Weill Cornell Medical College

BACKGROUND The development of thoracic aortic calcium (TAC) temporally precedes coronary artery calcium more often in women versus men. Whether TAC density and area confer sex-specific differences in atherosclerotic cardiovascular disease (ASCVD) risk is unknown. METHODS We studied 5317 primary prevention patients who underwent coronary artery calcium scoring on noncontrast cardiac gated computed tomography with TAC >0. The Agatston TAC score (Agatston units), density (Hounsfield units), and area (mm ² ) were compared between men and women. Cox proportional hazards regression calculated adjusted hazard ratios for TAC density-area groups with ASCVD mortality, adjusting for traditional risk factors, coronary artery calcium, and TAC. Multinomial logistic regression calculated adjusted odds ratios for the association between traditional risk factors and TAC density-area groups. RESULTS The mean age was 60.7 years, 38% were women, and 163 ASCVD deaths occurred over a median of 11.7-year follow-up. Women had higher median TAC scores (97 versus 84 Agatston units; P =0.004), density (223 versus 210 Hounsfield units; P <0.001), and area (37 versus 32 mm ² ; P =0.006) compared with men. There was a stepwise higher incidence of ASCVD deaths across increasing TAC density-area groups in men though women with low TAC density relative to TAC area (3.6 per 1000 person-years) had survival probability commensurate with the high-density-high-area group (4.8 per 1000 person-years). Compared with low TAC density-area, low TAC density/high TAC area conferred a 3.75-fold higher risk of ASCVD mortality in women (adjusted hazard ratio, 3.75 [95% CI, 1.13–12.44]) but not in men (adjusted hazard ratio, 1.16 [95% CI, 0.48–2.84]). Risk factors most strongly associated with low TAC density/high TAC area differed in women (diabetes: adjusted odds ratio, 2.61 [95% CI, 1.34–5.07]) versus men (hypertension: adjusted odds ratio, 1.45 [95% CI, 1.11–1.90]). CONCLUSIONS TAC density-area phenotypes do not consistently associate with ASCVD mortality though low TAC density relative to area may be a marker of increased ASCVD risk in women.

Mammalian embryogenesis commences with two pivotal and binary cell fate decisions that give rise to three essential lineages: the trophectoderm, the epiblast and the primitive endoderm. Although key signaling pathways and transcription factors that control these early embryonic decisions have been identified, the non-coding regulatory elements through which transcriptional regulators enact these fates remain understudied. Here, we characterize, at a genome-wide scale, enhancer activity and 3D connectivity in embryo-derived stem cell lines that represent each of the early developmental fates. We observe extensive enhancer remodeling and fine-scale 3D chromatin rewiring among the three lineages, which strongly associate with transcriptional changes, although distinct groups of genes are irresponsive to topological changes. In each lineage, a high degree of connectivity, or ‘hubness’, positively correlates with levels of gene expression and enriches for cell-type specific and essential genes. Genes within 3D hubs also show a significantly stronger probability of coregulation across lineages compared to genes in linear proximity or within the same contact domains. By incorporating 3D chromatin features, we build a predictive model for transcriptional regulation (3D-HiChAT) that outperforms models using only 1D promoter or proximal variables to predict levels and cell-type specificity of gene expression. Using 3D-HiChAT, we identify, in silico, candidate functional enhancers and hubs in each cell lineage, and with CRISPRi experiments, we validate several enhancers that control gene expression in their respective lineages. Our study identifies 3D regulatory hubs associated with the earliest mammalian lineages and describes their relationship to gene expression and cell identity, providing a framework to comprehensively understand lineage-specific transcriptional behaviors.

Objectives: Dysphagia is common in idiopathic Parkinson’s disease (IPD) and is associated with impairments in both swallowing safety and swallowing efficiency. The goals of this study were to define post-swallow residue patterns in people with IPD and describe pathophysiological endoscopic findings affecting residue accumulation. Methods: This was a prospective single-blinded cross-sectional cohort study of patients with the diagnosis of IPD recruited from a Movement Disorder Clinic. Clinical variables included patient age, cognitive function, and measures of disease severity, and laryngoscopic examinations with a flexible endoscopic evaluation of swallowing (FEES) were completed for each patient. Visual Analysis of Swallowing Efficiency and Safety (VASES) was used to analyze FEES. Post-swallow residue outcomes and non-residue endoscopic outcomes including the Bowing index, Penetration Aspiration Scale (PAS) score, premature leakage, and build-up phenomenon were evaluated. Multiple regression models were used to evaluate factors affecting the residue at different anatomic levels. Results: Overall 53 patients completed the study. The multiple regression analyses showed a relation between (1) the presence of residue at the level of oropharynx and epiglottis with premature leakage, (2) the presence of residue at the level of the laryngeal vestibule and vocal folds with build-up phenomenon, and (3) the presence of residue at the level of the hypopharynx, laryngeal vestibule, and subglottis with airway invasion. Conclusion: Residue pattern during FEES is associated with specific swallow dysfunctions in IPD. Using residue localization and quantification may be a helpful tool in assessing the impact of targeted swallowing interventions in patients with IPD and dysphagia.

Staphylococcus saprophyticus is the leading Gram-positive cause of uncomplicated urinary tract infections. Recent reports of increasing antimicrobial resistance (AMR) in S. saprophyticus warrant investigation of its understudied resistance patterns. Here, we characterized a diverse collection of S. saprophyticus ( n = 275) using comparative whole genome sequencing. We performed a phylogenetic analysis of core genes (1,646) to group our S. saprophyticus and investigated the distributions of antibiotic resistance genes (ARGs). S. saprophyticus isolates belonged to two previously characterized lineages, and 14.91% (41/275) demonstrated multidrug resistance. We compared antimicrobial susceptibility phenotypes of our S. saprophyticus with the presence of different ARGs and gene alleles. 29.8% (82/275) carried staphylococcal cassette chromosome mobile elements, among which 25.6% (21/82) were mecA ⁺ . Penicillin resistance was associated with the presence of mecA or blaZ . The mecA gene could serve as a marker to infer cefoxitin and oxacillin resistance of S. saprophyticus , but the absence of this gene is not predictive of susceptibility. Utilizing computational modeling, we found several genes were associated with cefoxitin and oxacillin resistance in mecA ⁻ isolates, some of which have predicted functions in stress response and cell wall synthesis. Furthermore, phenotype association analysis indicates ARGs against non-β-lactams reported in other staphylococci may serve as resistance determinants of S. saprophyticus . Lastly, we observed that two ARGs [ erm and erm (44)v ], carried by bacteriophages, were correlated with high phenotypic non-susceptibility against erythromycin (11/11 and 10/10) and clindamycin (11/11 and 10/10). The AMR-correlated genetic elements identified in this work can help to refine resistance prediction of S. saprophyticus during antibiotic treatment. IMPORTANCE Staphylococcus saprophyticus is the second most common bacteria associated with urinary tract infections (UTIs) in women. The antimicrobial treatment regimen for uncomplicated UTI is normally nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), or a fluoroquinolone without routine susceptibility testing of S. saprophyticus recovered from urine specimens. However, TMP-SMX-resistant S. saprophyticus has been detected recently in UTI patients, as well as in our cohort. Herein, we investigated the understudied resistance patterns of this pathogenic species by linking genomic antibiotic resistance gene (ARG) content to susceptibility phenotypes. We describe ARG associations with known and novel SCC mec configurations as well as phage elements in S. saprophyticus , which may serve as intervention or diagnostic targets to limit resistance transmission. Our analyses yielded a comprehensive database of phenotypic data associated with the ARG sequence in clinical S. saprophyticus isolates, which will be crucial for resistance surveillance and prediction to enable precise diagnosis and effective treatment of S. saprophyticus UTIs.

Oxytocin plays an important role in modulating social recognition memory. However, the direct implication of oxytocin neurons of the paraventricular nucleus of the hypothalamus (PVH) and their downstream hypothalamic targets in regulating short- and long-term forms of social recognition memory has not been fully investigated. In this study, we employed a chemogenetic approach to target the activity of PVH oxytocin neurons in male rats and found that specific silencing of this neuronal population led to an impairment in short- and long-term social recognition memory. We combined viral-mediated fluorescent labeling of oxytocin neurons with immunohistochemical techniques and identified the supramammillary nucleus (SuM) of the hypothalamus as a target of PVH oxytocinergic axonal projections in rats. We used multiplex fluorescence in situ hybridization to label oxytocin receptors in the SuM and determined that they are predominantly expressed in glutamatergic neurons, including those that project to the CA2 region of the hippocampus. Finally, we used a highly selective oxytocin receptor antagonist in the SuM to examine the involvement of oxytocin signaling in modulating short- and long-term social recognition memory and found that it is necessary for the formation of both. This study discovered a previously undescribed role for the SuM in regulating social recognition memory via oxytocin signaling and reinforced the specific role of PVH oxytocin neurons in regulating this form of memory.

Background: Breast anesthesia is commonly reported after mastectomy and reconstruction. During deep inferior epigastric perforator (DIEP) flap reconstruction, we coapt at least one of the T10–12 thoracoabdominal nerves within the flap to the anterior cutaneous branch of the 3rd intercostal nerve using a nerve allograft. We aim to evaluate the efficacy of nerve grafting in improving sensory recovery following neurotized DIEP flap reconstruction. Methods: Thirty patients (54 breasts) underwent immediate neurotized DIEP flap reconstruction using nerve grafts. Sensitivity evaluation was performed in nine breast regions. For each patient, sensation was compared between two time points: 3 to 6 months postoperatively versus 12 to 24 months postoperatively. The reconstructive BREAST-Q was used to survey patients’ satisfaction of their breasts, physical wellbeing, psychosocial wellbeing, and sexual wellbeing. Results: At 3 to 6 months postoperatively, patients had a mean sensitivity measurement of 52.1 g/mm2. At 12 to 24 months postoperatively, patients had a mean sensitivity measurement of 40.3 g/mm2. There was a significant decrease in the mean cutaneous threshold required for patients to perceive sensation between the two time points (–29.1 percent, p = 0.041). On the reconstructive BREAST-Q, patients scored significantly higher in breast satisfaction (56.7/100 versus 75.1/100, +32.5 percent, p = 0.032) and physical wellbeing (66.0/100 versus 85.5/100, +20.2 percent, p = 0.022) between the two time points. Conclusions: Patients who undergo nerve graft-based DIEP flap reconstruction can expect significant improvements in sensation to pressure over time. This improvement found on sensory testing correlates with significant improvement in patients’ BREAST-Q scores.

Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development. Expected final online publication date for the Annual Review of Cancer Biology, Volume 8 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Background Pancreatic cystic lesions (PCLs) are frequent on MRI and are thought to be associated with pancreatic adenocarcinoma (PDAC) necessitating long‐term surveillance based on older studies suffering from selection bias. Purpose To establish the percentage of patients with PCLs on MRI with a present or future PDAC. Study Type Systematic review, meta‐analysis. Population Adults with PCLs on MRI and a present or future diagnosis of PDAC were eligible. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus were searched to April 2022 (PROSPERO:CRD42022320502). Studies limited to PCLs not requiring surveillance, <100 patients, or those with a history/genetic risk of PDAC were excluded. Field Strength/Sequence ≥1.5 T with ≥1 T2‐weighted sequence. Assessment Two investigators extracted data, with discrepancies resolved by a third. QUADAS‐2 assessed bias. PDAC was diagnosed using a composite reference standard. Statistical Tests A meta‐analysis of proportions was performed at the patient‐level with 95% confidence intervals (95% CI). Results Eight studies with 1289 patients contributed to the percentage of patients with a present diagnosis of PDAC, and 10 studies with 3422 patients to the percentage with a future diagnosis. Of patients with PCLs on MRI, 14.8% (95% CI 2.4–34.9) had a PDAC at initial MRI, which decreased to 6.0% (2.2–11.3) for studies at low risk of bias. For patients without PDAC on initial MRI, 2.0% (1.1–3.2) developed PDAC during surveillance, similar for low risk of bias studies at 1.9% (0.7–3.6), with no clear trend of increased PDAC for longer surveillance durations. For patients without worrisome features or high‐risk stigmata, 0.9% (0.1–2.2) developed PDAC during surveillance. Of 10, eight studies had a median surveillance ≥3 years (range 3–157 months). Sources of bias included retrospectively limiting PCLs to those with histopathology and inconsistent surveillance protocols. Data Conclusion A low percentage of patients with PCLs on MRI develop PDAC while on surveillance. The first MRI revealing a PCL should be scrutinized for PDAC. Level of Evidence 3 Technical Efficacy Stage 2

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neo-plasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of chol-angiocarcinoma and have unique characteristics, namely im-munoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluo-rescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

OBJECTIVE To describe the acquisition and pitfalls of a 3-view transesophageal echocardiography (TEE) protocol in anesthetized, dorsally recumbent dogs. ANIMALS 8 beagles, 1 to 2 years old, 7.4 to 11.2 kg. METHODS Dogs were anesthetized, mechanically ventilated, and placed in dorsal recumbency. A TEE probe was advanced, and 3 views were performed: midesophageal 4-chamber and long axis (ME 4C and ME LAX) and caudal esophageal short axis (CE SAX) at the level of the papillary muscles. Probe insertion depth, flexion, omniplane angle, and image acquisition time were recorded. Two observers assessed 24 video clips each and identified anatomical structures. RESULTS The ME 4C and ME LAX were obtained at 35 (30 to 40) cm insertion depth, omniplane at 0° and 103° (90 to 116), respectively. Views were obtained in ≤30 seconds once the TEE was in the cervical esophagus. Left-sided structures were identified in all cases, whereas right-sided structures were not always simultaneously obtained in the ME 4C, requiring further probe manipulation. All structures were identified on ME LAX. CE SAX was obtained at 40 (35 to 45) cm, omniplane at 0°, and in 15 (10 to 90) seconds. A true SAX view (circular left ventricle at the level of papillary muscles) could not be obtained in all dogs. CLINICAL RELEVANCE A 3-view TEE protocol using core views as those described in humans may be applicable to dogs under general anesthesia and in dorsal recumbency. The CE SAX view at the level of the papillary muscles appears more difficult to obtain with consistency than midesophageal views.

BACKGROUND Patients with severe hypoglycemia (SH) or diabetic ketoacidosis (DKA) experience high hospital readmission after being discharged. Cognitive impairment (CI) may further increase the risk, especially in those experiencing an interruption of medical care after discharge. This study examined the effect modification role of postdischarge care (PDC) on CI-associated readmission risk among U.S. adults with diabetes initially admitted for DKA or SH. RESEARCH DESIGN AND METHODS We used the Nationwide Readmissions Database (NRD) (2016–2018) to identify individuals hospitalized with a diagnosis of DKA or SH. Multivariate Cox regression was used to compare the all-cause readmission risk at 30 days between those with and without CI identified during the initial hospitalization. We assessed the CI-associated readmission risk in the patients with and without PDC, an effect modifier with the CI status. RESULTS We identified 23,775 SH patients (53.3% women, mean age 65.9 ± 15.3) and 140,490 DKA patients (45.8% women, mean age 40.3 ± 15.4), and 2,675 (11.2%) and 1,261 (0.9%), respectively, had a CI diagnosis during their index hospitalization. For SH and DKA patients discharged without PDC, CI was associated with a higher readmission risk of 23% (adjusted hazard ratio [aHR] 1.23, 95% CI 1.08–1.40) and 35% (aHR 1.35, 95% CI 1.08–1.70), respectively. However, when patients were discharged with PDC, we found PDC was an effect modifier to mitigate CI-associated readmission risk for both SH and DKA patients (P < 0.05 for all). CONCLUSIONS Our results suggest that PDC can potentially mitigate the excessive readmission risk associated with CI, emphasizing the importance of postdischarge continuity of care for medically complex patients with comorbid diabetes and CI.

Hypertension (HTN), a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In the present study, in a mouse model of HTN, we find that the neurovascular and cognitive dysfunction depends on interleukin (IL)-17, a cytokine elevated in individuals with HTN. However, neither circulating IL-17 nor brain angiotensin signaling can account for the dysfunction. Rather, IL-17 produced by T cells in the dura mater is the mediator released in the cerebrospinal fluid and activating IL-17 receptors on border-associated macrophages (BAMs). Accordingly, depleting BAMs, deleting IL-17 receptor A in brain macrophages or suppressing meningeal T cells rescues cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. Our data unveil a critical role of meningeal T cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction in a mouse model of HTN.

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract. Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test. All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases. CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery. ClinicalTrials.gov identifier: NCT02881151.

I examine the impacts of extending residency training programs on the supply and quality of physicians practicing primary care. I leverage mandated extended residency lengths for primary care practitioners that were rolled out over 20 years in Canada on a province‐by‐province basis. I compare these primary care specialties to other specialties that did not change residency length (first difference) before and after the policy implementation (second difference) to assess how physician supply evolved in response. To examine quality outcomes, I use a set of scraped data and repeat this difference‐in‐differences identification strategy for complaints resulting in censure against physicians in Ontario. I find declines in the number of primary care providers by 5% for up to 9 years after the policy change. These changes are particularly pronounced in new graduates and younger physicians, suggesting that the policy change dissuaded these physicians from entering primary care residencies. I find no impacts on quality of physicians as measured by public censure of physicians. This suggests that extending primary care training caused declines in physician supply without improvement in the quality of these physicians. This has implications for current plans to extend residency training programs.