Characteristics of emerging new autoimmune diseases after COVID-19 vaccination: A sub-study by the COVAD group.

BACKGROUND: Despite the overall safety and efficacy of COVID-19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post-vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post-vaccination. METHODS: A cross-sectional study was conducted among participants with self-reported new-onset SAIDs using the COVID-19 Vaccination in Autoimmune Diseases (COVAD) 2 study dataset-a validated, patient-reported e-survey-to analyze the long-term safety of COVID-19 vaccines. Baseline characteristics of patients with new-onset SAIDs and vaccinated healthy controls (HCs) were compared after propensity score matching based on age and sex in a 1:4 ratio. RESULTS: Of 16 750 individuals, 74 (median age 52 years, 79.9% females, and 76.7% Caucasians) had new-onset SAID post-vaccination, mainly idiopathic inflammatory myopathies (IIMs) (n = 23, 31.51%), arthritis (n = 15; 20.53%), and polymyalgia rheumatica (PMR) (n = 12, 16.40%). Higher odds of new-onset SAIDs were noted among Caucasians (OR = 5.3; 95% CI = 2.9-9.7; p < .001) and Moderna vaccine recipients (OR = 2.7; 95% CI = 1.3-5.3; p = .004). New-onset SAIDs were associated with AID multimorbidity (OR = 1.4; 95% CI = 1.1-1.7; p < .001), mental health disorders (OR = 1.6; 95% CI = 1.3-1.9; p < .001), and mixed race (OR = 2.2; 95% CI = 1.2-4.2; p = .010), where those aged >60 years (OR = 0.6; 95% CI = 0.4-0.8; p = .007) and from high/medium human development index (HDI) countries (compared to very high HDI) reported fewer events than HCs. CONCLUSION: This study reports a low occurrence of new-onset SAIDs following COVID-19 vaccination, primarily IIMs, PMR, and inflammatory arthritis. Identified risk factors included pre-existing AID multimorbidity, mental health diseases, and mixed race. Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID-19 vaccination in the general population. However, long-term studies are needed to understand the autoimmune phenomena arising post-vaccination.

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia.

Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies.

INTRODUCTION: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the "Collating the Voice of People with Autoimmune Diseases" COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. METHODS: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients' lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. CONCLUSION: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.

Two into one does go: Formulation development of a multipurpose combination vaginal ring releasing dapivirine and metronidazole for prevention of HIV infection and treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common but often asymptomatic dysbiosis of the human vagina characterized by an imbalance in the normal vaginal microbiota due to loss of lactobacilli and an overgrowth of certain anaerobic bacteria. While BV itself is not a sexually transmitted infection, it is associated with an increased risk in women of various sexually acquired infections, including human immunodeficiency virus (HIV) infection. There is, therefore, a strong rationale for pursuing new multipurpose products that seek to treat or prevent BV alongside preventing HIV infection. With the dapivirine-releasing vaginal ring for HIV prevention now approved in several African countries, here we report formulation development of a next-generation ring product that releases both dapivirine (DPV) and the antibiotic drug metronidazole (MET). Following thermal analysis studies to characterize the phase behaviour of DPV-MET mixtures and rheological analysis to assess the cure characteristics of the active silicone elastomer mixes, matrix-type rings were manufactured containing 25 or 200 mg DPV in combination with 100, 250, 500, 1000 or 2000 mg MET. The results for drug content, in vitro release, mechanical testing, and Gardnerella vaginalis time-kill experiments demonstrate the feasibility of incorporating both DPV and MET in a matrix-type ring formulation and indicate that clinically effective release rates may be possible.

Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV - MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.

Extending the scope of dietetic practice in a regional setting: Dietitians credentialed to insert and manage nasogastric tubes.

BACKGROUND & AIMS: To describe the process of credentialing and implementing dietitian insertion of nasogastric tubes (NGTs) in a regional setting in Australia, and report on patient outcomes, timeliness and safety of insertion, and staff acceptance. METHODS: An observational, mixed-methods study of service and patient outcomes was undertaken during the 2 years (2018-2020) following the implementation of dietitian credentialling for the insertion and management of NGTs. Data relating to the insertion of NGTs by credentialled dietitians were collected prospectively. A staff survey was circulated during and after the data collection period. Data has been reported descriptively. RESULTS: The model of care was successfully implemented with two dietitians credentialed to insert NGTs. There were 38 unique occasions of NGT insertions for 31 individual patients. Eighty-seven percent (n = 33) of cases were inpatients. NGT insertion was successfully performed by the dietitian 82% of the time (n = 31). No medical complications relating to NGT insertion were reported following a dietitian inserted NGT, with the exception of one incidence of mild epistaxis. The average insertion time was 25.5 min (14.1), the average number of insertion attempts by a dietitian was 1.7 (1.27) and on one occasion more than one x-ray was required. CONCLUSION: This study supports the recommendations of Dietitians Australia that this model of care is viable as an extended scope of practice model of care for dietetic departments across Australia. This evaluation adds to the evidence base for extended scope of practice and informs future directions for the service and training of dietitians.

Refining the in vitro release test method for a dapivirine-releasing vaginal ring to match in vivo performance.

Previously reported in vitro release test methods for drug-releasing vaginal rings containing poorly water-soluble drugs have described use of water-alcohol systems or surfactant solutions in efforts to maintain sink conditions. Here, as part of efforts to more closely match in vitro and in vivo release for the 25 mg dapivirine matrix-type silicone elastomer vaginal ring for HIV prevention, we have investigated alternatives to the 1:1 v/v water/isopropanol medium described previously. Specifically, we evaluated dapivirine release from rings into (i) monophasic water/isopropanol mixtures of varying compositions and (ii) biphasic buffer/octanol systems using pH 4.2 and pH 7.0 buffers. The rate and mechanism of dapivirine release were dependent upon the isopropanol concentration in the release medium, in accordance with the observed trend in drug solubility. At 0 and 10% v/v isopropanol concentrations, dapivirine release followed a partition-controlled mechansim. For media containing ≥ 20% v/v isopropanol, in vitro release of dapivirine was significantly increased and obeyed permeation-controlled kinetics. Cumulative release of ~3.5 mg dapivirine over 28 days was obtained using a water isopropanol mixture containing 20% v/v isopropanol, similar to the ~4 mg dapivirine released in vivo. Dapivirine release into the biphasic buffer/octanol system (intended to mimic the fluid/tissue environment in vivo) was constrained by the limited solubility of dapivirine in the buffer component in which the ring resided, such that cumulative dapivirine release was consistently lower than that observed with the 20% v/v isopropanol in water medium. Release into the biphasic system was also pH dependent, in line with dapivirine's pKa and with potential implications for in vivo release and absorption in women with elevated vaginal pH.

Phase 1 Single Ascending and Multiple Ascending Dose Studies of Phosphodiesterase-9 Inhibitor E2027: Confirmation of Target Engagement and Selection of Phase 2 Dose in Dementia With Lewy Bodies Trial.

BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. METHODS: Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanese/non-Japanese), and food on pharmacokinetics (PK)/pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement. RESULTS: E2027 PK profiles were biphasic (elimination half-life: ~30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects. CONCLUSIONS: S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial.

A Comparison of Environmental Impact of Various Silicas Using a Green Chemistry Evaluator.

To answer questions surrounding the sustainability of silica production, MilliporeSigma's DOZN 2.0 Green Chemistry Evaluator was employed as it provides quantitative values based on the 12 principles of Green Chemistry. As a first study using DOZN 2.0 to evaluate the greenness of nanomaterials, a range of silica types were considered and their greenness scores compared. These included low- and high-value silicas, both commercial and emerging, such as precipitated, gel, fumed, colloidal, mesoporous, and bioinspired silicas. When surveying these different types of silicas, it became clear that while low value silicas have excellent greenness scores, high-value silicas perform poorly on this scale. This highlighted the tension between high-value silicas that are desired for emerging markets and the sustainability of their synthesis. The calculations were able to quantify the issues pertaining to the energy-intensive reactions and subsequent removal of soft templates for the sol-gel processes. The importance of avoiding problematic solvents during processes and particularly releasing them as waste was identified. The calculations were also able to compare the amount of waste generated as well as their hazardous nature. The effects of synthesis conditions on greenness scores were also investigated in order to better understand the relationship between the production process and their sustainability.

E2027 Cardiac Safety Evaluation With Concentration-Response Modeling of ECG Data to Inform Dose Selection in Studies in Patients With Dementia With Lewy Bodies.

BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. PATIENTS AND METHODS: A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. RESULTS: A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of ∼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. CONCLUSION: This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.

Intravenous Perampanel as an Interchangeable Alternative to Oral Perampanel: A Randomized, Crossover, Phase I Pharmacokinetic and Safety Study.

Intravenous (IV) drug administration enables treatment of epilepsy when oral administration is temporarily not feasible. Perampanel is a once-daily antiseizure medication currently available as oral formulations. Study 050 (NCT03376997) was an open-label, randomized, single-dose, crossover study to evaluate the interchangeability of oral and IV perampanel in healthy subjects (N = 48). Bioequivalence of single 12-mg doses of IV (30-, 60-, or 90-minute infusion) and oral perampanel, ≥6 weeks apart, was assessed. Analyses indicated bioequivalence of area under the plasma concentration-time curve extrapolated to infinity for 30- and 60-minute IV infusions and oral perampanel doses (geometric mean ratio [90% confidence interval], 0.93 [0.84-1.02] and 1.03 [0.97-1.09], respectively); however, IV maximum observed drug concentration (Cmax ) values were 1.35- to 1.61-fold higher than Cmax . Simulated plasma concentration-time profiles using pooled pharmacokinetic data further supported oral and IV perampanel interchangeability in two scenarios: 12-mg per day IV dosing during a temporary 7-day switch from oral steady-state maintenance therapy, and treatment initiation with 2-mg perampanel. Thirty-four (70.8%) subjects experienced treatment-related adverse events. The IV perampanel safety profile was similar to that of oral perampanel without new safety concerns. Perampanel IV infusions may be a suitable temporary alternative to oral perampanel for treatment maintenance and/or initiation.

Color, Scent and Size: Exploring Women's Preferences Around Design Characteristics of Drug-Releasing Vaginal Rings.

Steroid-releasing vaginal rings are available for contraception and estrogen replacement therapy, and a new antiretroviral-releasing ring was recently approved for HIV prevention. Marketed rings are white or transparent in appearance, non-scented, and supplied as one-size-fits-all devices with diameters ranging from 54 to 56 mm. In this study, drug-free silicone elastomer rings were manufactured in different sizes, colors and scents, and the opinions/preferences of 16 women (eThekwini District, South Africa; 20-34 years) assessed through focus group discussions and thematic analysis. Opinions varied on ring color and scent, with some women preferring specific colors or scent intensities, while for others these attributes were unimportant. Concerns about color and scent were linked to perceptions around vaginal health and safety related to chemical composition. There was greater agreement on preferred ring size; flexibility and width were considered important factors for insertion and comfort. Greater choice with ring products could facilitate acceptability and overall uptake.

In vitro drug release, mechanical performance and stability testing of a custom silicone elastomer vaginal ring releasing dapivirine and levonorgestrel.

We have previously reported a multipurpose silicone elastomer vaginal ring providing sustained release of dapivirine (an antiretroviral) and levonorgestrel (a progestin) for HIV prevention and hormonal contraception. During initial development, issues arose due to reaction between the ethynyl group in the levonorgestrel molecule and the hydride-functionalised polydimethylsiloxane components in the silicone elastomer formulation. This unwanted reaction occurred both during and to a lesser extent after ring manufacture, impacting the curing process, the mechanical properties of the ring, and the in vitro release of levonorgestrel. Recently, we reported custom silicone elastomer grades that minimise this reaction. In this follow-on study, we describe the manufacture, in vitro drug release, mechanical, and pharmaceutical stability testing of ring formulations prepared from a custom silicone elastomer and containing 200 mg dapivirine and 80, 160, 240 or 320 mg levonorgestrel. The rings showed mechanical properties similar to marketed ring products, sustained in vitro release of both drugs over 30 days in quantities deemed clinically relevant, offered acceptable assay values, and provided good product stability over 15 weeks at 40 °C and 75% relative humidity.

Domino transplantation for pediatric liver recipients: Obstacles, challenges, and successes.

BACKGROUND: Domino liver transplantation aims to address the need to increase the liver donor supply. In a domino liver transplant, the domino recipient receives the explanted liver from the recipient of a traditional liver transplant. The domino donor typically requires liver transplant to correct a metabolic disorder; the explanted liver thus has a single gene defect but otherwise normal structure and function. METHODS: In this review, we detail the history of domino liver transplantation, appropriate domino donor indications, the technical advances to the surgical approach, current outcomes, and future opportunities. RESULTS: Development of de novo disease in the domino recipient has relegated adult domino liver transplant to be considered a source of marginal donor livers. However, pediatric domino liver transplant has leveraged certain metabolic disorders, especially maple syrup urine disease, in which the liver enzyme deficiency can be compensated by the systemic presence of sufficient enzyme. Advances in the surgical aspects of assuring adequate length of vasculature have improved the safety of the procedure in both domino donors and recipients. CONCLUSIONS: Pediatric domino liver transplant utilizing domino donors with specific metabolic liver diseases should be considered a viable live donor option for children awaiting liver transplant.

The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug-Releasing Vaginal Rings.

The diversity and dynamics of the microbial species populating the human vagina are increasingly understood to play a pivotal role in vaginal health. However, our knowledge about the potential interactions between the vaginal microbiota and vaginally administered drug delivery systems is still rather limited. Several drug-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and many others are in preclinical and clinical development for these and other clinical indications. As with all implantable polymeric devices, drug-releasing vaginal rings are subject to surface bacterial adherence and biofilm formation, mostly associated with endogenous microorganisms present in the vagina. Despite more than 50 years since the vaginal ring concept was first described, there has been only limited study and reporting around bacterial adherence and biofilm formation on rings. With increasing interest in the vaginal microbiome and vaginal ring technology, this timely review article provides an overview of: (i) the vaginal microbiota, (ii) biofilm formation in the human vagina and its potential role in vaginal dysbiosis, (iii) mechanistic aspects of biofilm formation on polymeric surfaces, (iv) polymeric materials used in the manufacture of vaginal rings, (v) surface morphology characteristics of rings, (vi) biomass accumulation and biofilm formation on vaginal rings, and (vii) regulatory considerations.

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings.

Vaginal rings releasing antiretrovirals - either alone or in combination with contraceptive progestins - are being developed for prevention of human immunodeficiency virus (HIV) transmission via vaginal sex. Following Phase I trials, significant discolouration was observed on the surface of investigational silicone elastomer antiretroviral-contraceptive matrix-type vaginal rings containing either 25 mg dapivirine or 200 mg dapivirine plus levonorgestrel. In this study, potential causes of the discolouration have been assessed in vitro using simulated vaginal and menstrual fluids (SVF and SMF, respectively) to model in vivo exposure. The fluid compositions also included hydrogen peroxide (H2O2), hydrogen peroxide plus a copper intrauterine device (IUD), or synthetic dyes (representing personal care and household cleaning products). No discolouration was observed for rings exposed to SVF + hydrogen peroxide (with or without an IUD). However, the SVF + dye compositions showed significant ring discolouration, with staining patterns similar to those observed with rings that had been exposed to highly-coloured personal care and household cleaning products during clinical trial use. Exposure of rings to SMF compositions invariably caused yellow surface discolouration, dark spotting and markings, similar to the staining patterns observed following clinical use. The darker marks on the ring surface were identified as blood debris derived from the SMF. The study indicates that surface discolouration of rings in vivo can be attributed to exposure to menstrual fluid or highly coloured personal care or household cleaning products. Discolouration of the rings was not associated with any specific safety risks for the user, though severe discolouration could potentially impact acceptability and adherence.

Assessing the contagiousness of mass shootings with nonparametric Hawkes processes.

Gun violence and mass shootings are high-profile epidemiological issues facing the United States with questions regarding their contagiousness gaining prevalence in news media. Through the use of nonparametric Hawkes processes, we examine the evidence for the existence of contagiousness within a catalog of mass shootings and highlight the broader benefits of using such nonparametric point process models in modeling the occurrence of such events.

Effects of intermittent claudication due to arterial disease on pain-free gait.

INTRODUCTION: Studies of intermittent claudication gait report inconsistent outcomes. Changes in gait are often attributed to degradation of calf muscles, but causation has not been proven through real-time electromyographic data. Neither have effects of walking speed been fully considered. This study aimed to investigate the effect of intermittent claudication on kinematics, kinetics and muscle activity during pain-free gait. METHODS: 18 able bodied individuals and 18 with intermittent claudication walked at their preferred speed while lower limb kinematic, kinetic and electromyography data were collected. FINDINGS: People with intermittent claudication walk slower and with reduced step length. Internal ankle plantarflexion moment (P = 0.004, effect size = 0.96) and ankle power generation (P < 0.001, effect size = 1.36) in late stance were significantly reduced for individuals with intermittent claudication. Significant moment and power reductions at the knee and power reduction at hip occurred in early stance, with similar reductions in early and late stance for ground reaction forces. Peak electromyography of soleus activity was significantly reduced in late stance (P = 0.01, effect size = 1.1, n = 13). Effects were independent of walking speed. INTERPRETATION: Reductions in ankle plantarflexion moments and power generation were consistent with reduced soleus electromyography activity and reduced peak vertical ground reaction forces during late stance. These effects are not due to a reduced walking speed. Changes in knee and hip function are also unrelated to walking speed. These outcomes provide a platform for the design and evaluation of interventions that seek to restore normal walking and improve pain-free walking distances for people with intermittent claudication.

Prospective audit of the safety of endoscopist-directed nurse-administered propofol sedation in an Australian referral hospital.

BACKGROUND AND AIM: Endoscopist directed nurse administered propofol sedation (EDNAPS) is widely considered to be safe and efficient, but there are limited data from the Australian health-care setting, and Australian sedation guidelines do not support the practice. Thus, we report data from a prospective audit of EDNAPS over a 6.5-year period in an Australian referral hospital. METHODS: Consecutive endoscopic procedures performed between January 2013 and June 2019. Sedation protocol was an initial dose of midazolam 1-3 mg intravenously (i.v.) and propofol 10-50 mg i.v.. Further aliquots of propofol 10-30 mg i.v. were given as required. ProvationMD® endoscopic reporting system was used to prospectively record patient demographics, medication and dose, American Society of Anesthesiologist's (ASA) class, and sedation-related complications. RESULTS: During the 78-month period, 28 051 eligible procedures were performed; 3093 procedures performed with anesthetic support or without EDNAPS were excluded. In total, 24 958 procedures with EDNAPS were analyzed including 7563 gastroscopies, 12 941 colonoscopies, 2932 gastroscopy and colonoscopy, 1440 flexible sigmoidoscopies, and 82 combined gastroscopy and flexible sigmoidoscopy. Of these, 9539 were ASA 1 (38.2%), 13 680 were ASA 2 (54.8%), 1733 were ASA 3 (6.9%), and 4 were ASA 4 (0.02%). Sedation-related complications occurred in 66 patients (0.26%), predominantly transient hypoxic episodes. No patient required intubation for an airway emergency, and there was no sedation-related mortality. Sedation-related complications increased with ASA class and were significantly more common with gastroscopy. CONCLUSIONS: Endoscopist directed nurse administered propofol sedation is a safe way of performing endoscopic sedation in low-risk patients in the hospital setting.