Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.

Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1ß (IL-1ß)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin was substantially decreased, and the constitutive IL-1ß release from peripheral blood mononuclear cells of patients with FMF or HIDS was attenuated by activation of PKN1 and PKN2. Defects in prenylation, seen in HIDS, led to RhoA inactivation and consequent pyrin inflammasome activation. These data suggest a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders.

Intravascular Imaging-Guided or Angiography-Guided Complex PCI.

BACKGROUND: Data regarding clinical outcomes after intravascular imaging-guided percutaneous coronary intervention (PCI) for complex coronary-artery lesions, as compared with outcomes after angiography-guided PCI, are limited. METHODS: In this prospective, multicenter, open-label trial in South Korea, we randomly assigned patients with complex coronary-artery lesions in a 2:1 ratio to undergo either intravascular imaging-guided PCI or angiography-guided PCI. In the intravascular imaging group, the choice between intravascular ultrasonography and optical coherence tomography was at the operators' discretion. The primary end point was a composite of death from cardiac causes, target-vessel-related myocardial infarction, or clinically driven target-vessel revascularization. Safety was also assessed. RESULTS: A total of 1639 patients underwent randomization, with 1092 assigned to undergo intravascular imaging-guided PCI and 547 assigned to undergo angiography-guided PCI. At a median follow-up of 2.1 years (interquartile range, 1.4 to 3.0), a primary end-point event had occurred in 76 patients (cumulative incidence, 7.7%) in the intravascular imaging group and in 60 patients (cumulative incidence, 12.3%) in the angiography group (hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.89; P = 0.008). Death from cardiac causes occurred in 16 patients (cumulative incidence, 1.7%) in the intravascular imaging group and in 17 patients (cumulative incidence, 3.8%) in the angiography group; target-vessel-related myocardial infarction occurred in 38 (cumulative incidence, 3.7%) and 30 (cumulative incidence, 5.6%), respectively; and clinically driven target-vessel revascularization in 32 (cumulative incidence, 3.4%) and 25 (cumulative incidence, 5.5%), respectively. There were no apparent between-group differences in the incidence of procedure-related safety events. CONCLUSIONS: Among patients with complex coronary-artery lesions, intravascular imaging-guided PCI led to a lower risk of a composite of death from cardiac causes, target-vessel-related myocardial infarction, or clinically driven target-vessel revascularization than angiography-guided PCI. (Supported by Abbott Vascular and Boston Scientific; RENOVATE-COMPLEX-PCI ClinicalTrials.gov number, NCT03381872).

Precision targeting tumor cells using cancer-specific InDel mutations with CRISPR-Cas9.

An ideal cancer therapeutic strategy involves the selective killing of cancer cells without affecting the surrounding normal cells. However, researchers have failed to develop such methods for achieving selective cancer cell death because of shared features between cancerous and normal cells. In this study, we have developed a therapeutic strategy called the cancer-specific insertions-deletions (InDels) attacker (CINDELA) to selectively induce cancer cell death using the CRISPR-Cas system. CINDELA utilizes a previously unexplored idea of introducing CRISPR-mediated DNA double-strand breaks (DSBs) in a cancer-specific fashion to facilitate specific cell death. In particular, CINDELA targets multiple InDels with CRISPR-Cas9 to produce many DNA DSBs that result in cancer-specific cell death. As a proof of concept, we demonstrate here that CINDELA selectively kills human cancer cell lines, xenograft human tumors in mice, patient-derived glioblastoma, and lung patient-driven xenograft tumors without affecting healthy human cells or altering mouse growth.

Income variability and incident cardiovascular disease in diabetes: a population-based cohort study.

BACKGROUND AND AIMS: Longitudinal change in income is crucial in explaining cardiovascular health inequalities. However, there is limited evidence for cardiovascular disease (CVD) risk associated with income dynamics over time among individuals with type 2 diabetes (T2D). METHODS: Using a nationally representative sample from the Korean National Health Insurance Service database, 1 528 108 adults aged 30-64 with T2D and no history of CVD were included from 2009 to 2012 (mean follow-up of 7.3 years). Using monthly health insurance premium information, income levels were assessed annually for the baseline year and the four preceding years. Income variability was defined as the intraindividual standard deviation of the percent change in income over 5 years. The primary outcome was a composite event of incident fatal and nonfatal CVD (myocardial infarction, heart failure, and stroke) using insurance claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for potential confounders. RESULTS: High-income variability was associated with increased CVD risk (HRhighest vs. lowest quartile 1.25, 95% CI 1.22-1.27; Ptrend < .001). Individuals who experienced an income decline (4 years ago vs. baseline) had increased CVD risk, which was particularly notable when the income decreased to the lowest level (i.e. Medical Aid beneficiaries), regardless of their initial income status. Sustained low income (i.e. lowest income quartile) over 5 years was associated with increased CVD risk (HRn = 5 years vs. n = 0 years 1.38, 95% CI 1.35-1.41; Ptrend < .0001), whereas sustained high income (i.e. highest income quartile) was associated with decreased CVD risk (HRn = 5 years vs. n = 0 years 0.71, 95% CI 0.70-0.72; Ptrend < .0001). Sensitivity analyses, exploring potential mediators, such as lifestyle-related factors and obesity, supported the main results. CONCLUSIONS: Higher income variability, income declines, and sustained low income were associated with increased CVD risk. Our findings highlight the need to better understand the mechanisms by which income dynamics impact CVD risk among individuals with T2D.

Downregulation of otulin induces inflammasome activation in neutrophilic asthma.

BACKGROUND: Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1ß overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1ß production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients. OBJECTIVE: We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway. METHODS: We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed in vitro and in vivo. RESULTS: When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1ß production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1ß release in NA. CONCLUSIONS: IL-1ß overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.

Anti-inflammatory effect of Trichospira verticillata via suppression of the NLRP3 inflammasome in neutrophilic asthma.

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.

Empagliflozin attenuates epithelial-to-mesenchymal transition through senescence in peritoneal dialysis.

Epithelial-to-mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, antisenescence therapies effectively reduce EMT. Some models have shown antisenescence effects with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor. Therefore, our study investigated the antisenescence effects of empagliflozin as an SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with d-glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. HPMCs treated with glucose transformed from cobblestone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphological changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, cotreatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence, or EMT markers of the parietal peritoneum was observed, which, however, was attenuated by cotreatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared with those in the control group; however, these changes were decreased by empagliflozin. In conclusion, empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Cotreatment with empagliflozin improved peritoneal thickness and fibrosis in PD.NEW & NOTEWORTHY Epithelial-to-mesenchymal transition (EMT) is considered one of the senescence processes. Antisenescence therapies may effectively reduce EMT in peritoneal dialysis models. Human peritoneal mesothelial cells treated with glucose show an increase in senescence and EMT markers; however, empagliflozin attenuates these changes. Mice undergoing peritoneal dialysis exhibit increased senescence and EMT markers, which are decreased by empagliflozin. These findings suggest that empagliflozin may emerge as a novel strategy for prevention or treatment of peritoneal fibrosis.

Association between physical activity changes and risk of incident ischemic stroke following cancer diagnosis: A nationwide retrospective cohort study.

BACKGROUND: Physical inactivity is prevalent after cancer treatment, which could increase ischemic stroke risk in cancer survivors. This study investigated the association between physical activity change from pre- to post-diagnosis and ischemic stroke risk among cancer survivors. METHODS: Using data from the Korean National Health Insurance Service database, 269,943 cancer survivors (mean [SD] age, 56.3 [12.1] years; 45.7% male) with no history of cardiovascular disease were evaluated based on changes in physical activity from pre- to post-diagnosis. Using the Fine-Gray model, subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs) for ischemic stroke risk were calculated, considering death as a competing risk. RESULTS: After cancer diagnosis, 62.0% remained inactive, 10.1% remained active, 16.6% became active, and 11.4% became inactive. During a mean (SD) follow-up of 4.1 (2.0) years, being active both pre- and post-diagnosis was associated with a 15% decreased risk of ischemic stroke (sHR, 0.85; 95% CI, 0.75-0.96), compared with those who remained inactive. Cancer survivors who became active and inactive post-diagnosis showed a 16% and 11% lower ischemic stroke risk (sHR, 0.84; 95% CI, 0.75-0.93; sHR, 0.89; 95% CI, 0.79-0.99), respectively, than those who remained inactive. Analysis by the primary cancer site did not substantially differ from the main findings. CONCLUSIONS: Physical activity is associated with reduced ischemic stroke risk among cancer survivors. The potential benefits of physical activity are not limited to individuals who were physically active before cancer diagnosis, thus preventive strategies against ischemic stroke should emphasize physical activity throughout the cancer journey.

Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors.

BACKGROUND: The risk of incident atrial fibrillation (AF) among breast cancer survivors, especially for younger women, and cancer treatment effects on the association remain unclear. This study aimed to investigate the risk of AF among breast cancer survivors and evaluate the association by age group, length of follow-up, and cancer treatment. METHODS: Using data from the Korean Health Insurance Service database (2010-2017), 113,232 women newly diagnosed with breast cancer (aged ≥ 18 years) without prior AF history who underwent breast cancer surgery were individually matched 1:5 by birth year to a sample female population without cancer (n = 566,160) (mean[SD] follow-up, 5.1[2.1] years). Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) considering death as a competing risk were estimated, adjusting for sociodemographic factors and cardiovascular/non-cardiovascular comorbidities. RESULTS: BCS had a slightly increased AF risk compared to their cancer-free counterparts (sHR 1.06; 95% CI 1.00-1.13), but the association disappeared over time. Younger BCS (age < 40 years) had more than a 2-fold increase in AF risk (sHR 2.79; 95% CI 1.98-3.94), with the association remaining similar over 5 years of follow-up. The increased risk was not observed among older BCS, especially those aged > 65 years. Use of anthracyclines was associated with increased AF risk among BCS (sHR 1.57; 95% CI 1.28-1.92), which was more robust in younger BCS (sHR 1.94; 95% CI 1.40-2.69 in those aged ≤ 50 years). CONCLUSIONS: Our findings suggest that younger BCS had an elevated risk of incident AF, regardless of the length of follow-up. Use of anthracyclines may be associated with increased mid-to-long-term AF risk among BCS.

Depression and risk of stroke and mortality after percutaneous coronary intervention: A nationwide population study.

BACKGROUND: Limited evidence exists on the role of depression in the risk of developing stroke and other cardiovascular outcomes in patients who have undergone percutaneous coronary interventions (PCI). We investigated this relationship with data from the Korean National Health Insurance Service database. METHODS: Our nationwide retrospective cohort study included 164,198 patients who had undergone PCI between 2010 and 2017. Depression was defined with the ICD-10 codes recorded prior to the PCI. The primary outcome was a new-onset stroke following the PCI. Secondary outcomes included PCI with myocardial infarction (MI), revascularization (PCI or coronary artery bypass grafting), and all-cause mortality. A multivariable Cox proportional hazards regression analysis was used to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI), adjusting for potential confounders, including sociodemographic and lifestyle factors, comorbidities, and MI at the index PCI. RESULTS: Over a median follow-up of 5.0 years, acute stroke occurred in 5.7% of patients with pre-existing depression (17.4% of the study population), compared to 3.5% of those without depression. Depression was associated with a 27% increased risk of acute stroke (aHR 1.27, 95% CI 1.20-1.35). Additionally, depression was linked with a 25% elevated risk of all-cause death (aHR 1.25, 95% CI, 1.21-1.29) and an 8% increased risk of revascularization (aHR 1.08, 95% CI 1.04-1.11). The associations with the risk of stroke and all-cause mortality were stronger in patients under 65 years. CONCLUSIONS: Our findings suggest that pre-existing depression may increase the risk of stroke and all-cause mortality following PCI, particularly in patients under 65 years. Additionally, depression was significantly associated with an increased need for revascularization. This underscores the potential benefits of managing depression to reduce stroke risk and overall cardiovascular outcomes following PCI.

Diverse Self-assembly Pathways in Nematic Compartment Network: Topological Percolation and Pathfinding.

The self-assembly of nematic molecules in microcompartments with unambiguously defined surface anchoring is well predictable and is likely to have a single stable topological structure. Here, in contrast, a confined nematic system comprising an array of microcompartments interconnected by channels is demonstrated, exhibiting diverse molecular assembly pathways leading to the formation of four types of topological structures and twelve different patterns randomly distributed. Intercompartment communication via channels plays a crucial role in the diversity of patterns and distributions. It determines the sizes and structures of domains separated by channel defects. The domain structure, which features a pathfinding algorithm and reverse tree structure, can be modelled by an isotropically directed bond percolation with additional restrictions. This system serves as a model for controlled randomness and restricted growth of networks, with potential applications in anticounterfeit protection as a physically unclonable function (PUF) with multiple-level communication protocols.

Investigating the coverage of the Arkansas All-Payer Claims Database for examining health disparities related to persistent poverty areas in colorectal cancer patients.

PURPOSE: We aimed to (1) determine the extent of coverage of colorectal cancer patients in Arkansas All-Payer Claims Database (APCD), (2) assess coverage difference between persistent poverty and other areas, and (3) identify patient, tumor, and area factors associated with inclusion in APCD. METHODS: Data were from 2018 to 2020 Arkansas APCD linked with 2019 Arkansas Central Cancer Registry (ACCR). We constructed four cohorts to assess APCD's coverage of CRC patients: (Cohort 1) ≥ 1 day of medical coverage in APCD in 2019; (Cohort 2) APCD coverage in the diagnosis month; continuous APCD coverage in the 30; Year around diagnosis (six months before to five months after diagnosis month) (Cohort 3); or until death within six months (Cohort 4). We compared proportions in the cohorts by area persistent poverty designation. Logistic regressions identified factors associated with inclusion in APCD cohorts. PATIENT SELECTION: CRC patients diagnosed in 2019 from ACCR, excluding in situ disease. RESULTS: Of the 1,510 CRC patients diagnosed in 2019, 83% had ≥ 1 day of medical coverage in 2019 APCD (Cohort1), 81% had coverage in the diagnosis month (Cohort 2), and 63% had continuous coverage in the year around diagnosis (Cohort 3). Additionally, 11% died within six months but had continuous coverage until death (Cohort 4, 74%). No coverage difference was found between persist poverty and other areas. Age and primary payer type at diagnosis were the main predictors of inclusion in APCD. CONCLUSION: Arkansas APCD had high coverage of Arkansas CRC patients. No selection bias by area of persistent poverty designation was present.

Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne.

OBJECTIVES: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1. METHODS: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients. RESULTS: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement. CONCLUSION: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.

Hydramethylnon induces mitochondria-mediated apoptosis in BEAS-2B human bronchial epithelial cells.

Typically used household chemicals comprise numerous compounds. Determining mixture toxicity, as observed when using household chemicals containing multiple substances, is of considerable importance from a regulatory perspective. Upon examining the toxic effects of household chemical mixtures, we observed that hydramethylnon combined with tetramethrin resulted in synergistic toxicity. To determine the unknown toxicity mechanism of hydramethylnon, which carries the risk of inhalation exposure when using household chemicals, we conducted a further investigation using BEAS-2B cells, a human bronchial epithelial cell line. Hydramethylnon-induced cytotoxicity was determined following 24 and 48 h of exposure using the water-soluble tetrazolium 1 and lactate dehydrogenase assays. To elucidate the toxicity mechanism, we utilized flow cytometry and measured the levels of apoptosis-related proteins and caspase activities. Given that hydramethylnon, as an insecticide, disrupts the mitochondrial electron transfer chain, we analyzed the relevant mechanisms, including mitochondrial superoxide levels as well as the mitochondrial membrane potential (MMP). Hydramethylnon dose-dependently induced BEAS-2B cell apoptosis via the intrinsic pathway. Furthermore, it significantly increased mitochondrial superoxide levels and disrupted the MMP. Pre-treatment with a caspase inhibitor (Z-DEVD-FMK) confirmed that hydramethylnon induced caspase-dependent apoptosis. Apoptosis, a key event in the toxicological process of chemicals, can lead to lung diseases, including fibrosis and cancer. The results of the present study suggest a mechanism of toxicity of hydramethrylnon, an organofluorine biocide whose toxicity has been little studied, to the lung epithelium. Considering the potential risks associated with inhalation exposure, these results highlight the need for careful management and regulation of hydramethylnon.

The Association of Subspecialty and Sex with Industry Payments to Internal Medicine Physicians Who Recently Completed Training.

BACKGROUND: Financial relationships with drug and medical device companies may impact quality of care and academic research. However, little is known when and how these financial relationships develop among newly independent physicians who recently completed from residency or fellowship programs in internal medicine (IM). OBJECTIVE: To compare patterns of industry payments among IM graduates. DESIGN: Retrospective, observational cohort study. SUBJECTS: IM graduates from residency or fellowship programs between January 2015 and December 2019. MAIN MEASURES: We analyzed Open Payments reports made between July 2015 and June 2021 to recent graduates of U.S. Accreditation Council for Graduate Medical Education (ACGME)-accredited residency and fellowship programs in IM. The primary outcome was general payments accepted by these physicians, stratified by procedural (i.e., critical care medicine/pulmonary medicine, cardiac/cardiovascular disease, and gastroenterology) and non-procedural (i.e., infectious disease, general internal medicine, and other specialties) subspecialties. The secondary outcomes included general payments stratified by sex and age at residency or fellowship training completion. KEY RESULTS: There were 41,669 IM physicians with a median age of 33.0 years. In the first 3 years after completion, the proportion of physicians accepting any general payments was 72.6%, 91.9%, and 86.8% in Critical Care Medicine/Pulmonary Medicine, Cardiac/Cardiovascular Disease, and Gastroenterology, compared to 56.1%, 52.6%, and 52.3% in Infectious Disease, General Internal Medicine, and Other Specialties (p<0.0001). After adjusting for confounding variables, the procedural group showed an increased hazard ratio (HR) for accepting any general payments and at least $5000 of general payments compared to the non-procedural group. The HRs of accepting any general payments in the procedural subspecialty were 2.26 (95% CI, 2.11-2.42) and 2.83 (95% CI, 2.70-2.97) in female and male physicians, respectively (p-value < 0.0001). CONCLUSION: Industry financial relationships among newly independent physicians in IM exist immediately after completion of training and are influenced by subspecialty, sex, and age.

Pharmacoepidemiology and Clinical Correlates of Lithium Treatment for Bipolar Disorder in Asia.

BACKGROUND: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons. METHODS: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling. RESULTS: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not. CONCLUSIONS: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices.

Long-term survival outcomes of 'watch and wait' in patients with bronchus-associated lymphoid tissue lymphoma: a multicenter real-world data analysis in Korea.

Bronchus-associated lymphoid tissue (BALT) is a rare cause of extranodal marginal zone lymphoma (MZL). Although most patients with BALT lymphoma (BALToma) show an indolent clinical course and are monitored without treatment, there are limited real-world data on the long-term outcome of "watch-and-wait' strategy in comparison with other treatments. The survival outcomes of patients newly diagnosed with BALToma at three tertiary hospitals in Korea undergoing two treatment strategies were analyzed: group A, patients who were monitored without any treatment or received only radiotherapy after diagnosis; and group B, patients receiving any kind of systemic chemotherapy after diagnosis, regardless of their history of any local treatment such as surgery or radiotherapy. Of the 67 patients included in our analysis, the 10-year progression-free survival (PFS) and 10-year overall survival (OS) rates were 65.3% and 83.2%, respectively. The 10-year PFS rates for observation or localized treatment and systemic chemotherapy were 78.7% and 56.9%, respectively (p = 0.044). Ten-year OS rates for observation or localized treatment and systemic chemotherapy were 100% and 71.7%, respectively (p = 0.016). Multivariate analysis showed that bilateral lung (HR 2.462, p = 0.047) and extrapulmonary organ (HR 4.485, p = 0.004) involvement were the only significant factors associated with poor PFS. Prognostic factor analysis for OS did not yield significant results. Patients with BALToma show a favorable prognosis, suggesting that observation or localized therapy alone may be effective for patient management. However, patients with bilateral lung or extrapulmonary involvement may require careful monitoring for disease progression and more aggressive treatment approaches.

Analysis of host factor networks during hepatitis B virus infection in primary human hepatocytes.

BACKGROUND: Chronic hepatitis B virus (HBV) infection affects around 250 million people worldwide, causing approximately 887,000 deaths annually, primarily owing to cirrhosis and hepatocellular carcinoma (HCC). The current approved treatments for chronic HBV infection, such as interferon and nucleos(t)ide analogs, have certain limitations as they cannot completely eradicate covalently closed circular DNA (cccDNA). Considering that HBV replication relies on host transcription factors, focusing on host factors in the HBV genome may provide insights into new therapeutic targets against HBV. Therefore, understanding the mechanisms underlying viral persistence and hepatocyte pathogenesis, along with the associated host factors, is crucial. In this study, we investigated novel therapeutic targets for HBV infection by identifying gene and pathway networks involved in HBV replication in primary human hepatocytes (PHHs). Importantly, our study utilized cultured primary hepatocytes, allowing transcriptomic profiling in a biologically relevant context and enabling the investigation of early HBV-mediated effects. METHODS: PHHs were infected with HBV virion particles derived from HepAD38 cells at 80 HBV genome equivalents per cell (Geq/cell). For transcriptomic sequencing, PHHs were harvested 1, 2-, 3-, 5-, and 7 days post-infection (dpi). After preparing the libraries, clustering and sequencing were conducted to generate RNA-sequencing data. This data was processed using Bioinformatics tools and software to analyze DEGs and obtain statistically significant results. Furthermore, qRT-PCR was performed to validate the RNA-sequencing results, ensuring consistent findings. RESULTS: We observed significant alterations in the expression patterns of 149 genes from days 1 to 7 following HBV infection (R2 > 0.7, q < 0.05). Functional analysis of these genes identified RNA-binding proteins involved in mRNA metabolism and the regulation of alternative splicing during HBV infection. Results from qRT-PCR experiments and the analysis of two validation datasets suggest that RBM14 and RPL28 may serve as potential biomarkers for HBV-associated HCC. CONCLUSIONS: Transcriptome analysis of gene expression changes during HBV infection in PHHs provided valuable insights into chronic HBV infection. Additionally, understanding the functional involvement of host factor networks in the molecular mechanisms of HBV replication and transcription may facilitate the development of novel strategies for HBV treatment.

Mass production and characterization of an endoglucanase from Coleoptera insect (Monochamus saltuarius) in yeast Kluyveromyceslactis.

To harness the diverse industrial applications of cellulase, including its use in the food, pulp, textile, agriculture, and biofuel sectors, this study focused on the high-yield production of a bioactive insect-derived endoglucanase, Monochamus saltuarius glycoside hydrolase family 5 (MsGHF5). MsGHF5 was introduced into the genome of Kluyveromyces lactis to maintain expression stability, and mass production of the enzyme was induced using fed-batch fermentation. After 40 h of cultivation, recombinant MsGHF5 was successfully produced in the culture broth, with a yield of 29,000 U/L, upon galactose induction. The optimal conditions for the activity of purified MsGHF5 were determined to be a pH of 5 and a temperature of 35 °C, with the presence of ferrous ions enhancing the enzymatic activity by up to 1.5-fold. Notably, the activity of MsGHF5 produced in K. lactis was significantly higher than that produced in Escherichia coli, suggesting that glycosylation is crucial for the functional performance of the enzyme. This study highlights the potential use of K. lactis as a host for the production of bioactive MsGHF5, thus paving the way for its application in various industrial sectors.