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Studies have shown that natural products can induce paraptosis in tumour cell lines. Paraptosis is characterized by cytoplasmic vacuolation arising from the endoplasmic reticulum (ER) and mitochondria. The mechanism of paraptosis is unclear; however, dysregulation of Ca2+ homeostasis is believed to affect paraptosis induction. This study investigated the mechanism of cell death induced by a phytocannabinoid ratio in the MCF7 breast cancer cell line. The crystal violet assay was used to detect changes in viability and morphology changes were investigated using light and transmission electron microscopy. Various inhibitors, fluorescent staining with high‐content screening, and Western blot analysis were used to investigate different cell death mechanisms. The phytocannabinoid ratio induced significant cell death and cytoplasmic vacuolation in MCF7 cells; however, no apoptosis, necrosis, autophagy, or ferroptosis was detected. Vacuolation induced by phytocannabinoid treatment was inhibited by cycloheximide, suggesting paraptosis induction. The mechanism of paraptosis induction was investigated, and it was found that treatment (1) induced ER dilation and mitochondrial swelling, (2) induced significant ER stress and mitochondrial Ca2+ overload and dysfunction, which appeared to be mediated by the voltage‐dependent anion channel, and (3) significantly impaired all mitochondrial metabolic pathways. The data demonstrated that paraptosis induced by the cannabinoid ratio was mediated by Ca2+ flux from the ER to the mitochondria. These findings highlight a novel mechanism of cannabinoid‐induced cell death and emphasize the anti‐cancer potential of cannabinoid ratios, which exhibited enhanced effects compared to individual cannabinoids. [ABSTRACT FROM AUTHOR]

Background: Neonatal mortality in India has fallen steadily and was estimated to be 24 per 1000 live births in the year 2017. However, neonatal mortality remains high in rural parts of the country. The Community Health Promotion and Medical Provision and Impact On Neonates (CHAMPION2) trial investigates the effect of a complex health intervention on neonatal mortality in the Satna District of Madhya Pradesh., Methods/design: The CHAMPION2 trial forms one part of a cluster-randomised controlled trial with villages (clusters) randomised to receive either a health (CHAMPION2) or education (STRIPES2) intervention. Villages receiving the health intervention are controls for the education intervention and vice versa. The primary outcome is neonatal mortality. The effect of the active intervention on the primary outcome (compared to usual care) will be expressed as a risk ratio, estimated using a generalised estimating equation approach with robust standard errors that take account of clustering at village level. Secondary outcomes include maternal mortality, stillbirths, perinatal deaths, causes of death, health care and knowledge, hospital admissions of enrolled women during pregnancy or in the immediate post-natal care period or of their babies (during the neonatal period), maternal blood transfusions, and the cost effectiveness of the intervention. A total of 196 villages have been randomised and over 34,000 women have been recruited in CHAMPION2., Discussion: This update to the published trial protocol gives a detailed plan for the statistical analysis of the CHAMPION2 trial., Trial Registration: Registry of India: CTRI/2019/05/019296. Registered on 23 May 2019. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2., (© 2024. The Author(s).)

Water quality guidelines are an important tool for managing environmental pressures on freshwater streams. Currently, there is a lack of guideline values for fine sediment deposition in South Australian and, more broadly, Australian and overseas streams despite the potentially profound impacts of sediment deposition on aquatic communities. We used an outdoor recirculating stream mesocosm to assess the responses of freshwater diatoms and macroinvertebrates to fine sediment burial after six weeks following a pulsed event. Communities were exposed to five treatments of fine sediment deposition (inert sand) with an average depth between 1 and 20 mm, added on top of, and compared to, representative background sediments from a high-quality stream dominated by hard-bottom sediments and detritus. The most pronounced change was between the control and treatment one (1 mm sediment depth). Sediment deposition negatively affected diatom composition, with a decrease in functional diversity but a concurrent increase in taxonomic diversity arising from increased abundances of motile species. For macroinvertebrates, there was a clear negative response in the richness and abundance of the sensitive Ephemeroptera, Plecoptera and Trichoptera insect orders to fine sediment burial, and an associated higher macroinvertebrate drift propensity. This study highlights the importance of incorporating functional and behavioural responses in addition to taxonomic metrics when assessing biotic responses to stressors. This study recommends a new guideline which restricts additional fine sediment deposition to <1 mm in temperate South Australian freshwater streams, particularly those dominated by hard-bottom substrates and, or containing sensitive aquatic taxa. This threshold could act as an interim guideline for these stream types elsewhere in the absence of comparable studies., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

COVID-19 made apparent the devastating impact viral pandemics have had on global health and order. Development of broad-spectrum antivirals to provide early protection upon the inevitable emergence of new viral pandemics is critical. In this work, antiviral polymers are discovered using a combination of high-throughput polymer synthesis and antiviral screening, enabling diverse polymer compositions to be explored. Amphipathic polymers, with ionizable tertiary amine groups, are the most potent antivirals, effective against influenza virus and SARS-CoV-2, with minimal cytotoxicity. It is hypothesized that these polymers interact with the viral membrane as they showed no activity against a nonenveloped virus (rhinovirus). The switchable chemistry of the polymers during endosomal acidification was evaluated using lipid monolayers, indicating that a complex synergy between hydrophobicity and ionization drives polymer-membrane interactions. This new high-throughput methodology can be adapted to continue to engineer the potency of the lead candidates or develop antiviral polymers against other emerging viral classes.

Aim: The research aim was to understand the inpatient experience of women who received postoperative care for mastectomy surgery in an acute surgical ward., Design: A Qualitative Descriptive Research design was used., Methods: The lead researcher conducted individual semi-structured interviews with 10 women who received postoperative care following mastectomy surgery in an acute hospital surgical ward. The transcribed interview data was analysed using a thematic analysis., Results: A mastectomy is a momentous event in any woman's life. In the initial post-operative phase, the physical intrusion of surgery, aesthetics of the ward, and mixed-gender rooms were all found to influence the women's journey towards holistic recovery. Therapeutic care from all in the healthcare team and a ward setting conducive to recovery were identified as favourable influences towards physical and emotional healing., Conclusion: Recognising that a mastectomy 'is not just physical' may help the breast care team optimise the first 24 h of postoperative care in preparation for the challenges the women may face on discharge., Implications for the Profession And/or Patient Care: In an acute inpatient setting, a women's physical needs may be prioritised over the psychological and emotional ramifications of a mastectomy. Post-operative inpatient care for breast cancer surgery requires not only professional competency with clinical and technical tasks, but therapeutic nursing and communication skills to support women's psychological needs., Patient or Public Contribution: The findings were drawn from 10 women, narrating their inpatient experience for breast cancer surgery. All women had undergone a unilateral or bilateral mastectomy following breast cancer., (© 2024 The Author(s). Nursing Open published by John Wiley & Sons Ltd.)

Post COVID-19 condition or long COVID is highly prevalent and often debilitating, with key symptoms including fatigue, breathlessness, and brain fog. There is currently a lack of evidence-based treatments for this highly complex syndrome. There is a need for clinical trial platforms to rapidly evaluate nonpharmacological treatments to support affected individuals with symptom management. We co-produced a mixed methods feasibility study to evaluate a multi-arm digital decentralised clinical trial (DCT) platform to assess non-pharmacological interventions for Long COVID, using pacing interventions as an exemplar. The study demonstrated that the platform was able to successfully e-consent participants, randomise them into one of four intervention arms, capture baseline data, and capture outcomes relevant to a health economic evaluation. The study also highlighted several challenges, including difficulties with recruitment, imposter participants, and high attrition rates. We highlight how these challenges can potentially be mitigated to make a fully powered DCT more feasible., (© 2024. The Author(s).)

Introduction: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS., Methods and Analysis: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur., Ethics and Dissemination: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations., Trial Registration Numbers: NCT03387670; ISRCTN82598726., Competing Interests: Competing interests: JC has received support in the last 3 years from the Health Technology Assessment (HTA) Programme (National Institute for Health Research, NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by MS Canada. A local principal investigator for commercial trials funded by Ionis and Roche; and has taken part in advisory boards/consultancy for Biogen, Janssen, Lucid, Merck, NervGen, Novartis and Roche. OC declares being NIHR Research Professor (RP-2017-08-ST2-004); over the last 2 years, member of independent DSMB for Novartis; she gave a teaching talk in a Merck local symposium and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium; has received research grant support from the UK MS Society, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the US National MS Society and the NIHR-HTA. HLF has received honoraria for advisory boards and/or educational activities from Biogen, Merck, Novartis and Roche. HLF has research grant support from the NIHR Health Technology Assessment Programme and EME, UK MS Society and the Horne Family Charitable Trust. LF has received honoraria for speaking or as an advisory board member from Biogen, Novartis, Merck, Sanofi Genzyme and Roche, and received support for attending educational meetings from Biogen, Novartis, Merck, Sanofi Genzyme and Teva. GG declares that in the last 2 years he has received compensation for serving as a consultant or speaker or research support from Astoria Biologica, Aurinia Pharmaceuticals, Biogen, BMS-Celgene, GlaxoSmithKline, Janssens/J&J, Japanese Tobacco, Merck KGaA/EMD Serono, Moderna, Novartis, Sandoz, Sanofi, Roche/Genentech, Vir Biotechnology and Viracta. NJ is a principal investigator on commercial MS trials sponsored by Roche, Novartis and Biogen. He has received speakers honoraria from Merck and travel congress sponsorship from Novartis. MM has received travel support, speaker honoraria and consultation fees from Genzyme, Merck-Sereno, Novartis, Roche, the MS Academy and the Italian Multiple Sclerosis Foundation (FISM). RN attended paid advisory board for Novartis and Roche. SPavitt was MRC/National Institute for Health Research (NIHR)—Efficacy & Mechanism Evaluation Board Member from 2012–2018. SPluchino is founder, CSO and shareholder (>5%) of CITC and Chair of the Scientific Advisory Board at ReNeuron plc. CR declares research funding from Sanofi. DR declares consulting and/or speaker fees received from Biogen, Celgene, Janssen, MedDay, Merck, Novartis, Roche, Sanofi Genzyme and Teva. Additionally, research support paid to an institutional fund from Actelion, Biogen, GW Pharmaceuticals, Merck Serono, Mitsubishi, Novartis, Sanofi Genzyme, Teva and TG Therapeutics. AJT receives a fee from being Co-Chair, UCL-Eisai Steering Committee drug discovery collaboration; Member, National MS Society (USA) Research Programs Advisory Committee; Clinical Trials Committee, Progressive MS Alliance; Board member, European Charcot Foundation; Editor in Chief, Multiple Sclerosis Journal; Editorial Board Member, The Lancet Neurology. He receives no fee from being: Chair (Scientific Ambassadors), ‘Stop MS’ Appeal Board, UK MS Society; Research & academic counsellor, Fundació Privada Cemcat; Ambassador, European Brain Council. AJT additionally holds a patent for the MSIS-29 Impact Scale., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

DNA data storage is a potential alternative to magnetic tape for archival storage purposes, promising substantial gains in information density. Critical to the success of DNA as a storage media is an understanding of the role of environmental factors on the longevity of the stored information. In this paper, we evaluate the effect of exposure to ionizing particle radiation, a cause of data loss in traditional magnetic media, on the longevity of data in DNA data storage pools. We develop a mass action kinetics model to estimate the rate of damage accumulation in DNA strands due to neutron interactions with both nucleotides and residual water molecules, then utilize the model to evaluate the effect several design parameters of a typical DNA data storage scheme have on expected data longevity. Finally, we experimentally validate our model by exposing dried DNA samples to different levels of neutron irradiation and analyzing the resulting error profile. Our results show that particle radiation is not a significant contributor to data loss in DNA data storage pools under typical storage conditions., (© 2024. The Author(s).)

Background: Polyethylene glycol (PEG) can fuse severed closely apposed axolemmas and restore axonal continuity. The authors evaluated the effects of PEG fusion on functional recovery in a rodent forelimb model of peripheral nerve injury., Methods: The median nerves of male Lewis rats ( n = 5 per group) were transected and repaired with standard suture repair (SR), SR with PEG (PEG), or SR with PEG and 1% methylene blue (PEG+MB); a sham surgery group was also included. Proximal stimulation produced compound nerve and muscle action potentials recorded distally. The contralateral limb of each animal acted as an internal control for grip strength measurements., Results: Compound nerve and muscle action potentials immediately returned in all PEG and PEG+MB animals, but not in SR animals. The PEG and PEG+MB groups demonstrated earlier return of function by postoperative day (POD) 7 (62.6 ± 7.3% and 50.9 ± 6.7% of contralateral limb grip strength, respectively) compared with the SR group, in which minimal return of function was not measurable until POD 21. At POD 98, the PEG group grip strength recovered to 77.2 ± 2.8% and the PEG+MB grip strength recovered to 79.9 ± 4.4%, compared with 34.9 ± 1.8% recovery in the SR group ( P < 0.05). The PEG and PEG+MB groups reached 50% of the sham group grip strength on POD 3.8 and POD 6.3, respectively, whereas the SR group did not reach 50% grip strength recovery of the sham group throughout the study period., Conclusion: PEG fusion plus neurorrhaphy with or without MB reestablished axonal continuity, shortened recovery time, and augmented functional recovery compared with suture neurorrhaphy alone., Clinical Relevance Statement: PEG fusion with neurorrhaphy may bypass Wallerian degeneration, leading to augmented and shortened functional recovery., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Older people admitted to hospital in an emergency often have prolonged inpatient stays that worsen their outcomes, increase health-care costs, and reduce bed availability. Growing evidence suggests that the biopsychosocial complexity of their problems, which include cognitive impairment, depression, anxiety, multiple medical illnesses, and care needs resulting from functional dependency, prolongs hospital stays by making medical treatment less efficient and the planning of post-discharge care more difficult. We aimed to assess the effects of enhancing older inpatients' care with Proactive Integrated Consultation-Liaison Psychiatry (PICLP) in The HOME Study. We have previously described the benefits of PICLP reported by patients and clinicians. In this Article, we report the effectiveness and cost-effectiveness of PICLP-enhanced care, compared with usual care alone, in reducing time in hospital., Methods: We did a parallel-group, multicentre, randomised controlled trial in 24 medical wards of three English acute general hospitals. Patients were eligible to take part if they were 65 years or older, had been admitted in an emergency, and were expected to remain in hospital for at least 2 days from the time of enrolment. Participants were randomly allocated to PICLP or usual care in a 1:1 ratio by a database software algorithm that used stratification by hospital, sex, and age, and randomly selected block sizes to ensure allocation concealment. PICLP clinicians (consultation-liaison psychiatrists supported by assisting clinicians) made proactive biopsychosocial assessments of patients' problems, then delivered discharge-focused care as integrated members of ward teams. The primary outcome was time spent as an inpatient (during the index admission and any emergency readmissions) in the 30 days post-randomisation. Secondary outcomes were the rate of discharge from hospital for the total length of the index admission; discharge destination; the length of the index admission after random allocation truncated at 30 days; the number of emergency readmissions to hospital, the number of days spent as an inpatient in an acute general hospital, and the rate of death in the year after random allocation; the patient's experience of the hospital stay; their view on the length of the hospital stay; anxiety (Generalized Anxiety Disorder-2); depression (Patient Health Questionnaire-2); cognitive function (Montreal Cognitive Assessment-Telephone version); independent functioning (Barthel Index of Activities of Daily Living); health-related quality of life (five-level EuroQol five-dimension questionnaire); and overall quality of life. Statisticians and data collectors were masked to treatment allocation; participants and ward staff could not be. Analyses were intention-to-treat. The trial had a patient and public involvement panel and was registered with ISRTCN (ISRCTN86120296)., Findings: 2744 participants (1399 [51·0%] male and 1345 [49·0%] female) were enrolled between May 2, 2018, and March 5, 2020; 1373 were allocated to PICLP and 1371 to usual care. Participants' mean age was 82·3 years (SD 8·2) and 2565 (93·5%) participants were White. The mean time spent in hospital in the 30 days post-randomisation (analysed for 2710 [98·8%] participants) was 11·37 days (SD 8·74) with PICLP and 11·85 days (SD 9·00) with usual care; adjusted mean difference -0·45 (95% CI -1·11 to 0·21; p=0·18). The only statistically and clinically significant difference in secondary outcomes was the rate of discharge, which was 8.5% higher (rate ratio 1·09 [95% CI 1·00 to 1·17]; p=0·042) with PICLP-a difference most apparent in patients who stayed for more than 2 weeks. Compared with usual care, PICLP was estimated to be modestly cost-saving and cost-effective over 1 and 3, but not 12, months. No intervention-related serious adverse events occurred., Interpretation: This is the first randomised controlled trial of PICLP. PICLP is experienced by older medical inpatients and ward staff as enhancing medical care. It is also likely to be cost-saving in the short-term. Although the trial does not provide strong evidence that PICLP reduces time in hospital, it does support and inform its future development and evaluation., Funding: UK National Institute for Health and Care Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Liver grafts from controlled donation after circulatory death (cDCD) donors have lower utilization rates due to inferior graft and patient survival rates, largely attributable to the increased incidence of ischemic cholangiopathy, when compared with grafts from brain dead donors (DBD). Normothermic regional perfusion (NRP) may improve the quality of cDCD livers to allow for expansion of the donor pool, helping to alleviate the shortage of transplantable grafts. A systematic review and metanalysis was conducted comparing NRP cDCD livers with both non-NRP cDCD livers and DBD livers. In comparison to non-NRP cDCD outcomes, NRP cDCD grafts had lower rates of ischemic cholangiopathy [RR = 0.23, 95% CI (0.11, 0.49), p = 0.0002], primary non-function [RR = 0.51, 95% CI (0.27, 0.97), p = 0.04], and recipient death [HR = 0.5, 95% CI (0.36, 0.69), p < 0.0001]. There was no difference in outcomes between NRP cDCD donation compared to DBD liver donation. In conclusion, NRP improved the quality of cDCD livers compared to their non-NRP counterparts. NRP cDCD livers had similar outcomes to DBD grafts. This provides further evidence supporting the continued use of NRP in cDCD liver transplantation and offers weight to proposals for its more widespread adoption., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mastrovangelis, Frost, Hort, Laurence, Pang and Pleass.)

Introduction: There is an urgent need to build capacity among existing and incoming public health workers to enhance community-based work focused on prevention and health promotion. Public Health Essentials, a cohort-based facilitated asynchronous online capacity building intervention, was designed to build public health workers' strategic skills and professional confidence. Earlier research reported on the short-term learning outcomes of the intervention; in this paper, the authors report on results from a longer-term outcomes evaluation, including skill retention, skill application, and possible indicators of workforce retention and community health improvement., Methods: A sequential mixed-methods research design was used to assess and explore longer-term outcomes among a sample of Public Health Essentials graduates working in community public health roles., Results: Some 46% of eligible Public Health Essentials graduates ( n =70) completed a skills survey at 3 time points: before Public Health Essentials completion, after Public Health Essentials completion, and 3-6 months after Public Health Essentials completion. Longitudinal analysis of responses showed statistically significant skill gains over baseline (beginner → proficient, p <0.005), despite a slight drop in self-perceived ability 3-6 months after Public Health Essentials completion. Qualitative interviews with respondents and focus groups with their supervisors suggest that Public Health Essentials completion benefits participants' everyday work by developing strategic skills and grounding their work in shared public health language, paradigms, and values. Broader reported benefits include the ability to apply new skills to community public health prevention projects and expressed motivation to continue to work in public health., Conclusions: Successful completion of Public Health Essentials provides learners with durable skills applicable to public health work and may spur interest in continuing to work in the field of public health. The importance of developing and retaining a competent community-focused public health workforce cannot be overstated. Comprehensive-facilitated, online asynchronous capacity building programs may be an effective tool., (© 2024 The Author(s).)

Background: This update outlines amendments to the CHAMPION2/STRIPES2 cluster randomised trial protocol primarily made due to the COVID-19 pandemic and nationwide lockdown in India in 2020. These amendments were in line with national guidelines for health research during the COVID-19 pandemic., Methods: We did not change the original trial design, eligibility, and outcomes. Amendments were introduced to minimise the risk of COVID-19 transmission and ensure safety and wellbeing of trial staff, participants, and other villagers. CHAMPION2 intervention: participatory learning and action (PLA) and fixed day service (FDS) meeting were revised to incorporate social distancing and hygiene precautions. During the COVID-19 pandemic, PLA participation was limited to pregnant women and birthing partners. STRIPES2 intervention: before/after-school classes were halted for a period and then modified temporarily (reducing class sizes, and/or changing meeting places) with hygiene and safe distancing practices introduced., Data Collection: The research team gathered as much information as possible from participants by telephone. If the participant had no telephone or could not be contacted by telephone, data were collected in person. COVID-19 precautions: trial teams were trained on COVID-19 precautions and used personal protective equipment whilst in the villages for trial-related activities. After restarting the trial between June and September 2020 in a phased manner, some trial activities were suspended again in all the trial villages from April to June 2021 due to the second wave of COVID-19 cases and lockdown imposed in Satna, Madhya Pradesh. Trial timelines were also revised, with outcomes measured later than originally planned., Trial Registration: Clinical Trial Registry of India CTRI/2019/05/019296. Registered 23 May 2019. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2 ., (© 2024. The Author(s).)

Statistical models with random intercepts and slopes (RIAS models) are commonly used to analyze longitudinal data. Fitting such models sometimes results in negative estimates of variance components or estimates on parameter space boundaries. This can be an unlucky chance occurrence, but can also occur because certain marginal distributions are mathematically identical to those from RIAS models with negative intercept and/or slope variance components and/or intercept-slope correlations greater than one in magnitude. We term such parameters "pseudo-variances" and "pseudo-correlations," and the models "non-regular." We use eigenvalue theory to explore how and when such non-regular RIAS models arise, showing: (i) A small number of measurements, short follow-up, and large residual variance increase the parameter space for which data (with a positive semidefinite marginal variance-covariance matrix) are compatible with non-regular RIAS models. (ii) Non-regular RIAS models can arise from model misspecification, when non-linearity in fixed effects is ignored or when random effects are omitted. (iii) A non-regular RIAS model can sometimes be interpreted as a regular linear mixed model with one or more additional random effects, which may not be identifiable from the data. (iv) Particular parameterizations of non-regular RIAS models have no generality for all possible numbers of measurements over time. Because of this lack of generality, we conclude that non-regular RIAS models can only be regarded as plausible data-generating mechanisms in some situations. Nevertheless, fitting a non-regular RIAS model can be acceptable, allowing unbiased inference on fixed effects where commonly recommended alternatives such as dropping the random slope result in bias., (© 2024 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Charles Frost,1 Andrew Shenker,1 Stanford Jhee,2 Zhigang Yu,1 Jessie Wang,3 Alexander Bragat,1 Janice Pursley,4 Frank LaCreta1 1Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA; 2PAREXEL International Early Phase, Glendale, CA, USA; 3Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA; 4Analytical and Bioanalytical Development, Bristol Myers Squibb, Princeton, NJ, USA Purpose: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects. Subjects and methods: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration. Results: Ascending single doses of apixaban 2.5–50 mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10 mg. Apixaban reached maximum concentrations (Cmax) 3–4 h postdose, with mean Cmax ranging from 52.5–485.0 to 44.8–494.3 ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13 h and the renal clearance was 1.1 and 0.8 L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG. Conclusion: Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients. Keywords: safety, pharmacokinetics, pharmacodynamics, Japanese, apixaban, anticoagulation, Asian, novel, Eliquis

Charles Frost,1 Yan Song,1 Zhigang Yu,2 Jessie Wang,3 Lois S Lee,4 Alan Schuster,5 Allyson Pollack,1 Frank LaCreta1 1Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA; 2Medical Sciences, Amgen Asia R&D Center, Shanghai, People’s Republic of China; 3Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, 4Clinical Research, Intercept Pharmaceuticals, San Diego, CA, 5Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, NJ, USA Purpose: Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug−drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin® (digoxin) and single-dose Tenormin® (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies. Patients and methods: The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2–10, followed by apixaban 20 mg and digoxin 0.25 mg once daily on days 11–20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of apixaban 10 mg, atenolol 100 mg, or apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (Cmax) and area under the concentration–time curve (AUCtau), with and without apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%–125% (digoxin) or 70%–143% (atenolol). A similar analysis was performed to assess the effect of atenolol on apixaban. Results: Apixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol Cmax and AUC were entirely within their respective no-effect intervals. Apixaban Cmax and AUCinf were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study. Conclusion: Apixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between apixaban and atenolol. Coadministration of digoxin or atenolol with apixaban in healthy subjects was generally well tolerated. Keywords: oral anticoagulant, factor Xa inhibitor, drug–drug interaction, Phase 1