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Predicting risk of adverse drug reactions in older adults
Adverse drug reactions (ADRs) are common in older adults, with falls, orthostatic hypotension, delirium, renal failure, gastrointestinal and intracranial bleeding being amongst the most common clinical manifestations. ADR risk increases with age-related changes in pharmacokinetics and pharmacodynamics, increasing burden of comorbidity, polypharmacy, inappropriate prescribing and suboptimal monitoring of drugs. ADRs are a preventable cause of harm to patients and an unnecessary waste of healthcare resources. Several ADR risk tools exist but none has sufficient predictive value for clinical practice. Good clinical practice for detecting and predicting ADRs in vulnerable patients includes detailed documentation and regular review of prescribed and over-the-counter medications through standardized medication reconciliation. New medications should be prescribed cautiously with clear therapeutic goals and recognition of the impact a drug can have on multiple organ systems. Prescribers should regularly review medication efficacy and be vigilant for ADRs and their contributory risk factors. Deprescribing should occur at an individual level when drugs are no longer efficacious or beneficial or when safer alternatives exist. Inappropriate prescribing and unnecessary polypharmacy should be minimized. Comprehensive geriatric assessment and the use of explicit prescribing criteria can be useful in this regard.
Journal Article
The best horror of the year. Volume ten
A group of mountain climbers, caught in the dark, fights to survive their descent; An American band finds more than they bargained for in Mexico while scouting remote locations for a photo shoot; A young student's exploration into the origins of a mysterious song leads him on a winding, dangerous path through the US's deep south; A group of kids scaring each other with ghost stories discovers alarming consequences. The Best Horror of the Year showcases the previous year's best offerings in horror short fiction. This edition includes award-winning and critically acclaimed authors Mark Morris, Kaaron Warren, John Langan, Carole Johnstone, Brian Hodge, and others. For more than three decades, award-winning editor and anthologist Ellen Datlow has had her finger on the pulse of the latest and most terrifying in horror writing. Night Shade Books is proud to present the tenth volume in this annual series, a new collection of stories to keep you up at night.
BOOK
Frailty and Potentially Inappropriate Prescribing in Older People with Polypharmacy: A Bi-Directional Relationship?
Frail older adults commonly experience multiple co-morbid illnesses and other risk factors for potentially inappropriate prescribing. However, determination of frailty varies depending on the frailty instrument used. Older people’s degree of frailty often influences their care and treatment priorities. Research investigating the association between frailty and potentially inappropriate prescribing is hindered by a wide variety of frailty definitions and measurement tools. We undertook a narrative review of selected articles of PubMed and Google Scholar databases. Articles were selected on the basis of relevance to the core themes of frailty and potentially inappropriate prescribing. We identified observational studies that clearly link potentially inappropriate prescribing, potential prescribing omissions, and adverse drug reactions with frailty in older adults. Equally, the literature illustrates that measured frailty in older adults predisposes to inappropriate polypharmacy and associated adverse drug reactions and events. In essence, there is a bi-directional relationship between frailty and potentially inappropriate prescribing, the underlying substrates being multimorbidity and inappropriate polypharmacy. We conclude that there is a need for consensus on rapid and accurate identification of frailty in older people using appropriate and user-friendly methods for routine clinical practice as a means of identifying older multimorbid patients at risk of potentially inappropriate prescribing. Detection of frailty should, we contend, lead to structured screening for inappropriate prescribing in this high-risk population. Of equal importance, detection of potentially inappropriate prescribing in older people should trigger screening for frailty. All clinicians undertaking a medication review of multimorbid patients with associated polypharmacy should take account of the important interaction between frailty and potentially inappropriate prescribing in the interest of minimizing patient harm.
Journal Article
Methods to reduce prescribing errors in elderly patients with multimorbidity
The global population of multimorbid older people is growing steadily. Multimorbidity is the principal cause of complex polypharmacy, which in turn is the prime risk factor for inappropriate prescribing and adverse drug reactions and events. Those who prescribe for older frailer multimorbid people are particularly prone to committing prescribing errors of various kinds. The causes of prescribing errors in this patient population are multifaceted and complex, including prescribers' lack of knowledge of aging physiology, geriatric medicine, and geriatric pharmacotherapy, overprescribing that frequently leads to major polypharmacy, inappropriate prescribing, and inappropriate drug omission. This review examines the various ways of minimizing prescribing errors in multimorbid older people. The role of education in physician prescribers and clinical pharmacists, the use of implicit and explicit prescribing criteria designed to improve medication appropriateness in older people, and the application of information and communication-technology systems to minimize errors are discussed in detail. Although evidence to support any single intervention to prevent prescribing errors in multimorbid elderly people is inconclusive or lacking, published data support focused prescriber education in geriatric pharmacotherapy, routine application of STOPP/START (screening tool of older people's prescriptions/screening tool to alert to right treatment) criteria for potentially inappropriate prescribing, electronic prescribing, and close liaison between clinical pharmacists and physicians in relation to structured medication review and reconciliation. Carrying out a structured medication review aimed at optimizing pharmacotherapy in this vulnerable patient population presents a major challenge. Another challenge is to design, build, validate, and test by clinical trials suitably versatile and efficient software engines that can reliably and swiftly perform complex medication reviews in older multimorbid people. The European Union-funded SENATOR and OPERAM clinical trials commencing in 2016 will examine the impact of customized software engines in reducing medication-related morbidity, avoidable excess cost, and rehospitalization in older multimorbid people.
Journal Article
Treatment of Mycobacterium tuberculosis-Infected Macrophages with Poly(Lactic-Co-Glycolic Acid) Microparticles Drives NFκB and Autophagy Dependent Bacillary Killing
The emergence of multiple-drug-resistant tuberculosis (MDR-TB) has pushed our available repertoire of anti-TB therapies to the limit of effectiveness. This has increased the urgency to develop novel treatment modalities, and inhalable microparticle (MP) formulations are a promising option to target the site of infection. We have engineered poly(lactic-co-glycolic acid) (PLGA) MPs which can carry a payload of anti-TB agents, and are successfully taken up by human alveolar macrophages. Even without a drug cargo, MPs can be potent immunogens; yet little is known about how they influence macrophage function in the setting of Mycobacterium tuberculosis (Mtb) infection. To address this issue we infected THP-1 macrophages with Mtb H37Ra or H37Rv and treated with MPs. In controlled experiments we saw a reproducible reduction in bacillary viability when THP-1 macrophages were treated with drug-free MPs. NFκB activity was increased in MP-treated macrophages, although cytokine secretion was unaltered. Confocal microscopy of immortalized murine bone marrow-derived macrophages expressing GFP-tagged LC3 demonstrated induction of autophagy. Inhibition of caspases did not influence the MP-induced restriction of bacillary growth, however, blockade of NFκB or autophagy with pharmacological inhibitors reversed this MP effect on macrophage function. These data support harnessing inhaled PLGA MP-drug delivery systems as an immunotherapeutic in addition to serving as a vehicle for targeted drug delivery. Such \"added value\" could be exploited in the generation of inhaled vaccines as well as inhaled MDR-TB therapeutics when used as an adjunct to existing treatments.
Journal Article
Effects of Positive Airway Pressure Therapy on Neurobehavioral Outcomes in Children with Obstructive Sleep Apnea
Positive airway pressure therapy is frequently used to treat obstructive sleep apnea in children. However, it is not known whether positive airway pressure therapy results in improvements in the neurobehavioral abnormalities associated with childhood sleep apnea.
We hypothesized that positive airway pressure therapy would be associated with improvements in attention, sleepiness, behavior, and quality of life, and that changes would be associated with therapy adherence.
Neurobehavioral assessments were performed at baseline and after 3 months of positive airway pressure therapy in a heterogeneous group of 52 children and adolescents.
Adherence varied widely (mean use, 170 ± 145 [SD] minutes per night). Positive airway pressure therapy was associated with significant improvements in attention deficits (P < 0.001); sleepiness on the Epworth Sleepiness Scale (P < 0.001); behavior (P < 0.001); and caregiver- (P = 0.005) and child- (P < 0.001) reported quality of life. There was a significant correlation between the decrease in Epworth Sleepiness Scale at 3 months and adherence (r = 0.411; P = 0.006), but not between other behavioral outcomes and adherence. Behavioral factors also improved in the subset of children with developmental delays.
These results indicate that, despite suboptimal adherence use, there was significant improvement in neurobehavioral function in children after 3 months of positive airway pressure therapy, even in developmentally delayed children. The implications for improved family, social, and school function are substantial. Clinical trial registered with www.clinicaltrials.gov (NCT 00458406).
Journal Article
Sleep Architecture and Glucose and Insulin Homeostasis in Obese Adolescents
OBJECTIVE: Sleep deprivation is associated with increased risk of adult type 2 diabetes mellitus (T2DM). It is uncertain whether sleep deprivation and/or altered sleep architecture affects glycemic regulation or insulin sensitivity or secretion. We hypothesized that in obese adolescents, sleep disturbances would associate with altered glucose and insulin homeostasis. RESEARCH DESIGN AND METHODS: This cross-sectional observational study of 62 obese adolescents took place at the Clinical and Translational Research Center and Sleep Laboratory in a tertiary care children’s hospital. Subjects underwent oral glucose tolerance test (OGTT), anthropometric measurements, overnight polysomnography, and frequently sampled intravenous glucose tolerance test (FSIGT). Hemoglobin A1c (HbA1c) and serial insulin and glucose levels were obtained, indices of insulin sensitivity and secretion were calculated, and sleep architecture was assessed. Correlation and regression analyses were performed to assess the association of total sleep and sleep stages with measures of insulin and glucose homeostasis, adjusted for confounding variables. RESULTS: We found significant U-shaped (quadratic) associations between sleep duration and both HbA1c and serial glucose levels on OGTT and positive associations between slow-wave sleep (N3) duration and insulin secretory measures, independent of degree of obesity, pubertal stage, sex, and obstructive sleep apnea measures. CONCLUSIONS: Insufficient and excessive sleep was associated with short-term and long-term hyperglycemia in our obese adolescents. Decreased N3 was associated with decreased insulin secretion. These effects may be related, with reduced insulin secretory capacity leading to hyperglycemia. We speculate that optimizing sleep may stave off the development of T2DM in obese adolescents.
Journal Article
GLP-1 Receptor Antagonist Exendin-(9-39) Elevates Fasting Blood Glucose Levels in Congenital Hyperinsulinism Owing to Inactivating Mutations in the ATP-Sensitive K+ Channel
Infants with congenital hyperinsulinism owing to inactivating mutations in the K(ATP) channel (K(ATP)HI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1(-/-) mice. The aim of this study was to examine the effects of exendin-(9-39) on fasting blood glucose in subjects with K(ATP)HI. This was a randomized, open-label, two-period crossover pilot clinical study. Nine subjects with K(ATP)HI received either exendin-(9-39) or vehicle on two different days. The primary outcome was blood glucose; secondary outcomes were insulin, glucagon, and GLP-1. In all subjects, mean nadir blood glucose and glucose area under the curve were significantly increased by exendin-(9-39). Insulin-to-glucose ratios were significantly lower during exendin-(9-39) infusion compared with vehicle. Fasting glucagon and intact GLP-1 were not affected by treatment. In addition, exendin-(9-39) significantly inhibited amino acid-stimulated insulin secretion in pancreatic islets isolated from neonates with K(ATP)HI. Our findings have two important implications: 1) GLP-1 and its receptor play a role in the regulation of fasting glycemia in K(ATP)HI; and 2) the GLP-1 receptor may be a therapeutic target for the treatment of children with K(ATP)HI.
Journal Article
Inappropriate prescribing and adverse drug events in older people
Inappropriate prescribing (IP) in older patients is highly prevalent and is associated with an increased risk of adverse drug events (ADEs), morbidity, mortality and healthcare utilisation. Consequently, IP is a major safety concern and with changing population demographics, it is likely to become even more prevalent in the future. IP can be detected using explicit or implicit prescribing indicators. Theoretically, the routine clinical application of these IP criteria could represent an inexpensive and time efficient method to optimise prescribing practice. However, IP criteria must be sensitive, specific, have good inter-rater reliability and incorporate those medications most commonly associated with ADEs in older people. To be clinically relevant, use of prescribing appropriateness tools must translate into positive patient outcomes, such as reduced rates of ADEs. To accurately measure these outcomes, a reliable method of assessing the relationship between the administration of a drug and an adverse clinical event is required. The Naranjo criteria are the most widely used tool for assessing ADE causality, however, they are often difficult to interpret in the context of older patients. ADE causality criteria that allow for the multiple co-morbidities and prescribed medications in older people are required. Ultimately, the current high prevalence of IP and ADEs is unacceptable. IP screening criteria need to be tested as an intervention to assess their impact on the incidence of ADEs in vulnerable older patients. There is a role for IP screening tools in everyday clinical practice. These should enhance, not replace good clinical judgement, which in turn should be based on sound pharmacogeriatric training.
Journal Article