Efficacy of deprescribing on health outcomes: An umbrella review of systematic reviews with meta-analysis of randomized controlled trials.

BACKGROUND: Deprescribing is an important intervention across different settings in medicine, but the literature supporting such a practice is still conflicting. Therefore, we aimed to capture the breadth of outcomes reported and assess the strength of evidence of the use of deprescribing for health outcomes. METHODS: Umbrella review of systematic reviews of the use of deprescribing searching in Medline, Scopus, and Web of Science until 01 November 2023. The grading of evidence was carried out using the GRADE for intervention studies, whilst data regarding systematic reviews were reported as narrative findings. RESULTS: Among 456 papers, 12 systematic reviews (six with meta-analysis) for a total of 231 RCTs and 44,193 patients were included. In any setting, deprescribing was able to significantly reduce the number of total and of potentially inappropriate medications (PIMs) in older patients (low certainty of evidence) and to reduce the proportion of participants potentially having several or PIMs (moderate certainty of evidence). In community, supported by a high certainty of evidence, deprescribing was not more effective than standard care in decreasing injurious falls, any falls or number of fallers. In nursing home, deprescribing was associated with a significantly lower PIMs than standard care (very low certainty of evidence). In end-of-life situations, deprescribing significantly reduced mortality rate of approximately 41% (high certainty of evidence). CONCLUSIONS: Deprescribing is a promising intervention across different settings and situations, but a notable gap in the literature concerning its effects on substantial outcomes still exists.

Complex family planning and pediatric hematology oncology integrated clinic for young people with blood disorders and heavy or abnormal menstrual bleeding.

OBJECTIVES: To describe practice patterns of an integrated complex family planning-pediatric hematology oncology clinic for patients with blood disorders STUDY DESIGN: We retrospectively evaluated the outcomes of patients who had an initial consultation for blood disorders impacting menstrual bleeding in an integrated complex family planning-pediatric hematology oncology clinic from October 2015 to September 2020. We reviewed all charts to extract medical and gynecologic history, blood disorder diagnosis, hormonal treatment prior to and following initial consultation, subsequent visits to the integrated clinic, and hormonal treatment up to 24 months after initial consultation. RESULTS: We saw 47 patients; their most common blood disorder diagnosis was protein defect (14 of 47, 30%). Most patients (30 of 47, 64%) were not using any hormonal treatment prior to their initial consultation. After the initial consultation, 26 (55%) elected to start, change, or discontinue hormonal treatment for abnormal menstrual bleeding, the most common treatment being combined hormonal contraception (CHC, 22 of 47, 47%), alone or as dual therapy. Over the study duration, 36 patients (77%) initiated, changed, or discontinued their hormone treatment, 22 (61%) of whom changed their treatment plan more than once. CHC usage decreased from 19 of 47 (40%) to 8 of 37 (22%) and hormonal device usage, particularly the implant, increased from 9 of 47 (19%) to 11 of 37 (30%) over the 24 months from initial consultation. CONCLUSION: Most patients in an integrated complex family planning-pediatric hematology oncology clinic will change their menstrual bleeding hormone treatment with initial consultation, although management may require multiple changes. The most common treatment 24 months following the initial consultation was hormonal devices. IMPLICATIONS: Patients with blood disorders affecting menstrual bleeding have complex needs that could be addressed by an integrated complex family planning-pediatric hematology oncology clinic. Most patients require multiple changes in treatment to achieve adequate control of their bleeding, and patients were more likely to choose hormonal devices for management over time.

Sex and tissue-specific evolution of developmental plasticity in Drosophila melanogaster.

Developmental plasticity influences the size of adult tissues in insects. Tissues can have unique responses to environmental perturbation during development; however, the prevalence of within species evolution of tissue-specific developmental plasticity remains unclear. To address this, we studied the effects of temperature and nutrition on wing and femur size in D. melanogaster populations from a temperate and tropical region. Wings were more sensitive to temperature, while wings and femurs were equally responsive to nutrition in both populations and sexes. The temperate population was larger under all conditions, except for femurs of starved females. In line with this, we observed greater femur size plasticity in response to starvation in temperate females, leading to differences in sexual dimorphism between populations such that the slope of the reaction norm of sexual dimorphism in the tropical population was double that of the temperate population. Lastly, we observed a significant trend for steeper slopes of reaction norms in temperate than in tropical females, but not in males. These findings highlight that plasticity divergence between populations can evolve heterogeneously across sexes and tissues and that nutritional plasticity can alter sexual dimorphism in D. melanogaster.

Phenotypic coupling of sleep and starvation resistance evolves in D. melanogaster.

BACKGROUND: One hypothesis for the function of sleep is that it serves as a mechanism to conserve energy. Recent studies have suggested that increased sleep can be an adaptive mechanism to improve survival under food deprivation in Drosophila melanogaster. To test the generality of this hypothesis, we compared sleep and its plastic response to starvation in a temperate and tropical population of Drosophila melanogaster. RESULTS: We found that flies from the temperate population were more starvation resistant, and hypothesized that they would engage in behaviors that are considered to conserve energy, including increased sleep and reduced movement. Surprisingly, temperate flies slept less and moved more when they were awake compared to tropical flies, both under fed and starved conditions, therefore sleep did not correlate with population-level differences in starvation resistance. In contrast, total sleep and percent change in sleep when starved were strongly positively correlated with starvation resistance within the tropical population, but not within the temperate population. Thus, we observe unexpectedly complex relationships between starvation and sleep that vary both within and across populations. These observations falsify the simple hypothesis of a straightforward relationship between sleep and energy conservation. We also tested the hypothesis that starvation is correlated with metabolic phenotypes by investigating stored lipid and carbohydrate levels, and found that stored metabolites partially contributed towards variation starvation resistance. CONCLUSIONS: Our findings demonstrate that the function of sleep under starvation can rapidly evolve on short timescales and raise new questions about the physiological correlates of sleep and the extent to which variation in sleep is shaped by natural selection.

Parabrachial complex links pain transmission to descending pain modulation.

The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a "burst" of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of "bottom-up" nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.

Militarised natural history: tales of the avocet's return to postwar Britain.

Absent as a breeding bird from Britain for at least a century, avocets (Recurvirostra avosetta) began nesting on the east coast of Britain, in Suffolk, shortly after the end of the Second World War, having honed in on two spots on Britain's coast that had been flooded for war-related reasons. The avocets' presence was surrounded in secrecy, while a dedicated few kept up a protective watch over them. As the Royal Society for the Protection of Birds (RSPB) took over responsibility for the flourishing colony, they claimed the episode as a symbol of success for British protection, later making the bird their logo. Counter to the RSPB's story of protecting a British bird, I read the narratives of events in terms of making a bird British. I show how, as postwar Britain slumped economically and spiritually and tried to rebuild itself, the birds became a vehicle for formulating national identity: of Britain as a home to which to return and belong. Exploring the themes of returning servicemen and closed territories, the paper also examines the episode in terms of the naturalisation of the military and the militarisation of nature.

Robust and stable drinking behavior following long-term oral alcohol intake in rhesus macaques.

Face validity in animal models of alcohol abuse and dependence is often at odds with robust demonstrations of ethanol-seeking. This study determined the relative influence of ethanol and a flavorant in maintaining ethanol intake in a nonhuman primate model of "cocktail" drinking. Four-year-old male monkeys were maintained on a 6% ethanol/6% Tang solution made available in daily (M-F) 1-h sessions. Experiments determined the effect of (1) a second daily access session, (2) concurrent presentation of the Tang vehicle, (3) sequential presentation of the vehicle in the first daily session and the ethanol solution in the second session, (4) altering the Tang concentration, (5) altering the ethanol concentration, and (6) removal of the flavorant. Mean daily intake (2.7+/-0.2 g/kg/day) was stable over 7 months. Simultaneous availability of a large, but not a low-moderate, volume of the vehicle reduced ethanol intake by about 50%. Decreasing the concentration of Tang in the first daily session reduced ethanol intake, whereas intake of the standard solution was increased in the second session. Ethanol consumption was decreased by only 27% when the flavorant was removed. In summary, alterations that reduced intake in the first daily session resulted in compensatory increases in ethanol intake in the second session, suggesting that animals sought a specific level of ethanol intake per day. It is concluded that models with excellent face validity (flavored beverages) can produce reliable ethanol intake in patterns that are highly consistent with ethanol-seeking behavior.

Oral administration of (+/-)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques.

RATIONALE: Emergency Department visits and fatalities in which (+/-)3,4-methylenedioxymethamphetamine (MDMA) or (+)methamphetamine (METH) are involved frequently feature unregulated hyperthermia. MDMA and METH significantly elevate body temperature in multiple laboratory species and, most importantly, can also produce unregulated and threatening hyperthermia in nonhuman primates. A majority of prior animal studies have administered drugs by injection whereas human consumption of "Ecstasy" is typically oral, an important difference in route of administration which may complicate the translation of animal data to the human condition. OBJECTIVE: To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly. METHODS: Adult male rhesus monkeys were challenged intramuscularly (i.m.) and per os (p.o.) with 1.78 or 5 mg/kg (+/-)MDMA and with 0.1 or 0.32 mg/kg (+)METH. Temperature and activity were monitored with a radiotelemetry system. RESULTS: Oral administration of either MDMA or METH produced significant increases in body temperature. Locomotor activity was suppressed by MDMA and increased by METH following either route of administration. CONCLUSIONS: The data show that the oral route of administration is not likely to qualitatively reduce the temperature increase associated with MDMA or METH although oral administration did slow the rate of temperature increase. It is further established that MDMA reduces activity in monkeys even after relatively high doses and oral administration.

Impact of ambient temperature on hyperthermia induced by (+/-)3,4-methylenedioxymethamphetamine in rhesus macaques.

The ambient temperature (T(A)) under which rodents are exposed to (+/-)3,4-methylenedioxymethamphetamine (MDMA) affects the direction and magnitude of the body temperature response, and the degree of hypo/hyperthermia generated in subjects can modify the severity of lasting brain changes in 'neurotoxicity' models. The thermoregulatory effects of MDMA have not been well described in non-human primates and it is unknown if T(A) has the potential to affect acute hyperthermia and therefore other lasting consequences of MDMA. The objective of this study was to determine if the temperature alteration produced by MDMA in nonhuman primates depends on T(A) as it does in rats and mice. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetry. The subjects were challenged intramuscularly with 0.56-2.4 mg/kg (+/-)MDMA under each of three T(A) conditions (18, 24, and 30 degrees C) in a randomized order. The temperature was significantly elevated following injection with all doses of MDMA under each ambient temperature. The magnitude of mean temperature change was approximately 1 degrees C in most conditions suggesting a closely controlled thermoregulatory response in monkeys across a range of doses and ambient temperatures. Activity levels were generally suppressed by MDMA; however, a 50% increase over vehicle was observed after 0.56 MDMA under the 30 degrees C condition. It is concluded that MDMA produces a similar degree of hyperthermia in rhesus monkeys across a range of T(A) conditions that result in hypothermia or exaggerated hyperthermia in rodents. Monkey temperature responses to MDMA appear to be more similar to humans than to rodents and therefore the monkey may offer an improved model of effects related to MDMA-induced hyperthermia.

Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys.

RATIONALE: Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, attention deficit/hyperactivity disorder, Parkinson's disease, Huntington's disease, and substance abuse produce constellations of neuropsychological deficits in learning, memory, and attention in addition to other defining symptoms. OBJECTIVE: To delineate the role dopaminergic D1- and D2-like receptor subtypes play in complex brain functions. MATERIALS AND METHODS: Monkeys (N = 6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. The effects of the dopamine D2-like antagonist raclopride (10-56 microg/kg, i.m.) and the D1-like antagonist SCH23390 (SCH, 3.2-56 microg/kg, i.m.) on cognitive performance were then determined. RESULTS: Deficits on PR, RTT, and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH, which was unexpected, given prior reports on the involvement of D1 signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390. CONCLUSIONS: The intriguing results suggest a greater contribution of D2- over D1-like receptors to both spatial working memory and object-location associative memory.

Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys.

BACKGROUND: Exposure to (+/-)3,4-methylenedioxymethamphetamine ((+/-)MDMA) results in lasting reductions of many markers for serotonin terminals in a range of species. In rodents, the severity of insult depends in large part on the generation of hyperthermia in the subject. (+/-)MDMA can produce either hyperthermia or hypothermia in rodents depending on the ambient temperature and these effects may be limited to the S(+) enantiomer. Limited prior evidence suggests (+/-)MDMA does not produce hyperthermia in chair-restrained monkeys [Bowyer, J.F., Young, J.F., Slikker, W., Itzak, Y., Mayorga, A.J., Newport, G.D., Ali, S.F., Frederick, D.L., Paule, M.G., 2003. Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 24, 379-390]. This study was therefore conducted to determine if racemic MDMA and its enantiomers induce hyperthermia and increase spontaneous locomotor activity in unrestrained rhesus monkeys. METHODS: Body temperature and spontaneous home cage activity were monitored continuously in four monkeys via radiotelemetric devices. The subjects were challenged with 1.7 mg/kg, i.m., (+/-)MDMA, S(+)MDMA and R(-)MDMA in pseudorandomized order. RESULTS: Maximum and average temperature in the 4h interval post-dosing was elevated 0.7-0.9 degrees C by (+/-)MDMA and each enantiomer. Reductions in locomotor activity following dosing did not reliably differ from vehicle effects. CONCLUSIONS: MDMA produces an acute hyperthermia in unrestrained rhesus monkeys, much as it does with rats, mice, pigs, rabbits and humans. Hyperthermia occurs despite no increase in locomotor activity thus the effect does not depend on motor activation. Each enantiomer appears to be equivalently active thus primates may differ from rodents in thermoregulatory sensitivity to the R(-) enantiomer. Significant differences in outcome between this and a prior study in monkeys indicate a need for additional study of the thermoregulatory impact of MDMA in nonhuman primates.

Controlled and behaviorally relevant levels of oral ethanol intake in rhesus macaques using a flavorant-fade procedure.

BACKGROUND: Flavorant-fading procedures can initiate and maintain oral ethanol intake in rodents. The present study developed a similar procedure to achieve controlled and behaviorally relevant levels of ethanol intake in monkeys. METHODS: Male rhesus macaques (N = 13) were initially given the opportunity to consume 0.5 g/kg of a 1% (w/v) ethanol plus 4% (w/v) Tang solution in 1-hr limited-access sessions without the requirement of an operant response. Once consumption was stable at a particular concentration (%) and/or amount (g/kg), animals were given access to higher concentrations and/or amounts of ethanol. Animals were tested on a bimanual motor skill (BMS) task 20 and 90 min after consumption to assess behavioral impairment. Blood alcohol levels (BALs) were assessed after a session in which animals had the opportunity to consume up to 3.0 g/kg of 6% (w/v) ethanol. RESULTS: The gradual fading up of higher concentrations and amounts of ethanol resulted in controlled and robust levels (>2.0 g/kg) of ethanol intake in half of the subjects. Increasing the concentration of the sweetener from 4 to 6% (w/v) was effective in initiating consumption in three animals. Two monkeys required the additional step of presenting the increased-sweetener solutions after a meal (postprandial consumption) to initiate significant ethanol intake. Animals were significantly impaired on the BMS task after consumption of 2.0, 2.5, and 3.0 g/kg of ethanol. Individual consumption ranging from 0.8 to 3.0 g/kg of ethanol produced BALs of 18 to 269 mg/dl. CONCLUSIONS: The flavorant-fading procedure was effective in producing behaviorally relevant levels of ethanol consumption in rhesus macaques. This model facilitated a randomized-dose procedure to determine the behavioral effects of 0.5 to 3.0 g/kg of ethanol. This procedure therefore is of significant utility in determining behavioral or physiologic effects of specific doses of consumed ethanol in monkeys.

Modeling a task that is sensitive to dementia of the Alzheimer's type: individual differences in acquisition of a visuo-spatial paired-associate learning task in rhesus monkeys.

Early detection of progressive diseases such as Alzheimer's Disease (AD) is crucial for both the treatment and study of the disease. Performance on a visuo-spatial paired-associates learning (vsPAL) task was recently shown to reliably predict a diagnosis of AD in aged populations. The present study reports the development of this vsPAL task for use in nonhuman primates. Translation of vsPAL to a nonhuman model may provide improved preclinical tools for study of the etiology and treatment of dementia. Twelve young adult male rhesus monkeys were trained to perform the vsPAL task concurrently with tests comprising a nonhuman primate neuropsychological test battery. Monkeys successfully learned to perform vsPAL and did so in a task-difficulty ranked fashion. Despite significant individual differences in capability in the acquisition of the recognition memory aspects of the task, all monkeys evidenced the ability to learn within-trial, i.e. to improve with repeated stimulus-location pairings. These results support the use of vsPAL performance under various challenge conditions to investigate the possible substrates of early cognitive decline in AD. Comparison of performance on vsPAL with performance on other memory tasks in the battery will be of more general use in differentiating mechanisms involved in various aspects of mnemonic function.