Challenges and solutions to implementing cardiac rehabilitation in a low- and middle-income country.

BACKGROUND: Cardiac rehabilitation (CR) remains greatly underutilized, especially in low- and middle-income countries (LMIC). It is therefore important to explore factors that contribute to this, as perceived by health-care professionals (HCPs). RESEARCH DESIGN AND METHODS: This was a qualitative study using in-depth interviews that enrolled 18 HCPs (i.e. six each of physicians, physiotherapists, and nurses; mean experience in CR: 17.9 ± 11.8 yrs) working in cardiovascular care, and CR across private and government hospitals (both teaching and non-teaching) in India. RESULTS: The main challenges were related to lack of referrals, perceived lack of benefit from CR, poor infrastructure within hospitals and health systems, and differences in practice. The perceived inadequacies were lack of competencies in CR, limited task sharing strategies, and ineffective utilization of existing human resources. Devising strategies to improve awareness and competencies, facilitating task sharing, and remodeling holistic care with an active CR component may be beneficial to facilitate greater implementation of CR in India. CONCLUSIONS: Challenges, inadequacies, and solutions to implementing CR have been explored by involving various HCPs commonly involved in delivering CR across different health systems in a LMIC. TRIAL REGISTRATION: www.ctri.nic.in with identifier CTRI/2020/07/026807.

Role of Exercise in Pulmonary Hypertension: Evidence from Bench to Bedside.

Background: Pulmonary hypertension (PH) is a debilitating condition characterized by elevated pulmonary arterial pressure and progressive vascular remodelling, leading to exercise intolerance. The progression of PAH is regulated at a cellular and molecular level which influences various physiological processes. Exercise plays an important role in improving function in PH. Although the signalling pathways that regulate cardio-protection through exercise have not been fully understood, the positive impact of exercise on the various physiological systems is well established. Summary: Exercise has emerged as a potential adjunctive therapy for PH, with growing evidence supporting its beneficial effects on various aspects of the disease pathophysiology. This review highlights the contributions of cellular and molecular pathways and physiological processes to exercise intolerance. Preclinical studies have provided insight into the mechanisms underlying exercise-induced improvements in PH which are modulated through improvements in endothelial function, inflammation, oxidative stress, and mitochondrial function. Along with preclinical studies, various clinical studies have demonstrated that exercise training can lead to significant improvements in exercise capacity, haemodynamics, quality of life, and functional status. Moreover, exercise interventions have been shown to improve skeletal muscle function and enhance pulmonary vascular remodelling, contributing to overall disease management. Further research efforts aimed at better understanding the role of exercise in PH pathophysiology, and refining exercise interventions are warranted to realize its full potential in the management of this complex disease. Key Messages: Despite the promising benefits of exercise in PH, several challenges remain, including the optimal intensity, duration, and type of exercise training, as well as patient selection criteria and long-term adherence. Additionally, the mechanisms underlying the observed improvements require further elucidation to optimize exercise protocols and personalize treatment strategies. Nonetheless, exercise represents a promising therapeutic approach that can complement existing pharmacological therapies and improve outcomes in PH patients.

Human corneal endothelial cell transplantation with nanocomposite gel sheet preserves corneal stability in post-corneal transplant bullous keratopathy: a 16-year follow-up.

Post-corneal transplantation endothelial decompensation and subsequent bullous keratopathy often result in unfavorable clinical outcomes regardless of the treatment strategy employed. In this report, we present the outcomes of a patient managed with in vitro expanded human corneal endothelial cell (HCEC) transplantation facilitated by a nanocomposite gel (NC gel) sheet over 16 years. A 40-year-old male patient who presented with signs of graft failure after penetrating keratoplasty underwent HCEC transplantation. Additionally, HCECs were obtained from a deceased donor, cultured in vitro, and transplanted onto an NC gel sheet as a temporary scaffold to support the transplanted cells until engraftment. At the 16-year follow-up, the cornea had remained stable and did not exhibit active disease manifestations. Notably, no new bullae were formed, and the epithelial surface appeared smooth without signs of active fluid transport abnormalities. Although a slight reduction in corneal thickness was observed, the disease-free region at the time of the intervention remained transparent. HCEC transplantation with NC gel sheets is a promising, minimally invasive approach for achieving long-term corneal stability in cases of bullous keratopathy following corneal graft failure. Importantly, this technique circumvents the need for complex procedures and utilizes corneal endothelial precursors derived from donor corneas discarded for lack of sufficient endothelial cells. After in vitro culture, these cells were successfully transplanted in three patients, proving that one donated eye can be useful in treating three eyes of three patients. This technique addresses the donor cornea shortage concerns and makes our concept "an-eye-for-eyes", a reality.

3D bioprinting in bioremediation: a comprehensive review of principles, applications, and future directions.

Bioremediation is experiencing a paradigm shift by integrating three-dimensional (3D) bioprinting. This transformative approach augments the precision and versatility of engineering with the functional capabilities of material science to create environmental restoration strategies. This comprehensive review elucidates the foundational principles of 3D bioprinting technology for bioremediation, its current applications in bioremediation, and the prospective avenues for future research and technological evolution, emphasizing the intersection of additive manufacturing, functionalized biosystems, and environmental remediation; this review delineates how 3D bioprinting can tailor bioremediation apparatus to maximize pollutant degradation and removal. Innovations in biofabrication have yielded bio-based and biodegradable materials conducive to microbial proliferation and pollutant sequestration, thereby addressing contamination and adhering to sustainability precepts. The review presents an in-depth analysis of the application of 3D bioprinted constructs in enhancing bioremediation efforts, exemplifying the synergy between biological systems and engineered solutions. Concurrently, the review critically addresses the inherent challenges of incorporating 3D bioprinted materials into diverse ecological settings, including assessing their environmental impact, durability, and integration into large-scale bioremediation projects. Future perspectives discussed encompass the exploration of novel biocompatible materials, the automation of bioremediation, and the convergence of 3D bioprinting with cutting-edge fields such as nanotechnology and other emerging fields. This article posits 3D bioprinting as a cornerstone of next-generation bioremediation practices, offering scalable, customizable, and potentially greener solutions for reclaiming contaminated environments. Through this review, stakeholders in environmental science, engineering, and technology are provided with a critical appraisal of the current state of 3D bioprinting in bioremediation and its potential to drive forward the efficacy of environmental management practices.

Beneficial immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in Duchenne muscular dystrophy: Results of an open-label, prospective, exploratory case-control clinical study.

Background: This exploratory case-control study is to evaluate the effects of supplementation of Aureobasidium pullulans-N-163 strain produced 1,3-1,- 6 beta glucan in young patients with Duchenne muscular dystrophy (DMD). Methods: Twenty-seven male subjects aged 5-19 years with DMD were included, nine in the control arm and 18 in the treatment arm to receive N-163 beta glucan along with conventional therapies for 45 days. While performing the analysis, steroid usage was also taken into consideration, those not administered steroids (Steroid -ve) (Control, n = 5; treatment, n = 9), those administered steroids (Steroid +ve) (Control, n = 4; treatment, n = 9). Results: IL-6 showed a significant decrease in the treatment groups, especially the N-163 Steroid -ve group. IL-13 decreased in both treatment groups and TGF-ß levels showed a significant decrease in the treatment groups, especially the N-163 Steroid -ve group, (p < 0.05). Dystrophin levels increased by up to 32% in the treatment groups compared to the control. Medical research council (MRC) grading showed slight improvement in muscle strength improvement in 12 out of 18 patients (67%) in the treatment group and four out of nine (44%) subjects in the control group. Conclusion: Supplementation with the N-163 beta glucan food supplement produced beneficial effects: a significant decrease in inflammation and fibrosis markers, increase in serum dystrophin and slight improvement in muscle strength in DMD subjects over 45 days, thus making this a potential adjunct treatment for DMD after validation. Trial registration: The study was registered in Clinical trials registry of India, CTRI/2021/05/033346. Registered on 5th May, 2021.

Resolution of fibrosis in mdx dystrophic mouse after oral consumption of N-163 strain of Aureobasidium pullulans produced ß-glucan.

Recent advances in the management of Duchenne muscular dystrophy (DMD), such as exon skipping and gene therapy, though have reached a clinical stage, the outcome at its best is still considered suboptimal. In this study, we evaluated a novel N-163 strain of Aureobasidium pullulans produced ß-glucan (Neu-REFIX) for its potential as an adjuvant to slow down the progression of the disease by anti-inflammatory and anti-fibrotic effects. In this study, 45 mice in the three groups, 15 each in a group; Gr. 1 normal mice, Gr.2 mdx mice as vehicle, and Gr.3 mdx mice administered the N-163 ß-glucan for 45 days. The N-163 ß-glucan group showed a significant decrease in the plasma ALT, AST, and LDH levels (126 ± 69 U/l, 634 ± 371 U/l, 3335 ± 1258 U/l) compared with the vehicle group (177 ± 27 U/l, 912 ± 126 U/l, 4186 ± 398 U/l). Plasma TGF-ß levels increased, and plasma IL-13 levels decreased in the N-163 group. The inflammation score of HE-stained muscle sections in the N-163 group (1.5 ± 0.8) was lower than that in the vehicle group (2.0 ± 0.8). The N-163 strain ß-glucan group (24.22 ± 4.80) showed a significant decrease in the fibrosis area (Masson's Trichrome-positive area) compared with the vehicle group (36.78 ± 5.74). The percentage of centrally nucleated fibres evaluated by Masson's trichrome staining was 0 in the normal group, while it increased to 80% in the vehicle group but remained at 76.8% in the N-163 group. The N-163 ß-glucan group showed a significant decrease in the fibrosis area. Considering their safety and easy oral consumption, Neu-REFIX ß-glucan could be worth large multicentre clinical studies as adjuvant in slowing down the progress of DMD.

Re-examination of therapeutic management of muscular dystrophies using a vascular smooth muscle-centered approach.

In contrast to the long-standing focus on the pathophysiology of skeletal muscles in the hunt for a cure for Duchenne muscular dystrophy (DMD), we opine that the malfunctioning of dystrophin produced by vascular smooth muscle is a major contributor to the pathology of the illness. We believe that a biological response modifier glucan (BRMG), which has been shown in clinical studies of DMD to boost the expression of vascular smooth muscle dystrophin and provide anti-fibrotic and anti-inflammatory effects, may play a key role in reducing the pathogenesis of DMD. According to the evaluation of biomarkers, this BRMG, which is safe and side-effect-free, reduces the pathogenesis of DMD. We describe the possible mechanisms of action by which this BRMG helps in alleviating the symptoms of DMD by targeting smooth muscle dystrophin, in addition to its advantages over other therapeutic modalities, as well as how it can serve as a valuable adjunct to existing therapies. We suggest that using BRMG adjuncts that target smooth muscle dystrophin would be a potential therapeutic approach that prolongs the lifespan and extends the duration of ambulation from the onset of DMD. Further studies are needed to validate this hypothesis.

Beneficial effects of 1,3-1,6 ß-glucans produced by Aureobasidium pullulans on non-esterified fatty acid levels in diabetic KKAy mice and their potential implications in metabolic dysregulation.

Objectives: In this study, we used an obese and diabetic mouse model to compare two strains of Aureobasidium pullulans (AFO-202 and N-163) produced beta-glucans (ß-glucans), which alleviate lipotoxicity. Methods: Four groups of KK-Ay mice were used, with six subjects in each group. Group 1: sacrificed on day 0 for baseline values; Group 2: control (drinking water); Group 3: AFO-202 beta glucan-200 mg/kg/day; Group 4: N-163 beta glucan-300 mg/kg/day for 28 consecutive days. Results: Group 4 (N-163) had the lowest non-esterified fatty acids (NEFA) levels and marginally decreased triglyceride levels compared to the other groups. There were no significant differences in blood glucose, hemoglobin A1c (HbA1c), triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels. N-163 ß-glucans decreased NEFA levels after 28 days. Conclusion: These results, although modest, warrant further in-depth research into lipotoxicity and associated inflammatory cascades in both healthy and diseased subjects for the prevention and management of metabolic dysregulation and associated diseases such as non-alcoholic fatty liver disease (NAFLD).

Antibody dependent disease enhancement (ADE) after COVID-19 vaccination and beta glucans as a safer strategy in management.

A potential risk associated with vaccines for COVID-19 is antibody-dependent disease enhancement (ADE) in which vaccine induced antibody mediated immune responses may lead to enhanced SARS CoV- 2 acquisition or increased disease severity. Though ADE has not been clinically demonstrated with any of the COVID-19 vaccines so far, when neutralizing antibodies are suboptimal, the severity of COVID-19 has been reported to be greater. ADE is presumed to occur via abnormal macrophages induced by the vaccine based immune response by antibody-mediated virus uptake into Fc gamma receptor IIa (FcγRIIa) or by the formation of Fc-mediated excessive antibody effector functions. Beta-glucans which are naturally occurring polysaccharides known for unique immunomodulation by capability to interact with macrophages, eliciting a specific beneficial immune-response and enhancing all arms of the immune system, importantly without over-activation are suggested as safer nutritional supplement-based vaccine adjuvants for COVID-19.

Engraftment and Proliferation of Thermoreversible-Gelation-Polymer-Encapsulated Human Corneal Limbal-Stem-Cells on Ocular Surface of a Cadaver Cornea.

PURPOSE: Corneal limbal stem cell (LSC) transplantation has been reported as a potential approach to treat the damaged corneal epithelium. Scaffolds such as human amniotic membrane (hAM) are commonly employed for the in vitro culture and as a carrier during in vivo transplantation. However, they carry the risk of biological contamination and donor to donor variability. To overcome these disadvantages, we herein report the capabilities of a synthetic thermoreversible gelation polymer (TGP) scaffold to serve as an encapsulation support during LSC transplantation and to enable engraftment for corneal regeneration. METHODS: Sixteen discarded human corneas were used to isolate the corneal epithelium which was cultured in TGP and hAM. The cell proliferation and characteristics between TGP and hAM culture methods were evaluated by microscopic observation, 3H Thymidine incorporation assay, immunoperoxidase and immunofluorescence staining. RESULTS: The 3H Thymidine assay's results showed that TGP allowed human-donor cornea-derived LSCs to proliferate well in vitro, compared to hAM and the cells encapsulated in TGP and transplanted ex vivo onto a human cadaver donor cornea denuded of its epithelium, migrated on the ocular surface, and proliferated to form a continuous layer in 25 days. Immunoperoxidase and Immunofluorescence staining of TGP-cultured cells were positive for LSC markers (p63, ABCG2, Connexin 43 and Integrin ß), proving that the TGP helps to preserve the limbal cells' stemness. CONCLUSION: TGP is found to be a multipurpose scaffold for (i) in vitro culture, (ii) ex vivo encapsulation, and in vivo transplantation (iii), enabling engraftment of LSCs in this study, with potentials to extend its application in cell-based therapies in several regenerative medicine approaches.

Exercise Training in Pulmonary Hypertension: AN UPDATED SYSTEMATIC REVIEW WITH META-ANALYSIS.

PURPOSE: Given that previous reviews on exercise training in pulmonary hypertension (PH) were largely based on a small number of randomized controlled trials (RCT), their conclusions are subject to bias. This review sought to identify the impact of exercise training on functional capacity and health-related quality of life (HRQoL) in PH using advanced statistical approaches such as meta-analysis by stratification according to study design. REVIEW METHODS: Five databases were searched from January 2015 to April 2020 to update a previous review. Included articles had data extracted, risk of bias (ROB) assessed, and quality rating performed. Data were analyzed using meta-analysis with a random-effects model for 6-min walk test (6MWT) distance and HRQoL. Heterogeneity was explored using stratified meta-analysis, within patient correlation and meta-regression. RESULTS: A total of 28 studies (11 RCT, 12 pre-/post-studies, 2 two-group non-RCT, and three case series) consisting of 1264 patients were included. Meta-analysis of six RCT demonstrated an improved 6MWT distance by 49.5 m (95% CI, 27.2-71.8: I2 = 73%; 254 participants; low-moderate ROB) with a low correlation coefficient of 0.34, while the 12 pre-/post-non-RCT showed an improvement of 68.69 m (95% CI, 50.50-86.69: I2 = 36%; 784 participants; high ROB) along with improvements in V˙ o2peak (weighted mean difference [WMD] = 3.03 mL/kg/min, 95% CI, 2.17-3.90: I2 = 0%, P = .82), and HRQoL (WMD = 2.74: 95% CI, -0.82 to 6.30). Metaregression showed that the benefit of exercise on 6MWT distance did not significantly vary across the trial study characteristics. CONCLUSION: This updated review identified an additional body of evidence supporting the efficacy of exercise training on 6MWT distance and HRQoL in stable PH patients. These benefits appeared to be consistent across models of delivery.

Prevalence of sarcopenia in heart failure: A systematic review.

OBJECTIVE: Heart Failure (HF) is emerging as a crucial factor promoting muscle wasting and dysfunction contributing to sarcopenia. This modulates disease severity and reduces exercise capacity and leading to poorer outcomes. Therefore, we aimed to systematically investigate the overall prevalence of sarcopenia in HF. METHODS: An electronic search was carried out in selected databases until 21st January, 2021. Data was pooled from the included articles and represented as pooled prevalence of sarcopenia. Subgroup analysis was undertaken between methods of diagnosis of sarcopenia, gender, ejection fraction, median time point and geographical region. RESULTS: Amongst 32,643 citations imported from selected databases, 12 articles were included in final analysis. Analysis for prevalence of sarcopenia was 34%, with prevalence rates ranging from 10.1% to 68%. Subgroup analysis revealed strong associations between Dual-energy X-ray Absorptiometry (DXA) and Asian Working Group for Sarcopenia (AWGS) (chi square = 3.24; p < 0.001), with a good level of agreement (kappa = 0.76 [95% CI: 0.70-0.82]; p < 0.001). Gender wise analysis revealed higher prevalence of sarcopenia among males (66%) than females (34%). CONCLUSION: Sarcopenia is highly prevalent among those with HF (irrespective of type of HF) and is more commonly seen in males compared to females.

Benefits of Gut Microbiota Reconstitution by Beta 1,3-1,6 Glucans in Subjects with Autism Spectrum Disorder and Other Neurodegenerative Diseases.

BACKGROUND: Aureobasidium pullulans (black yeast) AFO-202 strain-produced beta glucan, Nichi Glucan, has been shown to improve the behavior and sleep pattern along with an increase in α-synuclein and melatonin in children with autism spectrum disorder (ASD). OBJECTIVE: In this randomized pilot clinical study, we have evaluated the gut microbiota of subjects with ASD after consumption of Nichi Glucan. METHODS: Eighteen subjects with ASD were randomly allocated: six subjects in the control group (Group 1): conventional treatment comprising remedial behavioral therapies and L-carnosine 500 mg per day, and 12 subjects (Group 2) underwent supplementation with Nichi Glucan 0.5 g twice daily along with the conventional treatment for 90 days. RESULTS: Whole genome metagenome (WGM) sequencing of the stool samples at baseline and after intervention showed that among genera of relevance, the abundance of Enterobacteriaceae was decreased almost to zero in Group 2 after intervention, whereas it increased from 0.36% to 0.85% in Group 1. The abundance of Bacteroides increased in Group 1, whereas it decreased in Group 2. The abundance of Prevotella increased while the abundance of Lactobacillus decreased in both Group 1 and Group 2. Among species, a decrease was seen in Escherichia coli, Akkermansia muciniphila CAG:154, Blautia spp., Coprobacillus sp., and Clostridium bolteae CAG:59, with an increase of Faecalibacterium prausnitzii and Prevotella copri, which are both beneficial. CONCLUSION: AFO-202 beta 1,3-1,6 glucan, in addition to balancing the gut microbiome in children with ASD and its role in effective control of curli-producing Enterobacteriaceae that leads to α-synuclein misfolding and accumulation, may have a prophylactic role in Parkinson's and Alzheimer's diseases as well.

Technology-based Comprehensive Cardiac Rehabilitation Therapy (TaCT) for women with cardiovascular disease in a middle-income setting: A randomized controlled trial protocol.

Women are underrepresented in cardiac rehabilitation (CR) despite the benefits, and this is exacerbated in lower-resource settings where CR is insufficiently available. In this randomized controlled trial, the effectiveness of the Technology-based Comprehensive Cardiac Rehabilitation Therapy (TaCT) electronic cardiac rehabilitation (eCR) intervention on functional capacity, risk factors, quality of life, heart-health behaviors, symptoms, and morbidity will be tested among women with CVD in a middle-income country. Following a pilot study, a single-center, single-blinded, 2 parallel-arm (1:1 SNOSE) superiority trial comparing an eCR intervention (TaCT) to usual care, with assessments pre-intervention and at 3 and 6 months will be undertaken. One hundred adult women will be recruited. Permuted block (size 10) randomization will be applied. The 6-month intervention comprises an app, website, SMS texts with generic heart-health management advice, and bi-weekly 1:1 telephone calls with a nurse trainee. Individualized exercise prescriptions will be developed based on an Incremental Shuttle Walk Test (primary outcome) and dietary plans based on 24 h dietary recall. A yoga/relaxation video will be provided via WhatsApp, along with tobacco cessation support and a moderated group chat. At 3 months, intervention engagement and acceptability will be assessed. Analyses will be conducted based on intent-to-treat. If results of this novel trial of women-focused eCR in a middle-income country demonstrate clinically-significant increases in functional capacity, this could represent an important development for the field considering this would be an important outcome for women and would translate to lower mortality.