Feasibility of Pharmacy-based Research Opportunity to Enhance Community Testing and Surveillance (PROTECTS).

BACKGROUND: Approximately 89% of the US population lives within five miles of a community pharmacy, which provides a network of geographically distributed recruitment nodes for testing and surveillance of infection and disease. OBJECTIVES: Establish feasibility of Pharmacy-based Research Opportunities To Enhance Community Testing and Surveillance (PROTECTS) in the context of SARS-CoV-2 infection in a community pharmacy setting with University of Kentucky serving as the coordinating center and research hub for sample analysis. METHODS: Two community pharmacies in Kentucky served as community-based recruitment sites to assess SARS-CoV-2 exposure through longitudinal (5 visits over 56 days) collection of nasal swabs and blood samples from subjects. RESULTS: Fifty subjects were recruited between May 2022 and December 2023 for longitudinal sample collection. Three phases of recruitment were investigated by first establishing standard operating procedures in an urban pharmacy, then expanding recruitment at a second pharmacy in a rural setting, and finally increasing recruitment at the urban pharmacy. During the first phase of recruitment, 12 participants were recruited. Of these participants, two never scheduled a visit after the initial screening. The median time for study completion from first to last visit within this phase was 59 days (IQR: 56-68 days). During the second phase of recruitment, eight of nine participants completed all five visits. The median time to complete all visits was 105 days (IQR: 98-112 days). During the ongoing third phase, 29 subjects were recruited, and 19 participants completed all required visits and the remainder continue to schedule follow-up appointments. CONCLUSION: Community pharmacies have a significant role in promoting public health. The geographic distribution of community pharmacies makes them appealing locations for recruitment of outpatient cohorts for local surveillance of infections and chronic inflammatory conditions with opportunities for broad implementation of this project for clinical trials in underserved communities.

Hip joint and muscle loading for persons with bilateral transfemoral/through-knee amputations: biomechanical differences between full-length articulated and foreshortened non-articulated prostheses.

BACKGROUND: Currently, there is little available in-depth analysis of the biomechanical effect of different prostheses on the musculoskeletal system function and residual limb internal loading for persons with bilateral transfemoral/through-knee amputations (BTF). Commercially available prostheses for BTF include full-length articulated prostheses (microprocessor-controlled prosthetic knees with dynamic response prosthetic feet) and foreshortened non-articulated stubby prostheses. This study aims to assess and compare the BTF musculoskeletal function and loading during gait with these two types of prostheses. METHODS: Gait data were collected from four male traumatic military BTF and four able-bodied (AB) matched controls using a 10-camera motion capture system with two force plates. BTF completed level-ground walking trials with full-length articulated and foreshortened non-articulated stubby prostheses. Inverse kinematics, inverse dynamics and musculoskeletal modelling simulations were conducted. RESULTS: Full-length articulated prostheses introduced larger stride length (by 0.5 m) and walking speed (by 0.3 m/s) than stubbies. BTF with articulated prostheses showed larger peak hip extension angles (by 10.1°), flexion moment (by 1.0 Nm/kg) and second peak hip contact force (by 3.8 bodyweight) than stubbies. There was no difference in the hip joint loading profile between BTF with stubbies and AB for one gait cycle. Full-length articulated prostheses introduced higher hip flexor muscle force impulse than stubbies. CONCLUSIONS: Compared to stubbies, BTF with full-length articulated prostheses can achieve similar activity levels to persons without limb loss, but this may introduce detrimental muscle and hip joint loading, which may lead to reduced muscular endurance and joint degeneration. This study provides beneficial guidance in making informed decisions for prosthesis choice.

Characterization of muscle recruitment during gait of bilateral transfemoral and through-knee persons with limb loss.

Introduction: Due to loss in musculoskeletal capacity, there is an increased burden on the residual limbs of bilateral transfemoral and through-knee persons with limb loss. This reduced capacity is associated with an increased cost of walking that is detrimental to functionality. Compensatory gait strategies are adopted by this population. However, how these strategies relate to specific muscle recruitment is not known. The primary aim of this study is to characterize muscle recruitment during gait of this population. The secondary aim is to assess whether the measured kinematics can be actuated when the endurance of specific muscles is reduced and if this is the case, which alternative muscles facilitate this. Methods: 3D gait data and high-resolution magnetic resonance images were acquired from six bilateral transfemoral and through-knee persons with limb loss. Subject-specific anatomical muscle models were developed for each participant, and a validated musculoskeletal model was used to quantify muscle forces in two conditions: during normal gait (baseline) and when muscles, which were identified as functioning above a "healthy" level at baseline, have a reduced magnitude of maximum force capacity (reduced endurance simulation). To test the hypothesis that there are differences in muscle forces between the baseline trials and the simulations with reduced muscular endurance, a Bonferroni corrected two-way ANOVA with repeated measures was completed between the two states. Results: The baseline analysis showed that the hip flexors experience relatively high muscle activations during gait. The reduced endurance simulation found two scenarios. First, for 5 out of the 12 simulations, the baseline kinematics could not be reproduced with the reduced muscular capacity. Second, for 7 out of 12 cases where the baseline kinematics were achieved, this was possible with compensatory increased activation of some muscles with similar functions (p ≤ 0.003). Discussion: Evidently, due to the loss of the ankle plantar flexors, gait imposes a high demand on the flexor muscle group of the residual limb. This study highlights how the elevated cost of gait in this population manifests in muscle recruitment. To enhance functionality, it is critical to consider the mechanical demand on the hip flexors and to develop rehabilitation interventions accordingly.

The effect of muscle atrophy in people with unilateral transtibial amputation for three activities: Gait alone does not tell the whole story.

Amputation imposes significant challenges in locomotion to millions of people with limb loss worldwide. The decline in the use of the residual limb results in muscle atrophy that affects musculoskeletal dynamics in daily activities. The aim of this study was to quantify the lower limb muscle volume discrepancy based on magnetic resonance (MR) imaging and to combine this with motion analysis and musculoskeletal modelling to quantify the effects in the dynamics of key activities of daily living. Eight male participants with traumatic unilateral transtibial amputation were recruited who were at least six months after receiving their definitive prostheses. The muscle volume discrepancies were found to be largest at the knee extensors (35 %, p = 0.008), followed by the hip abductors (17 %, p = 0.008). Daily activities (level walking, standing up from a chair and ascending one step) were measured in a motion analysis laboratory and muscle and joint forces quantified using a detailed musculoskeletal model for people with unilateral transtibial amputation which was calibrated in terms of the muscle volume discrepancies post-amputation at a subject-specific level. Knee extensor muscle forces were lower at the residual limb than the intact limb for all activities (p ≤ 0.008); residual limb muscle forces of the hip abductors (p ≤ 0.031) and adductors (p ≤ 0.031) were lower for standing-up and ascending one step. While the reduced knee extensor force has been reported by other studies, our results suggest a new biomechanically-based mitigation strategy to improve functional mobility, which could be achieved through strengthening of the hip abd/adductor muscles.

Understanding lower limb muscle volume adaptations to amputation.

Amputation of a major limb, and the subsequent return to movement with a prosthesis, requires the development of compensatory strategies to account for the loss. Such strategies, over time, lead to regional muscle atrophy and hypertrophy through chronic under or overuse of muscles compared to uninjured individuals. The aim of this study was to quantify the lower limb muscle parameters of persons with transtibial and transfemoral amputations using high resolution MRI to ascertain muscle volume and to determine regression equations for predicting muscle volume using femur- and tibia-length, pelvic-width, height, and mass. Twelve persons with limb loss participated in this study and their data were compared to six matched control subjects. Subjects with unilateral transtibial amputation showed whole-limb muscle volume loss in the residual-limb, whereas minor volume changes in the intact limb were found, providing evidence for a compensation strategy that is dominated by the intact-limb. Subjects with bilateral-transfemoral amputations showed significant muscle volume increases in the short adductor muscles with an insertion not affected by the amputation, the hip flexors, and the gluteus medius, and significant volume decreases in the longer adductor muscles, rectus femoris, and hamstrings. This study presents a benchmark measure of muscle volume discrepancies in persons with limb-loss, and can be used to understand the compensation strategies of persons with limb-loss and the impact on muscle volume, thus enabling the development of optimised intervention protocols, conditioning therapies, surgical techniques, and prosthetic devices that promote and enhance functional capability within the population of persons with limb loss.

An Anatomical Atlas-Based Scaling Study for Quantifying Muscle and Hip Joint Contact Forces in Above and Through-Knee Amputees Using Validated Musculoskeletal Modelling.

OBJECTIVE: Customisation of musculoskeletal modelling using magnetic resonance imaging (MRI) significantly improves the model accuracy, but the process is time consuming and computationally intensive. This study hypothesizes that linear scaling to a lower limb amputee model with anthropometric similarity can accurately predict muscle and joint contact forces. METHODS: An MRI-based anatomical atlas, comprising 18 trans-femoral and through-knee traumatic lower limb amputee models, is developed. Gait data, using a 10-camera motion capture system with two force plates, and surface electromyography (EMG) data were collected. Muscle and hip joint contact forces were quantified using musculoskeletal modelling. The predicted muscle activations from the subject-specific models were validated using EMG recordings. Anthropometry based multiple linear regression models, which minimize errors in force predictions, are presented. RESULTS: All predictions showed excellent (error interval c = 0-0.15), very good (c = 0.15-0.30) or good (c = 0.30-0.45) similarity to the EMG data, demonstrating accurate computation of muscle activations. The primary predictors of discrepancies in force predictions were differences in pelvis width (p < 0.001), body mass index (BMI, p < 0.001) and stump length to pelvis width ratio (p < 0.001) between the respective individual and underlying dataset. CONCLUSION: Linear scaling to a model with the most similar pelvis width, BMI and stump length to pelvis width ratio results in modelling outcomes with minimal errors. SIGNIFICANCE: This study provides robust tools to perform accurate analyses of musculoskeletal mechanics for high-functioning lower limb military amputees, thus facilitating the further understanding and improvement of the amputee's function. The atlas is available in an open source repository.

Liposomal delivery of azithromycin enhances its immunotherapeutic efficacy and reduces toxicity in myocardial infarction.

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug's efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

Association Between ApoA-I (Apolipoprotein A-I) Immune Complexes and Adverse Cardiovascular Events-Brief Report.

OBJECTIVE: The immune response is linked to the progression of atherosclerotic cardiovascular disease (CVD). Free autoantibodies targeting ApoA-I (apolipoprotein A-I) have been identified as a component of the inflammatory milieu in patients and have a moderate association with CVD progression. Based on the presence of these antibodies and the high concentration of circulating ApoA-I, we hypothesized that antibodies bound to ApoA-I as an immune complex would be predictive of incident adverse CVD outcomes. Approach and Results: The presence of ApoA-I/IgG immune complexes (ICs) in plasma was confirmed by ELISA in 3 subject cohorts. Characterization of the protein components of ApoAI/IgG ICs indicate that ICs are not correlated with total ApoA-I concentration and are enriched in the anti-inflammatory subclass, IgG4, relative to total plasma IgG (>30% versus 6%). In 359 patients with coronary artery disease (CAD), there were 71 incident adverse CVD events (death, myocardial infarction, and stroke) during a median 4.1-year follow-up. In Cox proportional hazard regression analysis, low levels of ApoA-I/IgG ICs were independent predictors of adverse cardiovascular outcomes after adjustment for age, sex, diabetes mellitus, estimated glomerular filtration rate, presence of obstructive CAD, heart failure, total cholesterol, and HDL (high-density lipoprotein) cholesterol (adjusted hazard ratio of 1.90 [95% CI, 1.03-3.49; P=0.038] between the lowest and the highest tertiles). CONCLUSIONS: Low levels of ApoA-I/IgG ICs are associated with an increased risk of adverse events in patients with CAD, raising their potential to be used as a biomarker to predict CVD progression.

Mental Health Literacy of Pharmacy Students Compared to Nursing and Medical Students.

OBJECTIVES: To determine and compare the mental health literacy of pharmacy, nursing, and medical students. METHODS: Pharmacy, nursing, and medical students in the final year of their didactic program were administered a widely used mental health literacy questionnaire either via paper (nursing) or via email (pharmacy and medicine). For email questionnaires, weekly reminder emails with links for survey completion were sent over a three-week period. The questionnaire consisted of a vignette describing either depression or schizophrenia followed by items about helpfulness of a variety of interventions, medications, and activities. Depression and schizophrenia versions of the questionnaire were randomly administered to respondents in the three programs such that respondents received either male (John) or female (Jane) versions of the vignettes. RESULTS: A total of 161 out of 253 potential students responded to the survey (63.6% response rate). Majority of the respondents were female (75%), white (84.6%), had currently or in the past year interacted with people diagnosed with mental disorders (90%), and had multiple opportunities for exposure to mental health content in their coursework (49%). While a majority of respondents in all three programs correctly identified the vignettes as either depression (87%) or schizophrenia (73%), depression was identified correctly by a greater percent of those in pharmacy (88.5%) and nursing (88.4%), and schizophrenia was identified by a greater percent in medicine (82%). However, there were no significant differences by program type for correct identification of vignette. Helpfulness of various interventions, medications, and activities did not differ significantly for the depression vignette. Two significant differences by program type were noted for the schizophrenia vignette. A larger percent (72%) of nursing students perceived antidepressants as helpful for schizophrenia as compared to pharmacy (55%) and medical (18%) students. Students from all three programs responded similarly to the question on likely prognosis for those with depression/schizophrenia, both with and without professional help (p>0.01). CONCLUSIONS: Majority of students in each discipline were able to correctly identify patients with depression or schizophrenia and have similar levels of mental health literacy. The profile of responses suggest that pharmacy and nursing students were more clear about helpfulness of interventions for depression, than for schizophrenia. Given the extent of the problem of mental health, additional and continuously reinforced training on mental health throughout the four-year curriculum is necessary for first line providers such as pharmacists, nurses, and physicians.

Latent tuberculosis infection is associated with increased unstimulated levels of interferon-gamma in Lima, Peru.

BACKGROUND: We previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru. METHODS: We analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay. Participants with a positive QFT test were defined as having LTBI, whereas participants with a negative QFT test were defined as non-LTBI. Unstimulated interferon-gamma was quantified via enzyme-linked immunosorbent assay in the QFT nil-tube, which does not contain antigens. We compared unstimulated interferon-gamma levels between LTBI and non-LTBI groups using the Wilcoxon rank sum test. We used proportional odds modeling for multivariable analysis. RESULTS: Data from 214 participants were included in this analysis. Of those, 120 (56%) had LTBI. There were no significant differences in age, sex and comorbidities between LTBI and non-LTBI participants, except for recent AMI that was more frequent in LTBI. LTBI participants had higher unstimulated interferon-gamma levels compared to non-LTBI participants (median, interquartile range; 14 pg/mL, 6.5-52.8 vs. 6.5 pg/mL, 4.5-15; P<0.01). LTBI remained associated with higher unstimulated interferon-gamma levels after controlling for age, sex, recent AMI, history of hypertension, diabetes mellitus, dyslipidemia, end stage renal disease, malignancy, obesity, and tobacco use (adjusted odds ratio, 2.93; 95% confidence interval, 1.8-4.9). In a sensitivity analysis that excluded participants with AMI, the association between unstimulated interferon-gamma and LTBI remained present (adjusted odds ratio; 3.93; 95% confidence interval, 1.9-8.2). CONCLUSIONS: LTBI was associated with higher unstimulated interferon-gamma levels. These data suggest ongoing immune activation in LTBI.

Diagnostic Performance and Repeatability of a Novel Game-Based Visual Field Test for Children.

Purpose: To demonstrate utility of a game-based test ("Caspar's Castle") for the detection of visual field defects in children. Methods: A validity and reliability study was carried out at Manchester Royal Eye Hospital Pediatric Ophthalmology Outpatients Department. We recruited 108 children with no eye pathology (aged 4-12 years) and examined a single eye with the Caspar's Castle system using either normal thresholds or thresholds artificially adapted to recreate defects to assess diagnostic utility. Number of peripheral stimuli missed was used to determine sensitivity and specificity of artificial defect detection and to plot receiver-operator characteristic curves. A further 21 children (aged 4-16 years) with pathology were recruited and Caspar's fields compared qualitatively with established field testing. A total of 106 of the Caspar's Castle examinations were able to be performed twice and repeatability was determined through coefficient of repeatability and Bland-Altman chart. Results: In diagnostic testing using children with no eye pathology, 45 children completed a test using normal thresholds and 43 with tests using artificial defects. Area under receiver-operator characteristic curves for artificial defect detection was 0.895. Of the 21 children with pathology, seven had completed standard Humphreys field testing and Caspar's Castle fields corresponded with each of these by expert opinion. Coefficient of repeatability for number of points missed across all cohorts of children (106 patients) was 6.9 (95% confidence interval: 6.16-8.07). Conclusions: The Caspar's Castle system of assessing visual fields using novel game-based strategies demonstrates encouraging levels of sensitivity, specificity, and reliability. It could help address current difficulties in perimetry in young children.

The Relationship Between Latent Tuberculosis Infection and Acute Myocardial Infarction.

Background: Tuberculosis has been associated with an increased risk of cardiovascular disease (CVD), including acute myocardial infarction (AMI). We investigated whether latent tuberculosis infection (LTBI) is associated with AMI. Methods: We conducted a case-control study in 2 large national public hospital networks in Lima, Peru, between July 2015 and March 2017. Case patients were patients with a first time diagnosis of type 1 (spontaneous) AMI. Controls were patients without a history of AMI. We excluded patients with known human immunodeficiency virus infection, tuberculosis disease, or prior LTBI treatment. We used the QuantiFERON-TB Gold In-Tube assay to identify LTBI. We used logistic regression modeling to estimate the odds ratio (OR) of LTBI in AMI case patients versus non-AMI controls. Results: We enrolled 105 AMI case patients and 110 non-AMI controls during the study period. Overall, the median age was 62 years (interquartile range, 56-70 years); 69% of patients were male; 64% had hypertension, 40% dyslipidemia, and 39% diabetes mellitus; 30% used tobacco; and 24% were obese. AMI case patients were more likely than controls to be male (80% vs 59%; P < .01) and tobacco users (41% vs 20%; P < .01). LTBI was more frequent in AMI case patients than in controls (64% vs 49% [P = .03]; OR, 1.86; 95% confidence interval [CI], 1.08-3.22). After adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, tobacco use, obesity, and family history of coronary artery disease, LTBI remained independently associated with AMI (adjusted OR, 1.90; 95% CI, 1.05-3.45). Conclusions: LTBI was independently associated with AMI. Our results suggest a potentially important role of LTBI in CVD.

Normal Threshold Size of Stimuli in Children Using a Game-Based Visual Field Test.

INTRODUCTION: The aim of this study was to demonstrate and explore the ability of novel game-based perimetry to establish normal visual field thresholds in children. METHODS: One hundred and eighteen children (aged 8.0 ± 2.8 years old) with no history of visual field loss or significant medical history were recruited. Each child had one eye tested using a game-based visual field test 'Caspar's Castle' at four retinal locations 12.7° (N = 118) from fixation. Thresholds were established repeatedly using up/down staircase algorithms with stimuli of varying diameter (luminance 20 cd/m2, duration 200 ms, background luminance 10 cd/m2). Relationships between threshold and age were determined along with measures of intra- and intersubject variability. RESULTS: The Game-based visual field test was able to establish threshold estimates in the full range of children tested. Threshold size reduced with increasing age in children. Intrasubject variability and intersubject variability were inversely related to age in children. CONCLUSIONS: Normal visual field thresholds were established for specific locations in children using a novel game-based visual field test. These could be used as a foundation for developing a game-based perimetry screening test for children.

Development of a Pediatric Visual Field Test.

PURPOSE: We describe a pediatric visual field (VF) test based on a computer game where software and hardware combine to provide an enjoyable test experience. METHODS: The test software consists of a platform-based computer game presented to the central VF. A storyline was created around the game as was a structure surrounding the computer monitor to enhance patients' experience. The patient is asked to help the central character collect magic coins (stimuli). To collect these coins a series of obstacles need to be overcome. The test was presented on a Sony PVM-2541A monitor calibrated from a central midpoint with a Minolta CS-100 photometer placed at 50 cm. Measurements were performed at 15 locations on the screen and the contrast calculated. Retinal sensitivity was determined by modulating stimulus in size. To test the feasibility of the novel approach 20 patients (4-16 years old) with no history of VF defects were recruited. RESULTS: For the 14 subjects completing the study, 31 ± 15 data points were collected on 1 eye of each patient. Mean background luminance and stimulus contrast were 9.9 ± 0.3 cd/m2 and 27.9 ± 0.1 dB, respectively. Sensitivity values obtained were similar to an adult population but variability was considerably higher - 8.3 ± 9.0 dB. CONCLUSIONS: Preliminary data show the feasibility of a game-based VF test for pediatric use. Although the test was well accepted by the target population, test variability remained very high. TRANSLATIONAL RELEVANCE: Traditional VF tests are not well tolerated by children. This study describes a child-friendly approach to test visual fields in the targeted population.

A feasibility study to prevent falls in older people who are sight impaired: the VIP2UK randomised controlled trial.

BACKGROUND: Published evaluations of successful interventions to prevent falls in people with sight impairment (SI) are limited. The aim of this feasibility study is to optimise the design and investigation of home safety (HS) and home exercise (HE) programmes to prevent falls in older people with SI. METHODS: A community-based feasibility study in north-west England comprising a three-arm randomised controlled trial (RCT) allocated participants to (1) a control group receiving usual care and social visits, (2) an experimental group receiving the HS programme and (3) an experimental group receiving the HS + HE programme. Participants were community-dwelling, aged 65 years and older and sight impaired. Primary outcome data on falls were collected continuously over 6 months. Secondary outcomes on physical activity (self-report and instrumented) and adherence were collected at baseline and 3 and 6 months for HE and at 6 months for the HS programme. Costs for the HS and HS + HE groups were calculated from logs of time spent on home visits, telephone calls and travel. The research assistant and statistician were blinded to group allocation. RESULTS: Altogether, 49 people were recruited over a 9-month period (randomised: 16 to control, 16 to HS, 17 to HS + HE). The interventions were implemented over 6 months by an occupational therapist at a cost per person (pounds sterling, 2011) of £249 (HS) and £674 (HS + HE). Eighty-eight percent (43/49) completed the trial and 6-month follow-up. At 6-month follow-up, 100 % reported partially or completely adhering to HS recommendations but evidence for adherence to HE was equivocal. Although self-reported physical activity increased, instrumented monitoring showed a decrease in walking activity. There were no statistically significant differences in falls between the groups; however, the study was not powered to detect a difference. CONCLUSION: It is feasible and acceptable for an occupational therapist to deliver HS and HE falls prevention programmes to people with SI living independently in the community. Future studies could access Local Authority Registers of people with SI to improve recruitment rates. Further research is required to identify how to improve adherence to HE and to measure changes in physical activity before conducting a definitive RCT. TRIAL REGISTRATION: ISRCTN53433311 , registered on 8 May 2014.

Tuberculosis and Cardiovascular Disease: Linking the Epidemics.

The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics. Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, subsets of mycobacteria actively replicate during latent tuberculosis infection (LTBI), and recent studies suggest that LTBI is associated with persistent chronic inflammation that may lead to CVD. Recent epidemiologic work has shown that the risk of CVD in persons who develop tuberculosis is higher than in persons without a history of tuberculosis, even several years after recovery from tuberculosis. Together, these data suggest that tuberculosis may play a role in the pathogenesis of CVD. Further research to investigate a potential link between tuberculosis and CVD is warranted.

A silencer-proximal intronic region is required for sustained CD4 expression in postselection thymocytes.

It has been proposed that differential kinetics of CD4/CD8 coreceptors regulate fate choice of selected thymocytes. Sustained signals by interaction between MHC class II and TCR/CD4 is required for commitment to the CD4 helper lineage. Although prematurely terminated MHC-TCR/CD4 interaction in transgenic mouse models results in lineage redirection, it is unclear whether CD4 expression is actively maintained by endogenous cis-elements to facilitate prolonged signaling under physiological conditions. In this article, we show that sustained CD4 expression in postselection thymocytes requires an intronic sequence containing an uncharacterized DNase I hypersensitivity (DHS) site located 3' to the silencer. Despite normal CD4 expression before selection, thymocytes lacking a 1.5-kb sequence in intron 1 including the 0.4-kb silencer and the DHS, but not the 0.4-kb silencer alone, failed to maintain CD4 expression upon positive selection and are redirected to the CD8 lineage after MHC class II-restricted selection. Furthermore, CpG dinucleotides adjacent to the DHS are hypermethylated in CD8(+) T cells. These results indicate that the 1.5-kb cis-element is required in postselection thymocytes for helper lineage commitment, presumably mediating the maintenance of CD4 expression, and suggest that inactivation of the cis-element by DNA methylation may contribute to epigenetic Cd4 silencing.