Search

Background: The aim of the present study was to compare the outcomes of pediatric LT with left liver grafts, obtained either from a living donor (LD) or a split deceased donor (sDD)., Methods: Retrospective single-center study from 2002 to 2022. All pediatric LT with left liver grafts (not including middle hepatic vein) from LD or sDD were included. Reduced grafts were not included., Results: A total of 112 pediatric LT were performed: 58 with LD grafts and 54 with sDD grafts (17 split ex situ and 37 in situ). Donor characteristics were similar, apart from donor age (33 years in LD vs. 30 years in sDD, p = 0.03). Indications were similar with 55% biliary atresia in each group. Retransplantation was more frequently performed in the sDD group (2% vs. 15%, p = 0.01). Recipient age, weight, and PELD score at transplant were not significantly different between groups. Cold ischemia time was longer for sDD (158 min in LD vs. 390 min in sDD; p < 0.0001). Posttransplant peak ALT was higher with sDD grafts (1470 vs. 1063, p = 0.018), and hospital stay was longer with sDD grafts (27 vs. 21 days, p = 0.005). However, there was no difference between groups in terms of major morbidity (Dindo-Clavien grade ≥3), vascular and biliary complications, and 90-day mortality. Patient survival at 10 years was 93.1% for LD and 92.8% for sDD (p = 0.807). Graft survival at 10 years was 89.7% for LD and 83.1% for sDD (p = 0.813)., Conclusions: Technically similar LD and sDD grafts achieve very similar postoperative and long-term outcomes with excellent patient and graft survival., (© 2024 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

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., (© 2024. The Author(s).)

Objective: European Alliance of Associations for Rheumatology (EULAR) task forces (TF) requires participation of ≥2 junior members, a health professional in rheumatology (HPR) and two patient research partners for the development of recommendations or points to consider. In this study, participation of these junior and representative members was compared with the one of traditional TF members (convenor, methodologist, fellow and expert TF members)., Methods: An online survey was developed and emailed to previous EULAR TF members. The survey comprised multiple-choice, open-ended and 0-100 rating scale (fully disagree to fully agree) questions., Results: In total, 77 responded, 48 (62%) women. In total, 46 (60%) had participated as a junior or representative TF member. Most junior/representative members reported they felt unprepared for their first TF (10/14, 71%). Compared with traditional members, junior/representative members expressed a significantly higher level of uncertainty about their roles within the TF (median score 23 (IQR 7.0-52.0) vs 7 (IQR 0.0-21.0)), and junior/representative members felt less engaged by the convenor (54% vs 71%). Primary factors that facilitated interaction within a TF were experience, expertise and preparation (54%), a supportive atmosphere (42%) and a clear role (12%)., Conclusion: Juniors, patients and HPR experience various challenges when participating in a EULAR TF. These challenges differ from and are generally less pronounced than those experienced by traditional TF members. The convenor should introduce the participants to the tasks, emphasise the value of their contributions and how to prepare accordingly for the TF meeting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications., Methods and Analysis: The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC., Ethics and Dissemination: All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals., Trial Registration Number: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2024 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

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., Competing Interests: Potential conflicts of interest. M.W.D. advises, is on the speakers’ bureau for Gilead, AbbVie, GSK, and Merck, and has received grants from Gilead and AbbVie. J.G. advises, is on the speakers’ bureau for, and received grants from Gilead; he advises and is on the speakers’ bureau for AbbVie and MSD. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

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/day ½ 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., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

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 pK a and with potential implications for in vivo release and absorption in women with elevated vaginal pH., (© 2021. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s).)

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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 (C max ) values were 1.35- to 1.61-fold higher than C max . 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., (© 2022 Eisai Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

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., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Karl Malcolm reports financial support was provided by 10.13039/501100000873Queen's University Belfast. Prof. Karl Malcolm has patent #US20190105192A1 pending to International Partnership for Microbicides. Prof. Karl Malcolm has patent #EP3209251A1 pending to International Partnership for Microbicides., (© 2022 The Author(s).)

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., (© 2021 Wiley Periodicals LLC.)

A dapivirine-releasing silicone elastomer vaginal ring for reducing women's risk of HIV acquisition has recently been approved. A next-generation multipurpose vaginal ring releasing dapivirine and levonorgestrel is currently in development, offering hormonal contraception and HIV prevention from a single device. Previously, we reported challenges with incorporating levonorgestrel into rings manufactured from addition-cure silicone elastomers due to an irreversible chemical reaction between the levonorgestrel molecule and the hydride-functionalised crosslinker component of the silicone elastomer formulation, leading to low drug content assay, cure inhibition, and reduced ring mechanical properties (which may account for the increased incidence of ring expulsion in vivo). Here, we report on the development and testing of various custom silicone elastomer materials specifically formulated to circumvent these issues. After extensive testing of the custom silicones and subsequent manufacture and testing (Shore M hardness, pot life, content assay, oscillatory rheology, mechanical testing) of rings containing both dapivirine and levonorgestrel, a lead candidate formulation was selected that was amenable to practical ring manufacture via injection molding, exhibited no substantial levonorgestrel binding, and offered suitable mechanical properties., Competing Interests: Leeanne Brown, Matthew Kihara, François Martin and Nicole McMullen are employees of Elkem Silicones. The other authors declare no competing financial or personal interest., (© 2021 The Author(s).)

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.

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 (H 2 O 2 ), 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., Competing Interests: All authors declare no actual or potential conflicts of interest., (© 2021 The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: There is considerable interest in vaginal ring technology for sustained/controlled administration of drugs to the human vagina. Seven drug-releasing vaginal rings have reached market and other experimental devices are in preclinical/clinical development. Although most women who have used rings are satisfied and find them acceptable, involuntary expulsions and voluntary removals are known to occur and are widely reported. There have been no previous efforts to review this topic and understand the factors contributing  to expulsions., Areas Covered: This article will help researchers, clinicians and product developers better understand the pertinent factors and issues around ring expulsions and removals, and inform new research aimed at optimizing ring product design. The review contains four sections: (i) introduction to vaginal ring technology; (ii) discussion of the anatomical, physiological, device, and user factors affecting ring expulsion; (iii) review of involuntary expulsions; (iv) review of voluntary removals; and (v) concluding remarks/opinions., Expert Opinion: Further research is needed to better understand the factors contributing to involuntary ring expulsions and removals so that rings can be better designed to minimize rates of expulsion and to reduce removals. Determination of optimum ring dimensions and stiffness are likely key factors, alongside better counseling around removal and reinsertion.

Introduction: Aboriginal and Torres Strait Islander Australians living in remote locations suffer disproportionately from chronic hepatitis B (CHB). Defining the temporospatial epidemiology of the disease-and assessing the ability of local clinicians to deliver optimal care-is crucial to improving patient outcomes in these settings., Methods: The demographic, laboratory and radiology findings in all patients diagnosed with CHB after 1990, and presently residing in remote Far North Queensland (FNQ), tropical Australia, were correlated with their management and clinical course., Results: Of the 602 patients, 514 (85%) identified as Aboriginal and Torres Strait Islander Australians, 417 (69%) of whom had Torres Strait Islander heritage. Among the 514 Aboriginal and Torres Strait Islander Australians, there were only 61 (12%) born after universal postnatal vaccination was introduced in 1985. Community CHB prevalence varied significantly across the region from 7/1707 (0.4%) in western Cape York to 55/806 (6.8%) in the Eastern Torres Strait Islands. Although 240/602 (40%) are engaged in care, with 65 (27%) meeting criteria for antiviral therapy, only 43 (66%) were receiving this treatment. Among 537 with complete data, 32 (6%) were cirrhotic, of whom 15 (47%) were engaged in care and 10 (33%) were receiving antiviral therapy. Only 64/251 (26%) in whom national guidelines would recommend hepatocellular carcinoma (HCC) surveillance are receiving screening, however, only 20 patients have been diagnosed with HCC since 1999., Conclusion: Vaccination has had a dramatic effect on CHB prevalence in FNQ in only a generation. However, although engagement in care is the highest in Australia, this is not translating into initiation of antiviral therapy in all those that should be receiving it, increasing their risk of developing cirrhosis and HCC. New strategies are necessary to improve the care of Indigenous Australians living with CHB to reduce the morbidity and mortality of this preventable disease., Competing Interests: The authors have declared that no competing interests exist.

Millions of distinct metal-organic frameworks (MOFs) can be made by combining metal nodes and organic linkers. At present, over 90,000 MOFs have been synthesized and over 500,000 predicted. This raises the question whether a new experimental or predicted structure adds new information. For MOF chemists, the chemical design space is a combination of pore geometry, metal nodes, organic linkers, and functional groups, but at present we do not have a formalism to quantify optimal coverage of chemical design space. In this work, we develop a machine learning method to quantify similarities of MOFs to analyse their chemical diversity. This diversity analysis identifies biases in the databases, and we show that such bias can lead to incorrect conclusions. The developed formalism in this study provides a simple and practical guideline to see whether new structures will have the potential for new insights, or constitute a relatively small variation of existing structures.

Here we report the first use of an additive manufacturing (AM) technique based on high pressure material jetting of molten thermoplastic for the fabrication of dapivirine (DPV) loaded vaginal rings (VRs). The VRs are compared to those produced conventionally using injection molding (IM). VRs (outer diameter 54.0 mm, cross-sectional diameter 4.0 mm) were manufactured by either injection molding or Arburg Plastic Freeforming (APF) - a proprietary droplet deposition modelling (DDM) process, using medical grade thermoplastic polyurethanes (TPUs) loaded with 10% w/w DPV. This unique DDM process was used to produce rings of 100, 50 and 10% matrix infill density. DDM printed VRs with 10% density (57-62 mg drug load) exhibited up to seven-fold increase in DPV release compared to injection molded rings containing 190-194 mg DPV. This work has shown that DDM using the APF technique can be used to manufacture drug delivery devices of varying geometries, densities and surface areas to give precise levels of control over the drug release kinetics. This work presents a new opportunity to increase the release of poorly water-soluble compounds or to achieve desired dosing levels using lower drug loadings than those required using conventional thermoplastic processing techniques., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Limiting the increase of CO 2 in the atmosphere is one of the largest challenges of our generation 1 . Because carbon capture and storage is one of the few viable technologies that can mitigate current CO 2 emissions 2 , much effort is focused on developing solid adsorbents that can efficiently capture CO 2 from flue gases emitted from anthropogenic sources 3 . One class of materials that has attracted considerable interest in this context is metal-organic frameworks (MOFs), in which the careful combination of organic ligands with metal-ion nodes can, in principle, give rise to innumerable structurally and chemically distinct nanoporous MOFs. However, many MOFs that are optimized for the separation of CO 2 from nitrogen 4-7 do not perform well when using realistic flue gas that contains water, because water competes with CO 2 for the same adsorption sites and thereby causes the materials to lose their selectivity. Although flue gases can be dried, this renders the capture process prohibitively expensive 8,9 . Here we show that data mining of a computational screening library of over 300,000 MOFs can identify different classes of strong CO 2 -binding sites-which we term 'adsorbaphores'-that endow MOFs with CO 2 /N 2 selectivity that persists in wet flue gases. We subsequently synthesized two water-stable MOFs containing the most hydrophobic adsorbaphore, and found that their carbon-capture performance is not affected by water and outperforms that of some commercial materials. Testing the performance of these MOFs in an industrial setting and consideration of the full capture process-including the targeted CO 2 sink, such as geological storage or serving as a carbon source for the chemical industry-will be necessary to identify the optimal separation material.

Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastic polymers or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drug-releasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13 C NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reactions with the hydrosiloxane groups in the silicone elastomer leading to covalent binding. The results also highlight potential strategies for further optimising the dapivirine + levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The primary aim was to investigate post-use ring weight as a potential measure of cumulative adherence to a progesterone-releasing vaginal ring., Study Design: We weighed and quantified residual progesterone in 115 vaginal rings following 90-day use by participants in an acceptability trial conducted in Nigeria, Senegal and Kenya. The primary objective was to correlate residual progesterone content with post-use ring weight. Secondary objectives included correlating ring weight with putative duration of ring use, and, where participants used two rings consecutively in the study, correlating residual content between these paired rings., Results: Mean ring weight and progesterone content of used rings was 8.62±0.24 g and 1245±245 mg respectively, versus 9.37±0.02 and 2058±21 mg for control rings. Most used rings (90.4%) had residual progesterone levels less than 85% of the nominal loading. Linear regression showed a strong positive linear trend between residual progesterone content and post-use ring weight for all rings (r 2 =0.82). Duration of ring use was inversely associated (p=.00020) with ring weight., Conclusions: Post-use ring weight is highly correlated with residual progesterone content, a benchmark objective cumulative measure of adherence, and thus potentially useful as a surrogate objective measure of cumulative adherence to a progesterone-releasing vaginal ring., Implication Statement: For vaginal rings containing a high initial drug loading and releasing a relatively large fraction of the initial loading during clinical use, post-use ring weight may offer a simple and inexpensive alternative to residual content testing for accurate monitoring of user adherence., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In two recent Phase III clinical trials, use of a 25 mg dapivirine vaginal ring significantly reduced HIV acquisition rates. Post hoc analysis from one of the trials indicated higher rates of protection among women over the age of 21 years when compared to younger women, most likely due to reduced adherence in the latter group. There is currently no information available on how release of dapivirine from the ring is affected by either its intermittent removal from the vagina or women's cleaning of the ring before re-insertion. Here, in vitro drug stability and product performance characteristics of the dapivirine ring were assessed under simulated conditions of real-world use. The impact of systematic deviations from the 28-day continuous use protocol upon in vitro release performance, was investigated. Also, the effect of ring exposure to a range of common household chemicals - including bath salts, bleach, detergent and personal lubricants - was examined through measurement of dapivirine content and stability. Dapivirine in vitro release under intermittent schedules was similar to that obtained under the normal continuous schedule ignoring the periods of interruption. Ring exposure to various household chemicals had no discernible impact on dapivirine assay value, degradation or stability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Limited information is available about hospitalization rates for cirrhosis in Australia., Methods: Using information on all hospital episodes of care for patients admitted to Queensland hospitals during 2008-2016, we report age-standardized hospitalization rates/10,000 person-years, in-hospital case-fatality rate among these admissions (n = 30,327), and examine the factors associated with hospital deaths using logistic regression analyses., Findings: Hospitalization rates increased from 8.50/10,000 (95% confidence interval (CI) 8.18-8.82) to 11.21/10,000 (95%CI 10.87-11.54) between 2008 and 2016, and peaked in men aged 55-59 years (34.03/10,000) and in Indigenous Australians (32.79/10,000). The number of admissions increased by 61.7% from 2701 admissions in 2008 to 4367 in 2016. During the same period, the percentage increase varied by socioeconomic disadvantage (3.2%/year in the most affluent vs. 9.4%/year in the most disadvantaged quintile; p < 0.001). Alcohol misuse was a contributing factor for cirrhosis in 55.1% of admissions, and socioeconomic disadvantage in 26.8%. The overall in-hospital case-fatality rate was 9.7% for males and 9.3% for females, and decreased in males (p < 0.001). Predictors of in-hospital mortality included hepatorenal syndrome (adjusted odds ratio (AOR) = 7.24, 95%CI 5.99-8.75), HCC (AOR = 2.53, 95%CI 2.20-2.91), hepatic encephalopathy (AOR = 1.94, 95%CI 1.61-2.34), acute peritonitis (AOR = 1.93, 95%CI 1.61-2.33), jaundice (AOR = 1.82, 95%CI 1.20-2.75), age ≥ 70 years (AOR = 1.63, 95%CI 1.38-1.92), a higher comorbidity index (p = 0.021), and residence outside of a "major city" (p < 0.001)., Interpretation: The increasing healthcare use by Australians with cirrhosis has resource and economic implications. Our data highlight the disproportionate impact of cirrhosis on Indigenous Australians and people from the most socioeconomically disadvantaged areas., Funding: Brisbane Diamantina Health Partners., Competing Interests: There are no financial disclosures.

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES is incorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Biologically derived metal-organic frameworks (bio-MOFs) are of great importance as they can be used as models for bio-mimicking and in catalysis, allowing us to gain insights into how large biological molecules function. Through rational design, here we report the synthesis of a novel bio-MOF featuring unobstructed Watson-Crick faces of adenine (Ade) pointing towards the MOF cavities. We show, through a combined experimental and computational approach, that thymine (Thy) molecules diffuse through the pores of the MOF and become base-paired with Ade. The Ade-Thy pair binding at 40-45% loading reveals that Thy molecules are packed within the channels in a way that fulfill both the Woodward-Hoffmann and Schmidt rules, and upon UV irradiation, Thy molecules dimerize into Thy<>Thy. This study highlights the utility of accessible functional groups within the pores of MOFs, and their ability to 'lock' molecules in specific positions that can be subsequently dimerized upon light irradiation, extending the use of MOFs as nanoreactors for the synthesis of molecules that are otherwise challenging to isolate.

Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture 'exposed-core' vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two ¼-length excipient-modified silicone elastomer cores - each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows - provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000 ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Vaginal rings (VRs) are currently marketed for contraceptive or hormone regulation purposes, and investigationally, have been widely reported for delivery of antiretrovirals to reduce HIV transmission. To date, there is no national or international standard for the mechanical testing and minimum performance characteristics of any VR based products. Here, we describe a series of mechanical tests examining the durometer hardness, static and dynamic compression response, tensile properties and twist resistance of vaginal rings. The tests were conducted on currently marketed VRs and a number of the International Partnership for Microbicides' (IPM) investigational VR formulations. With wider application in the field, the tests described herein could form the basis for a more standardised approach to the mechanical testing of VRs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Charge equilibration (Qeq) methods can estimate the electrostatic potential of molecules and periodic frameworks by assigning point charges to each atom, using only a small fraction of the resources needed to compute density functional (DFT)-derived charges. This makes possible, for example, the computational screening of thousands of microporous structures to assess their performance for the adsorption of polar molecules. Recently, different variants of the original Qeq scheme were proposed to improve the quality of the computed point charges. One focus of this research was to improve the gas adsorption predictions in metal-organic frameworks (MOFs), for which many different structures are available. In this work, we review the evolution of the method from the original Qeq scheme, understanding the role of the different modifications on the final output. We evaluated the result of combining different protocols and set of parameters, by comparing the Qeq charges with high quality DFT-derived DDEC charges for 2338 MOF structures. We focused on the systematic errors that are attributable to specific atom types to quantify the final precision that one can expect from Qeq methods in the context of gas adsorption where the electrostatic potential plays a significant role, namely, CO 2 and H 2 S adsorption. In conclusion, both the type of algorithm and the input parameters have a large impact on the resulting charges, and we draw some guidelines to help the user to choose the proper combination of the two for obtaining a meaningful set of charges. We show that, considering this set of MOFs, the accuracy of the original Qeq scheme is often still comparable with the most recent variants, even if it clearly fails in the presence of certain atom types, such as alkali metals.

This work investigates the impact of vaginal ring size and drug loading on the in vitro release, safety, ease of fit, and pharmacokinetics in cynomolgus macaques of matrix-type silicone elastomer vaginal rings containing a combination of the non-nucleoside reverse transcriptase inhibitor dapivirine and the protease inhibitor darunavir. Drug-free and drug-loaded vaginal rings having three different geometries were manufactured by reaction injection molding. In vitro drug release was assessed using both a solvent/water mixture and a vaginal fluid simulant. Macaques fitted with drug-free vaginal rings for 28 days were assessed by colposcopy, cytological evaluation of cervico-vaginal lavage and histological evaluation of tissue after ring removal. The 20 × 4.5 mm combination ring, deemed most appropriate for vaginal fit and comfort in the macaques, was evaluated for pharmacokinetics over 28 days. Substantial differences were observed in the in vitro release profiles between the three ring sizes. However, these differences were not manifest in vivo, where measured drug concentrations after 20 × 4.5 mm ring use were not significantly different from those reported previously with a 25 × 6 mm ring. These results suggest that ring placement and fit is an important species-specific study parameter that should be optimised prior to pharmacokinetic testing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this work, we report the synthesis of SION-8, a novel metal-organic framework (MOF) based on Ca(II) and a tetracarboxylate ligand TBAPy 4- endowed with two chemically distinct types of pores characterized by their hydrophobic and hydrophilic properties. By altering the activation conditions, we gained access to two bulk materials: the fully activated SION-8F and the partially activated SION-8P with exclusively the hydrophobic pores activated. SION-8P shows high affinity for both CO 2 ( Q st = 28.4 kJ/mol) and CH 4 ( Q st = 21.4 kJ/mol), while upon full activation, the difference in affinity for CO 2 ( Q st = 23.4 kJ/mol) and CH 4 ( Q st = 16.0 kJ/mol) is more pronounced. The intrinsic flexibility of both materials results in complex adsorption behavior and greater adsorption of gas molecules than if the materials were rigid. Their CO 2 /CH 4 separation performance was tested in fixed-bed breakthrough experiments using binary gas mixtures of different compositions and rationalized in terms of molecular interactions. SION-8F showed a 40-160% increase (depending on the temperature and the gas mixture composition probed) of the CO 2 /CH 4 dynamic breakthrough selectivity compared to SION-8P, demonstrating the possibility to rationally tune the separation performance of a single MOF by manipulating the stepwise activation made possible by the MOF's biporous nature.

Intravaginal rings (VRs) have been widely reported for administration of pharmaceutical drugs - most notably estrogens, progestogens and antiretrovirals - to the vagina for clinical benefit. Here, for the first time, we describe the design, manufacture and preclinical testing of VRs for sustained/controlled release of the cervical ripening agents isosorbide mononitrate (ISMN) and misoprostol (MP), either singly or in combination. Matrix-type silicone elastomer VRs containing ISMN showed declining daily release rates, ranging from 31 to 168 mg (Day 1) to 3-25 mg (Day 11). Novel orifice-type rings, in which a MP-containing silicone elastomer core is partially exposed to the external environment by overmolding with a non-medicated silicone elastomer sheath containing orifices, provided relatively constant daily MP release rates over 14 days (∼20 or 60 μg/day depending on the formulation type). Combination VRs offered simultaneous release of both ISMN and MP over 14 days, with an almost constant MP release rate (60 μg/day) and steadily declining daily ISMN release (295 mg on Day 1 and 24 mg on Day 11). The VR design can be readily tailored to provide sustained or controlled release of ISMN and MP at rates potentially useful for cervical ripening., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state 13 C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) - an estrogenic steroid molecule also containing an ethynyl functional group - to an addition cure silicone elastomer. By preparing silicone elastomer samples containing 13 C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Metal-organic frameworks (MOFs) have emerged as versatile materials for applications ranging from gas separation and storage, catalysis, and sensing. The attractive feature of MOFs is that, by changing the ligand and/or metal, they can be chemically tuned to perform optimally for a given application. In most, if not all, of these applications one also needs a material that has a sufficient mechanical stability, but our understanding of how changes in the chemical structure influence mechanical stability is limited. In this work, we rationalize how the mechanical properties of MOFs are related to framework bonding topology and ligand structure. We illustrate that the functional groups on the organic ligands can either enhance the mechanical stability through formation of a secondary network of nonbonded interactions or soften the material by destabilizing the bonded network of a MOF. In addition, we show that synergistic effect of the bonding network of the material and the secondary network is required to achieve optimal mechanical stability of a MOF. The developed molecular insights in this work can be used for systematic improvement of the mechanical stability of the materials by careful selection of the functional groups., Competing Interests: The authors declare no competing financial interest.

Aims: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers., Methods: This was a three-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampicin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count) and safety of avatrombopag were evaluated., Results: Coadministration of a single 20-mg dose of avatrombopag with fluconazole at steady-state resulted in 2.16-fold increase of AUC of avatrombopag, prolonged terminal elimination phase half-life (from 19.7 h to 39.9 h) and led to a clinically significant increase in maximum platelet count (1.66-fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Coadministration of rifampicin caused a 0.5-fold decrease in AUC and shortened terminal elimination phase half-life (from 20.3 h to 9.84 h), but has no impact on maximum platelet count. Coadministration with interacting drugs was found to be generally safe and well-tolerated., Conclusions: The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended., (© 2018 The British Pharmacological Society.)

Scientific interest in two-dimensional (2D) materials, ranging from graphene and other single layer materials to atomically thin crystals, is quickly increasing for a large variety of technological applications. While in silico design approaches have made a large impact in the study of 3D crystals, algorithms designed to discover atomically thin 2D materials from their parent 3D materials are by comparison more sparse. We hypothesize that determining how to cut a 3D material in half (i.e., which Miller surface is formed) by severing a minimal number of bonds or a minimal amount of total bond energy per unit area can yield insight into preferred crystal faces. We answer this question by implementing a graph theory technique to mathematically formalize the enumeration of minimum cut surfaces of crystals. While the algorithm is generally applicable to different classes of materials, we focus on zeolitic materials due to their diverse structural topology and because 2D zeolites have promising catalytic and separation performance compared to their 3D counterparts. We report here a simple descriptor based only on structural information that predicts whether a zeolite is likely to be synthesizable in the 2D form and correctly identifies the expressed surface in known layered 2D zeolites. The discovery of this descriptor allows us to highlight other zeolites that may also be synthesized in the 2D form that have not been experimentally realized yet. Finally, our method is general since the mathematical formalism can be applied to find the minimum cut surfaces of other crystallographic materials such as metal-organic frameworks, covalent-organic frameworks, zeolitic-imidazolate frameworks, metal oxides, etc., Competing Interests: The authors declare no competing financial interest.

We have developed a simple text mining algorithm that allows us to identify surface area and pore volumes of metal-organic frameworks (MOFs) using manuscript html files as inputs. The algorithm searches for common units (e.g., m 2 /g, cm 3 /g) associated with these two quantities to facilitate the search. From the sample set data of over 200 MOFs, the algorithm managed to identify 90% and 88.8% of the correct surface area and pore volume values. Further application to a test set of randomly chosen MOF html files yielded 73.2% and 85.1% accuracies for the two respective quantities. Most of the errors stem from unorthodox sentence structures that made it difficult to identify the correct data as well as bolded notations of MOFs (e.g., 1a) that made it difficult identify its real name. These types of tools will become useful when it comes to discovering structure-property relationships among MOFs as well as collecting a large set of data for references.

We report the syntheses and structures of five metal-organic frameworks (MOFs) based on transition metals (Ni II , Cu II , and Zn II ), adenine, and di-, tri-, and tetra-carboxylate ligands. Adenine, with multiple N donor sites, was found to coordinate to the metal centers in different binding modes including bidentate (through N7 and N9, or N3 and N9) and tridentate (through N3, N7, and N9). Systematic investigations of the protonation states of adenine in each MOF structure via X-ray photoelectron spectroscopy revealed that adenine can be selectively protonated through N1, N3, or N7. The positions of H atoms connected to the N atoms were found from the electron density maps, and further supported by the study of C-N-C bond angles compared to the literature reports. DFT calculations were performed to geometrically optimize and energetically assess the structures simulated with different protonation modes. The present study highlights the rich coordination chemistry of adenine and provides a method for the determination of its protonation states and the location of protonated N atoms of adenine within MOFs, a task that would be challenging in complicated adenine-based MOF structures.