A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.

AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

ILRUN Promotes Atherosclerosis Through Lipid-Dependent and Lipid-Independent Factors.

BACKGROUND: Common genetic variation in close proximity to the ILRUN gene are significantly associated with coronary artery disease as well as with plasma lipid traits. We recently demonstrated that hepatic inflammation and lipid regulator with ubiquitin-associated domain-like and NBR1-like domains (ILRUN) regulates lipoprotein metabolism in vivo in mice. However, whether ILRUN, which is expressed in vascular cells, directly impacts atherogenesis remains unclear. We sought to determine the role of ILRUN in atherosclerosis development in mice. METHODS: For our study, we generated global Ilrun-deficient (IlrunKO) male and female mice on 2 hyperlipidemic backgrounds: low density lipoprotein receptor knockout (LdlrKO) and apolipoprotein E knockout (ApoeKO; double knockout [DKO]). RESULTS: Compared with littermate control mice (single LdlrKO or ApoeKO), deletion of Ilrun in DKO mice resulted in significantly attenuated both early and advanced atherosclerotic lesion development, as well as reduced necrotic area. DKO mice also had significantly decreased plasma cholesterol levels, primarily attributable to non-HDL (high-density lipoprotein) cholesterol. Hepatic-specific reconstitution of ILRUN in DKO mice on the ApoeKO background normalized plasma lipids, but atherosclerotic lesion area and necrotic area remained reduced in DKO mice. Further analysis showed that loss of Ilrun increased efferocytosis receptor MerTK expression in macrophages, enhanced in vitro efferocytosis, and significantly improved in situ efferocytosis in advanced lesions. CONCLUSIONS: Our results support ILRUN as an important novel regulator of atherogenesis that promotes lesion progression and necrosis. It influences atherosclerosis through both plasma lipid-dependent and lipid-independent mechanisms. These findings support ILRUN as the likely causal gene responsible for genetic association of variants with coronary artery disease at this locus and suggest that suppression of ILRUN activity might be expected to reduce atherosclerosis.

ILRUN, a Human Plasma Lipid GWAS Locus, Regulates Lipoprotein Metabolism in Mice.

RATIONALE: Single-nucleotide polymorphisms near the ILRUN (inflammation and lipid regulator with ubiquitin-associated-like and NBR1 [next to BRCA1 gene 1 protein]-like domains) gene are genome-wide significantly associated with plasma lipid traits and coronary artery disease (CAD), but the biological basis of this association is unknown. OBJECTIVE: To investigate the role of ILRUN in plasma lipid and lipoprotein metabolism. METHODS AND RESULTS: ILRUN encodes a protein that contains a ubiquitin-associated-like domain, suggesting that it may interact with ubiquitinylated proteins. We generated mice globally deficient for Ilrun and found they had significantly lower plasma cholesterol levels resulting from reduced liver lipoprotein production. Liver transcriptome analysis uncovered altered transcription of genes downstream of lipid-related transcription factors, particularly PPARα (peroxisome proliferator-activated receptor alpha), and livers from Ilrun-deficient mice had increased PPARα protein. Human ILRUN was shown to bind to ubiquitinylated proteins including PPARα, and the ubiquitin-associated-like domain of ILRUN was found to be required for its interaction with PPARα. CONCLUSIONS: These findings establish ILRUN as a novel regulator of lipid metabolism that promotes hepatic lipoprotein production. Our results also provide functional evidence that ILRUN may be the casual gene underlying the observed genetic associations with plasma lipids at 6p21 in human.

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Who We Are Today: a National Survey of Diversity Among Psychiatry Program Directors.

OBJECTIVE: In March 2018, the American Association of Directors of Psychiatric Residency Training (AADPRT) formed the Diversity and Inclusion (D&I) Committee. One of the committee's goals was to understand the AADPRT membership's composition and their perceptions of D&I. This study's objective was to identify the demographic characteristics of the AADPRT membership. METHODS: Program directors were invited by email to participate in an anonymous survey. The survey collected participants' demographic information including gender, race/ethnicity, training background, age, disability/differently abled status, job role, geographic region where their program is located, type of program, and their program's community setting. RESULTS: Two hundred fifty six of 657 AADPRT members (39%) completed the survey. Respondents were mostly White (64.5%) followed by Asian/Southeast Asian (17.6%), Hispanic/Latinx (4.3%), and Black (1.6%). Only 13.3% of the participants were international medical graduates. Women were more prevalent (61.7%) than men (37.5%), and 9.4% self-identified as members of the LGBTQ+ Community. CONCLUSIONS: This study represents the first systematic investigation into the diversity among psychiatry program directors throughout the USA and Canada. Future qualitative studies are needed to better understand the reasons behind this initial study's findings. Potential concerns requiring exploration include the possibility of the program director role serving as a "glass ceiling" for some women and a "leaky pipeline" in academia for groups underrepresented in medicine.

Child Psychotherapy Training in the United States: A National Survey of Child and Adolescent Psychiatry Fellowship Program Directors.

OBJECTIVES: Training in child and adolescent psychotherapy continues to be emphasized by accrediting organizations (ACGME and ABPN) but it is not known how these skills are taught and what types of therapy are highlighted in fellowships across the United States. METHODS: A 16-question anonymous online survey was developed by the authors and covered six main areas: demographics, the priority of psychotherapy in training, the competency goals for different psychotherapy modalities, training strategies, types of supervision, and program directors' satisfaction of their training implementation and assessment of trainees. The survey was sent to every identified CAP program director during a three-month period in early 2017. RESULTS: Data was gathered from 53 of the 131 program directors surveyed, giving a 40% response rate. Ninety percent of CAP program directors strongly agree or agree that it is important to preserve and promote training and practice of psychotherapy. Most (83%) program directors indicated competence or expertise as a training goal for CBT with more variability among programs for other psychotherapies. Seventy percent of program directors agree that their program provides adequate time for learning and practicing psychotherapy but the allotted time for psychotherapy is low across majority of programs over both years of training. CONCLUSIONS: These results indicate that there is a gap between the goals of providing optimal training in psychotherapy with the low amount of protected time for the practice of psychotherapy. These results should provide a foundation for program directors to learn from each other about developing, improving, and implementing effective psychotherapy training.

Predictors of Disease-free Survival and Recurrence in Patients with Resected Bronchial Carcinoid Tumors.

BACKGROUND: Bronchial carcinoids are characterized by neuroendocrine differentiation and have distinct biological behavior, recurrence patterns, and prognosis compared with adenocarcinomas or squamous cell carcinomas. Because of their often indolent nature, it has been suggested that routine postoperative imaging surveillance may not be warranted in the majority of patients. This study aims to define the factors that predict disease-free survival (DFS) and recurrence after resection of these tumors, with the goal of identifying high-risk patients for whom image surveillance may be warranted. METHODS: We conducted a retrospective review of a prospective database to identify patients with completely resected bronchial carcinoid tumors. Surgical procedure, histology, pathological stage, follow-up, tumor recurrence, and survival were assessed. RESULTS: One hundred and forty-two patients were identified. Median age was 62 years and the majority was women (106). Surgical procedures included 20 wedge resections, 10 segmentectomies, 99 lobectomies, 3 bilobectomies, 2 pneumonectomies, 6 sleeve resections, and 2 bronchectomies. Pathologic stages included I (81%), II (10%), III (8%), and IV (1%). With a median follow-up of 31 months, there were seven recurrences. The 5- and 10-year overall survival rates were 92% and 75% and DFS rates were 88% and 72%, respectively. There were 34 patients with atypical carcinoids, and 6 (18%) developed recurrence, compared with 1 recurrence (1%) in the group of 108 patients with typical carcinoids (p = 0.0008). For atypical carcinoid tumors, the 5- and 10-year DFS rates were 72% and 32% versus 92% and 85% in typical carcinoid tumors (p = 0.001). Patients with more advanced tumor stage pT2-4 and pathologic N1/N2 nodal metastases had a significantly decreased 5- and 10-year DFS compared with those with early pT1 stage (p = 0.029) or those without nodal disease (p = 0.043). Multivariate Cox regression analyses showed advancing age (p = 0.001), atypical histology (p = 0.021), and advanced tumor stage (p = 0.047) were significant negative predictors for DFS. CONCLUSION: Long-term survival after resection of bronchial carcinoids is common, especially for patients with typical carcinoid tumors. DFS can be negatively influenced by atypical histology, advanced tumor, and nodal statuses. Efforts at postoperative image surveillance should target those patients with such high-risk factors.

Bilateral Pheochromocytomas in MEN2A Syndrome: A Two-Institution Experience.

BACKGROUND: Bilateral pheochromocytoma (PHEO) is more frequently found in patients with multiple endocrine neoplasia 2A carrying a RET germline mutation located in codon 634 (C634). However, it is unclear whether different amino acid substitutions within C634 cause differences in bilateral PHEOs expression. We aimed to answer this by pooling data from two Asian institutions. METHODS: Sixty-seven patients had confirmed C634 germline mutation. Age-dependent penetrance of bilateral PHEO was calculated from date of birth to the date when bilateral PHEO was first diagnosed or when the contralateral gland became a PHEO (if the patient already had one adrenal gland removed). Age-dependent penetrance was estimated by the Kaplan-Meier method and compared by log-rank test. RESULTS: The 4 different amino acid substitutions included C634R (arginine) (n = 19, 28.4 %), C634Y (tyrosine) (n = 36, 38.8 %), C634G (glycine) (n = 4, 6.0 %), and C634W (tryptophan) (n = 8, 11.9 %). The age-related penetrance of PHEO was similar between C634R, C634Y, C634G, and C634W (by age 40, 69.8, 55.2, 25.0, and 56.2 %, respectively) (p = 0.529). However, the age-related penetrance of bilateral PHEO in C634R was significantly higher than C634Y (by age of 40, 59.3 % vs. 25.2 %, p = 0.046) or C634Y, C634G, and C634W combined (59.3 % vs. 21.5 %, p = 0.024). Nevertheless, the accumulative risk of bilateral PHEOs across all four C634 mutations almost approached 100 % over time. CONCLUSION: The accumulative risk of bilateral PHEOs almost reached 100 % but its onset was significantly earlier in C634R mutation. These findings implied that those with C634R mutation might benefit from earlier screening of contralateral PHEO than other C634 mutations after an unilateral adrenalectomy.

Perioperative Outcomes after Lung Resection in Obese Patients.

BACKGROUND: Obesity is a growing epidemic in the developed world. However, little is known about the impact of obesity on the perioperative morbidity and mortality after lung resection. PATIENTS AND METHODS: We analyzed the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2010 to determine whether obesity is a risk factor for perioperative morbidity and mortality after pulmonary resection. Demographic, clinical, intraoperative, and morbidity and mortality data were collected. Multivariable predictors of morbidity and mortality were determined using regression analysis. RESULTS: A total of 5,216 lung resections were identified (1,372 wedges, 3,713 lobectomies, and 131 pneumonectomies). The median age was 66 years and 2,587 (49.6%) were females. The body mass index (BMI, kg/m(2)) of the patients was as follows: 192 (3.7%) < 18.5; 1,727 (33.1%) 18.5 to 24.9; 1,754 (33.6%) 25 to 29.9; and 1,488 (28.5%) > 30. In-hospital mortality and all-cause morbidity was 2.4% (n = 127) and 14.5% (n = 757) for the entire cohort of patients, respectively. BMI was not found to be a predictor of increased mortality or morbidity, even in the morbidly obese (BMI > 35). Rather, age, approach (video-assisted thoracoscopic surgery vs. open), parameters assessing performance status, operative time, and preoperative radiation therapy were the predictors of morbidity and mortality. Conversely, being overweight (BMI 25-30) approached significance as a multivariate predictor for decreased pulmonary complications (odds ratio, 0.77 [0.592-1.004]; p = 0.054) consistent with the "obesity paradox" observed after nonbariatric general surgery. CONCLUSION: Our large national study shows that obesity does not negatively impact perioperative mortality and morbidity in patients undergoing lung resection. Surgical resections should not be denied to obese (BMI > 30) patients.

Higher Circulating Neutrophil Counts Is Associated with Increased Risk of All-Cause Mortality and Cardiovascular Disease in Patients with Diabetic Kidney Disease.

BACKGROUND: Accumulating evidence has suggested the pathogenic roles of chronic inflammation and neutrophils in diabetic kidney disease (DKD). This study investigated the relationship between neutrophils, all-cause, and cardiovascular disease (CVD) mortality in type 2 diabetes mellitus (T2DM) patients with DKD. METHODS: We used data from the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2020 to investigate the relationship between circulating neutrophils counts, kidney function indices, all-cause, and CVD mortality in adult T2DM patients with DKD. Clinical predictive models and risk scores for long-term mortality were constructed. RESULTS: 44,332 patients [8034 with T2DM and 36,323 without T2DM] were included. Two thousand two hundred twenty patients had DKD, and 775 died (31.5% related to CVD) during a follow-up of 6.18 (range: 5.94-6.42) years. Higher neutrophil counts (Quartile 4, Q4) were associated with increased all-cause and CVD mortality [HR 1.73 (95% CI 1.34-2.25) and 1.81 (95% CI 1.14-2.89), respectively, p < 0.0001 and 0.01]. Neutrophil counts in Q4 showed a positive correlation with urine albumin-creatinine ratio (UACR) but a negative association with eGFR (p < 0.01 for all). Clinical predictive models incorporating neutrophil counts showed satisfactory performance in forecasting 5-year and 10-year CVD mortality-free survival (ROC AUC 0.824 and 0.842, respectively), and the nomogram-predicted survival demonstrated good concordance with observed survival. CONCLUSIONS: Higher levels of circulating neutrophil counts show a significant correlation with renal abnormalities and higher all-cause and CVD mortality in T2DM patients with DKD. The novel clinical predictive models and risk scores incorporating neutrophil counts may facilitate stratification and, hence, risk factor management in DKD patients.

Robotic hiatal hernia repair without mesh.

Background: Newer minimally invasive techniques have supplanted laparotomy and thoracotomy for management of hiatal hernias. Limited data exists on outcomes after robotic hiatal hernia repair without mesh despite the increasing popularity of this approach. We report our high-volume experience with durable robotic hiatal hernia repair with gastric fundoplication without mesh. Methods: A retrospective review was conducted on patients with type I-IV hiatal hernias who underwent an elective robotic-assisted repair from 2016 to 2019 using a novel technique of approximating the hiatus with running barbed absorbable (V-locTM) suture and securing it with interrupted silk sutures. Main outcomes included length of stay, readmission rate, and recurrence rate. Results: A total of 144 patients were reviewed. The average age of the patient was 61 years. Most of the patients were female [95 females (66%) to 49 males], and the average body mass index (BMI) was 29.96 kg/m2. The average operating time was 173 minutes (standard deviation 62 minutes). The average length of stay in the hospital was 2 days, and 89% of patients went home within the first 3 days. Ten patients (6.9%) were readmitted within 30 days, there were no mortalities in 30 days, and there were 6 (4.2%) recurrences on follow up requiring reoperation. Conclusions: Elective robotic hiatal hernia repair with fundoplication and primary closure of the hiatus with V-locTM and nonabsorbable suture without mesh is safe and effective. The robotic approach has similar operative times, lengths of stay, and complications compared to nationally published data on laparoscopic hiatal hernia repairs.

Instrumental variable and colocalization analyses identify endotrophin and HTRA1 as potential therapeutic targets for coronary artery disease.

Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease.

Management and outcomes of patients on preoperative plavix (clopidogrel) undergoing general thoracic surgery.

OBJECTIVES: Plavix (clopidogrel) is a potent antiplatelet agent used to prevent thrombosis in a variety of clinical settings. The perioperative management of thoracic surgery patients who are on clopidogrel at the time of surgery is not well defined. We conducted this review to examine the perioperative management and outcomes of patients undergoing general thoracic surgical procedures. METHODS: From January 2005 to January 2010, 165 patients on clopidogrel underwent 182 operative procedures. Three management strategies were identified: Group I: clopidogrel continued through surgery (n = 17), Group II: clopidogrel discontinued with a bridging agent (n = 44) and Group III clopidogrel discontinued without a bridging agent (n = 121). Propensity score matched cohorts (17 clopidogrel continued; 34 clopidogrel discontinued) were constructed based on age, clopidogrel indication, American Society of Anesthesiology status, and procedure and used to compare the impact of clopidogrel management on postoperative bleeding and cardiovascular morbidity. RESULTS: Unmatched analysis revealed a significantly higher rate of transfusion in the group of patients who continued on clopidogrel throughout the perioperative period, compared with patients who had clopidogrel discontinued. Although there were more cardiovascular events in Groups II and III, there were no significant differences between groups in postoperative mortality, myocardial infarction, stroke, or reoperation for bleeding. In propensity matched patients only the rate of postoperative transfusions was significantly higher in patients continued on clopidogrel compared with patients whose clopidogrel was discontinued (35.3 vs. 2.9%), p < 0.004. CONCLUSIONS: In selected patients, some thoracic surgical procedures can be performed safely on clopidogrel but are associated with higher rates of postoperative transfusion.

The emerging Janus face of SVEP1 in development and disease.

Sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) is a large extracellular matrix protein that is also detected in circulation. Recent plasma proteomic and genomic studies have revealed a large number of associations between SVEP1 and human traits, particularly chronic disease. These include associations with cardiac death and disease, diabetes, platelet traits, glaucoma, dementia, and aging; many of these are causal. Animal models demonstrate that SVEP1 is critical in vascular development and disease, but its molecular and cellular mechanisms remain poorly defined. Future studies should aim to characterize these mechanisms and determine the diagnostic, prognostic, and therapeutic value of measuring or intervening on this enigmatic protein.

A flexible symbolic regression method for constructing interpretable clinical prediction models.

Machine learning (ML) models trained for triggering clinical decision support (CDS) are typically either accurate or interpretable but not both. Scaling CDS to the panoply of clinical use cases while mitigating risks to patients will require many ML models be intuitively interpretable for clinicians. To this end, we adapted a symbolic regression method, coined the feature engineering automation tool (FEAT), to train concise and accurate models from high-dimensional electronic health record (EHR) data. We first present an in-depth application of FEAT to classify hypertension, hypertension with unexplained hypokalemia, and apparent treatment-resistant hypertension (aTRH) using EHR data for 1200 subjects receiving longitudinal care in a large healthcare system. FEAT models trained to predict phenotypes adjudicated by chart review had equivalent or higher discriminative performance (p < 0.001) and were at least three times smaller (p < 1 × 10-6) than other potentially interpretable models. For aTRH, FEAT generated a six-feature, highly discriminative (positive predictive value = 0.70, sensitivity = 0.62), and clinically intuitive model. To assess the generalizability of the approach, we tested FEAT on 25 benchmark clinical phenotyping tasks using the MIMIC-III critical care database. Under comparable dimensionality constraints, FEAT's models exhibited higher area under the receiver-operating curve scores than penalized linear models across tasks (p < 6 × 10-6). In summary, FEAT can train EHR prediction models that are both intuitively interpretable and accurate, which should facilitate safe and effective scaling of ML-triggered CDS to the panoply of potential clinical use cases and healthcare practices.

SVEP1 is an endogenous ligand for the orphan receptor PEAR1.

Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.