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Trypanosoma cruzi is the parasite that causes the chronic malady known as Chagas disease (CD). Only nifurtimox and benznidazole are currently approved to treat CD in acute and chronic phases. To minimize the danger of disease transmission and as a therapy, new compounds that are safer and more effective are required. It has been demonstrated that Amaryllidaceae plants suppress the growth of T. cruzi - the causative agent of CD. However, little research has been done on their potential protein targets in the parasite. In this study, an in-silico approach was used to investigate the interactions of the Amaryllidaceae alkaloids with trans-sialidase, a confirmed protein target of T. cruzi . The nature and efficiency of the main binding modes of the alkaloids were investigated by molecular docking. Trans-sialidase active site residues were bound by the alkaloids with binding energies varying from -8.9 to -6.9 kcal/mol. From the molecular docking investigation, all the alkaloids had strong interactions with the crucial amino acid residues (Glu230, Tyr342, and Asp59) required for trans-sialidase catalysis. Montanine was the most stable compound throughout the molecular dynamics simulation and had a favorable docking binding energy (-8.9 kcal/mol). The binding free energy (MM-GBSA) of the montanine complex was -14.6 kcal/mol. The pharmacokinetic properties investigated demonstrated that all the evaluated compounds exhibit suitable oral administration requirements. Overall, this in silico study suggests that the Amaryllidaceae alkaloids could potentially act as inhibitors of trans-sialidase.Communicated by Ramaswamy H. Sarma.

Importance: Antipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia., Objective: To estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia., Design, Setting, and Participants: This cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023., Exposures: Use of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (<0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to <1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high., Main Outcomes and Measures: The primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference., Results: The study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P < .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P < .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P < .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk., Conclusions and Relevance: Results of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.

Biofilm formation by Staphylococcus aureus is a major challenge in clinical settings due to its role in persistent infections. The AgrA protein, a key regulator in biofilm development, is a promising target for therapeutic intervention. This study investigates the antibiofilm potential of halogenated phenazine compounds by targeting AgrA and explores their molecular interactions to provide insights for drug development. We employed molecular docking, molecular dynamics simulations, and computational mutagenesis to evaluate the binding of halogenated phenazine compounds (C1 to C7, HP, and HP-14) to AgrA. Binding free energy analysis was performed to assess the affinity of these compounds for the AgrA-DNA complex. Additionally, the impact of these compounds on AgrA's structural conformation and salt bridge interactions was examined. The binding-free energy analysis revealed that all compounds enhance binding affinity compared to the Apo form of AgrA, which has a Δ G bind of -80.75 kcal/mol. The strongest binding affinities were observed with compounds C7 (-113.84 kcal/mol), HP-14 (-115.23 kcal/mol), and HP (-112.28 kcal/mol), highlighting their effectiveness. Molecular dynamics simulations demonstrated that these compounds bind at the hydrophobic cleft of AgrA, disrupting essential salt bridge interactions between His174-Glu163 and His174-Glu226. This disruption led to structural conformational changes and reduced DNA binding affinity, aligning with experimental findings on biofilm inhibition. The halogenated phenazine compounds effectively inhibit biofilm formation by targeting AgrA, disrupting its DNA-binding function. The study supports the potential of these compounds as antibiofilm agents and provides a foundation for rational drug design targeting the AgrA-DNA interaction. Future research should focus on further optimizing these lead compounds and exploring additional active sites on AgrA to develop novel treatments for biofilm-associated infections., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Prince Manu et al.)

The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR choking ). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR choking was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages., Competing Interests: Declaration of competing interest AT, HT, and JT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. JT has been a consultant to HLS Therapeutics, Janssen, Orion and WebMed Global and received lecture fees from Janssen and Otsuka. HT has received lecture fees Gedeon Richter, Janssen, Lundbeck and Otsuka. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. AH: editor of the German (DGPPN) schizophrenia treatment guidelines, first author of the WFSBP schizophrenia treatment guidelines; on advisory boards of and speaker fees from AbbVie (speaker fees only), Advanz (speaker fees only), Janssen-Cilag, Lundbeck, Recordati, Rovi, and Otsuka. ML has received honoraria from Janssen, Janssen-Cilag, Lundbeck, Otsuka, Recordati and Sunovion. The other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

This paper aims to identify construction robotics' potential to reduce airborne virus transmission, review factors limiting the technology's adoption and highlight how similar barriers have been addressed in other industries. Construction robotics were identified and classified into 8 themes with 25 categories through a critical literature review. We undertook interviews with 4 construction contractors and conducted an online questionnaire with 32 experts from the UK (n=14) and China (n=18) who reviewed the robotic systems we identified and ranked the potential ability of each to reduce airborne virus transmission within the construction industry. The results of this study showed that construction robotics is not only beneficial to reduce airborne virus transmission, but may also help to reduce the spread of future contagious viruses. We found no significant difference (P>0.05) in practical usage and implementation barriers to construction robotics between the UK and China. Cost, training and limited awareness of robotic technologies were the main implementation barriers we identified in both countries. Both the UK and China may need to adopt strategies such as providing more financial support to small construction industries and skill training which are utilised successfully in other sectors to realise the potential of construction robotic technologies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Cholera is a potentially lethal diarrheal disease produced by Vibrio cholerae serotypes O1 El Tor and O139. Known since antiquity, the condition causes epidemics in many areas, particularly in Asia, Africa, and South America. Left untreated, the mortality may reach 50%. The crucial therapeutic intervention is intravenous or oral rehydration and correction of acidosis, dyselectrolytemia, and renal impairment. Antibiotic use represents the main pharmacological intervention., Study Question: What are the milestones of the antibiotics use recommended by experts for the pharmacological management of cholera in the past century?, Study Design: To determine the changes in the experts' approach to the management of cholera and particularly the use of antibiotics as presented in a widely used textbook in the United States., Data Sources: The chapters describing the management of cholera in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Sulfonamides were recommended in 1947, followed by the introduction of tetracyclines, chloramphenicol, and furazolidone in 1955. The options were restricted in 2000 to doxycycline. In the past decade, patients infected with strains known to have a degree a resistance to tetracyclines were treated with azithromycin or ciprofloxacin. Antibiotic use decreases the volume of stool and the duration of diarrhea but has not been considered lifesaving. Drugs with antimotility, antiemetic, or antisecretory properties are not useful., Conclusions: The utility of antibiotic use in cholera has been endorsed by experts, but only as an adjunct to rapid and complete fluid and electrolyte replacement., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Complete bed rest has been a component of the management of acute myocardial infarction, which was first diagnosed in the United States in 1912. The prescribed duration of bed rest has been progressively shortened in the past century., Study Question: What are the milestones of the changes in the expert approach to the duration of bed rest for patients with acute myocardial infarction?, Study Design: To determine the changes in the experts' approach to the duration of bed rest after a diagnosis of acute myocardial infarction, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of myocardial infarction in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Complete rest for 2-6 weeks was recommended by the Cecil's experts from 1927 through 1967. The practice was questioned since the early 1950s, but the recommended duration of bed rest was decreased to 3-4 days only in 1971, after most US hospitals opened coronary care units. The required time in bed was further decreased to 1 day in 1992 and to 12 hours in 2004. By 2007, the literature contained data from 15 trials with a total of 1471 patients kept in bed "longer" and 1487 patients who had been prescribed bed rest for "shorter" periods after an acute uncomplicate myocardial infarction and there was no difference between the groups regarding reinfarction, cardiac mortality, or all-cause mortality., Conclusions: The duration of bed rest after acute myocardial infarction recommended by experts in the United States has had a downward trend with an inflection point in the early 1970s. The change reflected experts' opinion, rather than evidence produced by randomized controlled trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The Safety Risk Library [1] is a structured database [2] that integrates knowledge drawn from multiple sources to address the problem of information disaggregation in the construction industry. This knowledge base maps construction safety risk scenarios to treatment suggestions that help designers implement the concept of prevention through design. In the context of the Safety Risk Library, risk scenarios are characterised by six data categories based on a formalised ontology [3]. To build the first iteration of the Safety Risk Library, nine different risk scenarios were identified and mapped to relevant risk treatments in focus groups. Subsequently, the Safety Risk Library was pilot tested in six construction projects, and user feedback and input were used to expand the list of risk scenarios and treatment prompts. Additionally, public press releases reporting construction accidents were analysed to identify and characterise risk scenarios, which were then mapped to appropriate treatment suggestions and included in the Safety Risk Library. This dataset can assist construction industry stakeholders in identifying, characterising, communicating and mitigating safety risks in construction projects. It can also be integrated into building information modelling environments to assist designers to implement prevention through design., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

Introduction: The construction industry employs about 7% of global manpower and contributes about 6% to the global economy. However, statistics have depicted that the construction industry contributes significantly to workplace fatalities and injuries despite multiple interventions (including technological applications) implemented by governments and construction companies. Recently, immersive technologies as part of a suite of industry 4.0 technologies, have also strongly emerged as a viable pathway to help address poor construction occupational safety and health (OSH) performance., Method: With the aim of gaining a broad view of different construction OSH issues addressed using immersive technologies, a review on the application of immersive technologies for construction OSH management is conducted using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) approach and bibliometric analysis of literature. This resulted in the evaluation of 117 relevant papers collected from three online databases (Scopus, Web of Science, and Engineering Village)., Results: The review revealed that literature have focused on the application of various immersive technologies for hazard identification and visualization, safety training, design for safety, risk perception, and assessment in various construction works. The review identified several limitations regarding the use of immersive technologies, which include the low level of adoption of the developed immersive technologies for OSH management by the construction industry, very limited research on the application of immersive technologies for health hazards, and limited focus on the comparison of the effectiveness of various immersive technologies for construction OSH management., Conclusions and Practical Applications: For future research, it is recommended to identify possible reasons for the low transition level from research to industry practice and proffer solutions to the identified issues. Another recommendation is the study of the effectiveness of the use of immersive technologies for addressing health hazards in comparison to the conventional methods., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Advances in drug therapy for pulmonary tuberculosis have had an extraordinary impact on the incidence of tuberculosis in the United States in the past century, which has decreased from 113/100,000 persons in 1920 to 2.2/100,000 in 2020. Modern treatments have contributed to a remarkable decrease in hospitalizations and mortality and have had a significant impact on the duration and severity of illness, quality of life, and work potential of affected persons., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of pulmonary tuberculosis in the past century?, Study Design: To determine the changes in the experts' approach to the management of pulmonary tuberculosis, as presented in a widely used textbook in the United States., Data Sources: The chapters describing the management of pulmonary tuberculosis in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: In the preantibiotic era (1927-1943), the Cecil authors emphasized rest, good food, and fresh air as the treatment pillars for pulmonary tuberculosis. The modern era (1947-1971) recorded the discovery of all the drugs that are still used for the initial treatment, in the following order: streptomycin, para-aminosalicylic acid, isoniazid, pyrazinamide, ethambutol, cycloserine, kanamycin, ethionamide, capreomycin, and rifampin. In the postmodern era (1975-2020), therapeutic advances continued with trials of many drug combinations aimed at ameliorating the duration of treatment, drug resistance adverse effects, and poor the recent addition of fluoroquinolones, bedaquiline, and clofazimine., Conclusions: The pharmacological management of tuberculosis has remained archaic until the middle of the 20th century. Fundamental progress occurred in a very short period (1947-1971) and was because of the recognition of the antituberculous effect of many antibiotics and chemotherapy agents. The challenges created by mycobacterial infections resistant to multiple drugs remain and have prompted the addition of new drugs in the past decade., Competing Interests: The authors have no conflicts of interest to declare. P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining author has no conflict of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Patients with severe mental illness (SMI) have a high risk for diabetes, dyslipidemia, and other components of metabolic syndrome. Patients with these metabolic comorbidities and cardiac risk factors should receive not only antipsychotics but also medications aiming to reduce cardiovascular risk. Therefore, many patients may be exposed to clinically relevant drug-drug interactions., Areas Covered: This narrative review summarizes data regarding the known or potential drug-drug interactions between antipsychotics and medications treating metabolic syndrome components, except for hypertension, which has been summarized elsewhere. A literature search in PubMed and Scopus up to 7/31/2021 was performed regarding interactions between antipsychotics and drugs used to treat metabolic syndrome components, aiming to inform clinicians' choice of medication for patients with SMI and cardiometabolic risk factors in need of pharmacologic interventions., Expert Opinion: The cytochrome P450 system and, to a lesser extent, the P-glycoprotein transporter is involved in the pharmacokinetic interactions between antipsychotics and some statins or saxagliptin. Regarding pharmacodynamic interactions, the available information is based mostly on small studies, and for newer classes, like PCSK9 inhibitors or SGLT2 inhibitors, data are still lacking. However, there is sufficient information to guide clinicians in the process of selecting safer antipsychotic-cardiometabolic risk reduction drug combinations.

Background: Advances in drug therapy for inflammatory bowel disease (IBD) [Crohn disease and ulcerative colitis (UC)] have contributed to a decrease in the severity of these chronic and disabling conditions., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of IBD in the past century?, Study Design: To determine the changes in the experts' approach to the management of regional ileitis and UC, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of IBD in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: No specific interventions existed from 1927 through 1942. The pharmacological management of IBD has had 3 slightly overlapping eras starting in 1943. During the first period (1943-1951), the medical management relied on antibiotics, primarily sulfonamides and chloramphenicol. In the second (1955-75), experts recommended the use of adrenocorticotropic hormone or corticosteroids and 5-aminosalicylate. In the third era, which commenced in 1979 and is continuing to date, the pharmacological interventions have been expanded and refined to include 5 main drug classes, 5-aminosalicylates (sulfasalazine, mesalamine, and olsalazine), corticosteroids (prednisone and budesonide), immunomodulators (azathioprine, 6-mercaptopurine, cyclosporine, and tofacitinib), biologics (infliximab adalimumab certolizumab pegol, and natalizumab), and antibiotics (metronidazole and ciprofloxacin). A consensus exists that the monoclonal antibodies again tumor necrosis factor alpha are cost-effective for induction and maintenance of clinical remission in both UC (golimumab) and Crohn disease (certolizumab pegol). The newer agents ustekinumab (a monoclonal antibody to the interleukin p40 subunit) and vedolizumab (a monoclonal antibody to the homing receptor integrin complex) have also performed well., Conclusions: The pharmacological management of IBD has been the focus of intense research and development in the past 60 years. The pillars of drug treatment have been 5-aminosalicylates and corticosteroids. Recent pharmacological innovations (immunomodulators and biologicals) constitute an encouraging paradigm shift in the treatment of UC and Crohn disease., Competing Interests: P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The author has no conflicts of interest to declare.

Background: Innovations in drug therapy for obesity have had a limited impact on the body mass index, prevalence of medical complications, quality of life, and work potential of a substantial majority of affected persons., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of obesity in the past century?, Study Design: To determine the changes in the experts' approach to the management of obesity, as presented in a widely used textbook in the United States., Data Sources: The primary sources were chapters describing the management of obesity in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. Secondary sources were publications retrieved from Medline that clarified technical issues related to the development, regulatory approval, and use of the drugs mentioned in the Cecil Textbook of Medicine., Results: Pharmacological interventions aimed at increasing caloric expenditures through thermogenesis were recommended from 1927 through 1943. Thyroid extracts were prescribed even in the absence of demonstrated hypothyroidism or decreased basal metabolic rate throughout this period. Dinitrophenol was mentioned in 1937, but was banned soon thereafter. Appetite suppression with amphetamine was considered useful from 1943 through 1988, after which the drug was replaced with other centrally acting molecules, such as fenfluramine in 1988, sibutramine in 2000, and rimonabant in 2008, which were in turn withdrawn because of major adverse effects. In the past decade, obesity has been treated with the appetite suppressants phentermine-topiramate, bupropion-naltrexone, lorcaserin, and liraglutide, and with orlistat, a drug promoting fat malabsorption. The change in weight produced by these drugs is generally modest and transient., Conclusions: The pharmacological management of obesity has remained frustratingly inefficient. The reasons for the relative lack of success may reside in the ever-growing access to dense, palatable, and relatively inexpensive food, coupled with the decrease in energy expenditure created by a sedentary lifestyle., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Older adults with serious mental illness have a high prevalence of coronary artery disease and of its major risk factors, that is, arterial hypertension, dyslipidemia, and diabetes mellitus. The prevalence and clinical control of these conditions have not been compared in geropsychiatric inpatients with dementia versus those with mood or psychotic disorders., Study Question: What is the prevalence and acuity of coronary artery disease, arterial hypertension, dyslipidemia, and diabetes mellitus among patients with dementia, mood, and psychotic disorders admitted for geropsychiatric care?, Study Design: Patients 65 years of age or older were identified in a cohort of 1000 patients consecutively admitted over a 3-year period to the geropsychiatric unit of a 200-bed mental health hospital in suburban New York. All patients had a structured clinical and laboratory evaluation within 72 hours of admission., Data Sources: Primary psychiatric diagnoses, medical history, the frequency of poorly controlled cardiometabolic comorbidity requiring an immediate change in the management plan, and the Charlson Comorbidity Index (CCI)., Results: The 65 years and older patient sample (N = 689) had a mean age of 74.8 years, and 58.8% of the subjects were women. The 205 patients with dementia were older ( P < 0.001) than the 337 patients with mood disorders and the 147 patients with psychotic syndromes. The numbers of medical conditions and the CCI after exclusion of dementia were similar in patients with dementia versus patients without dementia. A substantial number of patients had poorly controlled arterial hypertension (51.2%), dyslipidemia (25.4%), diabetes (24.2%), and coronary artery disease (15.4%). Patients with dementia had a lower prevalence of poorly controlled dyslipidemia ( P = 0.0006), diabetes ( P = 0.0089), and coronary artery disease ( P = 0.045)., Conclusions: Compared with mood or psychotic disorder, a diagnosis of dementia with behavioral disturbance seemed to be associated with better control of coronary artery disease, dyslipidemia, and diabetes mellitus in geropsychiatric inpatients., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for primary (or essential) arterial hypertension have contributed to a significant decrease in the frequency and severity of strokes, coronary artery disease and heart failure, and chronic renal insufficiency., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of arterial hypertension in the past century?, Study Design: To determine the changes in the experts' approach to the management of arterial hypertension, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of arterial hypertension in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: The pharmacological management of arterial hypertension has had 3 overlapping eras in the timeframe subject to our investigation. In the empiric era (1927-1947), experts were recommending nonspecific interventions for sedation. The premodern era (1955-1963) relied on ganglion blockers, sympathetic blockers, and direct vasodilators. The modern era (1967-2020), which includes drugs used in current clinical practice, saw the introduction of diuretics (1967), beta-blockers (1971), alpha-blockers (1982), calcium channel blockers (1985), angiotensin-converting enzyme inhibitors (1985), angiotensin receptor blockers (2000), and direct renin inhibitors (2008)., Conclusions: The pharmacological management of arterial hypertension has been the focus of intense and successful research and development in the second half of the 20th century., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Antipsychotics represent the mainstay in the treatment of patients diagnosed with major psychiatric disorders. Hypertension, among other components of metabolic syndrome, is a common finding in these patients. For their psychiatric and physical morbidity, many patients receive polypharmacy, exposing them to the risk of clinically relevant drug-drug interactions., Areas Covered: This review summarizes the knowledge regarding the known or potential drug-drug interactions between antipsychotics and the main drug classes used in the treatment of hypertension. We aimed to provide the clinician an insight into the pharmacokinetic and pharmacodynamic interactions between these drugs for a better choice of combinations of drugs to treat both the mental illness and cardiovascular risk factors. For this, we performed a literature search in PubMed and Scopus databases, up to 31 July 2021., Expert Opinion: The main pharmacokinetic interactions between antipsychotics and antihypertensive drugs involve mainly the cytochrome P450 system. The pharmacodynamic interactions are produced by multiple mechanisms, leading to concurrent binding to the same receptors. The data available regarding drug-drug interactions is mostly based on case reports and small studies and therefore should be interpreted with caution. The current knowledge is sufficiently strong to guide clinicians in selecting safer drug combinations as summarized here.

Competing Interests: The author has no conflicts of interest to declare.

Background: Opioid use disorder continues to have a significant impact on public health morbidity and mortality throughout the United States and elsewhere. Managing opioid withdrawal is a critical treatment goal in individuals entering treatment with an active opioid use., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of heroin withdrawal syndrome in the past century?, Study Design: To determine the changes in the expert approach to the management of heroin withdrawal syndrome, as presented in a widely used textbook in the United States., Data Sources: The chapters on opioid dependence in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Opioid replacement taper with morphine (1927-1947), codeine (1931-1943), and methadone (1951-present) administered for 3-10 days has remained the main intervention. The anticholinergic drugs, scopolamine and atropine, were recommended from 1927 to 1943, but their use has never been backed by scientific evidence. Newer approaches relied on clonidine, an alpha-2 receptor agonist used since 1982, and buprenorphine, an opioid agonist/antagonist endorsed for the treatment of heroin withdrawal in 2000., Conclusions: The pharmacological management of heroin withdrawal syndrome in the past century has progressed from the introduction of methadone to the utilization of clonidine and buprenorphine. More recent advances in treating opioid use disorder have changed the goals of opioid withdrawal management to achievement of abstinence from all opioids to facilitation of long-term treatment with medications for opioid use disorder., Competing Interests: P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The author has no conflicts of interest to declare.

Background: Advances in drug therapy for atrial fibrillation (AF) have had a significant impact on the quality of life of a substantial majority of affected persons, which has contributed to a remarkable decrease in the frequency and severity of thromboembolic complications, hospitalizations, and mortality., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of AF in the past century?, Study Design: To determine the changes in the experts' approach to the management of AF, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of AF in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: AF was consistently described in Cecil Textbook of Medicine as the most common sustained arrhythmia in adults. The authors emphasized its thromboembolic complications and potential for hemodynamic deterioration. Rate control with digitalis and rhythm control with quinidine were the standard in 1927. The pharmacological advances have focused on atrioventricular nodal blocking for rate control, conversion to and maintenance of sinus rhythm, and preventive anticoagulation. The first new class of drugs for rate control was beta-adrenergic receptor blockers, starting with propranolol which was introduced in 1979, followed by the calcium channel blocker verapamil in 1988. Rhythm control with amiodarone, a potassium channel blocker, has been recommended since 2004, and the sodium channel blockers propafenone and flecainide became part of standard therapy in 2008. Anticoagulation with warfarin was recommended starting in 2000, followed by the introduction of direct thrombin inhibitor in 2012 and factor Xa inhibitors in 2016., Conclusions: The pharmacological management of AF was unchanged for more than 50 years (1927-1979), a period during which the devastating effects of thromboembolic complications were not addressed. The major therapeutic advance is represented by preventive anticoagulation with the newer, safer, and more user-friendly direct thrombin and factor Xa inhibitors., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for myasthenia gravis have had a significant impact on the quality of life and work potential of a substantial majority of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of myasthenia in the past century?, Study Design: To determine the changes in the experts' approach to the management of myasthenia gravis, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of myasthenia gravis in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020., Results: Adequate feeding, absolute rest in bed, and "tonics" were the only interventions recommended for the care of patients with myasthenia gravis in 1927. Ephedrine and glycine were used in the early 1930s. Treatment with the anticholinesterases physostigmine and neostigmine was recommended in 1937, 3 years after Mary Walker discovered it in the United Kingdom. Immunosuppressant pharmacological interventions with prednisone and azathioprine have been considered the standard since 1975, and intravenous immune globulin was added to usual care in 1996. The newer immunosuppressant drugs mycophenolate, cyclosporine, and tacrolimus have expanded the arsenal since 2008, and the monoclonal antibodies rituximab and eculizumab have been mentioned in the textbooks published in 2012-2020. The first randomized clinical trial of drug therapy for myasthenia gravis was published in 1987., Conclusions: The pharmacological management of myasthenia gravis was revolutionized by the epiphany of an astute clinician in the 1930s. Immunosuppressant treatment was a logical step once the autoimmune nature of the condition was established. The major therapeutic advances highlight the values of empiricism and persistent attention to detail in treating relatively rare chronic disorders., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for peptic ulcer have had a significant impact on quality of life and work potential of many millions of affected persons and have contributed to a remarkable decrease in the prevalence of the disease, frequency and severity of complications, hospitalizations, and mortality., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of peptic ulcer in the past century?, Study Design: To determine the changes in the experts' approach to the management of peptic ulcer, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of peptic ulcer in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Acid neutralization with alkalies was the only pharmacological intervention recommended in the textbooks published from 1927 to 1975. Atropine and other antimuscarinic agents were mainly used to relieve pain and acid secretion according to the paradigm "no acid no ulcer." The shift to the acid suppression paradigm started with the introduction of the histamine-2 receptor antagonist cimetidine in 1979, the proton-pump inhibitor omeprazole in 1988, and the prostaglandin agonist misoprostol in 1992. Finally, the eradication of Helicobacter pylori was codified in 1996., Conclusions: The pharmacological management of peptic ulcer has remained archaic well into the 20th century. Fundamental progress occurred in a very short period (1979-1996) and was due to paradigm shifts from acid neutralization to acid suppression and later the recognition of the role of H. pylori infection., Competing Interests: P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Drug therapy for diabetes mellitus (DM) has had a significant impact on quality of life and work potential of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality. The current approach is the result of incremental progress in using technological advances to increase the safety and effectiveness of insulin therapy and the introduction of new molecules as oral and injectable antidiabetic drugs., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of DM in the past century?, Study Design: To determine the changes in the experts' approach to the management of DM, as presented in a widely used textbook in the United States., Data Sources: The chapters on describing the management of DM in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020., Results: In 1927, DM was treated with insulin extracted from the pancreas of large animals (cattle, hogs, and sheep) and purified with alcohol to prevent the tissues' proteolytic action on the hormone. The therapeutic milestones in DM marked 2 avenues for innovation. The first created advances in insulin therapy, starting with processes that led to the production of crystalline insulin and protamine zinc insulin (1937), synthetic human insulin (1996), and prandial (2000) and basal (2004) insulin analogues. The second was an effort to develop and introduce in clinical practice in the United States oral antidiabetic drugs, starting with tolbutamide, a sulfonylurea (1955), followed by metformin, a biguanide (1996), thiazolidinediones, alpha-glucosidase inhibitors, and benzoic acid derivatives (2000), dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists (2008), and sodium glucose cotransporter 2 inhibitors (2020). A latent period of 40 years between significant advances was likely because of searches for new technologies (eg, recombinant DNA for the production of synthetic insulin and analogues) and, at least in part, to the impact of the controversial University Group Diabetes Project on the development and acceptance of oral antidiabetic drugs., Conclusions: The pharmacological management of DM has progressed unevenly, with a long latency period in the second half of the last century followed by highly encouraging advances in the first 2 decades of the 21st century. In chronological order, the major advances were synthetic insulins obtained through DNA recombinant technology, adoption of metformin as first line therapy, and introduction of antidiabetic medication classes that also promote weight reduction and cardiovascular health., Competing Interests: P. Manu has contributed a chapter to each of the last four editions of Cecil Medicine (2008, 2012, 2016 and 2020).The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Drug therapy for heart failure influences quality of life and work potential of affected persons and has contributed to decrease in hospitalizations and cardiovascular mortality. The current approach is the result of incremental progress in understanding the pathophysiology of the syndrome, introduction of new molecules, and repurposing existing drugs., Study Question: What are the milestones of the changes in the expert clinicians' approach to the pharmacological management in the past century?, Study Design: To determine the changes in the experts' approach to the management of heart failure, as presented in a widely used textbook in the United States., Data Sources: The chapters on the management of heart failure in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: In 1927, heart failure was treated with powdered leaf or tincture of digitalis, mercury chloride, and theophylline. Patients with acute pulmonary edema received injections of atropine, adrenaline, and ouabain. The therapeutic milestones in heart failure were the introduction of loop diuretics and aldosterone antagonists (1971), vasodilator treatment with hydralazine and nitroglycerine (1979-1985), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and selective beta-adrenergic blockers (1992-2000), and sacubitril-valsartan (2016). For acute pulmonary edema, the durable milestone was the treatment with morphine and furosemide (1971)., Conclusions: The pharmacological management of heart failure in the past century has progressed in fits and starts, with latent periods between significant advances lasting 8-40 years. In chronological order, the major advances were efficient diuresis, afterload reduction, and blunting the neurohormonal response to hemodynamic stress and cardiac remodeling., Competing Interests: P. Manu has contributed a chapter to each of the last four editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Fasting hyperglycemia, impaired glucose tolerance, prediabetes, and diabetes are frequently present in patients treated with second-generation antipsychotics (SGAPs) for schizophrenia, bipolar disorder, and other severe mental illnesses. These drugs are known to produce weight gain, which may lead to insulin resistance, glucose intolerance, and metabolic syndrome, which constitute important risk factors for the emergence of diabetes. The aim of this review was to formulate therapeutic guidelines for the management of diabetes in patients treated with SGAPs, based on the association between SGAP-induced weight gain and glucose dysregulation. A  systematic search in PubMed from inception to March 2020 for randomized controlled trials (RCTs) of diabetes or prediabetes in patients treated with SGAPs was performed. PubMed was also searched for the most recent clinical practice guidelines of interventions for co-morbid conditions associated with diabetes mellitus (DM) (arterial hypertension and dyslipidemia), lifestyle interventions and switching from high metabolic liability SGAPs to safer SGAPs. The search identified 14 RCTs in patients treated with SGAPs. Drug therapy using metformin as first-line therapy and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or perhaps sodium-glucose cotransporter-2 (SGLT2) inhibitors as add-on therapy, might be preferred in these patients as well, as they favorably influence glucose metabolism and body mass index, and provide cardio-renal benefits in general to the DM population, although for the SGLT-2 inhibitors there are no RCTs in this specific patient category so far. Metformin is also useful for treatment of prediabetes. Arterial hypertension should be treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and statins should be used for correction of dyslipidemia. The outcome of lifestyle-changing interventions has been disappointing. Switching from clozapine, olanzapine, or quetiapine to lower cardiometabolic-risk SGAPs, like aripiprazole, brexpiprazole, cariprazine, lurasidone, or ziprasidone, has been recommended.

Purpose . Whilst occupational safety and health (OSH) management is recognized as an important mechanism for addressing poor OSH performance, limited empirical insight is available on OSH management by construction companies in sub-Saharan Africa. This study investigated OSH management by construction companies (i.e., contractors) in Malawi in order to unpick implementation issues that need attention. Materials and methods . 46 OSH management practices were probed through a survey of contractors. Results . Implementation of OSH practices amongst contractors is low, particularly for practices related to the policy, organizing, measuring and reviewing, and auditing elements of OSH management. Company size is associated with implementation of nearly half of the 46 OSH practices. Certification of the company to Standard No. OHSAS 1800:2007 is associated with the implementation of fewer practices. Conclusions . OSH management improvement efforts would need to focus on the elements with particularly low implementation of practices as well as include initiatives that focus on helping microenterprises to improve their OSH management. The association between business characteristics and OSH management may be more evident with certain elements, such as the organizing element. Furthermore, certification to Standard No. OHSAS 1800:2007 may not necessarily translate into greater implementation of OSH management practices, especially in developing countries.

Objective: We aimed to investigate which clinical and metabolic tests offer optimal accuracy and acceptability to help diagnose diabetes among a large sample of people with serious mental illness in receipt of antipsychotic medication., Methods: A prospective observational study design of biochemical and clinical factors was used. Biochemical measures were fasting glucose, insulin and lipids, oral glucose tolerance testing (OGTT), hemoglobin A1c, and insulin resistance assessed with the homeostatic model (HOMA-IR) were determined in a consecutive cohort of 798 adult psychiatric inpatients receiving antipsychotics. Clinical variables were gender, age, global assessment of functioning (GAF), mental health clinicians' global impression (CGI), duration of severe mental illness, height, weight, BMI and waist/hip ratio. In addition, we calculated the risk using combined clinical predictors using the Leicester Practice Risk Score (LPRS) and the Topics Diabetes Risk Score (TDRS). Diabetes was defined by older criteria (impaired fasting glucose (IFG) or OGTT) as well as2010 criteria (IFG or OGTT or Glycated haemoglobin (HBA1c)) at conventional cut-offs., Results: Using the older criteria, 7.8% had diabetes (men: 6.3%; women: 10.3%). Using the new criteria, 10.2% had diabetes (men: 8.2%, women: 13.2%), representing a 30.7% increase (p = 0.02) in the prevalence of diabetes. Regarding biochemical predictors, conventional OGTT, IFG, and HbA1c thresholds used to identify newly defined diabetes missed 25%, 50% and 75% of people with diabetes, respectively. The conventional HBA1c cut-point of ≥6.5% (48 mmol/mol) missed 7 of 10 newly defined cases of diabetes while a cut-point of ≥5.7% improved sensitivity from 44.4% to up to 85%. Specific algorithm approaches offered reasonable accuracy. Unfortunately no single clinical factor was able to accurately rule-in a diagnosis of diabetes. Three clinical factors were able to rule-out diabetes with good accuracy namely: BMI, waist/hip ratio and height. A BMI < 30 had a 92% negative predictive value in ruling-out diabetes. Of those not diabetic, 20% had a BMI ≥ 30. However, for complete diagnosis a specific biochemical protocol is still necessary., Conclusions: Patients with SMI maintained on antipsychotic medication cannot be reliably screened for diabetes using clinical variables alone. Accurate assessment requires a two-step algorithm consisting of HBA1c ≥5.7% followed by both FG and OGTT which does not require all patients to have OGTT and FG., Competing Interests: Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Alexza; American Academy of Child and Adolescent Psychiatry, AstraZeneca, Biotis, Bristol-Myers Squibb, Cephalon, Desitin, Eli Lilly, Gerson Lehrman Group, GSK, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, National Institute of Mental Health, Novartis, Ortho-McNeill/Janssen/J&J, Otsuka, Pfizer, ProPhase, Sunovion, Takeda, Teva, and Vanda. He has received grant support from BMS, Feinstein Institute for Medical Research, Janssen/J&J, National Institute of Mental Health (NIMH), National Alliance for Research in Schizophrenia and Depression (NARSAD), and Otsuka. He is also a shareholder of Alexza stock options. Dr. van Winkel has received honoraria from Eli Lilly and Janssen-Cilag and has served as a consultant for Eli Lilly. Dr. De Hert has served as a consultant to, received grant/research support and honoraria from, and served on the speakers or advisory boards of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Sanofi-Adventis and Lundbeck. Drs. Manu, Vancampfort, Wampers, Yu and Mitchell report no financial or other relationships relevant to the subject of this article. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Design for safety (DfS) of workers is amongst the prominent ways of tackling poor occupational safety and health performance in construction. However, in developing countries there is extremely limited research on DfS. This study thus makes an important contribution to the subject of DfS in developing countries by specifically examining the awareness and practice of DfS amongst architects within the construction sector of Nigeria., Materials and Methods: A survey of architects, yielding 161 valid responses, was conducted., Results: While there is high awareness of the concept of DfS, the actual practice is low. Additionally, although there is high interest in DfS training, the engagement in DfS training is low. Significantly, awareness of DfS, training and education related to DfS, and membership of a design professional body have very limited bearing on the practice of DfS by architects., Conclusions: The findings are thus symptomatic of the prevalence of influential DfS implementation barriers within the construction sector. Industry stakeholders should seek to raise the profile of DfS practice within the sector. Furthermore, similar empirical studies in the construction sector of other developing countries would be useful in shedding light on the status of DfS in these countries.

Background: Recent epidemiological studies have identified an excess of pulmonary embolism (PE) cases in patients treated with antipsychotic drugs. The findings are particularly relevant for patients treated with clozapine, which has many potentially life-threatening adverse drug effects. Among these adverse drug effects are myocarditis and agranulocytosis that have early onset and are dose independent, but also seizures and myocardial repolarization delay, which are dose dependent and may occur at any time. Together with death rates, these variables have important implications for clinical practice., Areas of Uncertainty: Study Question: What are the time of onset, dose relationship, and mortality of clozapine-associated PE?, Data Sources: The published case reports of clozapine-associated PE were identified in a MEDLINE search. Cases occurring within 6 months of starting clozapine were considered to have early onset. Dosages of clozapine at the time of PE were defined as low (200 mg/d or less) or high (300 mg/d or greater). Patient outcome was divided into survival of the PE event and death., Results: The search identified 23 cases of clozapine-associated PE. The PE had early onset (6.4 ± 7.0 weeks) in 20 patients (87%, 95% confidence interval 67.9%-95.5%). PE occurred in 9 patients treated with low doses (152.8 ± 50.7 mg/d) and in 11 patients on high doses (372.7 ± 127.2 mg/d) of clozapine. Six patients (26.1%, 95% confidence interval 12.6%-46.5%) died., Conclusions: A systematic review of the published case reports of clozapine-associated PE indicates that this adverse effect is highly lethal, has early onset and is dose independent. The findings should prompt careful monitoring and consideration of prophylactic treatment for venous thromboembolism for 6 months after starting treatment with clozapine.

Introduction: The metabolic syndrome includes a constellation of several well-established risk factors, which need to be aggressively treated in order to prevent overt type 2 diabetes and cardiovascular disease. While recent guidelines for the treatment of individual components of the metabolic syndrome focus on cardiovascular benefits as resulted from clinical trials, specific recent recommendations on the pharmacological management of metabolic syndrome are lacking. The objective of present paper was to review the therapeutic options for metabolic syndrome and its components, the available evidence related to their cardiovascular benefits, and to evaluate the extent to which they should influence the guidelines for clinical practice. Areas covered: A Medline literature search was performed to identify clinical trials and meta-analyses related to the therapy of dyslipidemia, arterial hypertension, glucose metabolism and obesity published in the past decade. Expert commentary: Our recommendation for first-line pharmacological are statins for dyslipidemia, renin-angiotensin-aldosteron system inhibitors for arterial hypertension, metformin or sodium/glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1RAs) for glucose intolerance, and the GLP-1RA liraglutide for achieving body weight and waist circumference reduction.

Background: Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines., Study Questions: How safe is the clozapine rechallenge after life-threatening adverse effects?, Study Design: The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%., Results: A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%-69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%-44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%-84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1%-100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency., Conclusion: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects.

Clinical Features: We present a case of a middle-aged man admitted to an inpatient detoxification facility for withdrawal of intranasal heroin, alprazolam, and ethanol. The patient was placed on methadone and chlordiazepoxide tapers. Ondansetron and trazodone were prescribed as needed for symptom control. On the third hospital day, the patient was found unresponsive with blood glucose of 40 mg/dL. He had no history of glucose dysregulation. The patient was pronounced dead shortly thereafter. Methadone overdose was ruled the cause of death., Therapeutic Challenges: There have been studies linking methadone with glucose dysregulation. Hypoglycemia can induce changes in the electrical system in the heart, including lengthening QT interval, lengthening repolarization, and causing ST wave changes. In addition, there have been studies linking methadone treatment to QT interval prolongation and torsade de pointes. Ondansetron and trazodone have both been associated with cardiac conduction abnormalities., Solution: We recommend initial blood glucose and cardiac monitoring in patients taking methadone 40 mg daily or higher.

Frailty is common and associated with poorer outcomes in the elderly, but its role as potential cardiovascular disease (CVD) risk factor requires clarification. We thus aimed to meta-analytically evaluate the evidence of frailty and pre-frailty as risk factors for CVD. Two reviewers selected all studies comparing data about CVD prevalence or incidence rates between frail/pre-frail vs. robust. The association between frailty status and CVD in cross-sectional studies was explored by calculating and pooling crude and adjusted odds ratios (ORs) ±95% confidence intervals (CIs); the data from longitudinal studies were pooled using the adjusted hazard ratios (HRs). Eighteen cohorts with a total of 31,343 participants were meta-analyzed. Using estimates from 10 cross-sectional cohorts, both frailty and pre-frailty were associated with higher odds of CVD than robust participants. Longitudinal data were obtained from 6 prospective cohort studies. After a median follow-up of 4.4 years, we identified an increased risk for faster onset of any-type CVD in the frail (HR=1.70 [95%CI, 1.18-2.45]; I 2 =66%) and pre-frail (HR=1.23 [95%CI, 1.07-1.36]; I 2 =67%) vs. robust groups. Similar results were apparent for time to CVD mortality in the frail and pre-frail groups. In conclusion, frailty and pre-frailty constitute addressable and independent risk factors for CVD in older adults., (Copyright © 2017 Elsevier B.V. All rights reserved.)