis both for diagnosis and treatment response. Pertinent findings such as joint effusions, synovitis, bursitis, bone erosions, tenosynovitis, and enthesitis can all be readily evaluated sonographically. In this article, we describe specific considerations in the US evaluation of rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, crystalline arthritis (gout, calcium pyrophosphate deposition disease, and hydroxyapatite deposition disease), septic arthritis, and osteoarthritis with attention to certain differentiating features. The potential role of US in the diagnosis of specific arthritides is discussed, together with an overview of newer technologies and future directions.

OBJECTIVE/UNASSIGNED:Sentinel lymph node biopsy (SLNB) for endometrial cancer staging may identify isolated tumor cells (ITCs). Although guidelines do not classify nodes with ITCs as positive, earlier papers reported that a significant proportion of gynecologic oncologists treat ITCs as they would positive nodes. The objective of this study was to examine practice patterns and determine if the presence of ITCs in endometrial cancer affects adjuvant treatment decision-making. METHODS/UNASSIGNED:test, and logistic regression were used with significance set at p < 0.05. RESULTS/UNASSIGNED:Of seven hundred thirty-four patients included, ITCs were identified in 41 patients (5.6 %). Deep myometrial invasion (61.0 % vs 20.5 %, p < 0.001) and lymphovascular invasion (58.4 % vs 17.7 %, p < 0.001) were more common in patients with ITCs than in those with negative lymph nodes. Patients with ITCs were more likely to receive adjuvant treatment (30 of 41, 73.2 % vs 289 of 693, 41.7 %, p < 0.001). When controlling for age, stage, histology, grade, and lymphovascular space invasion, ITCs were not associated with an increased likelihood of adjuvant therapy receipt. CONCLUSIONS/UNASSIGNED:Although patients with ITCs were more likely to receive adjuvant treatment, this was accounted for by other clinical and histological factors. Clinicians were likely to make decisions based on established risk factors, and more data are needed on the role of ITCs in the landscape of molecularly based decision making.

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau₁₈₁:Aβ₄₂, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ⁺ and phosphorylated tau⁺ (A+T₁+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T₁+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10^-4) and A+T₁+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10^-16) over a 15-year follow-up, adjusting for CSF pTau₁₈₁:Aβ₄₂, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.

INTRODUCTION/BACKGROUND:Targeted immunomodulators (eg, advanced therapies) effectively achieve symptomatic remission in patients with inflammatory bowel disease (IBD). However, ~25%-50% of patients with IBD achieving symptomatic remission with an advanced therapy may have continued endoscopically/radiologically active bowel inflammation, and it is uncertain whether changing alternative advanced therapies in asymptomatic patients with IBD will reduce bowel inflammation and achieve durable deep remission. METHODS AND ANALYSIS/METHODS:The QUality Outcomes Treating IBD to Target (QUOTIENT) study is an open-label, multicentre, pragmatic, randomised, controlled trial that aims to compare the efficacy and safety of switching to an alternative advanced therapy targeting endoscopic/radiological remission (treat-to-target) versus continuing the initial, or index, advanced therapy, in asymptomatic patients with IBD with moderate-to-severe endoscopic/radiological bowel inflammation. Enrolment is planned for ~250 participants in Canada/USA, randomised 1:1 to switching to alternative advanced therapy or continuing index advanced therapy, and then followed 104 weeks within routine clinical practice. Patient-reported outcomes measure efficacy and quality of life/treatment burden/safety. Primary endpoint is the time from randomisation to treatment failure. ETHICS AND DISSEMINATION/BACKGROUND:The study is conducted in compliance with the protocol, ICH Good Clinical Practice, applicable regulatory requirements and appropriate review boards/independent ethics committees (approval numbers: Pro00077486; Pro00061437; STUDY00002062; 22-004171; i22-01269; IRB22-0890; IRB_00154397; 2000032384; SHIRB#2022.095-2; STUDY00007146; MMC#2024-18; REB#125290; 17784; Pro00142214; 20240660-01H), with documented written informed consent. Findings will be disseminated through peer-reviewed journals, scientific presentations, and publicly available Patient-Centered Outcomes Research Institute (PCORI) websites, including lay summaries. The Crohn's & Colitis Foundation Education, Support, and Advocacy Department, and our patient advocacy stakeholder, will develop educational and marketing resources to communicate findings to a broad audience (>250 000 patients/caregivers/healthcare professionals). TRIAL REGISTRATION NUMBER/BACKGROUND:NCT05230173.

BACKGROUND:Patients undergoing invasive mechanical ventilation often require pharmacologic sedation to facilitate tolerance of this life-sustaining intervention, but sedatives currently used in routine care have substantial limitations. Isoflurane is an inhaled volatile anesthetic with pharmacologic properties potentially suitable to sedation of ventilator-dependent critically ill patients, but need for specialized drug administration equipment has limited its use historically to general anesthesia in the operating theatre. This trial will evaluate isoflurane, administered using a novel drug delivery system, for sedation of ventilator-dependent adult intensive care unit (ICU) patients in the United States (US). METHODS:The Inhaled Sedation versus Propofol in Respiratory Failure in the ICU (INSPiRE-ICU2) is a phase 3, multicenter, randomized, controlled, assessor-blinded non-inferiority trial that will evaluate efficacy and safety of inhaled isoflurane delivered via the Sedaconda ACD-S, compared to intravenous propofol, for sedation of mechanically ventilated adult ICU patients. At 16 US hospitals, 235 enrolled patients requiring continuous sedation during invasive mechanical ventilation will be randomized in 1.5:1 ratio to inhaled isoflurane or intravenous propofol for sedation. Treatment duration is expected to be at least 12 h and may last up to 48 (± 6) h or until no longer needing continuous sedation, whichever occurs first. The primary endpoint is the percentage of time sedation depth is maintained within the targeted range (Richmond Agitation Sedation Scale - 1 to - 4), in the absence of rescue sedation, during the treatment period. Secondary superiority outcomes include opioid exposure, wake-up time, cognitive recovery after end-of-treatment, and preservation of spontaneous breathing effort. DISCUSSION/CONCLUSIONS:The INSPiRE-ICU2 trial will help determine the potential role of isoflurane for sedation of ventilator-dependent adult patients in the ICU. Key trial design features, including adoption of the estimand framework and blinded assessments of sedation depth, pain, and cognitive recovery, will ensure a rigorous evaluation of isoflurane for ICU sedation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05327296. First registered on April 5, 2022.

BACKGROUND:Changing from standing to sitting positions requires rotation of the femur from an almost vertical plane to the horizontal plane. Osteoarthritis of the hip limits hip extension, resulting in less ability to recruit spinopelvic tilt (SPT) while standing and requiring increased SPT while sitting to compensate for the loss of hip range of motion. To date, the effect of total hip arthroplasty (THA) on spinopelvic sitting and standing mechanics has not been reported, particularly in the setting of patients with coexistent sagittal plane spinal deformity. METHODS:A retrospective review was performed of patients ≥18 years of age undergoing unilateral THA for hip osteoarthritis with sitting and standing radiographs made before and after THA. Alignment was analyzed at baseline and follow-up after THA in both standing and sitting positions in a relaxed posture with the fingers resting on top of the clavicles. Patients were grouped according to the presence or absence of sagittal plane deformity preoperatively into 3 groups: no sagittal plane deformity (normal), thoracolumbar (TL) deformity (pelvic incidence-lumbar lordosis [PI-LL] mismatch > 10° and/or T1-pelvic angle [TPA] > 20°), or apparent deformity (PI-LL ≤ 10° and TPA ≤ 20°, but sagittal vertical axis [SVA] > 50 mm). RESULTS:In this study, 192 patients were assessed: 64 had TL deformity, 39 had apparent deformity, and 89 had normal alignment. Overall, patients demonstrated a reduction in standing SVA (45 to 34.1 mm; p < 0.001) and an increase in SPT (14.6° to 15.7°; p = 0.03) after THA. There was a greater change in standing SVA (p < 0.001) among patients with apparent deformity (-29.0 mm) compared with patients with normal alignment (0.9 mm) and patients with TL deformity (-16.3 mm). Those with apparent deformity also experienced the greatest difference (p = 0.03) in postural SPT change (moving from standing to sitting) (-10.1°) from before to after THA when compared with those with normal alignment (-3.6°) and TL deformity (-1.2°). The difference in postural SVA change from before to after THA was also greatest (p < 0.001) in those with apparent deformity (32.1 mm) compared with those with normal alignment (6.5 mm) and TL deformity (17.3 mm). CONCLUSIONS:Postural changes in spinopelvic alignment vary after THA depending on the presence of TL deformity or apparent deformity due to hip flexion contracture. Patients with apparent deformity had larger changes in standing and sitting alignment than patients with TL deformity or patients with normal alignment. The assessment of global sagittal alignment findings can be used to predict the likelihood of improvement in sagittal alignment after THA. LEVEL OF EVIDENCE/METHODS:Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND/UNASSIGNED:Myocardial injury detected after percutaneous coronary intervention (PCI) is associated with increased mortality. Predictors of post-PCI myocardial injury are not well established. The long-term prognostic relevance of post-PCI myocardial injury remains uncertain. METHODS/UNASSIGNED:Consecutive adults aged ≥18 years with stable ischemic heart disease who underwent elective PCI at NYU Langone Health between 2011 and 2020 were included in a retrospective, observational study. Patients with acute myocardial infarction or creatinine kinase myocardial band (CKMB) or troponin concentrations >99% of the upper reference limit before PCI were excluded. All patients had routine measurement of CKMB concentrations at 1 and 3 hours post-PCI. Post-PCI myocardial injury was defined as a peak CKMB concentration >99% upper reference limit. Linear regression models were used to identify clinical factors associated with post-PCI myocardial injury. Cox proportional hazard models were generated to evaluate relationships between post-PCI myocardial injury and all-cause mortality at long-term follow-up. RESULTS/UNASSIGNED:<0.001). After adjustment for demographics and clinical covariates, post-PCI myocardial injury was associated with an excess hazard for long-term mortality (hazard ratio, 1.46 [95% CI, 1.20-1.78]). CONCLUSIONS/UNASSIGNED:Myocardial injury defined by elevated CKMB early after PCI is common and associated with all-cause, long-term mortality. More complex coronary anatomy is predictive of post-PCI myocardial injury.