Assessing the quality of cardiac rehabilitation programs by measuring adherence to the Australian quality indicators.

BACKGROUND: Every year, over 65,000 Australians experience an acute coronary syndrome (ACS) and around one-third occur in people with prior coronary heart disease. Cardiac rehabilitation (CR) aims to prevent a repeat ACS by supporting patients' return to an active and fulfilling lifestyle. CR programs are efficacious, but audits of clinical practice show variability of program delivery, which may compromise patient outcomes. Core components, quality indicators and accreditation of programs have been introduced internationally to increase program standardisation. With Australian quality indicators (QIs) for cardiac rehabilitation recently introduced, we aimed to conduct a survey in one state of Australia to assess the extent to which programs adhere to the measurement of QIs comparing country, metropolitan, telephone and face to face programs. METHODS: A cross- sectional survey design with face validity testing was used to formulate questions to evaluate cardiac rehabilitation program and personnel characteristics and QI adherence. Between October 2020- December 2021, 23 cardiac rehabilitation programs across country and metropolitan areas were invited to participate. Quality improvement was defined as adherence to the Australian Quality Indicators, and we developed an objective score to calculate program performance categorised by quartiles. Significance of CR completion and time to enrolment between program type (telephone versus face to face) and location (country versus metropolitan were compared using Pearson's Chi-square and Mann-Whitney U tests. RESULTS: Among the 23 CR programs, 15 were country and 8 metropolitan-based and 22 were face to face and 1 telephone-based. Median wait time from discharge was 27.0 days, (interquartile range 19.3-46.0) across all programs and country completions of enrolled were 76.9% versus metropolitan 56.5%, p < 0.001 and telephone versus face to face 92.9% versus 59.6% p < 0.001. Pre-program QI adherence was higher than post program for depression, medication adherence, health-related quality of life and comprehensive re-assessment. Seventy four percent of programs were ranked at a medium level of performance (mean score: 11.4/16, SD ± 0.79). CONCLUSIONS: A survey of 23 cardiac rehabilitation programs, showed variability in adherence to measurement of the Australian Cardiovascular and Rehabilitation Association and Australian Heart Foundation Cardiac Rehabilitation Quality Indicators. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12621000222842 , registered 03/03/2021.

New tuberculosis vaccines: advances in clinical development and modelling.

Tuberculosis remains a major source of morbidity and mortality worldwide, with 10 million cases and 1.5 million deaths in 2018. Achieving 'End TB' prevention and care goals by 2035 will likely require a new tuberculosis vaccine. The tuberculosis vaccine development pipeline has seen encouraging progress; however, questions around their population impact and implementation remain. Mathematical modelling investigates these questions to inform vaccine development and deployment strategies. We provide an update on the current vaccine development pipeline, and a systematic literature review of mathematical modelling of the epidemiological impact of new tuberculosis vaccines. Fourteen prophylactic tuberculosis vaccine candidates are currently in clinical trials. Two candidates have shown promise in phase II proof-of-concept efficacy trials: M72/AS01E demonstrated 49.7% (95% CI; 2.1, 74.2) protection against tuberculosis disease, and BCG revaccination demonstrated 45.4% (95% CI; 6.4, 68.1) protection against sustained Mycobacterium tuberculosis infection. Since the last modelling review, new studies have investigated the epidemiological impact of differential vaccine characteristics, age targeting and spatial/risk group targeting. Critical research priorities for M72/AS01E include completing the currently in-design trial, powered to improve the precision of efficacy estimates, include uninfected populations and further assess safety and immunogenicity in HIV-infected people. For BCG revaccination, the priority is completing the ongoing confirmation of efficacy trial. Critical modelling gaps remain on the full value proposition of vaccines, comparisons with other interventions and more realistic implementation strategies. Using carefully designed trials and modelling, we must prepare for success, to ensure that new vaccines will be promptly received by those most in need.

Standing balance post total knee arthroplasty: sensitivity to change analysis from four to twelve weeks in 466 patients.

OBJECTIVE: Little is known about how static standing balance changes post total knee arthroplasty (TKA). The primary aim of this study was to examine the sensitivity to change and redundancy of center of pressure (COP) variables post-TKA. The secondary aim was to compare the sensitivity of these measures to standard clinical assessments of one repetition maximum knee extension strength and fast pace gait speed. DESIGN: 466 participants performed instrumented double-limb standing balance tests with eyes open at 4 and 12 weeks post-TKA. Measures of COP standard deviation, amplitude, root mean square (RMS), path length, detrended fluctuation analysis (DFA) and signal frequency content for the medial-lateral (ML) and anterior-posterior (AP) axes were examined. RESULTS: Significant decreases in total path length, ML variables related to sway velocity and AP signal complexity and frequency were observed. Inter-session Cohen's d effect size (ES) revealed the strongest effect was for high velocity ML path length, with a 12% decrease in this rapid sway. This variable, along with AP mean instantaneous frequency and AP DFA, were the only ones significantly different with effect sizes >0.20 and non-redundant (Spearman's rho <0.75). The ES of COP-derived variables (maximum = 0.45) were lower than gait speed (1.40) and knee extensor strength (1.54). CONCLUSION: Increased high velocity ML sway is present at four compared to 12 weeks post-TKA. This augmented rapid sway may provide increased challenges to the postural control system at a time coinciding with reduced strength levels, which could have implications for physical function during activities of daily living.

Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice.

PPARδ (peroxisome proliferator-activated receptor δ) mediates inflammation in response to lipid accumulation. Systemic administration of a PPARδ agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPARδ in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPARδ expression in these cells may mitigate atherogenesis. To advance this finding forward to potential clinical translation through hematopoietic stem cell transplantation-based gene therapy, we employed a microRNA (miRNA) approach to knock down PPARδ expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPARδ expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPARδ led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ß and IL-6. Expression of CCR2, a receptor for MCP-1, was also decreased. The downregulation of pro-inflammatory factors is consistent with significant reduction of macrophage presence in the lesions, which may also be attributable to elevation of ABCA1 (ATP-binding cassette, subfamily A, member 1) and depression of adipocyte differentiate-related protein. Furthermore, the abundance of both MCP-1 and matrix metalloproteinase-9 proteins was reduced in plaque areas. Our results demonstrate that miRNA-mediated PPARδ knockdown in hematopoietic cells is able to ameliorate atherosclerosis.

Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Novel application of high-dose rate brachytherapy for severe, recalcitrant palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is a chronic pustular dermatitis of the palms and soles, which is frequently associated with significant pruritus and pain, often limiting daily activities. We present the case of a 36-year-old man with severe PPP who had treatment failure with multiple medical therapies but showed marked improvement with high-dose rate brachytherapy. Brachytherapy has the advantage of providing a conformal dose distribution over complex curved surfaces, such as the foot and ankle. Our observations suggest that brachytherapy may be a well-tolerated treatment option for patients with severe, refractory PPP.

Heart failure following cancer treatment: characteristics, survival and mortality of a linked health data analysis.

BACKGROUND: Cardiotoxicity resulting in heart failure is a devastating complication of cancer therapy. A patient may survive cancer only to develop heart failure (HF), which has a higher mortality rate than some cancers. AIM: This study aimed to describe the characteristics and outcomes of HF in patients with blood or breast cancer after chemotherapy treatment. METHODS: Queensland Cancer Registry, Death Registry and Hospital Administration records were linked (1996-2009). Patients were categorised as those with an index HF admission (that occurred after cancer diagnosis) and those without an index HF admission (non-HF). RESULTS: A total of 15 987 patients was included, and 1062 (6.6%) had an index HF admission. Median age of HF patients was 67 years (interquartile range 58-75) versus 54 years (interquartile range 44-64) for non-HF patients. More men than women developed HF (48.6% vs 29.5%), and a greater proportion in the HF group had haematological cancer (83.1%) compared with breast cancer (16.9%). After covariate adjustment, HF patients had increased mortality risk compared with non-HF patients (hazard ratios 1.67 (95% confidence interval, 1.54-1.81)), and 47% of the index HF admission occurred within 1 year from cancer diagnosis and 70% within 3 years. CONCLUSION: Cancer treatment may place patients at a greater risk of developing HF. The onset of HF occurred soon after chemotherapy, and those who developed HF had a greater mortality risk.

Early changes in Achilles tendon behaviour in vivo following downhill backwards walking.

Downhill backwards walking causes repeated, cyclical loading of the muscle-tendon unit. The effect this type of repeated loading has on the mechanical behaviour of the Achilles tendon is presently unknown. This study aimed to investigate the biomechanical response of the Achilles tendon aponeurosis complex following a downhill backwards walking protocol. Twenty active males (age: 22.3 ± 3.0 years; mass: 74.7 ± 5.6 kg; height: 1.8 ± 0.7 m) performed 60 min of downhill (8.5°), backwards walking on a treadmill at -0.67 m · s(-1). Data were collected before, immediately post, and 24-, 48- and 168-h post-downhill backwards walking. Achilles tendon aponeurosis elongation, strain and stiffness were measured using ultrasonography. Muscle force decreased immediately post-downhill backward walking (P = 0.019). There were increases in Achilles tendon aponeurosis stiffness at 24-h post-downhill backward walking (307 ± 179.6 N · mm(-1), P = 0.004), and decreases in Achilles tendon aponeurosis strain during maximum voluntary contraction at 24 (3.8 ± 1.7%, P = 0.008) and 48 h (3.9 ± 1.8%, P = 0.002) post. Repeated cyclical loading of downhill backwards walking affects the behaviour of the muscle-tendon unit, most likely by altering muscle compliance, and these changes result in tendon stiffness increases.

Associations of calf inter- and intra-muscular adipose tissue with cardiometabolic health and physical function in community-dwelling older adults.

OBJECTIVES: To determine associations of inter- and intra-muscular adipose tissue (IMAT) with cardiometabolic health and physical function in older adults. METHODS: 48 community-dwelling older adults aged ⋝65 years (mean 71.6±4.8 years; 52% women) underwent whole-body dual-energy X-ray absorptiometry, to assess appendicular lean mass (ALM), and peripheral quantitative computed tomography (pQCT; 66% tibia), to assess calf IMAT cross-sectional area ([CSA]; cm2) and muscle density (mg/cm(3); higher values indicate lower fat infiltration). Fasting glucose, lipids, triglycerides and C-reactive protein (CRP) were analysed. Physical function was assessed by postural sway (computerised posturography; N=41), and gait analysis (GAITRite Electronic Walkway; N=40). RESULTS: Higher IMAT CSA and muscle density were associated with significantly higher (B=0.85 95%CI [0.34, 1.36]) and lower (-2.14 [-4.20, -0.08]) CRP and higher (0.93 [0.56, 1.30]) and lower postural sway (-3.12 [-4.74, -1.50]), respectively, after adjustment for age, sex and ALM/BMI. Higher IMAT CSA was associated with slower gait speed and cadence, and greater step time and step width (all P<0.03), while higher muscle density was associated with smaller step width (P<0.01) only. CONCLUSIONS: Older adults with higher calf IMAT have poorer balance, mobility and inflammatory status. Interventions aimed at improving physical function in older adults should incorporate strategies to reduce IMAT.

Does hospital design impact on patient activity levels and time spent alone?

PURPOSE: The aim of this study was to quantify changes in patients' activity levels, location and people present, within one acute stroke unit (ASU) and one inpatient rehabilitation unit (IRU) with respect to change in hospital design. METHODS: A prospective observational study using behavioural mapping. We observed participants from 8 am till 5 pm every 10 minutes across two days and compared participant activity (physical, social and cognitive), location and people present pre and post-transition to new units. Built design, staffing levels and models of care were contrasted. RESULTS: We recruited 73 participants (63% stroke): old-ASU (n = 19); new-ASU (n = 15); old-IRU (n = 19); new-IRU (n = 20). Compared to old, new units had more single rooms, larger floor spaces and higher staffing levels. We found no significant change in participants' activity levels between the old and new ASU. Participants in the new IRU showed increased physical activity (43.4% vs. 54.4%, p = 0.02) but social and cognitive activity remained similar. Participants were more alone (ASU 47.4% vs. 66.7%, p = 0.01; IRU 41.7% vs. 58.3%, p < 0.001), and less often with nursing staff (ASU 17.7% vs. 6.7%, p = 0.04; IRU 18.8% vs. 5.7%, p < 0.001) in new units. CONCLUSION: Hospital design appears to impact on patients' physical activity. Single rooms may increase isolation and reduce interaction with nursing staff.Implications for rehabilitationDesign of new rehabilitation units needs to consider patients' social engagement with family, friends, other patients and staff in addition to privacy and infection control.A change in built design of rehabilitation units should prompt observation of patients' activity levels and engagement with people and available space to ensure optimal use of new environments.Promotion of communal spaces and activities away from the bedroom to encourage social engagement is recommended for patients recovering in rehabilitation facilities.Less time in contact with nursing staff in rehabilitation environments with predominantly single rooms suggests a review of clinical practice and patient safety is warranted.

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR(-/-) mice.

Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRα (Lenti-SP-LXRα) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRα mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRα gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR(-/-) mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.

Wound repair in the context of extracellular matrix.

Wound repair requires a continually evolving network of interactions among cells, cytokines and the extracellular matrix. Cell-surface integrins provide a mechanical connection between matrix components and the cytoskeleton, and integrins can transduce an astonishing variety of signals along pathways that may intercept the pathways triggered by cytokine receptors.

Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-641 allele were found in African Americans but not in Caucasians, and the SDF1-3'A/3'A genotype was associated with an accelerated progression to death. In contrast, the CCR5-delta32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system.

A cytotoxic effect of human neutrophils on mammalian tumor cells is demonstrated. Cytotoxicity depends on the presence of intact neutrophils, phagocytosable particles, and a halide cofactor and is inhibited by azide, cyanide, and catalase. Neutrophils from patients with myeloperoxidase (MPO) deficiency or defective H1O2 production are not cytotoxic, but activity is resotred by addition of purified MPO or H2O2 respectively. The findings support a mechanism involving the phagocytosis-induced extracellular release of MPO and H2O2 and their reation with a halide cofactor to damage the target cells.

The selective eosinophil chemotactic activity of histamine.

Histamine diphosphate was shown to selectively attract human eosinophils from mixed granulocyte populations when over 20% eosinophils were used in a modified Boyden chamber chemotactic assay system. This effect of histamine is abolished by incubation with diamine oxidase (histaminase) and was generated by decarboxylation of L-histidine. A linear dose dependent increase in eosinophil migration was observed between 3 X 10(-7) M and 1.25 X 10(-6) M, while higher concentrations of histamine inhibited the migration of eosinophils. The attractant activity of histamine was not inhibited by H-1 or H-2 receptor antagonists, however, the inhibition of migration observed at higher histamine concentrations was reversed by metiamine, an H-2 receptor antagonist. The effects of histamine upon eosinophil migration were demonstrable using three different assays: (a) counting cells that had traversed 5-mum pore, 12-mum thick polycarbonate filters, (b) counting cells that had migrated various distances into a 3-mum pore, 145-mum cellulose nitrate filters, or (c) measuring the number of cells that had traversed an upper polycarbonate filter and migrated into a lower cellulose nitrate filter using 15Cr-labeled cells. The ability of histamine to enhance eosinophil migration was shown to be dependent upon the presence of a concentration gradient; histamine did not cause a dose-dependent increase in random motility. Furthermore, preincubation of the eosinophils with histamine deactivate the cells to further stimulation by histamine or by C5a. It is concluded that in low doses histamine is a chemoattractant for human eosinophils, while in higher doses histamine inhibits eosinophil migration. These observations may relate to the influx and localization of eosinophils in immediate hypersensitivity reactions.

Fibronectin is produced by blood vessels in response to injury.

During the time of tissue repair that ensues subsequent to tissue injury, blood vessel wall fibronectin increases concomitantly with endothelial proliferation and angiogenesis. However, the source of this blood vessel fibronectin had not been delineated. In this report we have demonstrated that microvascular fibronectin is produced in situ by the proliferating vessels surrounding excisional wounds. This finding was established by extirpating 3 mm of skin from the center of a well-healed rat xenograph on the flanks of immunosuppressed mice, harvesting the injured skin sites at various stages during the healing process, and staining the specimens with reciprocal species-specific anti-fibronectin. The proliferating donor vessels that surrounded the wounded graft had increased fluorescence staining with FITC conjugated mouse anti-rat fibronectin and no staining with rat anti-mouse fibronectin. This finding was taken as direct evidence that the fibronectin was produced in situ by the rat vessels and not derived from circulating mouse plasma.

Iliotibial band syndrome: an examination of the evidence behind a number of treatment options.

Iliotibial band (ITB) syndrome (ITBS) is a common cause of distal lateral thigh pain in athletes. Treatment often focuses on stretching the ITB and treating local inflammation at the lateral femoral condyle (LFC). We examine the area's anatomical and biomechanical properties. Anatomical studies of the ITB of 20 embalmed cadavers. The strain generated in the ITB by three typical stretching maneuvers (Ober test; Hip flexion, adduction and external rotation, with added knee flexion and straight leg raise to 30 degrees ) was measured in five unembalmed cadavers using strain gauges. Displacement of the Tensae Fasciae Latae (TFL)/ITB junction was measured on 20 subjects during isometric hip abduction. The ITB was uniformly a lateral thickening of the circumferential fascia lata, firmly attached along the linea aspera (femur) from greater trochanter up to and including the LFC. The microstrain values [median (IQR)] for the OBER [15.4(5.1-23.3)me], HIP [21.1(15.6-44.6)me] and SLR [9.4(5.1-10.7)me] showed marked disparity in the optimal inter-limb stretching protocol. HIP stretch invoked significantly (Z=2.10, P=0.036) greater strain than the SLR. TFL/ITB junction displacement was 2.0+/-1.6 mm and mean ITB lengthening was <0.5% (effect size=0.04). Our results challenge the reasoning behind a number of accepted means of treating ITBS. Future research must focus on stretching and lengthening the muscular component of the ITB/TFL complex.