Assessment of Disruptive Life Events for Individuals Diagnosed With Schizophrenia or Bipolar I Disorder Using Data From a Consumer Credit Reporting Agency.

Importance: There is a dearth of population-level data on major disruptive life events (defined here as arrests by a legal authority, address changes, bankruptcy, lien, and judgment filings) for patients with bipolar I disorder (BPI) or schizophrenia, which has limited studies on mental health and treatment outcomes. Objective: To conduct a population-level study on disruptive life events by using publicly available data on disruptive life events, aggregated by a consumer credit reporting agency in conjunction with electronic health record (EHR) data. Design, Setting, and Participants: This study used EHR data from 2 large, integrated health care systems, Kaiser Permanente Southern California and Henry Ford Health. Cohorts of patients diagnosed from 2007 to 2019 with BPI or schizophrenia were matched 1:1 by age at analysis, age at diagnosis (if applicable), sex, race and ethnicity, and Medicaid status to (1) an active comparison group with diagnoses of major depressive disorder (MDD) and (2) a general health (GH) cohort without diagnoses of BPI, schizophrenia, or MDD. Patients with diagnoses of BPI or schizophrenia and their respective comparison cohorts were matched to public records data aggregated by a consumer credit reporting agency (98% match rate). Analysis took place between November 2020 and December 2022. Main Outcomes and Measures: The differences in the occurrence of disruptive life events among patients with BPI or schizophrenia and their comparison groups. Results: Of 46 167 patients, 30 008 (65%) had BPI (mean [SD] age, 42.6 [14.2] years) and 16 159 (35%) had schizophrenia (mean [SD], 41.4 [15.1] years). The majoriy of patients were White (30 167 [65%]). In addition, 18 500 patients with BPI (62%) and 6552 patients with schizophrenia (41%) were female. Patients with BPI were more likely to change addresses than patients in either comparison cohort (with the incidence ratio being as high as 1.25 [95% CI, 1.23-1.28]) when compared with GH cohort. Patients with BPI were also more likely to experience any of the financial disruptive life events with odds ratio ranging from 1.15 [95% CI, 1.07-1.24] to 1.50 [95% CI, 1.42-1.58]). The largest differences in disruptive life events were seen in arrests of patients with either BPI or schizophrenia compared with GH peers (3.27 [95% CI, 2.84-3.78] and 3.04 [95% CI, 2.57-3.59], respectively). Patients with schizophrenia had fewer address changes and were less likely to experience a financial event than their matched comparison cohorts. Conclusions and Relevance: This study demonstrated that data aggregated by a consumer credit reporting agency can support population-level studies on disruptive life events among patients with BPI or schizophrenia.

Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor.

BACKGROUND: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. METHODS: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. RESULTS: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). CONCLUSIONS: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

Validation of the Enriching New-Onset Diabetes for Pancreatic Cancer Model in a Diverse and Integrated Healthcare Setting.

BACKGROUND: The risk of pancreatic cancer is elevated among people with new-onset diabetes (NOD). Based on Rochester Epidemiology Project Data, the Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) model was developed and validated. AIMS: We validated the END-PAC model in a cohort of patients with NOD using retrospectively collected data from a large integrated health maintenance organization. METHODS: A retrospective cohort of patients between 50 and 84 years of age meeting the criteria for NOD in 2010-2014 was identified. Each patient was assigned a risk score (< 1: low risk; 1-2: intermediate risk; ≥ 3: high risk) based on the values of the predictors specified in the END-PAC model. Patients who developed pancreatic ductal adenocarcinoma (PDAC) within 3 years were identified using the Cancer Registry and California State Death files. Area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated. RESULTS: Out of the 13,947 NOD patients who were assigned a risk score, 99 developed PDAC in 3 years (0.7%). Of the 3038 patients who had a high risk, 62 (2.0%) developed PDAC in 3 years. The risk increased to 3.0% in white patients with a high risk. The AUC was 0.75. At the 3+ threshold, the sensitivity, specificity, PPV, and NPV were 62.6%, 78.5%, 2.0%, and 99.7%, respectively. CONCLUSIONS: It is critical that prediction models are validated before they are implemented in various populations and clinical settings. More efforts are needed to develop screening strategies most appropriate for patients with NOD in real-world settings.

Operative Treatment of Acute Patellar Tendon Ruptures.

BACKGROUND: The gold standard for patellar tendon repair is a transosseous technique. Suture anchor repair has gained popularity, with recent biomechanical studies demonstrating significantly less gap formation during cyclic loading and significantly higher ultimate failure loads as compared with transosseous repair. These findings have not been substantiated in a large clinical cohort. PURPOSE: To report demographic and epidemiologic data, clinical and surgical findings, and outcomes and complications of anchor and transosseous suture repairs of acute patellar tendon ruptures. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All patients who underwent a primary repair of a traumatic patellar tendon rupture within 45 days of injury between 2006 and 2016 were retrospectively reviewed. Surgery was performed at a multisurgeon (120 surgeons) multicenter (14 centers) community-based integrated health care system. Patient demographic information, repair type, complications, and time from surgery to release from medical care were recorded. RESULTS: A total of 361 patients (374 knees) met our inclusion criteria. The mean age was 39.8 years (range, 9-86 years), and 91.7% were male. There were 321 transosseous and 53 anchor repairs. There was no significant difference in the mean age (P = .27), sex (P = .79), tourniquet time (P = .93), or body mass index (P = .78) between the groups. There was a significant difference in rerupture rate between transosseous and anchor repairs (7.5% vs 0%, respectively; P = .034). Based on logistic regression, transosseous repair had 3.24 times the odds of reoperation verseus anchor repair (95% CI, 0.757-13.895; P = .1129). The infection rate was 1.6% for transosseous repair and 7.5% for anchor repair (P = .160). There was no difference in time to release from medical care: 18.4 weeks for anchor and 17.1 weeks for transosseous repairs (P = .92). CONCLUSION: Anchor repair demonstrated a significant decrease in rerupture rate when compared with transosseous repair. There was no difference in reoperation rate, infection rate, or time to release from medical care.

Association of Glycated Hemoglobin Levels With Risk of Pancreatic Cancer.

Importance: New-onset diabetes after the age of 50 years is a potential indicator of pancreatic cancer. Understanding the associations between hyperglycemia, diabetes, and pancreatic cancer, including pancreatic ductal adenocarcinoma, is key to developing an approach to early detection. Objective: To assess the association of elevation in glycated hemoglobin (HbA1c) with the risk of pancreatic cancer. Design, Setting, and Participants: This cohort study was conducted using data collected from an integrated health care system in California. A total of 851 402 patients aged 50 to 84 years who had HbA1c measurements taken between 2010 and 2014 were identified as the base cohort, with 12 contemporaneous cohorts created based on varying HbA1c thresholds (ie, 6.1%, 6.3%, 6.5%, and 6.7%) and prior diabetes status. Data analysis was conducted from August 2018 to September 2019. Main Outcomes and Measures: New cases of pancreatic cancer identified through cancer registry and California death files during a 3-year period. Three-year risk, incidence rate, sensitivity, number of patients needed to screen to detect 1 case, timing, and stage at diagnosis were determined. Results: Among 851 402 patients in the base cohort, 447 502 (52.5%) were women, 255 441 (30.0%) were Hispanic participants, 383 685 (45.1%) were non-Hispanic white participants, 100 477 (11.8%) were Asian participants, and 88 969 (10.4%) were non-Hispanic black participants, with a median (interquartile range) age of 62 (56-69) years and a median (interquartile range) HbA1c level of 6.0% (5.7%-6.6%). The incidence rate of pancreatic cancer was 0.45 (95% CI, 0.43-0.49) per 1000 person-years. After excluding prior diabetes as well as confirmation of new-onset hyperglycemia based on an HbA1c level of 6.5%, a total of 20 012 patients remained, with 74 of 1041 pancreatic ductal adenocarcinoma cases (7.1%) from the base cohort included. The rate of pancreatic cancer was 0.72 (95% CI, 0.32-1.42) per 1000 person-years among Asian patients, 0.83 (95% CI, 0.35-1.71) per 1000 person-years among non-Hispanic black patients, 0.84 (95% CI, 0.48-1.37) per 1000 person-years among Hispanic patients, and 2.37 (95% CI, 1.75-3.14) per 1000 person-years among non-Hispanic white patients. Overall, 42 of 74 cancers (56.8%) were diagnosed within 1 year of the index laboratory test. Among 1041 total cases, 708 (68.0%) had staging information available, of whom 465 (65.7%) had stage III or IV disease at diagnosis. In the base cohort, the number needed to undergo evaluation to identify a single case of pancreatic ductal adenocarcinoma was 818 (95% CI, 770-869), with estimates ranging from 206 (95% CI, 160-264) to 600 (95% CI, 540-666) in the subcohorts. Conclusions and Relevance: The findings of this study suggest that screening patients for pancreatic cancer based solely on elevation in HbA1c level is unlikely to represent an effective strategy. Future efforts to identify a high-risk population based on changes in glycemic parameters should account for racial/ethnic differences.

Risk Factors and Complications Following Arthroscopic Tenotomy of the Long Head of the Biceps Tendon.

BACKGROUND: Controversy exits regarding performing a tenotomy versus a tenodesis of the long head of the biceps tendon (LHBT). PURPOSE: To evaluate the complications after arthroscopic tenotomy of the LHBT and characterize the incidence of cosmetic deformity, cramping, subjective weakness, and continued anterior shoulder pain (ASP). Additionally, to identify patient-related factors that may predispose a patient to these complications. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Records of patients who underwent an arthroscopic LHBT tenotomy at an integrated health care system under the care of 55 surgeons were retrospectively reviewed. Exclusion criteria included LHBT tenodesis, arthroplasty, neoplastic, or fracture surgery; age younger than 18 years; incomplete documentation of physical examination; or incomplete operative reports. Characteristic data, concomitant procedures, LHBT morphology, and postoperative complications were recorded. Patients with and without postoperative complications-including cosmetic deformity, subjective weakness, continued ASP, and cramping-were analyzed by age, sex, dominant arm, body mass index (BMI), smoking status, workers' compensation status, and intraoperative LHBT morphology to identify risk factors for developing these postoperative complications. RESULTS: A total of 192 patients who underwent LHBT tenotomy were included in the final analysis. Tenotomy was performed with concomitant shoulder procedures in all but 1 individual. The mean ± SD patient age was 60.6 ± 9.5 years, and 55% were male. The overall complication rate was 37%. The most common postoperative complications include cosmetic (Popeye) deformity (14.1%), subjective weakness (10.4%), cramping (10.4%), and continued postoperative ASP over the bicipital groove (7.8%). Every 10-year increase in age was associated with 0.52 (95% CI, 0.28-0.94) times the odds of continued ASP and 0.59 (95% CI, 0.36-0.98) times the odds of cramping pain. Male patients had 3.9 (95% CI, 1.4-10.8) times the odds of cosmetic (Popeye) deformity. Patients who had active workers' compensation claims had 12.5 (95% CI, 2.4-63.4) times the odds of having continued postoperative ASP. Tenotomy on the dominant arm, BMI, and active smoking status demonstrated no statistically significant association with postoperative complications. CONCLUSION: Patients experiencing complications after tenotomy were significantly younger and more likely to be male and to have a workers' compensation injury. LHBT tenotomy may best be indicated for elderly patients, female patients, and those without active workers' compensation claims.

Distributions of hypothalamic neuron populations coexpressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse.

The hypothalamus contains catecholaminergic neurons marked by the expression of tyrosine hydroxylase (TH). As multiple chemical messengers coexist in each neuron, we determined if hypothalamic TH-immunoreactive (ir) neurons express vesicular glutamate or GABA transporters. We used Cre/loxP recombination to express enhanced GFP (EGFP) in neurons expressing the vesicular glutamate (vGLUT2) or GABA transporter (vGAT), then determined whether TH-ir neurons colocalized with native EGFPVglut2 - or EGFPVgat -fluorescence, respectively. EGFPVglut2 neurons were not TH-ir. However, discrete TH-ir signals colocalized with EGFPVgat neurons, which we validated by in situ hybridization for Vgat mRNA. To contextualize the observed pattern of colocalization between TH-ir and EGFPVgat , we first performed Nissl-based parcellation and plane-of-section analysis, and then mapped the distribution of TH-ir EGFPVgat neurons onto atlas templates from the Allen Reference Atlas (ARA) for the mouse brain. TH-ir EGFPVgat neurons were distributed throughout the rostrocaudal extent of the hypothalamus. Within the ARA ontology of gray matter regions, TH-ir neurons localized primarily to the periventricular hypothalamic zone, periventricular hypothalamic region, and lateral hypothalamic zone. There was a strong presence of EGFPVgat fluorescence in TH-ir neurons across all brain regions, but the most striking colocalization was found in a circumscribed portion of the zona incerta (ZI)-a region assigned to the hypothalamus in the ARA-where every TH-ir neuron expressed EGFPVgat . Neurochemical characterization of these ZI neurons revealed that they display immunoreactivity for dopamine but not dopamine ß-hydroxylase. Collectively, these findings indicate the existence of a novel mouse hypothalamic population that may signal through the release of GABA and/or dopamine.

Factors Associated With Opioid Use in Patients Hospitalized for Acute Pancreatitis.

Importance: Limited guidance exists regarding the optimal approach to management of pain in acute pancreatitis (AP). Objectives: To investigate sources of variability in opioid use for treatment of acute pain in patients hospitalized for AP and to explore a potential association of opioid prescribing patterns with length of stay. Design, Setting, and Participants: This retrospective cohort study included 4307 patients 18 years and older hospitalized for AP in a community-based integrated health care system, from January 1, 2008, to June 30, 2015. Analysis began in November 2017. Exposures: Opioid use was quantified by morphine equivalent dose (MED). Main Outcomes and Measures: Three analyses were performed: (1) factors associated with increased opioid administration during the initial 12 hours of hospitalization (baseline), (2) association of baseline opioid use with length of stay, and (3) frequency of opioid use 90 days after hospital discharge (persistent use). Results: The cohort included 4307 patients (median [interquartile range] age, 57.4 [44.0-70.2] years; 2241 women [52.0%]) with AP. At baseline, 3443 patients (79.9%) received opioids, and 388 patients (9.6%) had persistent opioid use after discharge. After adjusting for pain and other clinical factors, women received less MED than men (adjusted event ratio, 0.83; 95% CI, 0.79-0.86; P < .001). Hispanic and Asian patients received less MED than non-Hispanic white patients (adjusted event ratio, 0.85; 95% CI, 0.81-0.90; P < .001; and adjusted event ratio, 0.79; 95% CI, 0.72-0.86; P < .001, respectively). Alcohol-related AP etiology was associated with increased MED vs gallstone disorders (adjusted event ratio, 1.11; 95% CI, 1.05-1.18; P < .001). Two of 13 hospitals administered significantly less opioids compared with the others. Median (interquartile range) length of stay was independently associated with MED at baseline, with 3.0 (2.1-4.5) days among patients not receiving opioids vs 5.0 (3.2-8.7) days among patients in the highest quintile of MED (P < .001). Conclusions and Relevance: In addition to pain and disease severity, opioid use varied by etiology of AP, sex, race/ethnicity, and institution of treatment. Increased opioid use at baseline was associated with longer hospitalization. These findings suggest opportunities for improved approaches to pain control for patients with AP.

Effect of a region-wide incorporation of an algorithm based on the 2012 international consensus guideline on the practice pattern for the management of pancreatic cystic neoplasms in an integrated health system.

AIM: To examine the practice pattern in Kaiser Permanente Southern California (KPSC), i.e., gastroenterology (GI)/surgery referrals and endoscopic ultrasound (EUS), for pancreatic cystic neoplasms (PCNs) after the region-wide dissemination of the PCN management algorithm. METHODS: Retrospective review was performed; patients with PCN diagnosis given between April 2012 and April 2015 (18 mo before and after the publication of the algorithm) in KPSC (integrated health system with 15 hospitals and 202 medical offices in Southern California) were identified. RESULTS: 2558 (1157 pre- and 1401 post-algorithm) received a new diagnosis of PCN in the study period. There was no difference in the mean cyst size (pre- 19.1 mm vs post- 18.5 mm, P = 0.119). A smaller percentage of PCNs resulted in EUS after the implementation of the algorithm (pre- 45.5% vs post- 34.8%, P < 0.001). A smaller proportion of patients were referred for GI (pre- 65.2% vs post- 53.3%, P < 0.001) and surgery consultations (pre- 24.8% vs post- 16%, P < 0.001) for PCN after the implementation. There was no significant change in operations for PCNs. Cost of diagnostic care was reduced after the implementation by 24%, 18%, and 36% for EUS, GI, and surgery consultations, respectively, with total cost saving of 24%. CONCLUSION: In the current healthcare climate, there is increased need to optimize resource utilization. Dissemination of an algorithm for PCN management in an integrated health system resulted in fewer EUS and GI/surgery referrals, likely by aiding the physicians ordering imaging studies in the decision making for the management of PCNs. This translated to cost saving of 24%, 18%, and 36% for EUS, GI, and surgical consultations, respectively, with total diagnostic cost saving of 24%.