Effectiveness and implementation of decentralized, community- and primary care-based strategies in promoting hepatitis B testing uptake: a systematic review and meta-analysis.

Background: Expanding chronic hepatitis B (CHB) testing through effective implementation strategies in primary- and community-care setting is crucial for elimination. Our study aimed to determine the effectiveness of all available strategies in the literature and evaluate their specifications and implementation outcomes, thereby informing future programming and policymaking. Methods: We conducted a systematic review and meta-analysis (PROSPERO CRD42023455781), searching Scopus, Embase, PubMed, and CINAHL databases up to June 05, 2024, for randomized controlled trials investigating primary- and community-care-based implementation strategies to promote CHB testing. Studies were screened against a priori eligibility criteria, and their data were extracted using a standardized protocol if included. ROB-2 was used to assess the risk of bias. Implementation strategies' components were characterized using the Behavior Change Wheel (BCW) framework. Random-effect models were applied to pool the effectiveness estimate by strategy. Mixed-effect meta-regression was employed to investigate if effectiveness varied by the number of strategy's BCW components. Findings: 7146 unique records were identified. 25 studies were eligible for the review, contributing 130,598 participants. 19 studies were included in the meta-analysis. No studies were conducted in low-and-middle-income countries. Implementation outcomes were reported in only ten studies (40%). Community-based strategies included lay health workers-led education (Pooled Risk Difference = 27.9% [95% Confidence Interval = 3.4-52.4], I2 = 99.3%) or crowdsourced education on social media (3.1% [-2.2 to 8.4], 0.0%). Primary care-based strategies consisted of electronic alert system (8.4% [3.7-13.1], 95.0%) and healthcare providers-led education (HCPs, 62.5% [53.1-71.9], 27.5%). The number of BCW-framework-driven strategy components showed a significant dose-response relationship with effectiveness. Interpretation: HCPs-led education stands out, and more enriched multicomponent strategies had better effectiveness. Future implementation strategies should consider critical contextual factors and policies to achieve a sustainable impact towards hepatitis B elimination targets. Funding: Tran Dolch Post-Doctoral Fellowship in Hepatology, Johns Hopkins University School of Medicine, Baltimore MD, USA.

Accurate PM2.5 urban air pollution forecasting using multivariate ensemble learning Accounting for evolving target distributions.

Over the past decades, air pollution has caused severe environmental and public health problems. According to the World Health Organization (WHO), fine particulate matter (PM2.5), a key component reflecting air quality, is the fourth leading cause of death worldwide after cardiovascular disease, smoking, and diet. Various research efforts have aimed to develop PM2.5 forecasting models that can be integrated into a solution to mitigate the adverse effects of air pollution. However, PM2.5 forecasting is challenging because air pollution data are non-stationary and influenced by multiple random effects. This paper proposes an effective multivariate multi-step ensemble machine learning model for predicting continuous 24-h PM2.5 concentrations, considering meteorological conditions, the rolling mean of PM2.5 time series, and temporal features. PM2.5 is strongly correlated with space and time. Therefore, forecasting results from one location are insufficient to represent the level of air pollution for an entire city. In this study, we established six real-time air quality monitoring sites in different regions, including traffic, residential, and industrial areas in Ho Chi Minh City (HCMC), and generated forecasting results for each station. Various statistical methods are incorporated to evaluate the performance of the model. The experimental results confirm that the model performs well, substantially improving its forecasting accuracy compared to existing PM2.5 forecasting models developed for HCMC. In addition, we analyze to determine the contribution of different feature groups to model performance. The model can serve as a reference for citizens scheduling local travel and for healthcare providers to provide early warnings.

A dual-acting DNASE1/DNASE1L3 biologic prevents autoimmunity and death in genetic and induced lupus models.

A defining feature of systemic lupus erythematosus (SLE) is loss of tolerance to self-DNA, and deficiency of DNASE1L3, the main enzyme responsible for chromatin degradation in blood, is also associated with SLE. This association can be found in an ultrarare population of pediatric patients with DNASE1L3 deficiency who develop SLE, adult patients with loss-of-function variants of DNASE1L3 who are at a higher risk for SLE, and patients with sporadic SLE who have neutralizing autoantibodies against DNASE1L3. To mitigate the pathogenic effects of inherited and acquired DNASE1L3 deficiencies, we engineered a long-acting enzyme biologic with dual DNASE1/DNASE1L3 activity that is resistant to DNASE1 and DNASE1L3 inhibitors. Notably, we found that the biologic prevented the development of lupus in Dnase1-/-Dnase1L3-/- double-knockout mice and rescued animals from death in pristane-induced lupus. Finally, we confirmed that the human isoform of the enzyme biologic was not recognized by autoantibodies in SLE and efficiently degraded genomic and mitochondrial cell-free DNA, as well as microparticle DNA, in SLE plasma. Our findings suggest that autoimmune diseases characterized by aberrant DNA accumulation, such as SLE, can be effectively treated with a replacement DNASE tailored to bypass pathogenic mechanisms, both genetic and acquired, that restrict DNASE1L3 activity.

Feasibility, safety and oncological short-term outcome of laparoscopic pancreaticoduodenectomy for periampullary cancer: Findings from a large sample from Vietnam.

Laparoscopic pancreaticoduodenectomy (LPD) is an alternative to open pancreaticoduodenectomy (OPD) for treatment of periampullary cancer in selected patients. However, this is a difficult procedure with a high complication rate. We conducted a prospective cohort study of 85 patients with suspected periampullary cancer who underwent LPD from February 2017 to January 2022 at University Medical Center at Ho Chi Minh City, Vietnam. Among these, 15 patients were excluded from the data analysis because of benign disease confirmed by postoperative pathological examination. Among 70 patients, the mean age was 58.9 ±â€…8.9 years old and 51.4% were female. The conversion rate to open surgery was 7.1% (n = 5). Among those underwent LPD, the mean operating time and estimated blood loss were 509 ±â€…94 minutes and 267 ±â€…102 mL, respectively. The median length of hospital stay was 8 days, interquartile range (IQR) 7-12 days. The percentage of cumulative morbidity, pancreatic fistula and major complication was 35.4%, 12.3%, and 13.8%, respectively. The median of comprehensive complication index (CCI) was 26.2 (IQR 20.9-29.6). Three patients required reoperation due to severe pancreatic fistula (n = 2) and necrotizing pancreatitis (n = 1). There was no death after ninety-day. The average number of harvested lymph nodes was 16.6 ±â€…5.1. The percentage of R0 resection was 100%. With properly selected patients, LPD can be a feasible, safe and effective approach with acceptable short-term outcomes.

Top-down control of flight by a non-canonical cortico-amygdala pathway.

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder1. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.

KTt-45, a T-type calcium channel blocker, acts as an anticancer agent by inducing apoptosis on HeLa cervical cancer cell line.

The abnormal expression in the T-type calcium channels is involved in various cancer types, thus inhibiting T-type calcium channels is one of approaches in cancer treatment. The fact that KTt-45 acted as a T-type calcium channel inhibitor as well as a pain-relief agent prompts us to address if KTt-45 plays any role against cancer cells. The results showed that KTt-45 caused cytotoxic effects towards HeLa cervical, Raji lymphoma, MCF-7 breast cancer, and A549 lung cancer cell lines with IC50 values less than 100 µM, in which highly selective toxicity was against HeLa cells (IC50 = 37.4 µM, SI > 3.2). Strikingly, the KTt-45 induced an accumulation of cytoplasmic vacuoles after 48 h treatment and mitochondrial-dependent apoptosis activation as evidenced by morphological features, chromatin condensation, nuclear fragmentation, and significant activation of caspase-9 as well as caspase-3. In conclusion, KTt-45 could inhibit cell growth and trigger mitochondrial-dependent apoptosis in HeLa cervical cancer cells. The results, taken together, strongly demonstrated that KTt-45 is a potential agent for further study on anticancer drug development which not only targets cancer cells but also helps to relieve neuropathic pain in cancer patients.

Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva.

BACKGROUND: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design. METHODS: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-|1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies. RESULTS: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes. CONCLUSIONS: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development. TRIAL REGISTRATION: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).

Cytotoxicity, anti-diabeticity, and phytocomposition investigation of Vietnamese Euphorbia tithymaloides Linn. (Euphorbiaceae).

In this study, the aerial parts of mature Vietnamese Euphorbia tithymaloides plants were put through cytotoxic, anti-diabetic, and phytocompositional evaluations. Specifically, four extracts (petroleum ether (PE), ethyl acetate (EA), methanol (Me), and aqueous (W)) were prepared by maceration at room temperature. All extracts, together with some isolated compounds, were investigated for cytotoxicity against some human normal and cancer cell lines (fibroblasts, HeLa, NCI-H460, HepG2, MCF-7, and Jurkat) using the standardized modified sulforhodamine B (SRB) assay. Additionally, the anti-diabetic activity of extracts and compounds was evaluated via their α-glucosidase inhibitory capacity. The obtained results indicated that Vietnamese E. tithymaloides extracts exhibited moderate cytotoxic activity, among which the PE extract possessed the highest values, on the NCI-H460 cell line. Second, the aqueous extract was revealed to possess very high α-glucosidase inhibitory activity (IC50 = 113.75 ± 14.02 µg ml-1). From the PE extract, three new jatrophane diterpenoids (named tithymal A, tithymal B, and tithymal C) and two known ones were isolated and structurally elucidated using NMR and MS spectroscopies. Noticeably, tithymal A exhibited significantly high inhibitory activity against α-glucosidase (IC50 = 10.71 ± 0.52 µg ml-1). These observations have significantly highlighted the medicinal potential of Vietnamese E. tithymaloides and expanded its scientific fascination.

The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug-Drug Interaction in Healthy Participants.

BACKGROUND AND OBJECTIVES: Palovarotene is under development for the treatment of fibrodysplasia ossificans progressiva (FOP). The objectives of this study were to evaluate palovarotene pharmacokinetics under fed versus fasted conditions and its induction potential towards cytochrome P450 3A4 (CYP3A4) substrate, midazolam. METHODS: In this phase I, open-label trial (NCT04829773), palovarotene pharmacokinetics were characterized after repeated once-daily dosing. In one cohort, healthy participants received three doses of palovarotene 20 mg on Days 1, 6, and 11, as whole capsules under fasted or fed conditions, or sprinkled on food under fed conditions. In another cohort, individuals received midazolam 2 mg on Days 1 and 15 and a daily dose of palovarotene 20 mg on Days 2-15. Palovarotene and midazolam pharmacokinetics, including area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and maximum observed plasma drug concentration (Cmax), were assessed. Adverse events (AEs) were recorded. RESULTS: Overall, 23 participants completed each part. Palovarotene Cmax and AUC(0-∞) increased by 16.5% and 39.7% under fed versus fasted conditions. Pharmacokinetics were comparable between the whole capsule and sprinkled on food, under fed conditions. Midazolam AUC(0-∞) and Cmax decreased by 13.3% and 9.7% upon palovarotene co-administration over 14 days, less than that required to be considered a weak CYP3A4 inducer. Plasma palovarotene exposures were comparable after single and multiple doses. No serious AEs were reported. CONCLUSIONS: These data support palovarotene administration after a meal, as a whole capsule or sprinkled on food. Palovarotene at 20 mg/day is a not a clinical inducer of CYP3A4. These results provide insights into palovarotene pharmacokinetics, aiding optimization of administration for patients with FOP. CLINICAL TRIALS REGISTRATION NUMBER: NCT04829773.

Fibrodysplasia ossificans progressiva, also known as FOP, is a very rare genetic condition where bone forms in places it is not usually found, such as in the muscles, tendons, and ligaments. Retinoids are molecules that the body produces from vitamin A to aid normal bone development. Palovarotene is a therapeutic retinoid that has been developed for the treatment of FOP. This article describes a clinical trial where people without FOP received oral palovarotene to determine how it is absorbed and broken down (metabolized) by the body when taken after a meal or after fasting (a period of not eating) as a whole capsule or when sprinkled on food. The trial also examined how palovarotene might interact with other treatments that are broken down by the body in the same way as palovarotene.The trial found that the amount of palovarotene that circulates in the blood increased more when taken after a meal compared with after fasting. Palovarotene was metabolized by the body in a similar way when taken as a whole capsule or when sprinkled on food. This finding is important as some people with FOP have difficulty swallowing. At a 20 mg dose, palovarotene was unlikely to interact with other treatments that are metabolized in the same way. No serious side effects were reported.These results show that palovarotene should be taken after a meal, either as a whole capsule or sprinkled on food.

Visible-Light-Mediated Three-Component Decarboxylative Coupling Reactions to Synthesize 1,4-Diol Monoethers.

An efficient approach for 1,2-difunctionalization of aromatic olefins and the synthesis of functionalized 1,4-diols monoethers has been established via a photoinduced three-component reaction of an α-alkoxycarboxylic acid, an aromatic olefin, and an aldehyde. The reaction proceeds by photoinduced oxidative decarboxylation of the carboxylic acid followed by the addition of the α-alkoxyalkyl radical to the olefin, one-electron reduction of the addition radical, and the nucleophilic attack of the resulting carbanion to the aldehyde. Besides the convenient one-pot protocol of the three-component reaction, this method offers several other advantages, including good functional group tolerance for the three substrates, gentle reaction conditions, and ease of scaling up. The reaction mechanism has been investigated through free radical trapping experiment and isotope labeling experiments.

EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes.

NUT carcinoma is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT's ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth. SIGNIFICANCE: Repression of tumor suppressor genes, including CDKN2A, by EZH2 provides a mechanistic rationale for combining EZH2 and BET inhibitors for the clinical treatment of NUT carcinoma. See related commentary by Kazansky and Kentsis, p. 3827.

EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes.

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT's ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. CDKN2A was identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort. STATEMENT OF SIGNIFICANCE: Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.

Identification of an Optimized Receptor-Binding Domain Subunit Vaccine against SARS-CoV-2.

Current vaccine efforts to combat SARS-CoV-2 are focused on the whole spike protein administered as mRNA, viral vector, or protein subunit. However, the SARS-CoV-2 receptor-binding domain (RBD) is the immunodominant portion of the spike protein, accounting for 90% of serum neutralizing activity. In this study, we constructed several versions of RBD and together with aluminum hydroxide or DDA (dimethyldioctadecylammonium bromide)/TDB (d-(+)-trehalose 6,6'-dibehenate) adjuvant evaluated immunogenicity in mice. We generated human angiotensin-converting enzyme 2 knock-in mice to evaluate vaccine efficacy in vivo following viral challenge. We found that 1) subdomain (SD)1 was essential for the RBD to elicit maximal immunogenicity; 2) RBDSD1 produced in mammalian HEK cells elicited better immunogenicity than did protein produced in insect or yeast cells; 3) RBDSD1 combined with the CD4 Th1 adjuvant DDA/TDB produced higher neutralizing Ab responses and stronger CD4 T cell responses than did aluminum hydroxide; 4) addition of monomeric human Fc receptor to RBDSD1 (RBDSD1Fc) significantly enhanced immunogenicity and neutralizing Ab titers; 5) the Beta version of RBDSD1Fc provided a broad range of cross-neutralization to multiple antigenic variants of concern, including Omicron; and 6) the Beta version of RBDSD1Fc with DDA/TDB provided complete protection against virus challenge in the knock-in mouse model. Thus, we have identified an optimized RBD-based subunit vaccine suitable for clinical trials.

Typhoid fever, complicated by syncope due to relative bradycardia: A case report.

In a United Nations (UN) staff member headquarters in South Sudan, we present a rare typhoid fever complicated by syncope due to relative bradycardia. A 25-year-old male presented to our hospital with a high fever, diarrhea, and no vomiting. He had no substantial medical background. He was diagnosed with an unspecified digestive disorder and received initial treatment. Two syncope episodes were recorded in the Level 1 hospital. He was referred to our hospital at the 30th hour and the third fainting occurred. Electrocardiogram showed bradycardia with a heart rate of 40 beats/min. The atropine test was negative; the initial diagnosis was sinus sickness syndrome. Microbiology tests later suggested typhoid infection. Then, the diagnosis changed to relative bradycardia caused by Salmonella typhi; and he was orally treated with the third-generation Quinolone antibiotic. He significantly improved and got discharged on the seventh day. In conclusion, typhoid remains a real and present threat to UN staff and civilians in South Sudan.

Multi-output machine learning model for regional air pollution forecasting in Ho Chi Minh City, Vietnam.

Air pollution concentrations in Ho Chi Minh City (HCMC) have been found to surpass the WHO standard, which has become a very serious problem affecting human health and the ecosystem. Various machine learning algorithms have recently been widely used in air quality forecasting studies to predict possible impacts. Training and constructing several machine learning models for different air pollutants, such as NO2, SO2, O3, and CO forecasts, is a time-consuming process that necessitates additional effort for deployment, maintenance, and monitoring. In this paper, an effort has been made to develop a multi-step multi-output multivariate model (a global model) for air quality forecasting, taking into account various parameters such as meteorological conditions, air quality data from urban traffic, residential, and industrial areas, urban space information, and time component for the prediction of NO2, SO2, O3, CO hourly (1 h to 24 h) concentrations. The global forecasting model can anticipate multiple air pollutant concentrations concurrently, based on past concentrations of covariate characteristics. The datasets on air pollution time series were gathered from six HealthyAir air quality monitoring sites in HCMC between February 2021 and August 2022. Darksky weather provided the hourly concentrations of meteorological conditions for the same period. This is the first model built using real-time air quality data for NO2, SO2, CO, and O3 forecasting in HCM city. To assess the effectiveness of the proposed model, it was evaluated using real data from HealthyAir stations and quantified using Root Mean Squared Error (RMSE), Mean Absolute Percentage Error (MAPE), and correlation indices. The results show that the global air quality forecasting model beats earlier models built for air quality forecasting of each specific pollutant in HCMC.

A Pharmacokinetic, Safety, and Tolerability Trial of Palovarotene in Healthy Japanese and Non-Japanese Participants.

BACKGROUND AND OBJECTIVE: Palovarotene is an oral, selective retinoic acid receptor gamma agonist under investigation for fibrodysplasia ossificans progressiva (FOP). Palovarotene is primarily metabolized by cytochrome P450 (CYP) 3A4. Differences in CYP-mediated metabolism of CYP substrates have been observed between Japanese and non-Japanese individuals. This phase I trial (NCT04829786) compared the pharmacokinetic profile of palovarotene in healthy Japanese and non-Japanese participants and evaluated the safety of single doses. METHODS: Healthy Japanese and non-Japanese participants were matched individually (1:1) and randomized to receive a single oral dose of palovarotene 5 or 10 mg, followed by the alternate dose after a 5-day washout period. Maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) were assessed. Estimates of the geometric mean difference between dose and Japanese and non-Japanese groups were calculated for natural log-transformed Cmax and AUC parameters. Adverse events (AEs), serious AEs, and treatment-emergent AEs were recorded. RESULTS: Eight pairs of matched non-Japanese and Japanese individuals and two unmatched Japanese individuals participated. Mean plasma concentration-time profiles were similar between the two cohorts at both dose levels, demonstrating that palovarotene absorption and elimination are similar irrespective of dose level. The pharmacokinetic parameters of palovarotene were similar between groups at both dose levels. Cmax and AUC values were dose-proportional between doses in each group. Palovarotene was well tolerated; there were no deaths or AEs leading to treatment discontinuation. CONCLUSIONS: Japanese and non-Japanese groups had similar pharmacokinetic profiles, indicating that palovarotene dose adjustments are not necessary for Japanese patients with FOP.

Outdoor air quality data for spatiotemporal analysis and air quality modelling in Ho Chi Minh City, Vietnam: A part of HealthyAir Project.

This article presents outdoor air pollution data acquired from the real-time Air Quality Monitoring Network (AQMN), which was established by the Healthyair project team in Ho Chi Minh City (HCMC), Vietnam. The AQMN is made up of six air pollution monitoring stations spread over the city (Traffic, Residential, and Industrial). Each station measures the same contaminants in the air, including PM2.5, TSP, NO2, SO2, O3, CO, and two meteorological factors, temperature and humidity. This data is crucial for air quality modelling, spatiotemporal analysis, correlation analysis, and assessing local air pollution around the city. The data was first obtained in minute frequency, then transformed and produced in hourly frequency for analysis and modelling. The PM2.5 data from this dataset was used to construct an hourly air quality PM2.5 forecasting model in the publication titled "AI-based Air Quality PM2.5 Forecasting Models for Developing Countries: A Case Study of Ho Chi Minh City, Vietnam" by Rakholia et. al. (2022).

Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP).

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effects of Nitisinone on Oxidative and Inflammatory Markers in Alkaptonuria: Results from SONIA1 and SONIA2 Studies.

Nitisinone (NTBC) was recently approved to treat alkaptonuria (AKU), but there is no information on its impact on oxidative stress and inflammation, which are observed in AKU. Therefore, serum samples collected during the clinical studies SONIA1 (40 AKU patients) and SONIA2 (138 AKU patients) were tested for Serum Amyloid A (SAA), CRP and IL-8 by ELISA; Advanced Oxidation Protein Products (AOPP) by spectrophotometry; and protein carbonyls by Western blot. Our results show that NTBC had no significant effects on the tested markers except for a slight but statistically significant effect for NTBC, but not for the combination of time and NTBC, on SAA levels in SONIA2 patients. Notably, the majority of SONIA2 patients presented with SAA > 10 mg/L, and 30 patients in the control group (43.5%) and 40 patients (58.0%) in the NTBC-treated group showed persistently elevated SAA > 10 mg/L at each visit during SONIA2. Higher serum SAA correlated with lower quality of life and higher morbidity. Despite no quantitative differences in AOPP, the preliminary analysis of protein carbonyls highlighted patterns that deserve further investigation. Overall, our results suggest that NTBC cannot control the sub-clinical inflammation due to increased SAA observed in AKU, which is also a risk factor for developing secondary amyloidosis.