Home exercise can prevent falls in the general older community but its impact in people recently discharged from hospital is not known. The study aimed to investigate the effects of a home-based ...exercise program on falls and mobility among people recently discharged from hospital.
This randomised controlled trial (ACTRN12607000563460) was conducted among 340 older people. Intervention group participants (n = 171) were asked to exercise at home for 15-20 minutes up to 6 times weekly for 12 months. The control group (n = 169) received usual care. Primary outcomes were rate of falls (assessed over 12 months using monthly calendars), performance-based mobility (Lower Extremity Summary Performance Score, range 0-3, at baseline and 12 months, assessor unaware of group allocation) and self-reported ease of mobility task performance (range 0-40, assessed with 12 monthly questionaries). Participants had an average age of 81.2 years (SD 8.0) and 70% had fallen in the past year. Complete primary outcome data were obtained for at least 92% of randomised participants. Participants in the intervention group reported more falls than the control group (177 falls versus 123 falls) during the 12-month study period and this difference was statistically significant (incidence rate ratio 1.43, 95% CI 1.07 to 1.93, p = 0.017). At 12-months, performance-based mobility had improved significantly more in the intervention group than in the control group (between-group difference adjusted for baseline performance 0.13, 95% CI 0.04 to 0.21, p = 0.004). Self-reported ease in undertaking mobility tasks over the 12-month period was not significantly different between the groups (0.49, 95% CI -0.91 to 1.90, p = 0.488).
An individualised home exercise prescription significantly improved performance-based mobility but significantly increased the rate of falls in older people recently discharged from hospital.
Australian New Zealand Clinical Trials Registry ACTRN12607000563460.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that ...T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes, and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, with T-bet- and NF-κB-mediated pathways instead converging to allow P-TEFb recruitment. These data provide insight into the mechanism through which lineage-specifying factors promote differentiation of alternative T cell fates.
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•Th1 genes and Th2 genes are associated with RNA pol II in the alternative lineage•T-bet acts to recruit Mediator and the SEC to activate Th1 genes and eRNAs•T-bet and NF-κB-dependent P-TEFb recruitment pathways converge at enhancers•P-TEFb inhibition silences T-bet target genes and abrogates uveitis in vivo
Lineage-specifying transcription factors control T helper cell fate choice, but the mechanisms underlying this are unclear. Hertweck et al. reveal that Th1 genes undergo transcriptional initiation in the alternative Th2 lineage and that the Th1 master regulator T-bet functions to recruit Mediator and the super-elongation complex to activate transcriptional elongation.
Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer
. The success of poly-ADP ribose polymerase inhibitors in the treatment of ...breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability
. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability
. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material-these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers.
Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety ...of this drug. Existing reports are limited to small studies and case reports.
To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide.
Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014.
The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia.
Children and infants with laboratory-confirmed diagnosis of HI.
Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors.
A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P < 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%).
In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide.
Background. Exercise interventions can enhance mobility after stroke as well as prevent falls in elderly persons. Objective. Investigate whether an exercise intervention can enhance mobility, prevent ...falls, and increase physical activity among community-dwelling people after stroke. Method. A randomized trial with blinding of physical outcome assessment was conducted through local stroke clubs. Both groups, on average 5.9 years poststroke, received exercise classes, advice, and a home program for 12 months. The experimental group (EG) program (n = 76) aimed to improve walking, prevent falls and increase physical activity. The control group (CG) program (n = 75) aimed to improve upper-limb and cognitive functions. The primary outcomes were walking capacity, walking speed measured before and after the intervention, and fall rates monitored monthly. Results. At 12 months, the EG walked 34 m further in 6 minutes (95% confidence interval CI = 19-50; P < .001) and 0.07 m/s faster over 10 m (95% CI = 0.01-0.14; P = .03) than the CG. The EG had 129 falls, and the CG had 133. There were no differences in proportion of fallers (relative risk = 1.22; 95% CI = 0.91-1.62; P = .19) or the rate of falls between groups (incidence rate ratio = 0.96; 95% CI = 0.59-1.51; P = .88). Conclusion. The experimental intervention delivered through stroke clubs enhanced aspects of mobility but had no effect on falls.
Abstract
Background
StandingTall uses eHealth to deliver evidence-based balance and functional strength exercises. Clinical trials have demonstrated improved balance, reduced falls and fall-related ...injuries and high adherence. This study aimed to evaluate the implementation of StandingTall into health services in Australia and the UK.
Methods
Two hundred and forty-six participants (Australia, n = 184; UK, n = 62) were recruited and encouraged to use StandingTall for 2 h/week for 6-months. A mixed-methods process evaluation assessed uptake and acceptability of StandingTall. Adherence, measured as % of prescribed dose completed, was the primary outcome.
Results
The study, conducted October 2019 to September 2021 in Australia and November 2020 to April 2022 in the UK, was affected by COVID-19. Participants’ mean age was 73 ± 7 years, and 196 (81%) were female. Of 129 implementation partners (e.g. private practice clinicians, community exercise providers, community service agencies) approached, 34% (n = 44) agreed to be implementation partners. Of 41 implementation partners who referred participants, 15 (37%) referred ≥5. Participant uptake was 42% (198/469) with mean adherence over 6 months being 41 ± 39% of the prescribed dose (i.e. 39 ± 41 min/week) of exercise. At 6 months, 120 (76%) participants indicated they liked using StandingTall, 89 (56%) reported their balance improved (moderately to a great deal better) and 125 (80%) rated StandingTall as good to excellent. For ongoing sustainability, health service managers highlighted the need for additional resources.
Conclusions
StandingTall faced challenges in uptake, adoption and sustainability due to COVID-19 and a lack of ongoing funding. Adherence levels were lower than the effectiveness trial, but were higher than other exercise studies. Acceptance was high, indicating promise for future implementation, provided sufficient resources and support are made available.
Trial registration
Australian and New Zealand Clinical Trials Registry ACTRN12619001329156.
Abstract
Background
The increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side ...effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects.
Methods
Blood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 A-3081T) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX).
Results
Systolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 T carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than A homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005).
Conclusions
Subanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines.
Older people who have been recently discharged from hospital are at increased risk of falls and deterioration in physical functioning.
To investigate the cost-effectiveness of a 12-month ...home-exercise program for older adults after hospitalization.
An economic evaluation was conducted alongside a randomized controlled trial. The analysis was conducted from the health and community service provider perspective. A total of 340 people aged 60 years and older, with a recent hospital admission, were randomized into exercise and usual care control groups. Incremental costs per extra person showing improvement in mobility performance (using the Short Physical Performance Battery), per person indicating improvement in health (self-reported using a 3-point Likert scale) and per quality-adjusted life year (QALY) gained (utility measured using the EQ-5D) were estimated. Uncertainty was represented using cost-effectiveness acceptability curves. Subgroup analyses for participants with better cognition (above the median MMSE score of 28) also were undertaken.
The average cost of the intervention was $A751 per participant. The incremental cost-effectiveness of the program relative to usual care was $A22,958 per extra person showing an improvement in mobility, $A19,020 per extra person indicating an improvement in health, and $A77,403 per QALY. The acceptability curve demonstrates that the intervention had an 80% probability of being cost-effective relative to the control at a threshold of $A48,000 per extra person achieving mobility improvement and $A36,000 indicating an improvement in self-reported health. There was no threshold value at which the program can be considered as having an 80% probability of cost-effectiveness for the QALY outcome. Subgroup analyses for participants with better cognitive status indicated improved cost-effectiveness for all outcomes.
The exercise intervention appeared to offer reasonable value for money for mobility outcomes and self-reported health status. Value for money for all measures was greater in the higher cognitive status subgroup.
Summary
Despite the obesity epidemic, there are relatively few multidisciplinary obesity services in Australia, and only limited data on the effectiveness of these services. The aim of this study was ...to evaluate the effectiveness of a university hospital‐based weight management clinic—the ‘Healthy Weight Clinic’ in supporting patients to achieve clinically significant weight loss (≥5% reduction in body weight), weight maintenance, and changes in body composition. A retrospective review was conducted to determine weight and associated health outcomes in patients who attended an initial consultation in the first 2 years of the clinic—between March 2017 and March 2019. Follow up was at least 1 year for all patients. Patients who underwent bariatric surgery were excluded. Of 213 total patients, 172 patients attended more than one follow‐up consultation for lifestyle modification. Mean weight change and percentage total weight change at last follow‐up was −6.2 kg (SD 7.4) and − 6.0% (SD 6.9), respectively. For every additional clinic follow‐up, there was 21.4% increased odds of achieving clinically significant weight loss, and for every additional month of follow‐up, there was 10.1% increased odds of achieving clinically significant weight loss. Twenty percent of patients (34/172) maintained ≥5% of initial body weight loss for at least 1 year. Body composition measurements were also favourable, with significant changes in percentage skeletal muscle mass of +0.8% (SD 1.5) and in percentage fat mass by −1.4% (SD 3.2). Regular support in a structured holistic multidisciplinary obesity service enables patients to achieve clinically meaningful weight loss and improved skeletal muscle mass to body fat ratio, and maintain this loss for at least 1 year. Improved weight loss was associated with more patient visits and longer duration of attendance at the clinic.
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