Recommendations for the delivery of therapeutic exercise for people with knee and/or hip osteoarthritis. An international consensus study from the OARSI Rehabilitation Discussion Group.

OBJECTIVE: To develop evidence-informed recommendations to support the delivery of best practice therapeutic exercise for people with knee and/or hip osteoarthritis (OA). DESIGN: A multi-stage, evidence-informed, international multi-disciplinary consensus process that included: 1) a narrative literature review to synthesise existing evidence; 2) generation of evidence-informed proposition statements about delivery of exercise for people with knee and/or hip OA by an international multi-disciplinary expert panel, with statements refined and analysed thematically; 3) an e-Delphi survey with the expert panel to gain consensus on the most important statements; 4) a final round of statement refinement and thematic analysis to group remaining statements into domains. RESULTS: The expert panel included 318 members (academics, health care professionals and exercise providers, patient representatives) from 43 countries. Final recommendations comprised 54 specific proposition statements across 11 broad domains: 1) use an evidence-based approach; 2) consider exercise in the context of living with OA and pain; 3) undertake a comprehensive baseline assessment with follow-up; 4) set goals; 5) consider the type of exercise; 6) consider the dose of exercise; 7) modify and progress exercise; 8) individualise exercise; 9) optimise the delivery of exercise; 10) focus on exercise adherence; and 11) provide education about OA and the role of exercise. CONCLUSION: The breadth of issues identified as important by the international diverse expert panel highlights that delivering therapeutic exercise for OA is multi-dimensional and complex.

Evaluation of the First Contact Physiotherapy (FCP) model of primary care: patient characteristics and outcomes.

OBJECTIVE: First Contact Physiotherapy (FCP) is a primary care model where expert musculoskeletal (MSK) physiotherapists undertake the first patient consultation, to enhance MSK-patient care and free-up GP capacity. The authors report the quantitative findings from the FCP National Evaluation (Phase 3) which evaluated the FCP model against success criteria. DESIGN AND SETTING: A mixed-methods 24-month service evaluation involving 40 FCP sites and 240 FCPs across England. METHODS: An online platform collected patient-reported experience and outcomes following the FCP consultation and at 1, 2 and 3-months follow-up. These included the Keele STarT MSK Tool, pain intensity (0-10 NRS scale), Musculoskeletal Health Questionnaire (MSK-HQ, range 0-56), and Friends-and-Family Test. RESULTS: Over 13 months, 2825 patients were invited by email and 24% (n=680) completed their initial questionnaire. Their mean age was 56.2 (SD 14.9), 61% were female, ethnicity was 97% white, mean pain intensity was 6.1 (SD 2.13) and mean MSK-HQ score was 33.8 (SD 9.5). At 3-months follow-up (n=370) there was a 2.8 (CI 2.5 to 3.1) mean pain intensity reduction from baseline, a mean 7.1 (6.0 to 8.2) score improvement in MSK-HQ and 64% reporting overall improvement (much better/better) since seeing the FCP. One of the six success criteria was not met; 29% of those in employment reported receiving specific work advice from the FCP (target ≥75%). CONCLUSION: Ahead of the planned scale-up of the FCP primary care model across the UK, this evaluation provides useful data on patients who access this service, their short-term clinical outcomes and whether key success criteria are being met.

Antifungal stewardship in critical care: Implementing a diagnostics-driven care pathway in the management of invasive candidiasis.

BACKGROUND: Invasive candidiasis (IC) is the most common invasive fungal disease in patients admitted to critical care and is associated with high mortality rates. Diagnosis can be delayed by the poor sensitivity of culture-based methods, leading to unnecessary use of empirical antifungal therapy (EAFT). The fungal biomarker (1-3)-ß-d-glucan (BDG) has been shown to aid in the diagnosis of IC in critical care and has been incorporated into antifungal stewardship (AFS) programmes. AIM: To describe our experience using a diagnostics-driven AFS programme incorporating the fungal biomarker BDG, analyse its impact on antifungal therapy (AFT), and gain an improved understanding of the epidemiology of IC in our critical care unit (CrCU). METHODS: An AFS care pathway incorporating BDG was introduced in the CrCU in St James's Hospital, Dublin. Following an educational programme, compliance with the pathway was prospectively audited between December 1st, 2017 and July 31st, 2018. RESULTS AND CONCLUSION: One hundred and nine AFT episodes were included, of which 95 (87%) had a BDG sent. Of those with BDG results available at the time of decision-making, 38 (63%) were managed in accordance with the care pathway. In compliant episodes without IC, median EAFT duration was 5.5 days [IQR 4-7] and no increase in mortality or subsequent IC was observed. Although adopting a diagnostics-driven approach was found to be useful in the cohort of patients with BDG results available, the use of once-weekly BDG testing did not result in an observed reduction in the consumption of anidulafungin, highlighting an important limitation of this approach.

Antenatal sildenafil citrate treatment increases offspring blood pressure in the placental-specific Igf2 knockout mouse model of FGR.

Fetal growth restriction (FGR), where a fetus fails to reach its genetic growth potential, affects up to 8% of pregnancies and is a major risk factor for stillbirth and adulthood morbidity. There are currently no treatments for FGR, but candidate therapies include the phosphodiesterase-5 inhibitor sildenafil citrate (SC). Randomized clinical trials in women demonstrated no effect of SC on fetal growth in cases of severe early onset FGR; however, long-term health outcomes on the offspring are unknown. This study aimed to assess the effect of antenatal SC treatment on metabolic and cardiovascular health in offspring by assessing postnatal weight gain, glucose tolerance, systolic blood pressure, and resistance artery function in a mouse model of FGR, the placental-specific insulin-like growth factor 2 (PO) knockout mouse. SC was administered subcutaneously (10 mg/kg) daily from embryonic day (E)12.5. Antenatal SC treatment did not alter fetal weight or viability but increased postnatal weight gain in wild-type (WT) female offspring (P < 0.05) and reduced glucose sensitivity in both WT (P < 0.01) and P0 (P < 0.05) female offspring compared with controls. Antenatal SC treatment increased systolic blood pressure in both male (WT vs. WT-SC: 117 ± 2 vs. 140 ± 3 mmHg, P < 0.0001; P0 vs. P0-SC: 113 ± 3 vs. 140 ± 4 mmHg, P < 0.0001; means ± SE) and female (WT vs. WT-SC: 121 ± 2 vs. 140 ± 2 mmHg, P < 0.0001; P0 vs. P0-SC: 117 ± 2 vs. 144 ± 4 mmHg, P < 0.0001) offspring at 8 and 13 wk of age. Increased systolic blood pressure was not attributed to altered mesenteric artery function. In utero exposure to SC may result in metabolic dysfunction and elevated blood pressure in later life.NEW & NOTEWORTHY Sildenafil citrate (SC) is currently used to treat fetal growth restriction (FGR). We demonstrate that SC is ineffective at treating FGR, and leads to a substantial increase systolic blood pressure and alterations in glucose homeostasis in offspring. We therefore urge caution and suggest that further studies are required to assess the safety and efficacy of SC in utero, in addition to the implications on long-term health.

A mixed methods exploration of physiotherapist's approaches to analgesic use among patients with hip osteoarthritis.

OBJECTIVE: To explore how physiotherapists currently address analgesic use among patients with hip osteoarthritis, and their beliefs about the acceptability of prescribing for these patients. METHODS: A cross-sectional questionnaire was mailed to 3126 UK-based physiotherapists. Approaches to analgesic use among patients with hip osteoarthritis were explored using a case vignette. Semi-structured telephone interviews were undertaken with 21 questionnaire responders and analysed thematically. SETTING: UK. PARTICIPANTS: Physiotherapists who had treated a patient with hip osteoarthritis in the previous 6 months. RESULTS: Questionnaire response: 53% (n=1646). One thousand one hundred forty eight physiotherapists reported treating a patient with hip osteoarthritis in the last 6 months (applicable responses), of whom nine (1%) were non-medical prescribers. Nearly all physiotherapists (98%) reported that they would address analgesic use for the patient with hip osteoarthritis, most commonly by signposting them to their GP (83%). Fifty six percent would discuss optimal use of current medication, and 33%, would discuss use of over-the-counter medications. Interviews revealed that variations in physiotherapists' approaches to analgesic use were influenced by personal confidence, patient safety concerns, and their perceived professional remit. Whilst many recognised the benefits of analgesia prescribing for both patients and GP workload, additional responsibility for patient safety was a perceived barrier. CONCLUSIONS: How physiotherapists currently address analgesic use with patients with hip osteoarthritis is variable. Although the potential benefits of independent prescribing were recognised, not all physiotherapist want the additional responsibility. Further guidance supporting optimisation of analgesic use among patients with hip OA may help better align care with best practice guidelines and reduce GP referrals.

Characterizing a "Big Data" Cohort of Over 200,000 Low-Income U.S. Infants and Children for Obesity Research: The ADVANCE Early Life Cohort.

Introduction Low-income populations have elevated exposure to early life risk factors for obesity, but are understudied in longitudinal research. Our objective was to assess the utility of a cohort derived from electronic health record data from safety net clinics for investigation of obesity emerging in early life. Methods We examined data from the PCORNet ADVANCE Clinical Data Research Network, a national network of Federally-Qualified Health Centers serving >1.7 million safety net patients across the US. This cohort includes patients who, in 2012-2014, had ≥1 valid body mass index measure when they were 0-5 years of age. We characterized the cohort with respect to factors required for early life obesity research in vulnerable subgroups: sociodemographic diversity, weight status based on World Health Organization (<2 years) or Centers for Disease Control (≥2 years) growth curves, and data longitudinality. Results The cohort includes 216,473 children and is racially/ethnically diverse (e.g., 17.9% Black, 45.4% Hispanic). A majority (56.9%) had family incomes below the Federal Poverty Level (FPL); 32% were <50% of FPL. Among children <2 years, 7.6 and 5.3% had high and low weight-for-length, respectively. Among children 2-5 years, 15.0, 12.7 and 2.4% were overweight, obese, and severely obese, respectively; 5.3% were underweight. In the study period, 79.2% of children had ≥2 BMI measures. Among 4-5 year olds, 21.9% had >1 BMI measure when they were <2 years. Discussion The ADVANCE Early Life cohort offers unique opportunities to investigate early life determinants of obesity in the understudied population of low income and minority children.

Heterogeneity in mantle carbon content from CO2-undersaturated basalts.

The amount of carbon present in Earth's mantle affects the dynamics of melting, volcanic eruption style and the evolution of Earth's atmosphere via planetary outgassing. Mantle carbon concentrations are difficult to quantify because most magmas are strongly degassed upon eruption. Here we report undegassed carbon concentrations from a new set of olivine-hosted melt inclusions from the Mid-Atlantic Ridge. We use the correlations of CO2 with trace elements to define an average carbon abundance for the upper mantle. Our results indicate that the upper mantle carbon content is highly heterogeneous, varying by almost two orders of magnitude globally, with the potential to produce large geographic variations in melt fraction below the volatile-free solidus. Such heterogeneity will manifest as variations in the depths at which melt becomes interconnected and detectable, the CO2 fluxes at mid-ocean ridges, the depth of the lithosphere-asthenosphere boundary, and mantle conductivity.

Evaluating community health centers' adoption of a new global capitation payment (eCHANGE) study protocol.

Primary care patient-centered medical homes (PCMHs) are an effective healthcare delivery model. Evidence regarding the most effective payment models for increased coordination efforts is sparse. This protocol paper describes the evaluation of an Alternative Payment Methodology (APM) implemented in a subset of Oregon community health centers (CHCs), using a prospective matched observational design. The APM is a primary care payment reform intervention that changed Oregon's Medicaid payment for several CHCs from fee-for-service reimbursement to a per-member-per-month capitated payment. We will implement a difference-in-difference analytic approach to evaluate pre-post APM changes between intervention and control groups, including: 1) clinic-level outcomes, 2) patient-level clinical outcomes, and 3) patient-level econometric outcomes. Findings from the project will be of national significance, as there is a need for evidence regarding how novel payment methods might enhance PCMH capabilities and support their capacity to produce better quality and outcomes. If this capitated payment method is proven effective, study findings will inform dissemination of similar APMs nationwide.

IFPA meeting 2015 workshop report I: placental mitochondrial function, transport systems and epigenetics.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops covered areas of placental regulation and nutrient handling: 1) placental epigenetics; 2) placental mitochondrial function; 3) placental transport systems.

Activation of KV7 channels stimulates vasodilatation of human placental chorionic plate arteries.

INTRODUCTION: Potassium (K(+)) channels are key regulators of vascular smooth muscle cell (VSMC) excitability. In systemic small arteries, Kv7 channel expression/activity has been noted and a role in vascular tone regulation demonstrated. We aimed to demonstrate functional Kv7 channels in human fetoplacental small arteries. METHODS: Human placental chorionic plate arteries (CPAs) were obtained at term. CPA responses to Kv7 channel modulators was determined by wire myography. Presence of Kv7 channel mRNA (encoded by KCNQ1-5) and protein expression were assessed by RT-PCR and immunohistochemistry/immunofluorescence, respectively. RESULTS: Kv7 channel blockade with linopirdine increased CPA basal tone and AVP-induced contraction. Pre-contracted CPAs (AVP; 80 mM K(+) depolarization solution) exhibited significant relaxation to flupirtine, retigabine, the acrylamide (S)-1, and (S) BMS-204352, differential activators of Kv7.1 - Kv7.5 channels. All CPAs assessed expressed KCNQ1 and KCNQ3-5 mRNA; KCNQ2 was expressed only in a subset of CPAs. Kv7 protein expression was confirmed in intact CPAs and isolated VSMCs. DISCUSSION: Kv7 channels are present and active in fetoplacental vessels, contributing to vascular tone regulation in normal pregnancy. Targeting these channels may represent a therapeutic intervention in pregnancies complicated by increased vascular resistance.

Foetal and placental 11ß-HSD2: a hub for developmental programming.

Foetal growth restriction (FGR), reflective of an adverse intrauterine environment, confers a significantly increased risk of perinatal mortality and morbidity. In addition, low birthweight associates with adult diseases including hypertension, metabolic dysfunction and behavioural disorders. A key mechanism underlying FGR is exposure of the foetus to glucocorticoids which, while critical for foetal development, in excess can reduce foetal growth and permanently alter organ structure and function, predisposing to disease in later life. Foetal glucocorticoid exposure is regulated, at least in part, by the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which catalyses the intracellular inactivation of glucocorticoids. This enzyme is highly expressed within the placenta at the maternal-foetal interface, limiting the passage of glucocorticoids to the foetus. Expression of 11ß-HSD2 is also high in foetal tissues, particularly within the developing central nervous system. Down-regulation or genetic deficiency of placental 11ß-HSD2 is associated with significant reductions in foetal growth and birth weight, and programmed outcomes in adulthood. To unravel the direct significance of 11ß-HSD2 for developmental programming, placental function, neurodevelopment and adult behaviour have been extensively investigated in a mouse knockout of 11ß-HSD2. This review highlights the evidence obtained from this mouse model for a critical role of feto-placental 11ß-HSD2 in determining the adverse programming outcomes.

Healthcare professionals' knowledge of calories.

AIM: To determine healthcare professionals' knowledge of the calorie content of foods and the relationship to weight maintenance. METHOD: A cross-sectional questionnaire was used to survey 179 clinical staff, non-clinical staff and life coaches working in health care. RESULTS: The response rate is 81%. The majority of respondents identified the weight loss requirements necessary to achieve marked health benefits in obese patients. Estimation of calorie and salt contents of specified foods was generally inaccurate. The majority of healthcare professionals did not know the amount of exercise required to burn off the calories of commonly consumed foods. CONCLUSION: Support and education are required for healthcare professionals to manage the challenges associated with obesity.

Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y.

BACKGROUND: Pups of normally nourished dams that are cross-fostered after birth to dams fed a low-protein (8% by weight) diet (postnatal low protein (PLP)) grow slower during the suckling period and remain small and lean throughout adulthood. At weaning, they have increased expression in the arcuate nucleus (ARC) of the hypothalamus of the orexigenic neuropeptide Y (NPY) and decreased expression of pro-opiomelanocortin, the precursor of anorexigenic melanocortins. OBJECTIVES AND METHODS: We investigated, using third ventricle administration, whether 3-month-old male PLP rats display altered sensitivity to leptin with respect to food intake, NPY and the melanocortin 3/4-receptor agonist MTII, and using in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR, whether the differences observed were associated with changes in the hypothalamic expression of NPY or the leptin receptor, NPY receptors and melanocortin receptors. RESULTS: PLP rats were smaller and had reduced percentage body fat content and plasma leptin concentration compared with control rats. Leptin (5 µg) reduced food intake over 0-48 h more in PLP than control rats (P<0.05). Submaximal doses of NPY increased the food intake less in PLP rats than in controls, whereas submaximal doses of MTII reduced the food intake more in PLP rats. Maximal responses did not differ between PLP and control rats. Leptin and melanocortin-3 receptor (MC3R) expression were increased in both ARC and ventromedial hypothalamic nuclei in PLP animals compared with the controls. MC4R, NPY Y1R, Y5R and NPY expression were unchanged. CONCLUSION: Postnatal undernourishment results in food intake in adult rats being more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. We propose that this contributes to increased leptin sensitivity and resistance to obesity. Increased expression of ObRb and MC3R may partly explain these findings but other downstream mechanisms must also be involved.

Early growth and ageing.

Effects of in utero and early life conditions on adult health and disease such as cardiovascular disease and type 2 diabetes are well documented by epidemiological and clinical observations. Animal models including intrauterine artery ligation, maternal restriction of iron, protein or general caloric intake, provide invaluable tools to understand mechanisms linking early growth and later diseases in adult life. In addition, the rodent model of maternal protein restriction has revealed that longevity can be influenced either positively or negatively by early growth patterns. Recent rapid advances in the ageing field using model organisms involving caloric restriction and genetic mutation as well as gene overexpression demonstrated the importance of insulin/ IGF-1 signaling pathways, oxidative damage and SIRT1 in the regulation of lifespan. Studies using rodent models of maternal protein restriction suggest that alteration in insulin metabolism, changes in expression of antioxidant defense systems and in levels of oxidative damage (including telomere attrition) may also play a key role in regulation of lifespan by the early environment. It is suggested that neuroendocrine systems and epigenetic modification may be the potential mechanisms underlying beneficial or detrimental effects of early growth on the regulation of lifespan. Further studies in this area are warranted.

Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat.

In the adult brain, leptin regulates energy homeostasis primarily via hypothalamic circuitry that affects food intake and energy expenditure. Evidence from rodent models has demonstrated that during early postnatal life, leptin is relatively ineffective in modulating these pathways, despite the high circulating levels and the presence of leptin receptors within the central nervous system. Furthermore, in recent years, a neurotrophic role for leptin in the establishment of energy balance circuits has emerged. The precise way in which leptin exerts these effects, and the site of leptin action, is unclear. To provide a detailed description of the development of energy balance systems in the postnatal rat in relation to leptin concentrations during this time, endogenous leptin levels were measured, along with gene expression of leptin receptors and energy balance neuropeptides in the medial basal hypothalamus, using in situ hybridization. Expression of leptin receptors and both orexigenic and anorexigenic neuropeptides increased in the arcuate nucleus during the early postnatal period. At postnatal day 4 (P4), we detected dense leptin receptor expression in ependymal cells of the third ventricle (3V), which showed a dramatic reduction over the first postnatal weeks, coinciding with marked morphological changes in this region. An acute leptin challenge robustly induced suppressor of cytokine signaling-3 expression in the 3V of P4 but not P14 animals, revealing a clear change in the location of leptin action over this period. These findings suggest that the neurotrophic actions of leptin may involve signaling at the 3V during a restricted period of postnatal development.

Early life programming of obesity and metabolic disease.

It is becoming increasingly apparent that conditions experienced in early life play an important role in the long-term health of individuals. Alterations in development due to impaired, excessive or imbalanced growth, both in utero and during critical periods of relative plasticity beyond birth, can lead to the permanent programming of physiological systems. The regulation of energy balance is one area that is receiving particular attention, as rates of obesity and associated metabolic and cardiovascular disease continue to rise. Over recent decades, much progress has been made toward understanding the way in which metabolic tissues and physiological systems develop, and the impact of early life events and nutrition on these processes. It is apparent within human populations that some individuals are better able to maintain an appropriate body weight in the face of an obesogenic environment. Animal models have been widely used for the investigation of differential susceptibility to diet-induced obesity (DIO) and impaired energy balance regulation, and are shedding light on key pathways that may be involved. Alterations in pathways mediating energy homeostasis, outlined below, are likely candidates for programming effects following disturbed growth in early life.

RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a debilitating disease characterized by exaggerated extracellular matrix deposition and aggressive lung structural remodeling. Disease pathogenesis is driven by fibroblastic foci formation, consequent on growth factor overexpression and myofibroblast proliferation. We have previously shown that both CTGF overexpression and myofibroblast formation in IPF cell lines are dependent on RhoA signaling. As RhoA-mediated regulation is also involved in cell cycle progression, we hypothesise that this pathway is key to lung fibroblast turnover through modulation of cyclin D1 kinetic expression. METHODS: Cyclin D1 expression was compared in primary IPF patient-derived fibroblasts and equivalent normal control cells. Quantitative real time PCR was employed to examine relative expression levels of cyclin D1 mRNA; protein expression was confirmed by western blotting. Effects of Rho signaling were investigated using transient transfection of constitutively active and dominant negative RhoA constructs as well as pharmacological inhibitors. Cellular proliferation of lung fibroblasts was determined by BrdU incorporation ELISA. To further explore RhoA regulation of cyclin D1 in lung fibroblasts and associated cell cycle progression, an established Rho inhibitor, Simvastatin, was incorporated in our studies. RESULTS: Cyclin D1 expression was upregulated in IPF compared to normal lung fibroblasts under exponential growth conditions (p < 0.05). Serum deprivation inhibited cyclin D1 expression, which was restored following treatment with fibrogenic growth factors (TGF-beta1 and CTGF). RhoA inhibition, using a dominant negative mutant and a pharmacological inhibitor (C3 exotoxin), suppressed levels of cyclin D1 mRNA and protein in IPF fibroblasts, with significant abrogation of cell turnover (p < 0.05). Furthermore, Simvastatin dose-dependently inhibited fibroblast cyclin D1 gene and protein expression, inducing G1 cell cycle arrest. Similar trends were observed in control experiments using normal lung fibroblasts, though exhibited responses were lower in magnitude. CONCLUSION: These findings report for the first time that cyclin D1 expression is deregulated in IPF through a RhoA dependent mechanism that influences lung fibroblast proliferation. This potentially unravels new molecular targets for future anti-IPF strategies; accordingly, Simvastatin inhibition of Rho-mediated cyclin D1 expression in IPF fibroblasts merits further exploitation.