The mutagenic forces shaping the genomic landscape of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock-Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR-mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10-5), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10-5). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

Standardization and quantification of backscattered electron imaging in scanning electron microscopy.

Backscattered electron (BSE) imaging based on scanning electron microscopy (SEM) has been widely used in scientific and industrial disciplines. However, achieving consistent standards and precise quantification in BSE images has proven to be a long-standing challenge. Previous methods incorporating dedicated calibration processes and Monte Carlo simulations have still posed practical limitations for widespread adoption. Here we introduce a bolometer platform that directly measures the absorbed thermal energy of the sample and demonstrates that it can help to analyze the atomic number (Z) of the investigated samples. The technique, named Atomic Number Electron Microscopy (ZEM), employs the conservation of energy as the foundation of standardization and can serve as a nearly ideal BSE detector. Our approach combines the strengths of both BSE and ZEM detectors, simplifying quantitative analysis for samples of various shapes and sizes. The complementary relation between the ZEM and BSE signals also makes the detection of light elements or compounds more accessible than existing microanalysis techniques.

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.

Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.

Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies. Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials. Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023. Exposure: Adoption of decentralized clinical trial technologies. Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics. Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term. Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Sequential removal of phosphate and copper(II) ions using sustainable chitosan biosorbent.

Although adsorbents are good candidates for removing phosphorus and heavy metals from wastewater, the use of biosorbents for the sequential treatment of phosphorus and copper has not yet been studied. Porous chitosan (CS)-based biosorbents (CGBs) were developed to adsorb phytic acid (PA), a major form of organic phosphate. This first adsorbate (PA) further served as an additional ligand (P-type ligand) for the CGBs (N-type ligand) to form a complex with the second adsorbate (copper). After the adsorption of PA (the first adsorbate), the spent CGBs were recycled and used as a new adsorbent to adsorb Cu(II) ions (the second adsorbate), which was expected to have a dual coordination effect through P, N-ligand complexation with copper. The interactions and complexation between CS, PA and Cu(II) ions on the PA-adsorbed CGBs (PACGBs) were investigated by performing FTIR, XPS, XRD, and SEM-EDS analyses. The PACGBs exhibited fast and enhanced adsorption of Cu(II) ions, owing to the synergistic effect of the amino groups of CS (the original ligand, N-type) and the phosphate groups of PA (an additional ligand, P-type) on the adsorption of Cu(II) ions. This is the first time that sequential removal of phosphorus and heavy metals by biosorbents has been performed using biosorbents.

Solution-Induced Degradation of the Silicon Nanobelt Field-Effect Transistor Biosensors.

Field-effect transistor (FET)-based biosensors are powerful analytical tools for detecting trace-specific biomolecules in diverse sample matrices, especially in the realms of pandemics and infectious diseases. The primary concern in applying these biosensors is their stability, a factor directly impacting the accuracy and reliability of sensing over extended durations. The risk of biosensor degradation is substantial, potentially jeopardizing the sensitivity and selectivity and leading to inaccurate readings, including the possibility of false positives or negatives. This paper delves into the documented degradation of silicon nanobelt FET (NBFET) biosensors induced by buffer solutions. The results highlight a positive correlation between immersion time and the threshold voltage of NBFET devices. Secondary ion mass spectrometry analysis demonstrates a gradual increase in sodium and potassium ion concentrations within the silicon as immersion days progress. This outcome is ascribed to the nanobelt's exposure to the buffer solution during the biosensing period, enabling ion penetration from the buffer into the silicon. This study emphasizes the critical need to address buffer-solution-induced degradation to ensure the long-term stability and performance of FET-based biosensors in practical applications.

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Evaluating polygenic risk scores for predicting cardiometabolic traits and disease risks in the Taiwan Biobank.

Type 2 diabetes (T2D) and hypertension are common comorbidities and, along with hyperlipidemia, serve as risk factors for cardiovascular diseases. This study aimed to evaluate the predictive value of polygenic risk scores (PRSs) on cardiometabolic traits related to T2D, hypertension, and hyperlipidemia and the incidence of these three diseases in Taiwan Biobank samples. Using publicly available, large-scale genome-wide association studies summary statistics, we constructed cross-ethnic PRSs for T2D, hypertension, body mass index, and nine quantitative traits typically used to define the three diseases. A composite PRS (cPRS) for each of the nine traits was constructed by aggregating the significant PRSs of its genetically correlated traits. The associations of each of the nine traits at baseline as well as the change of trait values during a 3- to 6-year follow-up period with its cPRS were evaluated. The predictive performances of cPRSs in predicting future incidences of T2D, hypertension, and hyperlipidemia were assessed. The cPRSs had significant associations with baseline and changes of trait values in 3-6 years and explained a higher proportion of variance for all traits than individual PRSs. Furthermore, models incorporating disease-related cPRSs, along with clinical features and relevant trait measurements achieved area under the curve values of 87.8%, 83.7%, and 75.9% for predicting future T2D, hypertension, and hyperlipidemia in 3-6 years, respectively.

Marine ecological security shelter in China: Concept, policy framework, mechanism and implementation obstacles.

Building a marine ecological security shelter (MESS) has become the main strategy to adapt marine ecological threats in China. As China's marine policy lacks a robust framework document, it is necessary to consider whether the policy system can effectively support the construction of MESS. However, the linkage between the construction measures of MESS and related policies is not clear. Therefore, the purpose of this paper is to clarify the concept of MESS and its connection with policy, by adopting the policy content analysis method to analyze the evolution process of MESS-related policy system. The legislative shortcomings and implementation obstacles of the MESS-related policy system are then summarized and discussed. The results show that from 1981 to 2021 the MESS-related policy system has been continuously improved. However, the policy system's support and guarantee capacity for building MESS still needs to be improved. (1) Due to the lack of basic laws and special laws, the coordination among governance subjects and among policies lacks legislative guarantee. (2) The construction of MESS continues the inter-regional and inter-department administrative barriers in collaborative governance of marine environment. To establish an effective collaborative governance model, it is essential to improve the governance structure and mechanism. (3) The government-led governance pattern faces the problem of mechanism failure. The command and control instrument accounts for more than 82%, and the public and enterprises lack strong policy guarantees to participate in marine governance. (4) The policy system's adaptability to emerging threats must be improved. Marine policies rarely involve emerging threats such as climate change and new pollutants. Meanwhile, the real-time supervision and monitoring mechanism is weak. The real-time supervision is only accounting for about 10%. Generally speaking, as a complex and long-term system engineering, the construction of MESS will inevitably encounter contradictions in politics, culture, and economy. China should deepen the construction of marine ecological civilization and form a governance concept based on ecosystems. Overall, this paper helps to understand the internal connection between MESS and policy comprehensively and provides a new perspective for improving China's marine governance capacity.

Eight-year chronic wound caused by Tarlov's cyst: a case report.

BACKGROUND: Tarlov's cyst is often underdiagnosed since it is difficult to identify without imaging assistance. Herein, we report the case of a young girl who presented with an 8-year history of chronic osteomyelitis of bilateral proximal phalanges and metatarsal bones caused by a Tarlov's cyst that did not contain a nerve root. The chronic wound in the forefoot is an unusual presentation and resulted from the Tarlov's cyst accompanied with tethered conus syndrome. CASE PRESENTATION: A 10-year-old Asian girl presented with an 8-year history of chronic osteomyelitis of bilateral proximal phalanges and metatarsal bones. She received sequestrectomy five times, however the immune function tests were all normal. A neurological examination revealed diminished sensation and a slapping gait pattern. Magnetic resonance imaging (MRI) demonstrated a lobulated cyst at the right aspect of the sacrum (S) 1 to sacrum (S) 3 canal near the dorsal root ganglion. Tethered conus syndrome was highly suspected. She received laminectomy of lumbar (L) 5 and S1-S2, which led to the diagnosis of a right S1-S3 epidural cyst. The final diagnosis from the histopathological examination was a right sacral Tarlov's cyst. The clinical conditions of diminished sensation and slapping gait pattern greatly improved after successful surgical treatment. CONCLUSION: In children who present with a recalcitrant chronic wound in the forefoot accompanied with a slapping gait pattern and foot hypoesthesia to pain, aggressive imaging examinations such as spine MRI should be arranged for further evaluation, especially in immunocompetent children.

Molecular Sieving of Propyne/Propylene by a Scalable Nanoporous Crystal with Confined Rotational Shutters.

Soft porous coordination polymers (PCPs) have the remarkable ability to recognize similar molecules as a result of their structural dynamics. However, their guest-induced gate-opening behaviors often lead to issues with selectivity and separation efficiency, as co-adsorption is nearly unavoidable. Herein, we report a strategy of a confined-rotational shutter, in which the rotation of pyridyl rings within the confined nanospace of a halogen-bonded coordination framework (NTU-88) creates a maximum aperture of 4.4 Å, which is very close to the molecular size of propyne (C3 H4 : 4.4 Å), but smaller than that of propylene (C3 H6 : 5.4 Å). This has been evidenced by crystallographic analyses and modelling calculations. The NTU-88o (open phase of activated NTU-88) demonstrates dedicated C3 H4 adsorption, and thereby leads to a sieving separation of C3 H4 /C3 H6 under ambient conditions. The integrated nature of high uptake ratio, considerable capacity, scalable synthesis, and good stability make NTU-88 a promising candidate for the feasible removal of C3 H4 from C3 H4 /C3 H6 mixtures. In principle, this strategy holds high potential for extension to soft families, making it a powerful tool for optimizing materials that can tackle challenging separations with no co-adsorption, while retaining the crucial aspect of high capacity.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Incidence of Lung Adenocarcinoma by Age, Sex, and Smoking Status in Taiwan.

Importance: Knowing whether the effects of smoking and other risk factors with lung adenocarcinoma (ADC) incidence varies by sex would provide information on lung cancer prevention strategies. Objective: To evaluate whether women in Taiwan have higher age- and tumor stage-specific lung ADC incidence rates than men irrespective of smoking status (ie, ever smoker or never smoker). Design, Setting, and Participants: This population-based cohort study used data sets synthesized from the Taiwan Cancer Registry (TCR) from 1979 to 2019; the TCR Long Form (TCRLF) from 2011 to 2019, which provides individual-level smoking and tumor stage information; the Taiwan Cause of Death Database (TCOD) from 1985 to 2019; the National Health Insurance Research Database (NHIRD) from 2000 to 2020; the Monthly Bulletin of Interior Statistics (MBIS) from 2011 to 2019; the National Health Interview Survey from 2001, 2005, 2009, 2013, and 2017; and Taiwan Biobank data from 2008 to 2021. Included patients were aged 40 to 84 years and had any invasive lung cancer from January 1, 2011, to December 31, 2019. Exposure: Smoking status. Main Outcomes and Measures: The main outcomes were age-specific female-to-male incidence rate ratios (IRRs) of lung ADC by smoking status and tumor stage. Linked data from the TCR, TCOD, NHIRD, Taiwan National Health Interview Survey, and MBIS were used to estimate the age- and sex-specific numbers of cancer-free individuals at midyears from 2011 to 2019 by smoking status. Using the TCR and TCRLF, age-, sex-, tumor stage-, and diagnosis year-specific numbers of patients with lung ADC from 2011 to 2019 by smoking status were estimated. Results: A total of 61 285 patients (32 599 women [53.2%]) aged 40 to 84 years (mean [SD] age, 64.66 [10.79] years) in the Taiwanese population of approximately 23 million were diagnosed with invasive lung ADC as their first lifetime cancer between 2011 and 2019. Among smokers, men had higher tobacco use by almost all examined metrics, including nearly twice the mean (SD) number of pack-years smoked (eg, 7.87 [8.30] for men aged 30-34 years vs 4.38 [5.27] for women aged 30-34 years). For 5-year age bands between 40 and 84 years, incidence of lung ADC was significantly higher among females than males for nearly all age groups irrespective of tumor stage and smoking status (eg, for the age group 70-74 years, the female-to-male IRR for late-stage lung ADC among never smokers was 1.38 [95% CI, 1.30-1.50]). Conclusions and Relevance: In this cohort study, women had higher age- and stage-specific lung ADC incidence rates than men in Taiwan for both never and ever smokers, suggesting the possibility of differential exposures between sexes to risk factors other than smoking and the potential modification of ADC risk factors by sex. Further work is needed to determine whether this pattern replicates in other populations, discover the causes of lung ADC, and put preventive measures in place.

Core and penumbra estimation using deep learning-based AIF in association with clinical measures in computed tomography perfusion (CTP).

OBJECTIVES: To investigate whether utilizing a convolutional neural network (CNN)-based arterial input function (AIF) improves the volumetric estimation of core and penumbra in association with clinical measures in stroke patients. METHODS: The study included 160 acute ischemic stroke patients (male = 87, female = 73, median age = 73 years) with approval from the institutional review board. The patients had undergone CTP imaging, NIHSS and ASPECTS grading. convolutional neural network (CNN) model was trained to fit a raw AIF curve to a gamma variate function. CNN AIF was utilized to estimate the core and penumbra volumes which were further validated with clinical scores. RESULTS: Penumbra estimated by CNN AIF correlated positively with the NIHSS score (r = 0.69; p < 0.001) and negatively with the ASPECTS (r = - 0.43; p < 0.001). The CNN AIF estimated penumbra and core volume matching the patient symptoms, typically in patients with higher NIHSS (> 20) and lower ASPECT score (< 5). In group analysis, the median CBF < 20%, CBF < 30%, rCBF < 38%, Tmax > 10 s, Tmax > 10 s volumes were statistically significantly higher (p < .05). CONCLUSIONS: With inclusion of the CNN AIF in perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke. CRITICAL RELEVANCE STATEMENT: With CNN AIF perfusion imaging pipeline, penumbra and core estimations are more reliable as they correlate with scores representing neurological deficits in stroke.

Outcomes of pediatric community-acquired pneumonia before and after national pneumococcal immunization in Taiwan.

OBJECTIVE: In Taiwan, the incidence of invasive pneumococcal disease (IPD) in children declined after the catch-up primary vaccination programs and the full national immunization program (NIP) with PCV13. The objective of the study was to investigate the clinical outcomes of pediatric community-acquired pneumonia (CAP) before and after the NIP. METHODS: The study included patients aged 3 months to 17 years who were diagnosed with CAP and treated at the National Taiwan University Hospital between 2007 and 2019. Patients were assigned to three birth cohorts according to their birth years and vaccination eligibility: non-NIP, catch-up, and full NIP. We compared the rates of severe outcomes, including case fatality and pathogens. RESULTS: A total of 6557 patients who met the CAP criteria were enrolled during the study period. The case-fatality rate decreased from 3.2% (94/2984) in the non-NIP cohort to 0.3% (7/2176) in the catch-up cohort and 0.8% (11/1397) in the full NIP cohort (p < 0.001). Furthermore, there was a significant decrease in invasive ventilation from the non-NIP (17.9%) to both catch-up (6.8%) and full NIP cohorts (9.1%). The rate of IPD declined from the non-NIP cohort to the catch-up cohort (1.8% vs. 0.6%, p < 0.001) and from the catch-up to the full NIP cohort (0.6% vs. 0.07%, p = 0.014). In contrast, the rates of infections with other pathogens increased after NIP. CONCLUSION: The introduction of PCV13 showed significant reduction in case-fatality and IPD rates. The increasing rates of other pathogens warrant further surveillance for their clinical significance.

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.

Mycobacterium tuberculosis (Mtb) persists in lung myeloid cells during chronic infection. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, we determined that in chronic phase, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb than alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Transcriptomic and functional studies of sorted cells revealed that the lysosome biogenesis pathway is underexpressed in MNC1, which have less lysosome content, acidification, and proteolytic activity than AM, and less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cells via its ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence, suggesting a potential target for host-directed tuberculosis therapy.

Comparative Efficacy of Pharmacological Treatments for Acne Vulgaris: A Network Meta-Analysis of 221 Randomized Controlled Trials.

PURPOSE: Acne is an extremely common skin disease with an estimated global prevalence of 9.4%. We aim to provide comprehensive comparisons of the common pharmacological treatments for acne. METHODS: Randomized controlled trials comparing the efficacy of pharmacological therapies for acne vulgaris in patients of any age and sex and with a treatment duration of >2 weeks were included. PubMed and Embase databases were searched from inception until February 2022. Our prespecified primary end points were mean percentage reduction in total, inflammatory, and noninflammatory lesions. Treatment ranking was determined by P values. RESULTS: There were 210 articles describing 221 trials and 37 interventions included in the analysis. Our primary analysis of percentage reduction in total lesion count had 65,601 patients enrolled. Across all trials, the mean age was 20.4 years. The median duration of treatment was 12 weeks. The median total, inflammatory, and noninflammatory lesion counts were 72, 27, and 44, respectively. The most effective treatment was oral isotretinoin (mean difference [MD] = 48.41; P = 1.00), followed by triple therapy containing a topical antibiotic, a topical retinoid, and benzoyl peroxide (BPO) (MD = 38.15; P = .95) and by triple therapy containing an oral antibiotic, a topical retinoid, and BPO (MD = 34.83; P = .90). For monotherapies, oral or topical antibiotics or topical retinoids have comparable efficacy for inflammatory lesions, while oral or topical antibiotics have less effect on noninflammatory lesions. CONCLUSION: The most effective treatment for acne is oral isotretinoin, followed by triple therapies containing a topical retinoid, BPO, and an antibiotic. We present detailed comparisons of each intervention to serve as a practical database.

Sex-specific incidence of hepatitis B virus flares among Bcr-Abl tyrosine kinase inhibitor users in Taiwan.

BACKGROUND: The use of Bcr-Abl TKI was found to be associated with hepatitis B (HBV) flares, with a more profound risk observed in females. This study was conducted to characterize the clinical features of patients with HBV flare among Bcr-Abl TKI users, to estimate sex-specific incidence rates of HBV flare, and to evaluate potential cumulative effect of Bcr-Abl TKI. METHODS: Bcr-Abl TKI users with chronic HBV infection were identified from Taiwan's National Health Insurance database. The HBV flare cases were identified within the cohort. Incidence rates of HBV flare between men and women were assessed. Nested case-control analysis was used to evaluate the cumulative effect of Bcr-Abl TKI use on HBV flare. RESULTS: Among 415 patients with chronic HBV infection treated with Bcr-Abl TKI from 2005 through 2018, 45 flare cases (28 males and 17 females) were identified. Days between Bcr-Abl TKI initiation and HBV flare was 319 days in women compared to 610 days in men. 66.7% of the flares occurred during TKI therapy. Twelve of the 45 patients died, half of them died around 6 months after hepatitis B flare. Incidence rates of HBV flare were 2.34 and 3.33 per 100 person-years in males and females, respectively. Higher incidence was observed among patients with chronic myeloid leukemia. Cumulative effect of Bcr-Abl TKI on HBV flare was not observed. CONCLUSION: Approximately 10% of HBV carriers who used Bcr-Abl TKI experienced HBV flare in Taiwan. The risk was higher in women and among patients with chronic myeloid leukemia.

Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires.

Cancer cell-derived extracellular vesicles (EVs) have unique protein profiles, making them promising targets as disease biomarkers. High-grade serous ovarian carcinoma (HGSOC) is the deadly subtype of epithelial ovarian cancer, and we aimed to identify HGSOC-specific membrane proteins. Small EVs (sEVs) and medium/large EVs (m/lEVs) from cell lines or patient serum and ascites were analyzed by LC-MS/MS, revealing that both EV subtypes had unique proteomic characteristics. Multivalidation steps identified FRα, Claudin-3, and TACSTD2 as HGSOC-specific sEV proteins, but m/lEV-associated candidates were not identified. In addition, for using a simple-to-use microfluidic device for EV isolation, polyketone-coated nanowires (pNWs) were developed, which efficiently purify sEVs from biofluids. Multiplexed array assays of sEVs isolated by pNW showed specific detectability in cancer patients and predicted clinical status. In summary, the HGSOC-specific marker detection by pNW are a promising platform as clinical biomarkers, and these insights provide detailed proteomic aspects of diverse EVs in HGSOC patients.