Crowdsourcing the Impact of Illustration in Cleft Surgery Education.

OBJECTIVE: This study aimed to (1) assess layperson preferences for how surgical information is presented; (2) evaluate how the format of visual information relates to layperson comfort with undergoing surgery, perceptions of surgeon character traits, and beliefs about artistic skill impacting plastic surgery practice; and (3) identify sociodemographic characteristics associated with these outcomes. DESIGN: A survey was developed in which one of five standardized sets of information depicting a unilateral cleft lip repair was presented as (1) text alone, (2) quick sketches, (3) simple drawings, (4) detailed illustrations, or (5) photographs. SETTING: Online crowdsourcing platform. PARTICIPANTS: Raters aged 18 years and older from the United States. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): After viewing the surgical information, participants answered three sets of Likert scale questions. Ratings were averaged to produce three composite scores assessing (1) comfort with undergoing surgery (2) perceptions of surgeon character traits, and (3) beliefs about plastic surgery and artistry. RESULTS: Four hundred seventy-nine participants were included. Surgeon character traits score was highest among participants who viewed detailed illustrations at 4.46 ± 0.59, followed by photographs at 4.43 ± 0.54, text alone at 4.28 ± 0.59, simple drawings at 4.17 ± 0.67, and quick sketches at 4.17 ± 0.71 (p = 0.0014). Participants who viewed detailed illustrations rated surgical comfort score and plastic surgery and artistry score highest, although differences did not achieve statistical significance. CONCLUSIONS: Viewing detailed cleft lip repair illustrations was significantly associated with positive perceptions of surgeon character traits. Our data help to contextualize methods of communication and education valued by the public when seeking cleft care.

Nasal Airway Volumes are More Asymmetric in Skeletally Mature Patients With Cleft lip and Palate Than Controls on 3-Dimensional Analysis.

BACKGROUND: This study assesses nasal airway volumes in skeletally mature patients with CLP and healthy controls and examines the relationship among nasal volumes, cleft laterality, and facial asymmetry. METHODS: Computed tomography images from patients with CLP and controls were analyzed using Mimics Version 23.0 (Materialise, Leuven, Belgium). Relationships among nasal airway volume, cleft laterality, and facial asymmetry were compared. RESULTS: The 89 patients in this study included 66 (74%) CLP and 23 (17%) controls. Nasal airway volumes in CLP were more asymmetric than controls (26.8±17.5% vs. 17.2±14.4%; P=0.015). In UCLP, the smaller nasal airway was on the cleft side 81% of the time (P<0.001). Maximum airway stenosis was on the cleft side 79% of the time (P<0.001), and maximum stenosis was on the same side as the smaller airway 89% of the time (P<0.001). There was a mild linear relationship between nasal airway asymmetry and maximum stenosis (r=0.247, P=0.023). On 3-dimensional image reconstruction, the septum often bowed convexly into the cleft-sided nasal airway with a caudal deviation towards the noncleft side. Nasal airway asymmetry was not associated with facial midline asymmetry (P>0.05). CONCLUSION: The nasal airway is more asymmetric in patients with cleft lip and palate compared with the general population, with the area of maximum stenosis usually occurring on the cleft-sided airway. In patients with unilateral cleft lip and palate, the septum often bows into the cleft side, reducing the size of that nasal airway. Nasal airway asymmetry did not correlate with facial asymmetry.

Squaric esters as peptide stapling reagents.

We report that squaric esters can serve as bifunctional reagents for selective peptide stapling reactions. Formation of the squaric amide staple occurs under mild conditions with amine-containing side chains. We show that short resin-bound peptides are readily stapled on solid phase and that stapling can occur at various relative positions along the peptide and with various amine tether lengths (e.g. Lysine, ornithine, etc). The squaric amide staples are stable to strong acid conditions used to cleave the stapled peptide from the resin and the stapled peptides show an increase in helicity as analyzed through circular dichroism.

Matrix-Induced Autologous Chondrocyte Implantation Versus Autologous Chondrocyte Implantation of the Knee A Retrospective Comparison.

OBJECTIVE: The purpose of this study was to compare the short-term clinical outcomes of matrix-induced autologous chondrocyte implantation (MACI) to those seen following traditional autologous chondrocyte implantation (ACI) in the management of symptomatic cartilage lesions of the knee. METHODS: This was a retrospective cohort study of patients who underwent either ACI or MACI from January 2011 to March 2018. Patients with a minimum postoperative follow-up of 18 months were contacted. Demographic information, intraoperative findings, and patient-reported functional outcomes scores were collected. Comparisons were made between the two cell-based cartilage repair techniques. RESULTS: Fifty-six patients were included in the study (39 ACI, 17 MACI). Visual analog scale (VAS) for pain scores improved significantly in both groups, with MACI patients demonstrating significantly lower postoperative pain scores compared to those treated with ACI. In the ACI group, there was a decrease in the Tegner Activity score compared to the preoperative baseline, while no significant difference was seen between pre- and postoperative activity levels in the MACI group. Patients were generally satisfied with the outcome of their procedures, and there was no significant difference in satisfaction between groups. No patients re-quired additional surgery during the follow-up period. CONCLUSION: Both ACI and MACI demonstrated good short-term postoperative clinical results with improved pain and activity levels compared to the preoperative baseline. Patients treated with the MACI technique demonstrated greater reductions in pain scores compared to ACI, and while ACI resulted in a decrease in levels of postoperative activity, activity levels for MACI remained stable.

Validating the Supraorbital Notch-Nasion-Supraorbital Notch Angle as a Marker for Metopic Craniosynostosis Severity.

OBJECTIVE: Metopic craniosynostosis (MCS) can be difficult to differentiate from metopic ridge (MR) or normal frontal morphology. This study assess whether the supraorbital notch-nasion-supraorbital notch (SNS) angle can help identify MCS. METHODS: Records of 212 patients with preoperative three-dimensional computed tomography scans were examined. The SNS angles, surgeon craniofacial dysmorphology rankings, and CranioRate metopic severity scores (MSSs) were compared with the Spearman rank correlation coefficient. Receiver operating characteristic (ROC) curves with Youden J-statistic and cross-validation of regression models assessed the ability of these measures to predict surgery. RESULTS: A total of 212 patients were included, consisting of 78 MCS, 37 MR, and 97 controls. Both the mean SNS angle (MCS: 111.7 ± 10.7 degrees, MR: 126.0 ± 8.2 degrees, controls: 130.7 ± 8.8 degrees P < 0.001) and MSS (MCS: 5.9 ± 2.0, MR: 1.4 ± 1.9, controls: 0.2 ± 1.9, P < 0.001) were different among the cohorts. The mean SNS angle (111.5 ± 10.7 versus 129.1 ± 8.8, P < 0.001) was lower in those who had surgery and CranioRate score (5.9 ± 2.1 versus 0.8 ± 2.2, P < 0.001) was higher in those who underwent surgery. SNS angles were positively correlated with surgeon craniofacial dysmorphology rankings (r = 0.41, P < 0.05) and CranioRate MSS (r = 0.54, P < 0.05). The ROC curve requiring high sensitivity revealed an SNS angle of 124.8 degrees predicted surgery with a sensitivity of 88.7% and a specificity of 71.3%. A ROC curve using the CranioRate MCC values ≥3.19 predicted surgery with 88.7% sensitivity and 94.7% specificity. CONCLUSION: Orbital dysmorphology in patients with MCS is well captured by the supraorbital-nasion angle. Both the SNS angle and CranioRate MSS scores accurately predict surgical intervention.

A critical eye on metopic craniosynostosis: A retrospective study assessing orbital dysmorphology as a marker of disease.

This investigation sought to ascertain whether orbital morphology could predict genuine metopic craniosynostosis (MCS). The study retrospectively analyzed preoperative three-dimensional computed tomography (3D-CT) scans of patients who underwent surgical correction for MCS. MCS severity was evaluated using the interfrontal angle (IFA). Orbital dysmorphology was assessed based on multiple angles, including supraorbital notches and nasion (SNS), infraorbital foramina and nasion (INI), zygomaticofrontal suture-supraorbital notch-dacryon (ZSD), and orbital long axis (OLA). Results were juxtaposed against age/gender-matched controls and individuals with non-synostotic metopic ridge (MR). The study included 177 patients: 68 MCS, 35 MR, and 74 control subjects. All orbital measurements exhibited significant differences across groups. IFA demonstrated a strong association with all orbital measurements, particularly SNS (B = 0.79, p < 0.001). SNS showed the highest area under the curve among orbital measurements (0.89). Using a 95% sensitivity threshold, the optimal diagnostic angle for SNS was 129.23° (specificity 54%, sensitivity 96%). These findings suggest a correlation between orbital dysmorphology and trigonocephaly severity. The observed dysmorphology manifested in a superomedially accentuated rotational pattern. Importantly, SNS angle predicted MCS, with an angle greater than 130° indicating <5% likelihood of MCS diagnosis. The simplicity of measuring SNS angle on any 3D-CT scan highlights its practical use for assisting with MCS diagnosis.

Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial.

Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARCEX Therapy to improve arm and hand functions in people with chronic SCI. ARCEX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARCEX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARCEX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARCEX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 .

Validation of an ICD-Code-Based Case Definition for Psychotic Illness Across Three Health Systems.

BACKGROUND AND HYPOTHESIS: Psychosis-associated diagnostic codes are increasingly being utilized as case definitions for electronic health record (EHR)-based algorithms to predict and detect psychosis. However, data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. STUDY DESIGN: Using EHRs at 3 health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into 5 higher-order groups. 1133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. STUDY RESULTS: PPVs across all diagnostic groups and hospital systems exceeded 70%: Mass General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the case definitions used in the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Anti-PD-1 alone or in combination with anti-CTLA-4 for advanced melanoma patients with liver metastases.

BACKGROUND: The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases. METHODS: We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival. RESULTS: With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42-51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 - 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 - 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 - 0.94; p = 0.018) compared to anti-PD1 monotherapy. CONCLUSIONS: Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients.

Incomes to Outcomes: A Global Assessment of Disparities in Cleft and Craniofacial Treatment.

OBJECTIVE: Recent investigations focused on health equity have enumerated widespread disparities in cleft and craniofacial care. This review introduces a structured framework to aggregate findings and direct future research. DESIGN: Systematic review was performed to identify studies assessing health disparities based on race/ethnicity, payor type, income, geography, and education in cleft and craniofacial surgery in high-income countries (HICs) and low/middle-income countries (LMICs). Case reports and systematic reviews were excluded. Meta-analysis was conducted using fixed-effect models for disparities described in three or more studies. SETTING: N/A. PATIENTS: Patients with cleft lip/palate, craniosynostosis, craniofacial syndromes, and craniofacial trauma. INTERVENTIONS: N/A. RESULTS: One hundred forty-seven articles were included (80% cleft, 20% craniofacial; 48% HIC-based). Studies in HICs predominantly described disparities (77%,) and in LMICs focused on reducing disparities (42%). Level II-IV evidence replicated delays in cleft repair, alveolar bone grafting, and cranial vault remodeling for non-White and publicly insured patients in HICs (Grades A-B). Grade B-D evidence from LMICs suggested efficacy of community-based speech therapy and remote patient navigation programs. Meta-analysis demonstrated that Black patients underwent craniosynostosis surgery 2.8 months later than White patients (P < .001) and were less likely to undergo minimally-invasive surgery (OR 0.36, P = .002). CONCLUSIONS: Delays in cleft and craniofacial surgical treatment are consistently identified with high-level evidence among non-White and publicly-insured families in HICs. Multiple tactics to facilitate patient access and adapt multi-disciplinary case in austere settings are reported from LMICs. Future efforts including those sharing tactics among HICs and LMICs hold promise to help mitigate barriers to care.

Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administrative purposes raise questions about the consistency and reproducibility of EHR-based multimorbidity research. Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combining data from multiple sources for online multimorbidity analysis. Findings: Analyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies ( Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest similar structures of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights. Interpretation: Our findings demonstrate the robustness of large-scale EHR data for studying phenome-wide multimorbidities. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared biology of diseases. The consistent core-periphery structure offers analytical insights to discover complex disease interactions. This work also sets the stage for advanced disease modeling, with implications for precision medicine. Funding: VUMC Biostatistics Development Award, the National Institutes of Health, and the VA CSRD.

Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network.

The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue.

Using implementation science to decrease variation and high opioid administration in a surgical ICU.

BACKGROUND: High doses and prolonged duration of opioids are associated with tolerance, dependence, and increased mortality. Unfortunately, despite recent efforts to curb outpatient opioid prescribing because of the ongoing epidemic, utilization remains high in the intensive care setting, with intubated patients commonly receiving infusions with a potency much higher than doses required to achieve pain control. We attempted to use implementation science techniques to monitor and reduce excessive opioid prescribing in ventilated patients in our Surgical ICU. METHODS: We conducted a prospective study investigating opioid administration in a closed SICU at an academic medical center over 18 months. Commonly accepted conversions were used to aggregate daily patient opioid use. Patients with a history of chronic opioid use and those being treated with an ICP monitor/drain, neuromuscular blocker, or ECMO were excluded. If the patient spent a portion of a day on a ventilator, that day's total was included in the "vent group." MMEs per patient were collected for each patient and assigned to the on-call intensivist. Intensivists were blinded to the data for the first seven months. They were then provided with academic detailing followed by audit & feedback over the subsequent 11 months, demonstrating how opioid utilization during their time in the SICU compared to the unit average and a blinded list of the other attendings. Student's T-tests were performed to compare opioid utilization before and after initiation of academic detailing and audit & feedback. RESULTS: Opioid utilization in patients on a ventilator decreased by 20.1% during the feedback period, including less variation among all intensivists and a 30.9% reduction by the highest prescribers. CONCLUSION: Implementation science approaches can effectively reduce variation in opioid prescribing, especially for high outliers in a SICU. These interventions may reduce the risks associated with prolonged use of high-dose opioids. LEVEL OF EVIDENCE: Prospective pre-post-intervention, Level II.

Long-term sequelae of normocephalic pansynostosis: a rare but insidious entity.

OBJECTIVE: Patients with normocephalic pansynostosis, who have a grossly normal head shape, are often overlooked early in life and present late with elevated intracranial pressure (ICP) requiring timely cranial vault expansion. This study evaluates the long-term clinical outcomes of patients with normocephalic pansynostosis. METHODS: We retrospectively reviewed patients with a clinical and radiographic diagnosis of primary pansynostosis who underwent vault reconstruction between 2000 and 2023. Clinical and treatment course after craniofacial interventions was followed in patients with normocephaly to assess outcomes. RESULTS: Thirty-five patients with primary pansynostosis were identified, of which eight (23.5%) had normocephaly and underwent initial vault expansion at a mean age of 5.0 ± 2.4 years. All eight patients (50.0% male) presented with symptoms of elevated ICP including headaches (50.0%), nausea and vomiting (50.0%), and developmental delay (62.5%) and/or signs of elevated ICP including papilledema (75.0%) and radiologic thumbprinting on head computed tomography scan (87.5%). Three of the four normocephalic patients who had over 7 years of postoperative follow-up developed subjective headaches, vision changes, or learning and behavioral issues in the long-term despite successful vault reconstruction. CONCLUSIONS: Our longitudinal experience with this rare but insidious entity demonstrates the importance of timely intervention and frequent postoperative monitoring, which are critical to limiting long-term neurological sequelae. Multidisciplinary care by craniofacial surgery, neurosurgery, ophthalmology, and neuropsychology with follow-up into adolescence are recommended to assess for possible recurrence of elevated ICP secondary to cranio-cerebral disproportion.

The time course of stimulus-specific perceptual learning.

Practice on perceptual tasks can lead to long-lasting, stimulus-specific improvements. Rapid stimulus-specific learning, assessed 24 hours after practice, has been found with just 105 practice trials in a face identification task. However, a much longer time course for stimulus-specific learning has been found in other tasks. Here, we examined 1) whether rapid stimulus-specific learning occurs for unfamiliar, non-face stimuli in a texture identification task; 2) the effects of varying practice across a range from just 21 trials up to 840 trials; and 3) if rapid, stimulus-specific learning persists over a 1-week, as well as a 1-day, interval. Observers performed a texture identification task in two sessions separated by one day (Experiment 1) or 1 week (Experiment 2). Observers received varying amounts of practice (21, 63, 105, or 840 training trials) in session 1 and completed 840 trials in session 2. In session 2, one-half of the observers in each group performed the task with the same textures as in session 1, and one-half switched to novel textures (same vs. novel conditions). In both experiments we found that stimulus-specific learning - defined as the difference in response accuracy in the same and novel conditions - increased as a linear function of the log number of session 1 training trials and was statistically significant after approximately 100 training trials. The effects of stimulus novelty did not differ across experiments. These results support the idea that stimulus-specific learning in our task arises gradually and continuously through practice, perhaps concurrently with general learning.

Orthognathic Considerations of Maxillary and Mandibular Asymmetry at Skeletal Maturity in Patients with Cleft Lip and Palate.

BACKGROUND: Improving occlusion and aesthetics is the primary objective of orthognathic surgery for patients with cleft lip and palate (CLP). However, these patients often suffer from horizontal, vertical, and rotational asymmetry in addition to maxillary retrusion. This study aims to describe maxillary and mandibular asymmetry in patients with CLP undergoing orthognathic surgery and analyze its anatomic basis. METHODS: Patients with isolated CLP undergoing CT imaging prior to orthognathic surgery were retrospectively reviewed. Maxillary and mandibular positioning and dimensional symmetry were evaluated. Incidence of clinically significant asymmetry, correlations between areas of asymmetry, and associations with clinical history were analyzed. RESULTS: Fifty-eight patients, with mean age 17 years were analyzed, including 32 patients with unilateral CLP and 26 with bilateral CLP. Twenty (34%) patients demonstrated chin deviation ≥4mm and 21 (36%) had a ≥5% discrepancy in mandibular ramus lengths. Horizontal occlusal plane cant of ≥2° was seen in 20 (34%) maxillae and 28 (48%) mandibles, with dental arch yaw ≥2° noted in 32 (55%) of both maxillae and mandibles. Chin deviation correlated with maxillary cant, discrepancy in ramus length, discrepancy in mandibular body length, and discrepancy in condylar volume (p<0.05). Bilateral and unilateral CLP did not show significantly different asymmetry on any measure (p>0.05). CONCLUSIONS: Both maxillary and mandibular asymmetry is common in skeletally mature patients with CLP and frequently results in notable chin deviation. Preoperative three-dimensional imaging and virtual surgical planning of orthognathic surgery aid in recognition of facial asymmetries and reveal opportunities to optimize results in this population.

Integrating Electronic Health Records and Polygenic Risk to Identify Genetically Unrelated Comorbidities of Schizophrenia That May Be Modifiable.

Background: Patients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations. Methods: Phenome-wide comorbidity was calculated from electronic health records of 250,000 patients across 2 independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham); associations with schizophrenia polygenic risk scores were calculated across the same phenotypes in linked biobanks. Results: Schizophrenia comorbidity was significantly correlated across institutions (r = 0.85), and the 77 identified comorbidities were consistent with prior literature. Overall, comorbidity and polygenic risk score associations were significantly correlated (r = 0.55, p = 1.29 × 10-118). However, directly testing for the absence of genetic effects identified 36 comorbidities that had significantly equivalent schizophrenia polygenic risk score distributions between cases and controls. This set included phenotypes known to be consequences of antipsychotic medications (e.g., movement disorders) or of the disease such as reduced hygiene (e.g., diseases of the nail), thereby validating the approach. It also highlighted phenotypes with less clear causal relationships and minimal genetic effects such as tobacco use disorder and diabetes. Conclusions: This work demonstrates the consistency and robustness of electronic health record-based schizophrenia comorbidities across independent institutions and with the existing literature. It identifies known and novel comorbidities with an absence of shared genetic risk, indicating other causes that may be modifiable and where further study of causal pathways could improve outcomes for patients.

Patients with schizophrenia have many co-occurring diseases that contribute substantially to premature mortality of 10 to 20 years. Conditions that are comorbid but lack shared genetic risk with schizophrenia are likely to have causes that are more modifiable. Here, we calculated comorbidity from electronic health records from 2 independent health care institutions and associations with schizophrenia polygenic risk scores across the same phenotypes in linked biobanks. We identified known and novel diseases comorbid with schizophrenia, thereby validating our approach.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Synthesis and crystal structures of bis-[1-oxopyridin-2-olato(1-)]bis-(penta-fluoro-phen-yl)silicon(IV)-tetra-hydro-furan-pentane (2/1/1), bis-[1-oxopyridin-2-olato(1-)]bis-(p-tol-yl)silicon(IV), and dimesitylbis[1-oxopyridin-2-olato(1-)]silicon(IV).

The neutral organosilicon(IV) complex, (C6F5)2Si(OPO)2 (OPO = 1-oxopyridin-2-one, C5H4NO2), was synthesized from (C6F5)2Si(OCH3)2 and 2 equiv. of 1-hy-droxy-pyridin-2-one in tetra-hydro-furan (THF). Single crystals grown from the diffusion of n-pentane into a THF solution were identified as a THF hemisolvate and an n-pentane hemisolvate, (C6F5)2Si(OPO)2·0.5THF·0.5C5H12 (1). p-Tol-yl2Si(OPO)2 (2) and mesit-yl2Si(OPO)2 (3) crystallized directly from reaction mixtures of 2 equiv. of Me3Si(OPO) with p-tol-yl2SiCl2 and mesit-yl2SiCl2, respectively, in aceto-nitrile. The oxygen-bonded carbon and nitro-gen atoms of the OPO ligands in 1, 2, and 3 were modeled as disordered indicating co-crystallization of up to three possible diastereomers in each. Solution NMR studies support the presence of exclusively the all-cis isomer in 1 and multiple isomers in 2. Poor solubility of 3 limited its characterization in solution.

Continuous-Time and Dynamic Suicide Attempt Risk Prediction with Neural Ordinary Differential Equations.

Suicide is one of the leading causes of death in the US, and the number of attributable deaths continues to increase. Risk of suicide-related behaviors (SRBs) is dynamic, and SRBs can occur across a continuum of time and locations. However, current SRB risk assessment methods, whether conducted by clinicians or through machine learning models, treat SRB risk as static and are confined to specific times and locations, such as following a hospital visit. Such a paradigm is unrealistic as SRB risk fluctuates and creates time gaps in the availability of risk scores. Here, we develop two closely related model classes, Event-GRU-ODE and Event-GRU-Discretized, that can predict the dynamic risk of events as a continuous trajectory based on Neural ODEs, an advanced AI model class for time series prediction. As such, these models can estimate changes in risk across the continuum of future time points, even without new observations, and can update these estimations as new data becomes available. We train and validate these models for SRB prediction using a large electronic health records database. Both models demonstrated high discrimination performance for SRB prediction (e.g., AUROC > 0.92 in the full, general cohort), serving as an initial step toward developing novel and comprehensive suicide prevention strategies based on dynamic changes in risk.