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In Caenorhabditis elegans, mitochondrial activity as measured by the frequency of the mitochondrial flash in young adult animals is a powerful predictor of lifespan across genetic, environmental and stochastic factors. Mitoflash activity tests ageing theory The mitochondrial theory of ageing, developed more than 40 years ago based on work on the roundworm Caenorhabditis elegans, proposes that the mitochondria are the main drivers of ageing -- defined as an increase in the probability of death with increasing chronological age. This study is a direct test of the theory using an approach made possible by the recent demonstration that mitochondria undergo stochastic bursts of superoxide production that can be visualized as mitochondrial flashes. The flash frequency of these 'mitoflashes' is sensitive to oxidative stress and metabolic changes. The authors observe that mitoflash activity in the pharyngeal muscles of a 3-day-old adult C. elegans worm inversely correlates with lifespan of the animal. A large variety of genetic mutations and environmental factors inversely modify the lifespan and the mitoflash frequency at day 3. Even within an isogenic population of worms the day-3 mitoflash frequency negatively correlates with lifespan. Day-3 mitoflash frequency is shown to be a powerful predictor of C. elegans lifespan reflecting a range of genetic and environmental influences, suggesting an intimate connection between mitochondrial function and ageing. It has been theorized for decades that mitochondria act as the biological clock of ageing.sup.1, but the evidence is incomplete. Here we show a strong coupling between mitochondrial function and ageing by in vivo visualization of the mitochondrial flash (mitoflash), a frequency-coded optical readout reflecting free-radical production and energy metabolism at the single-mitochondrion level.sup.2,3. Mitoflash activity in Caenorhabditis elegans pharyngeal muscles peaked on adult day 3 during active reproduction and on day 9 when animals started to die off. A plethora of genetic mutations and environmental factors inversely modified the lifespan and the day-3 mitoflash frequency. Even within an isogenic population, the day-3 mitoflash frequency was negatively correlated with the lifespan of individual animals. Furthermore, enhanced activity of the glyoxylate cycle contributed to the decreased day-3 mitoflash frequency and the longevity of daf-2 mutant animals. These results demonstrate that the day-3 mitoflash frequency is a powerful predictor of C. elegans lifespan across genetic, environmental and stochastic factors. They also support the notion that the rate of ageing, although adjustable in later life, has been set to a considerable degree before reproduction ceases., Author(s): En-Zhi Shen [sup.1] [sup.2] , Chun-Qing Song [sup.1] [sup.2] , Yuan Lin [sup.3] , Wen-Hong Zhang [sup.2] , Pei-Fang Su [sup.4] , Wen-Yuan Liu [sup.2] , Pan Zhang [sup.2] [...]

Statistical methods for analyzing recurrent events have attracted significant attention. The majority of existing works consider situations in which subjects are observed over time periods and events of interest that occurred during the course of follow-up are recorded. In some applications, a subject may leave the study for a period of time and then resume due to various reasons. During the absence, which is referred to as an intermittent gap in this study, it may be impossible to observe a recording of the event. A naive analysis disregards gaps and considers events to be a typical recurrent event dataset. However, this may result in biased estimations and misleading results. In this study, we build an additive rates model for recurrent event data considering intermittent gaps. We provide the asymptotic theories behind the proposed model, as well as the goodness of fit between observed and modeled values. Simulation studies reveal that the estimations perform well if intermittent gaps are taken into account. In addition, we utilized the longitudinal cohort of elderly patients who have type 2 diabetes and at least one record of a severe recurrent complication, hypoglycemia, from the National Health Insurance Research Database in Taiwan to demonstrate the proposed method. [ABSTRACT FROM AUTHOR]

Objective: We assessed the quality of life (QoL) and pregnancy outcomes of in vitro fertilization (IVF) treatment among infertile women with endometriosis, as compared to infertile women without endometriosis.Study Design: Eighty-one (81) endometriosis women (with 142 embryo transfer [ET] cycles) and 605 non-endometriosis women (with 1063 ET cycles) were included. QoL was measured by FertiQoL at the date before ET. Pregnancy outcomes included biochemical pregnancy, ongoing pregnancy and live birth. Generalized estimating equation analyses were performed to assess the association between QoL and IVF pregnancy.Results: Endometriosis-affected women had significantly lower QoL, as indicated by mind/body, treatment environment and total treatment scores, and total scores of FertiQoL (p < .05), compared to those without endometriosis. Among non-endometriosis women, QoL scores were significantly associated with successful IVF pregnancy; with one unit increase in QoL scores as measured by emotional domain of FertiQoL, the probabilities of ongoing pregnancy and live birth significantly increased by 2.5% and 2.8%, respectively (p < .05). This association was also observed among endometriosis women but it did not reach statistical significance.Conclusions: Lower QoL among women with endometriosis versus non-endometriosis during IVF treatment highlights the importance of developing strategies to improve their QoL, which may enhance following pregnancy rates in this population. [ABSTRACT FROM AUTHOR]

This study explored heterogeneous treatment effects (HTEs) of the real‐world use of dipeptidyl peptidase‐4 inhibitors (DPP‐4is) vs. sulfonylureas (SUs) on cardiovascular diseases (CVDs) and mortality in patients with type 2 diabetes. Utilizing Taiwan's National Health Insurance Research Database, 19,853 propensity score‐matched pairs of DPP‐4i and SU stable users were identified. Classification and regression tree analyses and Cox models were applied to explore HTEs, according to various patient characteristics, on the composite CVDs, three‐point major adverse cardiovascular event (MACE), and all‐cause mortality. The absolute risk difference (ARD), hazard ratio (HR), and 95% confidence interval (CI) were estimated for comparing treatment effects. CVD history, ischemic stroke, or transient ischemic attack (IS/TIA) history, and age at treatment initiation were significant treatment effect modifiers. Patients with prior IS/TIA but without any other prior CVDs benefited most in reduced risks of composite CVDs from using DPP‐4i vs. SU (ARD −4.31%, 95% CI −7.48% to −1.14%, HR 0.81, 95% CI 0.69 ~ 0.95), followed by those without prior IS/TIA and CVDs and initiated with DPP‐4i at age < 69.3 years (ARD −0.90%, 95% CI −1.47% to −0.32%, HR 0.86, 95% CI 0.77 ~ 0.97). Patients with prior IS/TIA benefited most in reduced risks of three‐point MACE from using DPP‐4i vs. SU (ARD −4.22%, 95% CV −6.66% to −1.78%, HR 0.80, 95% CI 0.69 ~ 0.93), followed by those without prior IS/TIA and initiated with DPP‐4i at age < 69.3 years (ARD −0.68%, 95% CI −1.08% to −0.29%, HR 0.81, 95% CI 0.70 ~ 0.93). Consideration of CVD and IS/TIA histories and age could facilitate individualized diabetes management of using DPP‐4i vs. SU. Future studies are warranted given the hypothesis‐generating nature in this exploratory research. [ABSTRACT FROM AUTHOR]

In long‐term clinical studies, recurrent event data are sometimes collected and used to contrast the efficacies of two different treatments. The event reoccurrence rates can be compared using the popular negative binomial model, which incorporates information related to patient heterogeneity into a data analysis. For treatment allocation, a balanced approach in which equal sample sizes are obtained for both treatments is predominately adopted. However, if one treatment is superior, then it may be desirable to allocate fewer subjects to the less‐effective treatment. To accommodate this objective, a sequential response‐adaptive treatment allocation procedure is derived based on the doubly adaptive biased coin design. Our proposed treatment allocation schemes have been shown to be capable of reducing the number of subjects receiving the inferior treatment while simultaneously retaining a test power level that is comparable to that of a balanced design. The redesign of a clinical study illustrates the advantages of using our procedure. [ABSTRACT FROM AUTHOR]

Older ICU survivors are often challenged with clusters of geriatric syndromes and functional decline. The purpose of this study was (a) to assess patterns of geriatric syndromes and functional status from admission to 6 months post discharge and (b) to examine the predictors of longitudinal functional status. This is a prospective cohort study. Demographic information, clinical variables, geriatric syndromes, and functional status were collected longitudinally. A total of 192 medical ICU older adult survivors were included in the analysis. Factors associated with reductions in functional status over 6 months were (a) institutionalized prior to hospitalization, (b) pressure sore before admission, (c) existing delirium, (d) impaired mobility at baseline, (e) increased APACHE II score upon ICU admission, and (f) use of mechanical ventilation during the ICU stay. Importantly, overweight was the only factor that was associated with increased functional level over 6 months. [ABSTRACT FROM AUTHOR]