Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute respiratory disease and multiorgan failure. Finding human host factors that are essential for SARS-CoV-2 infection could facilitate the formulation of treatment strategies. Using a human kidney cell line-HK-2-that is highly susceptible to SARS-CoV-2, we performed a genome-wide RNAi screen and identified virus dependency factors (VDFs), which play regulatory roles in biological pathways linked to clinical manifestations of SARS-CoV-2 infection. We found a role for a secretory form of SARS-CoV-2 receptor, soluble angiotensin converting enzyme 2 (sACE2), in SARS-CoV-2 infection. Further investigation revealed that SARS-CoV-2 exploits receptor-mediated endocytosis through interaction between its spike with sACE2 or sACE2-vasopressin via AT1 or AVPR1B, respectively. Our identification of VDFs and the regulatory effect of sACE2 on SARS-CoV-2 infection shed insight into pathogenesis and cell entry mechanisms of SARS-CoV-2 as well as potential treatment strategies for COVID-19.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

LIVERSTAT for risk stratification for patients with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIM: LIVERSTAT is an artificial intelligence-based noninvasive test devised to screen for and provide risk stratification for metabolic dysfunction-associated fatty liver disease (MAFLD) by using simple blood biomarkers and anthropometric measurements. We aimed to study LIVERSTAT in patients with MAFLD and to explore its role for the diagnosis of advanced fibrosis. METHODS: This is a retrospective study of data from MAFLD patients who underwent a liver biopsy. Patients with type 2 diabetes who underwent transient elastography and had liver stiffness measurement (LSM) < 5 kPa were included as patients with no fibrosis. Among these patients, controlled attenuation parameter <248 dB/m was considered as no steatosis. The LIVERSTAT results were generated based on a proprietary algorithm, blinded to the histological and LSM data. RESULTS: The data for 350 patients were analyzed (mean age 53 years, 45% male, advanced fibrosis 22%). The sensitivity, specificity, positive predictive value, negative predictive value, and misclassification rate of LIVERSTAT to diagnose advanced fibrosis were 90%, 50%, 30%, 95%, and 42%, respectively. The corresponding rates for Fibrosis-4 score (FIB4) were 56%, 83%, 44%, 89%, and 22%, respectively. When LSM was used as a second test, the corresponding rates for LIVERSTAT were 60%, 97%, 76%, 94%, and 8%, respectively, while the corresponding rates for FIB4 were 38%, 99%, 83%, 89%, and 11%, respectively. CONCLUSION: LIVERSTAT had a higher negative predictive value compared with FIB4 and a lower misclassification rate compared with FIB4 when used in a two-step approach in combination with LSM for the diagnosis of advanced fibrosis.

Physiotherapists' Perception of and Readiness to Use, Telerehabilitation for Musculoskeletal Disorders in Malaysia: A Cross-Sectional Study.

Introduction: Musculoskeletal ailments exert a significant impact on global populations. To address challenges posed by geographical constraints and financial limitations, physiotherapists have explored and found telerehabilitation to be a viable solution. Despite its proven effectiveness in clinical practice, the integration of telerehabilitation has been sluggish. This cross-sectional survey sought to delve into the perspectives and readiness of physiotherapists in Malaysia regarding telerehabilitation for musculoskeletal disorders. Methods: A customized survey instrument was developed and evaluated for face validity and reliability. The 36-item questionnaire was distributed through the Google Form platform, targeting respondents via social media channels such as Facebook and WhatsApp. Data analysis used descriptive statistics (frequency and percentage). Results: The survey garnered responses from 271 physiotherapists. A majority (76.3%, n = 202) expressed agreement regarding the potential benefits of telerehabilitation in physiotherapy practice. About 77% of the respondents also showcased greater readiness for monitoring client progress through telerehabilitation as opposed to assessment and treatment. Notable benefits identified by respondents included preventing cross-infection (98.5%) and reducing travel time for both clients (94.0%) and physiotherapists (90.6%). Conclusion: The study reveals that physiotherapists in Malaysia exhibit positive attitudes and preparedness for implementing telerehabilitation in managing musculoskeletal conditions.

WT1 regulates expression of DNA repair gene Neil3 during nephrogenesis.

Mammalian nephrons arise from a population of nephron progenitor cells (NPCs) expressing the master transcription factor Wilms tumor-1 (WT1), which is crucial for NPC proliferation, migration, and differentiation. In humans, biallelic loss of WT1 precludes nephrogenesis and leads to the formation of Wilms tumor precursor lesions. We hypothesize that WT1 normally primes the NPC for nephrogenesis by inducing expression of NPC-specific DNA repair genes that protect the genome. We analyzed transcript levels for a panel of DNA repair genes in embryonic day 17.5 (E17.5) versus adult mouse kidneys and noted seven genes that were increased >20-fold. We then isolated Cited1+ NPCs from E17.5 kidneys and found that only one gene, nei-like DNA glycosylase 3 (Neil3), was enriched. RNAscope in situ hybridization of E17.5 mouse kidneys showed increased Neil3 expression in the nephrogenic zone versus mature nephron structures. To determine whether Neil3 expression is WT1 dependent, we knocked down Wt1 in Cited1+ NPCs (60% knockdown efficiency) and noted a 58% reduction in Neil3 transcript levels. We showed that WT1 interacts with the Neil3 promoter and that activity of a Neil3 promoter-reporter vector was increased twofold in WT1+ versus WT1- cells. We propose that Neil3 is a WT1-dependent DNA repair gene expressed at high levels in Cited1+ NPCs, where it repairs mutational injury to the genome during nephrogenesis. NEIL3 is likely just one of many such lineage-specific repair mechanisms that respond to genomic injury during kidney development.NEW & NOTEWORTHY We studied the molecular events leading to Wilms tumors as a model for the repair of genomic injury. Specifically, we showed that WT1 activates DNA repair gene Neil3 in nephron progenitor cells. However, our observations offer a much broader principle, demonstrating that the embryonic kidney invests in lineage-specific expression of DNA repair enzymes. Thus, it is conceivable that failure of these mechanisms could lead to a variety of "sporadic" congenital renal malformations and human disease.

Progress Toward Measles Elimination - Worldwide, 2000-2022.

Measles is a highly contagious, vaccine-preventable disease that requires high population immunity for transmission to be interrupted. All six World Health Organization regions have committed to eliminating measles; however, no region has achieved and sustained measles elimination. This report describes measles elimination progress during 2000-2022. During 2000-2019, estimated coverage worldwide with the first dose of measles-containing vaccine (MCV) increased from 72% to 86%, then declined to 81% in 2021 during the COVID-19 pandemic, representing the lowest coverage since 2008. In 2022, first-dose MCV coverage increased to 83%. Only one half (72) of 144 countries reporting measles cases achieved the measles surveillance indicator target of two or more discarded cases per 100,000 population in 2022. During 2021-2022, estimated measles cases increased 18%, from 7,802,000 to 9,232,300, and the number of countries experiencing large or disruptive outbreaks increased from 22 to 37. Estimated measles deaths increased 43% during 2021-2022, from 95,000 to 136,200. Nonetheless, an estimated 57 million measles deaths were averted by vaccination during 2000-2022. In 2022, measles vaccination coverage and global surveillance showed some recovery from the COVID-19 pandemic setbacks; however, coverage declined in low-income countries, and globally, years of suboptimal immunization coverage left millions of children unprotected. Urgent reversal of coverage setbacks experienced during the COVID-19 pandemic can be accomplished by renewing efforts to vaccinate all children with 2 MCV doses and strengthening surveillance, thereby preventing outbreaks and accelerating progress toward measles elimination.

Exploring the health information-seeking practices of breast cancer patients in a middle-income country with a diverse ethnic population: a cross-sectional investigation.

Seeking health information is an important step for cancer patients to understand their condition and facilitate treatment. It also helps them deal with the unknown and aid in recovery. Therefore, it is vital to understand the factors that drive health information-seeking behavior. This study aims to achieve that objective in a localized context by surveying 421 breast cancer patients in an urban teaching hospital. The patients were presented with a 5-point questionnaire that explored their demography, health status, information-seeking behavior, and literacy level. The prevalence of health information-seeking initiatives reported was 60%. Patients with higher education (OR 3.31; 95% CI (1.39-7.87), p = 0.01), having their own business or were self-employed (OR 4.68; 95% CI (1.03-21.24), p = 0.046), and in a Medium 40 (M40) income level (OR 2.31; 95% CI (1.09-4.88), p = 0.03) and Top 20 (T20) level were more likely to seek health information. The mean e-Health Literacy Score (eHEALS) was 28.01 ± 5.0, with healthcare professionals having the highest level of trust (mean 4.22 ± 0.79) and most useful resource score (mean 4.21 ± 0.78). Even though Google was the most popular online search tool used by respondents, most of them seldom (23.77%) or had never (34.34%) discussed the online information they found with healthcare professionals. In conclusion, it is still best for patients to appraise the sought-after information with experts to avoid misinformation and treatment delay.

Breaking the Barrier: A Study on Multi-drug Resistance in Breast Abscess at an Academic Malaysian Hospital.

BACKGROUND: In recent years, the increase in antibiotics usage locally has led to a worrying emergence of multi-drug resistant organisms (MDRO), with the Malaysian prevalence rate of methicillin-resistant Staphylococcus aureus (MRSA) ranging from 17.2 to 28.1% between 1999 and 2017. A study has shown that 7% of all non-lactational breast abscesses are caused by MRSA. Although aspiration offers less morbidities compared to surgical drainage, about 20% of women infected by MRSA who initially underwent aspiration subsequently require surgical drainage. This study is conducted to determine the link between aetiology, antimicrobial resistance pattern and treatment modalities of breast abscesses. METHODS: Retrospective study of reviewing microbiology specimens of breast abscess patients treated at Universiti Malaya Medical Centre from 2015 to 2020. Data collected from microbiology database and electronic medical records were analysed using SPSS V21. RESULT: A total of 210 specimens from 153 patients were analysed. One-fifth (19.5%) of the specimens isolated were MDRO. Lactational associated infections had the largest proportion of MDR in comparison to non-lactational and secondary infections (38.5%, 21.7%, 25.7%, respectively; p = 0.23). Staphylococcus epidermidis recorded the highest number of MDR (n = 12) followed by S. aureus (n = 8). Adjusted by aetiological groups, the presence of MDRO is linked to failure of single aspirations (p = 0.554) and significantly doubled the risk of undergoing surgical drainage for resolution (p = 0.041). CONCLUSION: MDR in breast abscess should be recognised as an increasing healthcare burden due to a paradigm shift of MDRO and a rise of resistance cases among lactational associated infection that were vulnerable to undergo surgical incision and drainage for resolution.

Comparison of Clinical Outcomes Between Low- and High-Risk Groups of Early Breast Cancer Patients Treated with Intraoperative Radiotherapy in Addition to External Beam Radiation: A Multi-Centre Prospective Study.

BACKGROUND: There is a paucity of data on the use of intraoperative radiotherapy (IORT) with low-energy X-rays in Malaysian women with early breast cancer. The aim of this study is to evaluate the clinical, cosmetic, and patient-reported outcomes in low- and high-risk early breast cancer patients treated with breast conserving surgery (BCS) and IORT. METHODOLOGY: Patients suitable for BCS who were treated with IORT between January 2016 and June 2019 from three centres were analysed. They were divided into low-risk and high-risk groups based on the risk of recurrence according to the TARGeted Intraoperative radioTherapy (TARGIT) A and B study criteria. Outcomes of interest included local recurrence, wound complications, and radiation toxicity, with a subset analysed for cosmetic and patient-reported outcomes. RESULTS: Within a median follow-up of 31 months, there were 104 and 211 patients in the low- and high-risk groups, respectively. No significant difference was observed in local recurrence rates (low-risk, 1.0% vs. high-risk, 1.4%; p = 1.000). Both cohorts exhibited low frequencies of severe wound complications ranging between 1.4 and 1.9%. No major radiation toxicities were reported in either group. In the subgroup analysis, low-risk patients had significantly better mean scores in the subscales of inframammary fold and scar. Based on the BREAST-Q patient-reported outcomes questionnaire, seven out of nine parameters were scored similarly between both groups with no significant difference. CONCLUSION: This study showed that the use of IORT in both low- and high-risk early breast cancers is efficacious and safe with low recurrence rates and an acceptable toxicity profile.

Regulatory Oversight of Cell, Tissue, and Gene Therapy Products in Singapore.

The Health Sciences Authority of Singapore has implemented a fit-for-purpose regulatory framework for Cell, Tissue, and Gene Therapy Products (CTGTPs) on 1 March 2021. A total of 11 pieces of subsidiary legislation for CTGTP are gazetted under the Health Products Act as Health Products (CTGTP) Regulations 2021. The CTGTPs are stratified into lower-risk Class 1 CTGTP or moderate- to higher-risk Class 2 CTGTP based on their degree of manipulation, intended use, and if they are combined or used with therapeutic products or medical devices. The regulatory controls are calibrated to the different risk profiles of the products. This risk-based regulatory approach aims to facilitate successful product development and registration in Singapore for innovative CTGTP with a least burdensome regulatory framework while ensuring reasonable safeguards on the safety, quality, and efficacy of the products. This chapter describes the regulatory oversight of CTGTP in Singapore.

Interrogating the Role of miR-125b and Its 3'isomiRs in Protection against Hypoxia.

MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5' or 3' addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are few. In this study, we discovered using NGS, four 3'isomiRs of miR-125b, i.e., addition of A (adenosine), along with deletions of A, AG (guanosine) and AGU (uridine) from rat and sheep heart. These findings were validated using RT-qPCR. Comprehensive functional studies were carried out in the H9C2 hypoxia model. After miR-125b, isomiRs of Plus A, Trim A, AG and AGU mimic transfection, the H9C2 cells were subjected to hypoxic challenge. As assessed using cell viability, apoptosis, CCK-8 and LDH release, miR-125b and isomiRs were all protective against hypoxia. However, Plus A and Trim A were more effective than miR-125b, whilst Trim AG and Trim AGU had far weaker effects than miR-125b. Interestingly, both the gene regulation profile and apoptotic gene validation indicated a major overlap among miR-125b, Plus A and Trim A, whilst Trims AG and AGU revealed a different profile compared to miR-125b. Conclusions: miR-125b and its 3' isomiRs are expressed stably in the heart. miR-125b and isomiRs with addition or deletion of A might function concurrently and concordantly under specific physiological and pathophysiological conditions. In-depth understanding of isomiRs' metabolism and function will contribute to better miRNA therapeutic drug design.

Protective Effects of PEP-1-GSTA2 Protein in Hippocampal Neuronal Cell Damage Induced by Oxidative Stress.

Glutathione S-transferase alpha 2 (GSTA2), a member of the glutathione S-transferase family, plays the role of cellular detoxification against oxidative stress. Although oxidative stress is related to ischemic injury, the role of GSTA2 against ischemia has not been elucidated. Thus, we studied whether GSTA2 prevents ischemic injury by using the PEP-1-GSTA2 protein which has a cell-permeable protein transduction domain. We revealed that cell-permeable PEP-1-GSTA2 transduced into HT-22 cells and markedly protected cell death via the inhibition of reactive oxygen species (ROS) production and DNA damage induced by oxidative stress. Additionally, transduced PEP-1-GSTA2 promoted mitogen-activated protein kinase (MAPK), and nuclear factor-kappaB (NF-κB) activation. Furthermore, PEP-1-GSTA2 regulated Bcl-2, Bax, cleaved Caspase-3 and -9 expression protein levels. An in vivo ischemic animal model, PEP-1-GSTA2, markedly prevented the loss of hippocampal neurons and reduced the activation of microglia and astrocytes. These findings indicate that PEP-1-GSTA2 suppresses hippocampal cell death by regulating the MAPK and apoptotic signaling pathways. Therefore, we suggest that PEP-1-GSTA2 will help to develop the therapies for oxidative-stress-induced ischemic injury.

Targeted next-generation sequencing for the detection of cancer-associated somatic mutations in adenomyosis.

Adenomyosis is a condition characterised by the invasion of endometrial tissues into the uterine myometrium, the molecular pathogenesis of which remains incompletely elucidated. Lesion profiling with next-generation sequencing (NGS) can lead to the identification of previously unanticipated causative genes and the detection of therapeutically actionable genetic changes. Using an NGS panel that included 275 cancer susceptibility genes, this study examined the occurrence and frequency of somatic mutations in adenomyotic tissue specimens collected from 17 women. Extracted DNA was enriched using targeted formalin-fixed paraffin-embedded tissue cores prior to the identification of lesion-specific variants. The results revealed that KRAS and AT-rich interactive domain 1A (ARID1A) were the two most frequently mutated genes (mutation frequencies: 24% and 12%, respectively). Notably, endometrial atypical hyperplasia did not involve adenomyotic areas. We also identified, for the first time, two potentially pathogenic mutations in the F-box/WD repeat-containing protein 7 (FBXW7) and cohesin subunit SA-2 (STAG2) genes. These findings indicate that mutations in the KRAS, ARID1A, FBXW7 and STAG2 genes may play a critical role in the pathogenesis of adenomyosis. Additional studies are needed to assess whether the utilisation of oncogenic driver mutations can inform the surveillance of patients with adenomyosis who had not undergone hysterectomy.Impact statementWhat is already known on this subject? Although somatic point mutations in the KRAS oncogene have been recently detected in adenomyosis, the molecular underpinnings of this condition remains incompletely elucidated. Lesion profiling with next-generation sequencing (NGS) can lead to the identification of previously unanticipated causative genes and the detection of therapeutically actionable genetic changes.What do the results of this study add? The results of NGS revealed that KRAS and AT-rich interactive domain 1A (ARID1A) were the two most frequently mutated genes (mutation frequencies: 24% and 12%, respectively). We also identified, for the first time, two potentially pathogenic mutations in the F-box/WD repeat-containing protein 7 (FBXW7) and cohesin subunit SA-2 (STAG2) genes.What are the implications of these findings for clinical practice and/or further research? The utilisation of oncogenic driver mutations has the potential to inform the surveillance of patients with adenomyosis who had not undergone hysterectomy.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2021.

All six World Health Organization (WHO) regions have committed to eliminating measles.* The Immunization Agenda 2021-2030 (IA2030)† aims to achieve the regional targets as a core indicator of impact and positions measles as the tracer of a health system's ability to deliver essential childhood vaccines. IA2030 highlights the importance of ensuring rigorous measles surveillance systems to document immunity gaps and achieve 95% coverage with 2 timely doses of measles-containing vaccine (MCV) among children. This report describes progress toward measles elimination during 2000-2021 and updates a previous report (1). During 2000-2021, estimated global coverage with a first MCV dose (MCV1) increased from 72% to a peak of 86% in 2019, but decreased during the COVID-19 pandemic to 83% in 2020 and to 81% in 2021, the lowest MCV1 coverage recorded since 2008. All countries conducted measles surveillance, but only 47 (35%) of 135 countries reporting discarded cases§ achieved the sensitivity indicator target of two or more discarded cases per 100,000 population in 2021, indicating surveillance system underperformance in certain countries. Annual reported measles incidence decreased 88% during 2000-2016, from 145 to 18 cases per 1 million population, then rebounded to 120 in 2019 during a global resurgence (2), before declining to 21 in 2020 and to 17 in 2021. Large and disruptive outbreaks were reported in 22 countries. During 2000-2021, the annual number of estimated measles deaths decreased 83%, from 761,000 to 128,000; an estimated 56 million measles deaths were averted by vaccination. To regain progress and achieve regional measles elimination targets during and after the COVID-19 pandemic, accelerating targeted efforts is necessary to reach all children with 2 MCV doses while implementing robust surveillance and identifying and closing immunity gaps to prevent cases and outbreaks.

Outcomes of Treatment With Manipulative Reduction Combine With the Disc-condyle Repositioning Splint in Acute Anterior Disc Displacement Without Reduction.

ABSTRACT: In this report, the authors describe a case of the acute anterior disc displacement without reduction treated by manipulative reduction combined with the disc-condyle repositioning splint to improve the limited mouth opening and relieve the pain, including diagnostic images and treatment performed.

Clinical Effects of the Combination of Rhytidectomy and Temporomandibular Joint Disc Repositioning Surgery.

OBJECTIVE: This study aims to investigate the clinical effects of the combination of rhytidectomy and temporomandibular joint (TMJ) disc repositioning surgery in internal derangement (ID) stage IV-V and facial aging patients. METHODS: Eighteen facial aging with bilateral ID IV-V patients were enrolled in this study. All of them had undergone temporomandibular disc repositioning surgery and rhytidectomy by the same surgeon (Yao Min Zhu). Pre-/post-surgical clinical manifestations, facial photography, radiographic data were recorded and analyzed, as well as doctor, patient, third-party evaluation of postsurgical facial appearance satisfaction. RESULTS: The average age of 18 female patients was 52.9. The average of presurgical visual analog pain scale score was 5.94, ranged from 4 to 8. After 6 months, the average of postsurgical visual analog pain scale score was 0.28, ranged from 0 to 1 ( P   >  0.05). The average maximal mouth opening of presurgical and postsurgical was 2.19 and 3.29 cm, ranged from 1.2 to 2.8 cm and 3.0 to 3.5 cm, respectively ( P  < 0.05). Postoperative magnetic resonance imaging showed the location of the bilateral TMJ discs directly above the mandibular condyle. The satisfaction rate of doctors, patients and third-party with facial appearance was 95% to 98%, 96% to 99% and 96% to 99%, respectively, with an average of 95.72%, 98.11%, and 97.50%. CONCLUSIONS: For patients with bilateral ID IV-V and facial aging, the combination of disc repositioning surgery and rhytidectomy is a very feasible procedure to treat TMJ disorders and improve patients' facial appearance and satisfaction.

Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study.

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

The association between cigarette smoking and efavirenz plasma concentration using the population pharmacokinetic approach.

AIMS: Efavirenz is still widely used as the preferred first-line antiretroviral agent in middle- and low-income countries, including Malaysia. The efavirenz population pharmacokinetic profile among HIV-positive smokers is still unknown. We aimed to assess the association of smoking with efavirenz and the differences in HIV clinical outcomes. METHODS: A total of 154 stable HIV-positive patients on efavirenz in northern Malaysia were recruited with a sparse sampling for this multicentre prospective cohort study. The association between smoking and efavirenz pharmacokinetic parameters was determined using the nonlinear mixed-effect model. A mixture model of clearance was adopted to describe the metaboliser status because genetic data are unavailable. The effect of smoking on HIV clinical markers (CD4, CD4/CD8 ratio and viral blips) for at least 2 years after the antiretroviral initiation was also investigated. RESULTS: Our data were best fitted with a 1-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (ß = 1.39; 95% confidence interval: 1.07 to 1.91), while weight affected both clearance and volume. From the mixture model, 20% of patients were in the slow clearance group, which mimic the genotype distribution of slow metaboliser. An efavirenz dose reduction is not recommended for smokers ≥60 kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4/CD8 ratio. CONCLUSIONS: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.