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Summary: Bisphosphonates prevent future hip fractures. However, we found that one in six patients with hip fractures had a delay in bisphosphonate initiation and another one-sixth discontinued treatment within 12 months after discharge. Our results highlight the need to address hesitancy in treatment initiation and continuous monitoring. Purpose: Suboptimal antiresorptive use is not well understood. This study investigated trajectories of oral bisphosphonate use following first hip fractures and factors associated with different adherence and persistence trajectories. Methods: We conducted a retrospective study of all patients aged ≥ 50 years dispensed two or more bisphosphonate prescriptions following first hip fracture in Victoria, Australia, from 2012 to 2017. Twelve-month trajectories of bisphosphonate use were categorized using group-based trajectory modeling. Factors associated with different trajectories compared to the persistent adherence trajectory were assessed using multivariate multinomial logistic regression. Results: We identified four patterns of oral bisphosphonate use in 1811 patients: persistent adherence (66%); delayed dispensing (17%); early discontinuation (9%); and late discontinuation (9%). Pre-admission bisphosphonate use was associated with a lower risk of delayed dispensing in both sexes (relative risk [RR] 0.28, 95% confidence interval [CI] 0.21–0.39). Older patients (≥ 85 years old versus 50–64 years old, RR 0.38, 95% CI 0.22–0.64) had a lower risk of delayed dispensing. Males with anxiety (RR 9.80, 95% CI 2.24–42.9) and females with previous falls had increased risk of early discontinuation (RR 1.80, 95% CI 1.16–2.78). Conclusion: Two-thirds of patients demonstrated good adherence to oral bisphosphonates over 12 months following hip fracture. Efforts to further increase post-discharge antiresorptive use should be sex-specific and address possible persistent uncertainty around delaying treatment initiation. [ABSTRACT FROM AUTHOR]

Objective: To investigate symptomatic and preventive medication use according to age and frailty in Australian and Japanese nursing homes (NHs). Methods: Secondary cross-sectional analyses of two prospective cohort studies involving 12 Australian NHs and four Japanese NHs. Frailty was measured using the FRAIL-NH scale (non-frail 0–2; frail 3–6; most-frail 7–14). Regular medications were classified as symptomatic or preventive based on published lists and expert consensus. Descriptive statistics were used to compare the prevalence and ratio of symptomatic to preventive medications. Results: Overall, 550 Australian residents (87.7 ± 7.3 years; 73.3% females) and 333 Japanese residents (86.5 ± 7.0 years; 73.3% females) were included. Australian residents used a higher mean number of medications than Japanese residents (9.8 ± 4.0 vs 7.7 ± 3.7, p < 0.0001). Australian residents used more preventive than symptomatic medications (5.5 ± 2.5 vs 4.3 ± 2.6, p < 0.0001), while Japanese residents used more symptomatic than preventive medications (4.7 ± 2.6 vs 3.0 ± 2.2, p < 0.0001). In Australia, symptomatic medications were more prevalent with increasing frailty (non-frail 3.4 ± 2.6; frail 4.0 ± 2.6; most-frail 4.8 ± 2.6, p < 0.0001) but less prevalent with age (< 80 years 5.0 ± 2.9; 80–89 years 4.4 ± 2.6; ≥ 90 years 3.9 ± 2.5, p = 0.0042); while preventive medications remained similar across age and frailty groups. In Japan, there was no significant difference in the mean number of symptomatic and preventive medications irrespective of age and frailty. Conclusions: The ratio of symptomatic to preventive medications was higher with increasing frailty but lower with age in Australia; whereas in Japan, the ratio remained consistent across age and frailty groups. Preventive medications remained prevalent in most-frail residents in both cohorts, albeit at lower levels in Japan. [ABSTRACT FROM AUTHOR]

Optogenetic actuators are rapidly advancing tools used to control physiology in excitable cells, such as neurons and cardiomyocytes. In neuroscience, these tools have been used to either excite or inhibit neuronal activity. Cell type–targeted actuators have allowed to study the function of distinct cell populations. Whereas the first described cation channelrhodopsins allowed to excite specific neuronal cell populations, anion channelrhodopsins were used to inhibit neuronal activity. To allow for simultaneous excitation and inhibition, opsin combinations with low spectral overlap were introduced. BiPOLES (Bidirectional Pair of Opsins for Light-induced Excitation and Silencing) is a bidirectional optogenetic tool consisting of the anion channel Guillardia theta anion-conducting channelrhodopsin 2 (GtACR2 with a blue excitation spectrum and the red-shifted cation channel Chrimson. Here, we studied the effects of BiPOLES activation in cardiomyocytes. For this, we knocked in BiPOLES into the adeno-associated virus integration site 1 (AAVS1) locus of human-induced pluripotent stem cells (hiPSC), subjected these to cardiac differentiation, and generated BiPOLES expressing engineered heart tissue (EHT) for physiological characterization. Continuous light application activating either GtACR2 or Chrimson resulted in cardiomyocyte depolarization and thus stopped EHT contractility. In contrast, short light pulses, with red as well as with blue light, triggered action potentials (AP) up to a rate of 240 bpm. In summary, we demonstrate that cation, as well as anion channelrhodopsins, can be used to activate stem cell–derived cardiomyocytes with pulsed photostimulation but also to silence cardiac contractility with prolonged photostimulation. [ABSTRACT FROM AUTHOR]

Introduction: Implementation of the Drug Burden Index (DBI) as a risk assessment tool in clinical practice may facilitate deprescribing. Objective: The purpose of this study is to evaluate how a comprehensive intervention bundle using the DBI impacts (i) the proportion of older inpatients with at least one DBI-contributing medication stopped or dose reduced on discharge, compared with admission; and (ii) the changes in deprescribing of different DBI-contributing medication classes during hospitalisation. Methods: This before-and-after study was conducted in an Australian metropolitan tertiary referral hospital. Patients aged ≥ 75 years admitted to the acute aged care service for ≥ 48 h from December 2020 to October 2021 and prescribed DBI-contributing medication were included. During the control period, usual care was provided. During the intervention, access to the intervention bundle was added, including a clinician interface displaying DBI score in the electronic medical record. In a subsequent 'stewardship' period, a stewardship pharmacist used the bundle to provide clinicians with patient-specific recommendations on deprescribing of DBI-contributing medications. Results: Overall, 457 hospitalisations were included. The proportion of patients with at least one DBI-contributing medication stopped/reduced on discharge increased from 29.9% (control period) to 37.5% [intervention; adjusted risk difference (aRD) 6.5%, 95% confidence intervals (CI) −3.2 to 17.5%] and 43.1% (stewardship; aRD 12.1%, 95% CI 1.0–24.0%). The proportion of opioid prescriptions stopped/reduced rose from 17.9% during control to 45.7% during stewardship (p = 0.04). Conclusion: Integrating a comprehensive intervention bundle and accompanying stewardship program is a promising strategy to facilitate deprescribing of sedative and anticholinergic medications in older inpatients. [ABSTRACT FROM AUTHOR]

Summary: Hip fractures are a major public health concern. Number of hip fractures cases increased by 20% from 2012 to 2018. Factors associated with post-fracture mortality included men, those who are frail, living in a non-metropolitan region, or residing in a residential aged care facility. Our results are useful for planning healthcare interventions. Purpose: Hip fractures are a major public health concern in Australia. Data on hip fracture incidence and mortality are needed to plan and evaluate healthcare interventions. The aims of the study were to investigate (1) the time-trend in absolute number and incidence of first hip fractures, and (2) factors associated with mortality following first hip fractures in Victoria, Australia. Methods: A state-wide cohort study of all patients aged ≥ 50 years admitted to a Victorian hospital for first hip fracture between July 2012 and June 2018. Annual age-standardized incidence rates were calculated using population data from Australian Bureau of Statistics. Multivariate negative binomial regression was used to investigate factors associated with post-fracture mortality. Results: Overall, 31,578 patients had a first hip fracture, of whom two-thirds were women and 47% were ≥ 85 years old. Absolute annual numbers of first hip fractures increased by 20%. There was no significant change in age- and sex-adjusted incidence. In total, 8% died within 30 days and 25% within 1 year. Factors associated with 30-day mortality included age (≥ 85 years old versus 50–64 years old, mortality rate ratio [MRR] 8.05, 95% confidence interval [CI] 5.86–11.33), men (MRR 2.11, 95% CI 1.88–2.37), higher Hospital Frailty Risk Scores (high frailty versus no frailty, MRR 3.46, 95% CI 2.66–4.50), admission from a residential aged care facility (RACF) (MRR 2.28, 95% CI 1.85–2.82), and residing in a non-metropolitan region (MRR 1.22, 95% CI 1.09–1.38). The same factors were associated with 1-year mortality. Conclusion: The absolute increase in hip fractures highlights the need for interventions to reduce fracture risk, especially for those at higher risk of post-fracture mortality, including men and those who are frail, living in a non-metropolitan region, or residing in a RACF. [ABSTRACT FROM AUTHOR]

Background: Ensuring safe and effective analgesic use in residential aged care services is important because older adults are susceptible to analgesic-related adverse drug events (ADEs). Objective: The aim of this study was to identify the proportion and characteristics of residents of aged care services who may benefit from analgesic review based on indicators in the 2021 Society for Post-Acute and Long-Term Care Medicine (AMDA) Pain Management Guideline. Methods: Cross-sectional analyses of baseline data from the Frailty in Residential Sector over Time (FIRST) study (N = 550 residents) across 12 South Australian residential aged care services in 2019 were conducted. Indicators included the proportion of residents who received > 3000 mg/day of acetaminophen (paracetamol), regular opioids without a documented clinical rationale, opioid doses > 60 mg morphine equivalents (MME)/day, more than one long-acting opioid concurrently, and a pro re nata (PRN) opioid on more than two occasions in the previous 7 days. Logistic regression was performed to investigate factors associated with residents who may benefit from analgesic review. Results: Of 381 (69.3%) residents charted regular acetaminophen, 176 (46.2%) were charted > 3000 mg/day. Of 165 (30%) residents charted regular opioids, only 2 (1.2%) had no prespecified potentially painful conditions in their medical record and 31 (18.8%) received > 60 MME/day. Of 153 (27.8%) residents charted long-acting opioids, 8 (5.2%) received more than one long-acting opioid concurrently. Of 212 (38.5%) residents charted PRN opioids, 10 (4.7%) received more than two administrations in the previous 7 days. Overall, 196 (35.6%) of 550 residents were identified as potentially benefiting from analgesic review. Females (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.20–2.91) and residents with prior fracture (OR 1.62, 95% CI 1.12–2.33) were more likely to be identified. Observed pain (OR 0.50, 95% CI 0.29–0.88) was associated with a lower likelihood of being identified compared with residents with no observed pain. Overall, 43 (7.8%) residents were identified based on opioid-related indicators. Conclusions: Up to one in three residents may benefit from a review of their analgesic regimen, including 1 in 13 who may benefit from a specific review of their opioid regimen. Analgesic indicators represent a new approach to target analgesic stewardship interventions. [ABSTRACT FROM AUTHOR]

Excitable cells can be stimulated or inhibited by optogenetics. Since optogenetic actuation regimes are often static, neurons and circuits can quickly adapt, allowing perturbation, but not true control. Hence, we established an optogenetic voltage-clamp (OVC). The voltage-indicator QuasAr2 provides information for fast, closed-loop optical feedback to the bidirectional optogenetic actuator BiPOLES. Voltage-dependent fluorescence is held within tight margins, thus clamping the cell to distinct potentials. We established the OVC in muscles and neurons of Caenorhabditis elegans, and transferred it to rat hippocampal neurons in slice culture. Fluorescence signals were calibrated to electrically measured potentials, and wavelengths to currents, enabling to determine optical I/V-relationships. The OVC reports on homeostatically altered cellular physiology in mutants and on Ca2+-channel properties, and can dynamically clamp spiking in C. elegans. Combining non-invasive imaging with control capabilities of electrophysiology, the OVC facilitates high-throughput, contact-less electrophysiology in individual cells and paves the way for true optogenetic control in behaving animals. Optogenetic actuation regimes are often static, which allows perturbation, but not true control of neuronal activity. Here, the authors describe an all-optical method for bidirectional steering of membrane potential, in closed loop, in C. elegans muscles and neurons, and rat hippocampal slice culture. The 'optogenetic voltage clamp' uses two microbial rhodopsin actuators and the rhodopsin voltage indicator QuasAr. [ABSTRACT FROM AUTHOR]

We developed a family of genetically encoded serotonin (5-HT) sensors (sDarken) on the basis of the native 5-HT1A receptor and circularly permuted GFP. sDarken 5-HT sensors are bright in the unbound state and diminish their fluorescence upon binding of 5-HT. Sensor variants with different affinities for serotonin were engineered to increase the versatility in imaging of serotonin dynamics. Experiments in vitro and in vivo showed the feasibility of imaging serotonin dynamics with high temporal and spatial resolution. As demonstrated here, the designed sensors show excellent membrane expression, have high specificity and a superior signal-to-noise ratio, detect the endogenous release of serotonin and are suitable for two-photon in vivo imaging. Genetically encoded sensors have been developed and become versatile tools for imaging serotonin dynamics. Here, authors developed a family of serotonin (5-HT) sensors (sDarken), three variants with different affinities for 5-HT enable high spatiotemporal resolution of 5-HT dynamics. [ABSTRACT FROM AUTHOR]

Gq proteins are universally important for signal transduction in mammalian cells. The underlying kinetics and transformation from extracellular stimuli into intracellular signaling, however could not be investigated in detail so far. Here we present the human Neuropsin (hOPN5) for specific and repetitive manipulation of Gq signaling in vitro and in vivo with high spatio-temporal resolution. Properties and G protein specificity of hOPN5 are characterized by UV light induced IP3 generation, Ca2+ transients and inhibition of GIRK channel activity in HEK cells. In adult hearts from a transgenic animal model, light increases the spontaneous beating rate. In addition, we demonstrate light induced contractions in the small intestine, which are not detectable after pharmacological Gq protein block. All-optical high-throughput screening for TRPC6 inhibitors is more specific and sensitive than conventional pharmacological screening. Thus, we demonstrate specific Gq signaling of hOPN5 and unveil its potential for optogenetic applications. Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool. [ABSTRACT FROM AUTHOR]

Information processing in the brain is controlled by quantal release of neurotransmitters, a tightly regulated process. From ultrastructural analysis, it is known that presynaptic boutons along single axons differ in the number of vesicles docked at the active zone. It is not clear whether the probability of these vesicles to get released (pves) is homogenous or also varies between individual boutons. Here, we optically measure evoked transmitter release at individual Schaffer collateral synapses at different calcium concentrations, using the genetically encoded glutamate sensor iGluSnFR. Fitting a binomial model to measured response amplitude distributions allowed us to extract the quantal parameters N, pves, and q. We find that Schaffer collateral boutons typically release single vesicles under low pves conditions and switch to multivesicular release in high calcium saline. The potency of individual boutons is highly correlated with their vesicular release probability while the number of releasable vesicles affects synaptic output only under high pves conditions. It is not fully understood if the probability of synaptic vesicle release is homogenous or varies between individual boutons. Here the authors perform optical quantal analyses of individual Schaffer collateral synapses, showing that multivesicular release enables a tenfold increase in glutamate output and that the vesicular release probability is not uniform between synapses. [ABSTRACT FROM AUTHOR]

Shark attack-related injuries (SARIs) are rare but may result in highly complex wounds requiring reconstruction by plastic surgeons. Here, we present an unusual case of SARI of the breast and briefly review literature on reconstructive management of (1) breast injuries from other large animals and (2) SARIs to other parts of the body. Our patient was a 39-year-old woman who experienced massive bilateral breast tissue loss from a shark attack. After primary surgical wound management, including debridement and washout, the patient underwent completion mastectomy with bilateral deep inferior epigastric perforator flap breast reconstruction. Literature review revealed that reports of animal-related injuries to the breast are rare, with ours being the first on SARI to the breast and the only describing major reconstruction of animal-related breast injury. Literature on reconstruction of non-breast SARI wounds is limited to two case reports describing severe tissue damage akin to that seen in our patient, both necessitating extensive debridement followed by reconstruction. Overall, our findings demonstrate the uniquely devastating damage resulting from SARIs and the value of primary wound management and abdominally based free flaps in successfully reconstructing these wounds. Level of evidence: Level V, therapeutic study. [ABSTRACT FROM AUTHOR]

Optogenetic silencing allows to reveal the necessity of selected neuronal populations for various neurophysiological functions. These range from synaptic transmission and coordinated neuronal network activity to control of specific behaviors. An ideal single-component optogenetic silencing tool should be switchable between active and inactive states with precise timing while preserving its activity in the absence of light until switched to an inactive state. Although bistable anion-conducting channelrhodopsins (ACRs) were previously engineered to reach this goal, their conducting state lifetime was limited to only a few minutes and some ACRs were not fully switchable. Here we report Aion, a bistable ACR displaying a long-lasting open state with a spontaneous closing time constant close to 15 min. Moreover, Aion can be switched between the open and closed state with millisecond precision using blue and orange light, respectively. The long conducting state enables overnight silencing of neurons with minimal light exposure. We further generated trafficking-optimized versions of Aion, which show enhanced membrane localization and allow precisely timed, long-lasting all-optical control of nociceptive responses in larvae of Drosophila melanogaster. Thus, Aion is an optogenetic silencing tool for inhibition of neuronal activity over many hours which can be switched between an active and inactive state with millisecond precision. Aion is an anion-conducting, bistable channelrhodopsin that enables long-term silencing of neuronal networks, as demonstrated in organotypic hippocampal cultures and Drosophila melanogaster larvae. [ABSTRACT FROM AUTHOR]

This correction notice is related to an article titled "MerMAIDs: a family of metagenomically discovered marine anion-conducting and intensely desensitizing channelrhodopsins" published in Nature Communications. The correction states that Enrico Schiewer, one of the authors, has changed their name from Enrico Peter. The correction has been made in both the HTML and PDF versions of the article. The authors of the article are Johannes Oppermann, Paul Fischer, Arita Silapetere, Bernhard Liepe, Silvia Rodriguez-Rozada, José Flores-Uribe, Enrico Schiewer, Anke Keidel, Johannes Vierock, Joel Kaufmann, Matthias Broser, Meike Luck, Franz Bartl, Peter Hildebrandt, J. Simon Wiegert, Oded Béjà, Peter Hegemann, and Jonas Wietek. [Extracted from the article]

The acute effects of anesthesia and their underlying mechanisms are still not fully understood. Thus, comprehensive analysis and efficient generalization require their description in various brain regions. Here we describe a large-scale, annotated collection of 2-photon calcium imaging data and multi-electrode, extracellular electrophysiological recordings in CA1 of the murine hippocampus under three distinct anesthetics (Isoflurane, Ketamine/Xylazine and Medetomidine/Midazolam/Fentanyl), during natural sleep, and wakefulness. We cover several aspects of data quality standardization and provide a set of tools for autonomous validation, along with analysis workflows for reuse and data exploration. The datasets described here capture various aspects of neural activity in hundreds of pyramidal cells at single cell resolution. In addition to relevance for basic biological research, the dataset may find utility in computational neuroscience as a benchmark for models of anesthesia and sleep. Measurement(s) brain activity measurement • pupil dilation Technology Type(s) two-photon calcium imaging • local field potential recording • videography Factor Type(s) calcium imaging data • local field potentials Sample Characteristic - Organism Mus musculus [ABSTRACT FROM AUTHOR]

Salt Inducible Kinases (SIKs), of which there are 3 isoforms, are established to play roles in innate immunity, metabolic control and neuronal function, but their role in adaptive immunity is unknown. To address this gap, we used a combination of SIK knockout and kinase-inactive knock-in mice. The combined loss of SIK1 and SIK2 activity did not block T cell development. Conditional knockout of SIK3 in haemopoietic cells, driven by a Vav-iCre transgene, resulted in a moderate reduction in the numbers of peripheral T cells, but normal B cell numbers. Constitutive knockout of SIK2 combined with conditional knockout of SIK3 in the haemopoietic cells resulted in a severe reduction in peripheral T cells without reducing B cell number. A similar effect was seen when SIK3 deletion was driven via CD4-Cre transgene to delete at the DP stage of T cell development. Analysis of the SIK2/3 Vav-iCre mice showed that thymocyte number was greatly reduced, but development was not blocked completely as indicated by the presence of low numbers CD4 and CD8 single positive cells. SIK2 and SIK3 were not required for rearrangement of the TCRβ locus, or for low level cell surface expression of the TCR complex on the surface of CD4/CD8 double positive thymocytes. In the absence of both SIK2 and SIK3, progression to mature single positive cells was greatly reduced, suggesting a defect in negative and/or positive selection in the thymus. In agreement with an effect on negative selection, increased apoptosis was seen in thymic TCRbeta high/CD5 positive cells from SIK2/3 knockout mice. Together, these results show an important role for SIK2 and SIK3 in thymic T cell development. [ABSTRACT FROM AUTHOR]

Optogenetic manipulation of neuronal activity through excitatory and inhibitory opsins has become an indispensable experimental strategy in neuroscience research. For many applications bidirectional control of neuronal activity allowing both excitation and inhibition of the same neurons in a single experiment is desired. This requires low spectral overlap between the excitatory and inhibitory opsin, matched photocurrent amplitudes and a fixed expression ratio. Moreover, independent activation of two distinct neuronal populations with different optogenetic actuators is still challenging due to blue-light sensitivity of all opsins. Here we report BiPOLES, an optogenetic tool for potent neuronal excitation and inhibition with light of two different wavelengths. BiPOLES enables sensitive, reliable dual-color neuronal spiking and silencing with single- or two-photon excitation, optical tuning of the membrane voltage, and independent optogenetic control of two neuronal populations using a second, blue-light sensitive opsin. The utility of BiPOLES is demonstrated in worms, flies, mice and ferrets. Currently, bidirectional control of activity in the same neurons in the same experiment is difficult. Here the authors report a Bidirectional Pair of Opsins for Light-induced Excitation and Silencing, BiPOLES, which they use in a range of organisms including worms, fruit flies, mice and ferrets. [ABSTRACT FROM AUTHOR]

Janus Kinases (JAKs) have emerged as an important drug target for the treatment of a number of immune disorders due to the central role that they play in cytokine signalling. 4 isoforms of JAKs exist in mammalian cells and the ideal isoform profile of a JAK inhibitor has been the subject of much debate. JAK3 has been proposed as an ideal target due to its expression being largely restricted to the immune system and its requirement for signalling by cytokine receptors using the common γ-chain. Unlike other JAKs, JAK3 possesses a cysteine in its ATP binding pocket and this has allowed the design of isoform selective covalent JAK3 inhibitors targeting this residue. We report here that mutating this cysteine to serine does not prevent JAK3 catalytic activity but does greatly increase the IC50 for covalent JAK3 inhibitors. Mice with a Cys905Ser knockin mutation in the endogenous JAK3 gene are viable and show no apparent welfare issues. Cells from these mice show normal STAT phosphorylation in response to JAK3 dependent cytokines but are resistant to the effects of covalent JAK3 inhibitors. These mice therefore provide a chemical-genetic model to study JAK3 function. [ABSTRACT FROM AUTHOR]

Background: Fall-related hospitalisations from residential aged care services (RACS) are distressing for residents and costly to the healthcare system. Strategies to limit hospitalisations include preventing injurious falls and avoiding hospital transfers when falls occur. Aims: To undertake a root cause analysis (RCA) of fall-related hospitalisations from RACS and identify opportunities for fall prevention and hospital avoidance. Methods: An aggregated RCA of 47 consecutive fall-related hospitalisations for 40 residents over a 12-month period at six South Australian RACS was undertaken. Comprehensive data were extracted from RACS records including nursing progress notes, medical records, medication charts, hospital summaries and incident reports by a nurse clinical auditor and clinical pharmacist. Root cause identification was performed by the research team. A multidisciplinary expert panel recommended strategies for falls prevention and hospital avoidance. Results: Overall, 55.3% of fall-related hospitalisations were among residents with a history of falls. Among all fall-related hospitalisations, at least one high falls risk medication was administered regularly prior to hospitalisation. Potential root causes of falling included medication initiations and dose changes. Root causes for hospital transfers included need for timely access to subsidised medical services or radiology. Strategies identified for avoiding hospitalisations included pharmacy-generated alerts when medications associated with an increased risk of falls are initiated or changed, multidisciplinary audit and feedback of falls risk medication use and access to subsidised mobile imaging services. Conclusions: This aggregate RCA identified a range of strategies to address resident and system-level factors to minimise fall-related hospitalisations. [ABSTRACT FROM AUTHOR]

Neurological and psychiatric (mental health) disorders have a large impact on health burden globally. Cognitive disorders (including dementia) and stroke are leading causes of disability. Mental health disorders, including depression, contribute up to one-third of total years lived with disability. The Neurological and mental health Global Epidemiology Network (NeuroGEN) is an international multi-database network that harnesses administrative and electronic medical records from Australia, Asia, Europe and North America. Using these databases NeuroGEN will investigate medication use and health outcomes in neurological and mental health disorders. A key objective of NeuroGEN is to facilitate high-quality observational studies to address evidence-practice gaps where randomized controlled trials do not provide sufficient information on medication benefits and risks that is specific to vulnerable population groups. International multi-database research facilitates comparisons across geographical areas and jurisdictions, increases statistical power to investigate small subpopulations or rare outcomes, permits early post-approval assessment of safety and effectiveness, and increases generalisability of results. Through bringing together international researchers in pharmacoepidemiology, NeuroGEN has the potential to be paradigm-changing for observational research to inform evidence-based prescribing. The first focus of NeuroGEN will be to address evidence-gaps in the treatment of chronic comorbidities in people with dementia. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study is to investigate the association between multiple antihypertensive use and mortality in residents with diagnosed hypertension, and whether dementia and frailty modify this association. Methods: This is a two-year prospective cohort study of 239 residents with diagnosed hypertension receiving antihypertensive therapy across six residential aged care services in South Australia. Data were obtained from electronic medical records, medication charts and validated assessments. The primary outcome was all-cause mortality and the secondary outcome was cardiovascular-related hospitalizations. Inverse probability weighted Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. Covariates included age, sex, dementia severity, frailty status, Charlson's comorbidity index and cardiovascular comorbidities. Results: The study sample (mean age of 88.1 ± 6.3 years; 79% female) included 70 (29.3%) residents using one antihypertensive and 169 (70.7%) residents using multiple antihypertensives. The crude incidence rates for death were higher in residents using multiple antihypertensives compared with residents using monotherapy (251 and 173/1000 person-years, respectively). After weighting, residents who used multiple antihypertensives had a greater risk of mortality compared with monotherapy (HR 1.40, 95%CI 1.03–1.92). After stratifying by dementia diagnosis and frailty status, the risk only remained significant in residents with diagnosed dementia (HR 1.91, 95%CI 1.20–3.04) and who were most frail (HR 2.52, 95%CI 1.13–5.64). Rate of cardiovascular-related hospitalizations did not differ among residents using multiple compared to monotherapy (rate ratio 0.73, 95%CI 0.32–1.67). Conclusions: Multiple antihypertensive use is associated with an increased risk of mortality in residents with diagnosed hypertension, particularly in residents with dementia and among those who are most frail. [ABSTRACT FROM AUTHOR]

Information within the brain travels from neuron to neuron across billions of synapses. At any given moment, only a small subset of neurons and synapses are active, but finding the active synapses in brain tissue has been a technical challenge. Here we introduce SynTagMA to tag active synapses in a user-defined time window. Upon 395–405 nm illumination, this genetically encoded marker of activity converts from green to red fluorescence if, and only if, it is bound to calcium. Targeted to presynaptic terminals, preSynTagMA allows discrimination between active and silent axons. Targeted to excitatory postsynapses, postSynTagMA creates a snapshot of synapses active just before photoconversion. To analyze large datasets, we show how to identify and track the fluorescence of thousands of individual synapses in an automated fashion. Together, these tools provide an efficient method for repeatedly mapping active neurons and synapses in cell culture, slice preparations, and in vivo during behavior. [ABSTRACT FROM AUTHOR]

Background: Temporal changes in the dispensing of glucose-lowering drugs (GLD) and their associated costs among elderly populations is unclear. This information is especially relevant to countries in which medications are partly or fully government subsidized. Objective: Our objective was to estimate the trends in prevalence, incidence and costs associated with GLD dispensed to older Australians. Methods: We analysed Pharmaceutical Benefits Scheme data for 76,906 people aged ≥ 65 years dispensed diabetes medications over the period 2013–2016. Results: Older males were dispensed more GLD than were older females, with the marginal difference increasing from 3.2% in 2013 (age-sex adjusted incidence rate ratio [aIRR] 1.032; 95% confidence interval [CI] 1.024–1.041; p < 0.001) to 3.9% in 2016 (aIRR 1.039; 95% CI 1.030–1.047; p < 0.001). The number of GLD dispensed per person was consistently lower in those aged ≥ 75 years than in those aged 65–74 years, with the gap widening over the years. More patients were initiated with sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors over the study period, at the expense of older GLD. The proportion of users and attributed costs associated with the use of metformin, sulfonylureas, α-glucosidase inhibitors and thiazolidinediones decreased over time. The total subsidized costs of GLD is forecast to increase to $A395 million by 2020. Conclusions: The treatment landscape for diabetes in Australia is undergoing dynamic change. More patients were initiated with the newer but costlier GLD over the study period. [ABSTRACT FROM AUTHOR]

Background: Warfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known. Objective: The objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients. Methods: We conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation. Results: In total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively. Conclusions: The overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to investigate associations between proton pump inhibitor (PPIs) use and infection-related hospitalizations among residents of long-term care facilities (LTCFs). Methods: This was a case–control study of residents aged ≥ 65 years admitted to hospital between July 2013 and June 2015. Residents admitted for infections (cases) and falls or fall-related injuries (controls) were matched for age (± 2 years), sex, and index date of admission (± 6 months). Conditional logistic regression was used to estimate crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between PPI use and infection-related hospitalizations. Analyses were adjusted for age, sex, polypharmacy, diabetes, heart failure, chronic obstructive pulmonary disease, myocardial infarction, cerebrovascular accident, and concomitant use of cancer and immunosuppressant medications. Subgroup analyses were performed for high- and low/moderate-intensity PPIs and for respiratory and non-respiratory infections. Logistic regression was used to compare the odds of infection-related hospitalizations among users of high- and low/moderate-intensity PPIs. Results: Overall, 181 cases were matched to 354 controls. Preadmission PPI use was associated with infection-related hospitalizations (aOR 1.66; 95% CI 1.11–2.48). In subgroup analyses, the association was apparent only for respiratory infections (aOR 2.26; 95% CI 1.37–3.73) and high-intensity PPIs (aOR 1.93; 95% CI 1.23–3.04). However, the risk of infection-related hospitalization was not significantly higher among users of high- versus low/moderate-intensity PPIs (aOR 1.25; 95% CI 0.74–2.13). Conclusion: Residents who use PPIs may be at increased risk of infection-related hospitalizations, particularly respiratory infections. Study findings provide further support for initiatives to minimize unnecessary PPI use in the LTCF setting. [ABSTRACT FROM AUTHOR]

Introduction: Non-adherence and non-persistence to diabetes medications are associated with worse clinical outcomes. In this study, we aimed to characterise the 1-year switching, adherence, and persistence patterns among people with diabetes aged 18 years and older prescribed sodium-glucose co-transporter 2 inhibitors (SGLT2is) in Australia.Methods: Using data from Australia's national Pharmaceutical Benefits Scheme (PBS), we identified 11,981 adults (mean age 60.9 years; 40.5% female) newly initiated on SGLT2is (5993 dapagliflozin; 5988 empagliflozin) from September 2015 to August 2017. Adherence was assessed via the proportion of days covered (PDC), persistence was defined as the continuous use of SGLT2i without a gap of ≥ 90 days, and switching was defined as the first change from dapagliflozin to empagliflozin or vice versa. Generalised linear models (GLMs) were used to compare the adherence (PDC = continuous), logistic regression models were used to compare the likelihoods of being adherent (PDC ≥ 0.80), and Cox proportional hazard models were used to compare the likelihoods of persistence and switching between people prescribed empagliflozin and dapagliflozin.Results: Overall, 65.8% (7879/11,981) of people dispensed SGLT2is were adherent (PDC ≥ 0.80) and 72.1% (8644/11,981) were persistent at 12 months. The mean PDC was 0.79 ± 0.27. The use of empagliflozin was associated with higher adherence (PDC = continuous) [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.03-1.05], being adherent (OR 1.39, 95% CI 1.29-1.51), and persisting for 12 months [hazard ratio (HR) 1.14, 95% CI 1.06-1.22] compared with dapagliflozin. Only 4.3% (509/11,981) of people switched between the SGLT2i. Compared with dapagliflozin, people initiated on empagliflozin were less likely to switch [HR 0.46, 95% CI 0.38-0.55].Conclusions: A considerable proportion of Australians prescribed SGLT2is were non-adherent or non-persistent. However, empagliflozin was associated with better adherence and persistence rates and a lower likelihood of switching compared with dapagliflozin. [ABSTRACT FROM AUTHOR]

Aim: While proton pump inhibitors (PPIs) are generally considered safe and well tolerated, frail older people who take PPIs long term may be susceptible to adverse events. This study characterized PPI use and determined factors associated with high-dose use among older adults in residential aged care services (RACSs). Methods: A cross-sectional study of 383 residents of six South Australian RACSs within the same organization was conducted. Clinical, diagnostic, and medication data were collected by study nurses. The proportions of residents who took a PPI for > 8 weeks and without documented indications were calculated. Factors associated with high-dose PPI use compared to standard/low doses were identified using age- and sex-adjusted logistic regression models. Results: 196 (51%) residents received a PPI, with 45 (23%) prescribed a high dose. Overall, 173 (88%) PPI users had documented clinical indications or received medications that can increase bleeding risk. Three-quarters of PPI users with gastroesophageal reflux disease or dyspepsia had received a PPI for > 8 weeks. High-dose PPI use was associated with increasing medication regimen complexity [odds ratio (OR) 1.02; 95% confidence interval (CI) 1.01–1.04 per one-point increase in Medication Regimen Complexity Index score] and a greater number of medications prescribed for regular use (OR 1.11; 95% CI 1.01–1.21 per additional medication). Conclusions: Half of all residents received a PPI, of whom the majority had documented clinical indications or received medications that may increase bleeding risk. There remains an opportunity to review the continuing need for treatment and consider "step-down" approaches for high-dose PPI users. [ABSTRACT FROM AUTHOR]

Background: One quarter of residents in long-term care facilities (LTCFs) have a diagnosis of CHD or stroke and over half use at least one preventative cardiovascular medication. There have been no studies that have investigated the longitudinal change in secondary preventative cardiovascular medication use in residents in LTCFs over time. Objective: The aim of this study was to investigate the change in cardiovascular medication use among residents with coronary heart disease (CHD) and prior stroke in nursing homes (NHs) and assisted living facilities (ALFs) in Finland over time, and whether this change differs according to dementia status. Methods: Three comparable cross-sectional audits of cardiovascular medication use among residents aged 65 years and over with CHD or prior stroke in NHs in 2003 and 2011 and ALFs in 2007 and 2011 were compared. Logistic regression analyses adjusted for gender, age, mobility, cancer and length of stay were performed to examine the effect of study year, dementia and their interaction on medication use. Results: Cardiovascular medication use among residents with CHD (NHs: 89% vs 70%; ALFs: 89% vs 84%) and antithrombotic medication use among residents with stroke (NHs: 72% vs 63%; ALFs: 78% vs 69%) declined between 2003 and 2011 in NHs and 2007 and 2011 in ALFs. Decline in the use of diuretics, nitrates and digoxin were found in both groups and settings. Cardiovascular medication use among residents with CHD and dementia declined in NHs (88% [95% CI 85–91] in 2003 vs 70% [95% CI 64–75] in 2011) whereas there was no change among people without dementia. There was no change in cardiovascular medication use among residents with CHD in ALFs with or without dementia over time. Antithrombotic use was lower in residents with dementia compared with residents without dementia in NHs (p < 0.001) and ALFs (p = 0.026); however, the interaction between dementia diagnosis and time was non-significant. Conclusions: The decline in cardiovascular medication use in residents with CHD and dementia suggests Finnish physicians are adopting a more conservative approach to the management of cardiovascular disease in the NH population. [ABSTRACT FROM AUTHOR]

Purpose: Clinical guidelines specify who should receive high-intensity statins; however, it is unclear how high-intensity statins are used in Australia. Our objective was to determine the demographic, clinical, and lifestyle factors associated with high-intensity statin therapy in Australia.Methods: Data from the Australian Diabetes, Obesity and Lifestyle study collected in 2011-2012 were analyzed. High-, moderate-, and low-intensity statins were defined as use of statins at doses demonstrated to reduce low-density lipoprotein cholesterol levels by > 50, 30-50, and < 30%, respectively. Logistic regression was used to estimate adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for factors associated with high- versus low-to-moderate-intensity statin therapy.Results: Overall, 1108 (24%) study participants used a statin. Data on statin intensity were available for 1072 participants. The proportions of high-, moderate-, and low-intensity statin therapy were 32 (n = 341), 65 (n = 696), and 3% (n = 35), respectively. Overall, 51% of people with prior cardiovascular disease (CVD) used a high-intensity statin. In addition to prior CVD (OR = 3.34, 95% CI = 1.95-5.73), no (OR = 1.84, 95%CI 1.02-3.31) or insufficient physical activity (OR = 1.51, 95% CI = 1.01-2.25), obesity (OR = 1.87, 95% CI = 1.13-3.10), and consuming > 2 alcoholic drinks daily (OR = 1.66, 95% CI = 1.08-2.55) were associated with high versus low-to-moderate-intensity statin therapy. Conversely, age 65-74 vs. < 65 years was inversely associated with high-intensity statin therapy (OR = 0.62, 95% CI = 0.41-0.94).Conclusions: Prior CVD was the strongest factor associated with high-intensity statin therapy. Although the prevalence of CVD increases with age, older people were less likely to be treated with high-intensity statins. [ABSTRACT FROM AUTHOR]

Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 Å resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment. [ABSTRACT FROM AUTHOR]

Background: Residents of long-term care facilities (LTCFs) are at high risk of hospitalization. Medications are a potentially modifiable risk factor for hospitalizations.Objective: Our objective was to systematically review the association between medications or prescribing patterns and hospitalizations from LTCFs.Methods: We searched MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and International Pharmaceutical Abstracts (IPA) from inception to August 2017 for longitudinal studies reporting associations between medications or prescribing patterns and hospitalizations. Two independent investigators completed the study selection, data extraction and quality assessment using the Joanna Briggs Institute Critical Appraisal Tools.Results: Three randomized controlled trials (RCTs), 22 cohort studies, five case-control studies, one case-time-control study and one case-crossover study, investigating 13 different medication classes and two prescribing patterns were included. An RCT demonstrated that high-dose influenza vaccination reduced all-cause hospitalization compared with standard-dose vaccination (risk ratio [RR] 0.93; 95% confidence interval [CI] 0.88-0.98). Another RCT found no difference in hospitalization rates between oseltamivir as influenza treatment and oseltamivir as treatment plus prophylaxis (treatment = 4.7%, treatment and prophylaxis = 3.5%; p = 0.7). The third RCT found no difference between multivitamin/mineral supplementation and hospitalization (odds ratio [OR] 0.94; 95% CI 0.74-1.20) or emergency department visits (OR 1.05; 95% CI 0.76-1.47). Two cohort studies demonstrated influenza vaccination reduced hospitalization. Four studies suggested polypharmacy and potentially inappropriate medications (PIMs) increased all-cause hospitalization. However, associations between polypharmacy (two studies), PIMs (one study) and fall-related hospitalizations were inconsistent. Inconsistent associations were found between psychotropic medications with all-cause and cause-specific hospitalizations (11 studies). Warfarin, nonsteroidal anti-inflammatory drugs, pantoprazole and vinpocetine but not long-term acetylsalicylic acid (aspirin), statins, trimetazidine, digoxin or β-blockers were associated with all-cause or cause-specific hospitalizations in single studies of specific resident populations. Most cohort studies assessed prevalent rather than incident medication exposure, and no studies considered time-varying medication use.Conclusion: High-quality evidence suggests influenza vaccination reduces hospitalization. Polypharmacy and PIMs are consistently associated with increased all-cause hospitalization. [ABSTRACT FROM AUTHOR]

Introduction: Hypoglycaemia and hyperglycaemia are common adverse events associated with antidiabetic medications. They are also a common cause of hospital admissions for people with diabetes. The objective of the study was to explore the trends in hospital admissions due to hypoglycaemia and hyperglycaemia and in the prescriptions of antidiabetic medications in England and Wales.Methods: We conducted an observational study during the period 1999–2016. Hospital admission data for patients from all age groups were extracted from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Data on prescriptions of antidiabetic medications were extracted from the Prescription Cost Analysis database from 2004 to 2016.Results: Between 1999 and 2016, the hospital admission rate increased by 173.0% [from 17.2 (95% CI 16.9–17.6) to 47.1 (95% CI 46.5–47.6) per 100,000 persons] for hypoglycaemia and by 147.0% [from 22.8 (95% CI 22.4–23.2) to 56.3 (95% CI 55.7–56.9) per 100,000 persons] for hyperglycaemia. The prescription rate for all antidiabetic medications increased between 2004 and 2016 by 116.0% [from 373.0 (95% CI 373.0–373.0) to 806.0 (95% CI 806.0–806.0) prescriptions per 1000 persons]. There was a parallel increase in the rate of antidiabetic medication prescriptions during the same study period, with correlation coefficients of 0.94 for hypoglycaemia and 0.98 for hyperglycaemia, respectively.Conclusions: There have been parallel increases in the rate of admissions due to dysglycaemia and the rate of antidiabetic prescriptions in England and Wales. Further analytical studies are required to investigate whether increased admission for dysglycaemia is associated with increased use of antidiabetic medications. [ABSTRACT FROM AUTHOR]

Correction to: I Nature Communications i https://doi.org/10.1038/s41467-022-29265-w, published online 01 April 2022 The original version of this Article omitted a contributor, Michael Hesse, in the Acknowledgements section. These authors contributed equally: Ahmed Wagdi, Daniela Malan, Udhayabhaskar Sathyanarayanan. [Extracted from the article]

Purpose: Polypharmacy is often defined as use of 'five-or-more-medications'. However, the optimal polypharmacy cut-point for predicting clinically important adverse events in older people with cancer is unclear. The aim was to determine the sensitivities and specificities of a range of polypharmacy cut-points in relation to a variety of adverse events in older people with cancer.Methods: Data on medication use, falls and frailty criteria were collected from 385 patients aged ≥70 years presenting to a medical oncology outpatient clinic. Receiver operating characteristic (ROC) curves were produced to examine sensitivities and specificities for varying definitions of polypharmacy in relation to exhaustion, falls, physical function, Karnofsky Performance Scale (KPS) and frailty. Sub-analyses were performed when stratifying by age, sex, comorbidity status and analgesic use.Results: Patients had a mean age of 76.7 years. Using Youden's index, the optimal polypharmacy cut-point was 6.5 medications for predicting frailty (specificity 67.0 %, sensitivity 70.0 %), physical function (80.2 %, 49.3 %) and KPS (69.8 %, 52.1 %), 5.5 for falls (59.2 %, 73.0 %) and 3.5 for exhaustion (43.4 %, 74.5 %). For polypharmacy defined as five-or-more-medications, the specificities and sensitivities were frailty (44.9 %, 77.5 %), physical function (58.0 %, 69.7 %), KPS (47.7 %, 69.4 %), falls (44.5 %, 75.7 %) and exhaustion (52.6 %, 64.1 %). The optimal polypharmacy cut-points were similar when the sample was stratified by age, sex, comorbidity status and analgesic use.Conclusions: Our results suggest that no single polypharmacy cut-point is optimal for predicting multiple adverse events in older people with cancer. In this population, the common definition of five-or-more-medications is reasonable for identifying 'at-risk' patients for medication review. [ABSTRACT FROM AUTHOR]

Channelrhodopsins are light-gated cation channels that have been widely used for optogenetic stimulation of electrically excitable cells. Replacement of a glutamic acid in the central gate with a positively charged amino acid residue reverses the ion selectivity and produces chloride-conducting ChRs (ChloCs). Expressed in neurons, published ChloCs produced a strong shunting effect but also a small, yet significant depolarization from the resting potential. Depending on the state of the neuron, the net result of illumination might therefore be inhibitory or excitatory with respect to action potential generation. Here we report two additional amino acid substitutions that significantly shift the reversal potential of improved ChloC (iChloC) to the reversal potential of endogenous GABAA receptors. As a result, light-evoked membrane depolarization was strongly reduced and spike initiation after current injection or synaptic stimulation was reliably inhibited in iChloC-transfected neurons in vitro. In the primary visual cortex of anesthetized mice, activation of iChloC suppressed spiking activity evoked by visual stimulation. Due to its high operational light sensitivity, iChloC makes it possible to inhibit neurons in a large volume of brain tissue from a small, point-like light source. [ABSTRACT FROM AUTHOR]