The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®): A clinical part-randomised phase 1 study in healthy volunteers.

BACKGROUND: Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically. OBJECTIVES: Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation. DESIGN: Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings. SETTING: Single clinical centre in the UK, April to July 2021. PARTICIPANTS: Twenty-one healthy male and female individuals. INTERVENTIONS: Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas. MAIN OUTCOME MEASURES: Overall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored. RESULTS: Adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®. CONCLUSION: NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. TRIAL REGISTRATION: EudraCT Number: 2020-005719-35, MHRA approval.

Demystifying the role of anaesthetists in clinical coding in the Australian healthcare system.

Despite the self-evident importance of hospital funding, many anaesthetists remain unsure of exactly how their daily work relates to hospital reimbursement. A lack of awareness of the nuances of the Australian hospital activity-based funding system has the potential to affect anaesthetic department reimbursement and thus resourcing. Activity-based funding relies on clinical coders reviewing clinical documentation and quantifying the care given to a patient during an admission. Errors in funding allocation may arise when there is a disconnect between the work performed and the information coded. In anaesthesia, there are several factors impeding this process, including clinical understanding of coding, system setup and coders' understanding of anaesthesia. This article explores these factors from the clinical anaesthetist's point of view and suggests solutions, such as awareness and education, clinician-coder cooperation and redesign of documentation systems at a systems level that anaesthetic departments can incorporate.

Outcomes and Costs of Open and Endovascular Revascularisation for Chronic Limb Ischaemia in an Australian Cohort.

OBJECTIVE: The costs of open and endovascular revascularisation to treat peripheral artery disease (PAD) have not been fully established. This study examined the costs of both the index admission and any readmissions to hospital within 30 days of discharge for people having revascularisation at a single centre in Australia. METHODS: This was a retrospective analysis of prospectively collected data. Eligible participants were those presenting with chronic limb ischaemia requiring revascularisation between 2002 and 2017. Generalised linear modelling was used to estimate mean (95% confidence interval [95% CI]) hospital costs for the index and readmission hospital treatments. RESULTS: A total of 302 participants presenting with intermittent claudication (n=219; 72.5%) or chronic limb threatening ischaemia (n=83; 27.5%) treated by open (n=116; 38.4%) or endovascular (n=186; 61.6%) revascularisation were included. Forty-eight (48) (15.9%) participants were readmitted within 30 days of discharge from their index admission. The mean estimated index admission hospital cost was AUD$13,827 (95% CI, $11,935-$15,818) per person. This cost was significantly greater for open as compared to endovascular revascularisation (p<0.001). The mean estimated hospital cost was AUD$15,324 ($10,944-$19,966) per person readmitted. When comparing participants treated before and after 2010, the total hospital costs decreased, mainly due to decreased lengths of hospital stay for open procedures. CONCLUSIONS: In this study the hospital costs were less for endovascular than open revascularisation of chronic limb ischaemia. Costs decreased over time. Readmission is an important contributor to the overall costs of peripheral revascularisation.

A case report of iatrogenic gas gangrene post colonoscopy successfully treated with conservative management- is surgery always necessary?

BACKGROUND: Colonoscopy is a routine procedure in diagnosis and treatment of colonic disease. While generally regarded as a safe procedure, potentially fatal complications can occur. Gas gangrene is one such complication, with very high mortality. There are few cases of gas gangrene occurring after colonoscopy, making it one of the rarer complications of this procedure. There have been no previously reported cases of a patient surviving such an infection and the optimal treatment strategy is contentious. This report describes a case of intramural gas gangrene of the colon, treated conservatively with antibiotic therapy in which the patient survived with full recovery. CASE PRESENTATION: A 71-year-old, previously healthy male presented 6 h post apparently uncomplicated colonoscopic polypectomy with rigors, nausea, vomiting and right upper quadrant pain. At presentation he was febrile at 40.1 °C but hemodynamically stable. Abdominal computed tomography revealed substantial colonic thickening and several focal intramural gas bubbles (pneumatosis intestinalis) surrounding the polypectomy site. Within 24 h post procedure he became hypotensive and was admitted to ICU in frank septic shock requiring inotropes, and with demonstrable septic myocardial depression. Bloods showed multi-organ derangement with leukocytosis, lactic acidosis, haemolytic anaemia and hyperbilirubinemia. A diagnosis of presumed Clostridial gas gangrene was made, and treatment was initiated with benzylpenicillin, clindamycin, metronidazole and vancomycin. After 4 days in ICU he was stepped down, and discharged after a further 10 days with no surgical or endoscopic interventions. At three-month review he reported being back to full health. CONCLUSIONS: This case demonstrates that gas gangrene infection is a possible complication of colonoscopic polypectomy. This is a cause of rapid deterioration in post-colonoscopy patients and has been misdiagnosed as colonic perforation in previously reported cases of retroperitoneal gas gangrene. Such misdiagnosis delays antibiotic therapy, which likely plays a role in the high mortality of this condition. Early diagnosis and initiation of antibiotic therapy with benzylpenicillin and clindamycin as seen in this case is essential for patient survival. While surgery is typically performed, non-operative management of pneumatosis intestinalis, and potentially gas gangrene is becoming more common and was utilized effectively in this patient.

A systematic review and meta-analysis of risk factors for and incidence of 30-day readmission after revascularization for peripheral artery disease.

OBJECTIVE: Readmission to the hospital after revascularization for peripheral artery disease (PAD) is frequently reported. No consensus exists as to the exact frequency and risk factors for readmission. This review aimed to determine the incidence of and risk factors for 30-day readmission after revascularization for PAD. METHODS: PubMed/Medline (Ovid), Scopus, Web of Science, the Cochrane Library, and CINAHL were searched systematically from inception until May 20, 2018. Studies were eligible for inclusion if they included patients with diagnosed PAD undergoing revascularization and reported the readmission rate and a statistical evaluation of the association of at least one risk factor with readmission. Studies were excluded if data for other procedures could not be distinguished from revascularization. Two authors undertook study selection independently with the final inclusion decision resolved through consensus. The PRISMA and Meta-analyses of Observational Studies in Epidemiology guidelines were followed regarding data extraction and quality assessment, which was performed by two authors independently. Data were pooled using a random effects model. RESULTS: The primary outcome was readmission within 30 days of revascularization. Fourteen publications reporting the outcomes of 526,008 patients were included. Reported readmission rates ranged from 10.9% to 30.0% with a mean of 16.4% (95% confidence interval [CI], 15.1%-17.9%). Meta-analyses suggested the following risk factors had a significant association with readmission: female sex (odds ratio [OR], 1.13; 95% CI, 1.05-1.21), black race (OR, 1.36; 95% CI, 1.28-1.46), dependent functional status (OR, 1.72; 95% CI, 1.43-2.06), critical limb ischemia (OR, 2.12; 95% CI, 1.72-2.62), emergency admission (OR, 1.75; 95% CI, 1.43-2.15), hypertension (OR, 1.39; 95% CI, 1.26-1.54), heart failure (OR, 1.82; 95% CI, 1.50-2.20), chronic pulmonary disease (OR, 1.19; 95% CI, 1.08-1.32), diabetes (OR, 1.47; 95% CI, 1.32-1.63), chronic kidney disease (OR, 1.93; 95% CI, 1.62-2.31), dialysis dependence (OR, 2.08; 95% CI, 1.75-2.48), smoking (OR, 0.83; 95% CI, 0.78-0.89), postoperative bleeding (OR, 1.70; 95% CI, 1.23-2.35), and postoperative sepsis (OR, 4.13; 95% CI, 2.02-8.47). CONCLUSIONS: Approximately one in six patients undergoing revascularization for PAD are readmitted within 30 days of their procedure. This review identified multiple risk factors predisposing to readmission, which could potentially serve as a way to target interventions to reduce readmissions.

The future of quantum biology.

Biological systems are dynamical, constantly exchanging energy and matter with the environment in order to maintain the non-equilibrium state synonymous with living. Developments in observational techniques have allowed us to study biological dynamics on increasingly small scales. Such studies have revealed evidence of quantum mechanical effects, which cannot be accounted for by classical physics, in a range of biological processes. Quantum biology is the study of such processes, and here we provide an outline of the current state of the field, as well as insights into future directions.

Ultrafast charge separation and nongeminate electron-hole recombination in organic photovoltaics.

The mechanism of electron-hole separation in organic solar cells is currently hotly debated. Recent experimental work suggests that these charges can separate on extremely short timescales (<100 fs). This can be understood in terms of delocalised transport within fullerene aggregates, which is thought to emerge on short timescales before vibronic relaxation induces polaron formation. However, in the optimal heterojunction morphology, electrons and holes will often re-encounter each other before reaching the electrodes. If such charges trap and cannot separate, then device efficiency will suffer. Here we extend the theory of ultrafast charge separation to incorporate polaron formation, and find that the same delocalised transport used to explain ultrafast charge separation can account for the suppression of nongeminate recombination in the best devices.

Ultrafast long-range charge separation in organic semiconductor photovoltaic diodes.

Understanding the charge-separation mechanism in organic photovoltaic cells (OPVs) could facilitate optimization of their overall efficiency. Here we report the time dependence of the separation of photogenerated electron hole pairs across the donor-acceptor heterojunction in OPV model systems. By tracking the modulation of the optical absorption due to the electric field generated between the charges, we measure ~200 millielectron volts of electrostatic energy arising from electron-hole separation within 40 femtoseconds of excitation, corresponding to a charge separation distance of at least 4 nanometers. At this separation, the residual Coulomb attraction between charges is at or below thermal energies, so that electron and hole separate freely. This early time behavior is consistent with charge separation through access to delocalized π-electron states in ordered regions of the fullerene acceptor material.