Lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) lncRNA differentially regulates gene and protein expression, signaling and morphology of human ocular cells.

Pseudoexfoliation glaucoma (PEXG) is characterized by dysregulated extracellular matrix (ECM) homeostasis that disrupts conventional outflow function and increases intraocular pressure (IOP). Prolonged IOP elevation results in optic nerve head damage and vision loss. Uniquely, PEXG is a form of open angle glaucoma that has variable penetrance, is difficult to treat and does not respond well to common IOP-lowering pharmaceuticals. Therefore, understanding modulators of disease severity will aid in targeted therapies for PEXG. Genome-wide association studies have identified polymorphisms in the long non-coding RNA lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) as a risk factor for PEXG. Risk alleles, oxidative stress and mechanical stretch all alter LOXL1-AS1 expression. As a long non-coding RNA, LOXL1-AS1 binds hnRNPL and regulates global gene expression. In this study, we focus on the role of LOXL1-AS1 in the ocular cells (trabecular meshwork and Schlemm's canal) that regulate IOP. We show that selective knockdown of LOXL1-AS1 leads to cell-type-specific changes in gene expression, ECM homeostasis, signaling and morphology. These results implicate LOXL1-AS1 as a modulator of cellular homeostasis, altering cell contractility and ECM turnover, both of which are well-known contributors to PEXG. These findings support LOXL1-AS1 as a key target for modifying the disease.

ICAT: a novel algorithm to robustly identify cell states following perturbations in single-cell transcriptomes.

MOTIVATION: The detection of distinct cellular identities is central to the analysis of single-cell RNA sequencing (scRNA-seq) experiments. However, in perturbation experiments, current methods typically fail to correctly match cell states between conditions or erroneously remove population substructure. Here, we present the novel, unsupervised algorithm Identify Cell states Across Treatments (ICAT) that employs self-supervised feature weighting and control-guided clustering to accurately resolve cell states across heterogeneous conditions. RESULTS: Using simulated and real datasets, we show ICAT is superior in identifying and resolving cell states compared with current integration workflows. While requiring no a priori knowledge of extant cell states or discriminatory marker genes, ICAT is robust to low signal strength, high perturbation severity, and disparate cell type proportions. We empirically validate ICAT in a developmental model and find that only ICAT identifies a perturbation-unique cellular response. Taken together, our results demonstrate that ICAT offers a significant improvement in defining cellular responses to perturbation in scRNA-seq data. AVAILABILITY AND IMPLEMENTATION: https://github.com/BradhamLab/icat.

COSMIC-dFBA: A novel multi-scale hybrid framework for bioprocess modeling.

Metabolism governs cell performance in biomanufacturing, as it fuels growth and productivity. However, even in well-controlled culture systems, metabolism is dynamic, with shifting objectives and resources, thus limiting the predictive capability of mechanistic models for process design and optimization. Here, we present Cellular Objectives and State Modulation In bioreaCtors (COSMIC)-dFBA, a hybrid multi-scale modeling paradigm that accurately predicts cell density, antibody titer, and bioreactor metabolite concentration profiles. Using machine-learning, COSMIC-dFBA decomposes the instantaneous metabolite uptake and secretion rates in a bioreactor into weighted contributions from each cell state (growth or antibody-producing state) and integrates these with a genome-scale metabolic model. A major strength of COSMIC-dFBA is that it can be parameterized with only metabolite concentrations from spent media, although constraining the metabolic model with other omics data can further improve its capabilities. Using COSMIC-dFBA, we can predict the final cell density and antibody titer to within 10% of the measured data, and compared to a standard dFBA model, we found the framework showed a 90% and 72% improvement in cell density and antibody titer prediction, respectively. Thus, we demonstrate our hybrid modeling framework effectively captures cellular metabolism and expands the applicability of dFBA to model the dynamic conditions in a bioreactor.

Outcomes and predictors of amputation-free survival in patients undergoing below-knee popliteal-distal bypass.

OBJECTIVE: The infrageniculate popliteal artery is a potential source for inflow in lower extremity bypass surgery in patients with isolated tibial artery disease. The objective of our study was to assess the short- and long-term outcomes of popliteal-distal bypasses using data from the Vascular Quality Initiative (VQI). METHODS: The VQI registry was queried between 2003 and 2021 for patients undergoing surgical revascularizations with the below-knee popliteal artery serving as inflow. Demographics, comorbidities, intraoperative characteristics, and postoperative complications were analyzed. Kaplan-Meier models were used to estimate amputation-free survival, survival, and freedom from amputation. Cox regression analysis was conducted to determine factors associated with major amputation or death. RESULTS: A total of 1884 procedures were analyzed. The mean age of the included patients was 67.7 years. The most frequently observed preoperative comorbidities included insulin-dependent diabetes (52.3%), coronary disease (32.4%), and end-stage renal disease (14.4%). Of all the patients, 670 (35.6%) had a history of ipsilateral endovascular intervention. The procedures were performed for a variety of indications, including tissue loss (84.3%), rest pain (10.9%), and claudication (4.8%). Intraoperatively, the outflow targets were the dorsalis pedis (31.4%), the posterior tibial (24.4%), and the anterior tibial arteries (15.6%). Vein conduit was used in 92.1% of cases. The rate of perioperative myocardial infarction (MI) was 2.4%, and the 30-day mortality was 1.9%. The median length of follow up was 371 days. Amputation-free survival was found to be 85.6% (95% confidence interval [CI], 84.0%-87.2%) at 6 months and 78.6% (95% CI, 76.6%-80.4%) at 12 months. Survival was found to be 93.4% (95% CI, 92.2%-94.5%) at 6 months and 88.6% (95% CI, 87.1%-90.0%) at 12 months. Freedom from amputation was found to be 92.0% (95% CI, 90.7%-93.3%) at 6 months and 89.0% (95% CI, 87.3%-90.4%) at 12 months. Cox regression analysis demonstrated that age greater than 65 years, congestive heart failure, coronary artery disease, and end-stage renal disease were associated with a higher risk of major amputation or death (P < .05). CONCLUSIONS: Below-knee popliteal-distal bypass is a safe and effective approach to treat severe tibial vessel occlusive disease in this challenging patient cohort. Patients exhibited low perioperative complication rates and good amputation-free survival at 1 year.

Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis.

Not available.

Total RNA sequencing reveals gene expression and microbial alterations shared by oral pre-malignant lesions and cancer.

Head and neck cancers are a complex malignancy comprising multiple anatomical sites, with cancer of the oral cavity ranking among the deadliest and the most disfiguring cancers globally. Oral cancer (OC) constitutes a subset of head and neck cancer cases, presenting primarily as tobacco- and alcohol-associated oral squamous cell carcinoma (OSCC), with a 5-year survival rate of ~ 65%, partly due to the lack of early detection and effective treatments. OSCC arises from premalignant lesions (PMLs) in the oral cavity through a multi-step series of clinical and histopathological stages, including varying degrees of epithelial dysplasia. To gain insights into the molecular mechanisms associated with the progression of PMLs to OSCC, we profiled the whole transcriptome of 66 human PMLs comprising leukoplakia with dysplasia and hyperkeratosis non-reactive (HkNR) pathologies, alongside healthy controls and OSCC. Our data revealed that PMLs were enriched in gene signatures associated with cellular plasticity, such as partial EMT (p-EMT) phenotypes, and with immune response. Integrated analyses of the host transcriptome and microbiome further highlighted a significant association between differential microbial abundance and PML pathway activity, suggesting a contribution of the oral microbiome toward PML evolution to OSCC. Collectively, this study reveals molecular processes associated with PML progression that may help early diagnosis and disease interception at an early stage.

Polymer Coatings Affect Transport and Remobilization of Colloidal Activated Carbon in Saturated Sand Columns: Implications for In Situ Groundwater Remediation.

Colloidal activated carbon (CAC) is an emerging technology for the in situ remediation of groundwater impacted by per- and polyfluoroalkyl substances (PFAS). In assessing the long-term effectiveness of a CAC barrier, it is crucial to evaluate the potential of emplaced CAC particles to be remobilized and migrate away from the sorptive barrier. We examine the effect of two polymer stabilizers, carboxymethyl cellulose (CMC) and polydiallyldimethylammonium chloride (PolyDM), on CAC deposition and remobilization in saturated sand columns. CMC-modified CAC showed high mobility in a wide ionic strength (IS) range from 0.1 to 100 mM, which is favorable for CAC delivery at a sufficient scale. Interestingly, the mobility of PolyDM-modified CAC was high at low IS (0.1 mM) but greatly reduced at high IS (100 mM). Notably, significant remobilization (release) of deposited CMC-CAC particles occurred upon the introduction of solution with low IS following deposition at high IS. In contrast, PolyDM-CAC did not undergo any remobilization following deposition due to its favorable interactions with the quartz sand. We further elucidated the CAC deposition and remobilization behaviors by analyzing colloid-collector interactions through the application of Derjaguin-Landau-Verwey-Overbeek theory, and the inclusion of a discrete representation of charge heterogeneity on the quartz sand surface. The classical colloid filtration theory was also employed to estimate the travel distance of CAC in saturated columns. Our results underscore the roles of polymer coatings and solution chemistry in CAC transport, providing valuable guidelines for the design of in situ CAC remediation with maximized delivery efficiency and barrier longevity.

Insights into child abuse and neglect: Findings from the Minnesota Longitudinal Study of Risk and Adaptation.

The Minnesota Longitudinal Study of Risk and Adaptation (MLSRA) is a landmark prospective, longitudinal study of human development focused on a sample of mothers experiencing poverty and their firstborn children. Although the MLSRA pioneered a number of important topics in the area of social and emotional development, it began with the more specific goal of examining the antecedents of child maltreatment. From that foundation and for more than 40 years, the study has produced a significant body of research on the origins, sequelae, and measurement of childhood abuse and neglect. The principal objectives of this report are to document the early history of the MLSRA and its contributions to the study of child maltreatment and to review and summarize results from the recently updated childhood abuse and neglect coding of the cohort, with particular emphasis on findings related to adult adjustment. While doing so, we highlight key themes and contributions from Dr Dante Cicchetti's body of research and developmental psychopathology perspective to the MLSRA, a project launched during his tenure as a graduate student at the University of Minnesota.

Inequalities in adiposity trends between 1979 and 1999 in Guatemalan children.

BACKGROUND: Guatemala suffered from civil war and high levels of inequality and childhood stunting in the second half of the 20th century, but little is known about inequalities in secular trends in adiposity. OBJECTIVES: To investigate differences in childhood body mass index (BMI) and skinfold thickness trajectories from 1979 to 1999 between three groups of children: High socioeconomic position (SEP) Ladino, Low SEP Ladino, and Low SEP Indigenous Maya. METHODS: The sample comprised 19 346 children aged 7-17 years with 54 638 observations. The outcomes were height, BMI, triceps skinfold thickness (TST), and subscapular skinfold thickness (SST) Z-scores according to the Centers for Disease Control and Prevention (CDC) references. Sex-specific multilevel models were used to estimate and compare mean trajectories from 1979 to 1999 between the three groups. RESULTS: Mean Z-scores were always highest for High SEP Ladino children and lowest for Low SEP Maya children. Despite their very short stature, the Low SEP groups had SST trajectories that were above the 50th centile. The BMI trajectories were relatively flat and within one major centile band of the CDC median, with differences between the three groups that were small (0.2-0.3 Z-scores) and did not attenuate over time. Conversely, the TST Z-score trajectories demonstrated larger positive secular trends (e.g., from -1.25 in 1979 to -0.06 in 1999 for Low SEP Maya boys), with differences between the three groups that were large (0.5-1.2 Z-scores) and did attenuate over time (in boys). Secular trends and between-group difference in the SST Z-score trajectories were less pronounced, but again we found stronger evidence in boys that the estimated inequalities attenuated over time. CONCLUSIONS: Secular trends and inequalities in skinfolds differ from those for BMI in Guatemalan children. Differences between groups in skinfolds attenuated over time, at least in boys, but whether this is good news is questionable given the very short stature yet relatively large subscapular skinfolds of the Low SEP groups.

Supra-inguinal Inflow for Distal Bypasses Have Acceptable Patency and Limb Salvage Rates.

OBJECTIVE: There is a paucity of data evaluating outcomes of lower extremity bypass (LEB) using supra-inguinal inflow for revascularization of infra-inguinal vessels. The purpose of this study is to report outcomes after LEB originating from aortoiliac arteries to infra-femoral targets. METHODS: The Vascular Quality Initiative database (2003-2020) was queried for patients undergoing LEB from the aortoiliac arteries to the popliteal and tibial arteries. Patients were stratified into three cohorts based on outflow targets (above-knee popliteal, below-knee popliteal and tibial arteries). Perioperative and 1-year outcomes including primary patency, amputation-free survival, and major adverse limb events (MALEs) were compared. A Cox proportional hazards model was used to estimate the independent prognostic factors of outcomes. RESULTS: Of 403 LEBs, 389 (96.5%) originated from the external iliac artery, while the remaining used the aorta or common iliac artery as inflow. In terms of the distal target, the above knee popliteal was used in 116 (28.8%), the below knee popliteal in 151 (27.5%), and tibial vessels in 136 (43.7%) cases. Below-knee popliteal and tibial bypasses, compared to above knee popliteal bypasses, were more commonly performed in patients with chronic limb-threatening ischemia (69.5% and 69.9% vs 48.3%; P < .001). Vein conduit was more often used for tibial bypass than for above- and below-knee popliteal bypasses (46.3% vs 21.9% and 16.3%; P < .001). In the perioperative period, below-knee popliteal and tibial bypass patients had higher reoperation rates (16.9% and 13.2% vs 5.2%; P = .02) and lower primary patency (89.4% and 89% vs 95.7%; P = .04) than above-knee bypass patients. At 1 year, compared with above-knee popliteal bypasses, below-knee and tibial bypasses demonstrated lower primary patency (81.9% vs 56.7% vs 52.4%, p <.001) and freedom from MALE (77.6% vs 70.2% vs 63.1%, p = .04), although amputation free survival was not significantly different (89.7% vs 90.6% vs 83.8%, p = 0.19) .On multivariable analysis, compared with above-knee popliteal bypasses, tibial bypasses were independently associated with increased loss of primary patency (hazard ratio 1.9, 95% confidence interval, 1.03-3.51, p = .04). Sub-analysis of patients with CLTI, demonstrated significantly higher primary patency in the AK popliteal cohort at discharge and one-year, but no difference in amputation free-survival or freedom from MALE between the cohorts at follow-up. CONCLUSIONS: LEB with supra-inguinal inflow appear to have acceptable rates of 1-year patency and limb salvage in patients at high risk of bypass failure. Tibial outflow target was independently associated with worse primary patency but not with MALE or AFS.

Relationships Between Exposure to Gestational Diabetes Treatment and Neonatal Anthropometry: Evidence from the Born in Bradford (BiB) Cohort.

OBJECTIVES: To examine the relationships between gestational diabetes mellitus (GDM) treatment and neonatal anthropometry. METHODS: Covariate-adjusted multivariable linear regression analyses were used in 9907 offspring of the Born in Bradford cohort. GDM treatment type (lifestyle changes advice only, lifestyle changes and insulin or lifestyle changes and metformin) was the exposure, offspring born to mothers without GDM the control, and birth weight, head, mid-arm and abdominal circumference, and subscapular and triceps skinfold thickness the outcomes. RESULTS: Lower birth weight in offspring exposed to insulin (- 117.2 g (95% CI - 173.8, - 60.7)) and metformin (- 200.3 g (- 328.5, - 72.1)) compared to offspring not exposed to GDM was partly attributed to lower gestational age at birth and greater proportion of Pakistani mothers in the treatment groups. Higher subscapular skinfolds in offspring exposed to treatment compared to those not exposed to GDM was partly attributed to higher maternal glucose concentrations at diagnosis. In fully adjusted analyses, offspring exposed to GDM treatment had lower weight, smaller abdominal circumference and skinfolds at birth than those not exposed to GDM. Metformin exposure was associated with smaller offspring mid-arm circumference (- 0.3 cm (- 0.6, - 0.07)) than insulin exposure in fully adjusted models with no other differences found. CONCLUSIONS FOR PRACTICE: Offspring exposed to GDM treatment were lighter and smaller at birth than those not exposed to GDM. Metformin-exposed offspring had largely comparable birth anthropometric characteristics to those exposed to insulin.

The natural history of celiac artery aneurysms.

OBJECTIVES: The goal of this study was to document the natural history of celiac artery aneurysms (CAAs). BACKGROUND: Celiac artery aneurysms are rare. Existing literature is skewed towards outcomes after intervention of large, symptomatic aneurysms but the behavior of untreated CAAs is poorly understood. METHODS: This is a single institution, retrospective analysis of patients with CAA diagnosed by CT imaging (2015-2019) identified through an institutional radiology database. Radiologic, demographic, and follow-up data were analyzed. The primary endpoint was the mean growth rate of CAAs. RESULTS: Of the 76 patients included, 86.8% were men with a mean age at presentation of 69.8 years. The mean CAA diameter on index imaging was 15.4 +/- 3.8 mm (range, 7-30 mm). All were classified as true aneurysms and 76.3% were saccular. All patients had clinical follow-up with mean follow-up 31.2 months +/- 21.6 months. No patient developed symptoms or rupture. The mean radiological follow-up among 45 patients was 25.2 +/- 16.8 months. Over this period, 16 CAAs (35.6%) enlarged, while 29 (64.4%) remained stable. One patient (1.3%) underwent intervention for increasing size in the setting of a chronic dissection. On multivariate analysis, age <70 was significantly associated with increased risk of aneurysm growth. CONCLUSIONS: In this institutional review of patients with CAAs, the majority of aneurysms remained stable in size, with no patients developing symptoms or rupture over clinical follow-up. Given the observed benign behavior of these aneurysms, guidelines that suggest conservative management of CAAs less than 2 cm seems appropriate.

Short-term outcomes of endovascular management of acute limb ischemia using aspiration mechanical thrombectomy.

OBJECTIVE: Management of acute limb ischemia (ALI) has seen greater utilization of catheter-based interventions over the last two decades. Data on their efficacy is largely based on comparisons of catheter-directed thrombolysis (CDT) and open thrombectomy. During this time, many adjuncts to CDT have emerged with different mechanisms of action, including pharmacomechanical thrombolysis (PMT) and aspiration mechanical thrombectomy (AMT). However, the safety and efficacy of newer adjuncts like AMT have not been well established. This study is a retrospective analysis of the contemporary management of ALI comparing patients treated with aspiration mechanical thrombectomy to patients treated with the more established CDT adjunct, pharmacomechanical thrombolysis. METHODS: Patients undergoing peripheral endovascular intervention for ALI using an adjunctive device were identified through query of the Vascular Quality Initiative (VQI) Peripheral Vascular Intervention (PVI) module from 2014 to 2019. Patients with a nonviable extremity (Rutherford ALI Stage 3), prior history of ipsilateral major amputation, popliteal aneurysm, procedures that were deemed elective (>72 h from admission), procedures that did not utilize an endovascular adjunctive device, and patients without short-term follow-up were all excluded from analysis. The primary outcome was a composite outcome of freedom from major amputation and/or death in the perioperative time period. RESULTS: We identified 528 patients with Rutherford ALI Stage 1 or 2 who were treated with an endovascular adjunct. 433 patients did not undergo aspiration mechanical thrombectomy (no AMT group) and 95 patients did undergo aspiration mechanical thrombectomy (AMT group). The amputation-free survival across all patients was 93.4%. There were significant differences in demographic, comorbidity, and treatment variables between groups (e.g., gender, prior percutaneous coronary intervention (PCI), history of prior peripheral artery disease intervention, and history of prior infra-inguinal PVI), so a propensity score matched analysis was included to account for these group differences. In the propensity score matched analysis, there was no significant difference in major amputation (AMT 7.4% vs no AMT 3.2%, p = 0.13) or death (AMT 95.8% survival vs no AMT 98.4% survival, p = 0.23) with the use of aspiration mechanical thrombectomy. However, there was significantly worse amputation-free survival with the use of aspiration mechanical thrombectomy (AMT 88.4% vs no AMT 95.3%, p = 0.03). On multivariate analysis, prior supra-inguinal bypass (OR 4.85, 1.70-13.84, p = 0.003), Rutherford ALI Stage 2B (OR 3.13, 1.47-6.67, p = 0.003), and aspiration mechanical thrombectomy (OR 2.71, 1.03-7.17, p = 0.05) were associated with the composite outcome. CONCLUSIONS: Short-term amputation-free survival rates of endovascular management of acute limb ischemia are adequate across all modalities. However, aspiration mechanical thrombectomy was associated with significantly worse amputation-free survival compared to other endovascular adjuncts alone (i.e., pharmacomechanical thrombolysis). Severe limb ischemia (Rutherford ALI Stage 2B) and prior supra-inguinal bypass were associated with worse amputation-free survival regardless of the choice of endovascular intervention.

Socioeconomic inequalities in early child development in children aged under 36 months in South Asia: A systematic review.

BACKGROUND: In South Asia, 89 million children under 5 are at risk of not reaching their developmental potential. Household socioeconomic position (SEP) is a determinant of early child development (ECD). However, synthesised evidence for the association between ECD and SEP in young children in South Asia is not available. Therefore, this review synthesises evidence on the relationship of household SEP with ECD in children under 36 months of age in South Asia. METHOD: PubMed, Cochrane Library, MEDLINE and Scopus were systematically searched to identify studies from South Asian countries that reported evidence on the association between SEP and ECD. Search terms included items related to motor, cognitive, language and socioemotional development. Study quality was assessed using the QualSyst tool, with three quality levels (high/medium/low), and a narrative review for each ECD outcome was constructed (PROSPERO registration: CRD42019131533). RESULTS: Twelve of the 950 publications screened met the inclusion criteria (nine from India, two Nepal and one Bangladesh). The majority (n = 10, 83%) reported language development on its own or alongside another ECD outcome. Fewer articles assessed cognitive (n = 6, 50%), motor (n = 7, 58%) or socioemotional development (n = 3, 25%). Higher SEP was associated with better ECD for one third of the associations reported. One ECD outcome (socioemotional development) was negatively associated (with socioeconomic status) based on low quality evidence. Mother's education and family income were the major SEP constructs associated with ECD. One, four and seven studies were rated as having a low, medium and high risk of bias, respectively. CONCLUSION: This review reveals the scarcity of evidence exploring associations between household SEP and ECD in children under 36 months in South Asia, especially outside of India. Enhancing evidence for associations between ECD and SEP is needed for evidence-based policy making to reduce developmental delays associated with a disadvantaged SEP in the South Asian region.

Quadratus Lumborum Block and Transversus Abdominis Plane Block in Non-emergency Cesarean Delivery: A Systematic Review and Meta-analysis.

PURPOSE: Investigate the analgesic efficacy of quadratus lumborum (QL) block versus transversus abdominis plane (TAP) block in postoperative pain management in nonemergent cesarean section. DESIGN: Systematic review with meta-analysis. METHODS: PubMed, Cochrane, CINAHL, Google Scholar, and gray literature were searched for evidence. Only randomized controlled trials examining the effects of QL and TAP block for nonemergent cesarean delivery were included. Mean difference (MD) was used to estimate continuous outcomes with appropriate effect models. The quality of evidence was rated using the Risk of Bias and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. FINDINGS: Six studies involving 543 parturients were included. Compared to the TAP block, the cumulative 24-hour pain score at rest (MD, -0.60; 95% CI, -1.03 to -0.17; P = .007) and during activity (MD, -1.05; 95% CI, -1.54 to -0.56; P < .0001) were significantly lower in QL block. Time to the first analgesic rescue (MD, 21.67; 95% CI, -18.58 to 61.91; P = .29) and opioid consumption (MD, -1.96; 95% CI, -4.59 to 0.66; P = .14) were similar in both groups. No difference was found in the incidence of postoperative nausea and vomiting and sedation. However, patients treated with QL block reported higher patient satisfaction scores. CONCLUSIONS: There is limited evidence to suggest that QL block is superior to TAP block for postoperative pain management in nonemergent cesarean delivery. The study limitations must be considered when extrapolating the review's findings to clinical practice.

Weight Loss in Underserved Patients - A Cluster-Randomized Trial.

BACKGROUND: Evidence of the effectiveness of treatment for obesity delivered in primary care settings in underserved populations is lacking. METHODS: We conducted a cluster-randomized trial to test the effectiveness of a high-intensity, lifestyle-based program for obesity treatment delivered in primary care clinics in which a high percentage of the patients were from low-income populations. We randomly assigned 18 clinics to provide patients with either an intensive lifestyle intervention, which focused on reduced caloric intake and increased physical activity, or usual care. Patients in the intensive-lifestyle group participated in a high-intensity program delivered by health coaches embedded in the clinics. The program consisted of weekly sessions for the first 6 months, followed by monthly sessions for the remaining 18 months. Patients in the usual-care group received standard care from their primary care team. The primary outcome was the percent change from baseline in body weight at 24 months. RESULTS: All 18 clinics (9 assigned to the intensive program and 9 assigned to usual care) completed 24 months of participation; a median of 40.5 patients were enrolled at each clinic. A total of 803 adults with obesity were enrolled: 452 were assigned to the intensive-lifestyle group, and 351 were assigned to the usual-care group; 67.2% of the patients were Black, and 65.5% had an annual household income of less than $40,000. Of the enrolled patients, 83.4% completed the 24-month trial. The percent weight loss at 24 months was significantly greater in the intensive-lifestyle group (change in body weight, -4.99%; 95% confidence interval [CI], -6.02 to -3.96) than in the usual-care group (-0.48%; 95% CI, -1.57 to 0.61), with a mean between-group difference of -4.51 percentage points (95% CI, -5.93 to -3.10) (P<0.001). There were no significant between-group differences in serious adverse events. CONCLUSIONS: A high-intensity, lifestyle-based treatment program for obesity delivered in an underserved primary care population resulted in clinically significant weight loss at 24 months. (Funded by the Patient-Centered Outcomes Research Institute and others; PROPEL ClinicalTrials.gov number, NCT02561221.).

Invitation strategies and participation in a community-based lung cancer screening programme located in areas of high socioeconomic deprivation.

INTRODUCTION: Although lung cancer screening is being implemented in the UK, there is uncertainty about the optimal invitation strategy. Here, we report participation in a community screening programme following a population-based invitation approach, examine factors associated with participation, and compare outcomes with hypothetical targeted invitations. METHODS: Letters were sent to all individuals (age 55-80) registered with a general practice (n=35 practices) in North and East Manchester, inviting ever-smokers to attend a Lung Health Check (LHC). Attendees at higher risk (PLCOm2012NoRace score≥1.5%) were offered two rounds of annual low-dose CT screening. Primary care recorded smoking codes (live and historical) were used to model hypothetical targeted invitation approaches for comparison. RESULTS: Letters were sent to 35 899 individuals, 71% from the most socioeconomically deprived quintile. Estimated response rate in ever-smokers was 49%; a lower response rate was associated with younger age, male sex, and primary care recorded current smoking status (adjOR 0.55 (95% CI 0.52 to 0.58), p<0.001). 83% of eligible respondents attended an LHC (n=8887/10 708). 51% were eligible for screening (n=4540/8887) of whom 98% had a baseline scan (n=4468/4540). Screening adherence was 83% (n=3488/4199) and lung cancer detection 3.2% (n=144) over 2 rounds. Modelled targeted approaches required 32%-48% fewer invitations, identified 94.6%-99.3% individuals eligible for screening, and included 97.1%-98.6% of screen-detected lung cancers. DISCUSSION: Using a population-based invitation strategy, in an area of high socioeconomic deprivation, is effective and may increase screening accessibility. Due to limitations in primary care records, targeted approaches should incorporate historical smoking codes and individuals with absent smoking records.

The associations of maternal and paternal obesity with latent patterns of offspring BMI development between 7 and 17 years of age: pooled analyses of cohorts born in 1958 and 2001 in the United Kingdom.

OBJECTIVE: We aimed to 1) describe how the UK obesity epidemic reflects a change over time in the proportion of the population demonstrating adverse latent patterns of BMI development and 2) investigate the potential roles of maternal and paternal BMI in this secular process. METHODS: We used serial BMI data between 7 and 17 years of age from 13220 boys and 12711 girls. Half the sample was born in 1958 and half in 2001. Sex-specific growth mixture models were developed. The relationships of maternal and paternal BMI and weight status with class membership were estimated using the 3-step BCH approach, with covariate adjustment. RESULTS: The selected models had five classes. For each sex, in addition to the two largest normal weight classes, there were "normal weight increasing to overweight" (17% of boys and 20% of girls), "overweight increasing to obesity" (8% and 6%), and "overweight decreasing to normal weight" (3% and 6%) classes. More than 1-in-10 children from the 2001 birth cohort were in the "overweight increasing to obesity" class, compared to less than 1-in-30 from the 1958 birth cohort. Approximately 75% of the mothers and fathers of this class had overweight or obesity. When considered together, both maternal and paternal BMI were associated with latent class membership, with evidence of negative departure from additivity (i.e., the combined effect of maternal and paternal BMI was smaller than the sum of the individual effects). The odds of a girl belonging to the "overweight increasing to obesity" class (compared to the largest normal weight class) was 13.11 (8.74, 19.66) times higher if both parents had overweight or obesity (compared to both parents having normal weight); the equivalent estimate for boys was 9.01 (6.37, 12.75). CONCLUSIONS: The increase in obesity rates in the UK over more than 40 years has been partly driven by the growth of a sub-population demonstrating excess BMI gain during adolescence. Our results implicate both maternal and paternal BMI as correlates of this secular process.

Physical activity and weight loss in a pragmatic weight loss trial.

The purpose of this study was to determine the association between changes in physical activity and changes in body weight in a cluster-randomized weight loss trial conducted in an underserved population in Louisiana. This study reports analyses conducted in the intervention group only, which was a 24-month multi-component weight loss program delivered by health coaches embedded in primary care clinics. Physical activity was assessed at baseline and at 6, 12, and 24 months of follow-up and changes in body weight were expressed as percent weight change from baseline. Among the sample of 402 patients, percent changes in body weight (mean ± SE) across increasing tertiles of changes in walking between baseline and 24 months were -3.2 ± 1.0%, -5.5 ± 0.9%, and -7.3 ± 0.9%, respectively (p = 0.001). Changes in body weight across increasing tertiles of changes in moderate-to-vigorous-intensity activity between baseline and 24 months were -4.3 ± 1.0%, -5.0 ± 0.9%, and -7.0 ± 0.9%, respectively (p = 0.04). In conclusion, this multi-component intervention resulted in clinically significant weight loss, and greater increases in physical activity over the intervention period were associated with greater percent reductions in body weight. These results are consistent with those from other studies conducted primarily in non-underserved populations.

Effect of exercise training on insulin-stimulated glucose disposal: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults. SUBJECTS: MEDLINE, EMBASE, and CENTRAL databases were searched until January 2021. Randomized controlled trials lasting ≥4 weeks, including adults, and evaluating the effect of exercise on insulin-stimulated glucose disposal measured using the hyperinsulinemic euglycemic clamp, were included. METHODS: Three reviewers extracted summary data from published trials. The primary outcome was insulin-stimulated glucose disposal. Standardized weighted mean differences (SMD) in glucose disposal between intervention and control were compared. The PEDro scale was used to assess risk of bias. RESULTS: We included 25 trials (36 interventions, N = 851). Exercise increased insulin-stimulated glucose disposal relative to control, SMD = 0.52 (95% confidence interval [CI]: 0.39, 0.65; p < 0.001; I2 = 47%) without significantly suppressing hepatic glucose production. In trials without isotopic tracers, exercise increased glucose disposal (SMD = 0.63; 95% CI: 0.48, 0.77; p < 0.001, I2 = 55%). In trials with isotopic tracers, exercise increased glucose disposal only when tracers were added to the exogenous glucose used for clamping (SMD = 0.34; 95% CI: 0.03, 0.66, p = 0.034. I2 = 0%). In a meta-regression model including aerobic exercise, weight change, and tracer technique, only percent weight change explained between trial heterogeneity (ß = 0.069; 95% CI: 0.005, 0.013). The PEDro rating indicated relatively low risk of bias (5.8 ± 0.22). CONCLUSIONS: Exercise training for at least four weeks significantly increases insulin-stimulated glucose disposal. Weight loss maximizes the effect and may be needed to improve hepatic insulin sensitivity. Differences in tracer methodology contribute to divergent outcomes and should be considered when assessing conclusions from research examining the effect of exercise on insulin action. REGISTRATION: PROSPERO (CRD42019124381).