Oral Administration of Lactococcus lactis Expressing Mite and Cockroach Major Allergens Alleviates Progression of Atopic March in a Mouse Model.

PURPOSE: Atopic march is defined as the development of atopic dermatitis in early childhood. We recently developed an atopic march mouse model through skin sensitization with aeroallergens from house dust mites and cockroaches. Using this model, this study aimed to evaluate the oral immunotherapy efficacy of Lactococcus lactis harboring specific antigens on the progression of atopic march. METHODS: Dust mite major allergen Der p 2 and cockroach Per a 2-372 were expressed in L. lactis as a fusion recombinant clone (D2P2). L. lactis-D2P2 was administered intragastrically to Aeroallergen patch-sensitized mice once a day for a total of 35 times. The immunological variables in sera, scratching behavior, airway hyperresponsiveness (AHR), and pathology of lungs and skin were evaluated. RESULTS: Our data showed that L. lactis-D2P2 significantly lowered total immunoglobulin E levels, decreased scratch bouts, and relieved AHR compared with the control mice. Histological analysis of the skin and lung tissue demonstrated the therapeutic effects of L. lactis-D2P2 to modulate immune responses via decreased eosinophil infiltration and reduced expression of key cytokines, interleukin (IL)-31 and IL-13, respectively. CONCLUSIONS: The results imply that mucosal allergen-specific immunotherapy of L. lactis-D2P2 is a more cost-effective alternative to conventional subcutaneous allergen-specific immunotherapy. This study provides a promising platform for the development of novel oral protein-based vaccines in the early prevention of allergies.

Comparative Risk of Neuropsychiatric Adverse Events Associated With Leukotriene-Receptor Antagonists Versus Inhaled Corticosteroids.

BACKGROUND: Leukotriene-receptor antagonists (LTRA) and inhaled corticosteroids (ICS) are common controller medications for asthma, but limited studies examine their comparative risks on neuropsychiatric adverse events (NAEs) in asthma patients. OBJECTIVE: To investigate the comparative risks of LTRA versus ICS on seven distinct categories of NAEs in asthma patients at a nationwide level. METHODS: We conducted a nationwide cohort study during 2010-2021. Incident NAEs and its clinical subgroups (e.g., psychotic disorders, anxiety disorders, movement disorders, behavioral and emotional disorders, mood disorders, sleep-related disorders, and personality disorders) were assessed. Cox proportional hazards regressions were employed to quantify the comparative risks. RESULTS: There were 1,249,897 asthma patients aged 6-64 years. Incidence rates for NAEs were 25.10 per 1000 person-years among patients treated with LTRA, and 23.46 per 1000 person-years among those treated with ICS. The incidence rate difference was 1.64 [95%CI: 0.30-2.98] per 1000 person-years. Positive associations of NAEs and three clinical subgroups were found in patients treated with LTRA compared to ICS (hazard ratios (HR): 1.06 [95%CI: 1.00-1.12] for NAEs; HR: 1.88 [95%CI: 1.24-2.84] for psychotic disorders; HR: 1.10 [95%CI: 1.01-1.20] for anxiety disorders; and HR: 1.27 [95%CI: 1.02-1.58] for behavioral and emotional disorders), but not for movement disorders, mood disorders, sleep-related disorders, and personality disorders. CONCLUSIONS: This nationwide cohort study identified heightened risks, ranging from 6% to 88%, of NAEs and three clinical subgroups in asthma patients treated with LTRA compared to ICS. These findings underscore the necessity for clinicians to communicate with patients regarding potential neuropsychiatric harms when prescribing LTRA.

Assortative mating across nine psychiatric disorders is consistent and persistent over cultures and generations.

Emerging evidence has shown that assortative mating (AM) is a key factor that shapes the landscape of complex human traits. It can increase the overall prevalence of disorders, influence occurrences of comorbidities, and bias estimation of genetic architectures. However, there is lack of large-scale studies to examine the cultural differences and the generational trends of AM for psychiatric disorders. Here, using national registry datasets, we conduct the largest scale of AM analyses on nine psychiatric disorders, with up to 1.4 million mated cases and 6 million matched controls. We performed meta-analyses on AM estimates from Taiwan, Denmark, and Sweden, to examine the potential impact of cultural differences. Generational changes for people born after 1930s were investigated as well. We found that AM of psychiatric disorders are consistent across nations and persistent over generations, with a small proportion of disorders showing generational changes of AM. Our results provide additional insight into the mechanisms of AM across psychiatric disorders and have evident implications on the estimation of the genetic architectures of psychiatric disorders.

Prenatal and early childhood infections requiring hospitalization and risk of neurodevelopmental disorders in offspring: a population-based birth cohort study in Taiwan.

In utero and early childhood infections have been associated with an increased risk of neurodevelopmental disorders; however, the observed associations may be confounded by familial predispositions. This study examined the neurodevelopmental disorders attributable to maternal infections during pregnancy and early childhood infections during the first year of life, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), tic disorders, and mental retardation (MR). We performed population and sibling comparison analyses to account for unmeasured familial confounding factors. We conducted a register-based cohort study with 2,885,662 individuals (comprising 1,864,660 full siblings) born in Taiwan between 2001 and 2018 and followed up until 2021. We employed Cox regression analysis to assess the association between in utero and early childhood infections requiring hospitalization and the subsequent risk of neurodevelopmental disorders. In the population analyses, an offspring exposed to maternal infection had an increased risk for ASD (hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.13-1.26), ADHD (HR = 1.14, 95% CI: 1.11-1.18), and MR (HR = 1.21, 95% CI: 1.13-1.30). These associations attenuated toward null in the sibling analyses. Individuals exposed to early childhood infection had an increased risk for ASD (HR = 1.13, 95% CI: 1.10-1.16), ADHD (HR = 1.16, 95% CI: 1.15-1.18), tic disorders (HR = 1.12, 95% CI: 1.09-1.15), and MR (HR = 1.64, 95% CI: 1.60-1.69) in the population analyses; these associations were also significant for ASD (HR = 1.14, 95% CI: 1.07-1.21) and MR (HR = 1.52, 95% CI: 1.44-1.62) in the sibling analyses. The association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors. Conversely, infection in early childhood may be attributable to it being a sensitive period and may play a role in the subsequent risk of ASD and MR.

Spirocyclopropanes and Substituted Furans by Controlling Reactivity of 1,3-Enynoates: γ- and δ-Addition of Phosphines to Conjugate Acceptors.

In the Morita-Baylis-Hillman (MBH) reaction, a nucleophile undergoes ß-addition to activated alkenes or alkynes, forming reactive intermediates for subsequent carbon-carbon or carbon-hetero bond formation. By using a π-conjugated acceptor, however, an unprecedented reactivity of 1,3-enynoates and indane-1,3-diones was uncovered in the presence of phosphines. When indan-1,3-diones were used, Î³-addition of phosphines to 1,3-enynoates was observed for the first time; moderate to good yields were obtained for 14 substances containing the prominent spirocyclopropane scaffold with 100% retention of (Z)-alkene. When 2-methyl-indan-1,3-diones were used, di(tri)-substituted furans were produced through the δ-addition pathway, with 20 substances and a yield of up to 88% being achieved. Control experiments and density functional theory calculations were conducted to obtain insights into the unconventional γ-addition reaction pathway.

Survival After Simple Compared With Radical Hysterectomy for Patients With Early-Stage Cervical Cancer.

OBJECTIVE: To assess the effect on overall survival of simple hysterectomy with lymph node staging compared with radical hysterectomy with lymph node staging for patients with early-stage cervical cancer. METHODS: We conducted a retrospective cohort study of patients in the National Cancer Database diagnosed with early cervical carcinoma of 2 cm or smaller (stage IA1 with lymphovascular space invasion through IIA1, International Federation of Gynecology and Obstetrics staging) from 2010 to 2019. After 1:1 propensity score matching, we compared patients who underwent simple hysterectomy with lymph node staging and those with radical hysterectomy with lymph node staging. The variables used for matching were age, tumor size, race and ethnicity, lymphovascular space invasion, year of diagnosis, Charlson-Deyo comorbidity score, histology, and surgical approach. The primary outcome was overall survival at the end of follow-up. Secondary outcomes included 30-day readmission rate and 30- and 90-day mortality rates. RESULTS: In total, 4,167 patients met the inclusion criteria, of whom 2,637 patients (63.3%) underwent radical hysterectomy and lymph node staging and 1,530 patients (36.7%) underwent simple hysterectomy and lymph node staging. After propensity score matching, 1,529 patients in each group were included. There was no statistically significant difference in overall survival between patients who underwent simple hysterectomy and those who underwent radical hysterectomy (hazard ratio 1.25, 95% CI, 0.91-1.73, P=.17). Subgroup analysis by histology, lymphovascular space invasion, tumor size, and surgical approach did not reveal statistically significant differences in overall survival according to hysterectomy type. The hysterectomy groups also did not significantly differ in 30-day readmission rate (4.6% vs 4.2%, P=.73), 30-day mortality rate (0.1% vs 0%, P=.14), or 90-day mortality rate (0.1% vs 0.1%, P=.93). CONCLUSION: Patients with low-risk cervical cancer could undergo less radical surgery without a negative effect on their oncologic outcomes.

A simple and cost-effective strategy for electrochemiluminescence spectral determination.

BACKGROUND: Electrochemiluminescence (ECL), as a unique and powerful analytical technique, has been widely used in various fields. The determination of ECL spectra plays a crucial role in understanding ECL reaction mechanisms and conducting spectra-resolved ECL analysis. ECL intensity is typically detected using a photomultiplier tube, which offers high sensitivity for detecting extremely weak light signals but does not allow for spectral identification. Due to the time-dependent variation of ECL intensity caused by the applied potential and electrochemical reaction processes, it is challenging to perform ECL spectral detection using conventional wavelength-scanning spectrometers. RESULTS: In this study, we present a straightforward and cost-effective ECL spectral detection strategy by incorporating an automatically controlled tunable optical filter device between a commonly used PMT detector and a specially designed ECL reaction cell. The effectiveness of this approach was confirmed through initial validation, where the spectrum of a green LED spotlight was measured and compared with a commercial spectrometer. In a dynamic system with stable ECL signals, the ECL spectrum of the typical Ru(bpy)32+/TPA system was rapidly acquired by adjusting the bandpass filters. To account for time-varying ECL signals in practical measurements, time-based correction algorithms were implemented to rectify variations in ECL intensity. By integrating time-based correction algorithms and an automatically controlled tunable optical filter device into a commonly utilized PMT detector, the rapid and sensitive ECL spectra determination was achieved. Experimental results demonstrated the reliability of the proposed strategy. SIGNIFICANCE: This strategy is based on the widely used high-sensitivity PMT detection component, enabling the rapid and sensitive measurement of ECL spectra without altering the ECL detection hardware. It is simple, fast, efficient, and cost-effective, with the potential to be widely used for rapid ECL spectral detection and spectra-resolved ECL analysis.

A population-based study of familial coaggregation and shared genetic etiology of psychiatric and gastrointestinal disorders.

BACKGROUND: It has been proposed that having a psychiatric disorder could increase the risk of developing a gastrointestinal disorder, and vice versa. The role of familial coaggregation and shared genetic loading between psychiatric and gastrointestinal disorders remains unclear. METHODS: This study used the Taiwan National Health Insurance Research Database; 4,504,612 individuals born 1970-1999 with parental information, 51,664 same-sex twins, and 3,322,959 persons with full-sibling(s) were enrolled. Genotyping was available for 106,796 unrelated participants from the Taiwan Biobank. A logistic regression model was used to examine the associations of individual history, affected relatives, and polygenic risk scores (PRS) for schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), and obsessive-compulsive disorder (OCD), with the risk of peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD), and vice versa. RESULTS: Here we show that parental psychiatric disorders are associated with gastrointestinal disorders. Full-siblings of psychiatric cases have an increased risk of gastrointestinal disorders except for SCZ/BPD and IBD; the magnitude of coaggregation is higher in same-sex twins than in full-siblings. The results of bidirectional analyses mostly remain unchanged. PRS for SCZ, MDD, and OCD are associated with IBS, PUD/GERD/IBS/IBD, and PUD/GERD/IBS, respectively. PRS for PUD, GERD, IBS, and IBD are associated with MDD, BPD/MDD, SCZ/BPD/MDD, and BPD, respectively. CONCLUSIONS: There is familial coaggregation and shared genetic etiology between psychiatric and gastrointestinal comorbidity. Individuals with psychiatric disorder-affected relatives or with higher genetic risk for psychiatric disorders should be monitored for gastrointestinal disorders, and vice versa.

It has been proposed that people with psychiatric disorders such as depression could have an increased chance of developing gastrointestinal disorders such as irritable bowel syndrome. We looked at whether this was the case in a large number of people from Taiwan. We found that people with a psychiatric disorder, or with relatives having a psychiatric disorder, were more likely to have gastrointestinal disorders, and vice versa. These findings suggest that people who have psychiatric disorders or have psychiatric disorder-affected relatives should be monitored for gastrointestinal disorders, and vice versa, to enable them to benefit from all the treatments they might need to improve their health.

The ability of peripheral neurophysiological biomarkers to predict future psychological conditions among geriatric populations.

OBJECTIVE: Though the association between peripheral neurophysiological biomarkers and psychological conditions is widely discussed, there is still limited evidence about the ability of peripheral biomarkers to predict psychological outcomes, especially among geriatric populations. METHODS: The study is designed as a prospective cohort study. We collected information from participants aged over 55 years. The participants were evaluated at the start of the study (T0) and 6-9 months later (T1). Information about demographic profiles, peripheral neurophysiological biomarker recordings (including heart rate variability, finger temperature, skin conductance, and electromyogram), and psychological measurements (including Brief Symptom Rating Scale-5, Chinese Happiness Inventory, and Short Portable Mental Status Questionnaire) were collected at T0. At T1, participants reported self-rated questionnaires for psychological outcomes (Patient Health Questionnaire-15, health anxiety questionnaire, Beck Depression Inventory-II, and Beck Anxiety Inventory) and were evaluated with Mini-Mental State Examination by the staff. The association between the peripheral biomarkers and psychological outcomes was evaluated via multiple regression models. RESULTS: A total of 385 participants were included in the study and the average age was 74.49 ± 7.34 years. Both stepwise multiple linear and logistic models showed a significant association between decreased skin conductance and increased/presence of depression at T1. The receiver operating characteristic (ROC) curve analysis of skin conductance for depression was fair (area under curve = 0.812). CONCLUSIONS: The ability of skin conductance to predict depression among geriatric populations may facilitate the detection of geriatric depression and future research on the pathophysiology.

Distinct characteristics of various autoimmune liver diseases: A 22-year hospital-based study in Taiwan.

BACKGROUND AND AIM: The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC-AIH overlap syndrome (OS), have rarely been investigated and compared in Asia. METHODS: At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC-AIH OS patients (85.7% treated with UDCA and IST) were enrolled. RESULTS: Compared with AIH patients, PBC patients were older at baseline and had greater female-to-male sex ratios, alkaline phosphatase (ALP) and γ-glutamyl transferase (γ-GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22-year all-cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC-AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases. CONCLUSIONS: Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.

Estimating expected years of life lost of psychiatric disorders in Taiwan: A Nationwide cohort study.

OBJECTIVES: This study employed a national longitudinal cohort to assess expected years of life lost (EYLL) in newly diagnosed psychiatric patients. METHODS: Data from Taiwan's National Death Registry and Health Insurance Research Database were scrutinized to identify patients with various psychiatric disorders. Disorders were ranked hierarchically, and age groups were categorized as young, middle-aged, and older adults. We utilized the semiparametric survival extrapolation method to estimate life expectancy (LE) and EYLL. Modifying effect of comorbid conditions and socioeconomic characteristics were also explored. RESULTS: Among the 5,757,431 cases, young adults with dementia, alcohol use disorder, schizophrenia, and bipolar disorder experienced an excess of 15 years of EYLL. Middle-aged adults faced approximately 9 years or more of EYLL, while older adults had lower EYLL values. Comorbid conditions, low income levels, and living in rural areas were associated with higher EYLL. CONCLUSIONS: This study underscores the substantial EYLL among young adults with psychiatric disorders and the significant impact of specific disorders on EYLL. Early intervention, tailored support, and healthcare system readiness are imperative for improved outcomes. Resource allocation and targeted interventions focusing on early detection and comprehensive treatment can alleviate the economic burden.

Trends in the use of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and recently diagnosed colorectal, lung, or prostate cancer.

INTRODUCTION: Biologic disease-modifying antirheumatic drugs (bDMARD) are often discontinued when a patient with rheumatoid arthritis (RA) is diagnosed with cancer. Our aim was to determine trends in bDMARD utilization in patients with RA and recently diagnosed cancer. METHOD: We examined two national claims databases to identify adults with RA and recently diagnosed colorectal, lung, or prostate cancer (Optum's de-identified Clinformatics® Data Mart Database 2008-2022, and Surveillance, Epidemiology, and End Results Program (SEER) Medicare-linked 2008-2017). We determined time trends in bDMARD and tumor necrosis factor inhibitor (TNFi) prescriptions during the first 3 years after cancer with Cochram-Armitage tests and multivariable logistic regression. Cancer cohorts were analyzed separately. RESULTS: We included 3595 patients in all six cohorts (in Clinformatics® 503 with colorectal, 468 with lung, and 440 with prostate cancer; in SEER-Medicare 580 with colorectal, 1010 with lung, and 594 with prostate cancer). No significant increase was observed in bDMARD or TNFi utilization over time. Overall, use of bDMARD within the first 3 years of follow-up ranged from 16.7% (Clinformatics® lung cohort) to 29.7% (SEER-Medicare colorectal cohort). The major predictor of bDMARD utilization was prior use in the 3 months before cancer diagnosis (p < 0.001 for all cancers) and earlier cancer stage (p < 0.001 in colorectal and lung cancer and p = 0.05 in prostate cancer). CONCLUSIONS: Use of bDMARD in patients with RA and recently diagnosed common cancers has not increased since 2008. Additional evidence on the safety of bDMARD in patients with early cancer is needed to ensure appropriate management of their RA. Key Points • Use of bDMARD and TNFi in patients with RA and early colorectal, lung, or prostate cancer has been stable since 2008, with no significant increases over time. • The major determinant of receiving bDMARD after cancer diagnosis was prior treatment with bDMARD in the prior 3 months before cancer. • Patients with advanced cancer stage and distant metastases were less likely to receive bDMARD and TNFi than those at early stages of disease.

Financial toxicity in breast cancer patients receiving regional nodal irradiation: Variation by cancer subtype.

BACKGROUND: We evaluated sociodemographic and clinical predictors of financial toxicity (FT) among patients with breast cancer with higher risk clinical factors warranting regional nodal irradiation (RNI). METHODS: Among 183 participants in a clinical trial of conventional vs. hypofractionated treatment with RNI, 125 (68 %) completed a pilot survey of FT measured using the validated Economic Strain and Resilience in Cancer (ENRICh) instrument, scored from 0 (minimal) to 10 (severe) FT. Associations with predictors were evaluated using Pearson correlation coefficients and Kruskal Wallis, Mann-Whitney U, and Jonckheere-Terpstra tests. Predictors of severe FT (ENRICh≥5) were tested using multivariable logistic regression with odds ratios converted to relative risks (RR). RESULTS: Of the sample, all received RNI, 92 % chemotherapy, 67 % axillary dissection, 26 % mastectomy without reconstruction, and 32 % mastectomy with reconstruction. At a median follow up of 1.48 years, median FT score was 2.13 (IQR 0.93-4.6), with 20.8 % of patients experiencing severe FT. Unadjusted worse FT score was associated with younger age (P = 0.003), Hispanic ethnicity (P = 0.006), lower income (P = 0.02), shorter interval from diagnosis to FT assessment (P = 0.02), and chemotherapy receipt (P = 0.05), but not with breast surgery type (P = 0.42), axillary surgery type (P = 0.33), or pathologic T (P = 0.68) or N stage (P = 0.47). In multivariable analysis, triple negative subtype was the sole clinical factor predicting severe FT (RR = 3.38; 95 % CI 1.48-4.99; P = 0.01). CONCLUSION: Among patients with breast cancer receiving RNI, triple negative subtype was associated with severe FT, suggesting that tumor receptor subtype may help identify a key breast cancer subpopulation for early FT intervention.

Automated, Real-Time Integration of Biometric Data From Wearable Devices With Electronic Medical Records: A Feasibility Study.

PURPOSE: A major barrier to the incorporation of biometric data into clinical practice is the lack of device integration with electronic medical records (EMRs). We developed infrastructure to transmit biometric data from an Apple Watch into the EMR for physician review. The study objective was to test feasibility of using this infrastructure for patients undergoing radiotherapy. METHODS: The study included patients with breast or prostate cancer receiving ≥3 weeks of radiotherapy who reported owning an Apple Watch. Daily resting heart rate (HR), HR variability, step count, and exercise minutes were automatically transferred to our EMR using a custom app installed on each patient's iPhone. Biometric data were presented to the treating radiation oncologist for review on a weekly basis during creation of the on-treatment note. Feasibility was defined a priori as physician review of biometric data for at least 90% of patients. Time trends in biometric data were tested using the Jonckheere-Terpstra test. Patient satisfaction was assessed using the System Usability Scale (SUS), with scores above 80 considered above-average user experience. RESULTS: Of the 20 patients enrolled, biometric data were successfully transmitted to the EMR and reviewed by the radiation oncologist for 95% (n = 19) of patients, thus meeting the a priori feasibility threshold. For patients with radiation courses ≥4 weeks, exercise minutes decreased over time (P = .01) and daily mean HR variability increased over time (P = .02). The median SUS was 82.5 (IQR, 70-87.5). CONCLUSION: Our study demonstrates the feasibility of real-time integration of biometric data collected from an Apple Watch into the EMR with subsequent physician review. The high rates of physician review and patient satisfaction provide support for further development of large-scale collection of wearable device data.

Emerging Aspergillus lentulus infections in Taiwan: clinical and environmental surveillance.

Objectives: This study aimed to investigate the prevalence and characteristics of Aspergillus lentulus clinical and environmental isolates in Taiwan. Methods: Aspergillus isolates obtained from patients at three hospitals and from 530 soil samples across Taiwan were screened. A. lentulus, confirmed by calmodulin sequencing, was subjected to antifungal susceptibility testing and cyp51A analyses. Soil samples yielding A. lentulus were analysed for residues of 25 azole fungicides. Results: Nine A. lentulus isolates were identified, which included seven (1.2%, 7/601) isolates from three antifungal-naïve patients out of 601 Aspergillus section Fumigati clinical isolates and two (0.3%, 2/659) isolates out of 659 Aspergillus soil isolates. All isolates developed white colonies and failed to grow at 48°C. They were susceptible to anidulafungin but showed reduced susceptibility to amphotericin B (AmB), voriconazole and azole fungicides. One heart transplant recipient with proven invasive pulmonary aspergillosis (IPA) initially showed suboptimal response to voriconazole monotherapy but was cured with a combination of voriconazole-caspofungin, liposomal AmB (LAmB)-caspofungin, along with surgery, followed by voriconazole maintenance therapy. Among two critically ill patients with probable IPA, one survived with micafungin, while the other died of aspergillosis despite sequential isavuconazole and LAmB monotherapy. Clinical and environmental isolates sharing identical Cyp51A sequence are identified, matching the Cyp51A sequence of A. lentulus NIID0096. Flusilazole (0.0009 mg/kg) was detected in one soil sample. Conclusions: This study raises concerns about health threat posed by human pathogenic A. lentulus originating from natural environments and underscores the need for increased clinical and laboratory vigilance regarding A. lentulus infections.

Metabolomics and microbiomics revealed the combined effects of different-sized polystyrene microplastics and imidacloprid on earthworm intestinal health and function.

The coexistence of pesticides and plastic film residues in agricultural soils poses a significant threat to soil organisms due to their potential long-term contamination and combined toxic effects. Specifically, earthworms are at risk of simultaneously ingesting residual pesticides and microplastics, yet the impact of this combined exposure on their intestinal health and function remains poorly understood. In this study, earthworm (Eisenia fetida) were single and combined exposed to three particle sizes (10 µm, 500 µm, and 2 mm) of polyethylene microplastics (PE MPs) and imidacloprid (IMI) for 28 days, respectively. Our findings underscore that compared to single exposures, the combined exposure inflicted more profound injuries on intestinal tissues and elicited a heightened activation of intestinal digestive enzymes. Furthermore, the combined exposure significantly perturbed the relative abundance of several pivotal metabolic-associated gut microbiota, fostering an enrichment of pathogenic species. Metabolomics analysis showed combined exposure increased differential metabolites, disrupting amino acid, fatty acid, and carbohydrate metabolism in earthworm intestines, potentially hindering nutrient absorption and causing toxic metabolite accumulation. An integrated omics analysis implies that combined exposures have the potential to disrupt the relative abundance of crucial gut microbiota in earthworms, thereby altering their intestinal metabolism and subsequently impacting intestinal health and functionality. Overall, the results reveal that combined exposure of IMI and PE MPs exacerbate the negative effects on earthworm gut health, and this study holds significant implications for the holistic understanding of the combined toxic effects of microplastics and pesticide on soil ecosystems.

The Current Update of Conventional and Innovative Treatment Strategies for Central Nervous System Injury.

This review explores the complex challenges and advancements in the treatment of traumatic brain injury (TBI) and spinal cord injury (SCI). Traumatic injuries to the central nervous system (CNS) trigger intricate pathophysiological responses, frequently leading to profound and enduring disabilities. This article delves into the dual phases of injury-primary impacts and the subsequent secondary biochemical cascades-that worsen initial damage. Conventional treatments have traditionally prioritized immediate stabilization, surgical interventions, and supportive medical care to manage both the primary and secondary damage associated with central nervous system injuries. We explore current surgical and medical management strategies, emphasizing the crucial role of rehabilitation and the promising potential of stem cell therapies and immune modulation. Advances in stem cell therapy, gene editing, and neuroprosthetics are revolutionizing treatment approaches, providing opportunities not just for recovery but also for the regeneration of impaired neural tissues. This review aims to emphasize emerging therapeutic strategies that hold promise for enhancing outcomes and improving the quality of life for affected individuals worldwide.

Clinical Outcomes and Histologic Findings of Patients With Hepatocellular Carcinoma With Durable Partial Response or Durable Stable Disease After Receiving Atezolizumab Plus Bevacizumab.

PURPOSE: Durable partial response (PR) and durable stable disease (SD) are often seen in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus bevacizumab (atezo-bev). This study investigates the outcome of these patients and the histopathology of the residual tumors. PATIENTS AND METHODS: The IMbrave150 study's atezo-bev group was analyzed. PR or SD per RECIST v1.1 lasting more than 6 months was defined as durable. For histologic analysis, a comparable real-world group of patients from Japan and Taiwan who had undergone resection of residual tumors after atezo-bev was investigated. RESULTS: In the IMbrave150 study, 56 (77.8%) of the 72 PRs and 41 (28.5%) of the 144 SDs were considered durable. The median overall survival was not estimable for patients with durable PR and 23.7 months for those with durable SD. The median progression-free survival was 23.2 months for patients with durable PR and 13.2 months for those with durable SD. In the real-world setting, a total of 38 tumors were resected from 32 patients (23 PRs and nine SDs) receiving atezo-bev. Pathologic complete responses (PCRs) were more frequent in PR tumors than SD tumors (57.7% v 16.7%, P = .034). PCR rate correlated with time from atezo-bev initiation to resection and was 55.6% (5 of 9) for PR tumors resected beyond 8 months after starting atezo-bev, a time practically corresponding to the durable PR definition used for IMbrave150. We found no reliable radiologic features to predict PCR of the residual tumors. CONCLUSION: Durable PR patients from the atezo-bev group showed a favorable outcome, which may be partly explained by the high rate of PCR lesions. Early recognition of PCR lesions may help subsequent treatment decision.

PCR-Based Microarray Enhances Diagnosis of Culture-Negative Biopsied Tissue in Patients with Invasive Mold Infections: Real-World Experience in a Tertiary Medical Center.

A fungal polymerase chain reaction (PCR) amplifies conserved genes across diverse species, combined with the subsequent hybridization of amplicons using a specific oligonucleotide microarray, allowing for the rapid detection of pathogens at the species level. However, the performance of microarrays in diagnosing invasive mold infections (IMI) from infected tissue samples is rarely reported. During the 4-year study period, all biopsied tissue samples from patients with a suspected IMI sent for microarray assays were analyzed. A partial segment of the internal transcribed spacer (ITS) region was amplified by nested PCR after DNA extraction. Amplicons were hybridized with specific probes for a variety of mold species using an in-house oligonucleotide microarray. A total of 80 clinical samples from 74 patients were tested. A diagnosis of an IMI was made in 10 patients (4 proven, 1 probable, 3 possible, 2 clinical suspicion). The PCR/microarray test was positive for three out of four proven IMIs, one probable IMI, and one out of three possible IMIs. Two patients with positive PCR/microarray findings were considered to have clinical suspicion of an IMI, and their responsible physicians initiated antifungal therapy despite the absence of supporting microbiological and histological evidence. Clinical diagnoses were categorized into non-IMI and IMI groups (including proven, probable, possible, and clinical suspicion). The sensitivity and specificity of the microarray in diagnosing the IMIs were 70% and 95.7%, respectively, while the sensitivity and specificity of the culture and histological findings were 10%/96.3% and 40.0%/100%, respectively. PCR-based methods provide supportive microbiological evidence when culture results are inconclusive. The combination of a microarray with fungal culture and histology promotes the precise diagnosis of IMIs in difficult-to-diagnose patients.

Neuropsychological features of somatic symptom disorder and depression/anxiety in Taiwan: An analysis based on the comorbidity status.

Individuals with somatic symptom disorder (SSD) often have comorbid depression or anxiety, but whether SSD is associated with specific neuropsychological functions has yet to be fully examined. We analyzed which neuropsychological features are more closely associated with SSD, anxiety, and depression. In this case-control study, we recruited 140 individuals with SSD, 104 individuals with affective disorders without SSD, and 159 healthy controls in Taiwan. We collected DSM-5 diagnoses, questionnaire scores, and performance on eight tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) for each participant. Several CANTAB tasks involving attention, executive function, and social cognition showed significant group differences. In the adjusted analysis, the tasks significantly associated with SSD were the Match to Sample Visual Search (MTS) and the Emotion Recognition Task (ERT). Among the questionnaires, the Cognitions about Body and Health Questionnaire showed the most significant associations with the tasks, specifically with Rapid Visual Information Processing, MTS, Paired Associates Learning, Spatial Working Memory, Intra-Extra Dimensional Set Shift, and ERT. We conclude that the MTS and ERT tasks show significant relationships with both SSD diagnosis and related questionnaires. These tasks primarily involve selective attention and negative emotion regulation.