Incidence and co-infection with COVID-19 of dengue during the COVID-19 pandemic.

The co-infection of dengue and COVID-19 has been regarded as a public health issue for dengue-endemic countries during the COVID-19 pandemic. Travel restrictions might decrease the chance of mosquitoes biting and, thus, reduce the risk of dengue transmission. However, the spread of dengue was reported to increase with the policies of lockdowns and social distancing in specific areas due to delayed interventions in dengue transmission. Of cases experiencing dengue and COVID-19 co-infection, most recovered after receiving supportive care and/or steroid therapy. However, some episodes of severe or fatal diseases in specific individuals, such as pregnant women, have been reported, and the clinical course of this co-infection is unrecognized or unpredictable. Accordingly, it is crucial to promptly identify predictors of developing severe viral diseases among co-infection patients.

Epicardial Adipose Tissue is Associated with Geometry Alteration and Diastolic Dysfunction in Prediabetic Cardiomyopathy.

BACKGROUND: Diastolic dysfunction and alterations in cardiac geometry are early indicators of diabetic cardiomyopathy. However, the association between cardiac changes across the glucose continuum and the contribution of epicardial adipose tissue (EAT) to these changes has not yet been investigated. PURPOSE: In this study, we aim to investigated the EAT on cardiac diastolic function and structural alterations along the diabetic continuum using cardiac magnetic resonance imaging (CMRI). METHODS: We enrolled individuals who were categorized into groups based on glucose tolerance status. Left ventricular structure and diastolic function were assessed using echocardiography and CMRI to determine the EAT, intramyocardial fat, and associated parameters. Multivariable logistic regression models were also used. RESULTS: In a study of 370 patients (209 normal glucose tolerance, 82 prediabetes, 79 diabetes), those with prediabetes and diabetes showed increased heart dimensions and diastolic dysfunction, including E/E' (the ratio of early mitral inflow velocity to mitral annular early diastolic velocity) (7.9±0.51 vs. 8.5±0.64 vs. 10.0±0.93, p=0.010), left atrial volume index (28.21±14.7 vs. 33.2±12.8 vs. 37.4±8.2 mL/m2, p<0.001), and left ventricular peak filling rate (4.46±1.75 vs. 3.61±1.55 vs. 3.20±1.30 mL/s, p<0.001). EAT significantly increased in prediabetes and diabetes (26.3±1.16 vs. 31.3±1.83 vs. 33.9±1.9 gm, p=0.001), while intramyocardial fat did not differ significantly. Prediabetes altered heart geometry, but not diastolic function (OR 1.22 [1.02-1.83], p=0.012; and 1.70 [0.79-3.68], p=0.135). Diabetes significantly affected both heart structure and diastolic function (OR 1.42 [1.11-1.97], p=0.032; and 2.56 [1.03-5.40], p=0.034) after adjusting for covariates. CONCLUSIONS: Elevated EAT was observed in patients with prediabetes and is associated with adverse alterations in cardiac structure and diastolic function, potentially serving as an underlying mechanism for the early onset of diabetic cardiomyopathy.

Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

Effect of drug interactions with non-vitamin-K oral anticoagulants on thromboembolic events in patients with nonvalvular atrial fibrillation.

Introduction: Few real-world studies have investigated drug-drug interactions (DDIs) involving non-vitamin-K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation (NVAF). The interactions encompass drugs inducing or inhibiting cytochrome P450 3A4 and permeability glycoprotein. These agents potentially modulate the breakdown and elimination of NOACs. This study investigated the impact of DDIs on thromboembolism in this clinical scenario. Method: Patients who had NVAF and were treated with NOACs were selected as the study cohort from the National Health Insurance Research Database of Taiwan. Cases were defined as patients hospitalised for a thromboembolic event and who underwent a relevant imaging study within 7 days before hospitalisa-tion or during hospitalisation. Each case was matched with up to 4 controls by using the incidence density sampling method. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer or inhibitor or both with NOACs was identified. The effects of these interactions on the risk of thromboembolic events were examined with univariate and multivariate conditional logistic regressions. Results: The study cohort comprised 60,726 eligible patients. Among them, 1288 patients with a thromboembolic event and 5144 matched control patients were selected for analysis. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer resulted in a higher risk of thromboembolic events (adjusted odds ratio [AOR] 1.23, 95% confidence interval [CI] 1.004-1.51). Conclusion: For patients with NVAF receiving NOACs, the concurrent use of cytochrome P450 3A4/ permeability glycoprotein inducers increases the risk of thromboembolic events.

Prevalence and Sociodemographic Correlates of Chronic Pain Among A Nationally Representative Sample of Older Adults in the United States.

Subgroup analyses conducted among U.S. national survey data have estimated that 27-34% of adults aged ≥65 years have chronic pain. However, none of these studies focused specifically on older adults or examined disparities in chronic pain in those aged ≥65 years. To obtain current information on the prevalence and sociodemographic correlates of chronic pain in U.S. older adults, a cross-sectional analysis was conducted of data collected from 3,505 older adults recruited from the AmeriSpeak® Panel. Chronic pain was defined as pain on most or every day in the last three months. Nationally representative chronic pain prevalence estimates were computed by incorporating study-specific survey design weights. Logistic regression analyses evaluated differences in chronic pain status as a function of sociodemographic characteristics (e.g., gender, race/ethnicity, socioeconomic status). Results indicated that 37.8% of older adults reported chronic pain. Compared to White older adults, Black (OR = 0.6, 95% CI: 0.4-0.8) and Asian (OR = 0.2, 95% CI: 0.1-0.8) older adults were less likely to report chronic pain. The prevalence of chronic pain was also lower among those who reported the highest (vs. lowest) household income (OR = 0.6, 95% CI: 0.4-0.8). Those who were not working due to disability (vs. working as a paid employee) were more likely to report chronic pain (OR = 3.2, 95% CI: 2.1-5.0). This study was the first to recruit a large, representative sample of older adults to estimate the prevalence of chronic pain and extends prior work by identifying sub-groups of older adults that are disproportionately affected. PERSPECTIVE: This study was the first to estimate the prevalence and sociodemographic correlates of chronic pain among a large, representative sample of U.S. older adults. Findings underscore the high prevalence of chronic pain and highlight disparities in chronic pain prevalence rates among this historically understudied population.

The Prevalence and Risk Analysis of Cerebral Palsy and Other Neuro-Psychological Comorbidities in Children with Low Birth Weight in Taiwan: A Nationwide Population-Based Cohort Study.

Background: This study evaluated early childhood comorbidities of cerebral palsy (CP) in low birth weight (LBW) children and assessed the impact of maternal bio-psychosocial factors on CP risk in preterm infants of varying birth weights (BWs). Methods: Data from 15,181 preterm infants (2009-2013) and 151,810 controls were analyzed using Taiwan's National Health Insurance Research Database. CP prevalence and LBW-associated comorbidities were examined, and odds ratios (ORs) were calculated. Results: This study confirmed increasing prematurity and LBW rates in Taiwan, with LBW infants showing higher CP prevalence. Significant maternal risk factors included age extremes (<20 and >40 years). LBW infants exhibited higher risks for respiratory, circulatory, nervous system, and psycho-developmental comorbidities compared with controls, with the lowest BW having even higher ORs. Maternal factors such as family income, the number of hospital admissions, and length of hospital stay were remarkably correlated with BW and subsequent complications. Each additional gestational week crucially reduced the risk of complications in premature infants. Conclusions: LBW infants are at a higher risk for CP and various comorbidities, with maternal bio-psychosocial factors playing a critical role. Addressing these factors in prenatal care and interventions is essential to improve outcomes for premature infants.

Dual Antithrombotic Therapy versus Anticoagulant Monotherapy for Major Adverse Limb Events in Patients with Concomitant Lower Extremity Arterial Disease and Atrial Fibrillation: A Propensity Score Weighted Analysis.

OBJECTIVE: Patients with symptomatic lower extremity arterial disease (LEAD) are recommended to receive antiplatelet therapy, while direct oral anticoagulants (DOACs) are standard for stroke prevention in patients with atrial fibrillation (AF). For patients with concomitant LEAD and AF, data comparing dual antithrombotic therapy (an antiplatelet agent used in conjunction with a DOAC) vs. DOAC monotherapy are scarce. This retrospective cohort study, based on data from the Taiwan National Health Insurance Research Database, aimed to compare the efficacy and safety of these antithrombotic strategies. METHODS: Patients with AF who underwent revascularisation for LEAD between 2012 - 2020 and received any DOAC within 30 days of discharge were included. Patients were grouped by antiplatelet agent exposure into the dual antithrombotic therapy and DOAC monotherapy groups. Inverse probability of treatment weighting was used to mitigate selection bias. Major adverse limb events (MALEs), ischaemic stroke or systemic embolism, and bleeding outcomes were compared. Patients were followed until the occurrence of any study outcome, death, or up to two years. RESULTS: A total of 1 470 patients were identified, with 736 in the dual antithrombotic therapy group and 734 in the DOAC monotherapy group. Among them, 1 346 patients received endovascular therapy as the index revascularisation procedure and 124 underwent bypass surgery. At two years, dual antithrombotic therapy was associated with a higher risk of MALEs than DOAC monotherapy (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.15 - 1.56), primarily driven by increased repeat revascularisation. Dual antithrombotic therapy was also associated with a higher risk of major bleeding (SHR 1.43, 95% CI 1.05 - 1.94) and gastrointestinal bleeding (SHR 2.17, 95% CI 1.42 - 3.33) than DOAC monotherapy. CONCLUSION: In patients with concomitant LEAD and AF who underwent peripheral revascularisation, DOAC monotherapy was associated with a lower risk of MALEs and bleeding events than dual antithrombotic therapy.

Enhancing the sequence coverage of nanodiamond-extracted early secretory proteins from the Mycobacterium tuberculosis complex.

The unambiguous identification of protein species requires high sequence coverage. In this study, we successfully improved the sequence coverage of early secretory 10 kDa cell filtrate protein (CFP-10) and 6 kDa early secretory antigenic target (ESAT-6) proteins from the Mycobacterium tuberculosis complex (MTC) in broth culture media with the use of the 4-chloro-α-cyanocinnamic acid (Cl-CCA) matrix. Conventional matrices, α-cyano-hydroxy-cinnamic acid (CHCA) and 2,5-dihydroxybenzoic acid (DHB), were also used for comparison. After nanodiamond (ND) extraction, the sequence coverage of the CFP-10 protein was 87% when CHCA and DHB matrices were used, and the ESAT-6 protein was not detected. On the other hand, the sequence coverage for ND-extracted CFP-10 and ESAT-6 could reach 94% and 100%, respectively, when the Cl-CCA matrix was used and with the removal of interference from bovine serum albumin (BSA) protein and α-crystallin (ACR) protein. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was also adopted to analyze the protein mass spectra. A total of 6 prominent ion signals were observed, including ESAT-6 protein peaks at mass-to-charge ratios (m/z) of ∼7931, ∼7974, ∼9768, and ∼9813 and CFP-10 protein peaks at m/z of ∼10 100 and ∼10 660. The ESAT-6 ion signals were always detected concurrently with CFP-10 ion signals, but CFP-10 ion signals could be detected alone without the ESAT-6 ion signals. Furthermore, the newly found ESAT-6 peaks were also confirmed using a Mag-Beads-Protein G kit with an ESAT-6 antibody to capture the ESAT-6 protein, which was also consistent with the sequence coverage analysis.

Mitigating treatment failure of pulmonary pre-extensively drug-resistant tuberculosis: The role of new and repurposed drugs.

BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.

Use of defibrotide in COVID-19 pneumonia: comparison of a phase II study and a matched real-world cohort control.

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by 31st December 2023. The DEFI-VID19 study (ClinicalTrials.gov NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg/d intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was Respiratory Failure Free Survival (RFFS); Overall Survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (HR=0.71[0.95CI: 0.34 to 1.29, P= .138]) and OS (HR=0.78[0.95CI: 0.33 to 1.53, P= .248]) and showed a significantly increased number of post-recovery days (difference in means: 3.61[ 0.95CI: 0.97 to 6.26, P= .0037]). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.

Prognostic Value of Body Surface Area-Adjusted Oxygen Uptake Efficiency Slope in Heart Failure Patients.

Background: COVID-19 has been associated with a higher risk of developing heart failure (HF). Among the parameters derived from cardiopulmonary exercise testing (CPET), oxygen uptake efficiency slope (OUES) has become one of the most important parameters for predicting the prognosis of HF patients. However, the clinical utilization of OUES is limited owing to its variation with patient height and weight. This study aimed to evaluate the prognostic value of body surface area-adjusted OUES (OUES/BSA) in adults with HF. Methods: Thirty-six HF patients (mean age, 57 ± 12 years; 30 men) undergoing CPET between July 2019 and May 2020 who were followed up for 12 months were enrolled. The endpoints were major cardiovascular (CV) events, including hospitalization due to acute decompensated HF, left ventricular assist device implantation, heart transplantation, and cardiovascular-related death. We analyzed the correlations between clinical/CPET variables and major CV events. Results: Among the analyzed CPET variables, OUES/BSA had better correlation with maximal oxygen uptake (VO2max) than other variables. In univariate Cox proportional analysis, OUES/BSA and peak VO2 were both significant independent prognostic factors. The cutoff value of OUES/BSA was 595 ml/min/m2 with an area under the curve of 0.929. The patients with OUES/BSA < 595 ml/min/m2 had a lower CV event-free survival rate at 12 months of follow-up compared with the other group (33.3% and 100%, respectively; log-rank test, p < 0.001). Conclusions: BSA-adjusted OUES is an effective independent predictor for prognosis in HF patients and can be an alternative to peak VO2 for risk stratification in HF patients, regardless of exercise intensity. However, further large-scale studies are required to validate our findings.

A rare case of an endobronchial mass due to Neurospora intermedia.

The ascomycete filamentous fungus Neurospora intermedia is commonly used in the food industry and considered nonpathogenic to humans. This study characterizes four N. intermedia isolates recovered from three patients. The first patient had a mediastinal germ cell tumor with multiple metastases. N. intermedia was recovered from his endotracheal aspirate and from the endobronchial mass obtained by bronchoscopic forceps biopsy. Histopathology of the biopsy tissue revealed necrotic tissue mixed with septate fungal hyphae with right-angle branching. An endobronchial mass caused by N. intermedia was thus diagnosed. Another two N. intermedia isolates were recovered from the endotracheal aspirates of two critically ill patients. In vitro, N. intermedia grows rapidly and forms orange, conidiating colonies composed of septate hyphae. Two isolates from the first patient belong to mating type a; the other two isolates belong to mating type A. Coculture of isolates of opposite mating types yielded dark ascomata containing ascospores, supporting that N. intermedia is a heterothallic fungus. N. intermedia isolates cross-reacted with the Aspergillus galactomannan antigen assay and were susceptible to amphotericin B and voriconazole. In conclusion, this report describes the first human infection (endobronchial mass) caused by N. intermedia, highlighting its potential to invade the human respiratory tract.

Effects of SGLT2 Inhibitors with and without Metformin in High-Risk, Treatment-Naïve Patients with Diabetes.

Background: Contemporary evidence supports the cardiovascular and renal benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2is) in patients with diabetes. While metformin has traditionally been recommended as a first-line treatment, its exact role in improving cardiovascular outcomes remains uncertain. This study aims to evaluate the impact of combination therapy with metformin on the cardiovascular and renal outcomes in high-risk, treatment-naïve diabetic patients who have undergone SGLT2i therapy. Methods: Using the National Health Insurance Research Database in Taiwan, a retrospective cohort study was conducted. Treatment-naïve patients with diabetes and established atherosclerotic cardiovascular disease (ASCVD) undertaking SGLT2i therapy from 1 January 2016 to 31 December 2021 were included. Patients were categorized based on the concomitant use of metformin. Propensity score matching was employed to minimize confounding factors. The primary outcome was major adverse cardiovascular events (MACEs), with secondary outcomes including cardiovascular death, hospitalization for heart failure, and renal outcomes. Results: In total, 10,151 treatment-naïve diabetic patients with ASCVD were identified, with 2570 in the only SGLT2i therapy group and 7581 in the SGLT2i plus metformin group. In total, 2262 pairs were analyzed after propensity score adjustment. The risk of MACEs (36.6 vs. 42.1 events per 1000 person-years; hazard ratio 0.87, 95% confidence interval 0.70-1.09) and other outcomes did not significantly differ between the two treatment groups. Conclusions: In high-risk, treatment-naïve diabetic patients, initiating SGLT2i therapy alone or in combination with metformin resulted in comparable cardiovascular and renal outcomes. These findings suggest that metformin might not be mandatory as a first-line treatment for achieving cardiovascular benefits in such patients.

Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer.

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.