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Background Frail elderly people experience elevated mortality. However, no consensus exists on the definition of frailty, and many frailty scores have been developed. The main aim of this study was to compare the association between 35 frailty scores and incident cardiovascular disease (CVD), incident cancer, and all-cause mortality. Also, we aimed to assess whether frailty scores added predictive value to basic and adjusted models for these outcomes. Methods and findings Through a structured literature search, we identified 35 frailty scores that could be calculated at wave 2 of the English Longitudinal Study of Ageing (ELSA), an observational cohort study. We analysed data from 5,294 participants, 44.9% men, aged 60 years and over. We studied the association between each of the scores and the incidence of CVD, cancer, and all-cause mortality during a 7-year follow-up using Cox proportional hazard models at progressive levels of adjustment. We also examined the added predictive performance of each score on top of basic models using Harrell's C statistic. Using age of the participant as a timescale, in sex-adjusted models, hazard ratios (HRs) (95% confidence intervals) for all-cause mortality ranged from 2.4 (95% CI: 1.7-3.3) to 26.2 (95% CI: 15.4-44.5). In further adjusted models including smoking status and alcohol consumption, HR ranged from 2.3 (95% CI: 1.6-3.1) to 20.2 (95% CI: 11.8-34.5). In fully adjusted models including lifestyle and comorbidity, HR ranged from 0.9 (95% CI: 0.5-1.7) to 8.4 (95% CI: 4.9-14.4). HRs for CVD and cancer incidence in sex-adjusted models ranged from 1.2 (95% CI: 0.5-3.2) to 16.5 (95% CI: 7.8-35.0) and from 0.7 (95% CI: 0.4-1.2) to 2.4 (95% CI: 1.0-5.7), respectively. In sex- and age-adjusted models, all frailty scores showed significant added predictive performance for all-cause mortality, increasing the C statistic by up to 3%. None of the scores significantly improved basic prediction models for CVD or cancer. A source of bias could be the differences in mortality follow-up time compared to CVD/cancer, because the existence of informative censoring cannot be excluded. Conclusion There is high variability in the strength of the association between frailty scores and 7-year all-cause mortality, incident CVD, and cancer. With regard to all-cause mortality, some scores give a modest improvement to the predictive ability. Our results show that certain scores clearly outperform others with regard to three important health outcomes in later life. Finally, we think that despite their limitations, the use of frailty scores to identify the elderly population at risk is still a useful measure, and the choice of a frailty score should balance feasibility with performance., Author(s): Gloria A. Aguayo 1,*, Michel T. Vaillant 2, Anne-Françoise Donneau 3, Anna Schritz 2, Saverio Stranges 4, Laurent Malisoux 1, Anna Chioti 1, Michèle Guillaume 3, Majon Muller 5, [...]

Abstract Background Knowing the safety profile of anti-malarial treatments in routine use is essential; millions of patients receive now artemisinin combination therapy (ACT) annually, but the return on information through current systems is as yet inadequate. Cohort event monitoring (CEM) is a WHO (World Health Organization)-recommended practice; testing its performance and feasibility in routine practice in malaria-endemic is important. Methods A nine-year CEM-based study of the safety of artesunate-amodiaquine (ASAQ) at five peripheral health facilities in a rural district of South-western Senegal. Staff (nurses, health workers) were trained to collect actively and systematically information on the patient, treatment and events on a purposely designed questionnaire. The occurrence and severity of events was collected before, during and after treatment up to 28 days in order to generate information on all adverse events (AEs) as well as treatment-emerging signs/symptoms (TESS). Laboratory tests (haematology, liver and renal) was planned for at least 10% of cases. Results During 2001–2009, 3,708 parasitologically-confirmed malaria cases (mean age = 16.0 ± 12.7 years) were enrolled (26% and 52% of all and parasitologically-confirmed ASAQ treatments, respectively). Treatment was supervised in 96% of cases. Products changed over time: 49% were a loose combination of individually-packaged products (available 2001–03), 42% co-blistered products (2004–09) and 9% a fixed-dose co-formulation (2006–09); dosing was age-based for 42%, weight-based for 58%. AS and AQ were correctly dosed in 97% and 82% of cases with the loose and 93% and 86% with the fixed combination, but only 50% and 42% with the co-blistered product. Thirty-three per cent (33%) of patients had at least one sign/symptom pre-treatment, 12% had at least one AE and 9% a TESS (total events 3,914, 1,144 and 693, respectively). AEs overestimated TESS by 1.2-2 fold (average 1.7). Changes in laboratory value were insignificant. Over-dosing more than doubled the risk of TESS, though statistical significance was reached only during 2003–2007. The incidence of serious events (including death) was five per thousand. Conclusions The study was successful in quantifying and characterizing known reactions and has benchmarking value. Health staff performance varied. Investments in training, motivating and providing a quality control system would be needed. The study proved that a CEM-based system is feasible in this setting but more research is needed to assess whether it is sustainable and what conditions would make it cost-effective, including the amount and quality of data generated, and the use thereof for decision-making.

Abstract Background Malaria is reportedly receding in different epidemiological settings, but local long-term surveys are limited. At Mlomp dispensary in south-western Senegal, an area of moderate malaria transmission, year-round, clinically-suspected malaria was treated with monotherapy as per WHO and national policy in the 1990s. Since 2000, there has been a staggered deployment of artesunate-amodiaquine after parasitological confirmation; this was adopted nationally in 2006. Methods Data were extracted from clinic registers for the period between January 1996 and December 2010, analysed and modelled. Results Over the 15-year study period, the risk of malaria decreased about 32-times (from 0.4 to 0.012 episodes person-year), while anti-malarial treatments decreased 13-times (from 0.9 to 0.07 treatments person-year) and consultations for fever decreased 3-times (from 1.8 to 0.6 visits person-year). This was paralleled by changes in the age profile of malaria patients so that the risk of malaria is now almost uniformly distributed throughout life, while in the past malaria used to concern more children below 16 years of age. Conclusions This study provides direct evidence of malaria risk receding between 1996-2010 and becoming equal throughout life where transmission used to be moderate. Infection rates are no longer enough to sustain immunity. Temporally, this coincides with deploying artemisinin combinations on parasitological confirmation, but other contributing causes are unclear.

Background: Better knowledge of the efficacy and safety of single 40 mg/kg oral praziquantel in preschool-age children is required, should preventive chemotherapy programs for schistosomiasis be expanded to include this age group. Methodology: We analyzed individual participant-level data from 16 studies (13 single-arm or cohort studies and three randomized trials), amounting to 683 preschool-age children (aged <6 years) and 2,010 school-age children (aged 6–14 years). Children had a documented Schistosoma mansoni or S. haematobium infection, were treated with single 40 mg/kg oral praziquantel, and assessed between 21 and 60 days post-treatment. Efficacy was expressed as arithmetic mean and individual egg reduction rate (ERR) and meta-analyzed using general linear models and mixed models. Safety was summarized using reported adverse events (AEs). Principal findings: Preschool-age children had significantly lower baseline Schistosoma egg counts and more losses to follow-up compared to school-age children. No difference in efficacy was found between preschool- and school-age children using a general linear model of individual-participant ERR with baseline log-transformed egg count as covariate and study, age, and sex as fixed variables, and a mixed model with a random effect on the study. Safety was reported in only four studies (n = 1,128 individuals); few AEs were reported in preschool-age children 4 and 24 hours post-treatment as well as at follow-up. Three severe but not serious AEs were recorded in school-age children during follow-up. Conclusions/Significance: There is no indication that single 40 mg/kg oral praziquantel would be less efficacious and safe in preschool-age children compared to school-age children, with the caveat that only few randomized comparisons exist between the two age groups. Preventive chemotherapy might therefore be extended to preschool-age children, with proper monitoring of its efficacy and safety. Author summary: Schistosomiasis is a diseases caused by helminths (parasitic worms) which affects the intestinal and urinary systems. In areas where schistosomiasis is endemic, the disease is controlled by the large scale distributing of praziquantel, primarily targeting school-age children. Younger children (preschool-age) too might be affected by schistosomiasis, but are currently not receiving praziquantel within treatment campaigns. Instead, preschool-age children are treated on a case-by-case basis because the current praziquantel formulation is not adapted to young children. Questions have also been raised as to whether the standard dose of 40 mg/kg given once is effective in preschool-age children. To answer this question, we collected individual-participant data from a series of studies in which 40 mg/kg of praziquantel had been given to children with intestinal or urogenital schistosomiasis, and compared its efficacy and tolerability across age-groups. Since few direct comparisons had been made, we used statistical tools to make these comparisons. We found no evidence that treatment is less efficacious in preschool- than in school-age children and conclude that 40 mg/kg praziquantel may be given to preschool-age children in large-scale programs. When this happens, efficacy and tolerability will have to be closely monitored. [ABSTRACT FROM AUTHOR]

Objective: Frailty is a dynamic state of vulnerability in the elderly. We examined whether individuals with overt diabetes or higher levels of HbA1c or fasting plasma glucose (FG) experience different frailty trajectories with aging.Research Design and Methods: Diabetes, HbA1c, and FG were assessed at baseline, and frailty status was evaluated with a 36-item frailty index every 2 years during a 10-year follow-up among participants from the English Longitudinal Study of Ageing (ELSA). Mixed-effects models with age as time scale were used to assess whether age trajectories of frailty differed as a function of diabetes, HbA1c, and FG.Results: Among 5,377 participants (median age [interquartile range] 70 [65, 77] years, 45% men), 35% were frail at baseline. In a model adjusted for sex, participants with baseline diabetes had an increased frailty index over aging compared with those without diabetes. Similar findings were observed with higher levels of HbA1c, while FG was not associated with frailty. In a model additionally adjusted for income, social class, smoking, alcohol, and hemoglobin, only diabetes was associated with an increased frailty index. Among nonfrail participants at baseline, both diabetes and HbA1c level were associated with a higher increased frailty index over time.Conclusions: People with diabetes or higher HbA1c levels at baseline had a higher frailty level throughout later life. Nonfrail participants with diabetes or higher HbA1c also experienced more rapid deterioration of frailty level with aging. This observation could reflect a role of diabetes complications in frailty trajectories or earlier shared determinants that contribute to diabetes and frailty risk in later life. [ABSTRACT FROM AUTHOR]

Objective: Frailty is a dynamic state of vulnerability in the elderly. We examined whether individuals with overt diabetes or higher levels of HbA 1c or fasting plasma glucose (FG) experience different frailty trajectories with aging., Research Design and Methods: Diabetes, HbA 1c , and FG were assessed at baseline, and frailty status was evaluated with a 36-item frailty index every 2 years during a 10-year follow-up among participants from the English Longitudinal Study of Ageing (ELSA). Mixed-effects models with age as time scale were used to assess whether age trajectories of frailty differed as a function of diabetes, HbA 1c , and FG., Results: Among 5,377 participants (median age [interquartile range] 70 [65, 77] years, 45% men), 35% were frail at baseline. In a model adjusted for sex, participants with baseline diabetes had an increased frailty index over aging compared with those without diabetes. Similar findings were observed with higher levels of HbA 1c , while FG was not associated with frailty. In a model additionally adjusted for income, social class, smoking, alcohol, and hemoglobin, only diabetes was associated with an increased frailty index. Among nonfrail participants at baseline, both diabetes and HbA 1c level were associated with a higher increased frailty index over time., Conclusions: People with diabetes or higher HbA 1c levels at baseline had a higher frailty level throughout later life. Nonfrail participants with diabetes or higher HbA 1c also experienced more rapid deterioration of frailty level with aging. This observation could reflect a role of diabetes complications in frailty trajectories or earlier shared determinants that contribute to diabetes and frailty risk in later life., (© 2019 by the American Diabetes Association.)

Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria., Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites., Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites., Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.