Search

α‐Silylalkylamines and α‐borylalkylamines are versatile synthetic intermediates and attractive scaffolds found in pharmaceutical drugs and agrochemicals. Despite great progress on synthetic methods for preparation of α‐silylalkylamines or α‐borylalkylamines, there are no general strategies for preparation of α‐boryl‐α‐silylalkylamines and the reactivity has not been explored. Here we report deoxygenative geminal silylboration of amides using silylboronates in the presence of alkoxide base catalyst, producing α‐boryl‐α‐silylalkylamines. The silicon and boron groups in α‐boryl‐α‐silylalkylamines are found to be utilized to chemoselective transformations, such as protonation and alkylation. This protocol serves various α‐silylalkylamines and α‐borylalkylamines from readily available amides. [ABSTRACT FROM AUTHOR]

The complexity of the drug market and the constant updating of drugs have been challenging issues for drug regulatory authorities. With the emergence of new psychoactive substances (NPS) and the nonmedical use of prescription drugs, forensic and toxicology laboratories have had to adopt new drug screening methods and advanced instrumentation. Using high‐performance liquid chromatography coupled with Orbitrap mass spectrometry, we developed a screening method for common NPS and other drugs. Two milliliters of mixed solvent of n‐hexane and ethyl acetate (1:1, v:v) were added to 500 μL of blood or urine sample for liquid–liquid extraction, and methanol extraction was used for hair samples. The developed method was applied to 3897 samples (including 332 blood samples, 885 urine samples, and 2680 hair samples) taken from drug addicts in a province of China during 2019–2021. For urine and blood samples, the limits of detection (LODs) ranged from 1.68 pg/mL to 10.7 ng/mL. For hair samples, the LODs ranged from 3.30 × 10−5 to 4.21 × 10−3 ng/mg. The matrix effects of urine, blood, and hair samples were in the range of 47.6%–121%, 39.8%–139%, and 6.35%–118%, respectively. And the intra‐day precision was 3.5%–6.0% and the inter‐day precision was 4.18%–9.90%. Analysis of the actual samples showed an overall positive detection rate of 58.9%, with 5.32% of the samples indicating the use of multiple drugs. [ABSTRACT FROM AUTHOR]

This article examines the role of policy entrepreneurs in countering regulatory capture, a phenomenon whereby regulatory bodies influenced by industry lobbying often prioritize private over public interests. The study employs an abductive process‐tracing approach to investigate the 2013 drug pricing reform in Morocco, illustrating how substantial policy shifts can occur even in authoritarian contexts susceptible to regulatory capture. The findings underscore the pivotal role of Houcine El Ouardi, the former Minister of Health, whose strategic leadership exemplified policy entrepreneurship. His capacity to navigate and surmount industry resistance was instrumental to the reform's success, culminating in a significant reduction in drug prices. This case challenges conventional wisdom regarding regulatory capture, demonstrating that individual agency can reshape regulatory outcomes despite opposition. By elucidating how policy entrepreneurs can drive transformative change in resistant regulatory environments under authoritarian regimes, the study contributes to the literature on policy entrepreneurship and regulation. [ABSTRACT FROM AUTHOR]

Objective: Many guidelines recommend limiting glucocorticoids in patients with rheumatoid arthritis (RA), but 40% of patients remain on glucocorticoids long term. We evaluated the cardiovascular risk of long‐term glucocorticoid prescription by studying patients on stable disease‐modifying antirheumatic drugs (DMARDs). Methods: Using two claims databases, we identified patients with RA on stable DMARD therapy for >180 days. Proportional hazards models with inverse‐probability weights and clustering to account for multiple observations were used to estimate the effect of glucocorticoid dose on composite cardiovascular outcomes (stroke or myocardial infarction [MI]). Results: There were 135,583 patients in Medicare and 39,272 in Optum's de‐identified Clinformatics Data Mart (CDM) database. Medicare and CDM patients had an incidence of 1.3 and 0.8 composite cardiovascular outcomes per 100 person‐years, respectively. In the older, comorbid Medicare cohort, glucocorticoids were associated with a dose‐dependent increase in composite cardiovascular outcomes in adjusted models with predicted one‐year incidence of 1.4% (95% confidence interval [CI] 1.2%–1.6%) for ≤5 mg, 1.6% (95% CI 1.4%–1.9%) for >5 to 10 mg, and 1.8% (95% CI 1.2%–2.5%) for >10 mg versus 1.1% (95% CI 1.1%–1.2%) among patients not receiving glucocorticoids. There was no significant association among the CDM cohort. However, in the subgroup of younger patients with RA and higher cardiovascular risk, glucocorticoids were associated with a dose‐dependent increase in composite cardiovascular outcomes. Conclusion: Among older patients with more comorbidities and younger patients with higher cardiovascular risk with RA on stable DMARD therapy, glucocorticoids were associated with a dose‐dependent increased risk of MI and stroke, even at doses ≤5 mg/day. By contrast, no association was noted among younger, healthier patients with RA. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the association between adolescents' adherence to attention‐deficit/hyperactivity disorder (ADHD) medication and their risk of committing minor offenses. Methods: Using two Dutch databases, Statistics Netherlands (CBS) and the Foundation for Pharmaceutical Statistics (SFK), we aimed to investigate the association between adherence to ADHD medication and registered minor offenses between 2005 and 2019 of 18,234 adolescents (12–18 years). We used Cox regression analyses to compare the rate of committing minor offenses of adolescents during periods of high ADHD medication adherence compared to periods of low adherence (i.e., periods with or without sufficient amounts of dispensed medication). We additionally tested associations with adherence to selective serotonin reuptake inhibitors (SSRIs) as control medication and analyzed potential reverse causation. Results: High ADHD medication adherence was associated with a reduced risk of committing a minor offense of between 33% and 38% compared to low adherence periods of ≥3 months (hazard ratio [HR] 0.67, confidence interval [CI] 0.64–0.71) or ≥6 months (HR 0.62, CI 0.59–0.65). The reduction in risk can likely be attributed to ADHD medication, given the absence of effects of SSRIs and no reverse causation. The reduction rate remained between 16% and 55% per sex, stimulant versus non‐stimulant medication, different offense categories and further sensitivity analyses. Conclusions: Among adolescents using ADHD medication, rates of criminality were lower during periods of high medication adherence, suggesting that adherence to ADHD medication may contribute to prevention of minor offenses in adolescents. [ABSTRACT FROM AUTHOR]

Background: Generalized pustular psoriasis (GPP) is a rare, potentially life‐threatening skin disease often requiring long‐term therapy. We aimed to evaluate the use of Interleukin (IL)‐17A inhibitors (secukinumab and ixekizumab) in GPP patients over 96 weeks. Methods: We retrospectively analyzed a case series of 18 patients with GPP who received secukinumab (n = 13) and ixekizumab (n = 5) therapy with a 96‐week follow‐up period. The primary effectiveness analysis included determining the percentage of patients who achieved ≥90% or 100% improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score. Adherence was captured using the medication possession ratio (MPR). Results: Using the as‐observed (AO) method, 87% and 67% of patients treated with secukinumab or ixekizumab achieved GPPASI 90 and 100 responses, respectively. At Week 96, the mean GPPASI improvements from baseline GPPASI were 96.3% (95% CI: 0.91–1.01) using the AO method. After Week 48, 14 patients tapered (n = 8) or terminated (n = 6) the treatment. High‐adherence therapy (MPR ≥ 80%) was significantly superior to the low‐adherence group in the rate of patients achieving a GPPASI 100 response (AO, 100% vs. 38%, P < 0.05). By Week 96, 5 (27.8%) patients had new GPP flares, and 4 (80%) were in the low‐adherence group. No new safety signals occurred. Conclusion: IL‐17A inhibitors led to effective and sustained improvement in GPP patients, and high‐adherence therapy had long‐term positive effects on skin clearance. Given its relapsing nature, improving compliance is beneficial for long‐term clinical management. [ABSTRACT FROM AUTHOR]

Background and aims: Extended‐release naltrexone (XR‐NTX) and sublingual buprenorphine (SL‐BUP) are both approved for opioid use disorder (OUD) treatment in any medical setting. We aimed to compare the real‐world effectiveness of XR‐NTX and SL‐BUP. Design and setting: This was an observational active comparator, new user cohort study of Medicaid claims records for patients in New Jersey and California, USA, 2016–19. Participants/cases: The participants were adult Medicaid patients aged 18–64 years who initiated XR‐NTX or SL‐BUP for maintenance treatment of OUD and did not use medications for OUD in the 90 days before initiation. Our cohort included 1755 XR‐NTX and 9886 SL‐BUP patients. Measurements: We examined two outcomes up to 180 days after medication initiation: (1) composite of medication discontinuation and death and (2) composite of overdose and death. Findings In adjusted analyses, treatment with XR‐NTX was more likely to result in discontinuation or death by the end of follow‐up than treatment with SL‐BUP: cumulative risk 75.9% [95% confidence interval (CI) = 73.9%, 77.9%] versus 62.2% (95% CI = 61.2%, 63.2%), respectively (risk difference = 13.7 percentage points, 95% CI = 11.4, 16.0). There was minimal difference in the cumulative risk of overdose or death by the end of follow‐up: XR‐NTX 3.9% (95% CI = 3.0%, 4.8%) versus SL‐BUP 3.3% (95% CI = 2.9%, 3.7%); risk difference = 0.5 percentage points, 95% CI = –0.4, 1.5. Results were consistent across sensitivity analyses. Conclusions: Medicaid patients in California and New Jersey, USA, receiving treatment for opioid use disorder stayed in treatment longer on sublingual buprenorphine than on extended‐release naltrexone, but the risk of overdose was similar. Most patients in this study discontinued medication within 6 months, regardless of which medication was initiated. [ABSTRACT FROM AUTHOR]

Substance use is a global phenomenon that is particularly affecting the prison population. This study aimed to describe the prevalence of drug use among people in prison before and during incarceration in seven European countries and to compare it with the prevalence in the general population. Individual data collection was carried out between 2014 and 2018 with a model European Questionnaire on Drug Use among people in prison. A total of 12,918 people living in prison filled in the survey. People in prison report higher level of drug use when compared with the general population and the use of drug inside prison exist, although at lower levels when compared with predetention. Prisons can represent a point of access to engage individuals who use drugs in interventions that address drug use and risk factors related to both drug use and imprisonment. [ABSTRACT FROM AUTHOR]

Objectives: To present the Real‐World Progression In Diabetes (RAPIDS) 2.0 Risk Engine, the only simulation model to study the long‐term trajectories of outcomes arising from dynamic sequences of glucose‐lowering treatments in type 2 diabetes (T2DM). Research Design and Methods: The RAPIDS model's risk equations were re‐estimated using a Least Absolute Shrinkage and Selection Operator (LASSO)‐based regularization of features that spanned baseline data from the last two quarters of current time and interactions with age. These equations were supplemented with estimates for the impact of dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists, and sodium‐glucose cotransporter‐2 inhibitor classes of drugs as monotherapies and their combinations with metformin based on newer trial data and comprehensive meta‐analyses. The probabilistic RAPIDS 2.0 model was calibrated (N = 25 000) and validated (N = 263 816) using electronic medical records (EMR) data between 2008 and 2021 from a national network of US healthcare organizations. Results: The EMR‐based cohort had a mean age of 61 years at baseline, with 50% women, 70% non‐Hispanic White individuals and 20% non‐Hispanic Black individuals, and was followed for 17.5 quarters (range: 3–50). The final RAPIDS 2.0 risk engine accurately predicted the long‐term trajectories of all nine biomarkers and nine outcomes in the hold‐out validation sample. Similar accuracies in predictions were observed in each of the 14 subgroups studied. Conclusion: The RAPIDS 2.0 model demonstrated valid long‐term predictions of outcomes in individuals with T2DM in the United States as a function of dynamic sequences of treatment use patterns. This highlights its potential to project long‐term comparative effectiveness between alternative sequences of glucose‐lowering treatment uses in the United States. [ABSTRACT FROM AUTHOR]

Summary Background Methods Results Conclusions Different sedation regimens have been used to facilitate awake tracheal intubation, but the evidence has not been synthesised robustly, particularly with respect to clinically important outcomes. We conducted a systematic review and network meta‐analysis to determine the sedation techniques most likely to be associated with successful tracheal intubation, a shorter time to successful intubation and a lower risk of arterial oxygen desaturation.We searched for randomised controlled trials of patients undergoing awake tracheal intubation for any indication and reporting: overall tracheal intubation success rate; tracheal intubation time; incidence of arterial oxygen desaturation; and other related outcomes. We performed a frequentist network meta‐analysis for these outcomes if two or more sedation regimens were compared between included trials. We also performed a sensitivity analysis excluding trials with a high risk of bias.In total, 48 studies with 2837 patients comparing 33 different regimens were included. Comparing overall awake tracheal intubation success rates (38 studies, 2139 patients), there was no evidence suggesting that any individual sedation regimen was superior. Comparing times to successful tracheal intubation (1745 patients, 24 studies), any sedation strategy was superior to placebo. When we excluded trials with a high risk of bias, we found no evidence of a difference between any interventions for time to successful tracheal intubation. Thirty‐one studies (1753 patients) suggested that dexmedetomidine and magnesium sulphate were associated with a reduced risk of arterial oxygen desaturation compared with other interventions, but excluding trials with a high risk of bias suggested no relevant differences between interventions. The quality of evidence for each of our outcomes was low.To maximise effective and safe awake tracheal intubation, optimising oxygenation, topical airway anaesthesia and procedural performance may have more impact than any given sedation regimen. [ABSTRACT FROM AUTHOR]

Background Methods Results Discussion While drugs are sometimes taken during deliberate self‐harm (DSH), no study has attempted to analyze drugs in the blood of DSH patients and compare them with prescribed medications or other drugs. In this study, drugs were analyzed from the blood of DSH patients, and the detected, prescribed, and suspected drugs were documented.Patients who practiced DSH and were transferred to the emergency sites of Fukuoka University Hospital between April 2021 and September 2022 participated in the study. Psychiatrists assessed information such as the history of psychiatric treatment and recent methods of DSH, as well as prescribed drugs within 1 month of presenting to the hospital. Blood samples were analyzed using LC–MS/MS. Participants were divided into groups according to whether or not they were prescribed psychotropics within 1 month.Fifty‐five patients were enrolled in the study. Forty had been prescribed psychotropics within 1 month of hospital admission. However, non‐prescribed drugs (NPD) were detected in 42 of the 55 participants (76%). The detection of NPD was significantly high among patients with overdose of medications and OTC drugs (p = 0.036), but NPD were also detected in patients who engaged in other methods (n = 14), and in patients without prescribed medication (n = 10).This is the first study focused on the drug analysis of blood from patients engaging in DSH. Approximately 80% of the DSH patients in this study had taken NPD, revealing a large discrepancy between prescribed medications and those detected in the blood. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusions Judicious antimicrobial use is essential for the continued treatment of infections in small and mixed animal veterinary medicine. To better support Washington (WA) State veterinarians in antimicrobial stewardship, we surveyed licensed small and mixed animal veterinarians and led group conversations regarding antimicrobial prescription practices.Survey questions included demographic information, factors influencing prescription practices and clinical cases. Responses were summarised and logistic regressions were performed to identify factors associated with antibiotic treatment choices. Group conversations, led by a licensed veterinarian, focused on resource gaps for veterinarians, management of clinical scenarios and interpretation of minimum inhibitory concentrations (MICs) and breakpoints. A systematic qualitative analysis of conversation transcripts identified key themes such as common barriers to stewardship.Among 53 responses to clinical scenarios, veterinarians selected the most appropriate treatment choice, according to a veterinary microbiologist, 62% of the time. Variability was observed in culture and susceptibility practices and antibiotic choices. Survey respondents reported an influence of the client ability to medicate (92%), considerations of resistance (91%), client finances (75%) and availability of antimicrobials (75%) on their prescription decisions. There were no significant associations between opinions about contributing factors to antimicrobial resistance (AMR) or guidelines used and treatment choices in clinical scenarios. Among 15 veterinarians interviewed in group conversations, a systematic qualitative analysis of conversation transcripts revealed key themes, including reliance on human medicine as a resource and a lack of support for veterinarians in interpreting MICs and breakpoints.The variability in veterinary antibiotic treatment decisions in this study suggests a need for further dissemination of standardised antimicrobial stewardship resources for veterinarians. Client‐related challenges and the cost of culture and susceptibility are major barriers to stewardship. To address these barriers, it is necessary to provide standardised, easy‐to‐access guidance for veterinarians in interpreting MICs and breakpoints, as well as develop antimicrobial use resources for clients. [ABSTRACT FROM AUTHOR]

Here we critique recent arguments proposing to distinguish ictal from non‐ictal generalized periodic discharges (GPDs) based on etiology and stimulation response, arguing that these are unreliable. We advocate for an empirical approach to GPDs: describe objectively, interpret through medication trials, and base further treatment on response. We call for evidence‐based approaches considering meaningful clinical outcomes. [ABSTRACT FROM AUTHOR]

Key points Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol‐induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol‐induced AP. Intact guinea‐pig pancreatic ducts were pre‐treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX‐809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi‐treated guinea‐pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose‐dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol‐induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol‐induced pancreatitis. This is the first in vivo pre‐clinical evidence of Orkambi efficacy in the treatment of alcohol‐induced AP. Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3– secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol‐induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol‐induced pancreatitis by enhancing pancreatic functions or preventing recurrence. [ABSTRACT FROM AUTHOR]

Bipolar disorder is the fourth most debilitating psychiatric illness in the world regarding Disability Adjusted Life Years and manic episodes frequently lead to lengthy hospitalizations which restricts the freedom of patients. Therefore, decreasing the length of hospitalization with safer agents is of utmost importance in the treatment of manic episodes. Aripiprazole is a medication known for its efficacy in managing mania associated with bipolar disorder. Aripiprazole long‐acting injection is approved for the treatment of mania associated with bipolar disorder in adults and found efficacious as a maintenance treatment. In the treatment of schizophrenia, European Medicines Agency has approved a simplified starting strategy of aripiprazole once a month, with two 400 mg injections and a single oral 20 mg dose of aripiprazole. To the best of our knowledge, no previous study has reported the safety, tolerability, and efficacy of this regimen in adult bipolar disorder patients. We present a case series of eight patients who were admitted to the hospital in a manic episode with psychotic features. We observed that the double injection start regimen was effective in treating manic symptoms with no specific severe adverse events. We conclude from a small sample of manic patients that a double injection start regimen has good efficacy and tolerability. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions To evaluate and compare the long‐term efficacy of medical treatments for normal tension glaucoma (NTG) in controlling intraocular pressure (IOP), and establish a hierarchical ranking based on their effectiveness. ‘Long‐term’ is defined as a treatment duration of over 12 weeks in randomised controlled trials (RCTs).This systematic review and model‐based network meta‐analysis (MBNMA) collected data of 795 patients with 997 eyes from RCTs. Patients with NTG were selected based on strict inclusion/exclusion criteria, with randomsation procedures and masking as reported in the individual trials. Eight different medications were compared, including prostaglandin analogues, beta‐blockers, brimonidine, unoprostone isopropyl, brovincamine, and palmitoylethanolamide (PEA). Notably, PEA is an oral medication, while other drugs are topical agents.Primary outcome is the long‐term efficacy of IOP control across medications with different follow‐up durations. Among the eight medications, PEA demonstrates the highest efficacy (Surface under the cumulative ranking, SUCRA = 7.46%), followed by two prostaglandin analogues: travoprost (SUCRA = 6.86%) and latanoprost (SUCRA = 6.76%), then two beta‐blockers: nipradilol (SUCRA = 4.90%) and timolol (SUCRA = 4.89%). Both brimonidine and unoprostone isopropyl have SUCRA scores below 4.0%, indicating modest but limited efficacy. Brovincamine has the lowest SUCRA score (1.32%), reflecting minimal effectiveness.This study revealed PEA as a promising agent for long‐term IOP control in NTG patients, suggesting potential use as primary or adjunctive therapy. The outcomes call for PEA's consideration in clinical practice and highlight the need for further research into its long‐term efficacy and safety for NTG. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow‐up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c).We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first‐episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital‐based diagnosis and redeemed prescriptions for glucose‐lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within‐subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before.In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03–9.76] per 1000 person‐years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75–2.38). We found a dose–response association, particularly for second‐generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication.This comprehensive real‐world two‐cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES. [ABSTRACT FROM AUTHOR]

Although most drugs currently approved are meant to treat specific diseases or symptoms, it has been hypothesized that some might bear a beneficial effect on lifespan in healthy older individuals, outside of their specific disease indication. Such drugs include, among others, metformin, SGLT2 inhibitors and rapamycin. Since 2006, the UK biobank has recorded prescription medication and mortality data for over 500′000 participants, aged between 40 and 70 years old. In this work, we examined the impact of the top 406 prescribed medications on overall mortality rates within the general population of the UK. As expected, most drugs were linked to a shorter lifespan, likely due to the life‐limiting nature of the diseases they are prescribed to treat. Importantly, a few drugs were associated with increased lifespans, including notably Sildenafil, Atorvastatin, Naproxen and Estradiol. These retrospective results warrant further investigation in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case demonstrated with importance of recognizing DRESS syndrome presenting without the typical eosinophilia due to possible cross‐reactivity between amoxicillin and the well‐documented inciting medication lamotrigine. Steroid tapering is an effective treatment, but medication avoidance should be stressed to avoid symptom recurrence. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This report presents a 14‐year‐old male with seizures and facial port‐wine stains, who upon further evaluation was found to have SWS. Early diagnosis and consistent treatment of Sturge–Weber syndrome in children are essential to prevent seizures and improve quality of life. Anti‐seizure medications play a crucial role in preventing and controlling seizures. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi‐step, challenging, and time‐consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open‐source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter‐individual variability (IIV) model, the inter‐occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development. [ABSTRACT FROM AUTHOR]

Over the past decade, increasing off‐label use of quetiapine has been reported worldwide from various sources. We wanted to investigate how this is reflected in therapeutic drug monitoring (TDM) data. Requisitions for serum concentration measurements of quetiapine from a TDM service in Central Norway during 2001–2019 were obtained and analysed for age, gender, trends in quetiapine doses, serum concentrations and indicators of diagnoses. There were 19 759 requisitions from 7459 individuals. Daily doses of quetiapine decreased by 24 mg per year (95% CI: −25.61 to −21.48, p < 0.001, N = 4505). A corresponding decrease in quetiapine serum concentrations was not seen. The proportion of requisitions with diagnoses indicating reimbursable use was 13% for the whole study period. Mean daily doses were slightly higher in the reimbursable group, but declined over time in these samples, as well. To our understanding, these results signal a trend towards lower prescribed doses of quetiapine, possibly reflecting drug repurposing and/or off‐label use. The discrepancy in the decrease of doses versus serum concentrations may reflect the intake of higher doses than prescribed and/or inappropriate TDM sampling. Our findings show that TDM data have limitations when it comes to making inferences about the use of quetiapine based on serum concentrations and clinical information on the requisitions. [ABSTRACT FROM AUTHOR]

Aims: To summarize the results of clinical studies of insulin icodec, an investigational insulin analog designed for once‐weekly administration, in adults with type 1 and type 2 diabetes. Methods: Thirteen published articles describing clinical studies of insulin icodec were identified in PubMed, and data pertinent to key study outcomes were selected for inclusion in this review. Results: In insulin‐naïve and insulin‐treated individuals, icodec demonstrated efficacy in glycaemic control superior or noninferior to that of insulins glargine U100, glargine U300 and degludec. Icodec exhibited a safety profile comparable to marketed insulins, with the exception of hypoglycaemic event rates. Conclusions: As a once‐weekly alternative to daily basal insulin, icodec is expected to improve patient adherence and satisfaction, reducing the required number of injections per year from 365 to 52 and providing a dosing option potentially attractive to a wide range of insulin users. However, clinical data suggest a notable risk of hypoglycaemia with weekly icodec administration, especially in individuals with type 1 diabetes. [ABSTRACT FROM AUTHOR]

The article focuses on the environmental impact of insulin delivery methods within the UK's National Health Service (NHS) amid efforts to address the climate crisis. Topics include the carbon footprint and plastic waste associated with disposable versus reusable insulin pens, the lack of national guidelines for sustainable prescribing practices, and the need for data on the environmental effects of different insulin delivery systems to inform clinicians and patients.

Background: Essential tremor (ET) is a chronic, progressive neurological disease that affects an estimated 7 million individuals in the United States (ie, 2.2% of the entire U.S. population). Despite its high prevalence, there are a few published studies on patterns of prescription medication use among patients. Objective: The aim was to examine prescription drug medication use among ET patients. Methods: This is a cross‐sectional study of ET patients, age ≥40, with at least 1 prescription medication fill using the Optum's de‐identified Clinformatics Data Mart Database from 2018 through 2019. We examined patterns of fills of key agents used to treat ET. Results: The final sample comprised 36,839 ET patients in the United States; 89% had at least 1 prescription drug claim over a 2‐year period, indicating that 9 of 10 ET patients take a medication to treat their disease. For each of the 3 most frequently prescribed medications, only a modest fraction (1/5 to 1/4) of patients were taking that medication. Adherence to these agents was 52% to 61%. A high percentage of patients had fills for more than 1 of the main agents we studied. Conclusion: These data illustrate a need for medication in the ET population. There is only 1 FDA‐approved medication to treat ET, propranolol, and less than 25% of ET patients used this drug during our study period. At the same time, no single agent was utilized by more than one quarter of ET patients, adherence was low, and use of multiple agents was common. For such a common disease, the pharmacotherapeutic landscape is impoverished. [ABSTRACT FROM AUTHOR]

Summary: Immune thrombocytopenia (ITP) refractory to multiple therapies may require a combination of drugs targeting different mechanisms and targets. In this retrospective, multicentre, international study, we report the safety and effectiveness of avatrombopag and fostamatininb in combination administered to 18 patients with multirefractory ITP. Overall, the combination response was achieved in 15 patients (83.3%), with a median time from combination start to best response of 15 days (IQR: 8–35 days). After a median follow‐up of 256 days (IQR: 142.8–319), 5 patients relapsed (26.7%), all during tapering or stopping one drug. Adverse events were described in 6 of 18 patients (33%). [ABSTRACT FROM AUTHOR]

A wide range of particle‐based nano‐ to microsystems is currently under investigation for potential use in personalized nanomedicine. However, only a small fraction of these innovations is likely to make it to clinical use. In this concept article, we start by discussing the potential applications of inorganic nanoparticles in cancer treatment and diagnosis, and shed light on the challenges they must overcome to become clinically available. In the second part, we focus on engineered living materials, which have begun to revolutionize the way medical interventions could be performed. Finally, we share our insights and opinions to explain why, despite significant advancements in research on these technologies, their translation to clinical practice remains limited. [ABSTRACT FROM AUTHOR]

Objectives: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier‐related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. Materials and Methods: A CAL‐27‐LEC co‐culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT‐qPCR detected protein and mRNA expression under different conditions, respectively. CCK‐8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. Results: In high‐glucose co‐culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO‐1 and occludin, two tight‐junction proteins; conversely, the expression of PAR2, a high permeability‐related protein, was increased. Following linagliptin treatment, the expression levels of VEGF‐C, VEGFR‐3, and PAR2 decreased, while those of ZO‐1 and occludin increased. Considerably higher levels of LYVE‐1 expression in individuals with diabetes than in those without diabetes. Conclusions: By ameliorating the high glucose‐induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: With changing cognitive abilities, individuals with mild cognitive impairment (MCI) and dementia face challenges in successfully managing multidrug regimens. We sought to understand how individuals with MCI or dementia and their family caregivers manage multidrug regimens and better understand patient‐to‐caregiver transitions in medication management responsibilities. Methods: We conducted qualitative interviews among patient–caregiver dyads. Eligibility included: patients with a diagnosis of MCI, mild or moderate dementia, managing ≥3 chronic conditions, ≥5 prescription medications, who also had a family caregiver ≥18 years old. Semi‐structured interview guides, informed by the Medication Self‐Management model, ascertained roles and responsibilities for medication management and patient‐to‐caregiver transitions in medication responsibilities. Results: We interviewed 32 patient–caregiver dyads. Older adults and caregivers favored older adult autonomy in medication management, and individuals with MCI and mild dementia largely managed their medications independently using multiple strategies (e.g., establishing daily routines, using pillboxes). Among individuals with moderate dementia, caregivers assumed all medication‐related responsibilities except when living separately. In those scenarios, caregivers set up organizers and made reminder calls, but did not observe family members taking medications. Patient‐to‐caregiver transitions in medication responsibilities frequently occurred after caregivers observed older adults making errors with medications. As caregivers sought to assume greater responsibilities with family members' medicines, they faced multiple barriers. Most barriers were dyadic; they affected both the older adult and the caregiver and/or the relationship. Some barriers were specific to caregivers; these included caregivers' competing responsibilities or inaccurate perceptions of dementia, while other barriers were related to the healthcare system. Conclusions: To ease medication management transitions, balance must be sought between preservation of older adult autonomy and early family caregiver involvement. Clinicians should work to initiate conversations with family caregivers and individuals living with MCI or dementia about transitioning medication responsibilities as memory loss progresses, simplify regimens, and deprescribe, as appropriate. [ABSTRACT FROM AUTHOR]

High‐cost medicines (HCMs) can be clinically impactful for individual patients but are also subject to variable funding mechanisms. Public hospitals and health services are often asked to fund HCMs, but inconsistent processes frequently create large variations in care. CATAG (Council of Australian Therapeutic Advisory Groups) is the Australian peak national advisory body for the quality use of medicines in hospitals and health services, with all states and territories collaborating to support Drug and Therapeutics Committees (DTCs). CATAG has developed national Guiding Principles to assist DTCs to effectively govern HCMs. An established process for the development of CATAG Guiding Principles was undertaken to develop these Guiding Principles. This includes the formation of an Expert Advisory Group (EAG) comprising individuals with recognised expertise, development of draft principles and stakeholder consultation from within the CATAG membership and externally. All feedback was discussed, and changes were agreed upon. The final version was approved by the EAG and CATAG members. This document represents a summary of the seven Guiding Principles developed, covering the areas of governance, application and assessment, communication, training and resourcing. Although many outstanding priorities still exist, including the development of national coordination regarding HCM assessment, these Guiding Principles offer a basis to navigate this complex area. [ABSTRACT FROM AUTHOR]

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence‐based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady‐state concentration)–response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure–response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease–drug–dropout models were developed using patient‐level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure–response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure–response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13‐17 years with schizophrenia. [ABSTRACT FROM AUTHOR]

With the continuous development of genetics in healthcare, there has been a significant contribution to the development of precision medicine, which is ultimately aimed at improving the care of patients. Generally, drug treatments used in Oncology are characterized by a narrow therapeutic range and by their potential toxicity. Knowledge of pharmacogenomics and pharmacogenetics can be very useful in the area of Oncology, as they constitute additional tools that can help to individualize patients' treatment. This work includes a description of some genes that have been revealed to be useful in the field of Oncology, as they play a role in drug prescription and in the prediction of treatment response. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to analyse the initiation adherence phase to lipid‐lowering therapy for primary prevention of cardiovascular disease in a Spanish population aged 70 years or older. The secondary objective was to identify the determinants of initiation and early discontinuation. Methods: This was an observational study conducted in the CArdiovascular Risk factors for HEalth Service research (CARhES) cohort. People aged 70 and older with a first prescription of a lipid‐lowering drug and without a previous major adverse cardiovascular event (MACE) were selected (2018–2021). Data on sociodemographics, clinical conditions, drugs and use of health services were collected from clinical and administrative electronic databases. The study population was classified into: non‐initiation, early discontinuation (i.e., discontinuation after the first dispensing) and initiation with more than one dispensing. Their characteristics were compared. Determinants of initiation and early discontinuation were explored. Results: Among the 15 019 people studied, 80.2% initiated the medication, 11.2% showed an early discontinuation and 8.6% were non‐initiators. An older age or conditions such as dementia, diabetes or depression reduced the likelihood of initiation, while obesity and a high pharmacological burden increased it. People over 90 years of age or those prescribed a statin in combination were more likely to have an early discontinuation. Conclusions: Non‐initiation and early discontinuation are common among older people prescribed lipid‐lowering drugs as primary prevention of cardiovascular disease for the first time. The presence of chronic pathologies other than cardiovascular ones should be considered when assessing whether or not to prescribe these drugs in the elderly. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a complex health condition requiring medical therapy and lifestyle modifications to attain treatment targets. Previous studies have not fully explored factors associated with adherence to medication, diets and physical activity recommendations among individuals living with diabetes in rural South Africa. We examined the association between knowledge, health belief and adherence to medication, dietary, and physical activity recommendations and explored self‐reported reasons for non‐adherence. Methods: This cross‐sectional study was conducted among 399 individuals living with diabetes recruited over 12 weeks from six randomly selected primary healthcare centres in rural South Africa. Sociodemographic and clinical data were obtained by self‐report. Health beliefs, knowledge, and adherence were assessed using validated measures. Descriptive and inferential statistics were carried out. Results: The majority (81.7%) of the participants were females, with a mean age of 62 ± 11 years. Only 39% reported adhering to their prescribed medication regimen, 25% reported adhering to dietary recommendations, and 32% reported adhering to physical activity recommendations. The most cited reasons for non‐adherence were lack of access to (n = 64) and cost of drugs (n = 50), perceived high costs of healthy diets (n = 243), and lack of time (n = 181) for physical activity. Level of education was an independent predictor of medication adherence [odds ratio, OR = 2.02 (95% confidence interval, CI: 1.20–3.40)] while diabetes knowledge was independently associated with both medications [OR = 3.04 (95% CI: 1.78–45.12)]; and physical activity adherence [OR = 2.92 (95% CI: 1.04–2.96). Positive health belief was independently associated with adherence to medications [OR = 1.72 (95% CI: 1.15–2.57) and dietary recommendations [OR = 1.75 (95% CI: 1.04–2.96)]. Conclusion: Adherence to three important self‐care practices, medication, diet, and physical activity, was suboptimal in this study setting. Socioeconomic reasons and access barriers were significant drivers of non‐adherence, while increased knowledge and positive health beliefs were potential facilitators. Efforts to improve medication adherence and foster engagement in healthy lifestyle behaviours must consider patients' knowledge and health beliefs. Primary healthcare providers should create awareness on the importance of adherence on health outcomes for people with diabetes. Likewise, efforts to increase the availability and affordability of medications for socioeconomically disadvantaged populations should be prioritised by the key health stakeholders. [ABSTRACT FROM AUTHOR]

Rationale: In the Collaborative Network To Take Responsibility for Oral Anticancer Therapy (CONTACT) project, an evidence‐based and patient‐centred care(PCC) pathway was implemented in 12 oncology departments in Flanders. The care pathway was developed in cocreation by an interdisciplinary project team, and tailored to the local hospital context. Aims and Objectives: In this study, the impact of the care pathways on quality of PCC and other patient outcomes was investigated. Method: A pre−posttest study was performed in nine of the participating oncology departments. The primary outcome was quality of PCC. Furthermore, level of patient self‐management, medication adherence, satisfaction with information about the oral anticancer drug and quality of life were measured as secondary outcomes. Linear mixed models were used to investigate differences in outcomes between the pre‐ and posttest group. Results: Quality of PCC, as well as all secondary outcomes improved after implementation of the care pathway. However, the changes in pre‐ and posttest scores were not significant. The overall quality of PCC increased from 3.72 to 3.88, measured on a five‐point Likert scale (p = 0.124). Conclusion: This study showed small, however, no significant improvements in the quality of PCC and other patient outcomes. The lack of significant changes can be attributed to the complexity of the care pathway development, poor or unstable implementation of the care pathway and limited changes in follow‐up care. More insight in the actual implementation of the care pathway and potential contextual factors influencing its effect is needed to help understand the outcomes of this pre−posttest study. [ABSTRACT FROM AUTHOR]

A systematic review and meta‐analysis encompassing 79 studies has found that around one‐third of patients who discontinue antidepressant medication will experience adverse symptoms, but only around 1 in 30 will experience severe discontinuation symptoms. An analysis of individual antidepressants found that imipramine, desvenlafaxine, and venlafaxine were associated with the highest incidence of discontinuation symptoms. Results were published online June 5, 2024, in Lancet Psychiatry. [ABSTRACT FROM AUTHOR]

Drug checking is a harm reduction measure that provides people with the opportunity to confirm the identity and purity of substances before consumption. The CanTEST Health and Drug Checking Service is Australia's first fixed‐site drug checking service, where clients can learn about the contents of the samples they provide while receiving tailored harm reduction and health advice. Three samples were recently presented to the service with the expectation of 4‐fluoromethylphenidate (4F‐MPH) 1, methoxetamine (MXE) 2 and 3‐methylmethcathinone (3‐MMC) 3. The identity of all three samples did not meet these expectations and remained unknown on‐site, as no high confidence identifications were obtained. However, further analysis by nuclear magnetic resonance spectroscopy, high resolution gas chromatography‐electron ionisation‐mass spectrometry and liquid chromatography‐electrospray ionisation‐mass spectrometry at the nearby Australian National University allowed for the structure elucidation of the three samples as 4‐fluoro‐α‐pyrrolidinoisohexanophenone (4F‐α‐PiHP) 4, 1‐(4‐fluorobenzyl)‐4‐methylpiperazine (4F‐MBZP) 5 and N‐propyl‐1,2‐diphenylethylamine (propylphenidine) 6, respectively. Given all three samples were not of the expected identity and have not yet been described as new psychoactive substances in the literature, this study presents a full characterisation of each compound. As exemplified by this rapid identification of three unexpected new psychoactive substances, drug checking can be used as an effective method to monitor the unregulated drug market. [ABSTRACT FROM AUTHOR]

The impact of intoxicating substances both licit and illicit has been integral to expressions of colonial power and the control of colonised populations, including in Caribbean societies. Historically, licensing laws and carceral institutions were used to discipline workers, and the ongoing criminalisation of certain drugs illustrates the transhistorical legacies that continue to haunt former British colonies like Guyana. Focusing on prisons and prisoners to explore the histories and lingering legacies of colonial drug policies in the country, despite a much‐changed international context, this article documents experiences of, and approaches to, the management and prohibition of psychoactive substances. It reveals connections and continuities between substance use, enslavement, labour, and incarceration, and their relationship both to what we conceptualise as ‘the colonial imaginary’ and ‘booty capitalism’ of the modern age. The article will show how now and in the past, the colonisers partook in extractive booty capitalism (Weber, 1930), while in order to survive, the colonised partook in booty capitalism of the streets (Wacquant, 2003). [ABSTRACT FROM AUTHOR]

This study aims to describe the circumstances under which women obtained abortions in two sites, explore more nuanced approaches to classify abortion safety and examine the relationship between safety and self‐reported health outcomes. We analyze data on the most recent abortion or only abortion reported by 551 women in Nairobi slums and 479 women in rural Kaya ages 15–49 years within the three years preceding the study, recruited via respondent‐driven sampling. Using the most liberal safety classification, there were very few safe abortions (8 percent in Nairobi and 5 percent in Burkina Faso). A significant proportion of women reported using unidentified pills which we hypothesize may be medication abortion. Although a smaller proportion of women with safe abortions reported side effects, more of them reported side effects suggestive of infections and sought care for their symptoms. It is important that we explore and move towards more nuanced global safety classifications that more accurately reflect the risk associated with different methods and can capture women's access to comprehensive abortion care and its impact on their health. [ABSTRACT FROM AUTHOR]

The latest country‐specific regulatory guidance for assessing effectiveness of risk minimization measures (RMM) strategies was identified across five continents—Africa (Egypt, South Africa), Asia (Australia, China, Japan, South Korea, Singapore), Europe (EU‐27, United Kingdom), North America (Unites States, Canada) and South America (Brazil)—and compared to the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies (RIMES) checklist, developed to assess the quality of effectiveness evaluations and endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). RIMES checklist items address study hypothesis, participants, measures, statistical analysis and results. European Medical Agency (EMA) and Food and Drug Administration (FDA) guidance only partially aligned with RIMES, primarily for measures and results. In the absence of country‐specific guidance, most countries recommended following EMA or FDA guidelines; Japan and South Africa mentioned the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E2E) guideline; Brazil and China had no guidance/recommendations. Worldwide, there was a lack of RMM‐specific guidance and, when guidance existed, they were not harmonized, and alignment with the RIMES checklist was limited. [ABSTRACT FROM AUTHOR]

Spectrum‐based topological indices (eigenvalue‐based topological indices), a valuable tool for analyzing molecular structure. These topological indices are metrics that reflect the inherent characteristics of chemical substances, were employed in conjunction with quantitative structure‐property relationship (QSPR) to investigate nonsteroidal anti‐inflammatory drugs (NSAIDs) which are used toalleviate or eliminate pain sensations in affected areas. We have to use mathematica to compute various eigenvalue‐based indices and utilized statistical software to identify correlations between these indices and key physical properties of NSAIDs. The analysis revealed that specific indices, including EFZS$$ {E}_{FZS} $$ index, ρFZS$$ {\rho}_{FZS} $$ index, EISIS$$ {E}_{ISIS} $$ index, and EABCS$$ {E}_{ABCS} $$ index exhibited strong associations with properties like complexity and refractivity, boiling point, polarity, and molar weight, respectively. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Potentially inappropriate medications (PIMs) are medications whereby the harms may outweigh the benefits for a given individual. Although overprescribed to older adults, their direct costs on the healthcare system are poorly described.This was a cross‐sectional study of the cost of PIMs for Canadians aged 65 and older, using adapted criteria from the American Geriatrics Society. We examined prescription claims information from the National Prescription Drug Utilization Information System in 2021 and compared these with 2013. The overall levels of inflation‐adjusted total annual expenditure on PIMs, average cost per quarterly exposure, and average quarterly exposures to PIMs were calculated in CAD$.Exposure to most categories of PIMs decreased, aside from gabapentinoids, proton pump inhibitors, and antipsychotics, all of which increased. Canadians spent $1 billion on PIMs in 2021, a 33.6% reduction compared with 2013 ($1.5 billion). In 2021, the largest annual expenditures were on proton pump inhibitors ($211 million) and gabapentinoids ($126 million). The quarterly amount spent on PIMs per person exposed decreased from $95 to $57. In terms of mean cost per person, opioids and antipsychotics were highest ($138 and $118 per exposure). Some cost savings may have occurred secondary to an observed decline of 16.4% in the quarterly rate of exposure to PIMs (from 7301 per 10,000 in 2013 to 6106 per 10,000 in 2021).While expenditures on PIMs have declined in Canada, the overall cost remains high. Prescribing of some seriously harmful classes of PIMs has increased and so directed, scalable interventions are needed. [ABSTRACT FROM AUTHOR]

The first total syntheses of corallocins B and C are described herein. The Suzuki–Miyaura coupling was key to completion. Because these two natural products have been reported to induce neurotrophin expression in human astrocytes, they are expected to serve as new drug leads for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Key Clinical Message: In patients with anomalous origin of the left main coronary artery, accurate classification is essential for effective management. Despite surgical refusal, successful stenting and medication can lead to favorable outcomes. Regular monitoring ensures ongoing cardiac health. Coronary artery anomalies, including anomalous origin of the left main coronary artery from the right sinus of Valsalva, are rare occurrences with varying clinical significance. Accurate classification of these anomalies is crucial for determining their implications and guiding management. A 50‐year‐old man presented with chest pain and was diagnosed with an anomalous origin of the left main coronary artery. Despite refusing surgery, successful stenting and medication led to a favorable outcome. Regular monitoring is scheduled. Accurate classification of coronary anomalies, such as the left main coronary artery anomaly described, is vital for effective management. Even when surgical intervention is declined, alternative treatments, such as stenting, can be successful. Regular monitoring ensures ongoing cardiac health. [ABSTRACT FROM AUTHOR]

The motor impairments experienced by people with Parkinson's disease (PD) are exacerbated during memory‐guided movements. Despite this, the effect of antiparkinson medication on memory‐guided movements has not been elucidated. We evaluated the effect of antiparkinson medication on motor control during a memory‐guided reaching task with short and long retention delays in participants with PD and compared performance to age‐matched healthy control (HC) participants. Thirty‐two participants with PD completed the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS III) and performed a memory‐guided reaching task with two retention delays (0.5 s and 5 s) while on and off medication. Thirteen HC participants completed the MDS‐UPDRS III and performed the memory‐guided reaching task. In the task, medication increased movement velocity, decreased movement time, and decreased reaction time toward what was seen in the HC. However, movement amplitude and reaching error were unaffected by medication. Shorter retention delays increased movement velocity and amplitude, decreased movement time, and decreased error, but increased reaction times in the participants with PD and HC. Together, these results imply that antiparkinson medication is more effective at altering the neurophysiological mechanisms controlling movement velocity and reaction time compared with other aspects of movement control. [ABSTRACT FROM AUTHOR]

The present article discloses an improved, efficient, and simple resolution methodology for the preparation of (S)‐benoxaprofen which is a nonsteroidal anti‐inflammatory drug (NSAID). The resolution of racemic benoxaprofen uses an easily available, efficient, recoverable, and cost‐effective chiral reagent, namely, (1R,2S)‐(+)‐cis‐1‐amino‐2‐indanol. This novel resolution process is having a very high purity of (S)‐benoxaprofen, greater than 99%, substantially free from (R)‐benoxaprofen (less than 1%). [ABSTRACT FROM AUTHOR]

The understanding of schizophrenia has remarkably expanded over the past few decades, moving beyond the dopamine hypothesis to encompass neurotransmitter interplays, structural brain changes and genetic and environmental determinants. This has led to innovations in therapeutic interventions that offer improved outcomes. This paper explores past and current treatments available for schizophrenia, the latest pharmacological advances and the significance of psychotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Background and aims: Ukraine's Ministry of Health released urgent COVID‐19 guidelines, allowing for early implementation of take‐home dosing (THD) for opioid agonist therapies (OAT) such as methadone. Enrollment in OAT and retention in the program are the most effective HIV prevention strategies for people who inject drugs (PWID). This study aimed to evaluate the impact of Ukraine's COVID‐19 emergency guidance on OAT treatment enrollment, retention on treatment and mortality. Design and setting: Using Ukraine's national OAT registry for 252 governmental clinics across 25 regions, we conducted a 12‐month comparative prospective cohort survival analysis. This study compared newly enrolled methadone patients within the initial 6 months following the COVID‐19 guidance (COVID) with patients from the preceding year (pre‐COVID) in a country with high adult HIV prevalence (1.2%) that is concentrated in PWID. Participants: In the nation‐wide sample of newly enrolled PWID in Ukraine, comprising 2798 individuals, 1423 were in the COVID cohort and 1375 were in the pre‐COVID cohort. The majority were male (86.7%), with an average age of 39.3 years. Measurements: Primary outcomes were average monthly enrollment per cohort, treatment retention and mortality, with internal time‐dependent predictors, including THD and optimal (> 85 mg) methadone dosing. Results: Relative to the pre‐COVID period, the monthly average patient enrollment was statistically significantly higher during the COVID period (283.7 versus 236.0; P < 0.0001), where patients were more likely to transition to THD and achieve optimal dosing earlier. Significant differences were observed in the proportions of person‐months on THD (41 versus 13%, P < 0.0001) and optimal dosing (38 versus 31%, P < 0.0001) between the COVID and pre‐COVID cohorts. Predictors of treatment retention, expressed as adjusted hazard ratios (aHR), included early THD [aHR = 1.90, 95% confidence interval (CI) = 1.47–2.45], early optimal dosing (aHR = 1.71, 95% CI = 1.37–2.13) and prior methadone treatment (aHR = 1.39, 95% CI = 1.15–1.68). These factors persisted, respectively, in the pre‐COVID (aHR = 2.28, 95% CI = 1.41–3.70; aHR = 1.84, 95% CI = 1.32–2.56; and aHR = 1.36, 95% CI = 1.06–1.74) and COVID (aHR = 1.91, 95% CI = 1.40–2.59; aHR = 1.61, 95% CI = 1.20–2.16; and aHR = 1.49, 95% CI = 1.08–1.94) cohorts. Survival did not differ significantly between the two prospective cohorts. Conclusion: Ukraine's prompt adoption of early take‐home dosing for opioid agonist therapies, such as methadone, following the emergency COVID‐19 guidance appears to have increased enrollment into methadone and improved treatment retention for people who inject drugs without adverse effects on patient survival. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the surgical success and efficacy of XEN45 implantation (XEN45 μm, AbbVie Inc., USA) with and without combined cataract surgery up to the first 5 years. Methods: In a prospective observational monocentric trial, 192 eyes of 157 patients with open‐angle glaucoma received either XEN45 implants only (solo surgery group) or combined surgery/cataract surgeries (combined surgery group). Surgical success (qualified and full success; IOP‐limit: ≤12, 15, 18, 21 mmHg), time to secondary IOP‐lowering procedure, IOP and number of IOP‐lowering medications were analysed for 1, 2, 3, 4 and 5 years. Results: Compared to baseline, IOP (24.1 ± 8.1 to 12.6 ± 2.8 mmHg, −48%, p < 0.001) and the number of IOP‐lowering medications (3.0 ± 1.0 to 1.5 ± 1.2, −50%, p < 0.001) decreased significantly at 5 years. Although no differences between IOP and the number of IOP‐lowering medication courses between the groups were detected at 5 years (p > 0.11), the combined procedure (63%, 37%) showed better success rates compared to the solo procedure (36%, 13%) in the definition IOP ≤18 and ≤12 mmHg (p = 0.035, 0.028). Solo XEN45 procedures had a higher rate of secondary IOP‐lowering procedures compared to combined XEN45 cataract procedures (hazard ratio: 2.02, 95%CI: 1.03–3.97, p = 0.04). Twenty per cent of the eyes, including both procedures, required a secondary IOP‐lowering procedure within 5 years. Conclusions: The XEN45 implant is effective in lowering IOP and the number of IOP‐lowering medications in patients with open‐angle glaucoma in the mid‐term. Comparing XEN45 implant results with the results of trabeculectomy available in current literature, we speculate that there might be a higher surgical success rate without medications in favour of trabeculectomy. [ABSTRACT FROM AUTHOR]

Aims: To estimate the changes in intraocular pressure (IOP) during the first 24 h after transscleral cyclophotocoagulation (TCP). Methods: A prospective single‐centre study, where patients with glaucoma destined for treatment with TCP were asked for participation. The IOP was measured prior to TCP and at 1, 2, 4, 6 and 24 h post‐TCP. An IOP spike was defined as an elevation of IOP of ≥5 mmHg compared with baseline. The visual acuity (VA) was examined at baseline and after 24 h. Results: The mean IOP prior to TCP in 58 eyes of 58 patients was 26.2 (±8.9 SD) mmHg. Twenty‐three eyes (40%) experienced an IOP spike at some examination timepoint during the first 24 h. The mean value of the IOP spike was 12.1 (±6.9) mmHg. Fifty‐six per cent of the eyes with pseudoexfoliation glaucoma (PEXG) experienced an IOP spike, and 16% had an IOP spike ≥20 mmHg. The IOP was significantly reduced at the 24 h examination by 8.1 (±7.8) mmHg (n = 58). The VA 24 h after TCP was unchanged compared with baseline. Conclusion: Clinically significant IOP spikes were common in the first 24 h post‐TCP. Almost one in five eyes had an increase of 10 mmHg and in almost one in 10 eyes, the IOP increase was 20 mmHg or higher. Eyes with PEXG had a higher occurrence of IOP spikes and displayed a greater magnitude of IOP elevation. Prophylactic post‐operative IOP‐lowering medication should be considered to prevent further glaucoma damage. [ABSTRACT FROM AUTHOR]