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Jin Rong Low,1– 3 Chee Wai Wong,1,3– 6 Jing Liang Loo,1,3,5– 8 Dan Milea,3,5,7,8 Shamira A Perera,1– 3,5 Yi Fang Lee,3,9 Si Rui Ng,1– 3 Mani Baskaran,2,3,5 Monisha Esther Nongpiur,2,3,5 Sharon Lee Choon Tow1,3,5– 8 1Department of Cataract and Comprehensive Ophthalmology, Singapore National Eye Centre, Singapore; 2Department of Glaucoma, Singapore National Eye Centre, Singapore; 3Singapore Eye Research Institute, Singapore; 4Department of Surgical Retina, Singapore National Eye Centre, Singapore; 5Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore; 6Department of Ophthalmology, National University of Singapore, Singapore; 7Department of Neuro-Ophthalmology, Singapore National Eye Centre, Singapore; 8Neuroscience and Behavioral Disorders Program, Duke-NUS Medical School, Singapore; 9Department of Training and Education, Singapore National Eye Centre, SingaporeCorrespondence: Sharon Lee Choon Tow Tel +65 6322 7443Fax +65 6333 8339Email sharon.tow.l.c@singhealth.com.sgPurpose: The aim of the study is to examine the baseline intraocular pressure (IOP) and its changes after performing a water drinking test (WDT) in patients with unilateral hemifacial spasm (HFS).Patients and Methods: In this prospective observational study, patients aged 21 years and above diagnosed with unilateral HFS were recruited from the Singapore National Eye Centre between January 2015 and August 2016. The unaffected eye of each patient served as a matched control. An interviewer-administered standardized questionnaire on HFS symptoms and ophthalmic examination was performed. Automated perimetry, optical coherence tomography (OCT) of the optic nerve head, color disc stereophotography and water drinking test (WDT) were done. The primary outcome measure was the difference in IOP between eyes affected by HFS and fellow eyes at baseline and at 15, 30 and 45 minutes of the WDT.Results: Fifty-four patients with unilateral HFS were included. Mean age was 59.8± 9.9 years (range, 37.0– 84.0). Of these, 54% were female and 94% were Chinese. Mean baseline IOP was significantly higher in eyes with HFS (13.9± 3.1mmHg) compared to fellow eyes (13.3± 2.8mmHg) (p=0.008). There was no significant difference in absolute or percentage change in IOP from baseline between the 2 groups at 15, 30 and 45 minutes of the WDT. Mean vertical cup–disc ratio (VCDR) on clinical examination was significantly higher in eyes with HFS (0.5± 0.2) compared to fellow eyes (0.4± 0.2) (p=0.02). There was no significant difference between the groups for visual field parameters and mean retinal nerve fiber layer thickness on OCT.Conclusion: Hemifacial spasm is associated with a small but significant difference in mean baseline IOP and VCDR between affected and fellow eyes. However, when eyes affected by HFS and fellow eyes were challenged with the WDT, both responded in similar ways.Keywords: glaucoma, hemifacial spasm, intraocular pressure, water drinking test

Zhu Li Yap,1,2 Sushma Verma,2 Yi Fang Lee,1,2 Charles Ong,1,2 Aditi Mohla,1,2 Shamira A Perera1,2 1Singapore National Eye Center, 2Singapore Eye Research Institute, Singapore Abstract: There are two long-standing theories about the pathogenesis of glaucoma – barotrauma and the effect of vascular hypoxia. Currently, it is still unknown whether diminished blood flow is the cause or result of glaucomatous atrophy of ganglion cells and the optic nerve. Though many other imaging techniques used to directly assess ocular blood flow have been well studied, they are limited by their inability to directly assess metabolism in the ocular tissues or measure the oxygen carrying capacity in the vessels. Retinal oximetry is a relatively novel, noninvasive imaging technique that reliably measures oxygen saturation levels in the retinal vessels, offering surrogate markers for the metabolic demands of the eye. The clinical significance of these measurements has not been well established. Thus, this review gives an overview of ocular imaging and current retinal oximetry techniques, while contextualizing the important oximetry studies that have investigated the vascular theory behind glaucoma. Keywords: retinal oximetry, glaucoma, Oxymap, retinal vasculature, glaucoma imaging

Clarissa Shu Ming Cheng,1,2 Yi Fang Lee,2 Charles Ong,3 Zhu Li Yap,2 Andrew Tsai,2 Aditi Mohla,2 Monisha E Nongpiur,4 Tin Aung,2,4 Shamira A Perera2,4 1Department of Ophthalmology, Tan Tock Seng Hospital, 2Department of Ophthalmology, Singapore National Eye Centre, 3Yong Loo Lin School of Medicine, National University of Singapore, 4Singapore Eye Research Institute, Singapore National Eye Centre, Singapore Background: To compare retinal vessel oxygenation and vessel caliber in primary angle-closure glaucoma (PACG), primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and normal controls, as well as between eyes of asymmetrical glaucoma severity.Methods: This was a prospective, cross-sectional study. The 159 subjects (PACG, n=39; POAG, n=41; NTG, n=41; normal controls, n=38) underwent retinal oxygen saturation measurements using the Oxymap T1 Retinal Oximeter, optical coherence tomography, and Humphrey visual field testing. Retinal oxygen saturation and vessel diameter were compared between the glaucoma groups and normal controls, as well as between eyes of asymmetrical glaucoma severity. Kruskal–Wallis test was performed for comparison among different subtypes of glaucoma. Wilcoxon signed-rank test was used to compare the inter-eye differences.Results: Compared to normal controls, arteriolar oxygen saturation was increased in PACG eyes (P=0.048) but not in POAG or NTG eyes. There were no significant differences in oxygen saturation in venules or arteriovenous (AV) difference in all three glaucoma groups. Venular diameter was significantly reduced in all glaucoma groups compared to normal controls (P

Background: The COVID-19 pandemic has profoundly affected mental health, leading to an increased prevalence of depression and insomnia. Currently, artificial intelligence (AI) and deep learning have thoroughly transformed health care-related mobile apps, offered more effective mental health support, and alleviated the psychological stress that may have emerged during the pandemic. Early reviews outlined the use of mobile apps for dealing with depression and insomnia separately. However, there is now an urgent need for a systematic evaluation of mobile apps that address both depression and insomnia to reveal new applications and research gaps., Objective: This study aims to systematically review and evaluate mobile apps targeting depression and insomnia, highlighting their features, effectiveness, and gaps in the current research., Methods: We systematically searched PubMed, Scopus, and Web of Science for peer-reviewed journal articles published between 2017 and 2023. The inclusion criteria were studies that (1) focused on mobile apps addressing both depression and insomnia, (2) involved young people or adult participants, and (3) provided data on treatment efficacy. Data extraction was independently conducted by 2 reviewers. Title and abstract screening, as well as full-text screening, were completed in duplicate. Data were extracted by a single reviewer and verified by a second reviewer, and risk of bias assessments were completed accordingly., Results: Of the initial 383 studies we found, 365 were excluded after title, abstract screening, and removal of duplicates. Eventually, 18 full-text articles met our criteria and underwent full-text screening. The analysis revealed that mobile apps related to depression and insomnia were primarily utilized for early detection, assessment, and screening (n=5 studies); counseling and psychological support (n=3 studies); and cognitive behavioral therapy (CBT; n=10 studies). Among the 10 studies related to depression, our findings showed that chatbots demonstrated significant advantages in improving depression symptoms, a promising development in the field. Additionally, 2 studies evaluated the effectiveness of mobile apps as alternative interventions for depression and sleep, further expanding the potential applications of this technology., Conclusions: The integration of AI and deep learning into mobile apps, particularly chatbots, is a promising avenue for personalized mental health support. Through innovative features, such as early detection, assessment, counseling, and CBT, these apps significantly contribute toward improving sleep quality and addressing depression. The reviewed chatbots leveraged advanced technologies, including natural language processing, machine learning, and generative dialog, to provide intelligent and autonomous interactions. Compared with traditional face-to-face therapies, their feasibility, acceptability, and potential efficacy highlight their user-friendly, cost-effective, and accessible nature with the aim of enhancing sleep and mental health outcomes., (©Yi-Hang Chiu, Yen-Fen Lee, Huang-Li Lin, Li-Chen Cheng. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.10.2024.)

Despite advancements in targeted therapy, glioblastoma remains a challenging condition with limited treatment options. While surgical techniques and external radiation therapy have improved, the median survival for glioblastoma stands at around 12-18 months, with a 5-year survival rate of only 6.8%. Epithelioid glioblastoma (eGBM) represents a rare subtype within the glioma spectrum. Utilizing patient-derived xenograft (PDX) models in mice offers a promising avenue for drug screening and translational research, particularly for this specific glioblastoma subtype. Establishing a stable PDX model for eGBM revealed consistent genetic abnormalities, including BRAF V600E mutation and CDKN2A deletion, in both primary and PDX tumors. Leveraging a curated drug database, compounds potentially targeting these aberrations were identified. By using the novel PDX platform, the results presented in this study demonstrate that the treatments with Palbociclib or Dabrafenib/Trametinib significantly reduced tumor size. RNA sequencing analysis further validated the responsiveness of the tumors to these targeted therapies. In conclusion, PDX models offer a deeper understanding of eGBM at the genomic level and facilitate the identification of potential therapeutic targets. Further translational studies of this novel PDX model hold promise for advancing the diagnosis and treatment of this specific subtype of glioblastoma., Competing Interests: None., (AJCR Copyright © 2024.)

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by memory impairments and distinct histopathological features such as amyloid-beta (Aβ) accumulations. Alzheimer's patients experience sleep disturbances at early stages of the disease. APPswe/PS1dE9 (APP) mice exhibit sleep disruptions, including reductions in non-rapid eye movement (NREM) sleep, that contribute to their disease progression. In addition, astrocytic calcium transients associated with a sleep-dependent brain rhythm, slow oscillations prevalent during NREM sleep, are disrupted in APP mice. However, at present it is unclear whether restoration of circuit function by targeting astrocytic activity could improve sleep in APP mice. To that end, APP mice expressing channelrhodopsin-2 (ChR2) targeted to astrocytes underwent optogenetic stimulation at the slow oscillation frequency. Optogenetic stimulation of astrocytes significantly increased NREM sleep duration but not duration of rapid eye movement (REM) sleep. Optogenetic treatment increased delta power and reduced sleep fragmentation in APP mice. Thus, optogenetic activation of astrocytes increased sleep quantity and improved sleep quality in an AD mouse model. Astrocytic activity provides a novel therapeutic avenue to pursue for enhancing sleep and slowing AD progression., (© 2024. The Author(s).)

This study evaluated the acceptability and tolerability of three alcohol-based hand rubs (ABHRs) at Sarawak General Hospital, Malaysia. Conducted from 12-26 November 2021 using a modified WHO Protocol, it involved a survey among health workers and concessionaires, with a 35% response rate (1,598 of 4,628 participants). The majority were nurses (60.8%), with the medical division most represented (28.4%). Most respondents (93.2%) used ABHRs at least five days a week and found them easily accessible (72.3%). Product B was the preferred ABHR (65%), primarily for its color and fragrance, surpassing WHO's 50% approval rate in these aspects. However, no other product features met WHO criteria. There were no significant differences in self-reported skin tolerability across the products, and none achieved overall WHO approval. These results offer important insights for ABHR selection in developing countries and highlight the value of the WHO Protocol in assessing product acceptability and tolerability.

Fine-grain copper (Cu) films (grain size: 100.36 nm) with a near-atomic-scale surface (0.39 nm) were electroplated. Without advanced post-surface treatment, Cu-Cu direct bonding can be achieved with present-day fine-grain Cu films at 130℃ in air ambient with a minimum pressure of 1 MPa. The instantaneous growth rate on the first day is 164.29 nm d -1 . Also, the average growth rate (∆ R /∆ t ) is evaluated by the present experimental results: (i) 218.185 nm d -1 for the first-day period and (ii) 105.58 nm d -1 during the first 14-day period. Ultrafast grain growth and near-atomic-scale surface facilitate grain boundary motion across the bonding interface, which is the key to achieve Cu-Cu direct bonding at 130℃ in air ambient., Competing Interests: We declare we have no competing interests., (© 2024 The Author(s).)

Importance: Seizure is a common neurological problem among infants and children up to age 6 years. Prenatal exposure to maternal influenza infection has been reported to be associated with childhood seizures., Objective: To evaluate the association between maternal influenza infection and risk of childhood seizures., Designs, Setting, and Participants: This cohort study identified mother-offspring pairs from January 1, 2004, to December 31, 2013, using records in Taiwan's Maternal and Child Health Database. Mothers who had influenza infection during pregnancy and their first offspring were identified and assigned to the influenza group. Mothers in the control group were those without influenza during pregnancy and were matched 1:4 with mothers in the influenza group by maternal age, offspring sex, and date of delivery. Offspring were followed up until December 31, 2020. Data were analyzed between March 2023 and July 2024., Exposure: Diagnosis of influenza infection during pregnancy defined using International Classification of Diseases, Ninth Revision, Clinical Modification codes 487.0, 487.1, and 487.8, or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes J09, J10, and J11., Main Outcomes and Measures: The primary outcome was the association between maternal influenza infection during pregnancy and risk of any type of seizures during childhood, including both epilepsy and febrile seizures. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression models. Pregnancy-related complications were collected as covariates., Results: A total of 1 316 107 mother-offspring pairs were enrolled, of whom 75 835 mothers (predominant maternal age, 25-29 years; 39 324 male offspring [51.9%]) were assigned to the influenza group and 1 240 272 were matched and assigned to the control group (n = 303 340; predominant maternal age, 30-34 years; 157 296 male offspring [51.9%]). In the influenza group, there was a slightly higher prevalence of placenta previa or abruption compared with the control group (1.6% [1241] vs 1.4% [4350]; P < .001). The cumulative risk of seizures was higher among offspring whose mothers had influenza infection. After controlling for potential confounders, the AHRs were 1.09 (95% CI, 1.05-1.14) for seizures, 1.11 (95% CI, 1.06-1.17) for febrile convulsions, and 1.04 (95% CI, 0.97-1.13) for epilepsy. In the subgroup analysis, no statistically significant differences were observed between the trimesters regarding the timing of influenza infection., Conclusions and Relevance: Results of this cohort study suggest that maternal influenza infection during pregnancy was associated with an increased risk of childhood seizures, especially febrile seizures, but not epilepsy. Further studies are needed to elucidate the mechanisms underlying childhood neurological development.

Objective: To assess the safety of replacing the postoperative week 1 (POW1) clinic visit with a nurse-conducted telephone call., Design: Retrospective observational study that included cases from January 2019 to June 2021., Participants: Patients who had undergone uncomplicated phacoemulsification surgery with an unremarkable postoperative day 1 (POD1) examination., Methods: All patients were seen in clinic on POD1 by an ophthalmologist. They then had a telephone conversation with a nurse at POW1 and subsequently an in-person postoperative month 1 (POM1) clinic consultation with an ophthalmologist. Main outcome measure was the incidence of unexpected management changes related to cataract surgery within POM1. Data also were collected on the reasons for unscheduled patient-initiated visits, additional procedures or medications, and postoperative visual acuity worse than 6/12 at POM1., Results: Of the 20,475 patients, 541 patients (2.64%) had an unexpected management change within POM1. There were 565 patients (2.76%) who had self-initiated unscheduled visits between POD1 to POM1. There were 23 patients (0.11%) who required additional surgery within POM1 and 1 patient (0.005%) with endophthalmitis. The most common indication for additional surgical procedures was retained lens material (7 patients, 30.43%). Visual acuity was worse than 6/12 in 1,199 patients (6.22%), with the most common causes attributed to preexisting ocular conditions., Conclusions: These results suggest that replacing the POW1 visit with a nurse-conducted telephone consult for patients who have undergone uncomplicated phacoemulsification surgery and had a normal POD1 consultation is safe., Competing Interests: Footnotes and Disclosure The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: The survival of critically ill patients with acute kidney injury (AKI) undergoing continuous renal replacement therapy (CRRT) is highly dependent on their nutritional status., Objectives: The prognostic nutritional index (PNI) is an indicator used to assess nutritional status and is calculated as: PNI = (serum albumin in g/dL) × 10 + (total lymphocyte count in/mm 3 ) × 0.005. In this retrospective study, we investigated the correlation between this index and clinical outcomes in critically ill patients with AKI receiving CRRT., Methods: We analyzed data from 2076 critically ill patients admitted to the intensive care unit at Changhua Christian Hospital, a tertiary hospital in central Taiwan, between January 1, 2010, and April 30, 2021. All these patients met the inclusion criteria of the study. The relationship between PNI and renal replacement therapy-free survival (RRTFS) and mortality was examined using logistic regression models, Cox proportional hazard models, and propensity score matching. High utilization rate of parenteral nutrition (PN) was observed in our study. Subgroup analysis was performed to explore the interaction effect between PNI and PN on mortality., Results: Patients with higher PNI levels exhibited a greater likelihood of achieving RRTFS, with an adjusted odds ratio of 2.43 (95% confidence interval [CI]: 1.98-2.97, p -value < 0.001). Additionally, these patients demonstrated higher survival rates, with an adjusted hazard ratio of 0.84 (95% CI: 0.72-0.98) for 28-day mortality and 0.80 (95% CI: 0.69-0.92) for 90-day mortality (all p -values < 0.05), compared to those in the low PNI group. While a high utilization rate of parenteral nutrition (PN) was observed, with 78.86% of CRRT patients receiving PN, subgroup analysis showed that high PNI had an independent protective effect on mortality outcomes in AKI patients receiving CRRT, regardless of their PN status., Conclusions: PNI can serve as an easy, simple, and efficient measure of lymphocytes and albumin levels to predict RRTFS and mortality in AKI patients with require CRRT.

Purpose: Previous research has found that stigma, discrimination, and depression are associated with the sexual minority population's medical experiences. However, there is still a lack of relevant research results in Taiwan. This study investigated the health-seeking experiences and influencing factors of gay men and lesbian women in Taiwan. Methods: We recruited gay men and lesbian women through lesbian, gay, bisexual, and transgender (LGBT)-friendly websites and associations between November 2019 and June 2020. Surveys included the demographics, medical visiting experiences, Measure of Internalized Stigma, Patient Health Questionnaire-9, and Daily Heterosexist Experiences Questionnaire. Results: There were 270 participants, including 188 gay men and 82 lesbian women. Most respondents refused to disclose their sexual orientation to health care providers; some feared seeking medical care and preferred seeking LGBT-friendly health care services. Compared with lesbian women, gay men had higher levels of internalized sexual stigma, victimization, concealing sexual orientation, and experiences of medical staff denying services. Discrimination, depressive severity, and internalized sexual stigma affected the medical visit experience. Conclusion: In Taiwan, the health care experiences of gay men and lesbian women are affected by discrimination, internalized sexual stigma, and severe depression, while facing challenges of fear of seeking medical care or reluctance to disclose their sexual orientation.

Background: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4., Methods: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations., Results: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss., Conclusions: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis., (© 2024. The Author(s).)

Background: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca 2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca 2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions., Methods: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss -/- mice, Ctss +/+ mice and Ctss +/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions., Results: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis., Conclusion: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca 2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS., (© 2024. The Author(s).)

Multiple mating by avian females may increase hatching and overall brood success; however, reproductive effort and parental investment are costly, and females may be gradually depleted, with lowered outputs over time. Thus, males in social polyandry systems may differ greatly in their reproductive gains. In the present study, we investigated the reproductive outputs of social polyandrous and sex-role-reversed pheasant-tailed jacanas, Hydrophasianus chirurgus, to assess the effects of polyandry, seasonality, and male mating order on breeding success. Female jacanas produced multiple clutches, either by leaving two or more clutches with an individual male (22%), or by mating with two or more males (78%). The polyandrous females laid both the first and second clutches earlier and showed a breeding period more than twice as long as that of monandrous females. Both polyandry and seasonality affected the fate of a clutch, where clutches from polyandrous females and the early season had higher hatching and brood success rates, but the number of polyandrous females declined over the season. Polyandrous females not only laid more clutches and eggs, and gained more hatchlings and fledglings, but also achieved higher per-clutch outputs and hatching rates than monandrous females. In polyandry groups, males gained higher total hatchlings and fledglings, although not total clutches or eggs, than males in monandry or bi-andry groups. Moreover, males in polyandry groups achieved higher hatchlings and fledglings per clutch and higher hatching and brood success rates. In polyandry groups, the first-mating males obtained more clutches, eggs, and hatchlings; however, they did not have higher success rates, nor total fledglings and per-clutch outputs, than males who mated later. Overall, the results indicate a selective advantage of polyandry for the jacanas studied, particularly in the early breeding season. This advantage, however, differs both between the sexes and intra-sexually, suggesting strong connections with certain ecological/environmental conditions in addition to the jacanas' own quality., (© 2024. The Author(s).)

The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling processes in cancer cells; using patient "omics" datasets and single-cell and spatial approaches to investigate heterogeneity, understand therapy resistance, and identify targets; innovative strategies for inhibiting tumors, including rational drug combinations and improved drug delivery mechanisms; and advances in models that can facilitate screening for cancer vulnerabilities and drug testing. We hope the insights from this meeting will stimulate further progress in the field., (©2024 American Association for Cancer Research.)

The short-form video platform TikTok has become highly popular. This study explores how professional sports teams can effectively leverage short-form videos to promote green values such as environmental conservation and sustainable development, thereby capturing user attention and enhancing user engagement. This study primarily aimed to investigate the effects of a green brand image on green word of mouth (WOM), customer stickiness, and consumer purchase intention, with further examination regarding the moderating effect of green concerns on these relationships. Few studies have explored the presence of professional sports teams on TikTok, particularly in the context of green issues. Accordingly, this study adopts a novel method to develop specific and actionable recommendations for professional sports teams who have a presence on social media. Additionally, via the application of the Stimulus-Organism-Response theory, this study explains how the green brand image presented by professional sports teams on TikTok influences the interactive relationships among green WOM, customer stickiness, and consumer purchase intention. This study recruited 600 individuals who were either fans of the Taipei Fubon Braves, which is a team in Taiwan's professional basketball league P.LEAGUE+, or fans of other teams. After a confirmatory factor analysis, structural equation modeling was used to test the hypotheses. The results indicate positive correlations in all tested paths. The green concern of the Taipei Fubon Braves' fans moderated the relationship between green WOM and purchase intention; however, this moderating effect was not identified among the non-Taipei Fubon Braves fans. These findings introduce innovative concepts to the field of marketing, contributing substantially to both practical applications and academic research.

Background: To safeguard the most vulnerable individuals during the COVID-19 pandemic, numerous governments enforced measures such as stay-at-home orders, social distancing, and self-isolation. These social restrictions had a particularly negative effect on older adults, as they are more vulnerable and experience increased loneliness, which has various adverse effects, including increasing the risk of mental health problems and mortality. Chatbots can potentially reduce loneliness and provide companionship during a pandemic. However, existing chatbots do not cater to the specific needs of older adult populations., Objective: We aimed to develop a user-friendly chatbot tailored to the specific needs of older adults with anxiety or depressive disorders during the COVID-19 pandemic and to examine their perspectives on mental health chatbot use. The primary research objective was to investigate whether chatbots can mitigate the psychological stress of older adults during COVID-19., Methods: Participants were older adults belonging to two age groups (≥65 years and <65 years) from a psychiatric outpatient department who had been diagnosed with depressive or anxiety disorders by certified psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) criteria. The participants were required to use mobile phones, have internet access, and possess literacy skills. The chatbot's content includes monitoring and tracking health data and providing health information. Participants had access to the chatbot for at least 4 weeks. Self-report questionnaires for loneliness, depression, and anxiety were administered before and after chatbot use. The participants also rated their attitudes toward the chatbot., Results: A total of 35 participants (mean age 65.21, SD 7.51 years) were enrolled in the trial, comprising 74% (n=26) female and 26% (n=9) male participants. The participants demonstrated a high utilization rate during the intervention, with over 82% engaging with the chatbot daily. Loneliness significantly improved in the older group ≥65 years. This group also responded positively to the chatbot, as evidenced by changes in University of California Los Angeles Loneliness Scale scores, suggesting that this demographic can derive benefits from chatbot interaction. Conversely, the younger group, <65 years, exhibited no significant changes in loneliness after the intervention. Both the older and younger age groups provided good scores in relation to chatbot design with respect to usability (mean scores of 6.33 and 6.05, respectively) and satisfaction (mean scores of 5.33 and 5.15, respectively), rated on a 7-point Likert scale., Conclusions: The chatbot interface was found to be user-friendly and demonstrated promising results among participants 65 years and older who were receiving care at psychiatric outpatient clinics and experiencing relatively stable symptoms of depression and anxiety. The chatbot not only provided caring companionship but also showed the potential to alleviate loneliness during the challenging circumstances of a pandemic., (©Ya-Hsin Chou, Chemin Lin, Shwu-Hua Lee, Yen-Fen Lee, Li-Chen Cheng. Originally published in JMIR Formative Research (https://formative.jmir.org), 13.03.2024.)

Background: The COVID-19 pandemic has fueled the widespread adoption of telemedicine in healthcare, particularly in Sarawak, Malaysia. This study investigates the use and acceptance of Sarawak's inaugural multidisciplinary geriatric telemedicine service, TELEG., Methods: This cross-sectional study took place at the Sarawak Heart Centre's geriatric department from July 1, 2021, to April 30, 2022. Convenient sampling included all TELEG-enrolled patients during this period, to achieve minimum sample size of 148. TELEG's utilization was assessed in terms of medication therapy and treatment plan optimization, as well as enhanced healthcare accessibility. Participants' acceptance of TELEG was measured using the Service User Technology Acceptability Questionnaire (SUTAQ) administered through Google Forms. Descriptive statistics percentages illustrated the proportion of participants who found TELEG moderately to highly acceptable. Associations between baseline characteristics and overall acceptance were explored through bivariate analyses, including Pearson's correlation test, independent t-test, and ANOVA. The influence of six SUTAQ dimensions on overall acceptance, multivariable linear regression using enter method was employed. Statistical significance was determined by p-values less than 0.5., Results: Among 180 geriatric patients enrolled in TELEG during the study period, 149 agreed to participate. TELEG led to medication therapy optimization for 88.6% of participants, primarily involving dose adjustment (44.7%), de-prescribing (31.8%), and prescribing (15.9%). Additionally, 53.8% received treatment plan optimization, predominantly in the form of self-care education (56.3%), referrals for further treatment (33.8%), additional laboratory investigations (29.6%), and increased monitoring (26.8%). Among those educated in self-care (n = 40), dietary intake (27.5%), lower limb exercise (25.0%), and COVID-19 vaccination (12.5%) were the most common topics. All participants expressed moderate to high acceptance of TELEG (mean = 4.9, SD = 0.65, on a scale of 1 to 6). Notably, care personnel concern (B = 0.256; p < 0.001) had the most significant impact on overall acceptance., Conclusion: This pioneering study evaluates the utilization and user acceptance of a geriatric telemedicine service in the region, providing valuable insights to support its expansion. Follow-up surveys or interviews to gain insights into users' experiences are crucial to further enhance acceptance., (© 2024. The Author(s).)

Chronic Myeloid Leukemia (CML) is characterized by chromosomal aberrations involving the fusion of the BCR and ABL genes on chromosome 22, resulting from a reciprocal translocation between chromosomes 9 and 22. This fusion gives rise to the oncogenic BCR-ABL, an aberrant tyrosine kinase identified as Abl protein. The Abl protein intricately regulates the cell cycle by phosphorylating protein tyrosine residues through diverse signaling pathways. In CML, the BCR-ABL fusion protein disrupts the first exon of Abl, leading to sustained activation of tyrosine kinase and resistance to deactivation mechanisms. Pharmacological interventions, such as imatinib, effectively target BCR-ABL's tyrosine kinase activity by binding near the active site, disrupting ATP binding, and inhibiting downstream protein phosphorylation. Nevertheless, the emergence of resistance, often attributed to cap structure mutations, poses a challenge to imatinib efficacy. Current research endeavours are directed towards overcoming resistance and investigating innovative therapeutic strategies. This article offers a comprehensive analysis of the structural attributes of BCR-ABL, emphasizing its pivotal role as a biomarker and therapeutic target in CML. It underscores the imperative for ongoing research to refine treatment modalities and enhance overall outcomes in managing CML., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Limbal stem cell deficiency (LSCD) is a pathologic condition caused by the dysfunction and destruction of stem cells, stem cell precursors and limbal cell niche in the corneal epithelium, leading to severe conjunctivalization of the cornea. Etiologies for LSCD span from congenital (aniridia), traumatic (chemical or thermal injuries), autoimmune (Stevens-Johnson syndrome) and iatrogenic disease to contact lens (CL) wear. Of these, CL wear is the least understood and is often a subclinical cause of LSCD. Even with recent advances in LSCD research, limitations persist in establishing the pathogenesis and treatment guidelines for CL-induced LSCD. A literature search was conducted to include original articles containing patients with CL-induced LSCD. This review will critically discuss the complex pathophysiology behind CL-induced LSCD, the underlying risk factors and epidemiology of the disease as well as methods to obtain a diagnosis. Various treatment options will be reviewed based on proposed treatment strategies.

Background: Alzheimer's disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation., Methods: We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals. Optogenetic stimulation of GABAergic interneurons in the anterior cortex targeted with channelrhodopsin-2 (ChR2) allowed us to examine the role GABAergic interneurons play in sleep deficits. We also examined the effect of optogenetic stimulation on amyloid plaques, neuronal calcium as well as sleep-dependent memory consolidation. In addition, microglial morphological features and functions were assessed using confocal microscopy and flow cytometry. Finally, we performed sleep deprivation during optogenetic stimulation to investigate whether sleep restoration was necessary to slow AD progression., Results: APP-GAD-Cre mice exhibited impairments in sleep architecture including decreased time spent in NREM sleep, decreased delta power, and increased sleep fragmentation compared to nontransgenic (NTG) NTG-GAD-Cre mice. Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP-GAD-Cre animals. Furthermore, it slowed AD progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis, and improving memory function. These changes were accompanied by increased numbers and a morphological transformation of microglia, elevated phagocytic marker expression, and enhanced amyloid β (Aβ) phagocytic activity of microglia. Sleep was necessary for amelioration of pathophysiological phenotypes in APP-GAD-Cre mice., Conclusions: In summary, our study shows that optogenetic targeting of GABAergic interneurons rescues sleep, which then ameliorates neuropathological as well as behavioral deficits by increasing clearance of Aβ by microglia in an AD mouse model., (© 2023. The Author(s).)

Not a great deal is known about what study skills are essential for success in the science, technology, engineering, and mathematics' disciplines, particularly in information technology (IT) and computer science (CS) programs in the technical and vocational education (TVE) in Taiwanese higher education. Since TVE accounts for more than half of the post-secondary enrolments in the country, and with the increasing demand for IT and CS talents, we studied perceptions of the importance and competency of such skills to identify the students' needs and demographic factors influencing them. A survey was administered to 1398 students in IT and CS programs in Taiwanese TVE universities. General skills were seen as the most important one among the study skills examined, and students felt competent using them. The needs to manage time, perform quantitative/mathematical tasks, and delegate were identified and these needs were affected by institutional quality, gender, and academic achievement. The results might be useful for further investigation in this area and guiding future plan to improve student performance in TVE., 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., (© 2023 The Authors. Published by Elsevier Ltd.)

Introduction: Alzheimer's disease (AD) is a neurodegenerative disease with increasing relevance as dementia cases rise. The etiology of AD is widely debated. The Calcium Hypothesis of Alzheimer's disease and brain aging states that the dysfunction of calcium signaling is the final common pathway leading to neurodegeneration. When the Calcium Hypothesis was originally coined, the technology did not exist to test it, but with the advent of Yellow Cameleon 3.6 (YC3.6) we are able to test its validity., Methods: Here we review use of YC3.6 in studying Alzheimer's disease using mouse models and discuss whether these studies support or refute the Calcium Hypothesis., Results: YC3.6 studies showed that amyloidosis preceded dysfunction in neuronal calcium signaling and changes in synapse structure. This evidence supports the Calcium Hypothesis., Discussion: In vivo YC3.6 studies point to calcium signaling as a promising therapeutic target; however, additional work is necessary to translate these findings to humans., (© 2023 the Alzheimer's Association.)

The study aimed to determine whether using body composition data acquired through bio-electrical impedance analysis (BIA) to adjust diet formulas could improve outcomes in septic patients. There were 132 septic patients in medical intensive care units enrolled in the prospective, randomized, double-blind, interventional study. For the intervention group, dietitians had access to BIA data for adjusting diet formulas according to body composition variables on days 1, 3, and 8. The patients were also stratified based on nutritional risk using the modified Nutrition Risk in Critically ill (mNUTRIC) score. Patients with intervention were more likely to achieve caloric and protein intake goals compared to the control group, especially in the low-risk group. The intervention did not significantly affect mortality, but the survival curves suggested potential benefits. The high-risk group had longer ICU stays and mechanical ventilation duration, which were mitigated by the intervention. Certain body composition variables (e.g., extracellular water to total body water ratio and phase angle) showed differences between high-risk and low-risk groups and may be related to patient outcomes. Non-invasive body composition assessment using BIA can help dietitians adjust diet formulas for critically ill septic patients. Body composition variables may be associated with sepsis outcomes, but further research with larger patient numbers is needed to confirm these findings.

Patients with Alzheimer's disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP/PS1 mice. The power but not the frequency of astrocytic calcium transients was reduced in APP/PS1 mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression., (© 2023. Springer Nature Limited.)

Purpose: Virtual glaucoma clinics can help increase health care capacity, easing the disease burden of glaucoma. This study assesses the safety, rate of glaucoma progression, time efficiency, and cost-savings of our expanded Glaucoma Observation Clinic (GLOC) at the Singapore National Eye Centre over 3 years., Methods: All patients seen at GLOC between July 2018 and June 2021 were included. Visual acuity, intraocular pressure, and visual fields or optic nerve head imaging were recorded, followed by a virtual review of the data by an ophthalmologist. An objective review of the management of 100 patients was conducted by 2 senior consultants independently as a safety audit. Patient outcomes including the rate of instability (due to worsening of clinical parameters necessitating a conventional clinic visit), glaucoma progression, the consultation review time efficiency, and cost-savings of GLOC were measured., Results: Of 3458 patients, 16% had glaucoma, and the others had risk factors for glaucoma. The safety audit demonstrated a 95% interobserver agreement. The rate of instability was 14.6%, of which true progression was observed in 3.12%. The time taken for a glaucoma specialist to review a GLOC patient was 5.75±0.75 minutes compared with 13.7±2.3 minutes in a conventional clinic. The per capita manpower cost per GLOC patient per visit was $36.77 compared with $65.62 in the conventional clinic. This translates to a cost-saving of $280.65 over the lifetime of a hypothetical patient., Conclusions: Our expanded virtual glaucoma clinic is a safe, time-efficient, and cost-effective model with low rates of glaucoma progression, which could allow for significant health care capacity expansion., Competing Interests: The authors have no funding or conflicts of interest to declare., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Photoinduced metal-organic framework (MOF) enabled heterogeneous thiol catalysis has been achieved for the first time. MOF Zr-TPDCS-1, consisting of Zr 6 -clusters and TPDCS linkers (TPDCS=3,3'',5,5''-tetramercapto[1,1':4',1''-terphenyl]-4,4''-dicarboxylate), effectively catalyzed the borylation, silylation, phosphorylation, and thiolation of organic molecules. Upon irradiation, the fast electron transfer from TPDCS to Zr 6 -cluster is believed to facilitate the formation of the thiyl radical, a hydrogen atom transfer catalyst, which competently abstracts the hydrogen from borane, silane, phosphine, or thiol for generating the corresponding element radical to engender the chemical transformations. The elaborate control experiments evidenced the generation of thiyl radicals in MOF and illustrated a radical reaction pathway. The gram-scale reaction worked well, and the product was conveniently separated via centrifugation and vacuum with a turnover number (TON) of ≈3880, highlighting the practical application potential of heterogeneous thiyl-radical catalysis., (© 2023 Wiley-VCH GmbH.)

Patients undergoing kidney transplantation have a poor response to vaccination and a higher risk of disease progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effectiveness of vaccine doses and antibody titer tests against the mutant variant in these patients remains unclear. We retrospectively analyzed the risk of SARS-CoV-2 infection in a single medical center according to vaccine doses and immune responses before the outbreak. Among 622 kidney transplant patients, there were 77 patients without vaccination, 26 with one dose, 74 with two doses, 357 with three, and 88 with four doses. The vaccination status and infection rate proportion were similar to the general population. Patients undergoing more than three vaccinations had a lower risk of infection (odds ratio = 0.6527, 95% CI = 0.4324-0.9937) and hospitalization (odds ratio = 0.3161, 95% CI = 0.1311-0.7464). Antibody and cellular responses were measured in 181 patients after vaccination. Anti-spike protein antibody titer of more than 1,689.3 BAU/mL is protective against SARS-CoV-2 infection (odds ratio = 0.4136, 95% CI = 0.1800-0.9043). A cellular response by interferon-γ release assay was not correlated with the disease (odds ratio = 1.001, 95% CI = 0.9995-1.002). In conclusion, despite mutant strain, more than three doses of the first-generation vaccine and high antibody titers provided better protection against the omicron variant for a kidney transplant recipient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Hsu, Huang, Lai, Wu, Lin, Hung, Lin, Huang, Lee, Tsai and Lee.)

Study Design: A retrospective cohort study., Objective: To investigate the factors contributing to the development of postoperative distal junctional kyphosis (DJK) in adolescent idiopathic scoliosis (AIS) patients who underwent posterior spinal fusion (PSF) with lowest instrumented vertebrae (LIV) at or above L1., Methods: Patients with Lenke type 1 or 2 curves who underwent PSF with LIV at or above L1 with a minimum follow-up of 2 years were evaluated. The primary outcome measure was the occurrence of postoperative DJK. Radiographic parameters of sagittal alignment and inclusion/exclusion of sagittal stable vertebra (SSV) in PSF were analyzed to determine their associations with the occurrence of postoperative DJK., Results: Overall, 122 patients (mean age: 15.1 ± 3.2 years) were included. The overall incidence of postoperative DJK was 6.6%. DJK was observed in 19.0% (8/42) of patients whose SSV was not included in PSF and not in patients with SSV included in PSF (n = 80). In the SSV-excluded group, univariate analysis found two significant risk factors for DJK: postoperative thoracic kyphosis (TK, T5-12) and postoperative thoracolumbar kyphosis (TLK, T11-L2). The ROC curve revealed that postoperative TK ≥ 25° and TLK ≥ 10° best predicted the occurrence of postoperative DJK in the SSV-excluded group. The incidence was significantly higher in cases with postoperative TK ≥ 25° or TLK ≥ 10° (7/13 = 53.8%) than in those with postoperative TK < 25° and TLK < 10° (1/29 = 3.4%)., Conclusions: The current study revealed that postoperative TK ≥ 25° or postoperative TLK ≥ 10° with SSV excluded from PSF were related to DJK after PSF for Lenke type 1 and type 2 AIS. When the SSV is intended to be spared from PSF to save more motion segments, TK and TLK should be carefully evaluated and attained in a lesser magnitude (TK < 25°, TLK < 10°) after surgery.

Animals may show consistent among-individual behavioral differences over time and in different contexts, and these tendencies may be correlated to one another and emerge as behavioral syndromes. The cross-context variation in these behavioral tendencies, however, is rarely explored with animals in contexts associated with different locomotion modes. This study assessed the variation and repeatability in behavioral traits of bent-wing bats Miniopterus fuliginosus in southern Taiwan, and the effects of contextual settings associated with locomotion mode. The bats were sampled in the dry winter season, and their behaviors were measured in hole-board box (HB) and tunnel box (TB) tests, both suited for quadrupedal movements of the bats, and flight-tent (FT) tests that allowed for flying behaviors. The bats in the FT tests showed more interindividual and between-trial behavioral variation than those in the HB and TB tests. Nearly all of the behaviors in the TB and FT tests, but only half of those in the HB tests, showed medium to high repeatability. These repeatable behaviors were grouped into distinct behavioral traits of boldness, activity, and exploration, which were correlated to one another across contexts. In addition, we observed a consistently higher correlation between behavioral categories across the HB and TB contexts than between either of these contexts and the FT context. The results indicate consistent among-individual behavioral differences across time and contexts in wildly caught bent-wing bats. The findings of behavioral repeatability and cross-context correlations also indicate context-dependent variation and suggest that test devices which allow for flight behaviors, such as flight tents or cages, may provide a more suitable setting for measuring the behaviors and animal personalities of bats, particularly for those species that display less or little quadrupedal movements., (© 2023. The Author(s).)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental problem that presents with limited interests, repetitive behaviors, and deficits in reciprocal communication and social interactions. Mounting evidence indicates that an imbalanced gut microbiota contributes to autism via the gut-brain axis. Constipation may result in alteration of the gut microbiota. The clinical influence of constipation on ASD has not been fully researched. Thus, in this study we aimed to evaluate whether early childhood constipation influenced the risk of developing ASD using a nationwide population-based cohort study., Methods: We identified 12,935 constipated children aged 3 years or younger from the National Health Insurance Research Database (NHIRD) in Taiwan from 1997 to 2013. Non-constipated children were also selected from the database and propensity score matching of age, gender, and underlying comorbidities was conducted with a ratio of 1:1. Kaplan-Meier analysis was applied to determine different levels of constipation severity and cumulative incidence of autism. Subgroup analysis was also applied in this study., Results: The incidence rate of ASD was 12.36 per 100,000 person-months in the constipation group, which was higher than the rate of 7.84 per 100,000 person-months noted in the non-constipation controls. Constipated children had a significantly higher risk of autism when compared to the non-constipation group (crude relative risk = 1.458, 95% CI = 1.116-1.904; adjusted hazard ratio = 1.445, 95% CI = 1.095-1.907).Moreover, among constipated children, a higher number of laxative prescriptions, male gender, constipation during infancy, and atopic dermatitis were significantly associated with higher risks of ASD when compared to the non-constipation group., Conclusion: Constipation in early childhood was correlated with a significantly increased risk of ASD. Clinicians should pay attention to the possibility of ASD in constipated children. Further research is necessary to study the possible pathophysiological mechanisms of this association., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Wu, Ma, Huang and Wei.)

Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles. In multiple tissues, EGFR is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively. TAD mutants promote EGFR-mediated signaling by enhancing EGFR interaction with AKT via DDX31 in the cytosol. Conversely, DBD mutants maintain EGFR activity in the nucleus, by blocking EGFR interaction with the phosphatase SHP1, triggering c-Myc and Cyclin D1 upregulation. Our findings suggest that p53 mutants carrying gain-of-function, mis-sense mutations affecting two different domains form new protein complexes that promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms, exposing clinically relevant therapeutic vulnerabilities., (© 2023. The Author(s).)

Purpose: Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury., Methods and Materials: C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30 Gy or 3 fractions of 8 Gy (8 Gy × 3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, as well as an assessment of systemic changes in inflammatory-mediated circulating immune cells., Results: SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with nonirradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (P = .0428) and negatively correlated with number of voids (P = .028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways., Conclusions: This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The application efficiency of biodegradable polymers used in a natural environment requires improved resistance to ultraviolet (UV) photodegradation. In this report, 1,6-hexanediamine modified layered zinc phenylphosphonate (m-PPZn), utilized as a UV protection additive for acrylic acid-grafted poly(butylene carbonate-co-terephthalate) (g-PBCT), was successfully fabricated and compared to the solution mixing process. Experimental data of both wide-angle X-ray diffraction and transmission electron microscopy reveal that the g-PBCT polymer matrix was intercalated into the interlayer spacing of m-PPZn, which was approximately delaminated in the composite materials. The evolution of photodegradation behavior for g-PBCT/m-PPZn composites was identified using Fourier transform infrared spectroscopy and gel permeation chromatography after being artificially irradiated by a light source. The change of carboxyl group produced via photodegradation was used to show the enhanced UV protection ability of m-PPZn in the composite materials. All results indicate that the carbonyl index of the g-PBCT/m-PPZn composite materials after photodegradation for 4 weeks was extensively lower than that of the pure g-PBCT polymer matrix. These findings were also supported by the decrease in the molecular weight of g-PBCT after photodegradation for 4 weeks, from 20.76% to 8.21%, with the loading of 5 wt% m-PPZn content. Both observations were probably owing to the better UV reflection ability of m-PPZn. This investigation shows, through typical methodology, a significant advantage of fabricating the photodegradation stabilizer to enhance the UV photodegradation behavior of the biodegradable polymer using an m-PPZn compared to other UV stabilizer particles or additives.

The vaping of electronic cigarettes (E-cigarettes) has recently emerged as a popular alternative to traditional cigarette smoking, but its association with bladder cancer (BC) risk remains to be established. BC patients exhibit high rates of recurrent disease, possibly as a consequence of the field cancerization effect. We have shown that BC-derived extracellular vesicles (BCEVs) can permanently alter recipient urothelial cells in predisposed fields such that they become fully transformed malignant cells. To model the role that BCEVs may play in this potentially oncogenic setting, we treated TCCSUP BC cells with cigarette smoke extract, unflavored E-liquid, or menthol flavored E-liquid. Those treated BCEVs were then tested for their tumorigenic potential. We found that these smoking- and E-cigarette-related BCEVs were able to promote oxidative stress, inflammatory signaling, and DNA damage in recipient SV-HUC urothelial cells. Strikingly, menthol E-liquid-induced BCEVs significantly increased rates of malignant urothelial cell transformation. While further in vivo validation of the simultaneous effects of E-liquid and E-liquid-induced BCEVs on field cancerization is needed, these data highlight the possibility that E-cigarettes may compound user risk in a manner that can contribute to higher rates of BC incidence or recurrence., (© 2023. The Author(s).)

In recent decades, there has been a significant amount of research into breast cancer, with some important breakthroughs in the treatment of both primary and metastatic breast cancers. It's a well-known fact that treating breast cancer is still a challenging endeavour even though physicians have a fantastic toolset of the latest treatment options at their disposal. Due to limitations of current clinical treatment options, traditional chemotherapeutic drugs, and surgical options are still required to address this condition. In recent years, there have been several developments resulting in a wide range of treatment options. This review article discusses the cellular and molecular foundation of chemotherapeutic drugs, endocrine system-based treatments, biological therapies, gene therapy, and innovative techniques for treating breast cancer., (Copyright © 2022. Published by Elsevier Inc.)

The identification and characterization of circulating tumor cells (CTCs) are important for gaining insights into the biology of metastatic cancers, monitoring disease progression, and medical management of the disease. The limiting factor in the enrichment of purified CTC populations is their sparse availability, heterogeneity, and altered phenotypes relative to the primary tumor. Intensive research both at the technical and molecular fronts led to the development of assays that ease CTC detection and identification from peripheral blood. Most CTC detection methods based on single-cell RNA sequencing (scRNA-seq) use a mix of size selection, marker-based white blood cell (WBC) depletion, and antibodies targeting tumor-associated antigens. However, the majority of these methods either miss out on atypical CTCs or suffer from WBC contamination. We present unCTC, an R package for unbiased identification and characterization of CTCs from single-cell transcriptomic data. unCTC features many standard and novel computational and statistical modules for various analyses. These include a novel method of scRNA-seq clustering, named deep dictionary learning using k -means clustering cost (DDLK), expression-based copy number variation (CNV) inference, and combinatorial, marker-based verification of the malignant phenotypes. DDLK enables robust segregation of CTCs and WBCs in the pathway space, as opposed to the gene expression space. We validated the utility of unCTC on scRNA-seq profiles of breast CTCs from six patients, captured and profiled using an integrated ClearCell FX and Polaris workflow that works by the principles of size-based separation of CTCs and marker-based WBC depletion., (© 2023 Poonia et al.; Published by Cold Spring Harbor Laboratory Press.)

RAS-related nuclear protein(RAN) is a nuclear shuttle and normally regulates events in the cell cycle. When overexpressed in cultured cells, it causes increases in cell migration/invasion in vitro and its overexpression is associated with early breast cancer patient deaths in vivo. However, the underlying mechanism is unknown. The effect of RAN overexpression on potential targets MMP2, ATF3, CXCR3 was investigated by Real-Time PCR/Western blots in the triple receptor negative breast cancer(TRNBC) cell line MDA-MB231 and consequent biological effects were measured by cell adhesion, cell migration and cell invasion assays. Results showed that knockdown of RAN lead to a reduction of MMP2 and its potential regulators ATF3 and CXCR3. Moreover, knockdown of ATF3 or CXCR3 downregulated MMP2 without affecting RAN, indicating that RAN regulates MMP2 through ATF3 and CXCR3. Knockdown of RAN and MMP2 reduced cell adhesion, cell migration and cell growth in agar, whilst overexpression of MMP2 reversed the knockdown of RAN. Furthermore, immunohistochemical staining for RAN and MMP2 are positively associated with each other in the same tumour and separately with patient survival times in breast cancer specimens, suggesting that a high level of RAN may be a pre-requisite for MMP2 overexpression and metastasis. Moreover, positive immunohistochemical staining for both RAN and MMP-2 reduces further patient survival times over that for either protein separately. Our results suggest that MMP2 expression can stratify progression of breast cancers with a high and low incidence of RAN, both RAN and MMP2 in combination can be used for a more accurate patient prognosis. SIMPLE SUMMARY: Ran is an important regulator of normal cell growth and behaviour. We have established in cell line models of breast cancer (BC) a molecular pathway between RAN and its protein-degrading effector MMP-2 and properties related to metastasis in culture. Using immunohistochemistry (IHC) staining of primary BCs, we have shown that RAN and MMP-2 are on their own significantly associated with patient demise from metastatic BC. Moreover, when staining for MMP-2 is added to that for RAN in the primary tumours, there is a significant decrease in patient survival time over that for either protein alone. Thus a combination of staining for RAN and MMP2 is an excellent marker for poor prognosis in breast cancer., 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 Inc. All rights reserved.)

Since the outbreak of COVID-19, vaccination against the virus has been implemented and has progressed among various groups across all ethnicities, genders, and almost all ages in the United States. This study examines the impacts of socioeconomic status and political preference on COVID-19 vaccination in over 443 counties in the southwestern United States. Regression analysis was used to examine the association between a county’s vaccination rate and one’s personal income, employment status, education, race and ethnicity, age, occupation, residential area, and political preference. The results were as follows: First, counties with higher average personal income tend to have a higher vaccination rate (p < 0.001). Second, county-level vaccination is significantly associated with the percentage of Democrat votes (β = 0.242, p < 0.001). Third, race and ethnicity are vaccine-influencing factors. Counties with more Black residents have lower vaccine acceptance (β = −0.419, p < 0.001), while those where more Hispanics or Native Americans reside are more likely to accept vaccines for health protection (β = 0.202, p < 0.001; β = 0.057, p = 0.008, respectively). Lastly, pertaining to the age difference, seniors aged 65 and older show substantial support for vaccination, followed by the median age group (all p < 0.001).

Study Design: A retrospective cohort study., Objective: To determine radiographic parameters, including the lowest instrumented vertebral (LIV) tilt, related to the postoperative magnitude and progression of residual lumbar curves (LCs) in adolescent idiopathic scoliosis patients who underwent posterior spinal fusion with LIV at or above L1., Summary of Background Data: Although several guidelines have been proposed for thoracic curve fusion, factors related to the postoperative magnitude and potential progression of unfused LCs remained undetermined. The effect of the LIV tilt on residual LCs is also unclear., Materials and Methods: Patients with Lenke type 1 to 4 curves who underwent posterior spinal fusion with LIV at or above L1 with a minimum follow-up period of 2 years were evaluated. Prediction models for residual LCs were developed using multivariate linear regressions with selected radiographic parameters. Subgroup analyses, followed by sensitivity tests, were then performed for variables best predicting the progression of residual LCs., Results: A total of 130 patients were included. Multivariate linear regression analysis showed that the immediate postoperative LIV-tilt angle was associated with the immediate postoperative LCs and the prediction model for residual LCs, with high accuracy ( R =0.93 and 0.77, respectively). Sensitivity tests revealed immediate postoperative LIV-tilt angle <10° and correction rate of main thoracic curve Cobb angle >53% as predictors for progression of residual LCs, and they reached moderate discrimination when combined together as one criterion (odds ratio=16.3, 95% confidence interval=5.3-50.1; sensitivity=89%, specificity=67%, positive predicted value=51%, negative predicted value=94%)., Conclusion: The current study revealed that LIV tilt, as an operable factor during surgery, is not only a determinant in prediction models showing high correlation with the magnitude of postoperative LCs but a predictor for progression of residual LCs. "Immediate postoperative LIV-tilt angle <10° and correction rate of main thoracic curve Cobb angle >53%," as a united criterion, could serve as a predictor for progression of residual LCs., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Adoption of minimally invasive approaches continues to increase, and there is a need to reassess outcomes and cost. We aimed to compare open versus minimally invasive colectomy short- and long-term health-care utilization and payer/patient expenditures for benign disease., Methods: This is a retrospective analysis of IBM ® MarketScan ® Database patients who underwent left or right colectomy for benign disease between 2013 and 2018. Outcomes included total health-care expenditures, resource utilization, and direct workdays lost up to 365 days following colectomy. The open surgical approach (OS) was compared to minimally invasive colectomy (MIS) with subgroup analysis of laparoscopic (LS) and robotic (RS) approaches using inverse probability of treatment weighting., Results: Of 10,439 patients, 2531 (24.3%) had open, 6826 (65.4%) had laparoscopic, and 1082 (10.3%) had robotic colectomy. MIS patients had shorter length of stay (LOS; mean difference, - 1.71, p < 0.001) and lower average total expenditures (mean difference, - $2378, p < 0.001) compared with open patients during the index hospitalization. At 1 year, MIS patients had lower readmission rates, and fewer mean emergency and outpatient department visits than open patients, translating into additional savings of $5759 and 2.22 fewer days missed from work for health-care visits over the 365-day post-discharge period. Within MIS, RS patients had shorter LOS (mean difference, - 0.60, p < 0.001) and lower conversion-to-open rates (odds ratio, 0.31 p < 0.001) during the index hospitalization, and lower hospital outpatient visits (mean difference, - 0.31, p = 0.001) at 365 days than LS., Conclusion: MIS colectomy is associated with lower mean health-care expenditures and less resource utilization compared to the open approach for benign disease at index operation and 365-days post-discharge. Health-care expenditures for LS and RS are similar but shorter mean LOS and lower conversion-to-open surgery rates were observed at index operation for the RS approach., (© 2022. The Author(s).)

After kidney transplantation, patients exhibit a poor response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. However, the efficacy and adverse effects of vaccines based on different platforms in these patients remain unclear. We prospectively analyzed both anti-spike protein antibody and cellular responses 1 month after the first and second doses of SARS-CoV-2 vaccines in 171 kidney transplant patients. Four vaccines, including one viral vector (ChAdOx1 nCov-19, n = 30), two mRNA (mRNA1273, n = 81 and BNT162b2, n = 38), and one protein subunit (MVC-COV1901, n = 22) vaccines were administered. Among the four vaccines, mRNA1273 elicited the strongest humoral response and induced the highest interferon-γ levels in patients with a positive cellular response against the spike protein. Antiproliferative agents were negatively associated with both the antibody and cellular responses. A transient elevation in creatinine levels was noted in approximately half of the patients after the first dose of mRNA1273 or ChadOx1, and only one of them presented with borderline cellular rejection without definite causality to vaccination. In conclusion, mRNA1273 had better immunogenicity than the other vaccines. Further, renal function needs to be carefully monitored after vaccination, and vaccination strategies should be tailored according to the transplant status and vaccine characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Huang, Lai, Lin, Lin, Lin, Lin, Huang, Lee, Tsai and Lee.)