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Summary: Background: Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored. Methods: Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca2+ dynamics and decoders to elucidate the pathway from receptor to phenotype. Findings: CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state. This shifts the Ca2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca2+ dynamic changes. Ca2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation. Interpretation: CHRFAM7A introduces an additional, human specific, layer to Ca2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis. Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae).

The rate of change of frequency (ROCOF) has become a key parameter to be monitored under high penetration of renewable energy. Any significant ROCOF should be mitigated immediately to avoid any shutdown of power plants and hence power interruptions to the customers. However, ROCOF is found to be significant and often in a region near to equatorial line because the power output of PV is highly intermittent due to a large number of passing clouds. Demand response (DR) is one of the most cost-effective means for mitigating any high ROCOF through controlling heating elements, refrigerators, and air-conditioners. However, most of the DR controllers use pre-determined conditions, also known as the condition-based approach, to switch the loads for reducing frequency changes. This approach may not be effective enough to respond to a new load condition. Furthermore, many DR controllers, including those accompanied by machine learning, are mainly developed to mitigate frequency changes with little focus on the mitigation of high ROCOF. Hence, an artificial neural network (ANN)-based controller is proposed in this article for frequency regulation with auto corrective efforts on high ROCOF under high intermittency of PV systems. The proposed controller is designed to manage several controllable loads on a grid emulator with PV systems at Universiti Tunku Abdul Rahman, Malaysia. It is shown that the proposed controller can reduce the frequency deviation by 23% and improve ROCOF by 19.7% as compared to that without any controller.

Summary: Background: In June 2023, a local cluster of 15 Zika cases was reported in a neighbourhood in Northeastern Singapore. The last significant local transmission of Zika virus (ZIKV) with more than 450 cases was in 2016–2017. To monitor the situation and mitigate further transmission, case, entomological and wastewater-based surveillance were carried out. Methods: Primary healthcare practitioners and the community were alerted to encourage timely case identification. Surveillance was enhanced through testing of Aedes mosquitoes collected from the National Gravitrap surveillance system, and wastewater samples were collected from a network of autosamplers deployed at manholes across the country. Findings: ZIKV RNA was detected in mosquito pools (3/43; 7%) and individual mosquitoes (3/82; 3.7%) captured, and in wastewater samples (13/503) collected from the vicinity of the cluster of cases. Respective samples collected from other sites across the country were negative. The peak detection of ZIKV RNA in mosquitoes and wastewater coincided temporally with the peak in the number of cases in the area (15–25 May 2023). Interpretation: The restriction of ZIKV signals from wastewater and mosquitoes within the neighbourhood suggested limited ZIKV transmission. The subsequent waning of signals suggested effectiveness of control measures. We demonstrate the utility of wastewater-based surveillance of ZIKV, which complements existing case- and entomological-based surveillance. The non-intrusive approach is particularly useful to monitor diseases such as Zika, which generally causes silent or mild infections, but may cause severe outcomes such as congenital Zika syndrome. Funding: This study was funded by Singapore’s Ministry of Finance and the National Environment Agency, Singapore.

Background & Aims: Micro-elimination of hepatitis C virus (HCV) in high-risk populations is a feasible approach towards achieving the World Health Organization’s targets for viral hepatitis elimination by 2030. Prisons represent an area of high HCV prevalence and so initiatives that improve testing and treatment of residents are needed to eliminate HCV from prisons. This initiative aimed to improve the HCV screening and treatment rates of new residents arriving at prisons in England. Methods: A rapid test and treat pathway was developed and implemented in 47 prisons in England between May 2019 and October 2021 as a healthcare service improvement initiative. Prison healthcare staff performed opt-out HCV testing for all new residents at each prison within 7 days of arrival, and those who were positive for HCV RNA were offered treatment with direct-acting antivirals (DAAs). The Hepatitis C Trust provided peer support for all residents on treatment and those who were released into the community. Results: Of 107,260 new arrivals, 98,882 (92.2%) were offered HCV antibody testing, 63,137 (63.9%) were tested and 1,848 were treated. Testing rates increased from 53.7% in Year 1 to 86.0% in Year 3. Between May 2020 and October 2021, 40,727 residents were tested, 2,286 residents were positive for HCV antibodies and 940 residents were HCV RNA positive, giving an antibody prevalence of 5.6% and an RNA prevalence of 2.3%. A total of 921 residents were referred for treatment and 915 initiated DAA treatment (97.3% of whom were HCV RNA positive). Conclusions: This initiative showed that an opt-out HCV test and treat initiative in prison receptions is feasible and can be adapted to the needs of individual prisons as a viable way to achieve HCV micro-elimination. Impact and implications: Prisons represent an area of high HCV prevalence and so initiatives that improve testing and treatment of residents are needed to eliminate HCV from prisons. The reception testing protocol improved HCV screening in new arrivals across 47 prisons in England and could be a viable way for countries to achieve HCV micro-elimination in their prison systems. The reception testing protocol presented here can be adapted to the individual needs of prisons, globally, to improve HCV screening and treatment in this setting.

We conducted a prospective environmental surveillance study to investigate the air, surface, dust, and water contamination of a room occupied by a patient infected with mpox virus (MPXV) at various stages of the illness. The patient tested positive for MPXV from a throat swab and skin lesions. Environmental sampling was conducted in a negative pressure room with 12 unidirectional high efficiency particulate air filter (HEPA) air changes per hour and daily cleaning of the surfaces. A total of 179 environmental samples were collected on days 7, 8, 13, and 21 of illness. Among the days of sampling, air, surface, and dust contamination showed the highest contamination rates on day 7 and 8 of illness, with a gradual decline to the lowest contamination level by day 21. Viable MPXV was isolated from surfaces and dust samples and no viable virus was isolated from the air and water samples.

Objective: To design a simple, novel, economical apparatus which effectively provides reliable, real-time measurements of intrarenal pelvic pressure (IRPP) intraoperatively and to demonstrate clinical utility. Patients and Surgical Procedure: Patients undergoing robotic ureteral reconstruction from 10/2020 to 7/2021 for whom intraoperative IRPP measurement was conducted were included.Baseline opening pressure was noted with the pelvis completely drained. The kidney was intermittently drained when IRPP exceeded a certain threshold, returning the pressure to baseline. Relief of obstruction was defined as return of IRPP to physiologic value without further increases for the remainder of surgery.Demographic, intraoperative, and post-operative variables were collected and IRPP measurements extracted. Post-operative success was defined as resolution of obstruction by clinical symptoms and imaging. Results: Eleven patients met criteria including 4 (36.4%) men and 7 (63.6%) women. Median age and BMI was 61 years (range 14–23) and 26 kg/m2 (range 17.2–42), respectively. Six patients (54.5%) had undergone prior interventions.Ureteral reconstructive procedures included bilateral refluxing reimplants (2), unilateral reimplant with Boari flap (3), non-transecting reimplant (2), unilateral ileal ureter (1), bilateral ileal ureter (1), buccal ureteroplasty (1), and ureteroureterostomy (1). Median peak IRPP was 52 mmHg (range 27–59) and median nadir IRPP was 14 mmHg (range 1–24), with median decrease of 36 mmHg (range 26–84).At median follow-up of 120 days, all patients had successful repairs. Conclusions: Intraoperative measurement of IRPP can be utilized in patients with percutaneous nephrostomy tubes using readily available equipment. This measurement has the potential to ensure that ureteral obstruction is completely relieved and to prevent development of supraphysiologic IRPP during surgery.

Summary: Molecular interactions between anorexigenic leptin and orexigenic endocannabinoids, although of great metabolic significance, are not well understood. We report here that hypothalamic STAT3 signaling in mice, initiated by physiological elevations of leptin, is diminished by agonists of the cannabinoid receptor 1 (CB1R). Measurement of STAT3 activation by semi-automated confocal microscopy in cultured neurons revealed that this CB1R-mediated inhibition requires both T cell protein tyrosine phosphatase (TC-PTP) and β-arrestin1 but is independent of changes in cAMP. Moreover, β-arrestin1 translocates to the nucleus upon CB1R activation and binds both STAT3 and TC-PTP. Consistently, CB1R activation failed to suppress leptin signaling in β-arrestin1 knockout mice in vivo, and in neural cells deficient in CB1R, β-arrestin1 or TC-PTP. Altogether, CB1R activation engages β-arrestin1 to coordinate the TC-PTP-mediated inhibition of the leptin-evoked neuronal STAT3 response. This mechanism may restrict the anorexigenic effects of leptin when hypothalamic endocannabinoid levels rise, as during fasting or in diet-induced obesity.

Anxiety disorders are one of the most common psychiatric illnesses in the world's population. As current pharmacotherapy is not effective and safe for all patients, seeking complementary treatment has increased. Hydrocotyle umbellata L., Araliaceae, is an herb long recognized for its anxiolytic and memory stimulant effects. This work aimed to evaluate the anxiolytic-like effects and the impact on memory of the spray-dried Hydrocotyle umbellata L. extract (SDHUE) in mice and to assess its toxicological potential. The anxiolytic-like effects of SDHUE (75, 150, 300, or 600 mg/kg) were assessed on elevated plus maze (EPM) and light-dark box (LDB) tests, and the participation of the benzodiazepine site of GABAA and 5-HT1A receptors was investigated. The memory retention of the animals was evaluated in the step-down avoidance (SDA) test, and the possible effects on learning and memory processes were assessed by ex vivo cholinesterase (ChE) activity. The toxicity assays were evaluated in terms of cytotoxicity in RAW macrophage cells, mutagenic effects by the Ames test, and embryotoxic potential using the zebrafish (Danio rerio) model. Pretreatment with flumazenil (2 mg/kg) prevented the anxiolytic-like activity induced by SDHUE. No signs of memory impairment on short- and long-term memory were detected with SDHUE treatment in the SDA test. The inhibition of ChE activity in the prefrontal cortex and hippocampus was also observed with SDHUE treatment. Moreover, it was verified an absence of apparent toxic effects. Thus, this extract may offer a promising approach for further safe and effective application in the treatment of anxiety.

Human–elephant conflict (HEC) is a multifaceted complex phenomenon, and managing it requires multiple strategies. However, HEC remains prevalent in tropical areas due to a lack of “synergy of options”. Establishing synergistic HEC management strategies is thus crucial. We applied a choice experiment to capture the preference heterogeneity of the human population in Dong Nai Biosphere Reserve, Vietnam, regarding synergistic HEC management strategies and evaluate their marginal willingness to participate (MWTP) under multiple scenarios of HEC management. The following characteristics were found to affect this human population’s preferences regarding a HEC management program: 1) their attitude toward elephant conservation, 2) education and income level, and 3) employment status. Three promising guide scenarios were suggested based on the positive-preference attributes regarding HEC management. Among these, the scenario of a human–elephant coexistence program generated the highest MWTP compared to the scenarios of ‘building HEC prevention and mitigation’ and ‘protecting elephants and forest’. These outcomes can help managers adopt sustainable policies for mitigating HEC and facilitating human–elephant coexistence.

We share a rare case of an older adult patient with situs inversus totalis (mirror image of all viscera, including dextrocardia) and congenitally corrected transposition of the great arteries who presented with supraventricular tachycardia. We highlight the unique electrocardiographic characteristics of these rare conditions and the importance of electrocardiogram interpretation skills. (Level of Difficulty: Advanced.)

Chronic tic disorder and Gilles de la Tourette syndrome are very common childhood-onset diseases. However, the pathophysiology underlying these disorders is not yet clear and most studies focus on the disinhibition of the cortico-striatal-thalamo-cortical circuit. Although dysfunction of this circuit is possible, routine clinical neuroimaging studies such as T1-weighted or T2-weighted MRI usually reveal normal results. Therefore, special neuroimaging techniques may be needed to investigate the possible microstructural or functional changes in the brain. Previous structural studies, such as those using diffusion tensor imaging, and volumetric MRI studies, revealed the main abnormalities to be located in the cortico-striatal-thalamo-cortical circuit and to be related to brain regions such as basal ganglion, thalamus, frontal cortex, and motor cortex. Some other potential regions, such as the amygdala, hippocampus or cerebellum, are also occasionally reported. Perfusion studies, such as those using positron emission tomography or functional MRI, also suggest hemodynamic changes over those brain regions related to the cortico-striatal-thalamo-cortical circuit. However, the results can be different in adult and pediatric groups, and neuroimaging findings are also inconsistent between different studies, which may reflect the high diversity of this disease or differences in enrolled patient groups with different comorbidities. Therefore, in this review article, we will focus on the neuroimaging findings relating to Tourette syndrome in different age groups using different imaging techniques.

Tungsten (W) is considered as one of the promising candidates for plasma facing components in fusion reactors since it has high threshold energy, high melting point, low threshold shock resistance, and resistance against formation of co-deposits with tritium. Despite these commendable features, helium ions produced during fusion reaction are known to alter the microstructure of tungsten. In this work, dense plasma focus (DPF) device is used to study the effect of helium ion flux on double forged tungsten samples delivering a heat load of 6.27×104J/m2 per shot. The irradiation of virgin W samples is carried out at 5, 10, and 15 DPF helium shots. High heat loads resulted in blisters and micro-cracks on the sample surface. With an increase in the number of shots, the density of the blisters increased and craters on the W surface burst followed by re-solidification of the melted and sputtered surface. Surface nano-structurization, with nanoparticle formation, of W samples (nano-W) is realized by high-energy argon ion exposure of virgin samples in an argon filled DPF device. The average size of nanoparticles is found to increase with the number of shots and also leads to particle agglomeration. At 10 shots, uniformly distributed highly dense nanoparticles of 20–50 nm size have been synthesized. The nano-W samples are then irradiated by instability-accelerated high-energy helium ions in helium filled DPF device for 5, 10, and 15 shots to simulate fusion relevant conditions. The presence of the trapped helium bubbles in virgin-W and nano-W are examined by BSE imaging and XRD, respectively. The nanostructured tungsten shows improved structure and surface properties against Helium ion irradiation.

Organic matter in the environment is involved in many biogeochemical processes, including the mobilization of geogenic trace elements, such as arsenic, into groundwater. In this paper we present the use of fluorescence spectroscopy to characterize the dissolved organic matter (DOM) pool in heavily arsenic-affected groundwaters in Kandal Province, Cambodia. The fluorescence DOM (fDOM) characteristics between contrasting field areas of differing dominant lithologies were compared and linked to other hydrogeochemical parameters, including arsenic and dissolved methane as well as selected sedimentary characteristics. Absorbance-corrected fluorescence indices were used to characterize depth profiles and compare field areas. Groundwater fDOM was generally dominated by terrestrial humic and fulvic-like components, with relatively small contributions from microbially-derived, tryptophan-like components. Groundwater fDOM from sand-dominated sequences typically contained lower tryptophan-like, lower fulvic-like and lower humic-like components, was less bioavailable, and had higher humification index than clay-dominated sequences. Methane concentrations were strongly correlated with fDOM bioavailability as well as with tryptophan-like components, suggesting that groundwater methane in these arsenic-prone aquifers is likely of biogenic origin. A comparison of fDOM tracers with sedimentary OM tracers is consistent with the hypothesis that external, surface-derived contributions to the aqueous DOM pool are an important control on groundwater hydrogeochemistry. Keywords: Arsenic, Fluorescence spectroscopy, Organic matter characterization, Parallel factor analysis (PARAFAC), Groundwater quality

Background: Cholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models. Methods: Molecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aβ uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype. Findings: The direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aβ neurotoxicity. Pharmacological readout translates into both first exposure (p = 0.037) and disease modifying effect (p = 0.0048) in two double blind pharmacogenetic studies. Interpretation: CHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy.Funding:

More than eleven million U.S. Veterans are at least 65 years of age, an age group of which almost 20% suffers from clinically significant depressive symptoms. Available pharmacological treatments are suboptimal for patients, including veterans, with late-life depression. Ketamine has emerged as a potentially promising rapid-acting therapy for treatment-resistant depression (TRD). However, few studies have examined the safety, tolerability and efficacy of ketamine therapy for older adults with late-life TRD (LL-TRD). This study uses an adaptive randomization design to test the safety, tolerability, efficacy, and durability of three distinct, single sub-anesthetic doses of intravenous (IV) ketamine versus a single dose of active placebo (midazolam) in older depressed veterans. As the study progresses, Bayesian adaptive randomization recalibrates randomization ratios to allocate more participants to conditions demonstrating greater promise and fewer participants to conditions with less promise. Secondary analyses explore clinical and biological moderating and mediating factors of rapid treatment response. Results are expected to inform both the viability of ketamine treatment and optimal dosing strategies for patients with LL-TRD. Keywords: Ketamine, Late-life depression, Treatment-resistant depression, Veterans, Adaptive design, Bayesian trial design

Background and objectives: Combined spinal–epidural (CSE) has become an increasingly popular alternative to traditional labour epidural due to its rapid onset and reliable analgesia provided. This was a prospective, convenient sampling study to determine the effects of CSE analgesia on labour outcome. Methods: One hundred and ten healthy primigravida parturients with a singleton pregnancy of ≥37 weeks gestation and in the active phase of labour were studied. They were enrolled to the CSE (n = 55) or Non-CSE (n = 55) group based on whether they consented to CSE analgesia. Non-CSE parturients were offered other methods of labour analgesia. The duration of the first and second stage of labour, rate of instrumental vaginal delivery and emergency cesarean section, and Apgar scores were compared. Results: The mean duration of the first and second stage of labour was not significantly different between both groups. Instrumental delivery rates between the groups were not significantly different (CSE group, 11% versus Non-CSE group, 16%). The slightly higher incidence of cesarean section in the CSE group (16% versus 15% in the Non-CSE group) was not statistically significant. Neonatal outcome in terms of Apgar score of less than 7 at 1 and 5 min was similar in both groups. Conclusion: There were no significant differences in the duration of labour, rate of instrumental vaginal delivery and emergency cesarean section, and neonatal outcome in parturients who received compared to those who did not receive CSE for labour analgesia. Resumo: Justificativa e objetivos: A analgesia combinada raquiperidural (RP) tornou-se uma alternativa cada vez mais popular para o trabalho de parto tradicional devido ao seu rápido início de ação e analgesia confiável. Este foi um estudo prospectivo de amostragem conveniente para determinar os efeitos da RP sobre o desfecho do parto. Métodos: Cento e dez parturientes primigestas saudáveis, com gestação única de ≥ 37 semanas de gestação e na fase ativa do trabalho de parto foram incluídas. As pacientes foram designadas para os grupos RP (n = 55) ou não-RP (n = 55) com base em seus consentimentos para a analgesia combinada RP. As parturientes do grupo não-RP receberam outros métodos de analgesia para o parto. As durações do primeiro e segundo estágio do trabalho de parto, as taxas de parto vaginal instrumental e cesariana de emergência e os escores de Apgar foram comparados. Resultados: A média de duração do primeiro e segundo estágio do trabalho de parto não foi significativamente diferente entre os dois grupos. As taxas de parto instrumental não foram significativamente diferentes entre os grupos, grupo RP (11%) versus grupo não-RP (16%). A incidência ligeiramente maior de cesariana no grupo RP (16% versus 15% no grupo não RP) não foi estatisticamente significativa. O desfecho neonatal em termos de índice de Apgar inferior a 7. Conclusão: Não houve diferenças significativas em relação à duração do trabalho, às taxas de parto vaginal instrumental e cesariana de emergência e ao desfecho neonatal em parturientes que receberam RP para analgesia de parto em comparação com aquelas que não receberam. Keywords: Combined spinal–epidural, Labour analgesia, Foetal outcome, Duration of labour, Palavras-chave: Combinação raqui-peridural, Analgesia de parto, Resultado fetal, Duração do parto

This paper concerns the kinematic characteristics of a coupling device in a deep-seabed mining system. This coupling device connects the buffer system and the flexible pipe. The motion of the buffer system, flexible pipe and mining robot are affected by the coupling device. So the coupling device should be considered as a major factor when this device is designed. Therefore, we find a stable kinematic device, and apply it to the design coupling device through this study. The kinematic characteristics of the coupling device are analyzed by multi-body dynamics simulation method, and finite element method. The dynamic analysis model was built in the commercial software DAFUL. The Fluid Structure Interaction (FSI) method is applied to build the deep-seabed environment. Hydrodynamic force and moment are applied in the dynamic model for the FSI method. The loads and deformation of flexible pipe are estimated for analysis results of the kinematic characteristics

Abstract.: We investigated whether increased contractile responsiveness to epidermal growth factor (EGF) is associated with altered activation of mitogen-activated protein kinase (MAPK) in the aortic smooth muscle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. EGF induced contraction and MAPK activity in aortic smooth muscle strips, which were significantly increased in tissues from the DOCA-salt hypertensive rats compared with those from sham-operated rats. AG1478, PD98059, and LY294002, inhibitors of EGF receptor (EGFR) tyrosine kinase, MAPK/extracellular signal-regulated kinase (ERK) kinase, and phosphatidylinositol 3-kinase (PI3K), respectively, inhibited the contraction and the activity of ERK1/2 that were elevated by EGF. Y27632 and GF109203X, inhibitors of Rho kinase and protein kinase C, respectively, attenuated EGF-induced contraction, with no diminution of ERK1/2 activity. Although EGF also elevated the activity of EGFR tyrosine kinase in both sham-operated and DOCA-salt hypertensive rats, the expression and the magnitude of activation did not differ between strips. These results strongly suggest that EGF induces contraction by the activation of ERK1/2, which is regulated by the PI3K pathway in the aortic smooth muscle of DOCA-salt hypertensive rats. Keywords:: epidermal growth factor, hypertension, vasoconstriction, mitogen-activated protein kinase, phosphatidylinositol 3-kinase

Background & Aims: Ultrasound (US) is recommended for HCC surveillance in high-risk patients but has limited performance in detecting early-stage HCC. We aimed to compare the diagnostic performance of biannual US and annual non-contrast abbreviated magnetic resonance imaging (NC-AMRI) as HCC surveillance modalities in high-risk patients., Methods: This prospective, multicenter cohort study enrolled participants with an estimated annual risk of HCC greater than 5% between October 2015 and April 2017. Participants underwent six rounds of HCC surveillance at 6-month intervals, with both US and NC-AMRI at rounds 1, 3, and 5, and only US at rounds 2, 4, and 6. The sensitivity, diagnostic yield (DY), and false referral rate (FRR) for HCC detection by US and NC-AMRI were compared., Results: In total, 208 participants underwent 980 US and 516 NC-AMRI examinations during 30 months of follow-up. Among them, 34 HCCs were diagnosed in 31 participants, with 20 (64.5%) classified as very early-stage and 11 (35.5%) as early-stage HCC. The sensitivity of annual NC-AMRI (71.0%, 22/31) was marginally higher than that of biannual US (45.2%, 14/31; p = 0.077). NC-AMRI showed a significantly higher DY than US (4.26% vs. 1.43%, p <0.001), with a similar FRR (2.91% vs. 3.06%, p = 0.885). A simulation of alternating US and NC-AMRI at 6-month intervals yielded a sensitivity of 83.9% (26/31), significantly exceeding that of biannual US (p = 0.006)., Conclusions: Annual NC-AMRI showed a marginally higher sensitivity than biannual US for HCC detection in high-risk patients. The DY of annual NC-AMRI was significantly higher than that of biannual US, without increasing the FRR. Thus, alternating US and NC-AMRI at 6-month intervals could be an optimal surveillance strategy for high-risk patients., Impact and Implications: Current guidelines permit the use of magnetic resonance imaging (MRI) as a surveillance tool for hepatocellular carcinoma in patients in whom ultrasonography (US) is inadequate. However, the specific indications, imaging sequences, and intervals for MRI surveillance remain unclear. In our study, we found that annual non-contrast abbreviated MRI exhibited marginally higher sensitivity and significantly better diagnostic yield than biannual US in patients at high risk of hepatocellular carcinoma. Alternating US and non-contrast abbreviated MRI at 6-month intervals led to significantly improved sensitivity compared to biannual US, making it a potentially optimal surveillance strategy for high-risk patients., Gov Identifier: NCT02551250., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Engaging coastal communities in beach clean-up initiatives is crucial for the sustainability of marine ecosystems and the support of the blue economy. This study aims to examine the influence of various resilience attributes on community willingness to participate in these activities. It uses choice experiment framework to test three distinct scenarios: (1) cultural recycling education, (2) social media task force, and (3) resilience debris recovery. The study surveyed 647 valid samples from metropolitan Bali, Indonesia to assess their preferences across these scenarios. Advanced econometric models, specifically the Random Parameter Logit (RPL) and Latent Class Model (LCM), were used to analyze the data. The results indicate that integrating cultural and digital engagement strategies can significantly enhance community participation in beach clean-ups, providing a model that can be applied in various coastal regions. Each scenario improves community engagement by aligning beach clean-up efforts with broader economic and cultural dynamics., 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 © 2024 Elsevier Ltd. All rights reserved.)

Background: Protein phosphorylation by protein kinases plays a pivotal role in increasing protein diversity, thereby influencing various cellular functions. However, due to the relatively low abundance of phosphopeptides in a mixture of peptides and the ion-suppression effect of non-phosphorylated peptides, the detection of phosphopeptides is not straightforward., Results: Herein, a quantitative high-throughput platform was developed for assessing multikinase activity using nano-LC-MS/MS with a data-independent acquisition (DIA) approach. This platform was evaluated by studying the kinase activity in Taxol-treated SKOV3 cells. A library containing 38 peptide substrates was designed and analyzed to determine the activities of major kinases involved in cancer development. Twenty-three synthetic peptide substrates showed significant phosphorylation changes in triplicate biological experiments, as further verified by western blotting. Our findings reveal that Taxol suppressed SKOV3 cell survival by activating AMPK and suppressing the PI3K-Akt-dependent pathway, ultimately leading to mTOR inhibition. Furthermore, in combination with ERK, Akt, SGK, CK1, and ErbB2 inhibitors, Taxol enhanced the inhibitory effect on ovarian cancer., Significance: This platform can be an attractive approach for large-scale kinase activity studies to comprehensively uncover the mechanisms of drug-disease treatment and to investigate a more effective therapy strategy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chao-Jung Chen reports financial support was provided by National Science and Technology Council. If there are other authors, they 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 © 2024 Elsevier B.V. All rights reserved.)

This review investigates the therapeutic effects of Ulmus species extracts, traditionally used as tea ingredients in East Asia, on bone health and inflammatory conditions. Through the analysis of 9757 studies, narrowing down to 56 pertinent ones, we evaluated the safety and efficacy of Ulmus extracts. The focus was on catechin glycosides (CG) and flavonoid glycosides (FG), key compounds identified for their potential benefits. The research highlights the extracts' role in enhancing bone mineral density (BMD) by stimulating osteoblast activity and suppressing osteoclast differentiation, suggesting a protective effect against osteoporosis. Furthermore, the extracts demonstrated significant anti-inflammatory properties by modulating inflammatory markers and pathways. The findings confirm the historical use of Ulmus extracts in East Asia for health benefits and recommend further exploration into functional foods and nutraceuticals. The review calls for more rigorous research, including clinical trials, to establish optimal use and integration into modern health solutions. It underscores the potential of Ulmus extracts in promoting bone health and managing inflammation, advocating for a bridge between traditional practices and contemporary scientific validation. In conclusion, Ulmus extracts, a material long consumed as tea ingredients in East Asia, exhibit significant potential for improving bone health and reducing inflammation. This review calls for additional research to explore their full therapeutic capabilities, emphasizing the need for optimized extraction methods and clinical trials. It reinforces the importance of bridging traditional knowledge with contemporary scientific approaches to health and dietary solutions, promoting overall wellness., 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 © 2024. Published by Elsevier B.V.)

Background: Submucous cleft palate (SMCP) is a congenital anomaly characterized by the presence of Calnan's triad. However, in clinical practice, it is common for individuals to exhibit one or two anatomical abnormalities within the triad. Furthermore, the definition of SMCP has been diverse and ambiguous in literature. Therefore, this study aimed to analyze the correlation between anatomical abnormalities and development of velopharyngeal insufficiency (VPI)., Methods: We conducted a retrospective analysis of 99 patients referred to our clinic for speech issues or anatomical abnormalities identified during routine oral examinations from January 2012 to June 2023. A single surgeon performed all physical examinations. We evaluated the presence of bony notch, zona pellucida, and bifid uvula, assigned a score to each abnormality, and analyzed their correlation with VPI. The correlation of each of the abnormalities with VPI development was examined, along with the relationship between the number of abnormalities and VPI., Results: Among the 99 patients, 27 were diagnosed with VPI. Only the bony notch had a significant correlation with VPI development. The incidence of VPI tended to increase with the presence of more anatomical abnormalities. VPI occurred in approximately 40% of patients exhibiting all three anatomical abnormalities., Conclusion: The study findings highlight the importance of meticulous intraoral examinations in patients with SMCP and careful monitoring of patients with a bony notch or two or more anatomical abnormalities., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to create a molecular diagnostic platform and establish a diagnostic pipeline for patients highly suspected of mitochondrial disorders. The effectiveness of three methods, namely, traditional restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), Sanger sequencing for hotspot detection and whole mitochondrial DNA (mtDNA), and third-generation (Nanopore) whole mtDNA sequencing, will be compared in diagnosing patients with suspected primary mitochondrial diseases (PMDs). The strengths and limitations of different methods are also discussed., Material and Methods: A single-center prospective cohort study was conducted to validate the diagnostic pipeline for suspected mitochondrial diseases. In the first stage, a PCR-based method with five sets of primers was used to screen for eight hotspots (m.3243A>G, m.3460G>A, m.8344A>G, m.8993T>G, m.9185T>C, m.11778G>A, m.13513G>A, and m.4977deletion) using either RFLP or direct Sanger sequencing. Sanger sequencing was also used to confirm the RFLP-positive samples. In the second stage, for samples with negative screening results for the eight hotspots, mitochondrial whole-genome sequencing was performed using Sanger sequencing or third-generation nanopore sequencing., Results: Between June 2020 and May 2023, 30 patients from ages 0 to 63 with clinically suspected mitochondrial disease were enrolled. The positive yield for the diagnosis of PMDs was 8/30=26.7%, and the sensitivity of the heteroplasmy level for the RFLP-based method was approximately 5%. The remaining 22 patients who tested negative at the first stage were tested using Sanger sequencing or the third-generation sequencing Nanopore, and all tested negative for pathological mtDNA mutations. Compared to the Sanger sequencing method, the results of RFLP-PCR were compromised by the limitations of incomplete RFLP enzyme digestion. For whole-genome sequencing of mtDNA, Sanger sequencing, instead of nanopore sequencing, is preferred at our institution because of its cost-effectiveness., Conclusions: In our highly selective cohort, most tested positive in the first stage of the 8 hot spots screen. Sanger sequencing is a conventional and accurate method for mitochondrial disease screening, at least for the most common hot spots in the region. The results revealed that Sanger sequencing is an accurate method with the benefit of being more cost-effective. This integral platform of molecular diagnosis bears the advantages of being relatively low cost and having a shorter reporting time, facilitating crucial identification of patients with clinical evidence of such disorders. This diagnostic flowchart has also been translated into routine clinical use in the tertiary hospital., Competing Interests: Declaration of Competing Interest: This study was supported by CRRPG8K0021-3 and CMRPG8N1171 from the Chang Gung Memorial Hospital., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study aims to investigate the relationship between body mass index (BMI) and molecular subtypes of endometrial carcinoma using an immunohistochemistry (IHC)-based classification approach., Methods: We analyzed a consecutive series of endometrial cancer cases undergoing surgical staging in southern Alberta (2019-2021). Molecular classification was determined through IHC-based molecular typing, incorporating p53 and mismatch repair (MMR), and further characterized with the addition of ER and PR. BMI associations with molecular classification were assessed using t-tests. Hormone receptor status was further examined in a separate cohort of MMRd endometrial cancer patients undergoing surgical staging at Foothills Medical Centre (Alberta, Canada)., Results: Among 289 cases, comprising various histological subtypes, the pNSMP subtype exhibited the highest average BMI (33.93 kg/m 2 ) compared to the p53 abnormal subtype (30.40 kg/m 2 , p = 0.02). The MMRd subtype had an average BMI of 33.22 kg/m 2 . While there were no significant BMI differences between FIGO grade 1 and grade 2/3 tumours in the pNSMP or MMRd, a trend toward higher BMI in grade 1 tumours versus grade 2/3 tumours in the MMRd was observed (p = 0.13). A separate cohort of 53 MMRd endometrial carcinomas revealed that FIGO grade 1 tumours were associated with higher BMI (p < 0.05) and more frequent ER/PR expression compared to grade 2/3 tumours (p < 0.05)., Conclusions: This study suggests an association between obesity and NSMP endometrial carcinoma. The relationship between BMI and low-grade MMRd endometrial carcinomas with increased ER/PR expression warrants further exploration., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Martin Koebel is a consultant for Helix Biopharma. No other competing interests to disclose]., (© 2024 The Author(s).)

Marine plastic debris (MPD) is a potential threat to marine ecosystems, but its function as a vector for the transportation of harmful microalgae and its impact on the habitats of other marine organisms are uncertain. To address this gap in knowledge, we performed month-long experiments in 30 L microcosms that contained plates made of six different plastic polymers (polypropylene [PP], low-density polyethylene [LDPE], high-density polyethylene [HDPE], polyvinyl chloride [PVC], polyethylene terephthalate [PET], and polystyrene [PS]), and examined the time course of changes in planktonic and periphytic microalgae. There were no significant differences in the composition of periphytic microalgae or biomass among the different plastic polymers (p > 0.05). Nutrient depletion decreased the abundance of planktonic microalgae, but increased the biomass of attached periphytic microalgae (p < 0.05). In particular, analysis of the plastic plates showed that the abundance of benthic species that are responsible for harmful algal blooms (HABs), such as Amphidinium operculatum and Coolia monotis, significantly increased over time (days 21-28; p < 0.05). Our findings demonstrated that periphyton species, including benthic microalgae that cause HABs, can easily attach to different types of plastic and potentially spread to different regions and negatively impact these ecosystems. These observations have important implications for understanding the potential role of MPD in the spread of microalgae, including HABs, which pose a significant threat to marine ecosystems., 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 © 2024. Published by Elsevier B.V.)

Background: This study aimed to analyze the use of corticosteroids and epinephrine in neonates for the first extubation attempt and compared clinical characteristics of infants with successful and failed extubation events., Methods: This was a retrospective cohort study conducted at a single level III neonatal intensive care unit in Taiwan. The study included 215 infants born between 2020 and 2021 who had been intubated for more than 48 h before their first extubation attempt. We compared perinatal and peri-extubation characteristics and outcomes between the two groups. Successful extubation was defined as freedom from invasive ventilatory support 72 h after extubation. The relationship between corticosteroids, local epinephrine, and successful extubation was determined using multivariate logistic regression analysis., Results: In the univariate analysis, the failed extubation group received a significantly higher proportion of intravenous dexamethasone (p = 0.006) than the successful extubation group. Furthermore, the failed extubation group had a longer duration of nebulized epinephrine (p = 0.034) and more episodes of local application of epinephrine to the superior larynx (p = 0.003) than the successful extubation group. Multivariate analysis revealed that the absence of lung atelectasis, tachycardia 72 h after extubation, and lower post-extubation PCO 2 were the key factors associated with successful extubation., Conclusions: There were trends toward systemic dexamethasone, local application of epinephrine to the superior larynx, and longer duration of nebulized epinephrine in the reintubation group. However, corticosteroid or local epinephrine use was not significantly associated with successful extubation. Lung atelectasis, elevated levels of carbon dioxide, and tachycardia were identified as risk factors for extubation failure., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

This study focuses on the identification and characterization of a glycoprotein from Sargassum fusiforme (Harvey) Setchell (SFGP), as well as investigating its potential anti-inflammatory properties both in vitro and in vivo, along with the underlying mechanism. SDS-PAGE analysis revealed a prominent band with a molecular weight of <10 kDa, consisting of 58.39 % protein and 41.61 % carbohydrates, which was confirmed through glycoprotein staining and Coomassie blue staining. Various analytical techniques, including high-resolution mass spectrometry (HRMS), FTIR, amino acid analysis, and UV-visible spectrometry, provided evidence for the presence of monosaccharides (such as d-glucose and mannose) and 17 amino acids linked by an O-glycopeptide bond. In vitro and in vivo studies were conducted to assess the anti-inflammatory activities of SFGP. The results demonstrated that SFGP effectively attenuated nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in LPS-treated RAW264.7 cells. Moreover, SFGP administration significantly and dose-dependently suppressed TLR4/MyD88 signaling as well as the phosphorylation of MAPKs, IκB, and NF-κB, leading to a reduction in the production of TNF-α, IL-1β, and IL-6 in LPS-stimulated RAW264.7 cells. Furthermore, the anti-inflammatory efficacy of SFGP was validated in a carrageenan-induced inflammatory mouse model. These findings indicate that SFGP exhibits anti-inflammatory characteristics and has the potential to be utilized as a novel anti-inflammatory agent., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate the influence of gender on patient preferences during the selection of neurosurgeons., Methods: A mixed-method, cross-sectional study was conducted at Linkou Chang Gung Memorial Hospital in Taiwan, involving 60 patients. The study encompassed both structured questionnaires and in-depth interviews, administered postpatient-surgeon interactions to assess the nuanced effect of surgeon gender on patient choice. A balanced representation of both genders was ensured among the neurosurgeons involved. Thematic analysis was employed for textual data, while numeric data were analyzed using descriptive and Chi-square statistics., Results: The majority of participants (n = 40, 66.7%) expressed no preference regarding the gender of their neurosurgeon during outpatient consultations. Nonetheless, a notable fraction, predominantly female, preferred female neurosurgeons (n = 20, 33.3%). Statistical analysis highlighted a significant correlation between the gender of the patients and their preferred neurosurgeon's gender, with female patients predominantly favouring female neurosurgeons (P < 0.05). Qualitative insights indicate that, although professional skill and experience are primary factors in selecting a neurosurgeon, a latent gender preference exists, influenced by perceived privacy, empathetic care, and the surgical finesse associated with female neurosurgeons., Conclusions: Although expertise and professionalism are of paramount importance, there is a clear preference for female neurosurgeons, especially among female patients. These findings underscore the importance of recognizing and accommodating patients' preferences to ensure neurosurgical care aligns with patient comfort, expectations, and the broader movement towards gender equality., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prions, the misfolding form of prion proteins, are contagious proteinaceous macromolecules. Recent studies have shown that infectious prion fibrils formed in the brain and non-infectious fibrils formed from recombinant prion protein in a partially denaturing condition have distinct structures. The amyloid core of the in vitro-prepared non-infectious fibrils starts at about residue 160, while that of infectious prion fibrils formed in the brain involves a longer sequence (residues ∼90-230) of structural conversion. The C-terminal truncated prion protein PrP(23-144) can form infectious fibrils under certain conditions and cause disease in animals. In this study, we used cryogenic electron microscopy (cryo-EM) to resolve the structure of hamster sHaPrP(23-144) fibrils prepared at pH 3.7. This 2.88 Å cryo-EM structure has an amyloid core covering residues 94-144. It comprises two protofilaments, each containing five β-strands arranged as a long hairpin plus an N-terminal β-strand. This N-terminal β-strand resides in a positively charged cluster region (named PCC2; sequence 96-111), which interacts with the turn region of the opposite protofilaments' hairpin to stabilize the fibril structure. Interestingly, this sHaPrP(23-144) fibril structure differs from a recently reported structure formed by the human or mouse counterpart at pH 6.5. Moreover, sHaPrP(23-144) fibrils have many structural features in common with infectious prions. Whether this structure is infectious remains to be determined. More importantly, the sHaPrP(23-144) structure is different from the sHaPrP(108-144) fibrils prepared in the same fibrillization buffer, indicating that the N-terminal disordered region, possibly the positively charged cluster, influences the misfolding pathway of the prion protein., 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 © 2024 Elsevier Ltd. All rights reserved.)

Field-effect transistors (FETs) have been developed as pH sensors by using various device structures, fabrication technologies, and sensing film materials. Different transistor structures, like extended-gate (EG) FETs, floating-gate FET sensors, and dual-gate (DG) FETs, can enhance the sensor performance. In this article, we report the effects of using solution-gate and bottom-gate FET configurations on pH sensing and investigate the influence of different ionic concentrations of buffers in the measured signals. The surface charge of hafnium dioxide (HfO 2 ) affected by the buffer pH, with/without the modification of polyethylene glycol (PEG) terminated with hydroxyl groups, and the location of applied gate voltage are vital factors to the sensor performance in pH sensing. Based on the results, the solution-gate FET exhibits good pH sensitivity even in the high ionic strength solutions of bis-tris propane (BTP), and these values of pH sensitivity are close to the Nernst limit (59.2 mV/pH). In general, silane-PEG-OH modification can reduce the deviations of measured signals in pH sensing. The performance of bottom-gate FET is inferior in the BTP buffers with high ionic solutions but suitable to be operated in low ionic concentrations, such as 0.1, 1, and 10 mM BTP buffers. The size of the ions was also studied and discussed. The solution-gate FET demonstrates excellent performance under high ionic strengths, meaning a more significant potential for detecting biological molecules under physiological conditions., 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 © 2024 Elsevier B.V. All rights reserved.)

Aim: This study aimed to identify the optimal toothpaste for removing coffee-induced stains while also evaluating its impact on tooth enamel through roughness and abraded depth parameters, providing a comprehensive understanding of their effects., Materials and Methods: Three whitening toothpastes and 2 conventional toothpastes were prepared for a simulated brushing procedure on coffee-stained bovine enamel tooth specimens. Using a toothbrushing machine, up to 10,000 brushstrokes were completed, while spectrophotometric readings were taken at designated intervals. A mixed-effects model for statistical analysis determined the effects of toothpaste and brushing on colour change, roughness, and abraded depth., Results: Whitening toothpastes significantly deviated from the control (P < .001, P < .001, and P < .003, respectively), whereas the conventional toothpaste did not exhibit a significant contrast (P < .081). Regarding colour restoration following coffee staining, whitening toothpastes showed higher restoration than conventional toothpastes. Surface roughness and abraded depth parameters increased with accumulated brushing., Conclusions: Sodium hexametaphosphate-containing toothpaste demonstrated the highest efficacy in removing coffee-induced stains and restoring tooth colour. Nevertheless, this stronger whitening effect was associated with increased abrasion. While conventional toothpastes exhibited some whitening effects, the most substantial improvement in lightness was consistently observed with whitening toothpastes., Clinical Relevance: Understanding how whitening toothpaste affects enamel integrity is crucial for refining formulations and advancing dental care. This knowledge lays the groundwork for more effective oral care products and improved whitening procedures, ultimately enhancing the overall quality of dental treatments., Competing Interests: Conflict of interest None disclosed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bullous pemphigoid (BP) is an antibody-mediated blistering disease predominantly affecting the elderly. The pathogenesis involves both complement-dependent and complement-independent mechanisms. The therapeutic potential of targeting complement-independent mechanism has not yet been determined. The mainstay of treatment, corticosteroid, has many side effects, indicating the needs of better treatments., Objective: We tempted to establish an in vitro model of BP which resembles complement-independent mechanism and to examine the therapeutic potential of a novel anti-inflammatory agent, diacerein., Methods: Cultured HaCaT cells were treated with purified antibodies from BP patients, with or without diacerein to measure the cell interface presence of BP180, protein kinase C, and the production of proinflammatory cytokines. An open-label, randomized, phase 2 trial was conducted to compare topical diacerein and clobetasol ointments in patients with mild-to-moderate BP (NCT03286582)., Results: The reduced presentation of BP180 at cell interface after treating with BP autoantibodies was noticed in immunofluorescence and western blotting studies. The phenomenon was restored by diacerein. Diacerein also reduced the autoantibody-induced increase of pro-inflammatory cytokines. Reciprocal changes of BP180 and protein kinase C at the cell interface were found after treating with BP autoantibodies. This phenomenon was also reversed by diacerein in a dose-dependent manner. The phase 2 trial showed that topical diacerein reduced the clinical symptoms which were comparable to those of topical clobetasol., Conclusion: Diacerein inhibited BP autoantibody-induced reduction of BP180 and production of proinflammatory cytokines in vitro and showed therapeutic potential in patients with BP. It is a novel drug worthy of further investigations., Competing Interests: Declaration of Competing Interest Ms. Lee JY was an employee of Twi Biotechnology., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Objectives: WHO has recommended same-day antiretroviral therapy (SDART) initiation since 2017; however, higher attrition rates were noted in developing countries., Methods: We included newly diagnosed people with HIV (PWH) from 2018 to 2022 at 18 hospitals around Taiwan. SDART initiation was defined as starting ART on the same day of HIV diagnosis and rapid initiation as starting ART within 14 days of diagnosis. A composite unfavorable outcome was defined as death after 30 days of diagnosis, loss to follow-up (LTFU), or virologic failure or rebound at 12 months., Results: At 12 months, PWH on SDART initiation and those on rapid ART initiation showed similar rates of engagement in care with plasma HIV-1 RNA <50 copies/mL (87.5% vs 87.7%) and composite unfavorable outcome (7.7% vs 7.7%). PWH aged >30 years were less likely to have LTFU (aHR 0.44, 95% CI 0.28-0.70). PWH aged >30 years (aHR 0.59, 95% CI 0.41-0.85) and gay, bisexual, and men who have sex with men (GBMSM) (aHR 0.50, 95% CI 0.32-0.79) were less likely to have composite unfavorable outcomes., Conclusions: SDART and rapid ART initiation resulted in comparable clinical outcomes and viral suppression rates. PWH aged >30 years and GBMSM were less likely to have unfavorable outcomes., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polycyclic aromatic hydrocarbons (PAHs) are known to be representative carcinogenic environmental pollutants with high toxicity. However, information on the potential ecological and environmental risks of PAH contamination in soil remains scarce. Thus, this study was evaluated the potential ecological risks of PAHs in soils of five Korean areas (Gunsan (GS), Gwangju, Yeongnam, Busan, and Gangwon) using organic carbon (OC)-normalized analysis, mean effect range-median quotient (M-ERM-Q), toxic equivalent quantity (TEQ) analysis, and risk quotient (RQ) derived by the species sensitivity distribution model. In this study, atmospheric particulate matter has a significant effect on soil pollution in GS through the presence of hopanes and the similar pattern of PAHs in soil and atmospheric PAHs. From analysis of source identification, combustion sources in soils of GS were important PAH sources. For PAHs in soils of GS, the OC-normalized analysis, M-ERM-Q, and TEQ analysis have 26.78 × 10 5 ng/g-OC, 0.218, and 49.72, respectively. Therefore, the potential ecological risk assessment results showed that GS had moderate-high ecological risk and moderate-high carcinogenic risk, whereas the other regions had low ecological risk and low-moderate carcinogenic risk. The risk level (M-ERM-Q) of PAH contamination in GS was similar to that in Changchun and Xiangxi Bay in China. The Port Harcourt City in Nigeria for PAH has the highest risk (M-ERM-Q = 4.02 and TEQ = 7923). Especially, compared to China (RQ Phe =0.025 and 0.05), and Nigeria (0.059), phenanthrene showed the highest ecological risk in Korea (0.001-0.18). Korea should focus on controlling the release of PAHs originating from the PM in GS., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes., Objective: The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users., Methods: This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression., Results: Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95-4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44-3.66)., Conclusion: More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP., Competing Interests: Disclosures All authors have no conflicts to disclose., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: In 2016 we reported promising midterm outcomes of bicuspid pulmonary valve replacement using 0.1-mm polytetrafluoroethylene (PTFE) membrane. This follow-up study analyzes long-term outcomes and risk factors for reintervention and structural valve deterioration (SVD)., Methods: We performed a retrospective review of the original 119 patients who underwent PTFE bicuspid pulmonary valve replacement. Median patient age was 16.9 years (range, 0.4-57.1). Reintervention was defined as any surgical or percutaneous catheter procedure on the PTFE valve. SVD was defined as development of a peak pressure gradient ≥ 50 mm Hg or at least a moderate amount of pulmonary regurgitation on follow-up echocardiography., Results: The median follow-up duration was 9.5 years. The survival rate was 96.5% at 5 and 10 years, with 2 early and 2 late mortalities. Freedom from reintervention was 90.0% at 5 years and 63.3% at 10 years. Freedom from SVD was 92.8% at 5 years and 51.1% at 10 years, with regurgitation the predominant mode (64.6%). Freedom from both reintervention and SVD at 5 and 10 years were 89.1% and 49.5%, respectively. Multivariable analysis identified smaller valve diameter (hazard ratio, 0.82; P < .001) and more than trivial pulmonary regurgitation at discharge (hazard ratio, 5.81; P < .001) as risk factors for reintervention or SVD., Conclusions: Long-term results of the PTFE bicuspid pulmonary valve replacement were acceptable. However, improvements may be needed to reduce technical error and improve durability. Smaller valve diameter and more than trivial pulmonary regurgitation at discharge were risk factors for reintervention or SVD, warranting careful follow-up for timely reintervention., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Platelets are generated from megakaryocytes (MKs), mainly located in the bone marrow (BM). Megakaryopoiesis can be affected by genetic disorders, metabolic diseases, and aging. The molecular mechanisms underlying platelet count regulation have not been fully elucidated., Objectives: In the present study, we investigated the role of thioredoxin-interacting protein (TXNIP), a protein that regulates cellular metabolism in megakaryopoiesis, using a Txnip -/- mouse model., Methods: Wild-type (WT) and Txnip -/- mice (2-27-month-old) were studied. BM-derived MKs were analyzed to investigate the role of TXNIP in megakaryopoiesis with age. The global transcriptome of BM-derived CD41 + megakaryocyte precursors (MkPs) of WT and Txnip -/- mice were compared. The CD34 + hematopoietic stem cells isolated from human cord blood were differentiated into MKs., Results: Txnip -/- mice developed thrombocytopenia at 4 to 5 months that worsened with age. During ex vivo megakaryopoiesis, Txnip -/- MkPs remained small, with decreased levels of MK-specific markers. Critically, Txnip -/- MkPs exhibited reduced mitochondrial reactive oxygen species, which was related to AKT activity. Txnip -/- MkPs also showed elevated glycolysis alongside increased glucose uptake for ATP production. Total RNA sequencing revealed enrichment for oxidative stress- and apoptosis-related genes in differentially expressed genes between Txnip -/- and WT MkPs. The effects of TXNIP on MKs were recapitulated during the differentiation of human cord blood-derived CD34 + hematopoietic stem cells., Conclusion: We provide evidence that the megakaryopoiesis pathway becomes exhausted with age in Txnip -/- mice with a decrease in terminal, mature MKs that response to thrombocytopenic challenge. Overall, this study demonstrates the role of TXNIP in megakaryopoiesis, regulating mitochondrial metabolism., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to compare fracture characteristics and functional outcomes between patients with proximal humerus fractures with and without initial varus displacement., Methods: A retrospective review of 325 patients with proximal humerus fractures was performed. Patients with initial varus displacement were placed in Varus cohort and were age- and sex-matched 1:1 with a second cohort presenting proximal humerus fractures without varus displacement, referred to as Fracture cohort. Varus fracture displacement was defined when the most proximal aspect of humeral head was below the most proximal aspect of greater tuberosity on initial radiographs, and the head shaft angle was <130°., Results: There were 60 patients in V cohort and 60 patients in F cohort. Statistical analysis revealed that there were significant differences in initial horizontal offset (38.8 vs. 45.9 mm), initial anterior angulation angle (36.5° vs. 16.4°), postoperative head shaft angle (132.2° vs. 141.3°), last head shaft angle (122.2° vs. 138.5°), difference for head shaft angles (10.0° vs. 2.7°), postoperative horizontal offset (43.4 vs. 45.3 mm), last horizontal offset (38.4 vs. 42.8 mm), difference for offsets (4.9 vs. 2.5 mm), complications (15 vs. 7 cases), and revision surgery (7 vs. 1 case) between two cohorts. Overall satisfactory results were achieved in most patients regardless of varus displacement, pain-VAS and Constant scores in V cohort were inferior to the scores in F cohort. The cut-off value of postoperative head shaft angle for good/excellent outcomes was 135.5° using receiver operating characteristic curve analyses., Conclusion: Varus displaced proximal humerus fractures were accompanied by decreased horizontal offset and increased anterior angulation angle, and had a course of more varization and horizontal shortening compared with those without initial varus displacement. Patients with varus displaced fractures were associated with worse functional outcomes, and these factors might affect functional outcomes., Level of Evidence: Prognostic, cohort study, Level III., Competing Interests: Declaration of competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2024. Published by Elsevier B.V.)