CRISPR Screen Reveals BRD2/4 Molecular Glue-like Degrader via Recruitment of DCAF16.

Molecular glues (MGs) are monovalent small molecules that induce an interaction between proteins (native or non-native partners) by altering the protein-protein interaction (PPI) interface toward a higher-affinity state. Enhancing the PPI between a protein and E3 ubiquitin ligase can lead to degradation of the partnering protein. Over the past decade, retrospective studies of clinical drugs identified that immunomodulatory drugs (e.g., thalidomide and analogues) and indisulam exhibit a molecular glue effect by driving the interaction between non-native substrates to CRBN and DCAF15 ligases, respectively. Ensuing reports of phenotypic screens focused on MG discovery have suggested that these molecules may be more common than initially anticipated. However, prospective discovery of MGs remains challenging. Thus, expanding the repertoire of MGs will enhance our understanding of principles for prospective design. Herein, we report the results of a CRISPR/Cas9 knockout screen of over 1000 ligases and ubiquitin proteasome system components in a BRD4 degradation assay with a JQ1-based monovalent degrader, compound 1a. We identified DCAF16, a substrate recognition component of the Cul4 ligase complex, as essential for compound activity, and we demonstrate that compound 1a drives the interaction between DCAF16 and BRD2/4 to promote target degradation. Taken together, our data suggest that compound 1a functions as an MG degrader between BRD2/4 and DCAF16 and provides a foundation for further mechanistic dissection to advance prospective MG discovery.

Mapping hospital data to characterize residents' educational experiences.

BACKGROUND: Experiential learning through patient care is fundamental to graduate medical education. Despite this, the actual content to which trainees are exposed in clinical practice is difficult to quantify and is poorly characterized. There remains an unmet need to define precisely how residents' patient care activities inform their educational experience.  METHODS: Using a recently-described crosswalk tool, we mapped principal ICD-10 discharge diagnosis codes to American Board of Internal Medicine (ABIM) content at four training hospitals of a single Internal Medicine (IM) Residency Program over one academic year to characterize and compare residents' clinical educational experiences. Frequencies of broad content categories and more specific condition categories were compared across sites to profile residents' aggregate inpatient clinical experiences and drive curricular change. RESULTS: There were 18,604 discharges from inpatient resident teams during the study period. The crosswalk captured > 95% of discharges at each site. Infectious Disease (ranging 17.4 to 39.5% of total discharges) and Cardiovascular Disease (15.8 to 38.2%) represented the most common content categories at each site. Several content areas (Allergy/Immunology, Dermatology, Obstetrics/Gynecology, Ophthalmology, Otolaryngology/Dental Medicine) were notably underrepresented (≤ 1% at each site). There were significant differences in the frequencies of conditions within most content categories, suggesting that residents experience distinct site-specific clinical content during their inpatient training. CONCLUSIONS: There were substantial differences in the clinical content experienced by our residents across hospital sites, prompting several important programmatic and curricular changes to enrich our residents' hospital-based educational experiences.

Short-term outcomes of infants born to mothers with SARS-CoV-2 infection.

OBJECTIVE: The rate of transmission of SARS-CoV-2 from mothers to infants in the peri- and post-natal period remains an area of ongoing investigation. This study aims to determine rates of development of clinically significant COVID-19 disease within 1 month among infants born to symptomatic and asymptomatic SARS-CoV-2 positive mothers. MATERIALS AND METHODS: This was a single-center, retrospective cohort study of all infants born to SARS-CoV-2 positive mothers who were admitted to the Well Baby Nursery (WBN) at New York University Langone Hospital-Brooklyn from 23 March-23 September 2020. Infants born to asymptomatic mothers were allowed to room-in, while infants born to mothers with symptoms of SARS-CoV-2 were isolated and discharged home to an alternate primary caregiver. A phone follow-up program contacted mothers at 2 weeks and 1 month post discharge to inquire about newborn symptoms, maternal symptoms, personal protective equipment (PPE) usage, and any presentations to care. Medical records were also reviewed for clinic and hospital visits to determine if exposed infants developed any symptoms following discharge. RESULTS: Of 1903 deliveries during the study period, 131 mothers (21 symptomatic, 110 asymptomatic) tested positive for SARS-CoV-2 and had infants admitted to the WBN. 57 infants (21 born to symptomatic mothers, 36 born to asymptomatic mothers) were tested prior to discharge, and none were positive. 121 of 133 infants had at least 1 follow up call in the study period. Of these, 31 had symptoms potentially concerning for SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children, and 19 presented to medical care for these symptoms. 4 infants had SARS- CoV-2 testing after discharge, and none were positive. 2 infants were admitted to the hospital for fever but neither had a positive SARS-CoV-2 result. 65% of mothers reported always adhering to PPE recommendations. CONCLUSION: Our results suggest that infants born both to symptomatic and asymptomatic mothers are unlikely to develop clinically significant COVID-19 disease in the peri- and post-natal periods.

Experience and Education in Residency Training: Capturing the Resident Experience by Mapping Clinical Data.

PROBLEM: Internal medicine training programs operate under the assumption that the 3-year residency training period is sufficient for trainees to achieve the depth and breadth of clinical experience necessary for independent practice; however, the medical conditions to which residents are exposed in clinical practice are not easily measured. As a result, residents' clinical educational experiences are poorly understood. APPROACH: A crosswalk tool (a repository of International Classification of Diseases [ICD]-10 codes linked to medical content areas) was developed to query routinely collected inpatient principal diagnosis codes and translate them into an educationally meaningful taxonomy. This tool provides a robust characterization of residents' inpatient clinical experiences. OUTCOMES: This pilot study has provided proof of principle that the crosswalk tool can effectively map 1 year of resident-attributed diagnosis codes to both the broad content category level (e.g., "cardiovascular disease") and to the more specific condition category level (e.g., "myocardial disease"). The authors uncovered content areas in their training program that are overrepresented and some that are underrepresented relative to material on the American Board of Internal Medicine (ABIM) Certification Exam. NEXT STEPS: The crosswalk tool introduced here translated residents' patient care activities into discrete, measurable educational content and enabled 1 internal medicine residency program to characterize residents' inpatient educational experience with a high degree of resolution. Leaders of other programs seeking to profile the clinical exposure of their trainees may adopt this strategy. Such clinical content mapping drives innovation in the experiential curriculum, enables comparison across practice sites, and lays the groundwork to test associations between individual clinical exposure and competency-based outcomes, which, in turn, will allow medical educators to draw conclusions regarding how clinical experience reflects clinical competency.

Endoscopy-guided transesophageal echocardiography for large esophageal varices: Use of the "Double Barrel" technique.

Rhythm control strategies in patients with esophageal varices and atrial arrhythmias pose a unique challenge. The left atrium should be imaged for a thrombus prior to attempting cardioversion or ablation, but the presence of varices is a relative contraindication for transesophageal echocardiography. We present a safe, novel technique of evaluating for left atrial thrombus with simultaneous transesophageal echocardiography and esophagogastroduodenoscopy using slim probes in a patient with large, high-risk esophageal varices, and symptomatic atrial flutter with rapid ventricular rates despite medical therapy.

Mapping the Clinical Experience of a New York City Residency Program During the COVID-19 Pandemic.

The COVID-19 pandemic has dramatically disrupted the educational experience of medical trainees. However, a detailed characterization of exactly how trainees' clinical experiences have been affected is lacking. Here, we profile residents' inpatient clinical experiences across the four training hospitals of NYU's Internal Medicine Residency Program during the pandemic's first wave. We mined ICD-10 principal diagnosis codes attributed to residents from February 1, 2020, to May 31, 2020. We translated these codes into discrete medical content areas using a newly developed "crosswalk tool." Residents' clinical exposure was enriched in infectious diseases (ID) and cardiovascular disease content at baseline. During the pandemic's surge, ID became the dominant content area. Exposure to other content was dramatically reduced, with clinical diversity repopulating only toward the end of the study period. Such characterization can be leveraged to provide effective practice habits feedback, guide didactic and self-directed learning, and potentially predict competency-based outcomes for trainees in the COVID era.

Reevaluating the psychometric properties of symptom measures within longitudinal contexts: The Yale-Brown Obsessive Compulsive Scale and Dimensional Obsessive-Compulsive Scale.

As research and clinical settings increasingly emphasize questions of change, it is crucial that our mechanistic and outcome variables are established as reliable and valid measures of such change. However, there is often a mismatch between the purposes for which symptom measures were developed and validated versus their application. Traditional psychometric theory has focused largely on between-person change, whereas increasingly research and clinical questions concern within-person change. We examined the psychometric properties of two commonly used measures of obsessive-compulsive symptoms (Yale-Brown Obsessive Compulsive Scale, YBOCS; Dimensional Obsessive-Compulsive Scale, DOCS) within a longitudinal treatment context (N = 570). Regarding reliability, we applied traditional (i.e., internal consistency at each week) and novel methods that allow for examination of the reliability of both within- and between-person change (i.e., variance partitioning based on generalizability theory). We examined longitudinal concurrent validity by correlating per-person slopes of obsessive-compulsive and depression symptom measures obtained via mixed-effects models. Within-person change reliability was acceptable or good for the YBOCS and DOCS total scores (.77, .83), suggesting that these measures are capable of capturing meaningful changes that exist within persons over time, and between-person change reliability was excellent (.99-1.0). Per-person slopes analyses supported the longitudinal concurrent validity of both measures. Our data support the continued use of the YBOCS and DOCS as measures of obsessive-compulsive symptoms for the purpose of many longitudinal research questions. The current study provides a template for reestablishing the psychometric properties of other commonly used measures in the context of longitudinal investigations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Two cases of acute endocarditis misdiagnosed as COVID-19 infection.

The COVID-19 pandemic has presented countless new challenges for healthcare providers including the challenge of differentiating COVID-19 infection from other diseases. COVID-19 infection and acute endocarditis may present similarly, both with shortness of breath and vital sign abnormalities, yet they require very different treatments. Here, we present two cases in which life-threatening acute endocarditis was initially misdiagnosed as COVID-19 infection during the height of the pandemic in New York City. The first was a case of Klebsiella pneumoniae mitral valve endocarditis leading to papillary muscle rupture and severe mitral regurgitation, and the second a case of Streptococcus mitis aortic valve endocarditis with heart failure due to severe aortic regurgitation. These cases highlight the importance of careful clinical reasoning and demonstrate how cognitive errors may impact clinical reasoning. They also underscore the limitations of real-time reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 testing and illustrate the ways in which difficulty interpreting results may also influence clinical reasoning. Accurate diagnosis of acute endocarditis is critical given that surgical intervention can be lifesaving in unstable patients.

Incidence and Risk of Scleral-Fixated Akreos (AO60) Lens Opacification: A Case Series.

Purpose: Postoperative hydrophilic intraocular lens opacification can lead to decreased vision and may require intraocular lens exchange. This study aims to identify the incidence of scleral-fixated Akreos AO60's (Bausch + Lomb) lens opacification and risk factors for this phenomenon. Methods: This is a retrospective case series of all patients who underwent scleral-fixated Akreos AO60 lens at our institution between January 1, 2015 and December 31, 2019. The following data were recorded: age, sex, medical history, indication for Akreos AO60 implantation, laterality, ocular history, previous ocular surgical procedures, subsequent intraocular surgical procedures after the Akreos implantation, lens opacification, visual significance of opacification, and Akreos explantation. Intraoperative and postoperative complications were recorded. Main outcome measures were the overall incidence of Akreos lens opacification as well as the incidence of these eyes undergoing subsequent intraocular surgery. Results: A total of 262 eyes of 257 patients underwent Akreos lens implantation. Overall, 2% (5 of 262) developed lens opacification. Two patients had Descemet stripping automated endothelial keratoplasty (DSAEK) concurrently with Akreos implantation. One patient underwent subsequent Baerveldt glaucoma implantation and DSAEK. The fourth patient had vitrectomy with sulfur hexafluoride gas followed by DSAEK. This represents a 25% (4 of 16) opacification rate among all patients who underwent DSAEK (P ≤ .01, Fisher exact test). One patient developed opacification after undergoing 2 vitrectomies for retinal detachment in the absence of DSAEK. Conclusions: Akreos lens opacification can be visually significant and may occur after a retinal or corneal procedure that involves the use of intraocular gas or air.

Characteristics of Hospitalized Children With SARS-CoV-2 in the New York City Metropolitan Area.

OBJECTIVES: To describe the characteristics of hospitalized children with severe acute respiratory syndrome coronavirus 2 in New York City metropolitan area. PATIENTS AND METHODS: This was a multicenter, retrospective cohort study at 4 hospitals comprising 82 hospitalized children (0-21 years) who tested positive for severe acute respiratory syndrome coronavirus 2 after symptoms and risk screening between March 1 and May 10, 2020. We subdivided patients on the basis of their admission to acute or critical care units and by age groups. Further subanalyses were performed between patients requiring respiratory support or no respiratory support. RESULTS: Twenty-three (28%) patients required critical care. Twenty-nine (35%) patients requiring respiratory support, with 9% needing mechanical ventilation, and 1 required extracorporeal support. All patients survived to discharge. Children with any comorbidity were more likely to require critical care (70% vs 37%, P = .008), with obesity as the most common risk factor for critical care (63% vs 28%, P = .02). Children with asthma were more likely to receive respiratory support (28% vs 8%, P = .02), with no difference in need for critical care (P = .26). Children admitted to critical care had higher rates of renal dysfunction at presentation (43% vs 10%, P = .002). CONCLUSIONS: Children with comorbidities (obesity and asthma in particular) were at increased risk for critical care admission and/or need for respiratory support. Children with renal dysfunction at presentation were more likely to require critical care.

Surgical Outcomes of Epiretinal Membrane Removal Due to Combined Hamartoma of the Retina and RPE.

BACKGROUND AND OBJECTIVE: To evaluate the surgical outcomes of epiretinal membrane (ERM) associated with combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) after vitrectomy and membrane peel. PATIENTS AND METHODS: A retrospective review of 15 patients who underwent pars plana vitrectomy with membrane peeling. No plasmin enzyme was used. RESULTS: The mean age at surgery was 10 years old, with an average follow-up of 5.7 years. The average preoperative visual acuity (VA) was 20/514. The average postoperative VA was 20/138 (P = .0251) at 1-year follow-up and 20/89 (P = .0025) on the latest exam on final follow-up. VA was improved in 14 patients (93%) and deteriorated in one patient (7%). All 15 patients (100%) had improvement of retinal/macular anatomy postoperatively. CONCLUSION: In the treatment of patients with ERM due to CHRRPE, vitrectomy with membrane peeling without plasmin injection can result in improved VA and retinal structure. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:546-554.].

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation.

The N-terminal residue influences protein stability through N-degron pathways. We used stability profiling of the human N-terminome to uncover multiple additional features of N-degron pathways. In addition to uncovering extended specificities of UBR E3 ligases, we characterized two related Cullin-RING E3 ligase complexes, Cul2ZYG11B and Cul2ZER1, that act redundantly to target N-terminal glycine. N-terminal glycine degrons are depleted at native N-termini but strongly enriched at caspase cleavage sites, suggesting roles for the substrate adaptors ZYG11B and ZER1 in protein degradation during apoptosis. Furthermore, ZYG11B and ZER1 were found to participate in the quality control of N-myristoylated proteins, in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation. Thus, an additional N-degron pathway specific for glycine regulates the stability of metazoan proteomes.

ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection.

The Cullin-RING E3 ligase (CRL) family is commonly hijacked by pathogens to redirect the host ubiquitin proteasome machinery to specific targets. During HIV infection, CRL5 is hijacked by HIV Vif to target viral restriction factors of the APOBEC3 family for ubiquitination and degradation. Here, using a quantitative proteomics approach, we identify the E3 ligase ARIH2 as a regulator of CRL5-mediated APOBEC3 degradation. The CUL5Vif/CBFß complex recruits ARIH2 where it acts to transfer ubiquitin directly to the APOBEC3 targets. ARIH2 is essential for CRL5-dependent HIV infectivity in primary CD4+ T cells. Furthermore, we show that ARIH2 cooperates with CRL5 to prime other cellular substrates for polyubiquitination, suggesting this may represent a general mechanism beyond HIV infection and APOBEC3 degradation. Taken together, these data identify ARIH2 as a co-factor in the Vif-hijacked CRL5 complex that contributes to HIV infectivity and demonstrate the operation of the E1-E2-E3/E3-substrate ubiquitination mechanism in a viral infection context.

A Longitudinally Extensive Spinal Cord Lesion Restricted to Gray Matter in an Adolescent Male.

Longitudinally extensive spinal cord lesions (LECL) restricted to gray matter are poorly understood as are their neurodevelopmental repercussions in children. We herein report the critical case of a 13-year-old male presenting with progressive quadriparesis found to have cervical LECL restricted to the anterior horns. Challenged with a rare diagnostic dilemma, the clinical team systematically worked through potential vascular, genetic, infectious, rheumatologic, and paraneoplastic diagnoses before assigning a working diagnosis of acute inflammatory myelopathy. Nuanced consideration of and workup for both potential ischemic causes (arterial dissection, fibrocartilaginous embolism, vascular malformation) and specific inflammatory conditions including Transverse Myelitis, Neuromyelitis Optica Spectrum Disorders (NMOSD), Multiple Sclerosis (MS), Acute Disseminated Encephalomyelitis (ADEM), and Acute Flaccid Myelitis (AFM) is explained in the context of a comprehensive systematic review of the literature on previous reports of gray matter-restricted longitudinally extensive cord lesions in children. Treatment strategy was ultimately based on additional literature review of treatment-refractory acute inflammatory neurological syndromes in children. A combination of high-dose steroids and plasmapheresis was employed with significant improvement in functional outcome, suggesting a potential benefit of combination immune-modulatory treatment in these patients. This case furthermore highlights quality clinical reasoning with respect to the elusive nature of diagnosis, nuances in neuroimaging, and multifocal treatment strategies in pediatric LECL.

Late exudative retinopathy after laser treatment for retinopathy of prematurity in a child with dyskeratosis congenita.

Exudative retinopathy may be a manifestation of a variety of isolated ocular or systemic diseases in children. We report the case of a teenager with dyskeratosis congenita who developed a unilateral late exudative retinopathy after having previous laser treatment for threshold retinopathy of prematurity as an infant.

Hepcidin Deficiency Protects Against Atherosclerosis.

Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.