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Background and Aims: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate the effect of treatment with aficamten on biomarker concentrations., Methods: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and evaluated whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity., Results: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% confidence interval 76%-83%, P < .001) and hs-cTnI by 41% (95% confidence interval 32%-49%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. N-Terminal pro-B-type natriuretic peptide reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints., Conclusions: N-Terminal pro-B-type natriuretic peptide and hs-cTnI concentrations are associated with key variables in obstructive hypertrophic cardiomyopathy. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM., Methods: The Olink antibody-based proteomic platform was used to measure plasma proteins in patients with genotype positive (sarcomeric) HCM participating in the HCM Registry. We assessed associations between plasma protein levels with clinical features, cardiac magnetic resonance imaging metrics, and the development of atrial fibrillation., Results: We measured 275 proteins in 701 patients with sarcomeric HCM. There were associations between late gadolinium enhancement with proteins reflecting neurohormonal activation (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and ACE2 [angiotensin-converting enzyme 2]). Metrics of left ventricular remodeling had novel associations with proteins involved in vascular development and homeostasis (vascular endothelial growth factor-D and TM [thrombomodulin]). Assessing clinical features, the European Society of Cardiology sudden cardiac death risk score was inversely associated with SCF (stem cell factor). Incident atrial fibrillation was associated with mediators of inflammation and fibrosis (MMP2 [matrix metalloproteinase 2] and SPON1 [spondin 1])., Conclusions: Proteomic profiling of sarcomeric HCM identified biomarkers associated with adverse imaging and clinical phenotypes. These circulating proteins are part of both established pathways, including neurohormonal activation and fibrosis, and less familiar pathways, including endothelial function and inflammatory proteins less well characterized in HCM. These findings highlight the value of plasma profiling to identify biomarkers of risk and to gain further insights into the pathophysiology of HCM.

Background: An improved understanding of the natural history in NYHA functional class I patients with obstructive hypertrophic cardiomyopathy (oHCM) is needed., Objectives: Using a multicenter registry (SHaRe [Sarcomeric Human Cardiomyopathy Registry]), this study described the natural history in patients with oHCM who were classified as NYHA functional class I at the initial visit compared with patients classified as NYHA functional class II and reported baseline characteristics associated with incident clinical events., Methods: Incident events assessed included a composite of NYHA functional class III to IV symptoms, left ventricular ejection fraction <50%, atrial fibrillation, stroke, ventricular arrhythmias, septal reduction therapy, ventricular assist device or transplantation, or death. Factors associated with incident events were determined using Kaplan-Meier, Cox proportional hazards, and restricted cubic spline models., Results: Of 7,964 patients with HCM in SHaRe, 1,239 patients with oHCM met inclusion criteria; 598 were in NYHA functional class I at the initial visit (age 48 ± 17 years; 31.1% female; peak gradient, 75 ± 40 mm Hg). At 5-year follow-up, the composite event rate of NYHA functional class I patients was 28% compared with 44% (P < 0.001) in 641 NYHA functional class II patients with oHCM (age 54 ± 16 years; 46.5% female; peak gradient, 83 ± 39 mm Hg). Left atrial (LA) diameter ≥45 mm (HR: 1.56 [95% CI: 1.14-2.12]; P = 0.005), female sex (HR: 1.61 [95% CI: 1.16-2.24]; P = 0.003), and older age (HR: 1.21 per 10 years [95% CI: 1.09-1.34]; P < 0.001), but not the magnitude of left ventricular outflow tract obstruction, were associated with a higher risk of the composite outcome in NYHA functional class I patients., Conclusions: Although NYHA functional class I patients with oHCM fared better than NYHA functional class II patients, more than one-fourth experienced adverse events over 5-year follow-up, especially if they were older, female, and/or had LA enlargement. Strategies to reduce the rate of clinical outcomes in NYHA functional class I patients warrant further study., Competing Interests: Funding Support and Author Disclosures Funding for SHaRe has been provided through an unrestricted research grant from Bristol Myers Squibb. Bristol Myers Squibb had no role in approving the content of this manuscript. This work was also supported by the Sir Jules Thorn Charitable Trust [21JTA], the Medical Research Council (UK), the British Heart Foundation [RE/18/4/34215], and the National Institutes of Health R Imperial College Biomedical Research Centre. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising. Dr Ahluwalia has received modest consulting income from Bristol Myers Squibb. Dr Olivotto has received research grants from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire Takeda, Menarini international, Chiesi, Boston Scientific; and has received consulting income from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire Takeda, Chiesi, Boston Scientific, Tenaya, Rocket Pharma, and Lexeo. Dr Owens has received consulting fees from Bristol Myers Squibb, Cytokinetics, Pfizer, Edgewise, Stealth, Lexeo, Lexicon, Tenaya, and BioMarin; and has received research funds from Bristol Myers Squibb. Dr Ware has received research support from Bristol Myers Squibb; and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics. Dr Ho has received consulting fees and unrestricted research funding from Bristol Myers Squibb (MyoKardia), Pfizer, Cytokinetics, BioMarin, Tenaya, Lexicon, and Viz.ai. Dr Lakdawala has received consulting income from Bristol Myers Squibb, Pfizer, Cytokinetics, Tenaya, and Akros; and has received research support from Bristol Myers Squibb and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Background: Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined., Methods: Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome., Results: Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P <0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P <0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P <0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction., Conclusions: Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF., Competing Interests: Dr Ho is supported by funding from the National Institutes of Health (National Heart, Lung, and Blood Institute grant R01HL155568). Dr Day is supported by funding from the National Institutes of Health (National Heart, Lung, and Blood Institute grants R01 HL167524, R01 HL168841, and R61/R33 HL164376), Lexicon Pharmaceuticals, and the American Heart Association. Dr Ware is supported by the Wellcome Trust (grant 107469/Z/15/Z) and the UK Medical Research Council. Dr Scemsarian is the recipient of a National Health and Medical Research Council investigator grant (grant 2016822) and a New South Wales Health cardiovascular disease clinician scientist grant. Dr Ingles is the recipient of a National Heart Foundation of Australia future leader fellowship grant (grant 106732) and receives research grant support from Bristol Myers Squibb. Dr Reza is supported by funding from the National Institutes of Health (National Heart, Lung, and Blood Institute grant K23HL166961). Dr I. Olivotto has received grants from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, Bayer, Boston Scientific, and Menarini International; fees (honoraria or consulting) from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, and Boston Scientific; and served or is serving as principal investigator for EXPLORER‐HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), MAVA‐LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM), REDWOOD‐HCM (Randomized Evaluation of Dosing With CK-3773274 in Obstructive Outflow Disease in HCM), REDWOOD‐OLE (REDWOOD‐HCM Open Label Extension), and SEQUOIA‐HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM). Dr Maurizi has received fees (honoraria or consulting) from Bristol Myers Squibb. Dr Ho receives research funding from the National Institutes of Health and has received unrestricted research funding or consulting fees from Bristol Myers Squibb, Cytokinetics, Pfizer, Tenaya, Biomarin, viz.AI, and Lexicon Pharmaceuticals. Dr Lakdawala receives research funding from BMS and Pfizer and modest consulting incomes from BMS, Pfizer, Alexion, Tenaya, Akros, Neuvocor, and Cytokinetics. Dr Stendahl serves or has served as site principal investigator for MAVA-LTE, PIONEER-OLE (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction Open-Label Extension), and VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy), and serves or has served as site subinvestigator for ACACIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM), FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in HCM), MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), and SEQUOIA-HCM.

Oat is a minor forage crop grown in Taiwan. Only a few historical records of oat rust disease have been reported in the country. Therefore, the pathogen population remains poorly characterized. A rust-like disease outbreak was detected at the Experimental Farm of National Taiwan University in 2019, which caused significant damage to field experiments. To determine the identity of the pathogen responsible for this disease outbreak, we collected infected foliar material. Disease signs suggested infection by the oat crown rust fungus. Hence, common procedures in rust pathology were applied to confirm the identity of the pathogen with phenotypic and molecular diagnostic techniques. A total of 50 field pathogen samples from infected oat cultivars were collected in 2019 and five single pustule rust isolates were obtained in 2020 and 2021. These isolates were initially identified as Puccinia coronata var. avenae f. sp. avenae ( Pca ) based on the phylogenetic analysis of nrITS sequence data. This identification was subsequently confirmed through whole-genome phylogeny, which showed that the representative Taiwanese isolate NTU1 clustered with other Pca representative strains in Basidiomycota. Phenotyping assays across 36 oat differential lines demonstrated that Taiwanese isolates are phenotypically similar with relatively low virulence. This study presents the first molecular confirmation of Pca in Taiwan and reports the virulence profiles of Taiwanese Pca population.

Background: A combination treatment of surgery, chemotherapy, and radiotherapy can improve the survivals of pediatric patients with Ewing sarcoma (ES). However, prognosis remains poor for patients with metastatic disease at diagnosis or recurrence. Other high-risk (HR) features include large tumor burden, tumors of the axial skeleton and poor histologic response. Several studies have documented high dose chemotherapy with autologous stem cell rescue (HDC-ASCR) to be effective in such patients. In this retrospective study, we present the results of HDC-ASCR for high-risk Ewing sarcoma in children and young adults in a single institute., Methods: From March 2004 to March 2021, patients with ES, Ewing-like sarcoma, or round cell sarcoma received HDC-ASCR as part of treatment were included. The patients' characteristics, disease status, stem cell dose, engraftment status, post-transplant complications, and outcomes were analyzed., Results: Twenty patients receiving HDC-ASCR at complete response (n = 6), partial response (n = 13), and stable disease (n = 1) were enrolled. The male to female ratio was 11:9. Median age at diagnosis and transplant was 15.6 years old (range: 3.3-28.9) and 16.2 (range: 4.2-29.9), respectively. The conditioning regimens included ifosfamide-based in two and melphalan-based in 19. All patients achieved successful engraftment without tansplant-related mortality. The 5-year progression-free and overall survival (OS) rate were 35% and 54.5%, respectively. The causes of death (n = 8) were all contributed to disease progression. Patients in the complete response group or with localized HRES exhibited a higher 5-year OS (p = 0.047 and 0.05, respectively). Compared to the historical cohort without HDC-ASCR as part of primary treatment, the current cohort had a significantly better 5-year OS (p = 0.018)., Conclusion: HDC-ASCR seems promising as an alternative treatment for HRES in improving OS in this retrospective study with limited case number., Competing Interests: Conflicts of interest: Dr. Po-Kuei Wu and Dr. Wei-Ming Chen, editorial board member at the Journal of the Chinese Medical Association, had no role in the peer review process or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Background: Scabies is typically treated with scabicides like lindane, which poses a risk for acute neural toxicity. Lindane's prolonged use, particularly in agriculture, is linked to neurodegenerative diseases, including Parkinson's disease (PD), the second most common neurodegenerative disorder. This study aimed to evaluate whether scabies patients, particularly those treated with topical lindane, are at increased risk of developing PD., Methods: A nationwide population-based cohort study was conducted using data from Taiwan's National Health Research Institutes claims database from 2000 to 2018. The study included 27,173 patients with scabies, matched to a control group, with both groups followed for up to 18 years. The primary outcome was the incidence of newly diagnosed PD, and the hazard ratio (HR) for PD was calculated, focusing on those treated with topical lindane., Results: Among the 54,346 patients, 1639 (3.0%) were newly diagnosed with PD, with 993 (60.6%) from the scabies group and 646 (39.4%) from the control group. Scabies patients had an adjusted hazard ratio (aHR) of 1.46 (95% CI 1.32-1.63) for developing PD compared to controls. However, patients treated with topical lindane had a significantly lower aHR for PD at 0.15 (95% CI 0.12-0.19; p < 0.001), with a lower cumulative incidence of PD also observed in this group ( p < 0.001)., Conclusions: Scabies patients are at a 1.46-fold increased risk of developing PD, but those treated with lindane exhibit a significantly lower risk, suggesting potential protective effects of lindane against PD.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aβ axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Autologous peripheral blood stem cell (PBSC) transplantation is crucial in pediatric cancer treatment, and tandem transplantation is beneficial in certain malignancies. Collecting PBSCs in small children with low body weight is challenging. We retrospectively analyzed data of pediatric cancer patients weighing <15 kg who underwent autologous PBSC harvesting in our hospital. Collections were performed in the pediatric intensive care unit over 2 or 3 consecutive days, to harvest sufficient stem cells (goal ≥2 × 10 6 CD34 + cells/kg per apheresate). From April 2006 to August 2021, we performed 129 collections after 50 mobilizations in 40 patients, with a median age of 1.9 (range, 0.6-5.6) years and a body weight of 11.0 (range, 6.6-14.7) kg. The median CD34 + cells in each apheresate were 4.2 (range, 0.01-40.13) × 10 6 /kg. 78% and 56% of mobilizations achieved sufficient cell dose for single or tandem transplantation, respectively, without additional aliquoting. The preapheresis hematopoietic progenitor cell (HPC) count was highly correlated with the CD34 + cell yield in the apheresate (r = 0.555, P < 0.001). Granulocyte colony-stimulating factor alone was not effective for mobilization in children ≥2 years of age, even without radiation exposure. By combining the preapheresis HPC count ≥20/μL and the 3 significant host factors, including age <2 years, no radiation exposure and use of chemotherapy, the prediction rate of goal achievement was increased (area under the curve 0.787)., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Athletes commonly use compression garments (CGs) for perceived effectiveness in preventing injury occurrence. However, limited evidence is available on whether lower-limb CGs reduce the risk of injury. This study aimed at (1) evaluating the effects of CGs on mitigating the risk factors of cutting-related knee injuries; (2) identifying undesirable side-effects of CGs on other joints and cutting performance; and (3) identifying possible interactions between sex and condition. 62 healthy adults performed pre-planned 90˚ cutting tasks under four conditions: control, knee sleeves, placebo leggings and stiffness-altered leggings. Joint angle at initial contact, range of motion, moments, and ground reaction force were measured. A mixed two-way (sex*condition) ANOVA was performed, followed by post-hoc comparisons and subset analyses for sexes. Results showed that the leggings restricted hip sagittal (45.4 ± 1.3 vs. control 50.0 ± 1.3˚, p = 0.001) and rotational (16.8 ± 0.8 vs. control 22.5 ± 1.1˚, p < 0.001) motion. At initial contact, the stiffness-altered leggings reduced knee valgus (0.4 ± 0.8 vs. control -2.1 ± 0.8˚, p = 0.031). However, the altered alignment of lower-limb joints did not reduce multiplanar knee joint moments (p > 0.05). CGs were not effective protective equipment yet. There was no significant difference between knee sleeves and control, nor between leggings conditions (p > 0.05). Force plate measurements, such as increased rate of force development (stiffness-altered 42.6 ± 1.1 & placebo 42.9 ± 1.1 vs. control 39.9 ± 1.0 BW/s, p < 0.028), implied the possibility of performance enhancement through CGs. While further investigations on the optimal compression and stiffness alterations are warranted, athletes are recommended to be aware of the discrepancies between the claimed and actual biomechanical effects of CGs., 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.)

This study introduced a novel cross-hydroalkenylation approach for addressing a resilient challenge in C5- exo -selective norbornene derivative functionalization. The process, guided by mutual interactions among the NHC-Ni catalyst and the substrate pairs, ensured highly chemo- and regio-selective insertion.

Purpose: Misdiagnosis or delayed diagnosis of paravertebral and/or iliopsoas abscess (PVIPA) has been frequently reported to be associated with unfavorable prognosis. We aimed to develop a scoring algorithm that can easily and accurately identify patients at greater risk for PVIPA among individuals with community-onset bloodstream infections., Methods: In a multicenter, retrospective cohort study, the score was developed with the first four study years and validated with the remaining two years. Applying logistic regression, the score values of prediction determinants were derived from the adjusted odds ratios (AOR). The performance of the scoring algorithm was assessed with the receiver operating characteristic (ROC) curve., Results: In the derivation (3869 patients) and validation (1608) cohorts, patients with PVIPA accounted for 1.7% and 1.4%, respectively. In the derivation cohort, five independent predictors of PVIPA were recognized using multivariable analyses: time-to-defervescence > 5 days (AOR, 7.00; 2 points), Panton-Valentine Leukocidin (PVL)-producing Staphylococcus aureus (AOR, 5.98; 2 points), intravenous drug users (AOR, 2.60; 1 points), and comorbid hemato-oncology (AOR, 0.41; -1 point) or liver cirrhosis (AOR, 2.56; 1 points). In the derivation and validation cohorts, areas under ROC curves (95% confidence intervals) of the prediction algorithm are 0.83 (0.77-0.88) and 0.85 (0.80-0.90), and a cutoff score of + 2 represents sensitivity of 83.3% and 95.7%, specificity of 68.6% and 67.7%, positive predictive values of 4.4% and 4.1%, and negative predictive values of 99.6% and 99.9%, respectively., Conclusions: Of a scoring algorithm with substantial sensitivity and specificity in predicting PVIPA, PVL-producing S. aureus and Time-to-defervescence > 5 days were crucial determinants., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Tracheal squamous cell carcinoma is a rare and potentially fatal thoracic cancer mimicking common airway disorders. Accurate diagnosis requires a detailed history, thorough physical examination, and high clinical suspicion., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: Pediatric CKD is associated with a high risk of cardiovascular disease (CVD). Early detection of subclinical CVD in childhood CKD can be achieved through various cardiovascular (CV) assessments, including carotid intima-media thickness (cIMT), ambulatory blood pressure monitoring (ABPM), and arterial stiffness indices. Lactoferrin (LF), a key functional glycoprotein found in breast milk, has been linked to several diseases and has potential as a biomarker., Methods: In our study of 102 children with CKD stages G1-G4, we explored the relationship between LF and CV risk markers., Results: We found that LF concentration was not related to the severity or underlying causes of childhood CKD, but was positively correlated with overweight/obesity. Lower LF levels were correlated with increased cIMT and elevated arterial stiffness indices. Notably, abnormalities in ABPM profiles were observed in up to 60% of the children with CKD, with low LF levels linked to nighttime hypertension, nocturnal non-dipping, and ABPM abnormalities., Conclusions: In conclusion, LF shows promise as a biomarker for detecting subclinical CVD in children with CKD. Its potential utility in early detection could be instrumental in guiding timely interventions and improving long-term CV outcomes, although further research is needed to clarify the underlying mechanisms.

Background: Deep neck infection (DNI) involves the deep neck spaces and may lead to airway compromise. An intensive care unit (ICU) is a specialized unit of the hospital that provides intensive care. ICU care is required for patients with severe DNI, although the risk factors for need of ICU care in patients with DNI have not been investigated. Methods: The clinical and laboratory parameters of 350 patients aged >18 years who were diagnosed with DNI between October 2018 and October 2023 were evaluated. Of these patients, 62 were transferred to the ICU. Univariate and multivariate analyses were applied to assess the risk factors for need of ICU care. Results: Univariate analysis revealed that older age [odds ratio (OR) = 1.0324, 95% confidence interval (CI): 1.0155-1.0496, P = .0001], a higher C-reactive protein (CRP) level (OR = 1.0076, 95% CI: 1.0049-1.0103, P < .0001), and blood glucose level (OR = 1.0057, 95% CI: 1.0023-1.0091, P = .0011), involvement ≥3 spaces (OR = 2.2366, 95% CI: 1.2827-3.8998, P = .0046), and mediastinitis (OR = 4.7134, 95% CI: 2.3537-9.4391, P < .0001) were significant risk factors for ICU transfer in patients with DNI. In multivariate analysis, older age (OR = 1.0216, 95% CI: 1.0032-1.0403, P = .0210), higher CRP level (OR = 1.0063, 95% CI: 1.0033-1.0092, P < .0001), and mediastinitis (OR = 2.6103, 95% CI: 1.1974-5.6905, P = .0158) were independent risk factors of ICU transfer in patients with DNI. The ICU group had a longer hospital stay (23.98 ± 8.53 vs 7.44 ± 4.24, P < .0001) and higher rate of tracheostomy ( P < .0001) than the non-ICU group. However, there were no significant differences in the rate of incision and drainage open surgery or pathogens between the groups (all P > .05). Conclusions: Elder patients and those with advanced CRP levels and mediastinitis are more likely to be transferred to the ICU, leading to prolonged hospital stays and a higher risk of tracheostomy. Clinicians should assess the patient's need for ICU transfer and timely manage the airway according to the aforementioned laboratory parameters and complications carefully., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: Myelin maturation occurs in late fetal life to early adulthood, with the most rapid changes observed in the first few years of infancy. To quantify the degree of myelination, a specific MR imaging sequence is required to measure the changes in tissue proton relaxivity (R1). R1 positively correlates with the degree of myelination maturation at a given age. Similar to head circumference charts, these data can be used to develop normal growth charts for specific white matter tracts to detect pathologies involving abnormal myelination., Materials and Methods: This is a cross-sectional study using normal clinical pediatric brain MR images with the MP2RAGE sequence to generate T1 maps. The T1 maps were segmented to 75 brain regions from a brain atlas (white matter and gyri). Statistical modeling for all subjects across regions and the age range was computed, and estimates of population-level percentile ranking were computed to describe the effective myelination rate as a function of age. Test-retest analysis was performed to assess reproducibility. Logistic trendline and regression were performed for selected white matter regions and plotted for growth charts., Results: After exclusion for abnormal MR imaging or diseases affecting myelination from the electronic medical record, 103 subject MR images were included, ranging from birth to 17 years of age. Test-retest analysis resulted in a high correlation for white matter ( r  = 0.88) and gyri ( r  = 0.95). All white matter regions from the atlas had significant P values for logistic regression with R 2 values ranging from 0.41 to 0.99., Conclusions: These data can serve as a myelination growth chart to permit patient comparisons with normal levels with respect to age and brain regions, thus improving detection of developmental disorders affecting myelin., (© 2024 by American Journal of Neuroradiology.)

A weak van der Waals (vdW) force in layered materials enables their isolation into thin flakes through mechanical exfoliation while sustaining their intrinsic electronic and optical properties. Here, we introduce a universal roll-printing method capable of producing vdW multilayer films on wafer-to-meter scale. This process uses sequential exfoliation and transfer of layered materials from the powder sources to target substrates through a repeated rolling of a cylindrical metal drum. We achieve uniformly coated films with a library of vdW powders on various mechanically rigid and flexible substrates. The printed films are configured into different devices including light-emitting diodes and photodetectors. The presented technique offers substantial benefits in terms of cost efficiency and a low thermal budget while offering high material quality.

While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances., (© 2024. The Author(s).)

Objectives: Descending necrotizing mediastinitis (DNM) developing after deep neck infection (DNI) is a potentially lethal disease of the mediastinum with a mortality rate as high as 40% prior to the 1990s. No standard treatment protocol is available. Here, we present the outcomes of our multidisciplinary approaches for treating DNM originating from a DNI., Methods: Between June 2016 and July 2021, there were 390 patients with DNIs admitting to our tertiary hospital. A total 21 patients with DNIs complicated with DNM were enrolled. The multidisciplinary approaches included establishment of airway security, appropriate surgery and antibiotics, extracorporeal membrane oxygenation, and intensive care unit management. The clinical variables were analyzed., Results: Two patients died and 19 survived (mortality 9.5%). The patients who died had a higher mean C-reactive protein (CRP) level than did those who survived (420.0 ± 110.3 vs 221.8 ± 100.6 mg/L) (P = .038). The most common pathogens were Streptococcus constellatus and Streptococcus anginosus. From 2001 to 2021, the average mortality rate of studies enrolling more than 10 patients was 16.1%., Conclusion: Multidisciplinary approaches, early comprehensive medical treatment, and co-ordination among departments significantly reduce mortality. Patients with severe inflammation and high CRP levels require intensive and aggressive interventions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours., Methods: A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included., Results: Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated., Conclusion: Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms., (© 2023 John Wiley & Sons Ltd.)

Background: Recent studies document the rising prevalence of common ownership by institutional investors in specific industries. Those investors offer products, such as mutual and index funds, to trade securities on behalf of others and often own shares of multiple firms in the same industry to diversify portfolios. However, at present, few studies focus on common ownership trends in health care., Objectives: This paper examines institutional investors' common ownership in the major insurers offering plans in the Medicare Part D stand-alone prescription drug plan (PDP) market between 2013 and 2020., Research Design: Using data from the Securities and Exchange Commission (SEC) database and the Center for Research in Securities Prices, we compute the percentages of outstanding shares of each insurer owned by institutional investors. Data visualization and network analysis are employed to assess the trends in common ownership among major insurers., Results: We document a high prevalence of and substantial increase in shared institutional investors in the PDP market. From 2013 to 2020, the degree of common ownership increased by 7% on average, and the common ownership network became more connected. Common ownership also varies across the 34 PDP regions depending on their reliance on listed insurers, that are traded in the stock exchange, offering stand-alone PDPs., Conclusions: High and rising common ownership in the Medicare Part D PDP market raises policy questions about potential effects on plan offerings, premiums, and quality for consumers., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The lean soft tissue mass (LSTM) of the limbs is approximately 63% of total skeletal muscle mass. For athletes, measurement of limb LSTM is the basis for rapid estimation of skeletal muscle mass. This study aimed to establish the estimation equation of LSTM in Asian athletes using bioelectrical impedance analysis (BIA)., Methods: A total of 198 athletes (121 males, 77 females; mean age 22.04 ± 5.57 years) from different sports in Taiwan were enrolled. A modeling group (MG) of 2/3 (n = 132) of subjects and a validation group (VG) of 1/3 (n = 68) were randomly assigned. Using the InBody S-10, resistance and reactance were measured at 50 kHz from the right palm to the right sole while the participant was in the supine position. Predictor variables were height (h), weight (W), age, Sex, Xc, resistance index (RI; RI = h2 / R). LSTM of arms and legs measured by dual-energy X-ray absorptiometry (DXA) was the response variable. Multivariate stepwise regression analysis method was used to establish BIA estimation equations as ArmsLSTMBIA-Asian and LegsLSTMBIA-Asian. Estimation equations performance was confirmed by cross-validation., Results: Estimation equation "ArmsLSTMBIA-Asian = 0.096 h2/R- 1.132 Sex + 0.030 Weight + 0.022 Xc- 0.022 h + 0.905, r2 = 0.855, SEE = 0.757 kg, n = 132" and "LegsLSTMBIA Asian = 0.197h2/R" + 0.120 h- 1.242 Sex + 0.055 Weight- 0.052 Age + 0.033 Xc -16.136, r2 = 0.916, SEE = 1.431 kg, n = 132" were obtained from MG. Using DXA measurement results of VG for correlation analysis and Limit of Agreement (LOA) of Bland-Altman Plot, ArmsLST is 0.924, -1.53 to 1.43 kg, and LegsLST is 0.957, -2.68 to 2.90 kg., Conclusion: The established single-frequency BIA hand-to-foot (whole body) estimation equation quickly and accurately estimates LSTM of the arms and legs of Asian athletes., Competing Interests: The authors have read the journal’s policy and have the following competing interests: Dr. Kuen-Chang Hsieh was employed by a commercial company, StarBIA Meditek Co. Ltd., during this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare. All other authors have no conflicts of interest to declare. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright: © 2024 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pathogenic variation in genes encoding proteins of the cardiac sarcomere is responsible for 30%-40% of cases of hypertrophic cardiomyopathy. The main clinical utility of genetic testing is to provide diagnostic confirmation and facilitation of family screening. It also assists in the detection of aetiologies, which require distinct monitoring and treatment approaches. Other clinical applications, including the use of genetic information to inform risk prediction models, have been limited by the challenge of establishing robust genotype-phenotype correlations with actionable consequences, but new data on the interaction between rare and common genetic variation, as well as the emergence of therapies targeting disease-specific pathogenic mechanisms, herald a new era for genetic testing in routine practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca 2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including ECG abnormalities, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory., Competing Interests: The views expressed in this article are those of the authors who declare that they have no conflict of interest, except for Dr Moon who is the chief executive officer of MyCardium AI and has served on advisory boards for Genzyme and Sanofi.

Background: The health-related quality of life (HRQOL) and cardiopulmonary exercise testing (CPET) performance of individuals with subclinical and early stage hypertrophic cardiomyopathy (HCM) have not been systematically studied. Improved understanding will inform the natural history of HCM and factors influencing well-being., Methods: VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) participants with early stage sarcomeric HCM (primary analysis cohort) and subclinical HCM (sarcomere variant without left ventricular hypertrophy comprising the exploratory cohort) who completed baseline and year 2 HRQOL assessment via the pediatric quality of life inventory and CPET were studied. Metrics correlating with baseline HRQOL and CPET performance were identified. The impact of valsartan treatment on these measures was analyzed in the early stage cohort., Results: Two hundred participants were included: 166 with early stage HCM (mean age, 23±10 years; 40% female; 97% White; and 92% New York Heart Association class I) and 34 subclinical sarcomere variant carriers (mean age, 16±5 years; 50% female; and 100% White). Baseline HRQOL was good in both cohorts, although slightly better in subclinical HCM (composite pediatric quality of life score 84.6±10.6 versus 90.2±9.8; P =0.005). Both cohorts demonstrated mildly reduced functional status (mean percent predicted peak oxygen uptake 73±16 versus 78±12 mL/kg per minute; P =0.18). Percent predicted peak oxygen uptake and peak oxygen pulse correlated with HRQOL. Valsartan improved physical HRQOL in early stage HCM (adjusted mean change in pediatric quality of life score +4.1 versus placebo; P =0.01) but did not significantly impact CPET performance., Conclusions: Functional capacity can be impaired in young, healthy people with early stage HCM, despite New York Heart Association class I status and good HRQOL. Peak oxygen uptake was similarly decreased in subclinical HCM despite normal left ventricular wall thickness and excellent HRQOL. Valsartan improved physical pediatric quality of life scores but did not significantly impact CPET performance. Further studies are needed for validation and to understand how to improve patient experience., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534., Competing Interests: Dr Day is involved in consulting for Lexicon Pharmaceuticals; is on the Data Monitoring Committee of Cytokinetics; and receives funding from Lexicon Pharmaceuticals and Bristol Myers Squibb. Dr Canter is a consultant for Bristol Myers Squibb and receives research support from Tenaya, Merck, and Novartis (none relevant). Dr Bach receives research support (institutional only) from MyoKardia, Bristol Myers Squibb, and Cytokinetics, outside of the submitted work. Dr Wheeler receives research support and in-kind support from MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb, and research support from Cytokinetics Inc and Novartis Inc, all outside of the submitted work. Dr Rossano is a consultant for AskBio, American Regent, Bayer, BioMarin, Bristol Myers Squibb, Enzyvant, and Merck. Dr Owens has been consulting for Bristol Myers Squibb, Cytokinetics, Pfizer, Tenaya, BioMarin, Lexicon, Lexeo, Edgewise, and Stealth Therapeutics and receives research support from Bristol Myers Squibb. Dr Mestroni receives research funding from Bristol Myers Squibb, Tenaya Therapeutics, Pfizer, BioMarin, Greenstone Bioscience, and Spark Therapeutics. Dr Taylor receives research funding from Bristol Myers Squibb, Tenaya Therapeutics, Rocket Pharmaceuticals, BioMarin, and Spark Therapeutics. Dr Patel receives a research grant from GE Healthcare. Dr Soslow is involved in unrelated consulting for Sarepta, Pfizer, Immunoforge, and WCG Imaging. Dr Claggett is involved in statistical consulting for Alnylam, Cardurion, Corvia, CVRx, Cytokinetics, Intellia, and Rocket. Dr Ho is a consultant for and receives research funding from Bristol Myers Squib, Pfizer, Cytokinetics, Tenaya, BioMarin, viz.AI, and Lexicon (none relevant). The other authors report no conflicts.

Context.—: Spontaneous (nontraumatic) subdural hematomas have been reported yet have not been well studied., Objective.—: To identify the neuropathologic features of acute spontaneous SDHs (ASSDHs) and their associated medical conditions., Design.—: A retrospective study of 235 autopsy cases of SDH was conducted. Review of demographics, underlying medical conditions, and coagulation profile as well as gross and histopathologic examination of the brain and other organs were performed., Results.—: Among the 32 cases of ASSDH, 5 cases (15.6%) had severe hemorrhage and 4 (12.5%) demonstrated brain herniation. Twenty-two cases (68.8%) had concurrent but nonconnecting subarachnoid hemorrhage or intraparenchymal hemorrhage. The most common underlying medical condition was thrombocytopenia (n = 21; 65.6%), followed by immunosuppression (n = 15; 46.9), bloodstream infections or sepsis (n = 12; 37.5%), hypertension (n = 13; 40.6%), and coronary artery disease (n = 12; 37.5%). Many patients with thrombocytopenia or immunosuppression had underlying malignancies, with leukemia being the most common type (n = 11; 34.4%). The use of circulatory devices or hemodialysis was noted in a significant portion of ASSDH cases. In terms of coagulation factors, most of our ASSDH patients had normal prothrombin time and activated partial thromboplastin time, but abnormal platelet count and D-dimer levels., Conclusions.—: ASSDHs can be severe and are often associated with subarachnoid hemorrhage and/or intraparenchymal hemorrhage. The causes of ASSDH are limited to certain underlying medical conditions that ultimately lead to bleeding tendency. Autopsies are helpful in determining the etiology. Given their association with abnormal platelet count, correcting platelet deficiencies is a potential preventive measure for ASSDHs., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: Deep neck infections (DNIs) can compromise the airway and are associated with high morbidity and mortality rates. Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia that is associated with several comorbidities. We compared the clinical characteristics of DNI patients with and without DM., Methods: This study recorded the relevant clinical variables of 383 patients with DNIs between November 2016 and September 2022; of those patients, 147 (38.38%) had DM. The clinical factors between DNI patients with and without DM were assessed., Results: Patients with DM were older ( p < 0.001), had higher white blood cell counts ( p = 0.029) and C-reactive protein levels (CRP, p < 0.001), had a greater number of deep neck spaces ( p = 0.002) compared to patients without DM, and had longer hospital stays ( p < 0.001). Klebsiella pneumoniae was cultured more frequently from patients with DM than those without DM ( p = 0.002). A higher CRP level (OR = 1.0094, 95% CI: 1.0047-1.0142, p < 0.001) was a significant independent risk factor for DM patients with prolonged hospitalization. The lengths of hospital stays in patients with poorly controlled DM were longer than those with well-controlled DM ( p = 0.027)., Conclusions: DNI disease severity and outcomes were worse in patients with DM than those without DM. Antibiotics effective against Klebsiella pneumoniae should be used for DNI patients with DM. DNI patients with DM and high CRP levels had more prolonged hospitalizations. Appropriate blood glucose control is essential for DNI patients with DM.

Objectives: To compare upper airway changes following bimaxillary surgery for correction of Class III deformity between patients with unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) and to compare the preoperative and postoperative upper airway among patients with UCLP and BCLP to healthy controls., Materials and Methods: Sixty adults with CLP-related skeletal Class III deformity (30 UCLP and 30 BCLP) who consecutively underwent bimaxillary surgery were studied retrospectively. Cone-beam computed tomography (CBCT) was performed before and after surgery to measure upper airway and movements of facial skeletal and surrounding structures. CBCT images from 30 noncleft skeletal Class I adults, matched by age, gender, and body mass index and without surgical intervention, served as controls., Results: After surgery, the volume of the nasopharynx increased in patients with CLP (both P < .001). Patients with CLP did not differ from controls in postoperative volume of the nasopharynx or oropharynx. However, the nasal cavity differed significantly between patients with CLP and controls (P < .001)., Conclusions: After bimaxillary surgery, the nasal cavity of patients with CLP differed significantly compared with the controls. Volumes of the nasopharynx and oropharynx did not differ between patients with CLP after surgery and controls., (© 2024 by The EH Angle Education and Research Foundation, Inc.)

Chronic kidney disease (CKD) presents a substantial global public health challenge, with high morbidity and mortality. CKD patients often experience dyslipidaemia and poor glycaemic control, further exacerbating inflammation and oxidative stress in the kidney. If left untreated, these metabolic symptoms can progress to end-stage renal disease, necessitating long-term dialysis or kidney transplantation. Alleviating inflammation responses has become the standard approach in CKD management. Medications such as statins, metformin, and GLP-1 agonists, initially developed for treating metabolic dysregulation, demonstrate promising renal therapeutic benefits. The rising popularity of herbal remedies and supplements, perceived as natural antioxidants, has spurred investigations into their potential efficacy. Notably, lactoferrin, Boerhaavia diffusa , Amauroderma rugosum , and Ganoderma lucidum are known for their anti-inflammatory and antioxidant properties and may support kidney function preservation. However, the mechanisms underlying the effectiveness of Western medications and herbal remedies in alleviating inflammation and oxidative stress occurring in renal dysfunction are not completely known. This review aims to provide a comprehensive overview of CKD treatment strategies and renal function preservation and critically discusses the existing literature's limitations whilst offering insight into the potential antioxidant effects of these interventions. This could provide a useful guide for future clinical trials and facilitate the development of effective treatment strategies for kidney functions.

Aim: The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy., Methods: A comprehensive literature search was conducted from September 14, 2022, to November 22, 2022, encompassing studies, reviews, and other evidence on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through May 23, 2023, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate., Structure: Hypertrophic cardiomyopathy remains a common genetic heart disease reported in populations globally. Recommendations from the "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy" have been updated with new evidence to guide clinicians., (Copyright © 2024 American Heart Association, Inc., and the American College of Cardiology Foundation. Published by Elsevier. Published by Elsevier Inc. All rights reserved.)

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes., (© 2024 Wiley Periodicals LLC.)

Background: Bacteraemia is a critical condition that generally leads to substantial morbidity and mortality. It is unclear whether delayed antimicrobial therapy (and/or source control) has a prognostic or defervescence effect on patients with source-control-required (ScR) or unrequired (ScU) bacteraemia., Methods: The multicenter cohort included treatment-naïve adults with bacteraemia in the emergency department. Clinical information was retrospectively obtained and etiologic pathogens were prospectively restored to accurately determine the time-to-appropriate antibiotic (TtAa). The association between TtAa or time-to-source control (TtSc, for ScR bacteraemia) and 30-day crude mortality or delayed defervescence were respectively studied by adjusting independent determinants of mortality or delayed defervescence, recognised by a logistic regression model., Results: Of the total 5477 patients, each hour of TtAa delay was associated with an average increase of 0.2% (adjusted odds ratio [AOR], 1.002; P < 0.001) and 0.3% (AOR 1.003; P < 0.001) in mortality rates for patients having ScU (3953 patients) and ScR (1524) bacteraemia, respectively. Notably, these AORs were augmented to 0.4% and 0.5% for critically ill individuals. For patients experiencing ScR bacteraemia, each hour of TtSc delay was significantly associated with an average increase of 0.31% and 0.33% in mortality rates for overall and critically ill individuals, respectively. For febrile patients, each additional hour of TtAa was significantly associated with an average 0.2% and 0.3% increase in the proportion of delayed defervescence for ScU (3085 patients) and ScR (1266) bacteraemia, respectively, and 0.5% and 0.9% for critically ill individuals. For 1266 febrile patients with ScR bacteraemia, each hour of TtSc delay respectively was significantly associated with an average increase of 0.3% and 0.4% in mortality rates for the overall population and those with critical illness., Conclusions: Regardless of the need for source control in cases of bacteraemia, there seems to be a significant association between the prompt administration of appropriate antimicrobials and both a favourable prognosis and rapid defervescence, particularly among critically ill patients. For ScR bacteraemia, delayed source control has been identified as a determinant of unfavourable prognosis and delayed defervescence. Moreover, this association with patient survival and the speed of defervescence appears to be augmented among critically ill patients., (© 2024. The Author(s).)

Although prompt administration of an appropriate antimicrobial therapy (AAT) is crucial for reducing mortality in the general population with community-onset bacteremia, the prognostic effects of delayed AAT in older individuals with febrile and afebrile bacteremia remain unclear. A stepwise and backward logistic regression analysis was used to identify independent predictors of 30-day mortality. In a 7-year multicenter cohort study involving 3424 older patients (≥65 years) with community-onset bacteremia, febrile bacteremia accounted for 27.1% (912 patients). A crucial association of afebrile bacteremia and 30-day mortality (adjusted hazard ratio [AHR], 1.69; p < 0.001) was revealed using Cox regression and Kaplan-Meier curves after adjusting for the independent predictors of mortality. Moreover, each hour of delayed AAT was associated with an average increase of 0.3% (adjusted odds ratio [AOR], 1.003; p < 0.001) and 0.2% (AOR, 1.002; p < 0.001) in the 30-day crude mortality rates among patients with afebrile and febrile bacteremia, respectively, after adjusting for the independent predictors of mortality. Similarly, further analysis based on Cox regression and Kaplan-Meier curves revealed that inappropriate empirical therapy (i.e., delayed AAT administration > 24 h) had a significant prognostic impact, with AHRs of 1.83 ( p < 0.001) and 1.76 ( p < 0.001) in afebrile and febrile patients, respectively, after adjusting for the independent predictors of mortality. In conclusion, among older individuals with community-onset bacteremia, the dissimilarity of the prognostic impacts of delayed AAT between afebrile and febrile presentation was evident.

Abstract: Multiple myeloma (MM) cells are addicted to MYC and its direct transactivation targets IRF4 for proliferation and survival. MYC and IRF4 are still considered "undruggable," as most small-molecule inhibitors suffer from low potency, suboptimal pharmacokinetic properties, and undesirable off-target effects. Indirect inhibition of MYC/IRF4 emerges as a therapeutic vulnerability in MM. Here, we uncovered an unappreciated tumor-suppressive role of C-terminal binding protein 2 (CTBP2) in MM via strong inhibition of the MYC-IRF4 axis. In contrast to epithelial cancers, CTBP2 is frequently downregulated in MM, in association with shortened survival, hyperproliferative features, and adverse clinical outcomes. Restoration of CTBP2 exhibited potent antitumor effects against MM in vitro and in vivo, with marked repression of the MYC-IRF4 network genes. Mechanistically, CTBP2 impeded the transcription of MYC and IRF4 by histone H3 lysine 27 deacetylation (H3K27ac) and indirectly via activation of the MYC repressor IFIT3. In addition, activation of the interferon gene signature by CTBP2 suggested its concomitant immunomodulatory role in MM. Epigenetic studies have revealed the contribution of polycomb-mediated silencing and DNA methylation to CTBP2 inactivation in MM. Notably, inhibitors of Enhance of zeste homolog 2, histone deacetylase, and DNA methyltransferase, currently under evaluation in clinical trials, were effective in restoring CTBP2 expression in MM. Our findings indicated that the loss of CTBP2 plays an essential role in myelomagenesis and deciphers an additional mechanistic link to MYC-IRF4 dysregulation in MM. We envision that the identification of novel critical regulators will facilitate the development of selective and effective approaches for treating this MYC/IRF4-addicted malignancy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both G q -mediated calcium mobilization and G protein-independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug-evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo-electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design.

Olfactory dysfunction is one of the most common symptoms of COVID-19. In the first 2 years of the pandemic, it was frequently reported, although its incidence has significantly decreased with the emergence of the Omicron variant, which has since become the dominant viral strain. Nevertheless, many patients continue to suffer from persistent dysosmia and dysgeusia, making COVID-19-associated olfactory dysfunction an ongoing health concern. The proposed pathogenic mechanisms of COVID-19-associated olfactory dysfunction are complex and likely multifactorial. While evidence suggests that infection of sustentacular cells and associated mucosal inflammation may be the culprit of acute, transient smell loss, alterations in other components of the olfactory system (e.g., olfactory receptor neuron dysfunction, olfactory bulb injury and alterations in the olfactory cortex) may lead to persistent, long-term olfactory dysfunction. This review aims to provide a comprehensive summary of the epidemiology, clinical manifestations and current understanding of the pathogenic mechanisms of COVID-19-associated olfactory dysfunction., (© 2024 British Neuropathological Society.)

The study aimed to evaluate the impact of occupational noise on hearing loss among healthcare workers using audiometry. A longitudinal study was conducted with a six-month follow-up period in a hospital with 21 participants, divided into high-noise-exposure (HNE) and low-noise-exposure (LNE) groups. Mean noise levels were higher in the HNE group (70.4 ± 4.5 dBA), and hearing loss was measured using pure-tone audiometry at baseline and follow-up. The HNE group had significantly higher mean threshold levels at frequencies of 0.25 kHz, 0.5 kHz, 4.0 kHz, and an average of 0.5, 1, 2, and 4 kHz (all p-values < 0.05) after the follow-up period. After adjusting for confounding factors, the HNE group had significantly higher hearing loss levels at 0.25 kHz, 0.5 kHz, and average frequencies of 0.5, 1, 2, and 4 kHz compared to the LNE group at the second measurement. Occupational noise levels above 65 dBA over six months were found to cause significant threshold changes at frequencies of 0.25 kHz, 0.5 kHz, and an average of 0.5-4.0 kHz. This study highlights the risk of noise-induced hearing loss among healthcare workers and emphasizes the importance of implementing effective hearing conservation programs in the workplace. Regular monitoring and assessment of noise levels and hearing ability, along with proper use of personal protective equipment, are crucial steps in mitigating the impact of occupational noise exposure on the hearing health of healthcare workers., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: None.

Black phosphorus (BP) is a narrow bandgap (∼0.3 eV) semiconductor with a great potential for optoelectronic devices in the mid-infrared wavelength. However, it has been challenging to achieve a high-quality scalable BP thin film. Here we present the successful synthesis of optically active BP films on a centimeter scale. We utilize the pulsed laser deposition of amorphous red phosphorus, another allotrope of phosphorus, followed by a high-pressure treatment at ∼8 GPa to induce a phase conversion into BP crystals. The crystalline quality was improved through thermal annealing, resulting in the observation of photoluminescence emission at mid-infrared wavelengths. We demonstrate high-pressure conversion on a centimeter scale with a continuous film with a thickness of ∼18 nm using a flat-belt-type high-pressure apparatus. This synthesis procedure presents a promising route to obtain optical-quality BP films, enabling the exploration of integrated optoelectronic device applications such as light-emitting devices and mid-infrared cameras on a chip scale.

Osteoporosis is a usual bone disease in aging populations, principally in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are associated to a different of adverse effects. Du-Zhong is usually applied in Traditional Chinese Medicine to strengthen bone, regulate bone metabolism, and treat osteoporosis. Chlorogenic acid is a major polyphenol in Du-Zhong. In the current study, chlorogenic acid was found to enhance osteoblast proliferation and differentiation. Chlorogenic acid also inhibits the RANKL-induced osteoclastogenesis. Notably, ovariectomy significantly decreased bone volume and mechanical properties in the ovariectomized (OVX) rats. Administration of chlorogenic acid antagonized OVX-induced bone loss. Taken together, chlorogenic acid seems to be a hopeful molecule for the development of novel anti-osteoporosis treatment.

Patients with knee osteoarthritis (KOA) might have gait deviations, but few previous studies have discussed gait compensatory movements of the proximal and distal parts of muscle groups related to KOA. The study aimed to measure lumbar and hip movements during gait test and collect muscle activities of the lower extremities. Thirty-four participants with KOA and 28 healthy participants aged over 50 years were recruited for this study. Lumbar and hip motions during walking test were measured using inertial measurement units. Four muscle groups of the lower extremity (erector spinae, gluteus maximus, quadriceps muscle, and gastrocnemius) activities in gait were collected using surface EMGs. KOA patients used an 2.12∘anterior inclined lumbar spine (p = 0.007) and 22.94∘ flexed hip (p = 0.001) in gait compared to healthy participants. The KOA patients had a small hip movement range 30.19∘(p = 0.001) and a higher asymmetric stance time ratio 0.39 (p = 0.006). Patients with KOA showed decreased erector spinae and gluteus maximus muscle activation and increased activation of the quadriceps and gastrocnemius muscles during gait. In conclusion, patients with KOA used a hyperlordotic lumbar and hip flexed strategy, which overactivates distal extensor muscles through the whole gait and might cause overstress on the lower extremity joints., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest related to this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify causative variants in 30 to >60% of patients, with probability of a positive test varying with baseline characteristics such as known family history of HCM. Patients diagnosed with HCM should be offered genetic counseling and genetic testing as appropriate. Standard multigene panels evaluate sarcomeric genes known to cause HCM as well as genetic conditions that can mimic HCM but require different management. Positive genetic testing (finding a pathogenic or likely pathogenic variant) helps to clarify diagnosis and assists in family screening. If there is high confidence that an identified variant is the cause of HCM, at-risk family members can pursue predictive testing to determine if they are truly at risk or if they can be dismissed from serial screening based on whether they inherited the family's causative variant. Interpreting test results can be complex, and providers should make use of multidisciplinary teams as well as evidence-based resources to obtain the best possible understanding of pathogenicity., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Upper limb and core strength training is essential for older adults to safely perform daily activities. However, existing exercise programmes mainly focus on lower limb strength and are not designed or delivered to suit people with different functional capacities. This study describes the design of a two-arm cluster randomised controlled trial to examine the effects of a multicomponent physical activity (PA) programme, Mobility-Fit, on mobility and frailty in older adults living in care facilities., Methods and Analysis: 160 older adults from 20 care facilities in Hong Kong will be recruited and randomised by care facilities (1:1) to an intervention or a control group. Participants in the intervention group will attend the Mobility-Fit programme, led by facility-based instructors, three times per week, 45 min per session, for 12 weeks, while the control group will participate in a standard care lower limb strengthening programme offered by the care facility. Participants will then be followed up for 9 months. Mobility-Fit comprises agility, postural coordination, balance and strength training, with suitable dosage based on participant's baseline physical and cognitive function. The primary outcomes encompass upper and lower limb strength, trunk stability, reaction time, mobility function and fall efficacy. Secondary outcomes comprise daily PA level and performance, frailty, cognitive function and quality of life. A repeated measures analysis of variance (ANOVA) and generalised estimating equation (GEE) will be used to examine changes in outcomes over time and between groups. Data will be analysed following the intention-to-treat principles. We will also evaluate programme implementation and health economics throughout the follow-up period., Ethics and Dissemination: Ethical approval was acquired in November 2022 from the Joint CUHK-NTEC Clinical Research Ethics Committee in Hong Kong (CREC-2022-459). Informed consent will be obtained from participants. The results of the study will be disseminated through peer-reviewed articles, conference presentations and social media., Trial Registration Number: ChiCTR2300072709., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted., Methods: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up., Results: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7 ., Conclusions: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM., Competing Interests: Disclosures The views expressed in this article are those of the authors, who declare that they have no conflict of interest, except for Dr Moon, who is the chief executive officer of Mycardium AI and has served on advisory boards for Genzyme and Sanofi.

Our previous study reported that the heterodimer of Angiotensin II Type I Receptor (AT1R) and Mu-Opioid Receptor 1 (MOR1) involves Nitric Oxide (NO) reduction which leads to elevation of blood pressure. Secondly, we showed that Toll-like Receptor 4 (TLR4) may be involved in the heterodimerization of AT1R and MOR1 in the brainstem Nucleus Tractus Solitarii (NTS), which regulates systemic blood pressure and gastric nitric oxide through the insulin pathway. Here, we investigated the role of microglial activation and TLR4 in the heterodimerization of AT1R and MOR1. Hypertensive rats were established after four weeks of fructose consumption. SBP of rats was measured using non-invasive blood pressure method. PLA technique was utilized to determine protein-protein interaction in the nucleus tractus solitarii. Results showed that the level of MOR-1 and AT1R was induced significantly in the fructose group compared with control. PLA signal potentially showed that AT1R and MOR1 were formed in the nucleus tractus solitarii after fructose consumption. Meanwhile, the innate immune cell in the CNS microglia was observed in the nucleus tractus solitarii using biomarkers and was activated. TLR4 inhibitor CLI-095, was administered to animals to suppress the neuroinflammation and microglial activation. CLI-095 treatment reduced the heterodimer formation of AT1R and MOR1 and restored nitric oxide production in the nucleus tractus solitarii. These findings imply that TLR4-primed neuroinflammation involves formation of heterodimers AT1R and MOR1 in the nucleus tractus solitarii which leads to increase in systemic blood pressure., Competing Interests: Declaration of competing interest The authors hereby declare that they have no competing interests pertaining to the publication of this research. This encompasses financial, professional, or personal interests that might have influenced the performance or presentation of the work described in this manuscript., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The main goals of Phase II trials are to identify the therapeutic efficacy of new treatments and continue monitoring all the possible adverse effects. In Phase II trials, it is important to develop an adaptive randomization (AR) procedure that takes into account both the efficacy and toxicity. In most existing articles, toxicity is modeled as a binary endpoint through an unobservable random effect (frailty) to link the efficacy and toxicity. However, this approach does not capture toxicity profiles that evolve over time. In this article, we propose a new Bayesian adaptive randomization (BAR) procedure using the covariate-adjusted efficacy-toxicity ratio (ETR) index, where efficacy and toxicity are jointly modelled as time-to-event (TTE) outcomes. Furthermore, we also propose early stopping rules for toxicity and futility such that inferior treatments can be dropped at earlier time of trial. Simulation results show that compared to the BAR procedures based solely on the efficacy and that based on TTE efficacy and binary toxicity outcomes, the proposed BAR procedure can better identify the difference in treatment toxicity such that it can assign more patients to the superior treatment arm under some scenarios.

Cardiovascular disease (CVD), a global health concern, particularly coronary artery disease (CAD), poses a significant threat to well-being. Seeking safer and cost-effective diagnostic alternatives to invasive coronary angiography, noninvasive coronary computed tomography angiography (CCTA) gains prominence. This study employed OpenFOAM, an open-source Computational Fluid Dynamics (CFD) software, to analyze hemodynamic parameters in coronary arteries with serial stenoses. Patient-specific three-dimensional (3D) models from CCTA images offer insights into hemodynamic changes. OpenFOAM breaks away from traditional commercial software, validated against the FDA benchmark nozzle model for reliability. Applying this refined methodology to seventeen coronary arteries across nine patients, the study evaluates parameters like fractional flow reserve computed tomography simulation (FFRCTS), fluid velocity, and wall shear stress (WSS) over time. Findings include FFRCTS values exceeding 0.8 for grade 0 stenosis and falling below 0.5 for grade 5 stenosis. Central velocity remains nearly constant for grade 1 stenosis but increases 3.4-fold for grade 5 stenosis. This research innovates by utilizing OpenFOAM, departing from previous reliance on commercial software. Combining qualitative stenosis grading with quantitative FFRCTS and velocity measurements offers a more comprehensive assessment of coronary artery conditions. The study introduces 3D renderings of wall shear stress distribution across stenosis grades, providing an intuitive visualization of hemodynamic changes for valuable insights into coronary stenosis diagnosis.