Benfotiamine improves dystrophic pathology and exercise capacity in mdx mice by reducing inflammation and fibrosis.

Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease. Cycles of myofibre degeneration and regeneration are hallmarks of the disease where immune cells infiltrate to repair damaged skeletal muscle. Benfotiamine is a lipid soluble precursor to thiamine, shown clinically to reduce inflammation in diabetic related complications. We assessed whether benfotiamine administration could reduce inflammation related dystrophic pathology. Benfotiamine (10 mg/kg/day) was fed to male mdx mice (n = 7) for 15 weeks from 4 weeks of age. Treated mice had an increased growth weight (5-7 weeks) and myofibre size at treatment completion. Markers of dystrophic pathology (area of damaged necrotic tissue, central nuclei) were reduced in benfotiamine mdx quadriceps. Grip strength was increased and improved exercise capacity was found in mdx treated with benfotiamine for 12 weeks, before being placed into individual cages and allowed access to an exercise wheel for 3 weeks. Global gene expression profiling (RNAseq) in the gastrocnemius revealed benfotiamine regulated signalling pathways relevant to dystrophic pathology (Inflammatory Response, Myogenesis) and fibrotic gene markers (Col1a1, Col1a2, Col4a5, Col5a2, Col6a2, Col6a2, Col6a3, Lum) towards wildtype levels. In addition, we observed a reduction in gene expression of inflammatory gene markers in the quadriceps (Emr1, Cd163, Cd4, Cd8, Ifng). Overall, these data suggest that benfotiamine reduces dystrophic pathology by acting on inflammatory and fibrotic gene markers and signalling pathways. Given benfotiamine's excellent safety profile and current clinical use, it could be used in combination with glucocorticoids to treat DMD patients.

A phase 2 open-label study of the safety and efficacy of weekly dosing of ATL1102 in patients with non-ambulatory Duchenne muscular dystrophy and pharmacology in mdx mice.

BACKGROUND: ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment. METHODS: This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline. RESULTS: Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period. CONCLUSION: ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD. TRIAL REGISTRATION: Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.

A sensorised surgical glove to improve training and detection of obstetric anal sphincter injury: A preclinical study on a pig model.

OBJECTIVE: To create a sensorised surgical glove that can accurately identify obstetric anal sphincter injury to facilitate timely repair, reduce complications and aid training. DESIGN: Proof-of-concept. SETTING: Laboratory. SAMPLE: Pig models. METHODS: Flexible triboelectric pressure/force sensors were mounted onto the fingertips of a routine surgical glove. The sensors produce a current when rubbed on materials of different characteristics which can be analysed. A per rectum examination was performed on the intact sphincter of pig cadavers, analogous to routine examination for obstetric anal sphincter injuries postpartum. An anal sphincter defect was created by cutting through the vaginal mucosa and into the external anal sphincter using a scalpel. The sphincter was then re-examined. Data and signals were interpreted. MAIN OUTCOME MEASURES: Sensitivity and specificity of the glove in detecting anal sphincter injury. RESULTS: In all, 200 examinations were performed. The sensors detected anal sphincter injuries in a pig model with sensitivities between 98% and 100% and a specificity of 100%. The current produced when examining an intact sphincter and sphincter with a defect was significantly different (p < 0.001). CONCLUSION: In this preliminary study, the sensorised glove accurately detected anal sphincter injury in a pig model. Future plans include its clinical translation, starting with an in-human study on postpartum women, to determine whether it can accurately detect different types of obstetric anal sphincter injury in vivo.

ER procollagen storage defect without coupled unfolded protein response drives precocious arthritis.

Collagenopathies are a group of clinically diverse disorders caused by defects in collagen folding and secretion. For example, mutations in the gene encoding collagen type-II, the primary collagen in cartilage, can lead to diverse chondrodysplasias. One example is the Gly1170Ser substitution in procollagen-II, which causes precocious osteoarthritis. Here, we biochemically and mechanistically characterize an induced pluripotent stem cell-based cartilage model of this disease, including both hetero- and homozygous genotypes. We show that Gly1170Ser procollagen-II is notably slow to fold and secrete. Instead, procollagen-II accumulates intracellularly, consistent with an endoplasmic reticulum (ER) storage disorder. Owing to unique features of the collagen triple helix, this accumulation is not recognized by the unfolded protein response. Gly1170Ser procollagen-II interacts to a greater extent than wild-type with specific proteostasis network components, consistent with its slow folding. These findings provide mechanistic elucidation into the etiology of this disease. Moreover, the cartilage model will enable rapid testing of therapeutic strategies to restore proteostasis in the collagenopathies.

Use of Human-Centered Design Methodology to Develop a Digital Toolkit to Optimize Heart Failure Guideline-Directed Medical Therapy.

BACKGROUND: Guideline-directed medical therapies (GDMTs) improve quality of life and health outcomes for patients with heart failure (HF). However, GDMT utilization is suboptimal among patients with HF. OBJECTIVE: The aims of this study were to engage key stakeholders in semistructured, virtual human-centered design sessions to identify challenges in GDMT optimization posthospitalization and inform the development of a digital toolkit aimed at optimizing HF GDMTs. METHODS: For the human-centered design sessions, we recruited (a) clinicians who care for patients with HF across 3 hospital systems, (b) patients with HF with reduced ejection fraction (ejection fraction ≤ 40%) discharged from the hospital within 30 days of enrollment, and (c) caregivers. All participants were 18 years or older, English speaking, with Internet access. RESULTS: A total of 10 clinicians (median age, 37 years [interquartile range, 35-41], 12 years [interquartile range, 10-14] of experience caring for patients with HF, 80% women, 50% White, 50% nurse practitioners) and three patients and one caregiver (median age 57 years [IQR: 53-60], 75% men, 50% Black, 75% married) were included. Five themes emerged from the clinician sessions on challenges to GDMT optimization (eg, barriers to patient buy-in). Six themes on challenges (eg, managing medications), 4 themes on motivators (eg, regaining independence), and 3 themes on facilitators (eg, social support) to HF management arose from the patient and caregiver sessions. CONCLUSIONS: The clinician, patient, and caregiver insights identified through human-centered design will inform a digital toolkit aimed at optimizing HF GDMTs, including a patient-facing smartphone application and clinician dashboard. This digital toolkit will be evaluated in a multicenter, clinical trial.

Modeling human skeletal development using human pluripotent stem cells.

Chondrocytes and osteoblasts differentiated from induced pluripotent stem cells (iPSCs) will provide insights into skeletal development and genetic skeletal disorders and will generate cells for regenerative medicine applications. Here, we describe a method that directs iPSC-derived sclerotome to chondroprogenitors in 3D pellet culture then to articular chondrocytes or, alternatively, along the growth plate cartilage pathway to become hypertrophic chondrocytes that can transition to osteoblasts. Osteogenic organoids deposit and mineralize a collagen I extracellular matrix (ECM), mirroring in vivo endochondral bone formation. We have identified gene expression signatures at key developmental stages including chondrocyte maturation, hypertrophy, and transition to osteoblasts and show that this system can be used to model genetic cartilage and bone disorders.

A novel device for investigating structure-function relationships and mechanoadaptation of biological tissues.

Exploring the structure-function relationships of cartilage on a microstructural level is crucial for tissue engineering approaches aiming to restore function. Therefore, a combination of mechanical testing with cell and tissue-level imaging would allow for longitudinal studying loading mechanisms, biological responses and mechanoadaptation of tissues at a microstructural level. This paper describes the design and validation of FELIX, a custom-built device for non-destructive image-guided micromechanical evaluation of biological tissues and tissue-engineered constructs. It combines multiphoton microscopy with non-destructive mechanical testing of native soft tissues. Ten silicone samples of the same size were mechanically tested with FELIX by different users to assess the repeatability and reproducibility. The results indicate that FELIX can successfully substitute mechanical testing protocols with a commercial device without compromising precision. Furthermore, FELIX demonstrated consistent results across repeated measurements, with very small deviations. Therefore, FELIX can be used to accurately measure biomechanical properties by different users for separate studies. Additionally, cell nuclei and collagen of porcine articular cartilage were successfully imaged under compression. Cell viability remained high in chondrocytes cultured in agarose over 21 days. Furthermore, there were no signs of contamination indicating a cell friendly, sterile environment for longitudinal studies. In conclusion, this work demonstrates that FELIX can consistently quantify mechanical measures without compromising precision. Furthermore, it is biocompatible allowing for longitudinal measurements.

Proteome profiles of intramuscular connective tissue: influence of aging and physical training.

Both aging and physical activity can influence the amount of intramuscular connective tissue in skeletal muscle, but the impact of these upon specific extracellular matrix (ECM) proteins in skeletal muscle is unknown. We investigated the proteome profile of intramuscular connective tissue by label-free proteomic analysis of cellular protein-depleted extracts from lateral gastrocnemius muscle of old (22-23 mo old) and middle-aged (11 mo old) male mice subjected to three different levels of regular physical activity for 10 wk (high-resistance wheel running, low-resistance wheel running, or sedentary controls). We hypothesized that aging is correlated with an increased amount of connective tissue proteins in skeletal muscle and that regular physical activity can counteract these age-related changes. We found that dominating cellular proteins were diminished in the urea/thiourea extract, which was therefore used for proteomics. Proteomic analysis identified 482 proteins and showed enrichment for ECM proteins. Statistical analysis revealed that the abundances of 86 proteins changed with age. Twenty-three of these differentially abundant proteins were identified as structural ECM proteins (e.g., collagens and laminins) and all of these were significantly more abundant with aging. No significant effect of training or interaction between training and advance in age was found for any proteins. Finally, we found a lower protein concentration in the urea/thiourea extracts from the old mice compared with the middle-aged mice. Our findings indicate that the intramuscular ECM solubility is affected by increased age but is not altered by physical training.NEW & NOTEWORTHY We investigated the impact of aging and exercise on extracellular matrix components of intramuscular connective tissue using proteomics. Middle-aged and old mice were subjected to three different levels of regular physical activity for 10 wk (high-resistance wheel running, low-resistance wheel running, or sedentary controls). We prepared extracts of extracellular matrix proteins depleted of cellular proteins. Our findings indicate that intramuscular connective tissue alters its soluble protein content with age but is unaffected by training.

Using CRISPR/Cas9 to generate a heterozygous COL2A1 p.R719C iPSC line (MCRIi019-A-6) model of human precocious osteoarthritis.

The human iPSC line MCRIi019-A-6 was generated using CRISPR/Cas9-mediated gene editing to introduce a heterozygous COL2A1 exon 33 c.2155C>T (p.R719C) mutation into the control human iPSC line MCRIi019-A. Both the edited and parental lines display typical iPSC characteristics, including the expression of pluripotency markers, the ability to be differentiated into the three germ lines, and a normal karyotype. This cell line, along with the isogenic control line, can be used to study the molecular pathology of precocious osteoarthritis in a human model, more broadly understand type II collagenopathies, and explore novel therapeutic targets for this class of diseases.

A 62-Year-Old Immunocompromised Man With Halo Sign on Chest Imaging.

CASE PRESENTATION: A 62-year-old White man with a history of orthotopic liver transplantation 16 years ago for alcoholic liver cirrhosis on chronic immunosuppression and recurrent decompensated cirrhosis of his graft liver complicated by ascites, hepatic encephalopathy, and esophageal varices presented to the hospital with altered mental status. Over the last few weeks, he had reduced frequency of bowel movements and subsequently developed altered sensorium 3 days before presentation. On arrival to the hospital, he was disoriented and had asterixis consistent with hepatic encephalopathy. He was not in respiratory distress, he was saturating well on room air, and his lungs were clear to auscultation bilaterally. Plain chest radiograph showed multiple ill-defined bilateral airspace opacities. A CT scan of the abdomen and pelvis done on admission incidentally showed bilateral pulmonary nodules with surrounding ground-glass halo in the lower lung zones. Given these findings, a dedicated CT scan of his chest was performed that showed numerous bilateral randomly distributed nodular airspace opacities, many with a central solid component and surrounding ground-glass halo. Antifungal therapy was initiated empirically. Serum aspergillus antigen and 1,3 beta D-glucan were negative. He subsequently underwent a bronchoscopy with BAL and transbronchial biopsy. BAL fluid was negative for bacterial, fungal, and acid-fast bacilli cultures. Pathology from the transbronchial biopsy showed atypical epithelioid cells in intravascular spaces.

Impact of achieving euthyroidism on pulmonary artery systolic pressures in hyperthyroidism-associated pulmonary hypertension - a systematic review.

In this systematic review, we seek to clarify the impact of treatment of hyperthyroidism on pulmonary hypertension in patients with both these conditions. We included 39 of 709 articles retrieved, that studied patients with hyperthyroidism and pulmonary hypertension (PH). From these, those with a documented pre-treatment Pulmonary Artery Systolic Pressure (PASP) > 35 mmHg and complete follow up were analyzed, yielding 3 case series and 22 case reports with a total of 81 cases. A significant improvement in PASP was noted with achieving euthyroidism in the 3 case series. The case reports showed a significant reduction in mean PASP from 60.5 ± 13.2 mmHg to 37.5 ± 10.1 mmHg (p < 0.001) in patients with Grave's disease with achieving euthyroidism. No deaths were reported during the follow up period. Achievement of a euthyroid state in patients with hyperthyroidism is associated with statistically significant reductions in PASP.

Contribution of Sex Differences to HIV Immunology, Pathogenesis, and Cure Approaches.

Approximately 38 million people were living with human immunodeficiency virus (HIV) in 2020 and 53% of those infected were female. A variety of virological and immunological sex-associated differences (sexual dimorphism) in HIV infection have been recognized in males versus females. Social, behavioral, and societal influences play an important role in how the HIV pandemic has affected men and women differently. However, biological factors including anatomical, physiologic, hormonal, and genetic differences in sex chromosomes can each contribute to the distinct characteristics of HIV infection observed in males versus females. One striking example of this is the tendency for women to have lower HIV plasma viral loads than their male counterparts early in infection, though both progress to AIDS at similar rates. Sex differences in acquisition of HIV, innate and adaptive anti-HIV immune responses, efficacy/suitability of specific antiretroviral drugs, and viral pathogenesis have all been identified. Sex differences also have the potential to affect viral persistence, latency, and cure approaches. In this brief review, we summarize the major biological male/female sex differences in HIV infection and their importance to viral acquisition, pathogenesis, treatment, and cure efforts.

The effect of carbamazepine on bone structure and strength in control and osteogenesis imperfecta (Col1a2 +/p.G610C ) mice.

The inherited brittle bone disease osteogenesis imperfecta (OI) is commonly caused by COL1A1 and COL1A2 mutations that disrupt the collagen I triple helix. This causes intracellular endoplasmic reticulum (ER) retention of the misfolded collagen and can result in a pathological ER stress response. A therapeutic approach to reduce this toxic mutant load could be to stimulate mutant collagen degradation by manipulating autophagy and/or ER-associated degradation. Since carbamazepine (CBZ) both stimulates autophagy of misfolded collagen X and improves skeletal pathology in a metaphyseal chondrodysplasia model, we tested the effect of CBZ on bone structure and strength in 3-week-old male OI Col1a2 +/p.G610C and control mice. Treatment for 3 or 6 weeks with CBZ, at the dose effective in metaphyseal chondrodysplasia, provided no therapeutic benefit to Col1a2 +/p.G610C mouse bone structure, strength or composition, measured by micro-computed tomography, three point bending tests and Fourier-transform infrared microspectroscopy. In control mice, however, CBZ treatment for 6 weeks impaired femur growth and led to lower femoral cortical and trabecular bone mass. These data, showing the negative impact of CBZ treatment on the developing mouse bones, raise important issues which must be considered in any human clinical applications of CBZ in growing individuals.

Optimization of Benzoxazinorifamycins to Minimize hPXR Activation for the Treatment of Tuberculosis and HIV Coinfection.

Tuberculosis (TB) is one of the most significant world health problems, responsible for 1.5 M deaths in 2020, and yet, current treatments rely largely on 40 year old paradigms. Although the rifamycins (RIFs), best exemplified by the drug rifampin (RMP), represent a well-studied and therapeutically effective chemotype that targets the bacterial RNA polymerase (RNAP), these agents still suffer from serious drawbacks including the following: 3-9 month treatment times; cytochrome P450 (Cyp450) induction [particularly problematic for human immunodeficiency virus-Mycobacterium tuberculosis (MTB) co-infection]; and the existence of RIF-resistant (RIFR) MTB strains. We have utilized a structure-based drug design approach to synthesize and test 15 benzoxazinorifamycins (bxRIFs), congeners of the clinical candidate rifalazil, to minimize human pregnane X receptor (hPXR) activation while improving potency against MTB. We have determined the compounds' activation of the hPXR [responsible for inducing Cyp450 3A4 (CYP3A4)]. Compound IC50s have been determined against the wild-type and the most prevalent RIFR (ß-S450L) mutant MTB RNAPs. We have also determined their bactericidal activity against "normal" replicating MTB and a model for non-replicating, persister MTB. We have identified a minimal substitution and have probed larger substitutions that exhibit negligible hPXR activation (1.2-fold over the dimethyl sulfoxide control), many of which are 5- to 10-fold more potent against RNAPs and MTB than RMP. Importantly, we have analogues that are essentially equipotent against replicating MTB and non-replicating persister MTB, a property that is correlated with faster kill rates and may lead to shorter treatment durations. This work provides a proof of principle that the ansamycin core remains an attractive and effective scaffold for novel and dramatically improved RIFs.

Optimization of Benzoxazinorifamycins to Improve Mycobacterium tuberculosis RNA Polymerase Inhibition and Treatment of Tuberculosis.

Rifampin (RMP), a very potent inhibitor of the Mycobacterium tuberculosis (MTB) RNA polymerase (RNAP), remains a keystone in the treatment of tuberculosis since its introduction in 1965. However, rifamycins suffer from serious drawbacks, including 3- to 9-month treatment times, Cyp450 induction (particularly problematic for HIV-MTB coinfection), and resistant mutations within RNAP that yield RIF-resistant (RIFR) MTB strains. There is a clear and pressing need for improved TB therapies. We have utilized a structure-based drug design approach to synthesize and test novel benzoxazinorifamycins (bxRIF), congeners of the clinical candidate rifalazil. Our goal is to gain binding interactions that will compensate for the loss of RIF-binding affinity to the (RIFR) MTB RNAP and couple those with substitutions that we have previously found that essentially eliminate Cyp450 induction. Herein, we report a systematic exploration of 42 substituted bxRIFs that have yielded an analogue (27a) that has an excellent in vitro activity (MTB RNAP inhibition, MIC, MBC), enhanced (∼30-fold > RMP) activity against RIFR MTB RNAP, negligible hPXR activation, good mouse pharmacokinetics, and excellent activity with no observable adverse effects in an acute mouse TB model. In a time-kill study, 27a has a 7 day MBC that is ∼10-fold more potent than RMP. These results suggest that 27a may exhibit a faster kill rate than RMP, which could possibly reduce the clinical treatment time. Our synthetic protocol enabled the synthesis of ∼2 g of 27a at >95% purity in 3 months, demonstrating the feasibility of scale-up synthesis of bxRIFs for preclinical and clinical studies.

A Comparison of Long-Term Treatment Outcomes Between Giant and Nongiant Craniopharyngiomas.

BACKGROUND: There is limited literature on outcomes after surgical treatment of giant craniopharyngiomas in adult and pediatric patients. METHODS: A retrospective review of 159 patients undergoing surgery for craniopharyngiomas at a single institution was performed. Patients with giant craniopharyngiomas (maximum dimension ≥4.5 cm) were compared with nongiant tumors in terms of various clinical and radiological parameters and long-term surgical outcomes. Extent of resection was determined by postoperative magnetic resonance imaging. Factors associated with post-treatment obesity were also analyzed. RESULTS: Giant craniopharyngiomas (n = 66) were characterized by higher rates of childhood presentation, visual impairment, neurological deficits, multicompartmental involvement, and hydrocephalus as compared with nongiant tumors (n = 139). Giant tumors also were less likely to undergo transsphenoidal resection and were associated with a higher rate of postoperative neurological morbidity. There were no significant differences between the 2 groups in terms of extent of resection, use of postoperative radiation therapy, and long-term endocrinological outcomes. Overall recurrence rates over a mean follow-up period of 4.1 years were similar between giant and nongiant tumors; however, recurrences after presumed gross total resection/near total resection were significantly higher in the former subgroup versus the latter (39.4% vs. 18.4%; P = 0.044). Risk factors for post-treatment obesity in giant craniopharyngiomas included adult age (P = 0.001), preoperative obesity (P = 0.003), and hypothalamic involvement (P = 0.012). CONCLUSION: Gross total resection/near total resection of giant craniopharyngiomas can be achieved at rates comparable to nongiant tumors. However, there remains a greater risk of postoperative neurological morbidity. Radiation therapy mitigates the risk of recurrence on long-term follow-up.

Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology.

Mutations in collagen genes cause a broad range of connective tissue pathologies. Structural mutations that impact procollagen assembly or triple helix formation and stability are a common and important mutation class. How misfolded procollagens engage with the cellular proteostasis machinery and whether they can elicit a cytotoxic unfolded protein response (UPR) is a topic of considerable research interest. Such interest is well justified since modulating the UPR could offer a new approach to treat collagenopathies for which there are no current disease mechanism-targeting therapies. This review scrutinizes the evidence underpinning the view that endoplasmic reticulum stress and chronic UPR activation contributes significantly to the pathophysiology of the collagenopathies. While there is strong evidence that the UPR contributes to the pathology for collagen X misfolding mutations, the evidence that misfolding mutations in other collagen types induce a canonical, cytotoxic UPR is incomplete. To gain a more comprehensive understanding about how the UPR amplifies to pathology, and thus what types of manipulations of the UPR might have therapeutic relevance, much more information is needed about how specific misfolding mutation types engage differentially with the UPR and downstream signaling responses. Most importantly, since the capacity of the proteostasis machinery to respond to collagen misfolding is likely to vary between cell types, reflecting their functional roles in collagen and extracellular matrix biosynthesis, detailed studies on the UPR should focus as much as possible on the actual target cells involved in the collagen pathologies.

Supervised exercise therapy for patients with peripheral artery disease: Clinical update and pathways forward.

Peripheral artery disease (PAD) is an atherosclerotic vascular disease resulting in pervasive morbidity and mortality, particularly among older adults. One first-line therapy to improve symptoms, function, and clinical outcomes in PAD is supervised exercise therapy (SET), which is based primarily on a structured, start-and-stop walking protocol and is often implemented in cardiac rehabilitation programs. SET is supported by a Class IA guideline for patients with symptomatic PAD; however, despite the effectiveness of SET and the 2017 CMS decision to cover SET for PAD, challenges of awareness, access, and implementation of SET persist. Recent efforts to address these challenges include digital health and hybrid approaches to SET that may minimize barriers to care by delivering SET in more innovative, flexible formats. Further study is needed to understand barriers, improve awareness, and implement SET in more equitable and accessible ways.

Multiscale Strain Transfer in Cartilage.

The transfer of stress and strain signals between the extracellular matrix (ECM) and cells is crucial for biochemical and biomechanical cues that are required for tissue morphogenesis, differentiation, growth, and homeostasis. In cartilage tissue, the heterogeneity in spatial variation of ECM molecules leads to a depth-dependent non-uniform strain transfer and alters the magnitude of forces sensed by cells in articular and fibrocartilage, influencing chondrocyte metabolism and biochemical response. It is not fully established how these nonuniform forces ultimately influence cartilage health, maintenance, and integrity. To comprehend tissue remodelling in health and disease, it is fundamental to investigate how these forces, the ECM, and cells interrelate. However, not much is known about the relationship between applied mechanical stimulus and resulting spatial variations in magnitude and sense of mechanical stimuli within the chondrocyte's microenvironment. Investigating multiscale strain transfer and hierarchical structure-function relationships in cartilage is key to unravelling how cells receive signals and how they are transformed into biosynthetic responses. Therefore, this article first reviews different cartilage types and chondrocyte mechanosensing. Following this, multiscale strain transfer through cartilage tissue and the involvement of individual ECM components are discussed. Finally, insights to further understand multiscale strain transfer in cartilage are outlined.

Collagen VI Muscle Disorders: Mutation Types, Pathogenic Mechanisms and Approaches to Therapy.

Mutations in the genes encoding the major collagen VI isoform, COL6A1, COL6A2 and COL6A3, are responsible for the muscle disorders Bethlem myopathy and Ullrich congenital muscular dystrophy. These disorders form a disease spectrum from mild to severe. Dominant and recessive mutations are found along the entire spectrum and the clinical phenotype is strongly influenced by the way mutations impede collagen VI protein assembly. Most mutations are in the triple helical domain, towards the N-terminus and they compromise microfibril assembly. Some mutations are found outside the helix in the C- and N-terminal globular domains, but because these regions are highly polymorphic it is difficult to discriminate mutations from rare benign changes without detailed structural and functional studies. Collagen VI deficiency leads to mitochondrial dysfunction, deficient autophagy and increased apoptosis. Therapies that target these consequences have been tested in mouse models and some have shown modest efficacy in small human trials. Antisense therapies for a common mutation that introduces a pseudoexon show promise in cell culture but haven't yet been tested in an animal model. Future therapeutic approaches await new research into how collagen VI deficiency signals downstream consequences.