Once-weekly semaglutide in people with HIV-associated lipohypertrophy: a randomised, double-blind, placebo-controlled phase 2b single-centre clinical trial.

BACKGROUND: HIV-associated lipohypertrophy, which is characterised by an abnormal accumulation of abdominal visceral adipose tissue, remains problematic in people with HIV. Effective interventions are lacking, despite HIV-associated lipohypertrophy carrying a substantial risk of cardiometabolic comorbidity. The primary aim of this trial was to investigate effects of the GLP-1 receptor agonist, semaglutide, on adipose tissue in HIV-associated lipohypertrophy. METHODS: This randomised, double-blind, placebo-controlled phase 2b clinical trial was conducted at a single US site. Key inclusion criteria included people with HIV aged 18 years or older with controlled HIV-1, a BMI of 25 kg/m2 or more, and lipohypertrophy but without type 1 or type 2 diabetes. Participants were randomly assigned 1:1 to receive 32 weeks of once-weekly subcutaneous semaglutide (8-week dose titration and 24 weeks at 1·0 mg) or placebo; all research personnel and participants remained masked to treatment assignment. Primary outcomes were changes at 32 weeks in adipose tissue quantity by body compartment. Analyses, including safety, were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete. FINDINGS: Between June 10, 2019, and July 28, 2022, 108 participants were randomly assigned to receive semaglutide (n=54) or placebo (n=54). Eight (15%) in each group withdrew prematurely. Significant effects of semaglutide were seen over the 32-week study period in sex-adjusted multiplicative regression analyses for the primary outcome, abdominal visceral adipose tissue (ß -30·82 cm2, 95% CI -50·13 to -11·51; % change -30·6%). Decreases were also seen in other key measures, including abdominal subcutaneous adipose tissue (ß -42·01 cm2, 95% CI -75·49 to -8·52; % change -11·2%) and total body fat (natural logarithmic -0·21 kg, 95% CI -0·33 to -0·08; % change -18·9%). There were no statistically significant differences in possibly related or related adverse events (absolute risk difference 0·1111, 95% CI -0·0727 to 0·2869); however, one semaglutide-related grade 4 elevated lipase and two possibly related cases of cholelithiasis (grades 1 and 2) were observed. INTERPRETATION: Semaglutide holds promise as an effective treatment for HIV-associated lipohypertrophy. The potential risk of serious adverse events deserves further scrutiny in large trials in people with HIV. FUNDING: National Institutes of Health.

Same-day discharge vs. inpatient total shoulder arthroplasty: an age stratified comparison of postoperative outcomes and hospital charges.

BACKGROUND: As the number of total shoulder arthroplasty (TSA) procedures increases, there is a growing interest in improving patient outcomes, limiting costs, and optimizing efficiency. One approach has been to transition these surgeries to an outpatient setting. Therefore, the purpose of this study was to conduct an age-stratified analysis comparing the 90-day postoperative outcomes of primary TSA in the same-day discharge (SDD) and inpatient (IP) settings with a specific focus on the super-elderly. METHODS: This retrospective study included all patients who underwent primary anatomic or reverse TSA between January 2018 and December 2021 in ambulatory and IP settings. The outcome measures included length of stay (LOS), complications, hospital charges, emergency department (ED utilization), readmissions, and reoperations within 90 days following TSA. Patients with LOS ≤8 hours were considered as SDD, and those with LOS >8 hours were considered as IP. P < .05 was considered statistically significant. RESULTS: There were 121 and 174 procedures performed in SDD and IP settings, respectively. There were no differences in comorbidity indices between the SDD and IP groups (American Society of Anesthesiologists score P = .12, Elixhauser Comorbidity Index P = .067). The SDD cohort was younger than the IP group (SDD 67.0 years vs. 73.0 IP years, P < .001), and the SDD group higher rate of intraoperative tranexamic acid use (P = .015) and lower estimated blood loss (P = .009). There were no differences in 90-day overall minor (P = .20) and major complications (P = 1.00), ED utilization (P = .63), readmission (P = .25), or reoperation (P = .51) between the SDD and IP groups. When stratified by age, there were no differences in overall major (P = .80) and minor (P = .36) complications among the groups. However, the LOS was directly correlated with increasing age (LOS = 8.4 hours in ≥65 to <75-year cohort vs. LOS = 25.9 hours in ≥80-year cohort; P < .001). There were no differences in hospital charges between SDD and IP primary TSA in all 3 age groups (P = .82). CONCLUSION: SDD TSA has a shorter LOS without increasing postoperative major and minor complications, ED encounters, readmissions, or reoperations. Older age was not associated with an increase in the complication profile or hospital charges even in the SDD setting, although it was associated with increased LOS in the IP group. These results suggest that TSA can be safely performed expeditiously in an outpatient setting.

Outcomes of Geriatric Periprosthetic Distal Femur Fractures: Comparison of Fixation Versus Reconstruction.

OBJECTIVE: Comparing outcomes of periprosthetic distal femur fractures treated with open reduction and internal fixation (ORIF) versus distal femoral replacement (DFR). SETTING: Three major academic hospitals within one metropolitan area. DESIGN: Retrospective. PATIENTS/PARTICIPANTS: Three hundred seventy patients >64 years old with periprosthetic distal femur fractures were identified and 115 were included (65 ORIF vs. 50 DFR). INTERVENTION: ORIF with locked plating versus DFR. MAIN OUTCOME MEASUREMENT: One-year mortality, ambulatory status at 1 year, reoperations, and hospital readmissions. RESULTS: No differences were observed between ORIF and DFR cohorts regarding demographics or medical history, including Charleston Comorbidity Index. DFR was associated with longer hospital stay (6.09 days ORIF vs. 9.08 days DFR, P < 0.001) and more frequent blood transfusion (12.3% ORIF vs. 44.0% DFR, P < 0.001). Logistic regression analysis using propensity score matching (PSM) demonstrated no statistically significant difference in reoperation, hospital readmission, ambulatory status at 1 year, or 1-year mortality between the 2 cohorts. Finally, applying Bayesian model averaging using PSM to identify risk factors for 1-year mortality demonstrated that increasing age, length of index hospital stay, and 90-day hospital readmission were significantly associated with 1-year mortality, regardless of type of surgical treatment. CONCLUSION: Rehospitalization, reoperation, ambulatory status, and 1-year mortality are no different between ORIF and DFR in the treatment of geriatric periprosthetic distal femur fractures when PSM is applied to mitigate selection bias. Further study is warranted to elucidate functional outcomes, long-term sequelae, and costs of care related to these treatment options to better guide treatment planning. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Total Ankle Arthroplasty for Posttraumatic Fracture Versus Primary Osteoarthritis: An Analysis of Complications, Revisions, and Prosthesis Survival.

BACKGROUND: Most outcome studies of total ankle arthroplasty (TAA) do not discriminate by arthritis etiology. The primary purpose of this study was to compare the complications of TAA between posttraumatic fracture osteoarthritis (fracture PTOA) and primary osteoarthritis (POA). METHODS: Ninety-nine patients who underwent TAA were retrospectively evaluated with a mean follow-up of 3.2 years (range 2 to 7.6 years). 44 patients (44%) had a diagnosis of POA while 55 patients (56%) had a diagnosis of fracture PTOA (40 malleolar fractures [73%], 14 pilon fractures[26%], and 1 talar fracture [1%]). Patient demographics, preoperative coronal plane alignment, postoperative complications, and revision surgery data were collected. Categorical variables were compared with chi square and Fisher exact tests and means with the Student t -test. Survival was assessed with Kaplan-Meier and log-rank analyses. RESULTS: A higher overall complication rate was associated with fracture PTOA (53%) compared with POA (30%) ( P = 0.04). No difference was observed in rates of any specific complication by etiology. Survival, defined as revision surgery with TAA prosthesis retention, was comparable between POA (91%) and fracture PTOA (87%) ( P = 0.54). When defined as failure requiring prosthesis explant, POA demonstrated significantly greater survival (100%) as compared with fracture PTOA (89%) ( P = 0.03). A higher rate of talar implant subsidence and loosening was noted in TAA with prior pilon (29%) as compared to malleolar fractures (8%) that was not statistically significant ( P = 0.07). Fracture PTOA was associated with preoperative valgus deformity ( P = 0.04). Compared with varus and normal alignment, preoperative valgus deformity was associated with the need for any revision surgery ( P = 0.01) and prosthesis explant ( P = 0.02). CONCLUSIONS: Compared with POA, fracture PTOA was associated with a markedly higher complication rate after TAA and was at higher risk of failure requiring prosthesis explant. Fracture PTOA was markedly associated with preoperative valgus malalignment, an identified risk factor in this series for revision surgery and prosthesis explant. Pilon fractures may represent a group at risk of complications related to talar implant subsidence and loosening compared with malleolar fractures and thus warrants additional investigation. LEVEL OF EVIDENCE: III.

Longitudinal Changes in Subclinical Vascular Disease in Ugandan Youth With Human Immunodeficiency Virus.

BACKGROUND: Prospective investigations on the risk of cardiovascular disease among youth with perinatally acquired human immunodeficiency virus (PHIV) in sub-Saharan Africa are lacking. METHODS: A prospective observational cohort study was performed in 101 youth (aged 10-18 years) with PHIV and 97 who were human immunodeficiency virus (HIV) uninfected (HIV-), from 2017 to 2021 at the Joint Clinical Research Center in Uganda. Participants with PHIV were receiving antiretroviral therapy (ART) and had HIV-1 RNA levels ≤400 copies/mL. The common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and at 96 weeks. Groups were compared using unpaired t-test, and potential predictors of IMT and PWV were assessed using quantile regression. RESULTS: Of the 198 participants recruited at baseline, 168 (89 with PHIV, 79 HIV-) had measurements at 96 weeks. The median age (interquartile range) age was 13 (11-15) years; 52% were female, and 85% had viral loads <50 copies/mL that remained undetectable at week 96. The baseline mean common carotid artery IMT was slightly higher in participants with PHIV compared with controls (P < .01), and PWV did not differ between groups (P = .08). At week 96, IMT decreased and PWV increased in the PHIV group (P ≤ .03); IMT increased in the HIV- group (P = .03), with no change in PWV (P = .92). In longitudinal analyses in those with PHIV, longer ART duration was associated with lower PWV (ß = .008 [95% confidence interval, -.008 to .003]), and abacavir use with greater IMT (ß = .043 [.012-.074]). CONCLUSIONS: In healthy Ugandan youth with PHIV, virally suppressed by ART, the common carotid artery IMT did not progress over 2 years. Prolonged and early ART may prevent progression of subclinical vascular disease, while prolonged use of abacavir may increase it.

Comprehensive assessment of neurocognitive function, inflammation markers, and adiposity in treated HIV and control.

To compare the neurocognitive scores between persons living with human immunodeficiency virus (PLWH) and persons without human immunodeficiency virus (HIV) and assess the relationship between neurocognition, HIV status and variables, inflammation, and body composition measures. Cross-sectional study involving 225 participants (126 PLWH on antiretroviral therapy [ART] and 99 persons without HIV). For the first time in HIV, we used Cognivue®, an food and drug administration (FDA)-approved computer-based test to assess cognitive function. The test was calibrated to individuals' unique cognitive ability and measured 6 cognitive domains and 2 performance parameters. Markers of inflammation, immune activation, insulin resistance, and body fat composition (using dual-energy X-ray absorptiometry scan) were collected. Classical t tests, chi-square tests, and spearman correlations were used to compare and explore relationships between variables. Inverse probability weighting adjusted average treatment effect models were performed to evaluate the differences between PLWH and persons without HIV, adjusting for age, race, sex, and heroin use. Overall, 64% were male, 46% were Black, with a mean age of 43 years. Among PLWH, 83% had an undetectable HIV-1 RNA level (≤20 copies/mL). Compared persons without HIV, PLWH performed poorer across 4 domains: visuospatial (P = .035), executive function (P = .029), naming/language (P = .027), and abstraction (P = .018). In addition, PLWH had a significantly longer processing speed time compared to controls (1686.0 ms vs 1606.0 ms [P = .007]). In PLWH, lower cognitive testing domain scores were associated with higher inflammatory markers (high sensitivity C-reactive protein [hsCRP]) and with higher total fat and visceral adipose tissue (P < .05). Neurocognitive impairment (NCI) in HIV is associated with inflammation and total and central adiposity.

The Systematic Isolation of Key Parameters for Estimating Skeletal Maturity on Lateral Elbow Radiographs.

BACKGROUND: Skeletal maturity estimation is central in the management of scoliosis and lower-limb deformity. Utilizing demographic characteristics and modern computing, we sought to create a reliable, rapid, and accurate method for measuring skeletal maturity on an elbow radiograph. METHODS: Utilizing the Bolton-Brush Collection, 4 parameters from the modified Sauvegrain method and 7 novel parameters were screened. Ten parameters were evaluated on serial peripubertal elbow radiographs, using Greulich and Pyle (GP) skeletal age from corresponding hand radiographs as a comparison. Stepwise linear regression and generalized estimating equations were used to identify radiographic and demographic parameters for estimating skeletal maturity based on 90% of final height. The elbow system was compared with GP only; olecranon apophysis only; age, sex, and GP; age, sex, and olecranon apophysis; age, sex, and elbow system with anteroposterior and lateral parameters; age, sex, and elbow system with anteroposterior parameters; and age, sex, and elbow system with lateral parameters. RESULTS: In this study, 367 radiographs from 77 patients (40 girls and 37 boys) were included. Following stepwise linear regression, 4 radiographic parameters were included in the anteroposterior and lateral elbow system; 3 were included in the anteroposterior elbow system; and 4 were included in the lateral elbow system. The lateral elbow system predicted skeletal maturity with a mean discrepancy of 0.41 year and produced similar mean discrepancies to GP with age and sex (0.42; p = 0.93), and it trended toward better performance than the olecranon apophysis system with age and sex (0.43; p = 0.06). The lateral elbow system had the lowest percent of outlier predictions >1 year discrepant from the skeletal maturity reference (4.6%), although it was only significantly better than the GP-only group (29.4%) and the olecranon apophysis-only group (21.0%) (p < 0.001 for both). CONCLUSIONS: We systematically developed a lateral elbow system that performed equivalently to GP using 4 simple parameters and trended toward outperforming the olecranon apophysis systems in skeletal maturity estimation. Future clinical validation will be necessary to understand the utility of this system. CLINICAL RELEVANCE: The lateral elbow system may be a more accurate prediction of skeletal maturity compared with the previously described olecranon apophysis system and can be used to guide the management of many pediatric orthopaedic conditions.

Clinical parameters and radiographic resorption of a novel magnesium based bone void filler.

BACKGROUND: Bone voids can present challenging problems for the Orthopaedic surgeon, and are often treated with backfilling followed by structural stabilization. Recently, a magnesium based, and presumably resorbable, bone void filler (BVF) has been developed, but has limited longitudinal clinical data. Therefore, the purpose of this study was to investigate clinically relevant parameters and radiographic resorption characteristics of this novel magnesium based BVF (MgBVF) with long-term clinical data. METHODS: All patients who underwent surgery by a single surgeon in which MgBVF was utilized from 2019 to 2020 were retrospectively reviewed. Clinical parameters including evidence of infection, wound breakdown, and wound drainage were reviewed. Radiographic resorption, evidence of joint extrusion of BVF, heterotopic ossification, and subsidence was assessed at each post-operative visit. Those with less than 6 month follow up were excluded from radiographic analysis of resorption. Postoperative images at two weeks were compared to each subsequent radiograph during follow up, and reviewed by each of the three authors in blinded fashion. Interval radiographs were assigned a grade of radiographic resorption which corresponded to estimated percent resorption: grade 1 (0-25%), grade 2 (25-50%), grade 3 (50-75%), or grade 4 (75-100%). After 2 weeks, this process was repeated, and both inter and intraobserver reliability scores were calculated. RESULTS: Forty-two patients were identified for clinical review, and 18 for radiographic review. Average length of follow up was 209±113 days. Five patients experienced a postoperative complication: two wound infections, one delayed wound healing, one sterile serous drainage, and one catastrophic failure of the fixation construct. Four patients were noted to have postoperative joint subsidence of 2 mm or less. Average grade of resorption was found to be 1.5 ± 0.8, 1.7 ± 0.9, 2.9 ± 0.9, and 3.6 ± 0.6 at 6 weeks, 3 months, 6 months, and 1 year, respectively (p<0.001). Average kappa (intrarater reliability) was found to be 0.61, 0.41, 0.55, and 0.63 for each time interval, respectively. Interrater reliability increased form 0.19 at 6 weeks to 0.42 at 1 year. CONCLUSION: This novel MgBVF demonstrates clinically relevant resorption, provides structural support in challenging bone voids, and does not appear to significantly increase risk of complications, setting it apart from previously described BVF's.

Preliminary Efficacy of an Emotion Regulation Intervention on Physical Activity and Depressive and Anxious Symptoms in Individuals in Cardiac Rehabilitation.

BACKGROUND: For the 720 000 Americans expected to experience a new acute cardiac event this year, cardiac rehabilitation is an important part of recovery. Symptoms of depression and anxiety undermine recovery efforts, leaving recovering patients at risk for diminished functional capacity and heightened risk of mortality. Poor emotion regulation can worsen symptoms of depression and anxiety and hinder recovery efforts. OBJECTIVE: The purpose of this randomized controlled trial was to evaluate the early efficacy testing of a theoretically based emotion regulation treatment (Regulating Emotions to Improve Self-management of Nutrition, Exercise, and Stress [RENEwS]) designed to assist survivors of an acute cardiac event in cardiac rehabilitation to optimize recovery. METHODS: Survivors of an acute cardiac event in cardiac rehabilitation (n = 30, 83% men) were randomized to five 1-hour in-person group sessions of RENEwS or a phone-based attention-control group. Participants completed measures of depression and anxiety symptoms at 3 time points. Moderate to vigorous physical activity (MVPA) was objectively measured for 7 days at each time point using waist-worn actigraphy monitors. Between-group differences were calculated using analysis of variance with Cohen f effect sizes calculated to evaluate initial efficacy. RESULTS: There was no statistically significant difference in depression, anxiety, or MVPA over time based on group assignment (all P > .05). Compared with attention control participants, in RENEwS participants, preliminary effects showed greater reductions in depression (Cohen f = 0.34) and anxiety (Cohen f = 0.40) symptoms but only modest improvements in MVPA from baseline to 5 months (Cohen f = 0.08). CONCLUSIONS: Findings show that RENEwS is a promising emotion regulation intervention to enhance cardiac rehabilitation and potentially decrease symptoms of depression and anxiety.

Subclinical Vascular Disease in Children With Human Immunodeficiency Virus in Uganda Is Associated With Intestinal Barrier Dysfunction.

BACKGROUND: The risk of cardiovascular disease (CVD) and its mechanisms in children living with perinatally acquired HIV (PHIV) in sub-Saharan Africa has been understudied. METHODS: Mean common carotid artery intima-media thickness (IMT) and pulse-wave velocity (PWV) were evaluated in 101 PHIV and 96 HIV-negative (HIV-) children. PHIV were on ART, with HIV-1 RNA levels ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation, oxidized lipids, and gut integrity. RESULTS: Overall median (interquartile range, Q1-Q3) age was 13 (11-15) years and 52% were females. Groups were similar by age, sex, and BMI. Median ART duration was 10 (8-11) years. PHIV had higher waist-hip ratio, triglycerides, and insulin resistance (P ≤ .03). Median IMT was slightly thicker in PHIVs than HIV- children (1.05 vs 1.02 mm for mean IMT and 1.25 vs 1.21 mm for max IMT; P < .05), while PWV did not differ between groups (P = .06). In univariate analyses, lower BMI and oxidized LDL, and higher waist-hip ratio, hsCRP, and zonulin correlated with thicker IMT in PHIV (P ≤ .05). After adjustment for age, BMI, sex, CD4 cell count, triglycerides, and separately adding sCD163, sCD14, and hsCRP, higher levels of intestinal permeability as measured by zonulin remained associated with IMT (ß = 0.03 and 0.02, respectively; P ≤ .03). CONCLUSIONS: Our study shows that African PHIV have evidence of CVD risk and structural vascular changes despite viral suppression. Intestinal intestinal barrier dysfunction may be involved in the pathogenesis of subclinical vascular disease in this population.

Altered Intestinal Permeability and Fungal Translocation in Ugandan Children With Human Immunodeficiency Virus.

BACKGROUND: Children with perinatally acquired human immunodeficiency virus (HIV; PHIVs) face a lifelong cumulative exposure to HIV and antiretroviral therapy (ART). The relationship between gut integrity, microbial translocation, and inflammation in PHIV is poorly understood. METHODS: This is a cross-sectional study in 57 PHIVs, 59 HIV-exposed but uninfected children, and 56 HIV-unexposed and -uninfected children aged 2-10 years old in Uganda. PHIVs were on stable ART with HIV-1 RNA <400 copies/mL. We measured markers of systemic inflammation, monocyte activation, and gut integrity. Kruskal-Wallis tests were used to compare markers by group and the Spearman correlation was used to assess correlations between biomarkers. RESULTS: The mean age of all participants was 7 years and 55% were girls. Among PHIVs, the mean CD4 % was 34%, 93% had a viral load ≤20 copies/mL, and 79% were on a nonnucleoside reverse transcriptase inhibitor regimen. Soluble cluster of differentiation 14 (sCD14), beta-D-glucan (BDG), and zonulin were higher in the PHIV group (P ≤ .01). Intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide binding protein (LBP) did not differ between groups (P > .05). Among PHIVs who were breastfed, levels of sCD163 and interleukin 6 (IL6) were higher than levels in PHIV who were not breastfed (P < .05). Additionally, in PHIVs with a history of breastfeeding, sCD14, BDG, LBP, zonulin, and I-FABP correlated with several markers of systemic inflammation, including high-sensitivity C-reactive protein, IL6, d-dimer, and systemic tumor necrosis factor receptors I and II (P ≤ .05). CONCLUSIONS: Despite viral suppression, PHIVs have evidence of altered gut permeability and fungal translocation. Intestinal damage and the resultant bacterial and fungal translocations in PHIVs may play a role in the persistent inflammation that leads to many end-organ diseases in adults.Despite viral suppression, children with perinatally acquired human immunodeficiency virus (HIV) in Uganda have evidence of alterations in intestinal permeability and fungal translocation, compared to HIV-exposed but uninfected and HIV-unexposed children, which may play a role in HIV-associated chronic inflammation.

Time to antibody detection and associated factors for presence of anti-drug antibodies in pediatric inflammatory bowel disease patients treated with anti-TNF therapy.

BACKGROUND: Loss of response in pediatric inflammatory bowel disease patients treated with biologic medications can be due to development of anti-drug antibodies. Natural history of anti-drug antibodies development has not been well described in pediatric inflammatory bowel disease. The primary aim of this study was to describe a single-center experience for the temporal onset of anti-drug antibodies detection. METHODS: We performed a retrospective, single-center chart review of pediatric inflammatory bowel disease patients at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at Rainbow Babies and Children's Hospital from 2010 to 2015. Patients were treated with infliximab or adalimumab and had at least two evaluations for anti-drug antibodies with the homogenous mobility shift assay. Demographics, laboratory and medication data, and clinical disease activity were collected. RESULTS: A total of 75 subjects are included in the analysis. Eighty-one percent of subjects were treated with infliximab. Eleven subjects developed anti-drug antibodies; average time to anti-drug antibodies detection was 13.2 ± 7.3 months. Longer duration of inflammatory bowel disease, L1 location in Crohn's disease, and not having immunomodulatory therapy before biologic was associated with higher risk of antibody detection. Antibody detection occurred more frequently with infliximab vs. adalimumab. Time-to-antibody detection for infliximab and adalimumab was 14.83 and 23.48 months, respectively. CONCLUSION: Chances of anti-drug antibodies detection in the infliximab group were higher than the adalimumab group. Time-to-antibody detection was 8.65 months longer in patients who received adalimumab when compared to infliximab. These results may have implications for long-term therapy and help guide use of concomitant immunomodulators.

Neonatal intermittent hypoxemia events are associated with diagnosis of bronchopulmonary dysplasia at 36 weeks postmenstrual age.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease and major pulmonary complication after premature birth. We have previously shown that increased intermittent hypoxemia (IH) events have been correlated to adverse outcomes and mortality in extremely premature infants. We hypothesize that early IH patterns are associated with the development of BPD. METHODS: IH frequency, duration, and nadirs were assessed using oxygen saturation (SpO2) waveforms in a retrospective cohort of 137 extremely premature newborns (<28 weeks gestation). Daily levels of inspired oxygen and mean airway pressure exposures were also recorded. RESULTS: Diagnosis of BPD at 36 weeks postmenstrual age was associated with increased daily IH, longer IH duration, and a higher IH nadir. Significant differences were detected through day 7 to day 26 of life. Infants who developed BPD had lower mean SpO2 despite their exposure to increased inspired oxygen and increased mean airway pressure. CONCLUSIONS: BPD was associated with more frequent, longer, and less severe IH events in addition to increased oxygen and pressure exposure within the first 26 days of life. Early IH patterns may contribute to the development of BPD or aid in identification of neonates at high risk.

AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF. METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning. RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels. CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.

Serum Albumin Is Associated With Higher Inflammation and Carotid Atherosclerosis in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: This study was conducted to explore the associations between serum albumin and markers of inflammation and cardiovascular disease in treated human immunodeficiency virus (HIV)-infected adults. METHODS: We conducted a nested study within in the SATURN-HIV trial in which 147 HIV+ adults on stable antiretroviral therapy were (1) virally suppressed, (2) had a low-density lipoprotein (LDL)-cholesterol level <130 mg/dL, and (3) were randomized to 10 mg daily rosuvastatin or placebo. Measures of serum albumin, carotid intima media thickness ([cIMT] surrogate marker of atherosclerosis), inflammation, T cells, monocyte activation, and gut integrity were assessed at baseline, 48 and 96 weeks later. Spearman correlations and linear mixed-effect models were used to assess associations with serum albumin. RESULTS: Mean age was 45 years, 80% of participants were male, and 69% were African American. Mean serum albumin was similar between the groups at all time points (4.01-4.09 g/dL in statin arm vs 4.02-4.11 g/dL in placebo arm; P = .08-0.35). Lower baseline serum albumin significantly predicted larger changes in cIMT, interleukin 6, D-dimer, tumor necrosis factor α receptor 1, fibrinogen, and high-sensitivity C-reactive protein (P ≤ .03) over 96 weeks independently of statin therapy. After adjusting for age, gender, smoking, body mass index, creatinine clearance, and LDL cholesterol, every 1 g/dL decrease in serum albumin at baseline remained associated with a 0.05-mm increase in cIMT over 96 weeks (P = .05). CONCLUSIONS: Lower serum albumin in controlled HIV is associated with higher markers of chronic inflammation and hypercoagulation, which could explain the prior observation that serum albumin predicts nonacquired immune deficiency syndrome events in HIV. Serum albumin may predict progression of carotid atherosclerosis independent of traditional risk factors.

Dose of Early Therapeutic Mobility: Does Frequency or Intensity Matter?

OBJECTIVE: Investigate the feasibility of a nurse-led mobility protocol and compare the effects of once- versus twice-daily episodes of early therapeutic mobility (ETM) and low- versus moderate-intensity ETM on serum biomarkers of inflammation and selected outcomes in critically ill adults. DESIGN: Randomized interventional study with repeated measures and blinded assessment of outcomes. SETTING: Four adult intensive care units (ICUs) in two academic medical centers. SUBJECTS: Fifty-four patients with > 48 hr of mechanical ventilation (MV). INTERVENTION: Patients were assigned to once- or twice-daily ETM via sealed envelope randomization at enrollment. Intensity of (in-bed vs. out-of-bed) ETM was administered according to protocolized patient assessment. MEASUREMENTS: Interleukins 6, 10, 8, 15, and tumor necrosis factor-α were collected from serum before and after ETM; change scores were used in the analyses. Manual muscle and handgrip strength, delirium onset, duration of MV, and ICU length of stay (LOS) were evaluated as patient outcomes. MAIN RESULTS: Hypotheses regarding the inflammatory biomarkers were not supported based on confidence intervals. Twice-daily intervention was associated with reduced ICU LOS. Moderate-intensity (out-of-bed) ETM was associated with greater manual muscle test scores and handgrip strength and reduced occurrence of delirium. CONCLUSION: Findings from this study suggest that nurses can provide twice-daily mobility interventions that include sitting on the edge of the bed once patients have a stable status without altering a pro-inflammatory serum biomarker profile.

Does Lifestyle Exercise After a Cardiac Event Improve Metabolic Syndrome Profile in Older Adults?

BACKGROUND: Exercise is a common recommendation to reduce the risk factors of metabolic syndrome, yet there are limited data on the influence of lifestyle exercise after cardiac events on metabolic syndrome factors. OBJECTIVE: The purpose of this study was to determine whether lifestyle exercise improves metabolic syndrome profile in older adults after a cardiac event. METHODS: Participants were from a post-cardiac-event lifestyle exercise study. Five metabolic syndrome factors were assessed: waist circumference, triglycerides, high-density lipids, glucose, and systolic and diastolic blood pressure. Objective measures of exercise were obtained from heart rate monitors over a year. Logistic regression was used to determine whether participants who engaged in the minimum recommendation of 130 hours of exercise or greater during the 12-month period improved their metabolic syndrome profile by improving at least 1 metabolic syndrome factor. RESULTS: In the sample of 116 participants (74% men; average age, 67.5 years), 43% exercised at the recommended amount (≥130 h/y) and 28% (n = 33) improved their metabolic syndrome profile. After controlling for confounding factors of age, gender, race, diabetes, functional ability, and employment, subjects who exercised at least 130 hours a year were 3.6 times more likely to improve at least 1 metabolic syndrome factor (95% confidence interval, 1.24-10.49). Of the 28% who improved their metabolic syndrome profile, 72% increased their high-density lipoprotein and 60.6% reduced their waist circumference and glucose. CONCLUSIONS: After a cardiac event, older patients who engage in lifestyle exercise at the recommended amount have improvement in their metabolic syndrome profile.

Randomized Controlled Trial of the SystemCHANGE Intervention on Behaviors Related to Cardiovascular Risk in HIV+ Adults.

OBJECTIVE: To examine the effect of a lifestyle behavior intervention (SystemCHANGE) on physical activity and diet quality among sedentary people living with HIV (PLHIV). All participants expressed a desire to improve lifestyle health behaviors. METHODS: One hundred and seven HIV+ adults were randomized to either the intervention (6, in-person, standardized group sessions focusing on improving lifestyle behaviors) or a control condition (general advice on AHA diet and exercise guidelines). All participants wore an ActiGraph accelerometer and completed 24-hour dietary recalls at baseline, 3, and 6 months. Generalized estimating equations were used to examine intervention effects. The primary activity outcome was time spent in moderate-to-vigorous physical activity, and the primary dietary outcome was Healthy Eating Index. RESULTS: Mean age was 53 years, 65% were male, and 86% African American. Approximately 90% attended at least half of the sessions and 60% attended 5 or more sessions. The intervention did not significantly improve our primary lifestyle behavior endpoints (P ≥ 0.05); however, intervention participants consumed fewer carbohydrates-primarily sugar-sweetened beverages-per day and lost 0.732 kg body weight compared with a 0.153 weight gain in the control group (P = 0.03). CONCLUSIONS: Among sedentary PLHIV at high risk of cardiovascular disease, the SystemCHANGE intervention reduced daily carbohydrate intake and body weight, but did not increase physical activity or improve overall diet quality. Future work should identify fundamental personal, interpersonal, and contextual factors that will increase physical activity and improve overall diet quality among this population, and integrate these factors into tailored, lifestyle interventions for aging PLHIV.

The Influence of Exercise on Cardiovascular Health in Sedentary Adults With Human Immunodeficiency Virus.

BACKGROUND: Lifestyle physical activity (ie, moderate physical activity during routine daily activities most days of the week) may benefit human immunodeficiency virus (HIV)-positive adults who are at high risk for cardiovascular disease. OBJECTIVE: The aims of this study were to describe lifestyle physical activity patterns in HIV-positive adults and to examine the influence of lifestyle physical activity on markers of cardiovascular health. Our secondary objective was to compare these relationships between HIV-positive adults and well-matched HIV-uninfected adults. METHODS: A total of 109 HIV-positive adults and 20 control participants wore an ActiGraph accelerometer, completed a maximal graded cardiopulmonary exercise test, completed a coronary computed tomography, completed anthropomorphic measures, and had lipids and measures of insulin resistance measured from peripheral blood. RESULTS: Participants (N = 129) had a mean age of 52 ± 7.3 years, 64% were male (n = 82), and 88% were African American (n = 112). On average, HIV-positive participants engaged in 33 minutes of moderate-to-vigorous physical activity per day (interquartile range, 17-55 minutes) compared with 48 minutes in controls (interquartile range, 30-62 minutes, P = .05). Human immunodeficiency virus-positive adults had poor fitness (peak oxygen uptake [VO2], 16.8 ± 5.2 mL/min per kg; and a ventilatory efficiency, 33.1 [4.6]). A marker of HIV disease (current CD4+ T cell) was associated with reduced peak VO2 (r = -0.20, P < .05) and increased insulin resistance (r = 0.25, P < .01) but not with physical activity or other markers of cardiovascular health (P ≥ 0.05). After controlling for age, gender, body mass index, and HIV status, physical activity was not significantly associated with peak VO2 or ventilatory efficiency. CONCLUSION: Human immunodeficiency virus-positive adults have poor physical activity patterns and diminished cardiovascular health. Future longitudinal studies should examine whether HIV infection blunts the beneficial effects of physical activity on cardiovascular health.

Soluble TWEAK may predict carotid atherosclerosis in treated HIV infection.

BACKGROUND: Soluble Tumor Necrosis Factor Weak Inducer of Apoptosis (sTWEAK) has been proposed as a novel biomarker of cardiovascular disease risk. This study compares levels of sTWEAK, sCD163 and the sCD163/sTWEAK ratio in HIV-infected and uninfected patients and their associations with cardiovascular and inflammatory factors. METHODS: The data for our analysis come from 274 HIV-infected adults and 59 controls. HIV participants were on stable antiretroviral therapy (ART). Wilcoxon-Mann-Whitney tests were used for comparing markers between HIV-infected participants with HIV viral load <50 copies/mL (aviremic group), HIV-infected participants with detectable viremia (HIV-1 RNA ≥50 copies/mL; viremic group) and HIV negative participants. Multivariable quantile regression analyses were used to assess associations of sTWEAK and sCD163 with other markers of inflammation and carotid intima-media thickness (cIMT). RESULTS: Overall, 74% of participants were male; 59% were African-Americans; median age was 40 years and CD4 595 cells/mm3. Overall, HIV-infected participants had reduced sTWEAK and increased sCD163 levels compared to HIV-uninfected participants (p = 0.0001 for both markers). In addition, these biomarkers were significantly different between HIV-infected viremic and aviremic patients (p ≤ 0.01 for both markers). In multivariable models, sTWEAK and sCD163 in aviremic patients were significantly correlated with common carotid artery IMT (p ≤ 0.05). In HIV-infected aviremic participants, sTWEAK and sCD163 were both associated with IL-6, CD14 + CD16 + monocytes (p ≤ 0.02); additionally, sCD163 was associated with D-dimer- (ß = -69.5, 0.05), VCAM (ß = 72.4, p = 0.05), TNF RI (ß = 91.1, p < 0.01), and TNF RII (ß = 87.8, p < 0.01). CONCLUSIONS: HIV-infected participants showed increased systemic inflammatory and monocyte activation markers. Soluble CD163 and sTWEAK levels were associated with carotid intima-media thickness.