Analgesics use and ESRD in younger age: a case-control study

<p>Abstract</p> <p>Background</p> <p>An ad hoc peer-review committee was jointly appointed by Drug Authorities and Industry in Germany, Austria and Switzerland in 1999/2000 to review the evidence for a causal relation between phenacetin-free analgesics and nephropathy. The committee found the evidence as inconclusive and requested a new case-control study of adequate design.</p> <p>Methods</p> <p>We performed a population-based case-control study with incident cases of end-stage renal disease (ESRD) under the age of 50 years and four age and sex-matched neighborhood controls in 170 dialysis centers (153 in Germany, and 17 in Austria) from January 1, 2001 to December 31, 2004. Data on lifetime medical history, risk factors, treatment, job exposure and intake of analgesics were obtained in a standardized face-to-face interview using memory aids to enhance accuracy. Study design, study performance, analysis plan, and study report were approved by an independent international advisory committee and by the Drug Authorities involved. Unconditional logistic regression analyses were performed.</p> <p>Results</p> <p>The analysis included 907 cases and 3,622 controls who had never used phenacetin-containing analgesics in their lifetime. The use of high cumulative lifetime dose (3^rdtertile) of analgesics in the period up to five years before dialysis was not associated with later ESRD. Adjusted odds ratios with 95% confidence intervals were 0.8 (0.7 – 1.0) and 1.0 (0.8 – 1.3) for ever- compared with no or low use and high use compared with low use, respectively. The same results were found for all analgesics and for mono-, and combination preparations with and without caffeine. No increased risk was shown in analyses stratifying for dose and duration. Dose-response analyses showed that analgesic use was not associated with an increased risk for ESRD up to 3.5 kg cumulative lifetime dose (98 % of the cases with ESRD). While the large subgroup of users with a lifetime dose up to 0.5 kg (278 cases and 1365 controls) showed a significantly decreased risk, a tiny subgroup of extreme users with over 3.5 kg lifetime use (19 cases and 11 controls) showed a significant risk increase. The detailed evaluation of 22 cases and 19 controls with over 2.5 kg lifetime use recommended by the regulatory advisors showed an impressive excess of other conditions than analgesics triggering the evolution of ESRD in cases compared with controls.</p> <p>Conclusion</p> <p>We found no clinically meaningful evidence for an increased risk of ESRD associated with use of phenacetin-free analgesics in single or combined formulation. The apparent risk increase shown in a small subgroup with extreme lifetime dose of analgesics is most likely an indirect, non-causal association. This hypothesis, however, cannot be confirmed or refuted within our case-control study. Overall, our results lend support to the mounting evidence that phenacetin-free analgesics do not induce ESRD and that the notion of "analgesic nephropathy" needs to be re-evaluated.</p

Intelligent Cooperative Control Architecture: A Framework for Performance Improvement Using Safe Learning

Planning for multi-agent systems such as task assignment for teams of limited-fuel unmanned aerial vehicles (UAVs) is challenging due to uncertainties in the assumed models and the very large size of the planning space. Researchers have developed fast cooperative planners based on simple models (e.g., linear and deterministic dynamics), yet inaccuracies in assumed models will impact the resulting performance. Learning techniques are capable of adapting the model and providing better policies asymptotically compared to cooperative planners, yet they often violate the safety conditions of the system due to their exploratory nature. Moreover they frequently require an impractically large number of interactions to perform well. This paper introduces the intelligent Cooperative Control Architecture (iCCA) as a framework for combining cooperative planners and reinforcement learning techniques. iCCA improves the policy of the cooperative planner, while reduces the risk and sample complexity of the learner. Empirical results in gridworld and task assignment for fuel-limited UAV domains with problem sizes up to 9 billion state-action pairs verify the advantage of iCCA over pure learning and planning strategies

Neuroevolutionary reinforcement learning for generalized control of simulated helicopters

This article presents an extended case study in the application of neuroevolution to generalized simulated helicopter hovering, an important challenge problem for reinforcement learning. While neuroevolution is well suited to coping with the domain’s complex transition dynamics and high-dimensional state and action spaces, the need to explore efficiently and learn on-line poses unusual challenges. We propose and evaluate several methods for three increasingly challenging variations of the task, including the method that won first place in the 2008 Reinforcement Learning Competition. The results demonstrate that (1) neuroevolution can be effective for complex on-line reinforcement learning tasks such as generalized helicopter hovering, (2) neuroevolution excels at finding effective helicopter hovering policies but not at learning helicopter models, (3) due to the difficulty of learning reliable models, model-based approaches to helicopter hovering are feasible only when domain expertise is available to aid the design of a suitable model representation and (4) recent advances in efficient resampling can enable neuroevolution to tackle more aggressively generalized reinforcement learning tasks

Research priorities in pediatric parenteral nutrition: a consensus and perspective from ESPGHAN/ESPEN/ESPR/CSPEN

Parenteral nutrition is used to treat children that cannot be fully fed by the enteral route. While the revised ESPGHAN/ESPEN/ESPR/CSPEN pediatric parenteral nutrition guidelines provide clear guidance on the use of parenteral nutrition in neonates, infants, and children based on current available evidence, they have helped to crystallize areas where research is lacking or more studies are needed in order to refine recommendations. This paper collates and discusses the research gaps identified by the authors of each section of the guidelines and considers each nutrient or group of nutrients in turn, together with aspects around delivery and organization. The 99 research priorities identified were then ranked in order of importance by clinicians and researchers working in the field using a survey methodology. The highest ranked priority was the need to understand the relationship between total energy intake, rapid catch-up growth, later metabolic function, and neurocognitive outcomes. Research into the optimal intakes of macronutrients needed in order to achieve optimal outcomes also featured prominently. Identifying research priorities in PN should enable research to be focussed on addressing key issues. Multicentre trials, better definition of exposure and outcome variables, and long-term metabolic and developmental follow-up will be key to achieving this. Impact: The recent ESPGHAN/ESPEN/ESPR/CSPEN guidelines for pediatric parenteral nutrition provided updated guidance for providing parenteral nutrition to infants and children, including recommendations for practice.However, in several areas there was a lack of evidence to guide practice, or research questions that remained unanswered. This paper summarizes the key priorities for research in pediatric parenteral nutrition, and ranks them in order of importance according to expert opinion

KAP Degradation by Calpain Is Associated with CK2 Phosphorylation and Provides a Novel Mechanism for Cyclosporine A-Induced Proximal Tubule Injury

The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA

Altered Risk-Based Decision Making following Adolescent Alcohol Use Results from an Imbalance in Reinforcement Learning in Rats

Alcohol use during adolescence has profound and enduring consequences on decision-making under risk. However, the fundamental psychological processes underlying these changes are unknown. Here, we show that alcohol use produces over-fast learning for better-than-expected, but not worse-than-expected, outcomes without altering subjective reward valuation. We constructed a simple reinforcement learning model to simulate altered decision making using behavioral parameters extracted from rats with a history of adolescent alcohol use. Remarkably, the learning imbalance alone was sufficient to simulate the divergence in choice behavior observed between these groups of animals. These findings identify a selective alteration in reinforcement learning following adolescent alcohol use that can account for a robust change in risk-based decision making persisting into later life

Effects of Neonatal Nutrition Interventions on Neonatal Mortality and Child Health and Development Outcomes: A Systematic Review

Background The last two decades have seen a significant decrease in mortality for children \u3c 5 years of age in low and middle‐income countries (LMICs); however, neonatal (age, 0–28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs. Objectives To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period. Search Methods We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019. Selection Criteria We aimed to include randomized and quasi‐experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate. Data Collection and Analysis Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all‐cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta‐analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main Results Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low‐ and middle‐income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea‐Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all‐cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90–1.08; six studies with 126,548 participants, statistical heterogeneity I2 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89–1.07; 12 studies with 154,940 participants, statistical heterogeneity I2 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94–1.14; eight studies with 118,376 participants, statistical heterogeneity I2 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12–2.09; six studies with 100,256 participants, statistical heterogeneity I2 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty‐three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born \u3c 37 weeks gestation) and/or low birth weight (\u3c 2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all‐cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66–0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I2 0%, funnel plot symmetrical, GRADE quality high). Twenty‐nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35–0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I2 24%, funnel plot symmetrical, GRADE quality high). Twenty‐one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70–0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I2 23%, funnel plot symmetrical, GRADE quality high). Authors\u27 Conclusions Vitamin A supplementation during the neonatal period does not reduce all‐cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi‐experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all‐cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in‐home/community setting in LMICs

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p