Eosinophil Specialization Is Regulated by Exposure to the Esophageal Epithelial Microenvironment.

Distinct subsets of eosinophils are reported in inflammatory and healthy tissues, yet the functions of uniquely specialized eosinophils and the signals that elicit them, particularly in eosinophilic esophagitis (EoE), are not well understood. Herein, we report an ex-vivo system wherein freshly isolated human eosinophils were cocultured with esophageal epithelial cells and disease-relevant pro-inflammatory (IL-13) or pro-fibrotic (TGF-ß) cytokines. Compared with untreated cocultures, IL-13 increased expression of CD69 on eosinophils, whereas TGF-ß increased expression of CD81, CD62L, and CD25. Eosinophils from IL-13-treated cocultures demonstrated increased secretion of GRO-α, IL-8, and M-CSF and also generated increased extracellular peroxidase activity following activation. Eosinophils from TGF-ß-treated cocultures secreted increased IL-6 and exhibited increased chemotactic response to CCL11 compared with eosinophils from untreated or IL-13-treated coculture conditions. When eosinophils from TGF-ß-treated cocultures were cultured with fibroblasts, they upregulated SERPINE1 expression and fibronectin secretion by fibroblasts compared with eosinophils that were cultured with GM-CSF, alone. Translational studies revealed that CD62L was heterogeneously expressed by eosinophils in patient biopsies. Our results demonstrate that disease-relevant pro-inflammatory and pro-fibrotic signals present in the esophagus of EoE patients cause distinct profiles of eosinophil activation and gene expression.

Asynchronous Versus Synchronous Screening for Depression and Suicidality in a Primary Health Care System: Quality Improvement Study.

Background: Despite being a debilitating, costly, and potentially life-threatening condition, depression is often underdiagnosed and undertreated. Previsit Patient Health Questionnaire-9 (PHQ-9) may help primary care health systems identify symptoms of severe depression and prevent suicide through early intervention. Little is known about the impact of previsit web-based PHQ-9 on patient care and safety. Objective: We aimed to investigate differences among patient characteristics and provider clinical responses for patients who complete a web-based (asynchronous) versus in-clinic (synchronous) PHQ-9. Methods: This quality improvement study was conducted at 33 clinic sites across 2 health systems in Northern California from November 1, 2020, to May 31, 2021, and evaluated 1683 (0.9% of total PHQs completed) records of patients endorsing thoughts that they would be better off dead or of self-harm (question 9 in the PHQ-9) following the implementation of a depression screening program that included automated electronic previsit PHQ-9 distribution. Patient demographics and providers' clinical response (suicide risk assessment, triage nurse connection, medication management, electronic consultation with psychiatrist, and referral to social worker or psychiatrist) were compared for patients with asynchronous versus synchronous PHQ-9 completion. Results: Of the 1683 patients (female: n=1071, 63.7%; non-Hispanic: n=1293, 76.8%; White: n=831, 49.4%), Hispanic and Latino patients were 40% less likely to complete a PHQ-9 asynchronously (odds ratio [OR] 0.6, 95% CI 0.45-0.8; P<.001). Patients with Medicare insurance were 36% (OR 0.64, 95% CI 0.51-0.79) less likely to complete a PHQ-9 asynchronously than patients with private insurance. Those with moderate to severe depression were 1.61 times more likely (95% CI 1.21-2.15; P=.001) to complete a PHQ-9 asynchronously than those with no or mild symptoms. Patients who completed a PHQ-9 asynchronously were twice as likely to complete a Columbia-Suicide Severity Rating Scale (OR 2.41, 95% CI 1.89-3.06; P<.001) and 77% less likely to receive a referral to psychiatry (OR 0.23, 95% CI 0.16-0.34; P<.001). Those who endorsed question 9 "more than half the days" (OR 1.62, 95% CI 1.06-2.48) and "nearly every day" (OR 2.38, 95% CI 1.38-4.12) were more likely to receive a referral to psychiatry than those who endorsed question 9 "several days" (P=.002). Conclusions: Shifting depression screening from in-clinic to previsit led to a dramatic increase in PHQ-9 completion without sacrificing patient safety. Asynchronous PHQ-9 can decrease workload on frontline clinical team members, increase patient self-reporting, and elicit more intentional clinical responses from providers. Observed disparities will inform future improvement efforts.

Transhumeral prosthesis use affects upper body kinematics and kinetics.

BACKGROUND: Transhumeral (TH) limb loss leads to loss of body mass and reduced shoulder range of motion. Despite most owning a prosthesis, prosthesis abandonment is common. The consequence of TH limb loss and prosthesis use and disuse during gait may be compensation in the upper body, contributing to back pain or injury. Understanding the impact of not wearing a TH prosthesis on upper body asymmetries and spatial-temporal aspects of gait will inform how TH prosthesis use and disuse affects the body. RESEARCH QUESTION: Does TH limb loss alter upper body asymmetries and spatial-temporal parameters during gait when wearing and not wearing a prosthesis compared to able-bodied controls? METHODS: Eight male TH limb loss participants and eight male control participants completed three gait trials at self-selected speeds. The TH limb loss group performed trials with and without their prosthesis. Arm swing, trunk angular displacement, trunk-pelvis moment, and spatial-temporal aspects were compared using non-parametric statistical analyses. RESULTS: Both TH walking conditions showed greater arm swing in the intact limb compared to the residual (p≤0.001), resulting in increased asymmetry compared to the control group (p≤0.001). Without the prosthesis, there was less trunk flexion and lateral flexion compared to the control group (p≤0.001). Maximum moments between the trunk and pelvis were higher in the TH group than the control group (p≤0.05). Spatial-temporal parameters of gait did not differ between the control group and either TH limb loss condition. SIGNIFICANCE: Prosthesis use affects upper body kinematics and kinetics, but does not significantly impact spatial-temporal aspects of gait, suggesting these are compensatory actions. Wearing a prosthesis helps achieve more normative upper body kinematics and kinetics than not wearing a prosthesis, which may help limit back pain. These findings emphasize the importance of encouraging at least passive use of prostheses for individuals with TH limb loss.

The effect of amplitude normalization technique, walking speed, and reporting metric on whole-body angular momentum and its interpretation during normal gait.

Whole-body angular momentum (WBAM) represents the cancellations of angular momenta that are produced during a reciprocal gait pattern. WBAM is sensitive to small changes and is used to compare dynamic gait patterns under different walking conditions. Study designs and the normalization techniques used to define WBAM vary and make comparisons between studies difficult. To address this problem, WBAM about each anatomical axis of rotation from a healthy control population during normal gait were investigated within four metrics: 1) range of WBAM, 2) integrated WBAM, 3) statistical parametric mapping (SPM), and 4) principal component analysis (PCA). These data were studied as a function of walking speed and normalization. Normalization techniques included: 1) no normalization, 2) normalization by height, body mass and walking speed, and 3) normalization by height, body mass and a scalar number, gravity×height, that is independent of walking velocity. Significant results were obtained as a function of walking speed regardless of normalization technique. However, the interpretation of significance within each metric was dependent on the normalization technique. Method 3 was the most robust technique as the differences were not altered from the expected relationships within the raw data. Method 2 actually inverted the expected relationship in WBAM amplitude as a function of walking speed, which skewed the results and their interpretation. Overall, SPM and PCA statistical methods provided better insights into differences that may be important. However, depending on the normalization technique used, caution is advised when interpreting significant findings when comparing participants with disparate walking speeds.

Pathophysiology of Non-Esophageal Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorder (EGID) is an umbrella term encompassing a group of chronic, immune-mediated disorders characterized by eosinophil-rich inflammation affecting one or more segments of the gastrointestinal tract. A recent consensus in nomenclature and emerging data made possible through multi-center consortia are beginning to unravel the molecular and cellular underpinnings of EGIDs below the esophagus. These emerging findings are revealing both overarching commonalities related to a food allergen-driven, chronic, Th2-mediated immune response as well as location-specific nuances in the pathophysiology of the collective EGIDs. Altogether, these advances offer promise for improved diagnoses and more efficacious interventional strategies.

Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial.

BACKGROUND: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. METHODS: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. RESULTS: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. CONCLUSION: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05412004.

Extended physiological proprioception is affected by transhumeral Socket-Suspended prosthesis use.

The objective of this study was to define targeted reaching performance without visual information for transhumeral (TH) prosthesis users, establishing baseline information about extended physiological proprioception (EPP) in this population. Subjects completed a seated proprioceptive targeting task under simultaneous motion capture, using their prosthesis and intact limb. Eight male subjects, median age of 58 years (range 29-77 years), were selected from an ongoing screening study to participate. Five subjects had a left-side TH amputation, and three a right-side TH amputation. Median time since amputation was 9 years (range 3-54 years). Four subjects used a body-powered prosthetic hook, three a myoelectric hand, and one a myoelectric hook. The outcome measures were precision and accuracy, motion of the targeting hand, and joint angular displacement. Subjects demonstrated better precision when targeting with their intact limb compared to targeting with their prosthesis, 1.9 cm2 (0.8-3.0) v. 7.1 cm2 (1.3-12.8), respectively, p = 0.008. Subjects achieved a more direct reach path ratio when targeting with the intact limb compared to with the prosthesis, 1.2 (1.1-1.3) v. 1.3 (1.3-1.4), respectively, p = 0.039 The acceleration, deceleration, and corrective phase durations were consistent between conditions. Trunk angular displacement increased in flexion, lateral flexion, and axial rotation while shoulder flexion decreased when subjects targeted with their prosthesis compared to the intact limb. The differences in targeting precision, reach patio ratio, and joint angular displacements while completing the targeting task indicate diminished EPP. These findings establish baseline information about EPP in TH prosthesis users for comparison as novel prosthesis suspension systems become more available to be tested.

Malaria risk stratification in Lao PDR guides program planning in an elimination setting.

Malaria in Lao People's Democratic Republic (Lao PDR) has declined rapidly over the last two decades, from 279,903 to 3926 (99%) cases between 2001 and 2021. Elimination of human malaria is an achievable goal and limited resources need to be targeted at remaining hotspots of transmission. In 2022, the Center of Malariology, Parasitology and Entomology (CMPE) conducted an epidemiological stratification exercise to assign districts and health facility catchment areas (HFCAs) in Lao PDR based on malaria risk. The stratification used reported malaria case numbers from 2019 to 2021, risk maps derived from predictive modelling, and feedback from malaria staff nationwide. Of 148 districts, 14 were deemed as burden reduction (high risk) districts and the remaining 134 as elimination (low risk) districts. Out of 1235 HFCAs, 88 (7%) were classified as highest risk, an improvement from 187 (15%) in the last stratification in 2019. Using the HFCA-level stratification, the updated stratification resulted in the at-risk population (total population in Strata 2, 3 and 4 HFCAs) declining from 3,210,191 to 2,366,068, a 26% decrease. CMPE are using the stratification results to strengthen targeting of resources. Updating national stratifications is a necessary exercise to assess progress in malaria control, reassign interventions to the highest risk populations in the country and ensure greatest impact of limited resources.

Prevalence of maternal depression and anxiety symptoms and associations with child mental health outcomes in rural Nepal.

OBJECTIVES: This study describes the prevalence, associated factors and child mental health outcomes related to symptoms of maternal depression and anxiety within 5 years after childbirth in a rural district in Nepal. This association is not well-understood in rural, community-based settings in low- and middle-income countries (LMIC). METHODS: A sample of 347 women with children under 5 years was recruited in September 2019 for a cross-sectional study in the rural Saptari district in Nepal. Multivariable logistic regression was used to investigate the association between maternal depressive or anxiety symptoms and children's experience and impact of emotional and behavioural difficulties. RESULTS: In total, 144 women (41.5%) had moderate or severe depression symptoms and 118 (34%) had anxiety symptoms. Mothers with a lower income were more likely to have anxiety symptoms than the highest income group (OR: 1.8, 95% CI: 1.1-3.0). An association existed between maternal depressive symptoms and the impact of emotional or behavioural difficulties in children (OR: 2.44, 95% CI: 1.02-5.84). In contrast, there was no association between maternal anxiety and child outcomes. CONCLUSIONS: Our findings suggest that the prevalence of probable maternal anxiety and depression symptoms was relatively high in this rural, low-resourced and community-based setting in Nepal. Maternal depressive symptoms were associated with the degree of impact on children's mental health post-infancy, emphasising the importance of improving maternal mental health in the early years of a child's life.

Weight management treatment modalities in patients with overweight or obesity: A retrospective cohort study of administrative claims data.

Background: The purpose of this study was to describe demographic and clinical characteristics among patients who have medical encounters for weight management treatments and to investigate the association of those characteristics with treatment modality. Methods: This was a retrospective database study using medical claims, pharmacy claims, and enrollment information from commercial and Medicare Advantage with Part D members in the Optum Research Database from 01/01/2011-2/29/2020. Adult patients with a claim for a weight management treatment from 01/01/2012-2/28/2019 were categorized into cohorts according to the highest intensity intervention received. To examine the association between patient characteristics and treatment modality received, a multinomial logit model was performed. Results: Cohorts by increasing intensity included lifestyle intervention (LSI, n = 67,679), weight reduction pharmacotherapy (WRRx) with an anti-obesity medication (AOM, n = 6,905), weight reduction procedure (WRP, n = 1,172), and weight reduction surgery (WRS, n = 18,036). Approximately 32.1% and 16.6% of patients who received WRS or WRP had an LSI during the 12-month baseline, and only 0.6% and 0.4% had treatment with long-term AOMs. In a multinomial logit model, patients with type 2 diabetes (not including WRRx cohort), respiratory disorders, cardiovascular risk factors, pain disorders, and mental health conditions had increased odds of treatment with higher intensity intervention versus LSI. Patients who were male, received an intervention more recently (2016-2019), or had a Charlson comorbidity score of 1 (compared to 0) had decreased odds of treatment with higher intensity interventions. Conclusion: In this study, age, sex, body mass index, obesity-related complications, and Charlson comorbidity score appeared to influence the type of weight management treatment modality received. This study improves understanding of weight management treatment utilization and identifies gaps and opportunities to improve obesity care with the appropriate use of different treatment modalities.

Baseline soil-transmitted helminth and schistosome infection in the Geshiyaro project, Ethiopia: A unique transmission interruption project using biometric fingerprinting for longitudinal individual analysis.

BACKGROUND: The Geshiyaro project aims to assess the feasibility of interrupting transmission of soil-transmitted helminths (STH) and schistosome (SCH) infection in the Wolaita zone of southern Ethiopia through high coverage community-wide mass drug administration (MDA), in combination with improved water, sanitation, and hygiene services and behaviour change communication delivered through the existing health care infrastructure. To accurately measure treatment coverage a population census was conducted enrolling individuals with biometric fingerprinting and barcoded ID cards. This paper details the baseline census and parasitology surveys conducted before the start of any interventions. METHODS: The census was conducted in five of the 15 Wolaita districts between October 2018 and December 2019, enrolling all consenting participants from every household. Simultaneously, a cross-sectional parasitology survey was conducted in 130 out of 361 randomly selected communities from all 15 districts, with 100 individuals across all age groups (infant to adult) per community providing stool and urine for analysis by duplicate Kato-Katz and a point-of-care circulating cathodic antigen (POC-CCA) to test for Schistosoma mansoni and STH, and microhaematuria and urine filtration for Schistosoma haematobium. Of the 130 communities, 30 were randomly selected for annual, longitudinal parasitological monitoring, with 150 randomly selected individuals from infant to adult providing two days of stool and urine samples for analysis by the same diagnostic tests per community. RESULTS: In total 97,919 households participated in the baseline census enrolling 466,071 individuals, with parasitological data obtained from 10,785 people. At baseline, 15.5% were infected with at least one STH species, with Ascaris lumbricoides (9.5%), followed by hookworm (7.2%) and Trichuris trichiura (1.8%). Substantial heterogeneity in STH prevalence was observed between communities ranging from 0% to 61% where most infections were low intensity. Schistosoma mansoni infection was the dominant schistosome infection (0.85% by Kato-Katz and 13.3% by POC-CCA trace negative and 21.5% trace positive), with few Schistosoma haematobium infections identified (2.77% haematuria positive and 0.13% positive by urine filtration). CONCLUSIONS: While the national control program in Ethiopia has made good progress in reducing prevalence of STH and SCH in Wolaita since it was launched in 2015, there remain areas of persistent infection suggesting the existence of environmental or behavioural risk factors that contribute to ongoing transmission. This project aims to identify the most efficient intervention strategies to reduce community burden and reach interruption of transmission.

The Association Between Depression and Substance Use Among Primary Care Patients With Comorbid Medical and Behavioral Health Conditions.

INTRODUCTION: The scope of primary care increasingly encompasses patient behavioral health problems, manifest typically through depression screening and treatment. Although substance use is highly comorbid with depression, it is not commonly identified and addressed in the primary care context. This study aimed to examine the association between the likelihood of substance use disorder and increased depression severity, both cross-sectionally and longitudinally, among a sample of 2409 patients from 41 geographically dispersed and diverse primary care clinics across the US. METHODS: This is secondary analysis of data obtained from a multi-site parent study of integrated behavioral health in primary care, among patients with both chronic medical and behavioral health conditions. Patient reported outcome surveys were gathered from patients at 3 time points. The primary care practices were blind to which of their patients completed surveys. Included were standardized measures of depression severity (Patient Health Questionnaire-9) [PHQ-9] and substance use disorder likelihood (Global Appraisal of Individual Needs-Short Screener [GSS]). RESULTS: Four percent of the study population screened positive for substance use disorder. PHQ-9 scores indicated depression among 43% of all patients. There was a significant association between the likelihood of substance use disorder and depression initially, at a 9-month follow-up, and over time. These associations remained significant after adjusting for age, gender, race, ethnicity, education, income, and other patient and contextual characteristics. CONCLUSIONS: The findings suggest that substance use disorder is associated with depression severity cross-sectionally and over time. Primary care clinics and health systems might consider implementing substance use screening in addition to the more common screening strategies for depression. Especially for patients with severe depression or those who do not respond to frontline depression treatments, the undermining presence of a substance use disorder should be explored.

Real-world primary nonadherence to antiobesity medications.

BACKGROUND: Primary nonadherence (PNA), when a medication is newly prescribed but not filled, has been identified as a major research gap potentially impacting the optimal treatment of patients with overweight and obesity who are newly prescribed antiobesity medications (AOMs). OBJECTIVES: To assess PNA among patients with newly prescribed AOMs and to examine factors associated with PNA to AOMs. METHODS: This was a retrospective study that used the Optum Integrated Clinical plus Claims database to identify individuals who had at least 1 prescription order for an AOM the US Food and Drug Administration approved for long-term use. Individuals with prescription orders between January 1, 2012, and February 28, 2019, were identified, and patient demographics, clinical characteristics, medication prescribed, baseline health care utilization, and obesity-related complications were described by PNA status. PNA was defined as no pharmacy claim for the AOM within 60 days of the date of the new prescription order as identified in electronic health record data. A multivariable logistic regression model was used to examine factors associated with PNA. RESULTS: The study sample included a total of 1,563 patients. The mean body mass index was 38.4 kg/m2; 10.7% were prescribed liraglutide 3.0 mg, 26.0% were prescribed lorcaserin, 36.3% of patients were prescribed naltrexone-bupropion, 5.4% were prescribed orlistat, and 21.6% were prescribed phentermine-topiramate. Most patients (91.1%) exhibited PNA, with only 8.9% filling their newly prescribed AOM within 60 days. Both the adherent and nonadherent groups were predominately female sex, White, and covered by commercial insurance. The mean age was similar between the 2 groups. Most obesity-related complications were less prevalent in the adherent group, although the Charlson comorbidity index score was similar between the 2 groups. After adjustment for patient demographics and clinical characteristics, there was not a statistically significant association between the specific AOM and PNA (P = 0.299). Patients with depression or living in the Midwest or South regions were at significantly increased risk of PNA. CONCLUSIONS: The rate of PNA to AOMs was very high, suggesting barriers in effective medical management of patients with overweight and obesity. Future research is warranted to understand reasons for PNA to AOMs and how to address these barriers. DISCLOSURES: Dr Kan, Dr Bae, Dr Dunn, and Dr Ahmad are employees of Eli Lilly and Company. Ms Buysman and Dr Gronroos are employees of Optum. Dr Swindle was an employee of Optum at the time the study was conducted and is currently employed at Evidera. Dr Bengtson is employed at Boehringer Ingelheim Pharmaceuticals, Inc. (Boehringer Ingelheim has no connection to this study), and during the conduct of this study was employed at Optum.

Dorsal striatal response to taste is modified by obesity and insulin resistance.

OBJECTIVE: In preclinical models, insulin resistance in the dorsal striatum (DS) contributes to overeating. Although human studies support the concept of central insulin resistance, they have not investigated its effect on consummatory reward-induced brain activity. METHODS: Taste-induced activation was assessed in the caudate and putamen of the DS with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Three phenotypically distinct groups were studied: metabolically healthy lean, metabolically healthy obesity, and metabolically unhealthy obesity (MUO; presumed to have central insulin resistance). Participants with MUO also completed a weight loss intervention followed by a second functional magnetic resonance imaging session. RESULTS: The three groups were significantly different at baseline consistent with the design. The metabolically healthy lean group had a primarily positive BOLD response, the MUO group had a primarily negative BOLD response, and the metabolically healthy obesity group had a response in between the two other groups. Food craving was predicted by taste-induced activation. After weight loss in the MUO group, taste-induced activation increased in the DS. CONCLUSIONS: These data support the hypothesis that insulin resistance and obesity contribute to aberrant responses to taste in the DS, which is only partially attenuated by weight loss. Aberrant responses to food exposure may be a barrier to weight loss.

Weight-dependent and weight-independent effects of dulaglutide on blood pressure in patients with type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D. METHODS: Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo. RESULTS: Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was - 2.6 mmHg (95% CI - 3.8, - 1.5; p < 0.001) and was attributed to both a weight-dependent effect (- 0.9 mmHg; 95% CI: - 1.4, - 0.5; p < 0.001) and a weight-independent effect (- 1.5 mmHg; 95% CI: - 2.6, - 0.3; p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (- 2.5 mmHg; 95% CI: - 3.5, - 1.5; p < 0.001) was 14% weight-dependent and 86% weight-independent. For DBP there was limited impact of dulaglutide treatment, with only a small weight-mediated effect. Dulaglutide 4.5 mg demonstrated an effect on reduction in SBP and pulse pressure beyond that of dulaglutide 1.5 mg which was primarily weight mediated. CONCLUSIONS: Dulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension. Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102.

Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes.

OBJECTIVE: To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide. RESEARCH DESIGN AND METHODS: In a secondary analysis of a randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28. RESULTS: Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide. CONCLUSIONS: Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.

Stimulant use among patients in opioid treatment settings: Provider perspectives.

INTRODUCTION: Methadone maintenance therapy (MMT) has been a pillar of opioid addiction treatment. Opioid treatment programs (OTPs) have been faced with an escalating threat of stimulant use and related overdose deaths among patients. We know little about how providers currently address stimulant use while maintaining treatment for opioid use disorder. METHODS: We conducted 5 focus groups with 36 providers (n = 11 prescribers; 25 behavioral health staff), and collected an additional 46 surveys (n = 7 prescribers; 12 administrators; 27 behavioral health staff). Questions focused on perceptions of patient stimulant use and interventions. We applied inductive analysis to identify themes relevant to identification of stimulant use, use trends, intervention approaches, and perceived needs to improve care. RESULTS: Providers indicated a trend of rising stimulant use among patients, especially those experiencing homelessness or comorbid health conditions. They reported a range of approaches to patient screening and intervention, including medication and harm reduction, improving treatment engagement, increasing level of care, and providing incentives. Providers expressed less agreement as to which of these interventions were effective, and though providers saw stimulant use as a common and severe problem, they reported little problem recognition and interest in treatment from their patients. A particular concern of providers was the prevalence and danger of synthetic opioids, such as fentanyl. They sought more research and resources to identify effective interventions and medications to address these issues. Also notable was an interest in contingency management (CM) and use of reinforcements/rewards to encourage stimulant use reduction. CONCLUSION: Providers face challenges in treating patients who use both opioids and stimulants. Although methadone is available to treat opioid use, no such "silver bullet" exists for stimulant use disorder. The rise in stimulant and synthetic opioid (e.g., fentanyl) combination products is presenting an extraordinary challenge for providers whose patients are at unprecedented risk for overdose. Providing OTPs with more resources to address polysubstance use is critical. Existing research indicates strong support for CM in OTPs, but providers reported regulatory and financial barriers to implementation. Further research should develop effective interventions that are accessible to providers in OTPs.

Evaluation of genome skimming to detect and characterise human and livestock helminths.

The identification of gastrointestinal helminth infections of humans and livestock almost exclusively relies on the detection of eggs or larvae in faeces, followed by manual counting and morphological characterisation to differentiate species using microscopy-based techniques. However, molecular approaches based on the detection and quantification of parasite DNA are becoming more prevalent, increasing the sensitivity, specificity and throughput of diagnostic assays. High-throughput sequencing, from single PCR targets through to the analysis of whole genomes, offers significant promise towards providing information-rich data that may add value beyond traditional and conventional molecular approaches; however, thus far, its utility has not been fully explored to detect helminths in faecal samples. In this study, low-depth whole genome sequencing, i.e. genome skimming, has been applied to detect and characterise helminth diversity in a set of helminth-infected human and livestock faecal material. The strengths and limitations of this approach are evaluated using three methods to characterise and differentiate metagenomic sequencing data based on (i) mapping to whole mitochondrial genomes, (ii) whole genome assemblies, and (iii) a comprehensive internal transcribed spacer 2 (ITS2) database, together with validation using quantitative PCR (qPCR). Our analyses suggest that genome skimming can successfully identify most single and multi-species infections reported by qPCR and can provide sufficient coverage within some samples to resolve consensus mitochondrial genomes, thus facilitating phylogenetic analyses of selected genera, e.g. Ascaris spp. Key to this approach is both the availability and integrity of helminth reference genomes, some of which are currently contaminated with bacterial and host sequences. The success of genome skimming of faecal DNA is dependent on the availability of vouchered sequences of helminths spanning both taxonomic and geographic diversity, together with methods to detect or amplify minute quantities of parasite nucleic acids in mixed samples.

Evaluating the Implementation of a Model of Integrated Behavioral Health in Primary Care: Perceptions of the Healthcare Team.

OBJECTIVES: This study aims to compare primary care providers and medical assistants in degrees of comfort, confidence, and consistency when addressing behavioral health concerns with patients before and after the implementation of a model of integrated behavioral health in primary care (IBHPC), and evaluate whether these perceptions differ based on increased access to behavioral health clinicians. METHODS: This longitudinal study was conducted at 2 primary care clinics in Northern California while implementing an IBHPC model. The Integrated Behavioral Health Staff Perceptions Survey was administered to assess the comfort, confidence, and consistency of behavioral health practices. Confidential online surveys were distributed to primary care faculty and staff members before and post-implementation. Responses from providers and medical assistants were compared between pre- and post-implementation with linear regression analyses. The relationships between accessibility to behavioral health clinicians and a change in comfort, confidence, and consistency of behavioral health practices were explored using a linear mixed-effects model. RESULTS: A total of 35 providers and medical assistants completed the survey both before and post-implementation of IBHPC. Over time, there were increasingly positive perceptions about the consistency of behavioral health screening (P = .03) and overall confidence in addressing behavioral health concerns (P = .005). Comfort in addressing behavioral health concerns did not significantly change for either providers or staff over time. Medical assistants were initially more confident and comfortable addressing behavioral health concerns than providers, but providers' attitudes increased post-IBHPC implementation. Improved access to behavioral health clinicians was associated with greater consistency of screening and referral to specialty mental health care (P < .001). CONCLUSION: The present study is the first to explore differences in provider and medical assistant perceptions during the course of an IBHPC implementation. Findings underscore the importance of integrating medical assistants, along with providers, into all phases of the implementation process.

Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients.

OBJECTIVE: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. METHODS: SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA-seq). RESULTS: We used an unbiased approach to cluster patients into 3 groups (groups A-C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up-regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. CONCLUSION: We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.