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Brugada syndrome is characterised by specific electrocardiogram changes in the right precordial leads, a structurally normal heart and susceptibility to ventricular arrhythmias that may cause syncope or sudden death in otherwise fit young adults. Perioperative pharmacological and physiological changes may precipitate these events. Arrhythmias and symptoms typically occur at rest or sleep when vagal activity predominates. Although the condition is rare, the implications are serious and may result in death. Individual case reports describe diverse anaesthetic management. In this paper we critically appraise the literature to identify unifying features and determine whether specific management can be recommended. We found 18 clinical reports of anaesthesia including a total of 28 patients, most under general anaesthesia. Those with an implanted defibrillator should have it deactivated. All patients should have external defibrillator pads applied continuously throughout the perioperative period. Electrolyte imbalances should be corrected preoperatively. Propofol infusions for maintenance of general anaesthesia are probably safe if duration and dose are limited. Sevoflurane may be the preferred volatile anaesthetic. Autonomic changes, inadequate analgesia, light anaesthesia and postural changes should be all be minimised. The patient should be warmed or cooled to maintain normothermia. An isoprenaline infusion is advocated for intraoperative ST changes. Regional anaesthesia is possible if the dose is limited and systemic absorption restricted. Lignocaine is the drug of choice while bupivacaine is relatively contraindicated. Ropivacaine is possibly also not safe. Prolonged regional anaesthesia may therefore require continuous catheter techniques. Five-lead electrocardiogram monitoring and ST trend analysis should continue into the postoperative period. [ABSTRACT FROM AUTHOR]

Chagas disease is one of the world's neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi . There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. T. cruzi glucokinase ( Tc GlcK) is a potential drug target because its product, d-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of Tc GlcK inhibitors that also exhibited anti- T. cruzi efficacy called the 3-nitro-2-phenyl-2 H -chromene analogues. This was achieved by performing a target-based high-throughput screening (HTS) campaign of 13,040 compounds. The selection criteria were based on first determining which compounds strongly inhibited Tc GlcK in a primary screen, followed by establishing on-target confirmed hits from a confirmatory assay. Compounds that exhibited notable in vitro trypanocidal activity over the T. cruzi infective form (trypomastigotes and intracellular amastigotes) co-cultured in NIH-3T3 mammalian host cells, as well as having revealed low NIH-3T3 cytotoxicity, were further considered. Compounds GLK2-003 and GLK2-004 were determined to inhibit Tc GlcK quite well with IC 50 values of 6.1 µM and 4.8 µM, respectively. Illuminated by these findings, we herein screened a small compound library consisting of thirteen commercially available 3-nitro-2-phenyl-2 H -chromene analogues, two of which were GLK2-003 and GLK2-004 (compounds 1 and 9 , respectively). Twelve of these compounds had a one-point change from the chemical structure of GLK2-003 . The analogues were run through a similar primary screening and confirmatory assay protocol to our previous HTS campaign. Subsequently, three in vitro biological assays were performed where compounds were screened against (a) T. cruzi (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) T. brucei brucei (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the Tc GlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC 50 determinations, and an assessment of structure-activity relationships. Our results reveal that the 3-nitro-2-phenyl- 2H -chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research.

The hole mutagenesis approach was used to interrogate the importance of F337 in Trypanosoma cruzi glucokinase (TcGlcK) in order to understand the complete set of binding interactions that are made by d-glucosamine analogue inhibitors containing aromatic tail groups that can extend to the outer part of the active site. An interesting inhibitor of this analogue class includes 2-N-carboxybenzyl-2-deoxy-d-glucosamine (CBZ-GlcN), which exhibits strong TcGlcK binding with a K i of 710 nM. The residue F337 is found at the outer part of the active site that stems from the second protein subunit of the homodimeric assembly. In this study, F337 was changed to leucine and alanine so as to diminish phenylalanine's side chain size and attenuate intermolecular interactions in this region of the binding cavity. Results from enzyme - inhibitor assays revealed that the phenyl group of F337 made dominant hydrophobic interactions with the phenyl group of CBZ-GlcN as opposed to π - π stacking interactions. Moreover, enzymatic activity assays and X-ray crystallographic experiments indicated that each of these site-directed mutants primarily retained their activity and had high structural similarity of their protein fold. A computed structure model of T. cruzi hexokinase (TcHxK), which was produced by the artificial intelligence system AlphaFold, was compared to an X-ray crystal structure of TcGlcK. Our structural analysis revealed that TcHxK lacked an F337 counterpart residue and probably exists in the monomeric form. We proposed that the d-glucosamine analogue inhibitors that are structurally similar to CBZ-GlcN may not bind as strongly in TcHxK as they do in TcGlcK because of absent van der Waals contact from residue side chains., Competing Interests: Declaration of competing interest 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., (Copyright © 2023 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Eighteen amino sugar analogues were screened against Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the protozoan parasite in order to assess for viable enzyme inhibition. The analogues were divided into three amino sugar scaffolds that included d-glucosamine (d-GlcN), d-mannosamine (d-ManN), and d-galactosamine (d-GalN); moreover, all but one of these compounds were novel. TcGlcK is an important metabolic enzyme that has a role in producing G6P for glycolysis and the pentose phosphate pathway (PPP). The inhibition of these pathways via glucose kinases (i.e., glucokinase and hexokinase) appears to be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P and the formed G6P enters both pathways for catabolism. The compound screen revealed five on-target confirmed inhibitors that were all from the d-GlcN series, such as compounds 1, 2, 4, 5, and 6. Four of these compounds were strong TcGlcK inhibitors (1, 2, 4, and 6) since they were found to have micromolar inhibitory constant (K i ) values around 20 μM. Three of the on-target confirmed inhibitors (1, 5, and 6) revealed notable in vitro anti-T. cruzi activity with IC 50 values being less than 50 μM. Compound 1 was benzoyl glucosamine (BENZ-GlcN), a known TcGlcK inhibitor that was the starting point for the design of the compounds in this study; in addition, TcGlcK - compound 1 inhibition properties were previously determined [D'Antonio, E. L. et al. (2015) Mol. Biochem. Parasitol. 204, 64-76]. As such, compounds 5 and 6 were further evaluated biochemically, where formal K i values were determined as well as their mode of TcGlcK inhibition. The K i values determined for compounds 5 and 6 were 107 ± 4 μM and 15.2 ± 3.3 μM, respectively, and both of these compounds exhibited the competitive inhibition mode., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: We examined efforts by a Mississippi court to base pretrial release decisions on risk assessment rather than primarily on bond., Hypotheses: (a) Pretrial detention will be shorter than that associated with prevailing bond practices in the same counties. (b) Rearrest rates will be lower than a similar pretrial population in a nearby southern state. (c) False positive rates for predicting rearrests will be higher for African American than Caucasian participants. (d) Pretrial detention will be longer for African American participants because of higher risk scores or assessment overrides., Method: Pretrial defendants (N = 521) completed the Risk and Needs Triage (RANT) within 2 weeks of arrest, and outcomes examined included the length of pretrial detention, index case dispositions, and rearrest rates., Results: (a) Pretrial detention averaged approximately 60 days compared with prevailing detentions averaging approximately 90 and 180 days in the same counties. (b) Pretrial rearrest rates were 17 percentage points higher than a similar pretrial population; however, representative comparison data are unavailable to confidently measure recidivism impacts. (c) Positive predictive power did not differ by race in predicting pretrial rearrests, SE = .04, 95% CI [.11, -.06], z = .61, p = .54, d = .08. (d) Despite comparable risk scores, African American participants were detained significantly longer than Caucasian participants (M = 60.92 vs. 45.58 days), p = .038, d = .18, 95% CI [.01, .36], and were less likely to receive a diversion opportunity (11% vs. 23%), p = .009, V = .17., Conclusion: The observational design precludes causal conclusions; however, risk assessment was associated with shorter pretrial detention than prevailing bond practices with no racial disparities in risk prediction. Greater attention to risk assessment may reduce racial inequities in pretrial conditions. Representative comparison data are needed to measure the recidivism impacts of pretrial reform initiatives. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective: To describe the prevalence of postarrest hyperthermia among children during the first 24 hrs after inhospital cardiac arrest and to determine the association of persistent postarrest hyperthermia with neurologic outcome and death before hospital discharge., Design: Multicenter, national registry of inhospital cardiopulmonary resuscitation., Setting: A total of 196 hospitals reporting to the American Heart Association's National Registry of Cardiopulmonary Resuscitation from January 1, 2005 to December 31, 2007., Patients: A total of 547 pediatric patients who suffered inhospital pulseless cardiac arrests reported to the National Registry of Cardiopulmonary Resuscitation, who survived resuscitative efforts and who had the maximum and the minimum temperature in the first 24 hrs postresuscitation reported to the National Registry of Cardiopulmonary Resuscitation., Interventions: None., Measurements and Main Results: Among 547 children with pulseless cardiac arrests, 238 (43.5%) had at least one temperature of ≥38°C, and 30 (5.5%) had "persistent hyperthermia" (i.e., both the minimum and the maximum temperature of ≥38°C) during the first 24 hrs postarrest. After adjusting for potential confounders by multivariate logistic regression, persistent hyperthermia in the first 24 hrs postarrest was associated with unfavorable neurologic outcome (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-6.7), but not with death before hospital discharge (adjusted odds ratio, 1.2; 95% confidence interval, 0.4-3.4)., Conclusions: Despite current guidelines to avoid postarrest hyperthermia, a temperature of ≥38°C occurred commonly among children in the first 24 hrs postarrest. Persistent postarrest hyperthermia was associated with unfavorable neurologic outcomes, even after controlling for potential confounding factors.

Objective: We hypothesized that childhood obesity would be associated with decreased likelihood of survival to hospital discharge after in-hospital, pediatric cardiopulmonary resuscitation (CPR)., Methods: We reviewed 1477 consecutive, pediatric, CPR index events (defined as the first CPR event during a hospitalization in that facility for a patient <18 years of age) reported to the American Heart Association National Registry of Cardiopulmonary Resuscitation between January 2000 and July 2004. The primary outcome was survival to hospital discharge. A total of 1268 index subjects (86%) with complete registry data were included for analysis. Children were classified as obese (> or =95th weight-for-length percentile if <2 years of age or > or =95th BMI-for-age percentile if > or =2 years of age) or underweight (<5th weight-for-length percentile if <2 years of age or <5th BMI-for-age percentile if > or =2 years of age), with adjustment for gender., Results: Obesity was noted for 213 (17%) of 1268 subjects and underweight for 571 (45%) of 1268 subjects. Obesity was more likely to be associated with male gender, noncardiac medical illness, and cancer and inversely associated with heart failure. Underweight was more likely to be associated with male gender, cardiac surgery, and prematurity and inversely associated with age and cancer. Self-reported, process-of-care, CPR quality was generally worse for obese children. With adjustment for important potential confounding factors, obesity was independently associated with worse odds of event survival (adjusted odds ratio: 0.58 [95% confidence interval: 0.35-0.76]) and survival to hospital discharge (adjusted odds ratio: 0.62 [95% confidence interval: 0.38-0.93]) after in-hospital, pediatric CPR. Underweight was not associated with worse outcomes., Conclusions: Childhood obesity is associated with a lower rate of survival to hospital discharge after in-hospital, pediatric CPR.

Context: Occurrence of in-hospital cardiac arrest and survival patterns have not been characterized by time of day or day of week. Patient physiology and process of care for in-hospital cardiac arrest may be different at night and on weekends because of hospital factors unrelated to patient, event, or location variables., Objective: To determine whether outcomes after in-hospital cardiac arrest differ during nights and weekends compared with days/evenings and weekdays., Design and Setting: We examined survival from cardiac arrest in hourly time segments, defining day/evening as 7:00 am to 10:59 pm, night as 11:00 pm to 6:59 am, and weekend as 11:00 pm on Friday to 6:59 am on Monday, in 86,748 adult, consecutive in-hospital cardiac arrest events in the National Registry of Cardiopulmonary Resuscitation obtained from 507 medical/surgical participating hospitals from January 1, 2000, through February 1, 2007., Main Outcome Measures: The primary outcome of survival to discharge and secondary outcomes of survival of the event, 24-hour survival, and favorable neurological outcome were compared using odds ratios and multivariable logistic regression analysis. Point estimates of survival outcomes are reported as percentages with 95% confidence intervals (95% CIs)., Results: A total of 58,593 cases of in-hospital cardiac arrest occurred during day/evening hours (including 43,483 on weekdays and 15,110 on weekends), and 28,155 cases occurred during night hours (including 20,365 on weekdays and 7790 on weekends). Rates of survival to discharge (14.7% [95% CI, 14.3%-15.1%] vs 19.8% [95% CI, 19.5%-20.1%], return of spontaneous circulation for longer than 20 minutes (44.7% [95% CI, 44.1%-45.3%] vs 51.1% [95% CI, 50.7%-51.5%]), survival at 24 hours (28.9% [95% CI, 28.4%-29.4%] vs 35.4% [95% CI, 35.0%-35.8%]), and favorable neurological outcomes (11.0% [95% CI, 10.6%-11.4%] vs 15.2% [95% CI, 14.9%-15.5%]) were substantially lower during the night compared with day/evening (all P values < .001). The first documented rhythm at night was more frequently asystole (39.6% [95% CI, 39.0%-40.2%] vs 33.5% [95% CI, 33.2%-33.9%], P < .001) and less frequently ventricular fibrillation (19.8% [95% CI, 19.3%-20.2%] vs 22.9% [95% CI, 22.6%-23.2%], P < .001). Among in-hospital cardiac arrests occurring during day/evening hours, survival was higher on weekdays (20.6% [95% CI, 20.3%-21%]) than on weekends (17.4% [95% CI, 16.8%-18%]; odds ratio, 1.15 [95% CI, 1.09-1.22]), whereas among in-hospital cardiac arrests occurring during night hours, survival to discharge was similar on weekdays (14.6% [95% CI, 14.1%-15.2%]) and on weekends (14.8% [95% CI, 14.1%-15.2%]; odds ratio, 1.02 [95% CI, 0.94-1.11])., Conclusion: Survival rates from in-hospital cardiac arrest are lower during nights and weekends, even when adjusted for potentially confounding patient, event, and hospital characteristics.

Ciaglia Blue Rhino percutaneous dilatational tracheostomy is used as an aid to ventilatory weaning. It carries an immediate complication rate previously reported in 100 consecutive patients by Fikkers et al at 6% for "major" complications and 30% for "minor" complications. Mortality has been associated with the procedure. Our institution has performed dilatational percutaneous tracheostomy since 1998 and used the Blue Rhino technique since 2002. Consensus guidelines were developed following initial experiences. They focus on preoperative risk assessment including levels of ventilatory support and anatomical considerations, seniority of staff use of bronchoscopy and capnography and correction of coagulopathies. Following introduction of the guidelines we conducted an audit of the first 200 Ciaglia Blue Rhino tracheostomies performed. There was an immediate major complication rate of 3% and minor complication rate of 18%. No deaths occurred within 24 hours of the procedure. We conclude that applying our consensus guidelines produced an immediate complication rate for Ciaglia Blue Rhino percutaneous dilatational tracheostomy below published audits.

The rapid expansion of drug courts in California and the state's uncertain fiscal climate highlighted the need for definitive cost information on drug court programs. This study focused on creating a research design that can be utilized for statewide and national cost-assessment of drug courts by conducting in-depth case studies of the costs and benefits in nine adult drug courts in California. A Transactional Institutional Costs Analysis (TICA) approach was used, allowing researchers to calculate costs based on every individual's transactions within the drug court or the traditional criminal justice system. This methodology also allows the calculation of costs and benefits by agency (e.g., Public Defender's office, court, District Attorney). Results in the nine sites showed that the majority of agencies save money in processing an offender though drug court. Overall, for these nine study sites, participation in drug court saved the state over 9 million dollars in criminal justice and treatment costs due to lower recidivism in drug court participants. Based on the lessons learned in Phases I and II, Phase III of this study focuses on the creation of a web-based drug court cost self-evaluation tool (DC-CSET) that drug courts can use to determine their own costs and benefits.

Context: Cardiac arrests in adults are often due to ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT), which are associated with better outcomes than asystole or pulseless electrical activity (PEA). Cardiac arrests in children are typically asystole or PEA., Objective: To test the hypothesis that children have relatively fewer in-hospital cardiac arrests associated with VF or pulseless VT compared with adults and, therefore, worse survival outcomes., Design, Setting, and Patients: A prospective observational study from a multicenter registry (National Registry of Cardiopulmonary Resuscitation) of cardiac arrests in 253 US and Canadian hospitals between January 1, 2000, and March 30, 2004. A total of 36,902 adults (> or =18 years) and 880 children (<18 years) with pulseless cardiac arrests requiring chest compressions, defibrillation, or both were assessed. Cardiac arrests occurring in the delivery department, neonatal intensive care unit, and in the out-of-hospital setting were excluded., Main Outcome Measure: Survival to hospital discharge., Results: The rate of survival to hospital discharge following pulseless cardiac arrest was higher in children than adults (27% [236/880] vs 18% [6485/36,902]; adjusted odds ratio [OR], 2.29; 95% confidence interval [CI], 1.95-2.68). Of these survivors, 65% (154/236) of children and 73% (4737/6485) of adults had good neurological outcome. The prevalence of VF or pulseless VT as the first documented pulseless rhythm was 14% (120/880) in children and 23% (8361/36,902) in adults (OR, 0.54; 95% CI, 0.44-0.65; P<.001). The prevalence of asystole was 40% (350) in children and 35% (13 024) in adults (OR, 1.20; 95% CI, 1.10-1.40; P = .006), whereas the prevalence of PEA was 24% (213) in children and 32% (11,963) in adults (OR, 0.67; 95% CI, 0.57-0.78; P<.001). After adjustment for differences in preexisting conditions, interventions in place at time of arrest, witnessed and/or monitored status, time to defibrillation of VF or pulseless VT, intensive care unit location of arrest, and duration of cardiopulmonary resuscitation, only first documented pulseless arrest rhythm remained significantly associated with differential survival to discharge (24% [135/563] in children vs 11% [2719/24,987] in adults with asystole and PEA; adjusted OR, 2.73; 95% CI, 2.23-3.32)., Conclusions: In this multicenter registry of in-hospital cardiac arrest, the first documented pulseless arrest rhythm was typically asystole or PEA in both children and adults. Because of better survival after asystole and PEA, children had better outcomes than adults despite fewer cardiac arrests due to VF or pulseless VT.

Objective: To evaluate the effectiveness and financial impact of a drug dose consolidation (optimization) program using letter intervention., Methods: This pilot program in a large, mid-Atlantic health plan utilized a randomized controlled trial research design. A review of adjudicated pharmacy claims records was performed monthly for 3 consecutive months from November 2002 through February 2003 to identify inefficient (i.e., >once-daily) regimens for any one of 68 dosage strengths of 37 single-source maintenance drugs with once-daily dosing recommendations. Prescribers who had prescribed one or more inefficient regimens were identified and randomized to one of the 2 intervention arms or a control arm. Prescribers in both intervention arms were sent personalized letters with information on their patients. inefficient regimens and suggested dose consolidation options. Patients of prescribers in one intervention arm received a complementary, patient-oriented letter. Pharmacy claims for patients in all arms were examined at 180 days after the date of the letter mailing for conversion to an efficient (once-daily) regimen. Financial modeling analysis calculated net savings as changes in pharmacy expenditures minus administrative costs., Results: A total of 2,614 inefficient regimens, representing 6.7% of claims for the targeted medications, were identified. The rate of consolidation to a suggested dosing option was lower for the Physician Letter arm (7.3%) than for the Physician/Member Letter arm (10.2%) (P = 0.046). Both intervention arms had higher consolidation rates than the Control arm (3.9%) (P = 0.018 and P = 0.000, respectively.). Approximately 30% of the regimens in each study arm were never refilled after being targeted. Financial modeling indicated that a dose consolidation intervention could save 0.03 dollars to 0.07 dollars per member per month (PMPM) in 2003 dollars with full medication compliance but only 0.02 dollars to 0.03 dollars PMPM when savings were calculated with realistic, partial compliance rates. Subanalyses performed at the drug therapy class level revealed few opportunities to justify implementing a dose consolidation program., Conclusions: After taking into consideration program administrative costs, high rates of refill discontinuation, and dose consolidation that occurs naturally without intervention, the results indicated that a letter-based dose consolidation program did not appreciably decrease pharmacy expenditures.

The tolerability and efficacy of a 6-month daily regimen of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) were tested in 130 hospitalized patients, mostly Black, with previously untreated pulmonary tuberculosis. PZA was discontinued at the end of the 2nd month. In 6 cases treatment was discontinued because of drug intolerance. The symptoms were severe rash, mild thrombocytopenia, deteriorating haematological and renal condition and in the remaining 3 patients hyperbilirubinaemia. Of the 125 patients who could be assessed bacteriologically, 110 were infected with organisms which were fully susceptible to INH and RMP, and 95% of their cultures and 77% of their smears had converted to negative after 2 months of treatment. Similar results were obtained for all but 2 of the 15 patients with drug-resistant bacilli. Cavitation of the lungs was reduced in 78% of the patients and the extent of other tuberculous lesions diminished in 87%.