An unscheduled switch to endocycles induces a reversible senescent arrest that impairs growth of the Drosophila wing disc.

A programmed developmental switch to G / S endocycles results in tissue growth through an increase in cell size. Unscheduled, induced endocycling cells (iECs) promote wound healing but also contribute to cancer. Much remains unknown, however, about how these iECs affect tissue growth. Using the D. melanogasterwing disc as model, we find that populations of iECs initially increase in size but then subsequently undergo a heterogenous arrest that causes severe tissue undergrowth. iECs acquired DNA damage and activated a Jun N-terminal kinase (JNK) pathway, but, unlike other stressed cells, were apoptosis-resistant and not eliminated from the epithelium. Instead, iECs entered a JNK-dependent and reversible senescent-like arrest. Senescent iECs promoted division of diploid neighbors, but this compensatory proliferation did not rescue tissue growth. Our study has uncovered unique attributes of iECs and their effects on tissue growth that have important implications for understanding their roles in wound healing and cancer.

Enhancing the Flame Retardancy of Polyester/Cotton Blend Fabrics Using Biobased Urea-Phytate Salt.

The use of biobased flame-retardant (FR) agents for reducing the flammability of polyester/cotton (T/C) blend fabrics is highly desirable. In this study, a novel and sustainable phosphorus/nitrogen-containing FR, namely, phytic acid-urea (PA-UR) salt, was synthesized. The PA-UR salt was further used to enhance the FR performance of T/C fabric through surface modification. We further explored the potential chemical structure of PA-UR and the surface morphology, thermal stability, heat release capacity, FR properties, and mode of action of the coated fabric. The coated fabric achieved self-extinguishing and exhibited an increased limiting oxygen index of 31.8%. Moreover, the coated T/C blend fabric demonstrated a significantly reduced heat release capacity, indicating a decreased fire hazard. Thermogravimetric analysis revealed the anticipated decomposition of the coated T/C blend fabric and a subsequent increase in thermal stability. The burned char residues also maintained their fiber shape structures, suggesting the presence of condensed FR actions in the PA-UR-coated T/C blend fabric.

AMPK activation modulates IL-36-induced inflammatory responses by regulating IκBζ expression in the skin.

BACKGROUND AND PURPOSE: The interleukin (IL)-36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the anti-IL-36 receptor antibody). AMP-activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL-36-induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL-36-induced responses in the skin. EXPERIMENTAL APPROACH: IL-36-stimulated primary normal human epidermal keratinocytes (NHEKs) and IL-36-injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5-aminoimidazole-4-carboxamide riboside (AICAR) and A769662 served as AMPK activators. KEY RESULTS: AICAR and A769662 significantly suppressed the IL-36-induced IL-8 (CXCL8) and CCL20 production from NHEKs. IL-36-induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL-36-treated NHEKs. Furthermore, AICAR and A769662 enhanced IL-36-induced-IκBζ protein degradation via the proteasome-dependent but not the lysosome-dependent pathway. Pretreatment of NHEKs with IL-36 slightly suppressed the AICAR- and A769662-triggered phosphorylation of AMPK and acetyl-CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression. CONCLUSION AND IMPLICATIONS: AMPK activation suppresses IL-36-induced IL-8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL-36-induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL-36-mediated inflammatory skin disorders.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition.

BACKGROUND: Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analyses and proposes a potential targeted therapeutic approach. METHODS: In a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T. RESULTS: In cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T. CONCLUSIONS: CGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant.

Treatment outcome and prognostic factors of external auditory canal squamous cell carcinoma: A retrospective study in a tertiary center.

Objective: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare malignancy with various treatment strategies and outcomes. The purpose of this study was to evaluate the clinical characteristics and survival outcomes and identify prognostic factors in patients with SCC of EAC. Methods: Twenty-one patients with SCC of EAC treated in a single tertiary center between 2009 and 2021 were retrospectively reviewed and analyzed. The modified Pittsburgh classification system was applied for staging. Factors associated with survival were identified by univariate survival analysis. Results: The mean age at diagnosis was 61 years (range: 41-79 years). Early-stage (T1 + T2) accounts for 38.1% of the series and advanced-stage (T3 + T4) accounts for 61.9%. Eighteen (85.7%) patients underwent primary surgery with curative intent. The 5-year overall survival rate of the 21 patients was 67.4%. Tumor invasion to the otic capsule, eustachian tube, sigmoid sinus, and dura were associated with poor prognosis in univariate analysis (p = .046; .008; .027; and .08, respectively). Conclusions: Factors predictive of less favorable survival include the history of COM, tumor invasion to the otic capsule, eustachian tube, sigmoid sinus, and dura. It is important to make a precise and systemic preoperative evaluation of disease extent. Level of Evidence: 4.

Decomposition Mueller matrix polarimetry for enhanced miRNA detection with antimonene-based surface plasmon resonance sensor and DNA-linked gold nanoparticle signal amplification.

A decomposition Mueller matrix method is proposed for detection of miRNA and enhanced by using a surface plasmon resonance (SPR). In the proposed approach, a Mueller matrix decomposition method is employed to extract the linear birefringence (LB) and circular dichroism (CD) properties of the miRNA sample. The accuracy of the LB and CD measurements is enhanced through the use of a high-resolution antimonene-based SPR prism coupler with DNA-linked gold nanoparticles (AuNPs). The feasibility of the proposed method is demonstrated by measuring the LB orientation angle (α) and CD property (R) of two miRNA aqueous solutions (hsa-miR-125-5p and hsa-miR-21-5p) over the concentration range of 0∼1000 fM in both cases. The results show that, for both samples, α and R vary linearly with the change in the miRNA concentration. Furthermore, the values of α and R obtained for the two samples are quantifiably different, and hence the selectivity of the proposed SPR sensor is confirmed. Overall, the results highlight the potential of the proposed sensor as a valuable tool for miRNA detection with prospective applications in cancer diagnosis.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

The antagonistic relationship between apoptosis and polyploidy in development and cancer.

One of the important functions of regulated cell death is to prevent cells from inappropriately acquiring extra copies of their genome, a state known as polyploidy. Apoptosis is the primary cell death mechanism that prevents polyploidy, and defects in this apoptotic response can result in polyploid cells whose subsequent error-prone chromosome segregation are a major contributor to genome instability and cancer progression. Conversely, some cells actively repress apoptosis to become polyploid as part of normal development or regeneration. Thus, although apoptosis prevents polyploidy, the polyploid state can actively repress apoptosis. In this review, we discuss progress in understanding the antagonistic relationship between apoptosis and polyploidy in development and cancer. Despite recent advances, a key conclusion is that much remains unknown about the mechanisms that link apoptosis to polyploid cell cycles. We suggest that drawing parallels between the regulation of apoptosis in development and cancer could help to fill this knowledge gap and lead to more effective therapies.

Surgical and patient-reported outcomes in an Asian female population with or without adjuvant radiotherapy after immediate free perforator flap breast reconstruction: A retrospective review.

Background: The majority of English literature has reported on the somewhat conflicted outcomes of the effect of radiotherapy on immediate breast reconstruction. However, data specifically related to patients of Asian descent has been scarce. This retrospective study aims to shed light on this topic to aid in the management of this group of patients. Methods: All patients who received immediate free perforator flap-based breast reconstruction under a single surgeon over a 10-year period were included in the study. Patient characteristics, oncological and surgical data were collected. Patients were divided into post-mastectomy radiotherapy (PMRT) and non-PMRT groups. The final aesthetic outcome was assessed by a surgeon-reported outcome questionnaire. Patient satisfaction and psychological outcomes were assessed using validated patient-reported outcome (PRO) questionnaire (BREAST-Q), breast reconstruction, and postoperative module. Results: A total of 101 women, with an average age of 44.7 ± 8.4 underwent perforator flap-based reconstruction. Fifteen patients received PMRT, with remaining 86 patients in the non-PMRT group. The mean duration of follow-up was over 5 years (p = 0.514). The recurrence rate was acceptable in the PMRT group (3/15, p = 0.129). There were no significant differences in complication rates between the two groups (p = 1.000). The aesthetic outcomes were comparable (p = 0.342). PRO appears to be lower in the PMRT group. Conclusions: Immediate breast reconstruction with PMRT in the local patient cohort is oncologically safe, acceptable complication profile, revision rate, and aesthetic outcome. PRO showed lower scores in several categories, which differ from normative data generated in the Western population. Further studies will need to examine the confounding effects of radiation in this specific population.

Intra-Arterial Thrombectomy for Acute Ischemic Stroke Related to the Procoagulant Effect of Warfarin in A Patient with Atrial Fibrillation and Bioprosthetic Valve Replacement.

PURPOSE: Warfarin is associated with paradoxical procoagulant effect that leads to a transient hypercoagulable state and acute ischemic stroke (AIS). This clinical dilemma is further confounded when the patient has multiple comorbidities and the optimal treatment strategies are unclear. CASE REPORT: We report a 78-year-old male with valvular heart disease, congestive heart failure, and atrial fibrillation, who received bioprosthetic valve replacement and developed AIS related to the paradoxical procoagulant effect of warfarin. Emergent cerebral angiography with mechanical thrombectomy was performed, and recanalization was successfully achieved. After shifting warfarin to nonvitamin K oral anticoagulant (NOAC), the paradoxical procoagulant effect ameliorated. CONCLUSION: This report describes the roles of endovascular therapy and NOAC in patients with similar highly complex conditions and has clinical relevance for therapeutic plans in the clinical setting.

Evaluation of Polymer Gel Electrolytes for Use in MnO2 Symmetric Flexible Electrochemical Supercapacitors.

Flexible electrochemical supercapacitors (FESCs) are emerging as innovative energy storage systems, characterized by their stable performance, long cycle life, and portability/foldability. Crucial components of FESCs, such as electrodes and efficient electrolytes, have become the focus of extensive research. Herein, we examine deep eutectic solvent (DES)-based polymer gel systems for their cost-effective accessibility, simple synthesis, excellent biocompatibility, and exceptional thermal and electrochemical stability. We used a mixture a DES, LiClO4-2-Oxazolidinone as the electroactive species, and a polymer, either polyvinyl alcohol (PVA) or polyacrylamide (PAAM) as a redox additive/plasticizer. This combination facilitates a unique ion-transport process, enhancing the overall electrochemical performance of the polymer gel electrolyte. We manufactured and used LiClO4-2-Oxazolidinone (LO), polyvinyl alcohol-LiClO4-2-Oxazolidinone (PVA-LO), and polyacrylamide-LiClO4-2-Oxazolidinone (PAAM-LO) electrolytes to synthesize an MnO2 symmetric FESC. To evaluate their performance, we analyzed the MnO2 symmetric FESC using various electrolytes with cyclic voltammetry (CV), galvanostatic charge-discharge (GCD), and electrochemical impedance spectroscopy (EIS). The FESC featuring the PVA-LO electrolyte demonstrated superior electrochemical and mechanical performances. This solid-state MnO2 symmetric FESC exhibited a specific capacitance of 121.6 F/g within a potential window of 2.4 V. Due to the excellent ionic conductivity and the wide electrochemical operating voltage range of the PVA-LO electrolyte, a high energy density of 97.3 Wh/kg at 1200 W/kg, and a long-lasting energy storage system (89.7% capacitance retention after 5000 cycles of GCD at 2 A/g) are feasibly achieved. For practical applications, we employed the MnO2 symmetric FESCs with the PVA-LO electrolyte to power a digital watch and a light-emitting diode, further demonstrating their real-world utility.

Clinical outcomes in women with endometrial polyps underwent conservative management.

OBJECTIVE: To evaluate the regression rate of endometrial polyps (EPs) in a cohort of asymmetric women after conservative follow-up. MATERIALS AND METHODS: In this retrospective cohort study, a total of 1006 women with asymptomatic EPs were treated with expectant management or hormonal drugs between June 1999 and May 2018. Four hundred forty-eight women (44.5%) were administered with hormonal medications and 558 women were managed expectantly (55.5%). Office hysteroscopy was performed to confirm the diagnosis and regression of EPs. Hormonal administration included oral contraceptives, progestin and cyclic estrogen/progestin regimen according to physicians' preferences. Clinical characteristics, including the patient's age, body mass index, parity, and type of conservative management were collected. RESULTS: The mean observation time was 14.1 ± 18.5 months (range, 1-162 months). The overall regression rate of EPs in this cohort was 33.5%, 24.6% occurred after medication and 8.9% after expectant management. Patient age (<50 years) (p < 0.001), follow-up period (p = 0.005) and hormonal drugs used (p < 0.001) were significantly associated with EP regression. Twenty-four (7.1%) of the 337 EP regression patients later developed recurrent disease. Follow-up period (p < 0.001) and hormonal drugs used (p = 0.032) were closely related to polyp recurrence after initial regression. Nevertheless, multivariate logistic regression analysis revealed that hormonal drugs used was significantly associated with the regression (p < 0.001) and recurrence (p = 0.016) of EPs. CONCLUSION: Women aged 50 or less are more suitable for conservative treatment for EPs. Hormonal drugs used could increase the incidence of EP regression.

Decontextualized Utterances Contain More Typical and Stuttering-Like Disfluencies in Preschoolers Who Do and Do Not Stutter.

PURPOSE: Stuttering-like disfluencies (SLDs) and typical disfluencies (TDs) are both more likely to occur as utterance length increases. However, longer and shorter utterances differ by more than the number of morphemes: They may also serve different communicative functions or describe different ideas. Decontextualized language, or language that describes events and concepts outside of the "here and now," is associated with longer utterances. Prior work has shown that language samples taken in decontextualized contexts contain more disfluencies, but averaging across an entire language sample creates a confound between utterance length and decontextualization as contributors to stuttering. We coded individual utterances from naturalistic play samples to test the hypothesis that decontextualized language leads to increased disfluencies above and beyond the effects of utterance length. METHOD: We used archival transcripts of language samples from 15 preschool children who stutter (CWS) and 15 age- and sex-matched children who do not stutter (CWNS). Utterances were coded as either contextualized or decontextualized, and we used mixed-effects logistic regression to investigate the impact of utterance length and decontextualization on SLDs and TDs. RESULTS: CWS were more likely to stutter when producing decontextualized utterances, even when controlling for utterance length. An interaction between decontextualization and utterance length indicated that the effect of decontextualization was greatest for shorter utterances. TDs increased in decontextualized utterances when controlling for utterance length for both CWS and CWNS. The effect of decontextualization on TDs did not differ statistically between the two groups. CONCLUSIONS: The increased working memory demands associated with decontextualized language contribute to increased language planning effort. This leads to increased TD in CWS and CWNS. Under a multifactorial dynamic model of stuttering, the increased language demands may also contribute to increased stuttering in CWS due to instabilities in their speech motor systems.

Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia.

Diabetes mellitus during pregnancy, which can be classified into pregestational diabetes and gestational diabetes, has become much more prevalent worldwide. Maternal diabetes fosters an intrauterine abnormal environment for fetus, which not only influences pregnancy outcomes, but also leads to fetal anomaly and development of diseases in later life, such as metabolic and cardiovascular diseases, neuropsychiatric outcomes, reproduction malformation, and immune dysfunction. The underlying mechanisms are comprehensive and ambiguous, which mainly focus on microbiota, inflammation, reactive oxygen species, cell viability, and epigenetics. This review concluded with the influence of intrauterine hyperglycemia on fetal structure development and organ function on later life and outlined potential mechanisms that underpin the development of diseases in adulthood. Maternal diabetes leaves an effect that continues generations after generations through gametes, thus more attention should be paid to the prevention and treatment of diabetes to rescue the pathological attacks of maternal diabetes from the offspring.

Development and Utility of Practical Indicators of Critical Outcomes in Dengue Patients Presenting to Hospital: A Retrospective Cross-Sectional Study.

Global travel and climate change have drastically increased the number of countries with endemic or epidemic dengue. The largest dengue outbreak in Taiwan, with 43,419 cases and 228 deaths, occurred in 2015. Practical and cost-effective tools for early prediction of clinical outcomes in dengue patients, especially the elderly, are limited. This study identified the clinical profile and prognostic indicators of critical outcomes in dengue patients on the basis of clinical parameters and comorbidities. A retrospective cross-sectional study was conducted in a tertiary hospital from 1 July 2015 to 30 November 2015. Patients diagnosed with dengue were enrolled, and the initial clinical presentations, diagnostic laboratory data, details of the underlying comorbidities, and initial management recommendations based on 2009 World Health Organization (WHO) guidelines were used to evaluate prognostic indicators of critical outcomes in dengue patients. Dengue patients from another regional hospital were used to evaluate accuracy. A group B (4 points) classification, temperature < 38.5 °C (1 point), lower diastolic blood pressure (1 point), prolonged activated partial thromboplastin time (aPTT) (2 points), and elevated liver enzymes (1 point) were included in the scoring system. The area under the receiver operating characteristic curve of the clinical model was 0.933 (95% confidence interval [CI]: 0.905-0.960). The tool had good predictive value and clinical applicability for identifying patients with critical outcomes.

Mediation and instrumental variable analyses for vaccine-induced antibody titer against influenza B.

OBJECTIVE: Immune correlate analyses for vaccine trials have been applied to investigate associations of vaccine efficacy and surrogate markers such as vaccine-induced antibodies. However, the role of antibody as a surrogate marker in predicting the outcome can vary by time, and surrogate-outcome confounding may have resulted in bias even in randomized trials. We provide a framework for surrogate marker assessment to address the aforementioned issues. STUDY DESIGN AND SETTING: We reanalyzed the vaccine randomized trial for influenza B. We conducted a mediation analysis that enables estimation of vaccine efficacy, mediation effects and proportion of mediation on disease probabilities at various follow-up times. We proposed instrumental variable (IV) analyses with randomized vaccination as an IV accounting for potential unmeasured confounding. RESULTS: The mediation effect of vaccine efficacy by hemagglutination inhibition (HAI) titer was significantly protective at 181 days after vaccination: 63.2% [95% confidence interval, (CI) = (39.9%, 82.0%)], and HAI titer explained 61.1% [95% CI = (36.7%, 96.2%)] of the protective effect of vaccination. CONCLUSIONS: Most of vaccine efficacy is mediated by HAI titer, particularly in children 10 years and older. Our contribution is to provide causal analytics for the role of surrogate marker with weaker assumptions regarding surrogate-disease causation.

Risk factor identification and prediction models for prolonged length of stay in hospital after acute ischemic stroke using artificial neural networks.

Background: Accurate estimation of prolonged length of hospital stay after acute ischemic stroke provides crucial information on medical expenditure and subsequent disposition. This study used artificial neural networks to identify risk factors and build prediction models for a prolonged length of stay based on parameters at the time of hospitalization. Methods: We retrieved the medical records of patients who received acute ischemic stroke diagnoses and were treated at a stroke center between January 2016 and June 2020, and a retrospective analysis of these data was performed. Prolonged length of stay was defined as a hospital stay longer than the median number of days. We applied artificial neural networks to derive prediction models using parameters associated with the length of stay that was collected at admission, and a sensitivity analysis was performed to assess the effect of each predictor. We applied 5-fold cross-validation and used the validation set to evaluate the classification performance of the artificial neural network models. Results: Overall, 2,240 patients were enrolled in this study. The median length of hospital stay was 9 days. A total of 1,101 patients (49.2%) had a prolonged hospital stay. A prolonged length of stay is associated with worse neurological outcomes at discharge. Univariate analysis identified 14 baseline parameters associated with prolonged length of stay, and with these parameters as input, the artificial neural network model achieved training and validation areas under the curve of 0.808 and 0.788, respectively. The mean accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of prediction models were 74.5, 74.9, 74.2, 75.2, and 73.9%, respectively. The key factors associated with prolonged length of stay were National Institutes of Health Stroke Scale scores at admission, atrial fibrillation, receiving thrombolytic therapy, history of hypertension, diabetes, and previous stroke. Conclusion: The artificial neural network model achieved adequate discriminative power for predicting prolonged length of stay after acute ischemic stroke and identified crucial factors associated with a prolonged hospital stay. The proposed model can assist in clinically assessing the risk of prolonged hospitalization, informing decision-making, and developing individualized medical care plans for patients with acute ischemic stroke.

A Highly Translatable Dual-arm Local Delivery Strategy To Achieve Widespread Therapeutic Coverage in Healthy and Tumor-bearing Brain Tissues.

Drug delivery nanoparticles (NPs) based entirely on materials generally recognized as safe that provide widespread parenchymal distribution following intracranial administration via convection-enhanced delivery (CED) are introduced. Poly(lactic-co-glycolic acid) (PLGA) NPs are coated with various poloxamers, including F68, F98, or F127, via physical adsorption to render particle surfaces non-adhesive, thereby resisting interactions with brain extracellular matrix. F127-coated PLGA (F127/PLGA) NPs provide markedly greater distribution in healthy rat brains compared to uncoated NPs and widespread coverage in orthotopically-established brain tumors. Distribution analysis of variously-sized F127/PLGA NPs determines the average rat brain tissue porosity to be between 135 and 170 nm while revealing unprecedented brain coverage of larger F127/PLGA NPs with an aid of hydraulic pressure provided by CED. Importantly, F127/PLGA NPs can be lyophilized for long-term storage without compromising their ability to penetrate the brain tissue. Further, 65- and 200-nm F127/PLGA NPs lyophilized-reconstituted and administered in a moderately hyperosmolar infusate solution show further enhance particle dissemination in the brain via osmotically-driven enlargement of the brain tissue porosity. Combination of F127/PLGA NPs and osmotic tissue modulation provides a means with a clear regulatory path to maximize the brain distribution of large NPs that enable greater drug loading and prolong drug release.

Mutational analysis of epidermolysis bullosa in Taiwan by whole-exome sequencing complemented by RNA sequencing: a series of 77 patients.

BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of hereditary skin diseases characterized by skin fragility. Primary data on Taiwanese population remain scarce. METHODS: We gathered clinical information from EB patients at National Cheng Kung University Hospital from January, 2012, to June, 2021. Diagnostic tests including transmission electron microscopy, immunofluorescence studies, and whole-exome sequencing (WES) were performed. The pathogenicity of novel splice-site mutations was determined through reverse transcriptase-PCR of skin mRNA followed by Sanger and/or RNA sequencing. RESULTS: Seventy-seven EB patients from 45 families were included: 19 EB simplex, six junctional EB, and 52 dystrophic EB. Pathogenic variants were identified in 37 of 38 families (97.4%), in which WES was used as a first-line tool for mutational analysis; RNA sequencing determined pathogenic variants in the remaining one family. A total of 60 mutations in EB-related genes were identified, including 22 novel mutations. The mutations involved KRT5, KRT14, PLEC, COL17A1, LAMB3, LAMA3, ITGB4, and COL7A1. Over one-quarter of DEB patients had EB pruriginosa. CONCLUSIONS: The distinct clinical presentation and molecular pathology of EB in Taiwan expand our understanding of this disorder. WES was an effective first-line diagnostic tool for identifying EB-associated variants. RNA sequencing complemented WES when multiple potentially pathogenic splice-site mutations were found.