Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management

Objective: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. Methods: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multicomponent physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.E. Dent ... J. Beilby ... John E. Morley ... et al

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype. Keywords: Toxoplasma gondii, Drug discovery, Lead compounds, Anti-parasitic

Valvulogenesis: the moving target

Valvulogenesis is an extremely complex process by which a fragile gelatinous matrix is populated and remodelled during embryonic development into thin fibrous leaflets capable of maintaining unidirectional flow over a lifetime. This process occurs during exposure to constantly changing haemodynamic forces, with a success rate of approximately 99%. Defective valvulogenesis results in impaired cardiac function and lifelong complications. This review integrates what is known about the roles of genetics and mechanics in the development of valves and how changes in either result in impaired morphogenesis. It is hoped that appropriate developmental cues and phenotypic endpoints could help engineers and clinicians in their efforts to regenerate living valve alternatives

Temporal Exposure to Chondrogenic Factors Modulates Human Mesenchymal Stem Cell Chondrogenesis in Hydrogels

Tissue engineering utilizes scaffolds containing chondrogenic cells to promote cartilage development at a clinically relevant scale, yet there remains a limited understanding of the optimal conditions for inducing differentiation and matrix production. We investigated how cell density and temporal exposure to chondrogenic factors impacted chondrogenesis of human mesenchymal stem cells (hMSCs) encapsulated in poly(ethylene glycol) diacrylate hydrogels. We found maximal proteoglycan and collagen production in constructs seeded between 10 and 25 × 106 cells/mL. Matrix deposition was significantly less per cell in constructs seeded at either higher or lower densities, indicating that paracrine communications may remain important despite loss of direct cell–cell contact. In vitro chondrogenesis of hMSCs was first accomplished using pellet cultures and a defined medium containing transforming growth factor (TGF)-β1 and dexamethasone. The differentiation of hMSCs in hydrogels also required initial exposure to TGF-β1, with no chondrogenic matrix produced in its absence. If TGF-β1 was initially included for at least 7 days, its removal impacted collagen production per cell but also lead to an increase in cell number, such that total collagen deposition was equivalent to controls when TGF-β1 was included for at least 3 weeks. Further, proteoglycan content per construct was higher at 6 weeks after removal of TGF-β1 at any time. In contrast to TGF-β1, dexamethasone was not required for chondrogenesis of hMSCs in hydrogels: there was no difference in matrix deposition between hydrogels cultured with or without dexamethasone. Further, without dexamethasone, SOX9 gene expression was higher during early chondrogenesis and there was a significant reduction in collagen I deposition, suggesting that a more hyaline cartilage phenotype is achieved without dexamethasone. Collagen content at 6 weeks was lower if dexamethasone was excluded after the first 7 days, but was equivalent to control if dexamethasone was included for 2 weeks or longer. Proteoglycan deposition was unaffected by dexamethasone exclusion. These results indicate that modulating exposure to TGF-β1 is beneficial for cell survival/proliferation and matrix production from hMSCs in hydrogels, and that not only is dexamethasone dispensable but also its exclusion may be advantageous for forming hyaline cartilage