The C-degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes.

Protein termini are determinants of protein stability. Proteins bearing degradation signals, or degrons, at their amino- or carboxyl-termini are eliminated by the N- or C-degron pathways, respectively. We aimed to elucidate the function of C-degron pathways and to unveil how normal proteomes are exempt from C-degron pathway-mediated destruction. Our data reveal that C-degron pathways remove mislocalized cellular proteins and cleavage products of deubiquitinating enzymes. Furthermore, the C-degron and N-degron pathways cooperate in protein removal. Proteome analysis revealed a shortfall in normal proteins targeted by C-degron pathways, but not of defective proteins, suggesting proteolysis-based immunity as a constraint for protein evolution/selection. Our work highlights the importance of protein termini for protein quality surveillance, and the relationship between the functional proteome and protein degradation pathways.

Systemic inflammation and changes in physical well-being in patients with breast cancer: a longitudinal study in community oncology settings.

BACKGROUND: Chemotherapy adversely affects physical well-being and inflammation may be related to changes in physical well-being. We evaluated the association of systemic inflammation with changes in physical well-being. METHODS: In a prospective study of 580 patients with stages I-III breast cancer we assessed immune cell counts, neutrophil:lymphocyte ratio (NLR), lymphocyte:monocyte ratio (LMR), and platelet:lymphocyte ratio (PLR) within 7 days before chemotherapy (pre-chemotherapy). Physical well-being was assessed using the Functional Assessment of Cancer Therapy: General-Physical Well-being subscale (FACT-PWB) pre-chemotherapy and 1 month and 6 months post-chemotherapy. Clinically meaningful decline in physical well-being was determined as decreasing FACT-PWB by more than one point from pre-chemotherapy level, and non-resilience defined as having decline post-chemotherapy and not returning to within one-point of pre-chemotherapy FACT-PWB by 6 months post-chemotherapy. Multivariable logistic regressions examined the association between inflammation and changes in physical well-being, adjusting for sociodemographic and clinical characteristics. RESULTS: Fifty-nine percent (310/529) and 36% (178/501) of participants had physical well-being decline post-chemotherapy and 6 months post-chemotherapy, respectively. Fifty percent (147/294) were non-resilient. Low NLR and PLR were associated with 1.78 (P = .01) and 1.66 (P = .02) fold greater odds of having a decline in physical well-being 6 months post-chemotherapy compared to those with high NLR and PLR, respectively. Low NLR and PLR were associated with 1.92 (P = .02) and 2.09 (P = 0.01) fold greater odds of being non-resilient 6 months post-chemotherapy compared to those with high NLR and PLR, respectively. CONCLUSION: Low NLR and PLR were associated with chemotherapy-induced changes in physical well-being independent of sociodemographic and clinical risk factors.

Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model.

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). Using this model, we evaluated tumor burden, T-cell activation, and cytokine release in response to bispecific T-cell-engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD-scid Il2rgnull mice lacking expression of mouse MHC class I and II (NSG-MHC-DKO mice) and implanted with a tumor xenograft predict both efficacy for tumor control by CD19xCD3 BiTE and stimulated cytokine release. Moreover, our findings indicate that this PBMC-engrafted model captures variability among donors for tumor control and cytokine release following treatment. Tumor control and cytokine release were reproducible for the same PBMC donor in separate experiments. The PBMC humanized mouse model described here is a sensitive and reproducible platform that identifies specific patient/cancer/therapy combinations for treatment efficacy and development of complications.

Cellular and Molecular Biology of Mitochondria in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by enduring airflow limitation and chronic inflammation. Growing evidence highlights mitochondrial dysfunction as a critical factor in COPD development and progression. This review explores the cellular and molecular biology of mitochondria in COPD, focusing on structural and functional changes, including alterations in mitochondrial shape, behavior, and respiratory chain complexes. We discuss the impact on cellular signaling pathways, apoptosis, and cellular aging. Therapeutic strategies targeting mitochondrial dysfunction, such as antioxidants and mitochondrial biogenesis inducers, are examined for their potential to manage COPD. Additionally, we consider the role of mitochondrial biomarkers in diagnosis, evaluating disease progression, and monitoring treatment efficacy. Understanding the interplay between mitochondrial biology and COPD is crucial for developing targeted therapies to slow disease progression and improve patient outcomes. Despite advances, further research is needed to fully elucidate mitochondrial dysfunction mechanisms, discover new biomarkers, and develop targeted therapies, aiming for comprehensive disease management that preserves lung function and enhances the quality of life for COPD patients.

Exploring Molecular Mechanisms and Biomarkers in COPD: An Overview of Current Advancements and Perspectives.

Chronic obstructive pulmonary disease (COPD) plays a significant role in global morbidity and mortality rates, typified by progressive airflow restriction and lingering respiratory symptoms. Recent explorations in molecular biology have illuminated the complex mechanisms underpinning COPD pathogenesis, providing critical insights into disease progression, exacerbations, and potential therapeutic interventions. This review delivers a thorough examination of the latest progress in molecular research related to COPD, involving fundamental molecular pathways, biomarkers, therapeutic targets, and cutting-edge technologies. Key areas of focus include the roles of inflammation, oxidative stress, and protease-antiprotease imbalances, alongside genetic and epigenetic factors contributing to COPD susceptibility and heterogeneity. Additionally, advancements in omics technologies-such as genomics, transcriptomics, proteomics, and metabolomics-offer new avenues for comprehensive molecular profiling, aiding in the discovery of novel biomarkers and therapeutic targets. Comprehending the molecular foundation of COPD carries substantial potential for the creation of tailored treatment strategies and the enhancement of patient outcomes. By integrating molecular insights into clinical practice, there is a promising pathway towards personalized medicine approaches that can improve the diagnosis, treatment, and overall management of COPD, ultimately reducing its global burden.

Effectiveness of Auricular Acupressure on Improving Pain and Heart Rate Variability in Patients After Cervical Spine Surgery.

Cervical spine surgery is a common neurosurgical procedure; however, postoperative pain remains a problem. This study aimed to examine the effectiveness of auricular acupressure, which is considered a noninvasive, convenient, and safe method for pain reduction and heart rate variability in patients after surgery. A total of 62 patients who underwent cervical spine surgery were randomly divided into experimental (32 patients) and control (30 patients) groups. Both groups received routine care, whereas the experimental group received auricular acupressure three times a day for four days. The Short-Form McGill Pain Questionnaire was administered, and heart rate variability measurements were obtained on the first, second, third, and fourth postoperative days. The results indicated that auricular acupressure was effective in reducing pain ( P < .05) and improving heart rate variability ( P < .05) in patients. Based on the findings, this study suggests that auricular acupressure can be used as a complementary treatment to reduce pain in patients after cervical spine surgery.

Use of consecutive transcutaneous oxygen measurement when assessing the need for revascularization and association with the outcomes of ischemic diabetic ulcers.

This study compared the ankle-brachial index (ABI) with transcutaneous oxygen pressure (TcPO2 ) in assessing peripheral vascular disease (PVD) prevalence in 100 diabetic foot ulcer (DFU) patients. Patients were categorized into vascular or nonvascular reconstruction groups and underwent both ABI and TcPO2 measurements four times over 6 months. Predictive validity for PVD diagnosis was analysed using the area under the receiver-operating characteristic curve (AUC). The study found TcPO2 to be a superior predictor of PVD than ABI. Among the DFU patients, 51 with abnormal TcPO2 values underwent vascular reconstruction. Only TcPO2 values showed significant pretreatment differences between the groups and increased post-reconstruction. These values declined over a 6-month follow-up, whereas ABI values rose. For those with end-stage renal disease (ESRD), TcPO2 values saw a sharp decrease within 3 months. Pre-reconstruction TcPO2 was notably lower in amputation patients versus limb salvage surgery patients. In conclusion, TcPO2 is more effective than ABI for evaluating ischemic limb perfusion and revascularization necessity. It should be prioritized as the primary follow-up tool, especially for ESRD patients.

The Benefit of Hydrogen Gas as an Adjunctive Therapy for Chronic Obstructive Pulmonary Disease.

Background and Objectives: Recent studies suggest that hydrogen gas possesses anti-inflammatory, antioxidant, and anti-apoptotic properties. This study aimed to explore the therapeutic potential of hydrogen gas and assess its safety and tolerability in individuals with chronic obstructive pulmonary disease (COPD). Materials and Methods: Enrolled COPD patients received standard treatments along with additional hydrogen inhalation for 30 min in the morning, afternoon, and evening over a 30-day period. The assessment included changes in the COPD Assessment Test (CAT), the modified Medical Research Council (mMRC) Dyspnea Scale, lung function, sleep quality, inflammation markers, and oxidative stress markers before and after hydrogen inhalation. Results: Six patients participated in this study. Patients 2, 3, 4, 5, and 6 demonstrated improvements in CAT scores following hydrogen gas intervention, with patients 2, 4, 5, and 6 also showing improvements in mMRC scores. Statistically, this study revealed significant improvements in CAT [15.5 (10.5-19.75) vs. 8.5 (3-13.5); p = 0.043] and mMRC scores [2.5 (1-4) vs. 2 (0-3.25); p = 0.046] before and after intervention, respectively. However, no significant differences were observed in lung function, DLCO, sleep quality, and 6 MWT before and after hydrogen therapy. CBC examination showed a significant difference in platelet count before and after treatment [247 (209.75-298.75) vs. 260 (232.75-314.5); p = 0.043], respectively, while other blood tests, inflammation markers, and oxidative stress markers did not exhibit significant differences before and after hydrogen therapy. All patients experienced no obvious side-effects. Conclusions: Adjuvant therapy with hydrogen gas demonstrated symptom improvements in specific COPD patients, and no significant adverse effects were observed in any of the patients. Hydrogen gas may also exert a modulatory effect on platelet count.

Enhanced development of functional human NK cells in NOD-scid-IL2rgnull mice expressing human IL15.

Human innate immunity plays a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that have opposing roles in the tumor microenvironment, including NK cell subsets that mediate tumor cell cytotoxicity and subsets with regulatory function that contribute to the tumor immune suppressive environment. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function in tumorigenesis. Humanized mice are a powerful alternative to syngeneic mouse tumor models for the study of human immuno-oncology and have proven effective tools to test immunotherapies targeting T cells. However, human NK cell development and survival in humanized NOD-scid-IL2rgnull (NSG) mice are severely limited. To enhance NK cell development, we have developed NSG mice that constitutively expresses human Interleukin 15 (IL15), NSG-Tg(Hu-IL15). Following hematopoietic stem cell engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of functional human CD56+ NK cells are detectable in blood and spleen, as compared to NSG mice. Hematopoietic stem cell (HSC)-engrafted NSG-Tg(Hu-IL15) mice also supported the development of human CD3+ T cells, CD20+ B cells, and CD33+ myeloid cells. Moreover, the growth kinetics of a patient-derived xenograft (PDX) melanoma were significantly delayed in HSC-engrafted NSG-Tg(Hu-IL15) mice as compared to HSC-engrafted NSG mice demonstrating that human NK cells have a key role in limiting the tumor growth. Together, these data demonstrate that HSC-engrafted NSG-Tg(Hu-IL15) mice support enhanced development of functional human NK cells, which limit the growth of PDX tumors.

Lipids as Emerging Biomarkers in Neurodegenerative Diseases.

Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.

Experiences of oncology healthcare personnel in international medical service quality: a phenomenological study.

BACKGROUND: With the globalization of medical services on the rise, Asia has ascended to a destination of choice for its high-quality medical services at very reasonable rates. Monitoring the quality of the international medical industry is vital to maintain service demand. The experiences of healthcare personnel (HCP) involved in international medical services (IMS) regarding the provision of services to international cancer patients have not yet been discussed. This study aimed to explore oncology HCP experiences of IMS quality in caring for international cancer patients in Taiwan. METHODS: Descriptive phenomenological method and were analyzed through Colaizzi's seven-step approach. In this study, 19 respondents were collected data by using in-depth semi-structured interviews. An average interview lasted approximately 45 min. RESULTS: Four major themes were identified from the interviews: patient selection, psycho-oncology care, predicaments, and promoting suggestions. Additionally, thirteen subthemes emerged, including necessary selection of patients, reasons for unwillingness to enroll international patients, helpless patients, emotional distress, care with warmth, insufficient manpower, an unfair reward mechanism, poor hardware equipment, the predicaments of oncology care, various publicity strategies, one-on-one service model, design of a designated area, and reasonable benefit distribution. CONCLUSIONS: This study explored oncology HCP experiences of IMS quality in caring for international cancer patients, with implications for hospitals in developing high-quality IMS. Due to the fact that IMS is a global trend, HCPs, administrators, and policy-makers are advised to improve the quality of IMS in the oncology department, which has been the least studied field in IMS quality.

Global dynamics of two-strain epidemic model with single-strain vaccination in complex networks.

Contagious pathogens, such as influenza and COVID-19, are known to be represented by multiple genetic strains. Different genetic strains may have different characteristics, such as spreading more easily, causing more severe diseases, or even evading the immune response of the host. These facts complicate our ability to combat these diseases. There are many ways to prevent the spread of infectious diseases, and vaccination is the most effective. Thus, studying the impact of vaccines on the dynamics of a multi-strain model is crucial. Moreover, the notion of complex networks is commonly used to describe the social contacts that should be of particular concern in epidemic dynamics. In this paper, we investigate a two-strain epidemic model using a single-strain vaccine in complex networks. We first derive two threshold quantities, R 1 and R 2 , for each strain. Then, by using the basic tools for stability analysis in dynamical systems (i.e., Lyapunov function method and LaSalle's invariance principle), we prove that if R 1 < 1 and R 2 < 1 , then the disease-free equilibrium is globally asymptotically stable in the two-strain model. This means that the disease will die out. Furthermore, the global stability of each strain dominance equilibrium is established by introducing further critical values. Under these stability conditions, we can determine which strain will survive. Particularly, we find that the two strains can coexist under certain condition; thus, a coexistence equilibrium exists. Moreover, as long as the equilibrium exists, it is globally stable. Numerical simulations are conducted to validate the theoretical results.

The effects of regular dental scaling on the complications and mortality after stroke: a retrospective cohort study based on a real-world database.

BACKGROUND: Previous observational studies have shown that people with dental scaling (DS) had decreased risk of stroke. However, limited information is available on the association between DS and poststroke outcomes. The present study aimed to evaluate the effects of regular DS on the complications and mortality after stroke. METHODS: We conducted a retrospective cohort study of 49,547 hospitalized stroke patients who received regular DS using 2010-2017 claims data of Taiwan's National Health Insurance. Using a propensity-score matching procedure, we selected 49,547 women without DS for comparison. Multiple logistic regressions were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of poststroke complications and in-hospital mortality associated with regular DS. RESULTS: Stroke patients with regular DS had significantly lower risks of poststroke pneumonia (OR 0.58, 95% CI 0.54-0.63), septicemia (OR 0.58, 95% CI 0.54-0.63), urinary tract infection (OR 0.68, 95% CI 0.66-0.71), intensive care (OR 0.81, 95% CI 0.78-0.84), and in-hospital mortality (OR 0.66, 95% CI 0.62-0.71) compared with non-DS stroke patients. Stroke patients with regular DS also had shorter hospital stays (p < 0.0001) and less medical expenditures (p < 0.0001) during stroke admission than the control group. Lower rates of poststroke adverse events in patients with regular DS were noted in both sexes, all age groups, and people with various types of stroke. CONCLUSION: Stroke patients with regular DS showed fewer complications and lower mortality compared with patients had no DS. These findings suggest the urgent need to promote regular DS for this susceptible population of stroke patients.

The Relationship between Exertional Desaturation and Pulmonary Function, Exercise Capacity, or Medical Costs in Chronic Obstructive Pulmonary Disease Patients.

Background and Objectives: Exertional desaturation (ED) is common and is associated with poorer clinical outcomes in chronic obstructive pulmonary disease (COPD). The age, dyspnea, airflow obstruction (ADO) and body mass index, airflow obstruction, dyspnea, and exercise (BODE) indexes are used to predict the prognosis of COPD patients. This study aimed to investigate the relationship between these indexes, pulmonary function, medical costs, and ED in COPD patients. Materials and Methods: Data were collected from the electronic database of the Kaohsiung Chang Gung Memorial Hospital. This retrospective study included 396 patients categorized as either ED (n = 231) or non-ED (n = 165). Variables (including age, smoking history, body mass index (BMI), pulmonary function test, maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP), six minutes walking test distance (6MWD), SpO2, COPD Assessment Test (CAT) score, ADO index, BODE index, Charlson comorbidity index (CCI), and medical costs) were compared between the two groups, and their correlations were assessed. ED was defined as SpO2 less than 90% or SpO2 decrease of more than 4% compared to baseline levels during 6MWT. Results: A significant statistical difference was found regarding a lower score of the ADO index and the BODE index (both p < 0.001), better pulmonary function (forced expiratory volume in the first second (FEV1), p < 0.001; FEV1/ forced vital capacity (FVC), p < 0.001; diffusion capacity of the lung for carbon monoxide (DLCO), p < 0.001), and higher minimal oxygen saturation (p < 0.001) in non-ED COPD patients. No difference was found in the distance of the 6MWT (p = 0.825) and respiratory muscle strength (MIP; MEP, p = 0.86; 0.751). However, the adjusted multivariate logistic regression analysis showed that only SpO2 (minimal) had a significant difference between of the ED and non-ED group (p < 0.001). There was either no difference in the medical expenses between ED and non-ED COPD patients. Conclusions: SpO2 (minimal) during the 6MWT is the independent factor for ED. ED is related to BODE and ADO indices, but is not related to medical expense.

Comparison of BODE and ADO Indices in Predicting COPD-Related Medical Costs.

Background and Objectives:The ADO (age, dyspnea, and airflow obstruction) and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) indices are often used to evaluate the prognoses for chronic obstructive pulmonary disease(COPD); however, an index suitable for predicting medical costs has yet to be developed. Materials and Methods: We investigated the BODE and ADO indices to predict medical costs and compare their predictive power. A total of 396 patients with COPD were retrospectively enrolled. Results: For hospitalization frequencies, BODE was R2 = 0.093 (p < 0.001), and ADO was R2 = 0.065 (p < 0.001); for hospitalization days, BODE was R2 = 0.128 (p < 0.001), and ADO was R2 = 0.071 (p < 0.001); for hospitalization expenses, BODE was R2 = 0.020 (p = 0.047), and ADO was R2 = 0.012 (p = 0.179). BODE and ADO did not differ significantly in the numbers of outpatient visits (BODE, R2 = 0.012, p = 0.179; ADO, R2 = 0.017, p = 0.082); outpatient medical expenses (BODE, R2 = 0.012, p = 0.208; ADO, R2 = 0.008, p = 0.364); and total medical costs (BODE, R2 = 0.018, p = 0.072; ADO, R2 = 0.016, p = 0.098). In conclusion, BODE and ADO indices were correlated with hospitalization frequency and hospitalization days. However, the BODE index exhibits slightly better predictive accuracy than the ADO index in these items.

Erythrocytes efficiently utilize exogenous sphingosines for S1P synthesis and export via Mfsd2b.

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that exerts its activity via activation of five different G protein-coupled receptors, designated as S1P1-5. This potent lipid mediator is synthesized from the sphingosine precursor by two sphingosine kinases (SphK1 and 2) and must be exported to exert extracellular signaling functions. We recently identified Mfsd2b as the S1P transporter in the hematopoietic system. However, the sources of sphingosine for S1P synthesis and the transport mechanism of Mfsd2b in erythrocytes remain to be determined. Here, we show that erythrocytes efficiently take up exogenous sphingosine and that a de novo synthesis pathway in part provides sphingosines to erythrocytes. The uptake of sphingosine in erythrocytes is facilitated by the activity of SphK1. By converting sphingosine into S1P, SphK1 indirectly increases the influx of sphingosine, a process that is irreversible in erythrocytes. Our results explain for the abnormally high amount of sphingosine accumulation in Mfsd2b knockout erythrocytes. Furthermore, we show that Mfsd2b utilizes a proton gradient to facilitate the release of S1P. The negatively charged residues D95 and T157 are essential for Mfsd2b transport activity. Of interest, we also discovered an S1P analog that inhibits S1P export from erythrocytes, providing evidence that sphingosine analogs can be used to inhibit S1P export by Mfsd2b. Collectively, our results highlight that erythrocytes are efficient in sphingosine uptake for S1P production and the release of S1P is dependent on Mfsd2b functions.

Altered Expression of Interleukin-18 System mRNA at the Level of Endometrial Myometrial Interface in Women with Adenomyosis.

Adenomyosis is a uterine pathology characterized by a deep invasion of endometrial glands and stroma, disrupting the endometrial−myometrial interface (EMI). Interleukin-18 (IL-18) system is a dominant cytokine involved in the menstrual cycle of human endometrium. IL-18 may play a defensive role against maternal immune response in the uterine cavity. The present study was designed to determine IL-18-mediated immune response at the level of EMI. We uncovered that mRNA of IL-18 system, including IL-18, IL-18 receptor (IL-18R), and its antagonist, IL-18 binding protein (IL-18BP), expressed in eutopic, ectopic endometrium, and corresponding myometrium in patients with adenomyosis. IL-18 system was demonstrated in paired tissue samples by immunochemistry and immunofluorescence study. According to RT-PCR with CT value quantification and 2−∆∆Ct method, a significant down-regulation of IL-18BP in corresponding myometrium in comparison to eutopic endometrium (p < 0.05) indicates that the IL-18 system acts as a local immune modulator at the level of EMI and regulating cytokine networks in the pathogenesis of adenomyosis. Furthermore, an increased IL-18 antagonist to agonist ratio was noted in ectopic endometrium compared with corresponding myometrium. We suggest that altered IL-18 system expression contributes to immunological dysfunction and junctional zone disturbance in women with adenomyosis.

Efficacy of melatonin in the treatment of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

This study investigated the effect of melatonin on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). We searched PubMed, the Web of Science, the Cochrane Library, Ovid MEDLINE, and Clinicaltrials.gov for randomized controlled trials (RCTs) published before September 11, 2021. Only RCTs that compared the clinical efficacy of melatonin with a placebo in the treatment of patients with COVID-19 were included. The primary outcome measure was the clinical recovery rate. We included three RCTs in this meta-analysis. Melatonin 3 mg three times daily was administered in one RCT, and 3 or 6 mg daily before bedtime in the other two trials. Treatment duration was 14 days in two RCTs and 7 days in one trial. The clinical recovery rates were 94.2% (81/86) and 82.4% (70/85) in the melatonin and control groups, respectively. Overall, patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio [OR]: 3.67; 95% CI: 1.21-11.12; I2 = 0%, p = 0.02). The risk of intensive care unit admission was numerically lower in the melatonin group than in the control group (8.3% [6/72] vs. 17.6% [12/68], OR: 0.45; 95% CI: 0.16-1.25; I2 = 0%, p = 0.13), and the risk of mortality was numerically lower in the melatonin group than in the control group (1.4% [1/72] vs. 4.4% [3/68], OR: 0.32; 95% CI: 0.03-3.18; I2 = 0%, p = 0.33). In conclusion, melatonin may help improve the clinical outcomes of patients with COVID-19.

An efficient penalized estimation approach for semiparametric linear transformation models with interval-censored data.

We consider efficient estimation of flexible transformation models with interval-censored data. To reduce the dimension of semiparametric models, the unknown monotone function is approximated via a monotone B-spline. A penalization technique is used to provide computationally efficient estimation of all parameters. To accomplish model fitting and inference, an easy to implement nested iterative expectation-maximization (EM) algorithm is developed for estimation, and a simple variance-covariance estimation approach is proposed which makes large-sample inference for the regression parameters possible. Theoretically, we show that the estimator of the unknown monotone increasing function achieves the optimal rate of convergence, and the estimators of the regression parameters are asymptotically normal and efficient under the appropriate selection of the order of the smoothing parameter and the knots of the spline space. The proposed penalized procedure is assessed through extensive numerical experiments and implemented in R package PenIC. The proposed methodology is further illustrated via a signal tandmobiel study.

A novel co-amplification system for simultaneous amplification of 23 Y-STR and identification of spermatozoa.

In alleged sexual assault cases, identification of the presence of spermatozoa at the crime scene, or on items of eventual significance, or associated with the body of the victim, is integral to the forensic investigation to support or refute the proposition that sexual act has occurred. A 3-plex MSRE-PCR (methylation-sensitive restriction enzyme-PCR) system has been developed previously to identify spermatozoa based on the presence or absence of DNA methylation. This assay showed that 0.1 ng of DNA from a semen extract was sufficient to identify the presence of spermatozoa even when there was excessively more DNA isolated from vaginal fluid than DNA from a semen extract (80 ng/0.1 ng) or a mix of the menstrual blood/semen DNA (5 ng/0.1 ng). In this study, we combine spermatozoa detection with co-amplification of 23 Y-STR loci. We perform standard validation steps to present a novel test that saves time and uses the same sample for both DNA typing and spermatozoa detection in the same reaction. The combined assay can identify Y-STR and spermatozoa simultaneously using just 0.1 ng semen DNA, even in the presence of 5 ng of DNA from a female (male/female:1/50). No other body fluid tested, such as saliva, gave a result for the presence of spermatozoa. A total of 9 non-probative forensic samples from 7 sexual assault cases were tested by this co-amplification system. In all cases, the same sperm-positive data were obtained, concordant with our previous study analyzed by only 3-plex MSRE-PCR, and the Y-STR results were also consistent with that analyzed by only PowerPlex® Y23 kit. The co-amplification will be beneficial for the limited samples in many criminal cases.