Search

Background: The reported study illustrates a methodology for compiling training datasets to fine-tune Large Language Models (LLMs) for healthcare information in Vietnamese, a low-resource language. The objective is to bridge the gap in medical information accessibility and enhance healthcare communication in developing countries by adapting LLMs to specific linguistic nuances and domain needs., Method: The methodology involves selecting a base model, compiling a domain-specific dataset, and fine-tuning the model with this dataset. Three open-source models were selected. The dataset, comprising approximately 337,000 prompt-response pairs in Vietnamese, was compiled using existing datasets, data crawled from Vietnamese medical online forums, and distilled from Vietnamese medical textbooks. The three models were fine-tuned using the Low-Rank adaptation (LoRA) and Quantized Low-Rank adaptation (QLoRA) techniques. Models' performances were evaluated using BertScore score, Rouge-L score, and the "LLM-as-a-Judge" method., Results: The fine-tuned models showed enhancements in performance over their base versions across evaluation metrics in BertScore score, Rouge-L score and "LLM-as-a-Judge" method, confirming the effectiveness of the fine-tuning process. This study details the process of fine-tuning open-source LLMs for health information inquiries in Vietnamese, demonstrating its potential to improve healthcare communication in low-resource languages. Deploying the fine-tuned LLM on-premise enhances data privacy and security. However, the significant computing power and costs required pose challenges, especially for organizations in developing countries., Conclusion: This case study highlights the unique challenges faced by developing countries using low-resource languages. Initiatives are needed to emphasize efforts to bridge healthcare gaps in underserved areas and contribute to global health equity., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is pivotal in managing ALK-positive non-small cell lung cancer (NSCLC) due to its efficacy and favorable safety profile. However, severe renal toxicity, including acute kidney injury (AKI), remains a rare but significant adverse effect., Case Report: We present the case of a 71-year-old female with a history of diabetes and recently diagnosed ALK-positive NSCLC. She had been on alectinib therapy (600 mg twice daily) for two months. The patient was admitted with symptoms of shortness of breath and anuria. Initial laboratory results revealed a significant rise in serum creatinine from a baseline of 1.0 mg/dL to 3.64 mg/dL, indicating AKI. Alectinib was discontinued, and the patient underwent a single session of hemodialysis. The patient exhibited rapid clinical improvement with significant recovery of renal function, and she was discharged without the need for further dialysis. A subsequent switch to brigatinib was well-tolerated, with stable renal function observed at the 4-month follow-up., Conclusion: This case underscores the potential for severe AKI associated with alectinib therapy, highlighting the importance of vigilant renal function monitoring in patients undergoing treatment, especially those with predisposing conditions. Early recognition and prompt intervention are crucial to mitigate renal complications and optimize patient outcomes. Brigatinib may serve as a suitable alternative for patients intolerant to alectinib.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, impacting approximately 6.1 million adults in the United States, with projections to increase two-fold by 2030. AF significantly increases the risk of stroke and other adverse cardiovascular events, leading to increased morbidity and mortality. The 2023 ACC/AHA/ACCP/HRS guidelines present a paradigm shift in AF management, moving from a duration-based classification to a more comprehensive, patient-centered approach. This includes a novel AF classification system that emphasizes early detection and intervention, including risk factors and lifestyle modification tailored to each patient's risk profile. Moreover, the recommendations advocate for a multidisciplinary care model, ensuring coordinated management involving primary care providers and specialists. Primary care providers play a crucial role in initiating risk factor management and lifestyle interventions, even before the development of AF. This review aims to thoroughly examine the guidelines for the diagnosis and management of AF and equip general internists with the necessary insights to navigate the evolving landscape of AF care effectively.

Background We explored the impact of the COVID-19 pandemic on the prevalence and outcomes of takotsubo syndrome (takotsubo) using the National Inpatient Sample (NIS) to compare trends before and during the pandemic. Methods This retrospective study examined data from over 137 million admissions during 2017-2018 (pre-pandemic) and 2020-2021 (pandemic). Results Our analysis revealed a marked increase in takotsubo prevalence, from 109.07 to 131.19 per 100,000 admissions over each two-year period. The majority of patients were elderly females, with a notable rise in associated comorbidities such as hypertension and diabetes during the pandemic. Mortality among takotsubo patients rose significantly, with an adjusted odds ratio of 1.28. Patients with concurrent COVID-19 infection had a mortality rate of 23.02%, significantly higher than 7.61% for those without. The length of hospital stays also increased, particularly among COVID-19 patients. Interestingly, the odds of developing takotsubo were lower in COVID-19 patients than in non-infected individuals, suggesting a broader pandemic-related stress impact. Conclusion Our findings highlight a complex interaction between viral infections, stress, and cardiovascular health, underscoring the need for integrated care strategies during global health crises., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tran et al.)

Air temperature (Ta), snow depth (Sd), and soil temperature (Tg) are crucial variables for studying the above- and below-ground thermal conditions, especially in high latitudes. However, in-situ observations are frequently sparse and inconsistent across various datasets, with a significant amount of missing data. This study has assembled a comprehensive dataset of in-situ observations of Ta, Sd, and Tg for the Northern Hemisphere (higher than 30°N latitude), spanning 1960-2021. This dataset encompasses metadata and daily data time series for 27,768, 32,417, and 659 gages for Ta, Sd, and Tg, respectively. Using the ERA5-Land reanalysis data product, we applied deep learning methodology to reconstruct the missing data that account for 54.5%, 59.3%, and 74.3% of Ta, Sd, and Tg daily time series, respectively. The obtained high temporal resolution dataset can be used to better understand physical phenomena and relevant mechanisms, such as the dynamics of land-surface-atmosphere energy exchange, snowpack, and permafrost., (© 2024. The Author(s).)

There is currently no systematic review of the growing body of literature on using social robots in early developmental research. Designing appropriate methods for early childhood research is crucial for broadening our understanding of young children's social and cognitive development. This scoping review systematically examines the existing literature on using social robots to study social and cognitive development in infants and toddlers aged between 2 and 35 months. Moreover, it aims to identify the research focus, findings, and reported gaps and challenges when using robots in research. We included empirical studies published between 1990 and May 29, 2023. We searched for literature in PsychINFO, ERIC, Web of Science, and PsyArXiv. Twenty-nine studies met the inclusion criteria and were mapped using the scoping review method. Our findings reveal that most studies were quantitative, with experimental designs conducted in a laboratory setting where children were exposed to physically present or virtual robots in a one-to-one situation. We found that robots were used to investigate four main concepts: animacy concept, action understanding, imitation, and early conversational skills. Many studies focused on whether young children regard robots as agents or social partners. The studies demonstrated that young children could learn from and understand social robots in some situations but not always. For instance, children's understanding of social robots was often facilitated by robots that behaved interactively and contingently. This scoping review highlights the need to design social robots that can engage in interactive and contingent social behaviors for early developmental research., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Flatebø et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin-2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio-target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma., Methods and Results: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial-to-mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient-derived xenograft models. Using an oligonucleotide anti-sense anti-PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop., Conclusion: Our results open the way for further studies using PROM2 as a bio-target in resort situations in human metastatic melanoma and also in other cancer types., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Purpose: To evaluate the knowledge, practices and attitudes of Ohio school nurses regarding school absenteeism (SA) for dental treatment. Methods: A 40-item questionnaire was generated and distributed to 246 attendees at an annual conference for Ohio school nurses in December 2019. Results: The response rate was 65.9 percent (n=162 out of 246 attendees) and 136 surveys were eligible for inclusion. The sample was female (100 percent), worked at public schools (86.0 percent, n=117) and trained as registered nurses (83.8 percent, n=114). Nurses reported no change in concerns over children missing school for dental appointments in the last five years (69.9 percent, n=95) and most agreed that SA for dental visits "almost never" negatively impacted the educational needs of children. The medical history of the patient was the most common factor when determining the duration of a school excuse (81.6 percent, n=111) and the potential for pain was the most common dental consideration (93.4 percent, n=127). Nurses reported that they "sometimes" had problems with a child after a dental visit (44.9 percent, n=61) and pain was the most reported problem (83.8 percent, n=114). Conclusion: Nurses did not feel that SA for dental treatment negatively impacted the educational needs of children.

Lilial (also called lysmeral) is a fragrance ingredient presented in many everyday cosmetics and household products. The concentrations of lilial in the final products is rather low. Its maximum concentration in cosmetics was limited and recently, its use in cosmetics products was prohibited in the EU due to the classification as reproductive toxicant. Additionally, according to the European Chemicals Agency, it was under assessment as one of the potential endocrine disruptors, i.e. a substance that may alter the function of the endocrine system and, as a result, cause health problems. Its ability to act as an androgen receptor agonist and the estrogenic and androgenic activity of its metabolites, to the best of our knowledge, have not yet been tested. The aim of this work was to determine the intestinal absorption, cytotoxicity, nephrotoxicity, mutagenicity, activation of cellular stress-related signal pathways and, most importantly, to test the ability to disrupt the endocrine system of lilial and its Phase I metabolites. This was tested using set of in vitro assays including resazurin assay, the CHO/HPRT mutation assay, γH2AX biomarker-based genotoxicity assay, qPCR and in vitro reporter assays based on luminescence of luciferase for estrogen, androgen, NF-κB and NRF2 signalling pathway. It was determined that neither lilial nor its metabolites have a negative effect on cell viability in the concentration range from 1 nM to 100 µM. Using human cell lines HeLa9903 and MDA-kb2, it was verified that this substance did not have agonistic activity towards estrogen or androgen receptor, respectively. Lilial metabolites, generated by incubation with the rat liver S9 fraction, did not show the ability to bind to estrogen or androgen receptors. Neither lilial nor its metabolites showed a nephrotoxic effect on human renal tubular cells (RPTEC/TERT1 line) and at the same time they were unable to activate the NF-κB and NRF2 signalling pathway at a concentration of 50 µM (HEK 293/pGL4.32 or pGL4.37). Neither lilial nor its metabolites showed mutagenic activity in the HPRT gene mutation test in CHO-K1 cells, nor were they able to cause double-strand breaks in DNA (γH2AX biomarker) in CHO-K1 and HeLa cells. In our study, no negative effects of lilial or its in vitro metabolites were observed up to 100 µM using different in vitro tests., (© 2023. The Author(s).)

Background: Postoperative nausea and vomiting (PONV) is a common complication following surgery. Only a few risk factors have consistently been reported to be independent predictors for PONV., Aim: To report Apfel scores for orthopedic patients then correlate these scores to the number of antiemetics prescribed and subsequently administered in both the perioperative and post operative setting and determine if screening for Apfel scores is beneficial to predict PONV., Methods: A retrospective analysis of patients admitted under orthopedic units between 1st July 2020 and 31st July 2020 was conducted at a tertiary teaching hospital in Australia. Patients were screened and allocated an Apfel score and antiemetics agents prescribed and subsequently administered were recorded., Results: A total of 115 patients were screened for inclusion. Of these 4 patients met this exclusion criteria, resulting in a total sample size of 111 patients. An Apfel score of 2 was reported in 45.0% of patients, followed by 28.8% of patients scoring 3, with 12.6% scoring one. Only 5.4% of patients scored the highest risk of 4, with 8.2% of patients with no Apfel score documented., Conclusion: Orthopedic patients tend to score 2 or more in their Apfel score placing them at higher risk of postoperative nausea and/or vomiting according to the collectively validated Apfel's simplified risk score. There was no statistically significant relationship between the Apfel score and the number of antiemetic agents prescribed or administered from both the perioperative and post-operative setting following orthopedic surgery in this cohort of adult patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Cannabidiol (CBD) is the non-psychoactive component of the plant Cannabis sativa (L.) that has great anti-inflammatory benefits and wound healing effects. However, its high lipophilicity, chemical instability, and extensive metabolism impair its bioavailability and clinical use. Here, we report on the preparation of a human cornea substitute in vitro and validate this substitute for the evaluation of drug penetration. CBD nanoemulsion was developed and evaluated for stability and biological activity. The physicochemical properties of CBD nanoemulsion were maintained during storage for 90 days under room conditions. In the scratch assay, nanoformulation showed significantly ameliorated wound closure rates compared to the control and pure CBD. Due to the lower cytotoxicity of nanoformulated CBD, a higher anti-inflammatory activity was demonstrated. Neither nanoemulsion nor pure CBD can penetrate the cornea after the four-hour apical treatment. For nanoemulsion, 94 % of the initial amount of CBD remained in the apical compartment while only 54 % of the original amount of pure CBD was detected in the apical medium, and 7 % in the cornea, the rest was most likely metabolized. In summary, the nanoemulsion developed in this study enhanced the stability and biological activity of CBD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Elevated levels of galectin-3 are associated with tumorigenesis. Its inhibition with high-affinity carbohydrate ligands opens new therapeutic routes. Targeting of intracellular galectin-3 is challenging for polar inhibitors like carbohydrates. We demonstrate the potential of novel biomedical research tools, glycocalix[4]arenes, to enter epithelial cells, which may allow their interaction with galectin-3.

Aim: Fluoroquinolone (FQ) is a potent antibiotic class. However, resistance to this class emerges quickly which hinders its application. In this study, mechanisms leading to the emergence of multidrug-resistant (MDR) Staphylococcus aureus (S. aureus) strains under FQ exposure were investigated., Methodology: S. aureus ATCC 29213 was serially exposed to ciprofloxacin (CIP), ofloxacin (OFL), or levofloxacin (LEV) at sub-minimum inhibitory concentrations (sub-MICs) for 12 days to obtain S. aureus -1 strains and antibiotic-free cultured for another 10 days to obtain S. aureus-2 strains. The whole genome (WGS) and target sequencing were applied to analyze genomic alterations; and RT-qPCR was used to access the expressions of efflux-related genes, alternative sigma factors, and genes involved in FQ resistance., Results: A strong and irreversible increase of MICs was observed in all applied FQs (32 to 128 times) in all S. aureus-1 and remained 16 to 32 times in all S. aureus-2. WGS indicated 10 noticeable mutations occurring in all FQ-exposed S. aureus including 2 insdel mutations in SACOL0573 and rimI; a synonymous mutation in hslO; and 7 missense mutations located in an untranslated region. GrlA, was found mutated (R570H) in all S. aureus-1 and -2. Genes encoding for efflux pumps and their regulator (norA, norB, norC, and mgrA); alternative sigma factors (sigB and sigS); acetyltransferase (rimI); methicillin resistance (fmtB); and hypothetical protein BJI72_0645 were overexpressed in FQ-exposed strains., Conclusion: The emergence of MDR S. aureus was associated with the mutations in the FQ-target sequences and the overexpression of efflux pump systems and their regulators., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Huynh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The clinical use of urethral stents is usually complicated by various adverse effects, including dysuria, fever, and urinary tract infection (UTI). Biofilms (formed by bacteria, such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) adhering to the stent cause UTIs in stented patients (approximately 11%). The undesirable consequences of antibiotics use include bacterial resistance, weight gain, and type 1 diabetes, which occur when antibiotics are used for a long time. We aimed to assess the efficacy of a new optical treatment with a 405 nm laser to inhibit bacterial growth in a urethral stent in vitro. The urethral stent was grown in S. aureus broth media for three days to induce biofilm formation under dynamic conditions. Various irradiation times with the 405 nm laser light were tested (5, 10, and 15 min). The efficacy of the optical treatment on biofilms was evaluated quantitatively and qualitatively. The production of reactive oxygen species helped eliminate the biofilm over the urethral stent after 405 nm irradiation. The inhibition rate corresponded to a 2.2 log reduction of colony-forming units/mL of bacteria after 0.3 W/cm 2 of irradiation for 10 min. The treated stent showed a significant reduction in biofilm formation compared with the untreated stent, as demonstrated by SYTO 9 and propidium iodide staining. MTT assays using the CCD-986sk cell line revealed no toxicity after 10 min of irradiation. We conclude that optical treatment with 405 nm laser light inhibits bacterial growth in urethral stents with no or minimal toxicity., (© 2023. The Author(s).)

STEAM education has significant impacts on improving preschoolers' learning engagement, cognition, confidence, and innovative thinking skills. The integration of content about local culture into STEAM projects also triggers students' awareness and engagement with surrounding communities and societies. However, teachers' competencies and willingness to implement STEAM activities are irreplaceable in determining STEM projects' frequency and effectiveness. This dataset surveyed 754 preschool teachers across ten cities and provinces in Vietnam from 8 Apr 2022 to 15 May 2022. The dataset includes seven main sections: (i) Demographics; (ii) Teachers' know-how about STEAM education; (iii) Teachers' competencies; (iv) Conditions to implement STEAM projects; (v) School policies; (vi) Local culture factors integrated with STEAM projects; and (vii) Teachers' willingness to implement STEAM education., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Bacterial infection is a major complication associated with bioimplant materials, including titanium (Ti) based orthopedic joints and dental implants. Thus, the fabrication of Ti surfaces with antibacterial activity is highly important. Black phosphorus (BP) is a recently discovered promising two-dimensional semiconductor for various biomedical applications due to its tunable bandgap and physicochemical properties. The present study aimed to synthesize zinc oxide (ZnO) laden BP nanohybrids (NH) and their coatings on a Ti bioimplant surface for improving the antibacterial activities against pathogenic bacteria with and without near-infrared (NIR) light irradiation. Nanohybrids were produced with the slightly oxidized BP NF and electrostatically laden ZnO NP. The produced BP-ZnO NH was a NIR active nanomaterial (up to ∼1000 nm), demonstrating a photothermal effect against bacterial infection and showing improved activity by damaging the cell membrane towards S. aureus in comparison to E. coli. Ti surface coated with BP-ZnO NH embedded chitosan (CS) demonstrated better antibacterial activity than BP NF, especially with NIR light treatment. Additionally, the produced BP nanoflakes and BP-ZnO NH, and their coatings over the Ti surface were found to be toxic at a negligible level. Electrochemical studies revealed the high corrosion resistance of the Ti surface coated with the synthesized antibacterial agents without altering its characteristic passive behavior. Owing to the interactions between the charged groups between chitosan and cell surfaces, a slight increase in antibacterial activities was noticed. Chitosan-based coating matrix embedded with nanoagents has adhered well over the Ti surface due to its inherent film-forming and high adhesion properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The protozoan pathogen Giardia lamblia is an important worldwide cause of diarrheal disease and malabsorption. Infection is managed with antimicrobials, although drug resistance and treatment failures are a clinical challenge. Prior infection provides significant protection, yet a human vaccine has not been realized. Individual antigens can elicit partial protection in experimental models, but protection is weaker than after prior infection. Here, we developed a multivalent nanovaccine by coating membranes derived from the parasite onto uniform and stable polymeric nanoparticles loaded with a mucosal adjuvant. Intranasal immunization with the nanovaccine induced adaptive immunity and effectively protected mice from G. lamblia infection., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Cardiac papillary fibroelastoma (CPF) is a benign primary cardiac neoplasm, commonly found in men and above 40 years old. The clinical presentation of CPF ranges from asymptomatic to embolism-related complications such as stroke, myocardial ischemia, infarction, or ventricular fibrillation. Acute coronary syndrome is a rare complication of CPF, which was reported only in a few cases in medical literature. Hence, we report a case of a 50-year-old female with a CPF on the right coronary cusp of the aortic valve diagnosed with multi-modality imaging with definitive diagnosis through histopathologic confirmation. The patient presented with acute onset of fatigue, diaphoresis, and vomiting. Initial electrocardiogram (ECG) demonstrated T wave inversion in aVL. Repeated ECG two hours later showed persistent T wave inversion in aVL with new T wave inversions in lead I and ST depression in V2-V6. Troponin levels were elevated from 3.6 ng/L to 1503 ng/L but the patient did not report chest pain, abdominal pain, or dyspnea. Computed tomography coronary angiography did not show any significant coronary stenosis but revealed a low attenuation node with 7 × 6 mm in dimension attached to the right coronary cusp of the aortic valve. Treatment was discussed among a multidisciplinary team and the CPF was surgically removed., Learning Objective: Acute coronary syndrome is a rare, but potentially fatal complication of cardiac papillary fibroelastoma (CPF). Multi-modality imaging is valuable in delineating the evaluation of exact position, dimensions, nature of cardiac masses, diagnostic workup, and preliminary assessment before the surgery. There are no clear guidelines for the treatment of CPF., Competing Interests: None., (© 2022 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. .)

Recently, self-supervised learning methods have been shown to be very powerful and efficient for yielding robust representation learning by maximizing the similarity across different augmented views in embedding vector space. However, the main challenge is generating different views with random cropping; the semantic feature might exist differently across different views leading to inappropriately maximizing similarity objective. We tackle this problem by introducing H euristic A ttention R epresentation L earning (HARL). This self-supervised framework relies on the joint embedding architecture in which the two neural networks are trained to produce similar embedding for different augmented views of the same image. HARL framework adopts prior visual object-level attention by generating a heuristic mask proposal for each training image and maximizes the abstract object-level embedding on vector space instead of whole image representation from previous works. As a result, HARL extracts the quality semantic representation from each training sample and outperforms existing self-supervised baselines on several downstream tasks. In addition, we provide efficient techniques based on conventional computer vision and deep learning methods for generating heuristic mask proposals on natural image datasets. Our HARL achieves +1.3% advancement in the ImageNet semi-supervised learning benchmark and +0.9% improvement in AP 50 of the COCO object detection task over the previous state-of-the-art method BYOL. Our code implementation is available for both TensorFlow and PyTorch frameworks.

In a human host, bacterial Staphylococcus aureus and fungal Candida albicans pathogens form a mixed biofilm that causes severe mortality and morbidity. However, research on the formation and eradication of mixed biofilms under dynamic conditions is lacking. Thus, this study employed a microfluidic technique to analyze the real-time formation of mono- and dual-species (S. aureus and C. albicans) biofilms and noninvasive optical treatment of the established mature biofilm using 405-nm laser light. A herringbone mixer thoroughly mixed both bacterial and fungal cells in the growth media before being injected into the observation channels on the microfluidic chip. At a flow rate of 1.0 µL/min of growth media for 24 h, the bacterial biofilm coverage was up to 15% higher than that of the fungal biofilm (50% for bacteria vs. 35% for fungus). On the other hand, the dual-species biofilm yielded the highest coverage of ~ 96.5% because of the collective interaction between S. aureus and C. albicans. The number of cell proliferation events in S. aureus was higher than that of C. albicans for 12 h, which indicates that the S. aureus biofilm was developed faster than C. albicans. The novel in situ test platform showed a significant bactericidal effect (80%) of the 405-nm laser light at 1080 J/cm 2 towards the established S. aureus biofilm, whereas the same treatment removed approximately 69% of the mixed cells in the dual-species biofilm. This study revealed that the developed microfluidic platform could be utilized to monitor the formation of dual-species biofilms in real-time and laser-induced antimicrobial effects on dual-species biofilms., (© 2022. The Author(s).)

Giardia lamblia is a leading protozoal cause of diarrheal disease worldwide. Infection is associated with abdominal pain, malabsorption and weight loss, and protracted post-infectious syndromes. A human vaccine is not available against G. lamblia. Prior studies with human and murine immune sera have identified several parasite antigens, including surface proteins and metabolic enzymes with intracellular functions. While surface proteins have demonstrated vaccine potential, they can exhibit significant variation between G. lamblia strains. By comparison, metabolic enzymes show greater conservation but their vaccine potential has not been established. To determine whether such proteins can serve as vaccine candidates, we focused on two enzymes, α-enolase (ENO) and ornithine carbamoyl transferase (OCT), which are involved in glycolysis and arginine metabolism, respectively. We show in a cohort of patients with confirmed giardiasis that both enzymes are immunogenic. Intranasal immunization with either enzyme antigen in mice induced strong systemic IgG1 and IgG2b responses and modest mucosal IgA responses, and a marked 100- to 1,000-fold reduction in peak trophozoite load upon oral G. lamblia challenge. ENO immunization also reduced the extent and duration of cyst excretion. Examination of 44 cytokines showed only minimal intestinal changes in immunized mice, although a modest increase of CCL22 was observed in ENO-immunized mice. Spectral flow cytometry revealed increased numbers and activation state of CD4 T cells in the small intestine and an increase in α4β7-expressing CD4 T cells in mesenteric lymph nodes of ENO-immunized mice. Consistent with a key role of CD4 T cells, immunization of CD4-deficient and Rag-2 deficient mice failed to induce protection, whereas mice lacking IgA were fully protected by immunization, indicating that immunity was CD4 T cell-dependent but IgA-independent. These results demonstrate that conserved metabolic enzymes can be effective vaccine antigens for protection against G. lamblia infection, thereby expanding the repertoire of candidate antigens beyond primary surface proteins., Competing Interests: The authors have declared that no competing interests exist.

Photothermal therapy (PTT) requires tight thermal dose control to achieve tumor ablation with minimal thermal injury on surrounding healthy tissues. In this study, we proposed a real-time closed-loop system for monitoring and controlling the temperature of PTT using a non-contact infrared thermal sensor array and an artificial neural network (ANN) to induce a predetermined area of thermal damage on the tissue. A cost-effective infrared thermal sensor array was used to monitor the temperature development for feedback control during the treatment. The measured and predicted temperatures were used as inputs of fuzzy control logic controllers that were implemented on an embedded platform (Jetson Nano) for real-time thermal control. Three treatment groups (continuous wave = CW, conventional fuzzy logic = C-Fuzzy, and ANN-based predictive fuzzy logic = P-Fuzzy) were examined and compared to investigate the laser heating performance and collect temperature data for ANN model training. The ex vivo experiments validated the efficiency of fuzzy control with temperature method on maintaining the constant interstitial tissue temperature (80 ± 1.4  ° C) at a targeted surface of the tissue. The linear relationship between coagulation areas and the treatment time was indicated in this study, with the averaged coagulation rate of 0.0196 cm 2 /s. A thermal damage area of 1.32 cm 2 (diameter ∼1.3 cm) was observed under P-Fuzzy condition for 200 s, which covered the predetermined thermal damage area (diameter ∼1 cm). The integration of real-time feedback temperature control with predictive ANN could be a feasible approach to precisely induce the preset extent of thermal coagulation for treating papillary thyroid microcarcinoma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: As antibiotic resistance creates a significant global health threat, we need not only to accelerate the development of novel antibiotics but also to develop better treatment strategies using existing drugs to improve their efficacy and prevent the selection of further resistance. We require new tools to rationally design dosing regimens from data collected in early phases of antibiotic and dosing development. Mathematical models such as mechanistic pharmacodynamic drug-target binding explain mechanistic details of how the given drug concentration affects its targeted bacteria. However, there are no available tools in the literature that allow non-quantitative scientists to develop computational models to simulate antibiotic-target binding and its effects on bacteria., Results: In this work, we have devised an extension of a mechanistic binding-kinetic model to incorporate clinical drug concentration data. Based on the extended model, we develop a novel and interactive web-based tool that allows non-quantitative scientists to create and visualize their own computational models of bacterial antibiotic target-binding based on their considered drugs and bacteria. We also demonstrate how Rifampicin affects bacterial populations of Tuberculosis bacteria using our vCOMBAT tool., Conclusions: The vCOMBAT online tool is publicly available at https://combat-bacteria.org/ ., (© 2021. The Author(s).)

Mechanistic pharmacodynamic models that incorporate the binding kinetics of drug-target interactions have several advantages in understanding target engagement and the efficacy of a drug dose. However, guidelines on how to build and interpret mechanistic pharmacodynamic drug-target binding models considering both biological and computational factors are still missing in the literature. In this chapter, current approaches of building mechanistic PD models and their advantages are discussed. We also present a methodology on how to select a suitable model considering both biological and computational perspectives, as well as summarize the challenges of current mechanistic PD models., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

The present study proposes an innovative opto-chemical treatment using a basket-integrated optical device (BIOD) to disinfect mature bacterial biofilm on endoscope channels. A BIOD was designed to position an optical diffuser on the central axis of an endoscope channel and to distribute laser light concentrically to the bacterial biofilm on the channel surface. To apply thermal damage and oxidative stress to the bacterial biofilm, a low concentration of a crosslinking agent (glutaraldehyde ~0.5%) was combined with 808 nm infrared (IR) and 405 nm blue (BL) laser lights. The applied irradiances of IR and BL were 10 W/cm 2 and 1.6 W/cm 2 for Teflon channel model and 20 W/cm 2 and 3.2 W/cm 2 for a clinical model, respectively. Individual irradiation of either IR or BL for 180 s induced the maximum temperatures of 62 ± 2 °C and 53 ± 3 °C on the biofilm, respectively. The simultaneous opto-chemical treatment reduced a significant population of the bacterial biofilms (7.5-log 10 for Staphylococcus aureus and 7.1-log 10 for Pseudomonas aeruginosa), which were 2.9-fold and 3.9-fold higher than that of the standard treatment with 2% glutaraldehyde (GA) solution, respectively. The proposed opto-chemical disinfection method can help reduce multi-drug resistant bacteria and prevent cross-infection during the clinical usage of a flexible endoscope., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: COVID-19 vaccines have been speedily developed and deployed. The more vaccine doses are delivered to users, the more common adverse events following immunization (AEFI) are reported. This study aimed to identify factors affecting AEFI in Vietnamese people receiving the COVID-19 vaccine AZD1222 developed by AstraZeneca and Oxford University., Methods: In July 2021, an online cross-sectional survey was conducted among Vietnamese who have been vaccinated with COVID-19 vaccines. The questionnaire collected demographic characteristics, medical history, types of injected vaccines, common AEFI, and post-vaccination activities from respondents. The effects of host-related factors on AEFI including 24 specific symptoms were also explored., Results: After screening, 1028 participants who were Vietnamese, over 18 years old and received at least one dose of AZD1222, were included in the study. Only 40/1028 (3.9%) participants reported not having any AEFI, whereas 25/1028 (2.4%) reported to have severe symptoms. The most common AEFI were moderate fever (69.4%), muscle aches (68.6%), followed by fatigue/ sleepiness (62.5%), body aches (59.4%), headache (58.5%), pain at injection site (58.3%) and chills (45.7%). Data analysis showed that females complained about AEFI particularly gastrointestinal symptoms more frequently than males. Age of participants and number of doses were also important factors affecting AEFI as the increase of age or number of vaccine doses was associated with the decrease of self-reported AEFI frequency., Conclusions: This study provides a detailed assessment of risk factors associated with AEFI in Vietnamese people vaccinated with AZD1222. It seems that gender, age and vaccine doses are important factors affecting AEFI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Medical societies and public health agencies rigorously emphasize the importance of adequate disinfection of flexible endoscopes. The aim of this work was to propose a novel opto-chemical disinfection treatment against Staphylococcus aureus grown in mature biofilm on Teflon-based endoscope channel models. Laser irradiation using near-infrared and blue wavelengths combined with a low concentration of chemical disinfectant induced both irreversible thermal denaturation and intercellular oxidative stress as a combined mechanism for an augmented antimicrobial effect. The opto-chemical method yielded a 6.7-log 10 reduction of the mature Staphylococcus aureus biofilms (i.e., approximately 1.0-log 10 higher than current requirement of standard treatment). The proposed technique may be a feasible disinfection method for mitigating the risk associated with infection transmission., Competing Interests: The authors declare no conflicts of interest. A patent on the opto-chemical disinfection technology has been granted as US 10,780,187 B2 and is titled “Apparatus and method for sterilizing internal channel surface of endoscope” (H.W.K.)., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

This study aims to demonstrate the feasibility of cylindrical interstitial laser ablation (CILA) in porcine pancreatic tissue to develop a EUS-guided PC ablation technique with enhanced safety. A diffusing applicator created a uniformly symmetrical laser ablation in pancreatic tissue. Ex vivo tests presented that both ablation thickness and volume increased linearly with the applied power (R 2  = 0.96 and 0.90, respectively) without carbonization and fiber degradation. The numerical simulations matched well with the experimental results in terms of temperature development and thermal damage (deviation of ≤ 15%). In vivo tests with EUS confirmed easy insertion and high durability of the diffusing applicator. EUS-guided CILA warranted a feasible therapeutic capacity of ablating in vivo pancreatic tissue. The proposed EUS-guided CILA can be a feasible therapeutic approach to treat PC with predictable thermal ablation and enhanced safety., Competing Interests: The authors declare that there are no conflicts of interest related to this article., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. Clozapine's main metabolite, N-desmethylclozapine (NDMC), has potent 5-HT2C antagonist properties which may explain this metabolic dysfunction, thus the CLZ:NDMC ratio is of particular interest. High insulin resistance states could be associated with CYP1A2 induction and lower CLZ:NDMC ratios. Additionally, lower CLZ:NDMC ratios have been associated with better cognitive, but worse metabolic functioning. This study investigated associations between metabolic and cognitive parameters with the CLZ/NDMC ratio. Primary outcomes included relationships between the CLZ:NDMC ratio to the homeostatic model assessment for insulin resistance (HOMA-IR) and Brief Assessment of Cognition in Schizophrenia (BACS) composite z-scores. Secondary outcomes assessed relationships between CLZ:NDMC ratios to fasting insulin, BMI, weight, fasting glucose, and BACS digit sequencing z-scores. 38 patients who were overweight or obese with schizophrenia or schizoaffective disorder completed fasting bloodwork, anthropometric, psychopathological, and cognitive assessments. Multivariate regressions found a statistically significant inverse association between the CLZ/NDMC ratio and HOMA-IR (B = - 1.028, SE B = .473, β = - 0.348 p = 0.037), which may have been driven by fasting insulin levels (B = - 27.124, SE B = 12.081, β = - 0.351 p = 0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.

Background: The therapeutic capacity of multiple cylindrical interstitial laser ablations (CILAs) of pancreatic tissue was evaluated with 1064 nm laser light in ex vivo and in vivo porcine pancreatic models., Methods: A diffusing applicator was sequentially employed to deliver 1064 nm laser light in a cylindrical distribution to ablate a large volume of pancreatic tissue. Ex vivo tissue was tested at various power levels (5, 7, and 10 W) under US imaging. An in vivo porcine model was used to evaluate the clinical feasibility of multiple CILAs on pancreatic tissue at 5 W via laparotomy ( N  = 3)., Results: Multiple CILAs symmetrically ablated a range of ex vivo tissue volumes (2.4-6.0 cm 3 ) at various power levels. Multiple CILAs warranted a therapeutic capacity of symmetrically ablating in vivo pancreatic tissue. Both ex vivo and in vivo pancreatic tissues after multiple CILAs at 5 W confirmed the absence of or minimal thermal injury to the peripheral tissue and carbonization., Conclusions: The current findings suggest that the collective thermal effects from multiple CILAs can help widely ablate pancreatic tissue with minimal thermal injury. Further in vivo studies will investigate the safety of the proposed CILA treatment as well as acute/chronic responses of pancreatic tissue for clinical translations.

Background: We report an unusual case of non-sustained ventricular tachycardia (NSVT) from the epicardial part of the right ventricular outflow tract (RVOT)., Case Summary: A 37-year-old woman who underwent in 2006 an ablation for idiopathic ventricular premature beats (VPBs) from the RVOT presented with pre-syncopal NSVT in 2016. A cardiac workup showed no coronary disease, normal biventricular function, and no enhancement on cardiac magnetic resonance imaging. A metabolic positron emission tomography scan excluded inflammation. Biopsies revealed normal desmosomal proteins. An endocardial mapping revealed an area of low voltage potential (<0.5 mV) at the antero-septal aspect of the RVOT corresponding to the initial site of ablation from 2006. Activation mapping revealed poor prematurity and pace-mapping showed unsatisfactory morphologies in the RVOT, the left ventricle outflow tract and the right coronary cusp. An epicardial map revealed a low voltage area at the antero-septal aspect of the RVOT with fragmented potentials opposite to the endocardial scar. Pace-mapping demonstrated perfect match. An NSVT was induced and local electrocardiogram showed mid-diastolic potentials. Ablation was applied epicardially and endocardially without any complication. The patient was arrhythmia free at 4-year follow-up., Discussion: Cardiac workup allowed to exclude specific conditions such as arrhythmogenic cardiomyopathy, tetralogy of Fallot, sarcoidosis, or myocarditis as a cause for NSVT from the RVOT. The epi and endocardial map showed residual scar subsequent to the first ablation which served as substrate for the re-entrant NSVT. This is the first case which describes NSVT from the epicardial RVOT as a complication from a previous endocardial ablation for idiopathic VPB., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The objective of the study was to review the current literature for prophylactic enoxaparin dosing in obese orthopedic patients. Method: A literature search was undertaken using OVID Medline, OVID Embase, and Cochrane Central databases, accessed through hospital library websites. Key search terms (in UK and US spelling) included orthopaedics, low-molecular-weight heparin, enoxaparin, venous thromboembolism prophylaxis, weight, obese, morbid obesity. Possible related subheadings, such as bone, fractures, anticoagulants, overweight, body mass index, deep vein thrombosis, pulmonary embolism, were also included in the database search to optimize the search strategies. The search was restricted to human subjects and limited to articles published from 1998 to the present. Results: The search identified 429 potentially relevant articles. Once duplicates were removed, 345 were screened for inclusion in this review. Only 3 articles (a case-control study, an observational prospective study, and a case report) met both the inclusion and exclusion criteria. The findings from this review need to be interpreted cautiously due to limitations in study designs and the potential for confounding bias. Conclusion: The results of a multiple database search draw one to the conclusion that there is very limited evidence in the literature with regard to prophylactic enoxaparin dosing in obese orthopedic-specific patients. Orthopedic patients are among the highest risk of all surgical specialties for venous thromboembolism. There is strong evidence to support an increased prophylactic low-molecular-weight heparin doses in obese patients; thus, the authors recommend higher prophylactic enoxaparin dosing in obese orthopedic patients., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

This study develops an energy modulation technique to attain a constant interstitial tissue temperature and to induce the predetermined thermal coagulation without carbonization in tissue. An optical diffuser was employed to deliver 1064 nm light to the biological tissue. The combined mode maintained the interstitial temperature at 70 °C for longer durations compared to the continuous wave mode. Coagulation volumes increased linearly with the time and met the predetermined treatment volume range (0.32-0.52 cm 3 ) after the combined treatment for 100 s. The combined modulation can be a feasible modality to induce the predetermined extent of thermal coagulation for treating papillary thyroid microcarcinoma., Competing Interests: The authors declare no competing interests., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

The determination of mycotoxins content in food is not sufficient for the prediction of their potential in vivo cytotoxicity because it does not reflect their bioavailability and mutual interactions within complex matrices, which may significantly alter the toxic effects. Moreover, many mycotoxins undergo biotransformation and metabolization during the intestinal absorption process. Biotransformation is predominantly the conversion of mycotoxins meditated by cytochrome P450 and other enzymes. This should transform the toxins to nontoxic metabolites but it may possibly result in unexpectedly high toxicity. Therefore, the verification of biotransformation and bioavailability provides valuable information to correctly interpret occurrence data and biomonitoring results. Among all of the methods available, the in vitro models using monolayer formed by epithelial cells from the human colon (Caco-2 cell) have been extensively used for evaluating the permeability, bioavailability, intestinal transport, and metabolism of toxic and biologically active compounds. Here, the strengths and limitations of both in vivo and in vitro techniques used to determine bioavailability are reviewed, along with current detailed data about biotransformation of mycotoxins. Furthermore, the molecular mechanism of mycotoxin effects is also discussed regarding the disorder of intestinal barrier integrity induced by mycotoxins.

Objectives: Our goal was to analyse the implantation and outcome of thoracoscopic epicardial leads after a failed endovascular approach or follow-up (FU) complications after endovascular implantation., Methods: We reviewed the records of patients with failed endovascular left ventricular (LV) lead placement or complications during FU, who were subsequently referred to cardiac surgeons for treatment with thoracoscopic LV lead implantation. We analysed the reasons for endovascular failure; the indications for the surgical procedures; and the clinical, echocardiographic and device FU results., Results: Between 2010 and 2013, a total of 23 patients were included. Among them, 17 of the patients had no previous cardiothoracic surgery, 13 (76%) had successful video-assisted thoracoscopy (VAT) LV lead implantation, 3 (18%) had a conversion to thoracotomy and 1 (6%) failed. Of the 6 patients with prior cardiothoracic surgery, 2 (33%) had VAT only, 3 (50%) had primary thoracotomies and 1 (17%) had a conversion. Two major complications occurred. The reasons for LV endovascular lead failure were subclavian vein occlusion (n = 2), implant failure (n = 13) and complications during the FU period (n = 8). FU information was available for 20 patients: 17 (85%) had improved symptoms. The median FU period was 33 months. A total of 78% of patients were in New York Heart Association (NYHA) functional class III-IV before the operation; 30% were in NYHA functional class III-IV at the last FU examination. The left ventricular ejection fraction increased from 25% before surgery to 31% at the last FU examination. Overall, sensing and pacing threshold values remained stable over time. In 1 patient, lead revision was necessary due to an increase in the pacing threshold., Conclusions: VAT implantation of LV leads had an excellent response rate with an improvement in NYHA functional class and left ventricular ejection fraction. The lead measurements were mainly stable over time., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Mycotoxins found in randomly selected commercial milk thistle dietary supplement were evaluated for their toxicity in silico and in vitro. Using in silico methods, the basic physicochemical, pharmacological, and toxicological properties of the mycotoxins were predicted using ACD/Percepta. The in vitro cytotoxicity of individual mycotoxins was determined in mouse macrophage (RAW 264.7), human hepatoblastoma (HepG2), and human embryonic kidney (HEK 293T) cells. In addition, we studied the bioavailability potential of mycotoxins and silibinin utilizing an in vitro transwell system with differentiated human colon adenocarcinoma cells (Caco-2) simulating mycotoxin transfer through the intestinal epithelial barrier. The IC 50 values for individual mycotoxins in studied cells were in the biologically relevant ranges as follows: 3.57-13.37 nM (T-2 toxin), 5.07-47.44 nM (HT-2 toxin), 3.66-17.74 nM (diacetoxyscirpenol). Furthermore, no acute toxicity was obtained for deoxynivalenol, beauvericin, zearalenone, enniatinENN-A, enniatin-A1, enniatin-B, enniatin-B1, alternariol, alternariol-9-methyl ether, tentoxin, and mycophenolic acid up to the 50 nM concentration. The acute toxicity of these mycotoxins in binary combinations exhibited antagonistic effects in the combinations of T-2 with DON, ENN-A1, or ENN-B, while the rest showed synergistic or additive effects. Silibinin had a significant protective effect against both the cytotoxicity of three mycotoxins (T-2 toxin, HT-2 toxin, DAS) and genotoxicity of AME, AOH, DON, and ENNs on HEK 293T. The bioavailability results confirmed that AME, DAS, ENN-B, TEN, T-2, and silibinin are transported through the epithelial cell layer and further metabolized. The bioavailability of silibinin is very similar to mycotoxins poor penetration.

Aims: During atrial fibrillation ablation, oesophageal heating typically prompts reduction or termination of radiofrequency energy delivery. We previously demonstrated oesophageal temperature rises are associated with posterior left atrial pulmonary vein reconnection (PVR) during redo procedures. In this study, we assessed whether mechanical oesophageal deviation (MED) during an index procedure minimizes posterior wall PVRs during redo procedures., Methods and Results: Patients in whom we performed a first-ever procedure followed by a clinically driven redo procedure were divided based on both the use of MED for oesophageal protection and the ablation catheter employed (force or non-force sensing) in the first procedure. The PVR sites were compared between MED using a force-sensing catheter (MEDForce), or no MED with a non-force (ControlNoForce) or force (ControlForce) sensing catheter. Despite similar clinical characteristics, the MEDForce redo procedure rate (9.2%, 26/282 patients) was significantly less than the ControlNoForce (17.2%, 126/734 patients; P = 0.002) and ControlForce (17.5%, 20/114 patients; P = 0.024) groups. During the redo procedure, the posterior PVR rate with MEDForce (2%, 1/50 PV pairs) was significantly less than with either ControlNoForce (17.7%, 44/249 PV pairs; P = 0.004) or ControlForce (22.5%, 9/40 PV pairs; P = 0.003), or aggregate Controls (18.3%, 53/289 PV pairs; P = 0.006). However, the anterior PVR rate with MEDForce (8%, 4/50 PV pairs) was not significantly different than Controls (aggregate Controls-3.5%, 10/289 PV pairs, P = 0.136; ControlNoForce-2.4%, 6/249 PV pairs, P = 0.067; ControlForce-10%, 4/40 PV pairs, P = 1.0)., Conclusion: Oesophageal deviation improves the durability of the posterior wall ablation lesion set during AF ablation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Introduction : Clozapine remains the most effective antipsychotic for treatment-refractory schizophrenia. However, ~40% of the patients respond insufficiently to clozapine. Clozapine's effects, both beneficial and adverse, have been proposed to be partially attributable to its main metabolite, N-desmethylclozapine (NDMC). However, the relation of the clozapine to norclozapine ratio (CLZ:NDMC; optimally defined as ~2) to clinical response and metabolic outcomes is not clear. Areas covered : This narrative review comprehensively examines the clinical utility of the CLZ:NDMC ratio to reduce metabolic risk and increase treatment efficacy. The association of the CLZ:NDMC ratio with changes in psychopathology, cognitive functioning, and cardiometabolic burden will be explored, as well as adjunctive treatments and their effects. Expert opinion : The literature suggests a positive association between the CLZ:NDMC ratio and better cardiometabolic outcomes. Conversely, the CLZ:NDMC ratio appears inversely associated with better cognitive functioning but less consistently with other psychiatric domains. The CLZ:NDMC ratio may be useful for predicting and monitoring cardiometabolic adverse effects and optimizing potential cognitive benefits of clozapine. Future studies are required to replicate these findings, which if substantiated, would encourage examination of adjunctive treatments aiming to alter the CLZ:NDMC ratio to best meet the needs of the individual patient, thereby broadening clozapine's clinical utility.

Aims: Leadless pacemakers are implanted in Switzerland since June 2015. Large worldwide registries have shown high implant success, low complication rates, and good electrical parameters up to 12 months' follow-up. However, data are scarce outside the investigational setting. The purpose of this study is to assess the real-world experience regarding clinical safety and efficacy of Micra TPS (transcatheter pacing system) leadless pacemakers., Methods and Results: Retrospective observational, multi-centre study designed to assess initial safety and efficacy of the Micra TPS in the Swiss Romande region. A total of 92 patients were included from four different centres with an implantation success rate of 97.8% (90 of 92). Thresholds were overall low at implantation (median 0.38 V/0.24 ms, ranging from 0.13 to 2.88 V/0.24 ms) and remained stable over 1-year follow-up. The perioperative serious adverse event rate was 6.5% in six patients which lead to prolonged hospitalization in five patients and death in one patient. In addition, three further major events (3.3%) occurred during an average follow-up of 1 year, requiring implantation of a standard transvenous pacemaker in two patients, and surgical explantation of the Micra TPS in one patient due to intractable ventricular tachycardia., Conclusion: Leadless pacemakers are a valuable adjunct for treating selected patients requiring single-chamber pacing. However, in this initial experience, major complication rates were high (9.8%). The implant procedure requires proper training and should be performed in an adequate setting.

Healthcare-associated infections have increasingly become problematic in the endoscopic procedures resulting in several severe diseases such as carbapenem-resistant Enterobacteriaceae (CRE)-related infections, pneumonia, and bacteremia. Especially, some bacterial strains are resistant to traditional antimicrobials. Therefore, the necessity of developing new antibiotics or management to deal with bacterial infections has been increasing. The current study combined a low concentration of glutaraldehyde (GTA) with near-infrared (NIR) light and 405-nm laser to entail antibacterial activity on Staphylococcus aureus biofilm. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and colony forming unit (CFU) counting were used to quantify the viable cells while fluorescent and scanning electron microscopic images were used to qualitatively evaluate the cell membrane integrity and structural deformation, respectively. Practically, S. aureus biofilm was highly susceptible (7% cell viability and 6.8-log CFU/cm2 bacterial reduction for MTT assay and CFU analysis, respectively) to the combination of GTA (0.1%), NIR light (270 J/cm2), and 405-nm laser (288 J/cm2) exposure. GTA could form either DNA-protein or protein-protein crosslinks to inhibit DNA and protein synthesis. The NIR light induced the thermal damage on protein/enzymes while 405-nm laser could induce reactive oxygen species (ROS) to damage the bacterial membrane. Thus, the proposed technique may be a feasible modality for endoscope cleaning to prevent any secondary infection in the healthcare industry., Competing Interests: The authors have declared that no competing interests exist.

Background: Dengue virus infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic infection through to severe dengue. Although prior infection with another viral serotype, i.e. secondary dengue, is known to be an important factor influencing disease severity, current methods to determine primary versus secondary immune status during the acute illness do not consider the rapidly evolving immune response, and their accuracy has rarely been evaluated against an independent gold standard., Methods: Two hundred and ninety-three confirmed dengue patients were classified as experiencing primary, secondary or indeterminate infections using plaque reduction neutralisation tests performed 6 months after resolution of the acute illness. We developed and validated regression models to differentiate primary from secondary dengue on multiple acute illness days, using Panbio Indirect IgG and in-house capture IgG and IgM ELISA measurements performed on over 1000 serial samples obtained during acute illness., Results: Cut-offs derived for the various parameters demonstrated progressive change (positively or negatively) by day of illness. Using these time varying cut-offs it was possible to determine whether an infection was primary or secondary on single specimens, with acceptable performance. The model using Panbio Indirect IgG responses and including an interaction with illness day showed the best performance throughout, although with some decline in performance later in infection. Models based on in-house capture IgG levels, and the IgM/IgG ratio, also performed well, though conversely performance improved later in infection., Conclusions: For all assays, the best fitting models estimated a different cut-off value for different days of illness, confirming how rapidly the immune response changes during acute dengue. The optimal choice of assay will vary depending on circumstance. Although the Panbio Indirect IgG model performs best early on, the IgM/IgG capture ratio may be preferred later in the illness course.

The aim of the current study is to investigate the effect of radial and cylindrical light distributions on the response of vascular tissue during 1470-nm irradiation in ex vivo models. Due to a low irradiance (5.3 W/cm 2 ) and wide light distribution, cylindrically diffusing irradiation yielded uniform thermal coagulation while radial irradiation accompanied delamination of layers in leporine veins. Bovine foot model testing verified that the diffusing irradiation was associated with the steady maximum temperature and no tissue attachment, compared with the radial irradiation. The proposed cylindrical light application can be a feasible way to treat varicose veins in an effective manner., Competing Interests: The authors declare that there are no conflicts of interest related to this article.