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Subclinical myocardial dysfunction is prevalent among well-treated persons with HIV (PWH). We have previously demonstrated unique renin-angiotensin-aldosterone system physiology among PWH with metabolic dysregulation. Mineralocorticoid receptor blockade may be a targeted treatment strategy for subclinical heart disease in PWH. Forty-six PWH were randomized to receive either eplerenone 50 mg daily or placebo in a 6-month randomized, double-blinded, placebo-controlled trial. We assessed changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker of cardiac stretch, under controlled posture and dietary conditions. The eplerenone- and placebo-treated groups demonstrated a long duration of HIV with good immunological control. NT-proBNP levels were similar between the groups at baseline (41.1 [20.2, 97.9] vs 48.9 [29.2, 65.4] ng/L, P =.80) and decreased significantly more in the eplerenone- vs placebo-treated groups after 6 months (change NT-proBNP -9.6 [-46.8, 0.3] vs -3.0 [-17.0, 39.9] ng/L, P =.02 for comparison of change between groups). Decreases in NT-proBNP were independent of changes in systolic and diastolic blood pressure, and related to decreases in high-sensitivity C-reactive protein (ρ = 0.32, P =.05) and inversely to increases in serum aldosterone (ρ = -0.33, P =.04) among all participants. Treatment with eplerenone for 6 months vs placebo significantly decreases NT-proBNP levels among PWH, independent of eplerenone's known blood pressure-lowering effects. Further studies should elucidate whether lowering NT-proBNP in this at-risk metabolic population with subclinical heart disease will offer cardioprotection. Clinical Trial Registration NCT01405456 [ABSTRACT FROM AUTHOR]

This study examined the effects of an inspiratory muscle exercise as part of a warm-up (IMW) using a resisted breathing trainer on running performance. In a randomized crossover design, 17 trained distance runners completed two 3,200-m performance trials on separate days, preceded by 2 different warm-up procedures: IMW or sham IMW (CON). In each condition, subjects performed 30 breaths against either 50% of each athlete's peak strength (IMW) or 30 slow protracted breaths against negligible resistance (CON). Perceived race readiness and inspiratory muscle strength, flow, power, and volume were measured before and after each warm-up. Heart rate (HR), rating of perceived exertion (RPE) and dyspnea (RPD), and expired gases were collected during each trial. A 3,200-m run performance was 2.8% ± 1.5% (20.4-second) faster after IMW (effect size [ES] = 0.37, p = 0.02). After each warm-up condition, there was as small effect on peak inspiratory strength (6.6 ± 4.8%, ES = 0.22, p = 0.02), flow (5.2 ± 4.4%, ES = 0.20, p = 0.03), power (17.6 ± 16.7%, ES = 0.22, p = 0.04), and volume (6.7 ± 6.3%, ES = 0.24, p = 0.01) after IMW compared with CON. There were no differences in HR, minute volume, peak VO2, or VO2 at each 800-m interval between conditions (ES ≤ 0.13, p > 0.17). There were small differences in RPE at 800 m and 1,600 m (ES = 0.32, p = 0.17; ES = 0.21, p = 0.38, respectively), but no difference at the last 1,600 m (p = 1.0). There was a moderate positive effect on RPD (ES = 0.81, p < 0.001) and race readiness (ES = 0.76, p < 0.01) after IMW. Overall, the data suggest that IMW improves 3,200-m performance because of enhancements in inspiratory muscle function characteristics and reduction in dyspnea. [ABSTRACT FROM AUTHOR]

The article reports on the importance and guidelines of injection techniques for diabetes. Topics discussed include the lack of detailed advice on injection technique, the introduction of the Forum for Injection Technique (FIT), and how to improve the knowledge and skills of nurses on the subject. Also provided is information on the consequence of a poor injection method on glycaemic control.

Background: Self-monitoring of glucose is an essential component of type 1 diabetes (T1D) management. In recent years, continuous glucose monitoring (CGM) has provided an alternative to daily fingerstick testing for the optimisation of insulin dosing and general glucose management in people with T1D. While studies have been conducted to evaluate the impact of CGM on clinical outcomes in the US, Europe and Australia, there are limited data available for low- and middle-income countries (LMICs) and further empirical evidence is needed to inform policy decision around their use in these countries., Methods: This trial was designed as a pragmatic, parallel-group, open-label, multicentre, three-arm, randomised (1:1:1) controlled trial of continuous or periodic CGM device use versus standard of care in people with T1D in South Africa and Kenya. The primary objective of this trial will be to assess the impact of continuous or periodic CGM device use on glycaemic control as measured by change from baseline glycosylated haemoglobin (HbA1c). Additional assessments will include clinical outcomes (glucose variation, time in/below/above range), safety (adverse events, hospitalisations), quality of life (EQ-5D, T1D distress score, Glucose Monitoring Satisfaction Survey for T1D), and health economic measures (incremental cost-effectiveness ratios, quality adjusted life years)., Discussion: This trial aims to address the substantial evidence gap on the impact of CGM device use on clinical outcomes in LMICs, specifically South Africa and Kenya. The trial results will provide evidence to inform policy and treatment decisions in these countries., Trial Registration: NCT05944731 (Kenya), July 6, 2023; NCT05944718 (South Africa), July 13, 2023., (© 2024. The Author(s).)

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective preventive vaccination to reduce burden and spread of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) in humans. Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry before viral spread to the lung. Although SARS-CoV-2 vaccine development is rapidly progressing, the current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. Here, we show that AdCOVID, an intranasal adenovirus type 5 (Ad5)-vectored vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, elicits a strong and focused immune response against RBD through the induction of mucosal IgA, serum neutralizing antibodies and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. Therefore, AdCOVID, which promotes concomitant systemic and local mucosal immunity, represents a promising COVID-19 vaccine candidate.

Introduction: The aim of this study was to evaluate the spectrum of skeletal findings on dual-phase fluorine-18-fluoroethylcholine (F-FECH) PET/CT performed during the work-up of patients referred for suspected prostate cancer relapse., Materials and Methods: Three hundred F-FECH PET/CT scans were evaluated prospectively. The low-dose CT features of all cases were categorized as isodense, sclerotic, lytic or mixed lytic/sclerotic and maximum standardized uptake value (SUVmax) values were calculated. Findings on F-FECH PET/CT were correlated with Technetium-99m-methylene diphosphonate planar bone scans and serum prostate-specific antigen., Results: Patient age range was 50-90 years (median 71 years) and prostate-specific antigen values were in the range 0.04-372 ng/ml (Roche Modular method). Seventy-two lesions were detected on F-FECH PET/CT in 45 patients, including 31 (43%) in the pelvis, 17 (23%) in the spine (cervical 3, thoracic 8 and lumbar spine 6) and 10 (13%) in the ribs. Evaluation of low-dose CT in combination with PET helped to characterize benign findings in 21 (29%) lesions. The SUVmax for all except one benign lesion ranged from 0.49 to 2.15. In 51 (71%) lesions because of metastatic disease, SUVmax was 0.6-11.6 for those classified as sclerotic on low-dose CT, 0.7-8.58 for lytic lesions, 1.1-7.65 for isodense lesions and 1.27-3.53 for mixed lytic/sclerotic lesions. Of the 56 F-FECH-avid lesions, 21 lesions showed avidity on bone scan [3 (23%) of the 13 isodense lesions, 14 (40%) of the 35 sclerotic lesions, 2 (50%) of the lytic lesions and 2 (50%) of the mixed sclerotic/lytic lesions]., Conclusion: F-FECH PET/CT identified bone lesions in 15% of patients with suspected prostate cancer relapse. SUVmax in isolation cannot be used to characterize these lesions as benign or malignant. Minimal overlap of benign and malignant lesions was observed above SUVmax of 2.5. Low-dose CT of PET/CT is a useful tool to aid characterization.

Myocardial perfusion imaging is a well-established and widely used imaging technique for the assessment of patients with known or suspected coronary artery disease. Pitfalls and artifacts associated with conventional gamma cameras are well known, and the ways to avoid and correct them have been described. In recent years solid-state detector dedicated cardiac cameras were introduced and have been shown to offer improved accuracy in addition to new imaging protocols and novel applications. The purpose of this manuscript is to familiarize the readers with the causes and effects of technical, patient-related, and operator-related pitfalls and artifacts associated with the D-SPECT dedicated cardiac camera with solid-state detectors. The manuscript offers guidance on how to avoid these factors, how to detect them, and how to correct better for them, providing high-quality diagnostic images.

Background: Bone marrow stem cell (BMSC) therapy for cardiovascular disease has shown considerable preclinical and clinical promise, but there remains a need for mechanistic studies to help bridge the transition from bench to bedside. We have designed a substudy to our REGENERATE-IHD trial (ClinicalTrial.gov Identifier: NCT00747708) to assess the feasibility of a novel imaging technique to detect angiogenesis following BMSC therapy., Methods and Results: Nine patients who had been randomized to receive intracoronary injection of G-CSF-mobilized BMSCs or control (serum) were included in this substudy. Patients underwent SPECT imaging using a novel radiolabelled peptide (Tc-NC100692), which has a high affinity for the αvβ3 integrin, an angiogenesis-related integrin. This was repeated 4 days after intracoronary injection of BMSCs/control to assess for neoangiogenesis. The imaging study was well tolerated with no adverse effects. Myocardial tracer uptake was detectable at baseline in all nine patients, with no myocardial uptake seen in two control patients used for comparison. Baseline uptake appeared to correlate with baseline ejection fraction but changes with therapy did not reach statistical significance., Conclusion: SPECT imaging with a Tc-NC100692 is feasible in patients with heart failure, with baseline activity suggesting persistent angiogenesis in patients with remote myocardial infarction.

Purpose: We have assessed whether additional upright imaging increases the confidence of interpretation of stress only supine myocardial perfusion imaging (MPI) in obese patients., Methods and Results: Tc-MIBI stress MPI of 101 consecutive patients (M = 49, 62 ± 12 years) with BMI ≥30 scanned on the D-SPECT cardiac camera were assessed. Images were interpreted as diagnostic or equivocal and the need for a rest study was recorded. Stress supine MPI was interpreted first, then gated and finally upright data were added. Defects on supine but not on upright were defined as artefacts and defects seen on both as abnormal. The total perfusion deficit (TPD) was also quantified. There were 27 normal, 22 abnormal, and 52 equivocal supine scans. The median EF was 52%, unaffecting the need for rest imaging. Upright imaging reclassified 32/52 (62%) equivocal studies as normal and 6/52 (11%) as abnormal (P < 0.001). Rest scan was deemed needed in 74/101 patients on supine vs 42/101 on supine/upright (P < 0.001). Supine TPD was normal in 53 and supine/upright TPD was normal in 70 patients (P < 0.001)., Conclusion: Supine stress MPI is inadequate in obese patients. The addition of upright imaging significantly increases the ability to interpret scans as diagnostic and may reduce considerably the need for rest imaging.

Objectives: The aim of the study was to evaluate the value of single-photon emission computerized tomography/computed tomography (SPECT/CT) in the clinical assessment of painful knee prostheses., Materials and Methods: Between 2009 and 2011 we identified 105 patients who had undergone Tc-hydroxydiphosphonate SPECT/CT for painful knee prosthesis. Complete follow-up data were available for 69 patients (50 women and 19 men; mean age, 71 years) with painful knee prostheses (59 total, nine unicompartmental, one patellofemoral) and clinical suspicion of infection or loosening. The imaging test report in conjunction with the clinical data from the patient's notes was used to gauge how useful the test had been in terms of patient management., Results: SPECT/CT confirmed the suspected clinical diagnosis of loosening in nine patients (13%) and of infection in two (2.9%) and identified other causes in 43 patients (62.3%). In 85.5% of patients, SPECT/CT was clinically useful (both positive and negative results), whereas in 14.5% it had no clinical impact on patient management. Revision surgery was performed in 24/69 (34.8%) patients and confirmed the SPECT/CT diagnosis in 21 patients (seven loosening, one infection, two subchondral fractures, two postoperative inflammation and nine patellofemoral osteoarthritis)., Conclusion: SPECT/CT is a useful tool for the evaluation of painful knee prosthesis in 85.5% of cases and helps in confirming mechanical loosening and in excluding other causes such as infection and patellofemoral osteoarthritis.

Unlabelled: Myocardial perfusion imaging (MPI) is well established in the diagnosis and workup of patients with known or suspected coronary artery disease (CAD); however, it can underestimate the extent of obstructive CAD. Quantification of myocardial perfusion reserve with PET can assist in the diagnosis of multivessel CAD. We evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional myocardial perfusion reserve using a dedicated solid-state cardiac camera., Methods: Ninety-five consecutive patients (64 men and 31 women; median age, 67 y) underwent dynamic SPECT imaging with (99m)Tc-sestamibi at rest and at peak vasodilator stress, followed by standard gated MPI. The dynamic images were reconstructed into 60-70 frames, 3-6 s/frame, using ordered-subsets expectation maximization with 4 iterations and 32 subsets. Factor analysis was used to estimate blood-pool time-activity curves, used as input functions in a 2-compartment kinetic model. K1 values ((99m)Tc-sestamibi uptake) were calculated for the stress and rest images, and K2 values ((99m)Tc-sestamibi washout) were set to zero. Myocardial perfusion reserve (MPR) index was calculated as the ratio of the stress and rest K1 values. Standard MPI was evaluated semiquantitatively, and total perfusion deficit (TPD) of at least 5% was defined as abnormal., Results: Global MPR index was higher in patients with normal MPI (n = 51) than in patients with abnormal MPI (1.61 [interquartile range (IQR), 1.33-2.03] vs. 1.27 [IQR, 1.12-1.61], P = 0.0002). By multivariable regression analysis, global MPR index was associated with global stress TPD, age, and smoking. Regional MPR index was associated with the same variables and with regional stress TPD. Sixteen patients undergoing invasive coronary angiography had 20 vessels with stenosis of at least 50%. The MPR index was 1.11 (IQR, 1.01-1.21) versus 1.30 (IQR, 1.12-1.67) in territories supplied by obstructed and nonobstructed arteries, respectively (P = 0.02). MPR index showed a stepwise reduction with increasing extent of obstructive CAD (P = 0.02)., Conclusion: Dynamic tomographic imaging and quantification of a retention index describing global and regional perfusion reserve are feasible using a solid-state camera. Preliminary results show that the MPR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. Further studies are needed to establish the clinical role of this technique as an aid to semiquantitative analysis of MPI.

We investigated CD45RA and CCR7 expression in CD4+ and CD8+ subsets of cerebrospinal fluid (CSF) lymphocytes, both immediately ex vivo and after stimulation, from 134 patients with a variety of inflammatory and non-inflammatory neurological diseases. Most inflammatory diseases had a higher CD4+:CD8+ ratio and higher percentage of effector memory T cells (T(EM)) than non-inflammatory controls, excluding active infection. Moreover, we found that patients with highly elevated cell counts in the CSF tended to have a lower percentage of central memory T cells (T(CM)) than patients with low or absent pleocytosis, with a concomitant increase in T(EM). We also found that samples with elevated IgG index or presence of oligoclonal bands had a significantly higher CD4+:CD8+ ratio than normal samples, consistent with increased CD4+ help for intrathecal IgG synthesis by B cells., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8+ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4+ T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8+ memory T cells specific for shared melanoma/melanocyte antigens. CD8+ T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8+ T cell immunity to melanoma. Vitiligo-associated memory CD8+ T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.

Neuroinflammatory diseases such as multiple sclerosis (MS) are characterized by focal regions of demyelination and axonal loss associated with infiltrating T cells. However, the role of activated T cells in causing neuronal injury remains unclear. CD4 and CD8 T cells were isolated from normal donors and polyclonally activated using plate-bound anti-CD3 and soluble anti-CD28. The conditioned T cell supernatants caused toxicity to cultured human fetal neurons, which could be blocked by immunodepleting the supernatants of granzyme B (GrB). Recombinant GrB also caused toxicity in neurons by caspase-dependent pathways but no toxicity was seen in astrocytes. The neurotoxicity was independent of perforin and could not be blocked by mannose-6-phosphate. However, GrB-induced neurotoxicity was sensitive to pertussis toxin, implicating the stimulation of Gialpha protein-coupled receptors. GrB caused a decrease in cAMP levels but only modest increases in intracellular calcium. The effect on intracellular calcium could be markedly potentiated by stromal-derived factor 1alpha. GrB-induced neurotoxicity could also be blocked by vitamin E and a neuroimmunophilin ligand. In conclusion, GrB may be an important mediator of neuronal injury in T cell-mediated neuroinflammatory disorders.

Multiple Sclerosis (MS) is characterized by central nervous system perivenular and parenchymal mononuclear cell infiltrates consisting of activated T cells and macrophages. We recently demonstrated that elevated expression of the voltage-gated potassium channel, Kv1.3, is a functional marker of activated effector memory T (T(EM)) cells in experimental allergic encephalomyelitis and in myelin-specific T cells derived from the peripheral blood of patients with MS. Herein, we show that Kv1.3 is highly expressed in postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3(+) T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7(-)), consistent with an effector memory phenotype. Using double-labeling immunohistochemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7(+) central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3(high)/CCR7(-) T(EM), suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become T(EM). These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.

Background: Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting T(H)2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials., Objective: To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes., Design: Before-and-after trial., Setting: A university MS specialty center., Patients: Ten patients with relapsing-remitting MS., Interventions: Treatment with glatiramer for 12 months and serial phlebotomy., Main Outcome Measures: Cytokine production, CKR expression, and cell migration., Results: The glatiramer-reactive T cells were T(H)2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the T(H)1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells., Conclusions: Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery.

We explored the kinetics of CCR7 expression on T(H)1 and T(H)2 polarized cells as well as on antigen-specific T cell lines at various stages of differentiation. A striking pattern of early (days 7-14) inducible CCR7 expression was seen preferentially on primary T(H)1 cell lines, as compared to T(H)2 cells, and was dependent on the strength and duration of the T cell receptor signal. Upon repeated restimulation (days 21-28) and differentiation, a switch occurred in which T(H)2 cells had high CCR7 expression, whereas T(H)1 cells lost CCR7 expression. Chronic (8 weeks and later) effector memory cell lines were 95% CCR7 negative. These data demonstrate an ordered pattern of CCR7 expression that suggest more rapid priming of T(H)1 cells in the lymph node, and delayed priming with prolonged CCR7 expression during T(H)2 responses, and may have implications for tracking T(H)1 effector T cells ex vivo in autoimmune diseases.

Through a combination of fluorescence microscopy and patch-clamp analysis we have identified a striking alteration in K(+) channel expression in terminally differentiated human CCR7(-)CD45RA(-) effector memory T lymphocytes (T(EM)). Following activation, T(EM) cells expressed significantly higher levels of the voltage-gated K(+) channel Kv1.3 and lower levels of the calcium-activated K(+) channel IKCa1 than naive and central memory T cells (T(CM)). Upon repeated in vitro antigenic stimulation, naive cells differentiated into Kv1.3(high)IKCa1(low) T(EM) cells, and the potent Kv1.3-blocking sea anemone Stichodactyla helianthus peptide (ShK) suppressed proliferation of T(EM) cells without affecting naive or T(CM) lymphocytes. Thus, the Kv1.3(high)IKCa1(low) phenotype is a functional marker of activated T(EM) lymphocytes. Activated myelin-reactive T cells from patients with MS exhibited the Kv1.3(high)IKCa1(low) T(EM) phenotype, suggesting that they have undergone repeated stimulation during the course of disease; these cells may contribute to disease pathogenesis due to their ability to home to inflamed tissues and exhibit immediate effector function. The Kv1.3(high)IKCa1(low) phenotype was not seen in glutamic acid decarboxylase, insulin-peptide or ovalbumin-specific and mitogen-activated T cells from MS patients, or in myelin-specific T cells from healthy controls. Selective targeting of Kv1.3 in T(EM) cells may therefore hold therapeutic promise for MS and other T cell-mediated autoimmune diseases.

Cytokine-polarized T cells have distinct chemokine receptor (CKR) expression patterns associated with their cytokine secretion profiles. In order to investigate this paradigm in autoreactive human T cells, we have determined the CKR expression pattern of myelin basic protein (MBP)-reactive T cell lines (TCL) and compared these profiles to those of TCL-generated in response to tetanus toxoid (TT). Expression of CXCR6 and CXCR3 on TCL was significantly positively correlated with IFNgamma, and inversely correlated with IL-5 production. TT TCL had significantly higher expression of CCR7(-)/CD45RA(-) T effector memory (Tem) cells than MBP TCL. However, in MBP-specific TCL, CXCR6 was found to be the best marker of conversion to the Tem phenotype. CXCR6 and CXCR3 are likely to be important in the migration of effector memory T cells in Th1-mediated inflammatory diseases such as multiple sclerosis (MS).