Simplified clinical frailty scale design, validation, and adaptation in older patients.

OBJECTIVE: The clinical frailty scale (CFS) evaluates the level of frailty based on clinical examination, comorbidities, and functional and activity levels of older patients. However, there are many difficulties for internists in evaluating frailty with this scale. Therefore, simplifying the CFS with good design and application is required for better treatment outcomes. Our study was conducted to design and evaluate the correlation of a simplified clinical frailty scale (sCFS) with CFS in older patients. PATIENTS AND METHODS: We undertook a cross-sectional analysis involving 279 older patients, which comprised two steps. Step 1 involves the implementation of sCFS, a protocol that has been endorsed by the Geriatrics Professional Council (GPC). Step 2 entails the enrollment of older patients for frailty assessment using sCFS, comparing it with CFS. RESULTS: The study was conducted on 279 older patients; the average age was 75.7 ± 8.4 (years old), and men accounted for 34.8%. There was a high correlation between the sCFS and CFS (Pearson's r = 0.996; p < 0.001). The similarity of the sCFS to the CFS was very high, with Kappa coefficient = 0.984 (p < 0.001). Compared with the CFS, the sCFS had a Youden index of 98% with 100% sensitivity and 98% specificity assessed through the receiver operating characteristic (ROC) with the CFS threshold of 5. CONCLUSIONS: The sCFS can be used to assess frailty with high sensitivity and specificity.

Quercetin improves and protects Calu-3 airway epithelial barrier function.

Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function. Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3. Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α. Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex.

Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

The KNee OsteoArthritis Prediction (KNOAP2020) challenge: An image analysis challenge to predict incident symptomatic radiographic knee osteoarthritis from MRI and X-ray images.

OBJECTIVES: The KNee OsteoArthritis Prediction (KNOAP2020) challenge was organized to objectively compare methods for the prediction of incident symptomatic radiographic knee osteoarthritis within 78 months on a test set with blinded ground truth. DESIGN: The challenge participants were free to use any available data sources to train their models. A test set of 423 knees from the Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study consisting of magnetic resonance imaging (MRI) and X-ray image data along with clinical risk factors at baseline was made available to all challenge participants. The ground truth outcomes, i.e., which knees developed incident symptomatic radiographic knee osteoarthritis (according to the combined ACR criteria) within 78 months, were not provided to the participants. To assess the performance of the submitted models, we used the area under the receiver operating characteristic curve (ROCAUC) and balanced accuracy (BACC). RESULTS: Seven teams submitted 23 entries in total. A majority of the algorithms were trained on data from the Osteoarthritis Initiative. The model with the highest ROCAUC (0.64 (95% confidence interval (CI): 0.57-0.70)) used deep learning to extract information from X-ray images combined with clinical variables. The model with the highest BACC (0.59 (95% CI: 0.52-0.65)) ensembled three different models that used automatically extracted X-ray and MRI features along with clinical variables. CONCLUSION: The KNOAP2020 challenge established a benchmark for predicting incident symptomatic radiographic knee osteoarthritis. Accurate prediction of incident symptomatic radiographic knee osteoarthritis is a complex and still unsolved problem requiring additional investigation.

Ultrasound Localization of Nitinol Wire of Sub-Wavelength Dimension.

Goal: To enhance endovascular navigation using surgical guidewires and the use of ionizing radiation, we demonstrate a method for ultrasonic localization of wires with diameters less than the wavelength of ultrasound in the medium. Methods: Nitinol wires with diameters ranging from 50 µm to 250 µm were imaged ultrasonically in a 0.25-in-diameter water-filled tube in a gelatin medium. Imaging frequencies were 5 MHz, 7.5 MHZ, and 10 MHz. Results: For the full range of diameters traversing the phantom, the wires were localized successfully via visual inspection of both regular and difference ultrasound images. Similarly, two convolutional neural networks were trained, and both achieved an accuracy of over 95%. Conclusions: Wires with diameters as small as 50 µm were localized successfully in a water-based gelatin phantom, indicating the potential use of ultrasound to enhance endovascular navigation and surgical treatment.

Associations of dietary patterns with bone density and fractures in adults: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Although nutrition is important to bone health, the impact of different dietary patterns on bone density and fracture is unclear. The aim of this study was to synthesise conflicting evidence from observational studies to determine associations of empirically derived dietary patterns with bone density and fracture in healthy adults. METHOD: A systematic review (PROSPERO CRD42017071676) with meta-analysis where possible (for hip fracture) and otherwise with best-evidence synthesis. RESULTS: Twenty-one studies were included in the best-evidence synthesis and four in the meta-analysis. Meta-analysis demonstrated a protective association between 'healthy' pattern score and hip fracture (risk ratio 0.73; 95% confidence interval: 0.56, 0.96; I2 = 95%) for highest compared to lowest 'healthy' pattern score category. In best-evidence synthesis, there was conflicting evidence for associations of both pattern scores with bone density at all sites and total fractures and for 'Western' score and hip fracture. No study reported detrimental effects of 'healthy' patterns, or beneficial effects of 'Western' patterns. DISCUSSION: The results suggest that general practitioners promoting a 'healthy' dietary pattern is, at worst, unlikely to be detrimental for bone health and, at best, may reduce hip fracture.

New insights into the diagnosis and management of bone health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI), defined as a loss of ovarian function before the age of 40 years, is a life-changing diagnosis that has numerous long-term consequences. Musculoskeletal complications, including osteoporosis and fractures, are a key concern for women with POI. The risk of bone loss is influenced by the underlying etiology of POI, and the degree and duration of estrogen deficiency. A decline in muscle mass as a result of estrogen and androgen deficiency may contribute to skeletal fragility, but has not been examined in women with POI. This article aims to review musculoskeletal health in POI; summarize the traditional and novel modalities available to screen for skeletal fragility and muscle dysfunction; and provide updated evidence for available management strategies.

Olfactory bulb atrophy and caspase activation observed in the BACHD rat models of Huntington disease.

Olfactory dysfunction is observed in several neurological disorders, including Huntington disease (HD), and correlates with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the underlying mechanisms are unknown. In order to determine if alterations in the olfactory bulb (OB) are observed in HD we assessed OB weight or area from 3 to 12 months of age in the BACHD transgenic lines (TG5 and TG9). A significant decrease in the OB was observed at 6 and 12 months of age compared to WT. We also detected increased mRNA and protein expression of mutant huntingtin (mHTT) in the OB of TG5 compared to TG9 at specific ages. Despite the higher expression of mHTT in the TG5 OBs, there was increased nuclear accumulation of mHTT in the OB of TG9 compared to WT and TG5 rats. As we observed atrophy of the OB in the BACHD rats we assessed for caspase activation, a known mechanism underlying the cell death observed in HD. We characterized caspase-3, -6, -8 and - 9 mRNA and protein expression levels in the OB of the BACHD transgenic lines at 3, 6 and 12 months of age. Alterations in caspase mRNA and protein expression were detected in the TG5 and TG9 lines. However, the changes observed in the mRNA and protein levels are in some cases discordant, suggesting that the caspase protein modifications detected may be more attributable to post-translational modifications. The caspase activation studies support that cell death may be increased in the rodent HD OB and further our understanding of the olfactory dysfunction and the role of caspases in the pathogenesis of HD.

Care of the adult woman with Turner syndrome.

Turner syndrome (TS) is the most common chromosomal abnormality in females, affecting up to 1/2000 live female births. TS is associated with partial or complete loss of the second X-chromosome in phenotypic females and is associated with increased morbidity and mortality. There are many challenges in providing optimal care for the adult TS women. This review highlights uncertainties that remain in hormone replacement therapy, bone health and cardiovascular optimization and discusses current management recommendations based on the recently published international guidelines and the experience at the TS clinic at Monash Health.

A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults.

Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.

The deadliest form of tuberculosis is tuberculosis meningitis (TBM), which causes inflammation in the brain. Even with the best treatment available, about half of patients with TBM become disabled or die, often because they have a stroke. Strokes are caused by blood clots or other blockages in blood vessels in the brain. Aspirin is known to prevent blood clots and helps reduce inflammation. Some scientists wonder if it might help patients with TBM by preventing blockages in blood vessels. Now, Nguyen et al. show that adding aspirin to existing TBM treatments may reduce strokes in some patients. In the experiments, 120 patients with TBM were randomly assigned to receive a low dose of aspirin (81 mg/day), a high dose of aspirin (1000mg/day), or an identical tablet that contained no medication. All the patients also took the anti-tuberculosis drugs and steroids usually used to treat the condition. Both doses of aspirin appeared to be safe. Patients who received aspirin were less likely to have a stroke or die in the first two months of treatment than patients who received the fake pill. But the difference was so small it could have been caused by chance. In the 92 patients with clear evidence of tuberculosis bacteria in their brains, the benefit of aspirin was larger and unlikely to be due to chance. The benefit was greatest for those who received the higher dose of aspirin, only 10.7% of these patients died or had a stroke, compared with 14.8% of those who received a low dose of aspirin, or 34% of those who received the fake pill. Next, Nguyen et al. looked at brain fluid taken from the TBM patients before and after they received the aspirin or fake medication. The experiments showed that patients treated with high dose aspirin had much lower levels of a clot-promoting substance called thromboxane A2 and more anti-inflammatory molecules. Larger studies are needed in children and adults to confirm that aspirin helps prevent strokes or death in patients with TBM. Studies are also needed on patients who have both TBM and HIV infections. But if more studies show aspirin is safe and effective, adding this medication to TBM treatment may be an inexpensive way to prevent death or disability.

Increased detection of co-morbidities with evaluation at a dedicated adult Turner syndrome clinic.

OBJECTIVES: Turner syndrome (TS), resulting from complete/partial X chromosomal monosomy, is associated with multiple co-morbidities and increased mortality. Although multidisciplinary management is recommended, TS women's health care is sub-optimal. This study evaluates a multidisciplinary adult TS service. METHODS: Retrospective cohort study of 82 patients attending the quarterly TS clinic from December 2003 to December 2014. Evaluation included (1) demographics, (2) TS standardized co-morbidity screening, and (3) estrogen therapy use. Data analysis involved frequency statistics, T tests and polychoric correlation analysis. RESULTS: Median age at TS diagnosis was 14 years (range 0-65 years), with 12% of women aged >18 years. Median age at initial consultation was 31 years (range 16-65 years). Only 14% of patients were transition program referrals. XO karyotype occurred in 30%. Primary amenorrhea predominated; however, 37% of TS women were not taking estrogen therapy. The proportion of patients not previously screened (44-76%) and those with positive screening diagnoses (5-53%) varied according to co-morbidity. The mean (± standard deviation) number of co-morbidities identified increased following TS clinic screening (7.0 ± 2.6 post-screening vs. 4.4 ± 2.3 pre-screening; p < 0.0001). Polychoric correlation analysis identified particular co-morbidity groupings (including metabolism-related) and increased co-morbidities with primary amenorrhea. CONCLUSION: A multidisciplinary adult TS clinic improves health surveillance with increased identification of co-morbidities and initiation of estrogen therapy.

Delay in estrogen commencement is associated with lower bone mineral density in Turner syndrome.

OBJECTIVE: Turner syndrome (TS) is associated with hypogonadism, osteoporosis and fractures. We investigated the prevalence and risk factors for low bone density and fractures in a TS cohort. METHODS: We included 76 TS patients (median age 28.5 years) attending a tertiary hospital between 1998 and 2015 who underwent dual-energy X-ray absorptiometry. Spine and femoral neck (FN) areal bone mineral density (aBMD) were compared with those of a control group. To adjust for smaller bone size, bone mineral apparent density (BMAD) was calculated. RESULTS: Primary amenorrhea was common (83%) in the TS cohort; the median age of pubertal induction was 15 years (range 11-30 years), and non-continuous estrogen therapy (ET) recorded in 40%. Almost one-third of TS patients reported fractures. TS patients had lower median spinal aBMD (1.026 g/cm2 vs. 1.221 g/cm2) and BMAD (0.156 g/cm3 vs. 0.161 g/cm3) than controls, and lower median FN aBMD (0.850 g/cm2 vs. 1.026 g/cm2) (all p < 0.01). More women with TS had spinal Z-score < -2.0 compared to controls (26.0% vs. 3.6%, p = 0.001). Spine and FN aBMD, BMAD and Z-scores were inversely associated with age commencing ET or years of estrogen deficiency. CONCLUSIONS: Delay in ET commencement was an independent risk factor for the lower bone density observed in women with TS. Early pubertal induction and ET compliance are important targets to optimize aBMD.

Effect of the lipoxygenase-inhibitors baicalein and zileuton on the vertebra in ovariectomized rats.

Osteoporosis is one of the most common diseases worldwide. In osteoporosis, vertebral fractures represent a major burden. Lipoxygenase (LOX) inhibitors such as baicalein and zileuton may represent a promising therapeutic option owing to their antioxidative effects and suppression of various inflammatory processes in muscle and bone. The effect of these LOX inhibitors on the spine was studied in osteopenic rats. Female Sprague-Dawley rats were divided two times into five groups: four groups each were ovariectomized (OVX) and one control group was non-ovariectomized (NON-OVX). Eight weeks after ovariectomy, three concentrations of baicalein (1mg/kg body weight [BW], 10mg/kgBW, and 100mg/kgBW) were administered subcutaneously daily in three OVX groups for 4weeks. Similarly, zileuton was administered in three concentrations via food for 5weeks. In vivo computed tomography (pQCT) of the spine was performed before the treatments and at the end of the experiment. Lumbar vertebrae were subjected to a compression test, micro-CT, and ashing analyses. After baicalein treatment, cortical bone mineral density (BMD) was improved; trabecular connectivity and trabecular BMD were diminished at high dose. After zileuton treatment, the total BMD, anorganic weight, trabecular nodes, and trabecular area were improved. The in vivo stress-strain index was increased and alkaline phosphatase activity in serum was enhanced after both treatments. A dose-dependent effect was not clearly observed after both treatments. The treatments using baicalein for 4 and zileuton for 5weeks were not sufficient to change the biomechanical properties and bone volume fraction (BV/TV). Overall, baicalein improved the cortical bone parameters whereas zileuton had a favorable effect on the trabecular structure. Moreover, both treatments increased the bone formation rate. Longer trials, a combination of both LOX inhibitors, and their effect at the cellular and molecular levels should be investigated in further studies.

2,6-Dipicolinoylbis(N,N-dialkylthioureas) as versatile building blocks for oligo- and polynuclear architectures.

Similar reactions of 2,6-dipicolinoylbis(N,N-diethylthiourea) (H2L(a)) with: (i) Ni(NO3)2·6H2O, (ii) a mixture of Ni(NO3)2·6H2O and AgNO3, (iii) a mixture of Ni(OAc)2·4H2O and PrCl3·7H2O and (iv) a mixture of Ni(OAc)2·4H2O and BaCl2·2H2O give the binuclear complex [Ni2(L(a))2(MeOH)(H2O)], the polymeric compound [NiAg2(L(a))2]∞, and the heterobimetallic complexes [Ni2Pr(L(a))2(OAc)3] and [Ni2Ba(L(a))3], respectively. The obtained assemblies can be used for the build up of supramolecular polymers by means of weak and medium intermolecular interactions. Two prototype examples of such compounds, which are derived from the trinuclear complexes of the types [MLn(III)(L)2(OAc)3] and [MBa(L)3], are described with the compounds {[CuDy(III)(L(a))2(p-O2C-C6H4-CO2)(MeOH)4]Cl}∞ and [MnBa(MeOH)(L(b))3]∞, H2L(b) = 2,6-dipicolinoylbis(N,N-morpholinoylthiourea).

Doubly thermo-responsive copolymers in ionic liquid.

We report the behaviour of thermoresponsive block copolymers of n-butyl acrylate and N-alkyl acrylamides in [C2mim][NTf2]. Poly(N-isopropylacrylamide) exhibits an upper critical solution temperature in [C2mim][NTf2] whereas poly(n-butyl acrylate) has a lower critical solution temperature. Consequently, these polymers exhibit double thermo-responsiveness correlated with the macromolecular structure. Moreover, a switching from micellar to reverse micellar structures was induced by a change in temperature. This property enables the development of reversible shuttles between ionic liquids and water.

Longitudinal sedentary behavior changes in adolescents in Ho Chi Minh City.

BACKGROUND: Sedentary behavior is associated with increased risk of chronic disease and sedentary behavior is increasing among adolescents. Data on changes in sedentary behavior in developing countries are limited. PURPOSE: To describe 5-year longitudinal changes in nonschool sedentary hours among urban adolescents in Ho Chi Minh City, and to identify correlates with this change. METHODS: This is a 5-year longitudinal cohort with systematic random sampling of 759 students from 18 junior high schools. All measures were taken annually between 2004 and 2009. Sedentary behavior was assessed by self-report and accelerometry. Generalized linear latent and mixed models were used to analyze the data in 2011. RESULTS: Between 2004 and 2009, self-reported time spent in nonschool sedentary behavior increased from 498 to 603 minutes/day. In the 5th survey year, boys and girls (aged 16 years) were, respectively, 3.6 times (95% CI=2.3, 6.0) and 3.1 times (95% CI= 1.8, 5.0) more likely to spend ≥2 hours/day on screen time compared with baseline (aged 12 years). Accelerometer data adjusted for wearing time revealed that boys and girls aged 16 years had, respectively, 78 minutes/day (95% CI=48, 104) and 69 minutes/day (95% CI=34, 95) more nonschool sedentary time than those at the first accelerometer assessment (at age 13 years). Girls in the highest socioeconomic quartile spent an additional 90 minutes/day in sedentary behavior compared with girls in the lowest quartile (95% CI=52, 128). CONCLUSIONS: Nonschool sedentary behavior increased among Vietnamese adolescents with age. The largest increase was in recreational screen time (28%), which would be the most obvious target for preventive health strategies.

Active commuting to school among adolescents in Ho Chi Minh City, Vietnam: change and predictors in a longitudinal study, 2004 to 2009.

BACKGROUND: Active commuting (walking or cycling) to/from school is an important part of the overall physical activity levels of children but is on the decline in many countries. Data for adolescents on mode of transportation to and from school are limited for low- and middle-income countries, including Vietnam. PURPOSE: This paper aims to describe the changes in the prevalence of active commuting to and from school, and to examine prospectively the predictors of active commuting, among adolescents from Ho Chi Minh City (HCMC). METHODS: The data are from a 5-year cohort study from 2004 of a representative sample of 759 adolescents from 18 schools in HCMC. Data were obtained at five annual assessments using validated questionnaires to capture commuting behaviors, socioeconomic and demographic factors, individual and family characteristics, and physical and social environmental factors. Height and weight were measured by trained staff using standardized guidelines. Generalized linear latent and mixed models with a hierarchic approach were used to analyze the data in 2011. RESULTS: The results show a remarkable decrease in the prevalence of active commuting in adolescents from 27.8% in 2004 to 19.6% in 2009. Male students, from the least-wealthy families, living in suburban areas, close to school, studying at schools in less-wealthy districts, were more likely to actively commute. CONCLUSIONS: In the context of an epidemic of childhood and adolescent obesity in urban Vietnam, the decline in active commuting over the 5 years of this study highlights the need for development of urban physical environments favorable for active commuting and education campaigns to promote active commuting in adolescents.