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Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRβ) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRβ + cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRβ + cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFβ activation in primary human skeletal muscle and cardiac PDGFRβ + cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses. The mechanisms underlying tissue fibrosis are unclear. The authors show that mesenchymal cells expressing PDGFRβ mediate fibrosis in skeletal muscle and heart via a mechanism involving αv integrin, and that inhibitors of αv integrins attenuate fibrotic responses in mice.

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG’s glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies. FKRP mutations cause muscular dystrophies with varied clinical presentations. The target of FKRP is α-dystroglycan, but here the authors show that FKRP also directs sialylation of fibronectin, a process that is essential for recruitment o collagen to the muscle basement membrane.

Electron density irregularities in the ionosphere modify the phase and amplitude of trans-ionospheric radio signals. We aim to characterize the spectral and morphological features of E- and F-region ionospheric irregularities likely to produce these fluctuations or “scintillations”. To characterize them, we use a three-dimensional radio wave propagation model—“Satellite-beacon Ionospheric scintillation Global Model of upper Atmosphere” (SIGMA), along with the scintillation measurements observed by a cluster of six Global Positioning System (GPS) receivers called Scintillation Auroral GPS Array (SAGA) at Poker Flat, AK. An inverse method is used to derive the parameters that describe the irregularities by estimating the best fit of model outputs to GPS observations. We analyze in detail one E-region and two F-region events during geomagnetically active times and determine the E- and F-region irregularity characteristics using two different spectral models as input to SIGMA. Our results from the spectral analysis show that the E-region irregularities are more elongated along the magnetic field lines with rod-shaped structures, while the F-region irregularities have wing-like structures with irregularities extending both along and across the magnetic field lines. We also found that the spectral index of the E-region event is less than the spectral index of the F-region events. Additionally, the spectral slope on the ground at higher frequencies is less than the spectral slope at irregularity height. This study describes distinctive morphological and spectral features of irregularities at E- and F-regions for a handful of cases performed using a full 3D propagation model coupled with GPS observations and inversion.

OBJECTIVE:--To explore the nature of functional impairment in older people with diabetes. RESEARCH DESIGN AND METHODS--A population-based case-control study with detailed assessment of diabetes and functional status was undertaken. RESULTS:--Altogether, 403 case subjects and 403 matched control subjects were studied (median age 75 years, 51% female). Subjects with diabetes had more comorbidities than control subjects (mean 2.5 vs. 1.9, P < 0.0001) and were more likely to have severe functional impairment (4 vs. 1%, Barthel score <5, P < 0.001). Health status pertaining to physical function was reduced in case subjects (SF36 60 vs. 40, P < 0.0001). In a multivariate model controlling for age, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, cancer, osteoarthritis, and dementia, diabetes remained significantly associated with mobility limitation (odds ratio 2.1, P < 0.001). CONCLUSIONS:--Older people with diabetes have considerable functional impairment associated with reduced health status. This population may benefit from comprehensive geriatric assessment and tailored diabetes management.

Nonunion bone fractures can impact the quality of life and represent a major economic burden. Scaffold-based tissue engineering has shown promise as an alternative to bone grafting. Achieving desirable bone reconstruction requires appropriate surface properties, together with optimizing the internal architecture of 3D scaffolds. This study presents the surface modification of poly(lactic-co-glycolic acid) (PLGA), collagen, and PLGA-collagen via an argon plasma treatment. Argon plasma can modify the surface chemistry and topography of biomaterials and improve in vivo integration. Solvent-cast films were prepared using 1,1,1,3,3,3-hexafluoro-2-propanol and characterized via differential scanning calorimetry, thermogravimetric analysis, contact angle measurement, and critical surface tension analysis. For PLGA films, the water contact angle dropped from 70° to 42°, whereas the diiodomethane contact angle reduced from 53° to 32° after the plasma treatment. A set of PLGA-collagen formulations were loaded with nanohydroxyapatite (nHA) and polyethylene glycol (PEG) to enhance their osteoconductivity and hydrophilicity. Then, 3D scaffolds were fabricated using a 3D Bioplotter and characterized via Fourier-transform infrared (FTIR) spectroscopy. A bicinchoninic acid assay (BCA) was used to compare the protein release from the untreated and plasma-treated scaffolds into phosphate-buffered saline (PBS). The plasma-treated scaffolds had a lower protein release, and the difference compared to the untreated scaffolds was statistically significant.

In 27 C4 grasses grown under adequate or deficient nitrogen (N) supplies, N-use efficiency at the photosynthetic (assimilation rate per unit leaf N) and whole-plant (dry mass per total leaf N) level was greater in NADP-malic enzyme (ME) than NAD-ME species. This was due to lower N content in NADP-ME than NAD-ME leaves because neither assimilation rates nor plant dry mass differed significantly between the two C4 subtypes. Relative to NAD-ME, NADP-ME leaves had greater in vivo (assimilation rate per Rubisco catalytic sites) and in vitro Rubisco turnover rates (kcat; 3.8 versus 5.7 s-1 at 25°C). The two parameters were linearly related. In 2 NAD-ME (Panicum miliaceum and Panicum coloratum) and 2 NADP-ME (Sorghum bicolor and Cenchrus ciliaris) grasses, 30% of leaf N was allocated to thylakoids and 5% to 9% to amino acids and nitrate. Soluble protein represented a smaller fraction of leaf N in NADP-ME (41%) than in NAD-ME (53%) leaves, of which Rubisco accounted for one-seventh. Soluble protein averaged 7 and 10 g (mmol $\\text{chlorophyll})^{-1}$ in NADP-ME and NAD-ME leaves, respectively. The majority (65%) of leaf N and chlorophyll was found in the mesophyll of NADP-ME and bundle sheath of NAD-ME leaves. The mesophyll-bundle sheath distribution of functional thylakoid complexes (photosystems I and II and cytochrome f) varied among species, with a tendency to be mostly located in the mesophyll. In conclusion, superior N-use efficiency of NADP-ME relative to NAD-ME grasses was achieved with less leaf N, soluble protein, and Rubisco having a faster kcat.

Background Although outcome goals for acute healthcare among older people living with frailty often include Health-Related Quality of Life (HRQoL) and other patient-reported outcome measures (PROMs), current quality metrics usually focus on waiting times and survival. Lay and patient review have identified the EuroQol EQ-5D as a candidate measure for this setting. This research appraised the EQ-5D for feasibility, psychometric performance, and respondents’ outcomes in the acute frailty setting. Methods People aged 65 + with Clinical Frailty Scale (CFS) 5–8 were recruited from eight UK hospitals’ emergency care and acute admissions settings. They completed the five-level EQ-5D and the EQ-VAS. Feasibility was assessed with completion times and completeness. For reliability, response distributions and internal consistency were analysed. Finally, EQ-Index values were compared with demographic characteristics and service outcomes for construct validity. Results The 232 participants were aged 65–102. 38% responded in emergency departments and 62% in admissions wards. Median completion time was 12 (IQR, 11) minutes. 98% responses were complete. EQ-5D had acceptable response distribution (SD 1.1–1.3) and internal consistency (Cronbach’s alpha 0.69). EQ-VAS demonstrated a midpoint response pattern. Median EQ-Index was 0.574 (IQR, 0.410) and was related positively with increasing age ( p  = 0.010) and negatively with CFS ( p  < 0.001). Participants with higher CFS had more frequent problems with mobility, self-care, and usual activities. Conclusions Administration of the EQ-5D was feasible in these emergency and acute frailty care settings. EQ-5D had acceptable properties, while EQ-VAS appeared problematic. Participants with more severe frailty had also poorer HRQoL.

Background Dysarthria after stroke is when speech intelligibility is impaired, and this occurs in half of all stroke survivors. Dysarthria often leads to social isolation, poor psychological well-being and can prevent return to work and social lives. Currently, a variety of outcome measures are used in clinical research and practice when monitoring recovery for people who have dysarthria. When research studies use different measures, it is impossible to compare results from trials and delays our understanding of effective clinical treatments. The aim of this study is to develop a core outcome set (COS) to agree what aspects of speech recovery should be measured for dysarthria after stroke (COS-Speech) in research and clinical practice. Methods The COS-Speech study will include five steps: (1) development of a long list of possible outcome domains of speech that should be measured to guide the survey; (2) recruitment to the COS-Speech study of three key stakeholder groups in the UK and Australia: stroke survivors, communication researchers and speech and language therapists/pathologists; (3) two rounds of the Delphi survey process; (4) a consensus meeting to agree the speech outcomes to be measured and a follow-up consensus meeting to match existing instruments/measures (from parallel systematic review) to the agreed COS-Speech; (5) dissemination of COS-Speech. Discussion There is currently no COS for dysarthria after stroke for research trials or clinical practice. The findings from this research study will be a minimum COS, for use in all dysarthria research studies and clinical practice looking at post-stroke recovery of speech. These findings will be widely disseminated using professional and patient networks, research and clinical forums as well as using a variety of academic papers, videos, accessible writing such as blogs and links on social media. Trial registration COS-Speech is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database, October 2021 https://www.comet-initiative.org/Studies/Details/1959 . In addition, “A systematic review of the psychometric properties and clinical utility of instruments measuring dysarthria after stroke” will inform the consensus meeting to match measures to COS-Speech. The protocol for the systematic reviews registered with the International Prospective Register of Systematic Reviews. PROSPERO registration number: CRD42022302998 .

IntroductionUrinary tract infections (UTIs) are highly prevalent and pose a significant burden among older adults. Accurate diagnosis in this population is challenging due to the high prevalence of pre-existing lower urinary tract symptoms, inability to express symptoms and asymptomatic bacteriuria. Current diagnostic tests are unreliable, often resulting in over- and underdiagnosis. A previous pilot study proposed a higher cut-off for pyuria and identified five promising biomarkers for the diagnosis of UTIs in older adults. The UTI-GOLD study aims to validate these five new biomarkers and the higher leucocyte cut-off as a diagnostic tool for UTIs in older people in a real-world setting.Methods and analysisBetween August 2024 and December 2027, an observational multicentre diagnostic accuracy study is being conducted across primary, secondary and tertiary healthcare facilities in the Netherlands and the UK. Adults ≥65 years with a suspected UTI will be considered eligible. Patients with pre-existing decision-making incapacity or an indwelling catheter will be excluded. UTI will be defined according to an international consensus-based reference standard. Biomarkers will be measured by liquid chromatography-mass spectrometry (neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase 2 and CXC motif chemokine ligand 9) and enzyme-linked immunosorbent assay (interleukin 6 and azurocidin). Pyuria will be quantified by automated microscopy and/or flow cytometry. Diagnostic accuracy measures will be calculated using the receiver operating characteristic curves, and sensitivity, specificity, likelihood ratios and predictive values will be reported for optimal cut-offs.Ethics and disseminationThe protocol was reviewed by the local Leiden University Medical Center research committee, who declared on 15 April 2024 that the medical research involving human subject act (Dutch abbreviation: WMO) does not apply to the current study (reference number nWMODIV2_2024025). The study also received approval from the NHS Research Ethics Committee in the UK (reference number 24/LO/0649).The study findings will be published in a peer-reviewed journal, presented at academic congresses and shared with healthcare providers.Trial registration numberThe study was registered at clinicaltrial.gov on the 24 September 2024 with registration number: NCT06610721.

Background Current acute healthcare service metrics are not meaningful for older people living with frailty. Healthcare knowledge, situational security, and physical and psychosocial function are important outcomes typically not collected. The use of patient-reported outcome measures (PROMs) could support these assessments. Existing instruments are not comprehensive as they typically consider function, while older people with frailty also value enablement (self-determination and security in health and healthcare). This study field-tested and validated a PROM for older people with frailty receiving acute care (PROM-OPAC) to measure enablement. Methods People aged 65+ with Clinical Frailty Scale 5–8 were recruited within seventy-two hours of an emergency attendance. Iterations of the novel instrument were administered over three stages: (1) preliminary field-testing for reliability (response distribution and internal consistency) and structure (exploratory factor analysis, EFA); (2) intermediate field-testing of an improved instrument for reliability and structure; (3) final draft validation assessing reliability, structure (confirmatory factor analysis, CFA), and construct validity based on a priori hypotheses. Feasibility was appraised throughout using data completeness and response rates and times. Results 241 people participated. Three items of a preliminary seven-item measure had poor response distribution or loading and were accordingly improved. The intermediate instrument had interpretability issues and three items required further improvement. The final eight-item draft had acceptable reliability (Cronbach’s alpha: 0.71), structure (two factors for self-determination and security; RMSEA: 0.065; TLI: 0.917; CFI: 0.944), and construct validity (lower scores from respondents waiting longer and requiring admission). Feasibility was promising (response rate 39%; 98% responses complete; median completion time 11 (IQR: 12) minutes). Conclusions Administration of the PROM-OPAC appeared feasible and the instrument had acceptable psychometric properties. Further evaluation is required to assess generalisability.