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BackgroundGenetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration.MethodsGenotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.ResultsA total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P

Author(s): Jason A. Roberts [sup.1] [sup.2] [sup.3] [sup.4], Rinaldo Bellomo [sup.5] [sup.6] [sup.7] [sup.8], Menino O. Cotta [sup.1], Birgit C. P. Koch [sup.9], Haifa Lyster [sup.10] [sup.11], Marlies Ostermann [sup.12], [...], Intensive care unit (ICU) patients with end-organ failure will require specialised machines or extracorporeal therapies to support the failing organs that would otherwise lead to death. ICU patients with severe acute kidney injury may require renal replacement therapy (RRT) to remove fluid and wastes from the body, and patients with severe cardiorespiratory failure will require extracorporeal membrane oxygenation (ECMO) to maintain adequate oxygen delivery whilst the underlying pathology is evaluated and managed. The presence of ECMO and RRT machines can further augment the existing pharmacokinetic (PK) alterations during critical illness. Significant changes in the apparent volume of distribution (V.sub.d) and drug clearance (CL) for many important drugs have been reported during ECMO and RRT. Conventional antimicrobial dosing regimens rarely consider the impact of these changes and consequently, are unlikely to achieve effective antimicrobial exposures in critically ill patients receiving ECMO and/or RRT. Therefore, an in-depth understanding on potential PK changes during ECMO and/or RRT is required to inform antimicrobial dosing strategies in patients receiving ECMO and/or RRT. In this narrative review, we aim to discuss the potential impact of ECMO and RRT on the PK of antimicrobials and antimicrobial dosing requirements whilst receiving these extracorporeal therapies. The potential benefits of therapeutic drug monitoring (TDM) and dosing software to facilitate antimicrobial therapy for critically ill patients receiving ECMO and/or RRT are also reviewed and highlighted.

BackgroundInsight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration.MethodsPatients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.ResultsA total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P

This study examined diets of two predatory fish species, the native Sacramento Pikeminnow (Ptychocheilus grandis) and the introduced Striped Bass (Morone saxatilis), in the Sacramento River, California, USA. Both species have been implicated in native species declines through predation, eliciting our investigation of their diets in the Sacramento River. Sampling occurred between March and November 2017, and was conducted via hook and line on a 35-km reach near Chico, California. Habitat types sampled include engineered structures (water diversions and beam bridges), rip-rapped channel edges, and natural riverbank. Stomach contents were collected via gastric lavage and later processed using visual, gravimetric, and genetic techniques. Diets of Sacramento Pikeminnow and Striped Bass were highly similar as determined through index of relative importance and PERMANOVA modeling. Water temperature was the only variable that significantly affected diet composition. Results reflect similar dietary niches for both species in the Sacramento River.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Platform trials have become widely adopted across multiple disease areas over recent years, however, guidelines for operationalising these trials have not kept pace. We outline a series of documents that summarise the statistical components, and implicit processes, of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial to provide an informal template for other researchers and reviewers of platform trials. We briefly summarise the content and role of the core protocol, statistical appendix, domain-specific appendices, simulation report, statistical implementation guides, data safety and monitoring committee (DSMC) reports, and domain-specific statistical analysis plans and final reports, and a transparent governance structure that ensures separate blinded and unblinded statistical teams. In the absence of guidelines or checklists for platform trial statistical documents, we hope to provide useful guidance to others in terms of what has worked so far for the SNAP trial, stimulate discussion, and inform a future consensus. Trial registrationNCT05137119. Registered on 30 November 2021. [ABSTRACT FROM AUTHOR]

Background Carbapenem-resistant Gram-negative bacteria (CR-GNB) develop resistance to many antimicrobials. To effectively manage infections caused by these organisms, novel agents and/or combinations of antimicrobials are required. Objectives Evaluated the in vitro efficacy of ceftazidime/avibactam in combination with other antimicrobials against CR-GNB. Methods PubMed, Web of Science, Embase and Scopus were searched. Study outcomes were quantified by counting the number of isolates exhibiting synergy, defined as a fractional inhibitory concentration index ≤ 0.5 for checkerboard and Etest, and a >2 log cfu/mL reduction for time-kill studies. The proportion of synergy was calculated as the ratio of isolates exhibiting synergy to the total number of isolates tested. These proportions were analysed using a random-effects model, following the Freeman–Tukey double-arcsine transformation. Results Forty-five in vitro studies were included. A total of 734 isolates were tested, and 69.3% of them were resistant to ceftazidime/avibactam. The combination of ceftazidime/avibactam with aztreonam showed a high synergy rate against carbapenem-resistant Klebsiella pneumoniae (effect size, ES = 0.91–0.98) and Escherichia coli (ES = 0.75–1.00). Ceftazidime/avibactam also demonstrated a high synergy rate (ES = 1) in time-kill studies when combined with azithromycin, fosfomycin and gentamicin against K. pneumoniae. Compared to ceftazidime/avibactam alone, a higher bactericidal rate was reported when ceftazidime/avibactam was combined with other antimicrobials against carbapenem-resistant K. pneumoniae (57% versus 31%) and E. coli (93% versus 0%). Conclusions Ceftazidime/avibactam frequently demonstrates synergistic bactericidal activity when combined with various antimicrobials against CR-GNB in in vitro tests. Further pre-clinical and clinical studies are warranted to validate the utility of ceftazidime/avibactam-based combination regimens for CR-GNB infections. [ABSTRACT FROM AUTHOR]

Background Catheter-associated urinary tract infections (CA-UTIs) are a common hospital-acquired infection. We examined ciprofloxacin activity in a novel CA-UTI in vitro model. Methods Three ATCC strains [ Escherichia coli (ECO)-25922, Klebsiella pneumoniae (KPN)-700721, Pseudomonas aeruginosa (PAE)-27853] and 45 clinical urinary isolates were assessed. Biofilm mass and planktonic bacterial density were quantified during drug-free incubation (72 h) and following ciprofloxacin exposure (equivalent 750 mg orally q12h, 3 days). Results ECO produced smaller biofilms (6.3 ± 1.1 log10 cfu/cm2) compared with KPN (7.1 ± 0.7 log10 cfu/cm2) and PAE (7.0 ± 1.2 log10 cfu/cm2), which extended along the entire catheter length. Following ciprofloxacin, all isolates with MIC > 4 mg/L had minimal biofilm disruption or planktonic kill. Ciprofloxacin resistance was most common in PAE isolates (10/16 isolates), compared with ECO (3/16 isolates) and KPN (6/16 isolates). Greater ciprofloxacin exposure (AUC0–24/MIC) was required for a 3 log10 biofilm kill for KPN (5858; R 2 = 0.7774) compared with ECO (2117; R 2 = 0.7907) and PAE (2485; R 2 = 0.8260). Due to persistent growth in the bladder, ECO required greater ciprofloxacin exposure for a 3 log10 planktonic kill (5920; R 2 = 0.8440) compared with KPN (2825; R 2 = 0.9121) and PAE (1760; R 2 = 0.8781). Monte Carlo simulation supported a 95% PTA for both a 3 log10 biofilm and planktonic kill for ECO and KPN isolates with MIC ≤ 0.5 mg/L and PAE isolates with MIC ≤ 1 mg/L. Conclusions In a novel CA-UTI model, following simulated ciprofloxacin therapy, KPN biofilms were comparatively more difficult to disrupt, ECO planktonic growth frequently persisted in the bladder, and PAE had greater propensity for emergence of ciprofloxacin resistance. [ABSTRACT FROM AUTHOR]

Background Subcutaneous (SC) administration of antibiotics is a practical alternative to IV administration. Cefazolin is widely used for skin and soft tissue infections and other complex infections by IV administration. Methods In this prospective, cross-over self-controlled study, a single dose of SC cefazolin was administered to 15 stable inpatients established on IV cefazolin as part of their management plan. The equivalent dose of cefazolin was diluted in 50 mL of normal saline via gravity feed over 30 min. Venous blood samples were collected at baseline and 0.5, 1, 2, 4 and 8 h following both the SC and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were evaluated. Results SC cefazolin was well tolerated. The bioavailability of SC administration was 74.8% (95% CI 66.7%–81.7%). Slower absorption from SC tissue was associated with a BMI of ≥30. Lower peak, and higher trough concentrations were observed with SC administration. Although lower bioavailability was observed with SC administration, the PTA for unbound drug concentrations greater than the MIC for more than 90% of the time between doses was higher for SC compared with IV administration at MICs between 0.25 and 4 mg/L. Simulated SC doses of 3 g twice daily had similar PTA to standard IV dosing of 2 g three times daily. A simulated 6 g continuous 24 h infusion of SC cefazolin had a favourable pharmacokinetic profile. Conclusion SC cefazolin appears to be well tolerated, with an improved pharmacokinetic profile compared with IV administration. Either 3 g twice daily, or 6 g as a 24 h SC infusion could be considered for future evaluation. [ABSTRACT FROM AUTHOR]

Enterococcus faecalis is responsible for numerous serious infections, and treatment options often include ampicillin combined with an aminoglycoside or dual beta-lactam therapy with ampicillin and a third-generation cephalosporin. The mechanism of dual beta-lactam therapy relies on the saturation of penicillin-binding proteins (PBPs). Ceftobiprole exhibits high affinity binding to nearly all E. faecalis PBPs, thus suggesting its potential utility in the treatment of severe E. faecalis infections. The availability of therapeutic drug monitoring (TDM) for ampicillin and ceftobiprole has prompted the use of this drug combination in our hospital. Due to the time-dependent antimicrobial properties of these antibiotics, an infusion administration longer than indicated was chosen. From January to December 2020, twenty-one patients were admitted to our hospital for severe E. faecalis infections and were treated with this approach. We retrospectively analyzed their clinical characteristics and pharmacological data. Most patients achieved an aggressive PK/PD target (T > 4–8 minimum inhibitory concentration, MIC) when this alternative drug combination regimen was used. Our analysis included the study of E. faecalis biofilm production, as well as the kinetics of bacterial killing of ceftobiprole alone or in combination with ampicillin. Time-kill experiments revealed strong bactericidal activity of ceftobiprole alone at concentrations four times higher than the MIC for some enterococcal strains. In cases where a bactericidal effect of ceftobiprole alone was not evident, synergism with ampicillin and bactericidal activity were demonstrated instead. The prolonged infusion of ceftobiprole, either alone or with ampicillin, emerges as a valuable option for the treatment of severe invasive E. faecalis infections. [ABSTRACT FROM AUTHOR]

Background Subcutaneous delivery of antibiotics is a practical alternative to IV administration. Meropenem is commonly used to treat infections caused by resistant Gram-negative organisms. Methods This was a prospective, crossover self-controlled study in 11 stable inpatients established on meropenem. Participants received a single dose of subcutaneous meropenem, in 50 mL normal saline via gravity feed. Venous blood sampling was performed at baseline, 0.5, 1, 2, 4 and 8 h following the subcutaneous and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were assessed. Results Subcutaneous meropenem was well tolerated. The bioavailability of subcutaneous administration was 81.5% (95% CI 71.6%–93.2%). Increasing BMI was associated with slower absorption from subcutaneous tissue. Compared with IV, subcutaneous administration resulted in lower peak and higher trough concentrations. Despite the lower bioavailability observed, the PTA for free drug concentrations greater than the MIC for more than 40% of the time between doses was higher for subcutaneous than IV administration at MIC values between 0.03 and 8 mg/L. Simulated subcutaneous doses of 1.5 g twice daily, or 3 g continuous 24 h infusion had improved PTA relative to standard IV dosing of 1 g three times daily. Conclusions Subcutaneous meropenem appears to be well tolerated and has a favourable pharmacokinetic profile. Either 1.5 g twice daily or 3 g as a 24 h subcutaneous infusion could be considered for future evaluation. [ABSTRACT FROM AUTHOR]

A retrospective audit at Prince of Wales Hospital and Sydney Children's Hospital evaluated the impact of implementing a preoperative team huddle in theatre settings. The study found that the team huddle led to increased frequency of full multidisciplinary attendance, improving awareness, communication, and efficiency among staff. While there was a slight decrease in staff attitudes towards safety and teamwork, the team huddle was well-received and positively impacted theatre operations. The report, authored by a diverse group of individuals, emphasizes the importance of effective communication and teamwork in enhancing perioperative care. [Extracted from the article]

Polyanion rotations are often linked to cation diffusion, but the study of multiple polyanion systems is scarce due to the complexities in experimentally determining their dynamic interactions. This work focuses on BH4‐based argyrodites, synthesized to achieve a high conductivity of 11 mS cm−1. Advanced tools, including high‐resolution X‐ray diffraction, neutron pair distribution function analysis, and mutinuclear magic‐angle‐spinning nuclear magnetic resonance (NMR) spectroscopy and relaxometry, along with theoretical calculations, are employed to unravel the dynamic intricacies among the dual polyanion lattice and active charge carriers. The findings reveal that the anion sublattice of Li5.07PS4.07(BH4)1.93 affords an even temporal distribution of Li among PS43− and BH4−, suggesting minimal trapping of the charge carriers. Moreover, the NMR relaxometry unveils rapid BH4− rotation on the order of ∼GHz, affecting the slower rotation of neighboring PS43− at ∼100 MHz. The PS43− rotation synchronizes with Li+ motion and drives superionic transport. Thus, the PS43− and BH4− polyanions act as two‐staged dual motors, facilitating rapid Li+ diffusion. [ABSTRACT FROM AUTHOR]

The article focuses on the potential benefits of prolonged infusions of beta-lactam antibiotics for treating sepsis. Topics include the time-dependent bactericidal activity of beta-lactams, research findings from the BLING III trial on the effectiveness of continuous versus intermittent infusions in ICU patients, and the debate over applying this strategy beyond critical care settings.

The antimicrobial concentration–time profile in humans affects antimicrobial activity, and as such, it is critical for preclinical infection models to simulate human-like dynamic concentration–time profiles for maximal translatability. This review discusses the setup, principle, and application of various dynamic in vitro PK/PD infection models commonly used in the development and optimisation of antimicrobial treatment regimens. It covers the commonly used dynamic in vitro infection models, including the one-compartment model, hollow fibre infection model, biofilm model, bladder infection model, and aspergillus infection model. It summarises the mathematical methods for the simulation of the pharmacokinetic profile of single or multiple antimicrobials when using the serial or parallel configurations of in vitro systems. Dynamic in vitro models offer reliable pharmacokinetic/pharmacodynamic data to help define the initial dosing regimens of new antimicrobials that can be developed further in clinical trials. They can also help in the optimisation of dosing regimens for existing antimicrobials, especially in the presence of emerging antimicrobial resistance. In conclusion, dynamic in vitro infection models replicate the interactions that occur between microorganisms and dynamic antimicrobial exposures in the human body to generate data highly predictive of the clinical efficacy. They are particularly useful for the development new treatment strategies against antimicrobial-resistant pathogens. [ABSTRACT FROM AUTHOR]