tRNA-derived small RNAs in human cancers: roles, mechanisms, and clinical application.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a new type of non-coding RNAs (ncRNAs) produced by the specific cleavage of precursor or mature tRNAs. tsRNAs are involved in various basic biological processes such as epigenetic, transcriptional, post-transcriptional, and translation regulation, thereby affecting the occurrence and development of various human diseases, including cancers. Recent studies have shown that tsRNAs play an important role in tumorigenesis by regulating biological behaviors such as malignant proliferation, invasion and metastasis, angiogenesis, immune response, tumor resistance, and tumor metabolism reprogramming. These may be new potential targets for tumor treatment. Furthermore, tsRNAs can exist abundantly and stably in various bodily fluids (e.g., blood, serum, and urine) in the form of free or encapsulated extracellular vesicles, thereby affecting intercellular communication in the tumor microenvironment (TME). Meanwhile, their abnormal expression is closely related to the clinicopathological features of tumor patients, such as tumor staging, lymph node metastasis, and poor prognosis of tumor patients; thus, tsRNAs can be served as a novel type of liquid biopsy biomarker. This review summarizes the discovery, production, and expression of tsRNAs and analyzes their molecular mechanisms in tumor development and potential applications in tumor therapy, which may provide new strategies for early diagnosis and targeted therapy of tumors.

Description of the COVID-19 epidemiology in Malaysia.

Introduction: Since the COVID-19 pandemic began, it has spread rapidly across the world and has resulted in recurrent outbreaks. This study aims to describe the COVID-19 epidemiology in terms of COVID-19 cases, deaths, ICU admissions, ventilator requirements, testing, incidence rate, death rate, case fatality rate (CFR) and test positivity rate for each outbreak from the beginning of the pandemic in 2020 till endemicity of COVID-19 in 2022 in Malaysia. Methods: Data was sourced from the GitHub repository and the Ministry of Health's official COVID-19 website. The study period was from the beginning of the outbreak in Malaysia, which began during Epidemiological Week (Ep Wk) 4 in 2020, to the last Ep Wk 18 in 2022. Data were aggregated by Ep Wk and analyzed in terms of COVID-19 cases, deaths, ICU admissions, ventilator requirements, testing, incidence rate, death rate, case fatality rate (CFR) and test positivity rate by years (2020 and 2022) and for each outbreak of COVID-19. Results: A total of 4,456,736 cases, 35,579 deaths and 58,906,954 COVID-19 tests were reported for the period from 2020 to 2022. The COVID-19 incidence rate, death rate, CFR and test positivity rate were reported at 1.085 and 0.009 per 1,000 populations, 0.80 and 7.57%, respectively, for the period from 2020 to 2022. Higher cases, deaths, testing, incidence/death rate, CFR and test positivity rates were reported in 2021 and during the Delta outbreak. This is evident by the highest number of COVID-19 cases, ICU admissions, ventilatory requirements and deaths observed during the Delta outbreak. Conclusion: The Delta outbreak was the most severe compared to other outbreaks in Malaysia's study period. In addition, this study provides evidence that outbreaks of COVID-19, which are caused by highly virulent and transmissible variants, tend to be more severe and devastating if these outbreaks are not controlled early on. Therefore, close monitoring of key epidemiological indicators, as reported in this study, is essential in the control and management of future COVID-19 outbreaks in Malaysia.

Prognostic value and therapeutic potential of IAP family in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) ranks as the eighth most prevalent malignancy globally and has the eighth greatest fatality rate when compared to all other forms of cancer. The inhibitor of apoptosis protein (IAP) family comprises a collection of apoptosis-negative modulators characterized by at least one single baculovirus IAP repeat (BIR) domain in its N-terminal region. While the involvement of the IAP family is associated with the initiation and progression of numerous tumours, its specific role in HNSCC remains poorly understood. Thus, this study aimed to comprehensively examine changes in gene expression, immunomodulatory effects, prognosis, and functional enrichment of HNSCC utilising bioinformatics analysis. Elevated levels of distinct IAP family members were observed to varying degrees in HNSCC, with high BIRC2 expression indicating a worse prognosis. Additionally, Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to probe the enrichment of gene expression and biological processes related to the IAP family in HNSCC. The infiltration levels of immune cells were shown to be strongly associated with the IAP gene expression, as determined by subsequent analysis. Hence, BIRC2 could be an effective immunotherapy target for HNSCC. Collectively, novel knowledge of the biological roles and prognostic implications of IAP family members in HNSCC is presented in this study.

Feature Selection Based on Intrusive Outliers Rather Than All Instances.

Feature selection (FS) has recently attracted considerable attention in many fields. Highly-overlapping classes and skewed distributions of data within classes have been found in various classification tasks. Most existing FS methods are all instance-based, which ignores the significant differences in characteristics between the particular outliers and the main body of the class, causing confusion for classifiers. In this paper, we propose a novel supervised FS method, Intrusive Outliers-based Feature Selection (IOFS), to find out what kind of outliers lead to misclassification and exploit the characteristics of such outliers. In order to accurately identify the intrusive outliers (IOs), we provide a density-mean center algorithm to obtain the appropriate representative of a class. A special distance threshold is given to obtain the candidate for IOs. Combining with several metrics, mathematical formulations are provided to evaluate the overlapping degree of the intrusive class pairs. Features with high overlapping degrees are assigned to low rankings in IOFS method. An extension of IOFS based on a small number of extreme IOs, called E-IOFS, is also proposed. Three theoretical proofs are provided for the essential theoretical basis of IOFS. Experiments comparing against various state-of-the-art methods on eleven benchmark datasets show that IOFS is rational and effective, especially on the datasets with higher overlapping classes. And E-IOFS almost always outperforms IOFS.

Cervical Conjoined Nerve Root During Posterior Percutaneous Endoscopic Cervical Diskectomy.

Cervical conjoined nerve root is rare, and medical imaging, such as magnetic resonance imaging and computed tomography, cannot give an accurate preoperative diagnosis.1 Treatment of cervical radiculopathy with root anomaly can be challenging. We report here a case of cervical conjoined nerve root with a 2-dimensional video. A 41-year-old woman without systemic disease presented with a 2-month history of neck and bilateral shoulder pain, upper back tightness, and left upper limb painful numbness, especially of the first to third fingers. The visual analog scale scores of the neck and left upper limb were 4 and 8, respectively. The Neck Disability Index was 26. The diagnosis of retrolisthesis at C5-C6 and cervical disk herniation with severe neuroforaminal narrowing at the left C5-C6 and C6-C7 levels were made with radiographs and magnetic resonance imaging. Posterior percutaneous endoscopic cervical diskectomy at the left C5-C6 and C6-C7 levels via an interlaminar shoulder approach was performed. During operation, a left-sided conjoined nerve root at the C6-C7 level was found (Video 1). Upon removal of a calcified disk and osteophytes at the C6-C7 level, the dura was torn slightly with traction without nerve root exposure or cerebrospinal fluid leakage. The 3-month postoperative follow-up visual analog scale scores of the neck and left upper limb were 0 and 0, respectively. The 3-month postoperative follow-up Neck Disability Index was 1. Posterior percutaneous endoscopic cervical diskectomy has become a favored treatment for cervical disk herniation because it offers sufficient decompression, smaller incisions, minimal blood loss, shorter hospital stay, and less postoperative pain.2,3 Nonetheless, if unexpected variation of the nerve root is noted during decompressive procedures, iatrogenic nerve root injury is a risk. Seven cases of cervical nerve root anomalies have been reported; all were found during posterior cervical surgery, which may indicate that the posterior approach provides better visualization of nerve root variants, especially in endoscopic surgery.4.

Termitidicoccus mucosus gen. nov. sp. nov. a novel Verrucomicrobiota species isolated from Reticulitermes chinensis gives insights of high adaptability of symbiotic bacteria to termite gut ecosystem.

Verrucomicrobiota is widely distributed in various habitats including insect guts. It was found to be prevalent in almost all investigated termite guts, whereas their physiological functions are not very clear. In this study we characterized the physiological and genomic properties of Verrucomicrobiota strain TSB47T isolated from Reticulitermes chinensis. The cells of strain TSB47T were Gram-stain-negative, non-motile, and non-spore-forming coccoid with one or more warts. 16S rRNA gene analysis showed that the closest relatives of strain TSB47T were Opitutaceae strain TAV1 and Ereboglobus luteus Ho45T (98.3% and 95.4% sequence similarity, respectively). Whole genome analysis revealed that there are a large number of glycoside hydrolase genes, amino acid metabolism genes, complete Mo-Fe nitrogenase and Fe-Fe nitrogenase gene clusters, as well as cbb3-type cytochrome oxidase gene in the genome of strain TSB47T. Strain TSB47T grows well under anaerobic and microaerophilic conditions with a strong tolerance to oxygen. Physiological and genomic characters of strain TSB47T indicated its high adaptability to termite gut ecosystem. Based on phenotypic and phylogenetic evidence, we suggest strain TSB47T as the type species of a novel genus in the family Opitutaceae, for which the name Termitidicoccus mucosus sp. nov. is proposed. The type strain is TSB47T (CCTCC AB2022447T; KCTC 102044T).

Exosome derived from tumor-associated macrophages: biogenesis, functions, and therapeutic implications in human cancers.

Tumor-associated macrophages (TAMs), one of the most abundant immune cell types in the tumor microenvironment (TME), account for approximately 50% of the local hematopoietic cells. TAMs play an important role in tumorigenesis and tumor development through crosstalk between various immune cells and cytokines in the TME. Exosomes are small extracellular vesicles with a diameter of 50-150 nm, that can transfer biological information (e.g., proteins, nucleic acids, and lipids) from secretory cells to recipient cells through the circulatory system, thereby influencing the progression of various human diseases, including cancer. Recent studies have suggested that TAMs-derived exosomes play crucial roles in malignant cell proliferation, invasion, metastasis, angiogenesis, immune responses, drug resistance, and tumor metabolic reprogramming. TAMs-derived exosomes have the potential to be targeted for tumor therapy. In addition, the abnormal expression of non-coding RNAs and proteins in TAMs-derived exosomes is closely related to the clinicopathological features of patients with cancer, and these exosomes are expected to become new liquid biopsy markers for the early diagnosis, prognosis, and monitoring of tumors. In this review, we explored the role of TAMs-derived exosomes in tumorigenesis to provide new diagnostic biomarkers and therapeutic targets for cancer prevention.

Joint Associations of Pregnancy Complications and Postpartum Maternal Renal Biomarkers With Severe Cardiovascular Morbidities: A US Racially and Ethnically Diverse Prospective Birth Cohort Study.

Background Pregnancy complications are risk factors for cardiovascular disease (CVD). Little is known about the role of renal biomarkers measured shortly after delivery, individually or in combination with pregnancy complications, in predicting subsequent severe maternal CVD. Methods and Results This study included 566 mothers of diverse races and ethnicities from the Boston Birth cohort, enrolled at delivery and followed prospectively. Plasma creatinine and CysC (cystatin C) were measured 1 to 3 days after delivery. CVD during follow-up was defined by physician diagnoses in electronic medical records. Associations of renal biomarkers and pregnancy complications with time-to-CVD events were assessed using Cox proportional hazards models. During an average of 10.3±3.2 years of follow-up, 30 mothers developed 1 or more CVDs. Only a modest association was observed between creatinine and risk of CVD. In comparison, we found that per 0.1 mg/L increase of CysC was associated with a hazard ratio (HR) of 1.2 (95% CI, 1.1-1.4) for CVD after adjusting for covariates. Compared with those without preeclampsia and with normal CysC level (≤75th percentile), mothers with preeclampsia and elevated CysC (>75th percentile) had the highest risk of CVD (HR, 4.6 [95% CI, 1.7-17.7]), whereas mothers with preeclampsia only or with elevated CysC only did not have significantly increased CVD risk. Similar synergistic effects for CVD were observed between CysC and preterm delivery. Conclusions In this sample of US, traditionally underrepresented multiracial and multiethnic high-risk mothers, elevated maternal plasma CysC, independently and jointly with pregnancy complications, increased risk of CVD later in life. These findings warrant further investigation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03228875.

Phenotypic and Genetic Analyses of In Vitro Embryo Production Traits in Chinese Holstein Cattle.

Ovum pick up and in vitro embryo production (OPU-IVEP) is an essential technique in the dairy industry. The production efficiency of OPU-IVEP is significantly influenced by various factors, and phenotypic and genetic characteristics are highly variable in different populations. The objectives of this study were (1) to reveal the phenotypic characteristics, including population distribution, and impacts of donor age and month on in vitro embryo production and (2) to estimate genetic parameters for five in vitro embryo production traits in Chinese Holstein cattle. A total of 7311 OPU-IVEP records of 867 Holstein heifers from August 2021 to March 2023 were collected in this study. Five in vitro embryo production traits were defined, including the number of cumulus-oocyte complexes (NCOC), the number of cleaved embryos (NCLV), the number of grade I embryos (NGE), and the proportion of NCLV to NCOC (PCLV) and NGE to NCOC (PGE). A univariate repeatability animal model was employed to estimate heritability and repeatability, and a bivariate repeatability animal model was employed to estimate the genetic correlations among five in vitro embryo production traits. It was found that the in vitro embryo production traits were significantly influenced by season, as the NGE and PGE were significantly decreased from June to August. In addition, the production efficiency of OPU-IVEP was also influenced by donor age. On the observed scale, the estimates of heritability were 0.33 for NCOC, 0.24 for NCLV, 0.16 for NGE, 0.06 for PCLV, and 0.10 for PGE, respectively. On the log-transformed scale, the estimates of heritability of NCOC, NCLV, and NGE were 0.34, 0.18, and 0.13. The genetic correlations among NCOC, NCLV, and NGE ranged from 0.61 (NCLV and NGE) to 0.95 (NCOC and NCLV), considering both scales. However, there were low genetic correlations between NCOC and proportion traits (PCLV and PGE) on both the observed scale and the log-transformed scale. In the end, the variation in Chinese Holstein cattle was found to be considerable. The EBV value and average NCOC, NGE, and PGE for the top 10% donors presented extreme differences to those for the bottom 10% donors for NCOC (24.02 versus 2.60), NGE (3.42 versus 0.36), and PGE (30.54% versus 3.46%). Overall, the results of this study reveal that in vitro embryo production traits are heritable with low to high heritability, and the count traits (NCOC, NCLV, and NGE) and proportion traits (PCLV and PGE) reflect different aspects of in vitro embryo production and should be incorporated into genetic selection for improving the embryo production efficiency of dairy cattle.

Forecasting the effects of vaccination on the COVID-19 pandemic in Malaysia using SEIRV compartmental models.

OBJECTIVES: This study aimed to develop susceptible-exposed-infectious-recovered-vaccinated (SEIRV) models to examine the effects of vaccination on coronavirus disease 2019 (COVID-19) case trends in Malaysia during Phase 3 of the National COVID-19 Immunization Program amidst the Delta outbreak. METHODS: SEIRV models were developed and validated using COVID-19 case and vaccination data from the Ministry of Health, Malaysia, from June 21, 2021 to July 21, 2021 to generate forecasts of COVID-19 cases from July 22, 2021 to December 31, 2021. Three scenarios were examined to measure the effects of vaccination on COVID-19 case trends. Scenarios 1 and 2 represented the trends taking into account the earliest and latest possible times of achieving full vaccination for 80% of the adult population by October 31, 2021 and December 31, 2021, respectively. Scenario 3 described a scenario without vaccination for comparison. RESULTS: In scenario 1, forecasted cases peaked on August 28, 2021, which was close to the peak of observed cases on August 26, 2021. The observed peak was 20.27% higher than in scenario 1 and 10.37% lower than in scenario 2. The cumulative observed cases from July 22, 2021 to December 31, 2021 were 13.29% higher than in scenario 1 and 55.19% lower than in scenario 2. The daily COVID-19 case trends closely mirrored the forecast of COVID-19 cases in scenario 1 (best-case scenario). CONCLUSIONS: Our study demonstrated that COVID-19 vaccination reduced COVID-19 case trends during the Delta outbreak. The compartmental models developed assisted in the management and control of the COVID-19 pandemic in Malaysia.

The effects of the COVID-19 pandemic on dengue cases in Malaysia.

Background: Globally, the COVID-19 pandemic has affected the transmission dynamics and distribution of dengue. Therefore, this study aims to describe the impact of the COVID-19 pandemic on the geographic and demographic distribution of dengue incidence in Malaysia. Methods: This study analyzed dengue cases from January 2014 to December 2021 and COVID-19 confirmed cases from January 2020 to December 2021 which was divided into the pre (2014 to 2019) and during COVID-19 pandemic (2020 to 2021) phases. The average annual dengue case incidence for geographical and demographic subgroups were calculated and compared between the pre and during the COVID-19 pandemic phases. In addition, Spearman rank correlation was performed to determine the correlation between weekly dengue and COVID-19 cases during the COVID-19 pandemic phase. Results: Dengue trends in Malaysia showed a 4-year cyclical trend with dengue case incidence peaking in 2015 and 2019 and subsequently decreasing in the following years. Reductions of 44.0% in average dengue cases during the COVID-19 pandemic compared to the pre-pandemic phase was observed at the national level. Higher dengue cases were reported among males, individuals aged 20-34 years, and Malaysians across both phases. Weekly dengue cases were significantly correlated (ρ = -0.901) with COVID-19 cases during the COVID-19 pandemic. Conclusion: There was a reduction in dengue incidence during the COVID-19 pandemic compared to the pre-pandemic phase. Significant reductions were observed across all demographic groups except for the older population (>75 years) across the two phases.

Cerebrospinal Fluid Alzheimer's Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. OBJECTIVE: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. METHODS: Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aß42, Aß40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. RESULTS: Among participants who progressed to MCI, Aß42/Aß40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aß 42/Aß40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aß 42/Aß40), and t-tau/(Aß 42/Aß 40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aß 42/Aß 40), and p-tau181/(Aß 42/Aß 40). CONCLUSIONS: These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD.

Research on equity of medical resource allocation in Yangtze River Economic Belt under healthy China strategy.

Objective: This study aimed to assess the fairness of medical resource allocation in the Yangtze River Economic Belt, based on the Healthy China strategy. It aimed to identify the issues with resource allocation fairness and provide optimization suggestions. Methods: To assess the allocation fairness from a geographical population perspective, the study used the Health Resource Concentration and Entropy Weight TOPSIS methods. Additionally, the study analyzed the allocation fairness from an economic level angle, using the Concentration Curve and Concentration Index. Results: The study found that the downstream area had higher resource allocation fairness than the midstream and upstream areas. The middle reaches had more resources than the upper and lower reaches, based on population concentration. The Entropy Weight TOPSIS method found that Shanghai, Zhejiang, Chongqing, and Jiangsu had the highest comprehensive score index of agglomeration. Furthermore, from 2013 to 2019, the fairness of medical resource distribution gradually improved for different economic levels. Government health expenditure and medical beds were distributed more equitably, while general practitioners had the highest level of unfairness. However, except for medical and health institutions, traditional Chinese medicine institutions, and primary health institutions, other medical resources were mostly distributed to areas with better economic conditions. Conclusion: The study found that the fairness of medical resource allocation in the Yangtze River Economic Belt varied greatly based on geographical population distribution, with inadequate spatial accessibility and service accessibility. Although the fairness of distribution based on economic levels improved over time, medical resources were still concentrated in better economic areas. The study recommends improving regional coordinated development to enhance the fairness of medical resource allocation in the Yangtze River Economic Belt.

External validation of a deep learning detection system for glaucomatous optic neuropathy: a real-world multicentre study.

OBJECTIVES: To conduct an external validation of an automated artificial intelligence (AI) diagnostic system using fundus photographs from a real-life multicentre cohort. METHODS: We designed external validation in multiple scenarios, consisting of 3049 images from Qilu Hospital of Shandong University in China (QHSDU, validation dataset 1), 7495 images from three other hospitals in China (validation dataset 2), and 516 images from high myopia (HM) population of QHSDU (validation dataset 3). The corresponding sensitivity, specificity and accuracy of this AI diagnostic system to identify glaucomatous optic neuropathy (GON) were calculated. RESULTS: In validation datasets 1 and 2, the algorithm yielded accuracy of 93.18% and 91.40%, area under the receiver operating curves (AUC) of 95.17% and 96.64%, and significantly higher sensitivity of 91.75% and 91.41%, respectively, compared to manual graders. On the subsets complicated with retinal comorbidities, such as diabetic retinopathy or age-related macular degeneration, in validation datasets 1 and 2, the algorithm achieved accuracy of 87.54% and 93.81%, and AUC of 97.02% and 97.46%, respectively. In validation dataset 3, the algorithm achieved comparable accuracy of 81.98% and AUC of 87.49%, with a sensitivity of 83.61% and specificity of 81.76% on GON recognition specifically in the HM population. CONCLUSIONS: With acceptable generalization capability across varying levels of image quality, different clinical centres, or certain retinal comorbidities, such as HM, the automatic AI diagnostic system had the potential to provide expert-level glaucoma detection.

Pseudoaneurysm formation of segmental artery with retroperitoneal hematoma after percutaneous transpedicular screws insertion.

Vascular injury is one of the potential complications of percutaneous transpedicular screws fixation. Carefully review the vascular anatomy preoperatively is important. Once unexpected low blood pressure or anemia occurs, vascular injury should be taken into consideration.

Impact of Accessory Corpus Luteum Induced by Gonadotropin-Releasing Hormone or Human Chorionic Gonadotropin on Pregnancy Rates of Dairy Cattle following Embryo Transfer: A META-Analysis.

The circulation of progesterone (P4) concentrations of recipients has positive correlations with embryo survival and pregnancy success of embryo transfer (ET) in dairy cows. One strategy to improve P4 concentration is the administration of gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG), thereby inducing the formation of accessory corpus luteum (CL). This study aimed at determining the efficacy of GnRH or hCG treatment regarding embryo transfer (ET) and providing a better clinical veterinary practice guidance. A meta-analysis was conducted on the data from 2048 treated recipient cows and 1546 untreated cows. By inducing the formation of accessory CL with GnRH (100 µg), GnRH analogue Buserelin (8-10 µg), or hCG (≥1500 IU) 5-11 days after synchronized ovulation, hCG alone achieved an improvement (RR = 1.39, p < 0.05), while GnRH and GnRH analogue did not result in significant changes (RR = 1.04, p = 0.26). Treatment with GnRH or hCG 5-7 days after synchronized ovulation was associated with increased chances of pregnancy compared with later treatment (11-14 days). Owing to the treatment, the pregnancy rate of cows with very poor fertility (<40%) was improved, while that of cows with good fertility (≥40%) was not affected. Treatment with GnRH or hCG greatly improved pregnancy rates of parous lactating cows (RR = 1.32, p < 0.05) compared with heifers (RR = 1.02, p > 0.05). Additionally, as indicated by pregnancy loss analysis, the treatment had no benefit on late embryo/early fetus survival at days 28-81. In conclusion, the induction of accessory CL with GnRH or hCG may benefit fertility and have important implications for the management of reproductive performance in the dairy industry.

Simultaneous hypothesis testing for multiple competing risks in comparative clinical trials.

Competing risks data are commonly encountered in randomized clinical trials or observational studies. Ignoring competing risks in survival analysis leads to biased risk estimates and improper conclusions. Often, one of the competing events is of primary interest and the rest competing events are handled as nuisances. These approaches can be inadequate when multiple competing events have important clinical interpretations and thus of equal interest. For example, in COVID-19 in-patient treatment trials, the outcomes of COVID-19 related hospitalization are either death or discharge from hospital, which have completely different clinical implications and are of equal interest, especially during the pandemic. In this paper we develop nonparametric estimation and simultaneous inferential methods for multiple cumulative incidence functions (CIFs) and corresponding restricted mean times. Based on Monte Carlo simulations and a data analysis of COVID-19 in-patient treatment clinical trial, we demonstrate that the proposed method provides global insights of the treatment effects across multiple endpoints.

Joint associations of pregnancy complications and postpartum maternal renal biomarkers with severe cardiovascular morbidities: A US racially diverse prospective birth cohort study.

Rationale & Objective: Pregnancy complications are risk factors for cardiovascular diseases (CVD). Little is known about the role of renal biomarkers measured shortly after delivery, individually or in combination with pregnancy complications, in predicting subsequent severe maternal CVD. Methods: This study included 576 mothers of diverse ethnicities from the Boston Birth cohort, enrolled at delivery and followed prospectively. Plasma creatinine and cystatin C were measured 1-3 days after delivery. CVD during follow-up was defined by physician diagnoses in electronic medical records. Associations of renal biomarkers and pregnancy complications with time-to-CVD events were assessed using Cox proportional hazards models. Results: During an average of 10.3±3.2 years of follow-up, 34 mothers developed one or more CVD events. Although no significant associations were found between creatinine and risk of CVD, per unit increase of cystatin C (CysC) was associated with a hazard ratio (HR) of 5.21 (95%CI = 1.49-18.2) for CVD. A borderline significant interactive effect was observed between elevated CysC (≥75th percentile) and preeclampsia. Compared to those without preeclampsia and with normal CysC level (<75 th percentile), mothers with preeclampsia and elevated CysC had the highest risk of CVD (HR=3.8, 95%CI = 1.4-10.2), while mothers with preeclampsia only or with elevated CysC only did not have significantly increased CVD risk. Similar synergistic effects for CVD were observed between CysC and preterm delivery. Conclusions: In this sample of US, traditionally under-represented multi-ethnic high-risk mothers, elevated maternal plasma cystatin C and pregnancy complications synergistically increased risk of CVD later in life. These findings warrant further investigation. Clinical Perspectives: What is new?Maternal postpartum elevated levels of cystatin C are independently associated with higher risk of cardiovascular diseases (CVD) later in life.Maternal pregnancy complications coupled with postpartum elevated levels of cystatin C synergistically increased future risk of CVD.What are the clinical implications?These findings, if further confirmed, suggest that women with pregnancy complications and elevated postpartum cystatin C may be at particular high risk for CVD later in life compared to women without these risk factors.

Expression profile and prognostic values of GATA family members in kidney renal clear cell carcinoma.

To investigate the possible diagnostic and prognostic biomarkers of kidney renal clear cell carcinoma (KIRC), an integrated study of accumulated data was conducted to obtain more reliable information and more feasible measures. Using the Tumor Immune Estimation Resource (TIMER), University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), Human Protein Atlas (HPA), Kaplan-Meier plotter database, Gene Expression Profiling Interactive Analysis (GEPIA2) database, cBioPortal, and Metascape, we analyzed the expression profiles and prognoses of six members of the GATA family in patients with KIRC. Compared to normal samples, KIRC samples showed significantly lower GATA2/3/6 mRNA and protein expression levels. KIRC's pathological grades, clinical stages, and lymph node metastases were closely related to GATA2 and GATA5 levels. Patients with KIRC and high GATA2 and GATA5 expression had better overall survival (OS) and recurrence-free survival (RFS), while those with higher expression of GATA3/4/6 had worse outcomes. The role and underlying mechanisms of the GATA family in cell cycle, cell proliferation, metabolic processes, and other aspects were evaluated based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. Furthermore, we found that infiltrating immune cells were highly correlated with GATA expression profiles. These results showed that GATA family members may serve as prognostic biomarkers and therapeutic targets for KIRC.

Longitudinal genome-wide association studies of milk production traits in Holstein cattle using whole-genome sequence data imputed from medium-density chip data.

Longitudinal traits, such as milk production traits in dairy cattle, are featured by having phenotypic values at multiple time points, which change dynamically over time. In this study, we first imputed SNP chip (50-100K) data to whole-genome sequence (WGS) data in a Chinese Holstein population consisting of 6,470 cows. The imputation accuracies were 0.88 to 0.97 on average after quality control. We then performed longitudinal GWAS in this population based on a random regression test-day model using the imputed WGS data. The longitudinal GWAS revealed 16, 39, and 75 quantitative trait locus regions associated with milk yield, fat percentage, and protein percentage, respectively. We estimated the 95% confidence intervals (CI) for these quantitative trait locus regions using the logP drop method and identified 581 genes involved in these CI. Further, we focused on the CI that covered or overlapped with only 1 gene or the CI that contained an extremely significant top SNP. Twenty-eight candidate genes were identified in these CI. Most of them have been reported in the literature to be associated with milk production traits, such as DGAT1, HSF1, MGST1, GHR, ABCG2, ADCK5, and CSN1S1. Among the unreported novel genes, some also showed good potential as candidate genes, such as CCSER1, CUX2, SNTB1, RGS7, OSR2, and STK3, and are worth being further investigated. Our study provided not only new insights into the candidate genes for milk production traits, but also a general framework for longitudinal GWAS based on random regression test-day model using WGS data.