Miracle-dz/UniFAR-FTUs huggingface dataset:
Improvement of early mortality in single‐unit cord blood transplantation for Japanese adults from 1998 to 2017

The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality in CBT. We evaluated early overall survival (OS), non‐relapse mortality (NRM), neutrophil engraftment, acute graft‐vs‐host disease, and cause of early death among 9678 adult patients who received single‐unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry‐based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long‐term OS after CBT.
Relapse recovery

Objective To determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability accumulation in a multiple sclerosis (MS) evidence-based setting. Methods We analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale [EDSS] score of 0 at enrollment maintained ≥6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit ≥ median). Time from recovery assignment to future disability (EDSS score ≥ 2.5 or ≥4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs). Results One hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score ≥2.5 outcome were: delayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR6th-month: 0.67, p = 0.207; HR1st-year: 0.40, p = 0.027), immediate treatment without good recovery (HR6th-month: 0.56, p = 0.061; HR1st-year: 0.40, p = 0.011), and immediate treatment with good recovery (HR6th-month: 0.43, p = 0.014; HR1st-year: 0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score ≥4.0 outcome events were available to study. Conclusions In patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse. Classification of evidence This study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.
Cyclooxygenase-2 Gene Polymorphisms –765G>C and –1195A>G and Mycosis Fungoides Risk

Background: Cyclooxygenase-2 (COX-2) is an inducible modulator of inflammation that acts through increasing prostaglandin levels and has been described as a major mediator linking inflammation to cancer. Previous studies supported that COX-2–765G>C and –1195A>G polymorphisms were associated with increased risk of several solid tissue cancers as well as some hematological malignancies. Objective: The aim of the study was to elucidate the association between functional COX-2 genotypes (–765G>C and –1195A>G) polymorphisms and the risk of developing mycosis fungoides (MF). Methods: This was a hospital-based, case-control study of 70 MF patients and 100 MF-free controls. We genotyped COX-2 –1195A>G, –765G>C, and –8473T>C polymorphisms by using the PCR-restriction fragment length polymorphism method. Results: The AA genotype in the COX-2 –1195A>G gene polymorphism and the GC genotype in the COX-2 −765G>C gene were significantly more frequent among MF patients compared to controls (p< 0.001 and p = 0.002, respectively). Conclusion: The results indicate a possible role of COX-2 genes in the pathogenesis of MF. These novel findings may allow for notable future advances, as it will enable the identification of the individuals most susceptible to MF.
Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer.

BACKGROUND The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA. MATERIALS AND METHODS A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data. RESULTS RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer-predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status. CONCLUSION Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA. IMPLICATIONS FOR PRACTICE Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right- and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right- and left-sided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.
Angelica polysaccharide ameliorates memory impairment in Alzheimer’s disease rat through activating BDNF/TrkB/CREB pathway

This study aimed to investigate the effect of Angelica sinensis polysaccharides (ASP) on Alzheimer’s disease (AD) and its underlying mechanisms. In our study, we build the AD model by injecting Aβ25–35. Morris water maze (MWM) was applied to investigate learning and memory. Moreover, neurotransmitters, free radical, and inflammatory factors were also measured. Pathological change and neuronal death in hippocampus CA1, CA3, and DG region were detected by HE staining and Nissl staining. The neuronal apoptosis was detected by TUNEL. The expressions of caspase-3, Bcl-2 and Bax were measured by immunohistochemistry and Western blot. The expressions of BDNF, TrkB, p-Akt, Akt, p-CREB, and CREB were measured by Western blot. Our results showed that ASP could ameliorate spatial learning and memory deficiency in AD rats. ASP decreased AchE level and increased the levels of Ach and chAT in AD rats. ASP could increase the activity of SOD and CAT, decrease MDA activity, and inhibit the expression levels of inflammatory factors and neurons apoptosis in AD rats. Pathological change of hippocampus CA1, CA3, and DG region was ameliorated by ASP. In addition, the effects of ASP were reversed by K252a (TrkB inhibitor). Our study demonstrated that ASP could ameliorate memory impairment in AD rat through activating BDNF/TrkB/CREB pathway. Impact statement The present study demonstrated that ASP could ameliorate memory impairment through regulation of the balance of neurotransmitters, free radical metabolism, inflammation, and neurons apoptosis. Moreover, the mechanism of ASP on memory impairment may be related to BDNF/TrkB/CREB pathway in AD. Our research provides an innovatively regulatory mechanism about the ASP in AD rat and points a new way to the treatment of AD.
LDAKM-EIoT: Lightweight Device Authentication and Key Management Mechanism for Edge-Based IoT Deployment

In recent years, edge computing has emerged as a new concept in the computing paradigm that empowers several future technologies, such as 5G, vehicle-to-vehicle communications, and the Internet of Things (IoT), by providing cloud computing facilities, as well as services to the end users. However, open communication among the entities in an edge based IoT environment makes it vulnerable to various potential attacks that are executed by an adversary. Device authentication is one of the prominent techniques in security that permits an IoT device to authenticate mutually with a cloud server with the help of an edge node. If authentication is successful, they establish a session key between them for secure communication. To achieve this goal, a novel device authentication and key management mechanism for the edge based IoT environment, called the lightweight authentication and key management scheme for the edge based IoT environment (LDAKM-EIoT), was designed. The detailed security analysis and formal security verification conducted by the widely used “Automated Validation of Internet Security Protocols and Applications (AVISPA)” tool prove that the proposed LDAKM-EIoT is secure against several attack vectors that exist in the infrastructure of the edge based IoT environment. The elaborated comparative analysis of the proposed LDAKM-EIoT and different closely related schemes provides evidence that LDAKM-EIoT is more secure with less communication and computation costs. Finally, the network performance parameters are calculated and analyzed using the NS2 simulation to demonstrate the practical facets of the proposed LDAKM-EIoT.
Hourly Fluid Balance in Patients Receiving Continuous Renal Replacement Therapy

Introduction: Little is known about early (first 48 h) hourly and cumulative fluid balance (FB) during continuous renal replacement therapy (CRRT). Objectives: To study the characteristics and outcome associations of early hourly and cumulative FB. Methods: We studied FB in CRRT patients (2016–2018). Results: Among 350 patients, mean hourly FB became negative after 20 CRRT hours, but within 6 CRRT hours in patients with baseline fluid overload. A negative early FB was never achieved in patients receiving vasopressor therapy (p < 0.001). Mortality was 31%. The percentage of hourly negative FB was independently associated with decreased ICU mortality. A time-weighted hourly FB between 18.5 and –33 mL/h was also significantly and independently associated with decreased mortality. Conclusions: In CRRT patients, an early FB conservative approach is possible, modulated by patient characteristics, and associated with a low mortality. Moreover, avoidance of an early positive FB is associated with decreased mortality.
The effect of anticipatory stress and openness and engagement on subsequently perceived sleep quality–An Experience Sampling Method study

High stress levels can influence sleep quality negatively. If this also applies to anticipatory stress is poorly documented, however. Across insomnia severity levels, this study examined participants’ evening levels of (a) anticipatory stress and (b) their skills hypothesized to downregulate the impact of stress, namely openness to internal experiences and continuous engagement in meaningful activities (openness and engagement) and their association with the quality of the subsequent night's sleep. The moderating role of insomnia severity was also tested. We used a quasi‐experimental longitudinal design with Experience Sampling Method using smartphones over the course of 1 week (3,976 assessments; 93.2% of prompted queries). Participants recorded their sleep quality, anticipatory stress, and openness and engagement within their daily context. Participants included in the study were diagnosed with major depressive disorder (n = 118), social phobia (n = 47) or belonged to the control group (n = 119). Both anticipatory stress and openness and engagement predicted subsequent sleep quality. Diagnostic group was associated with overall sleep quality, but did not interact with the predictors. These findings were invariant across levels of self‐reported insomnia severity. Furthermore, openness and engagement and anticipatory stress did not interact in their effect on sleep quality. The results suggest that both stress reduction and increased openness and engagement are associated with improved subjective sleep quality on a day to day basis, regardless of insomnia severity. Targeting these variables may help improve sleep quality. Future research should disentangle the effects of openness and engagement on anticipatory stress.
SEROPREVALENCE OF HEPATITIS B AND C AMONG BLOOD DONORS IN HYDERABAD, PAKISTAN

Background: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the main transfusion-transmitted infections (TTIs) especially in developing countries like Pakistan. Hence it is mandatory to screen all blood donors for both important infections. The objective of the present study was to determine the prevalence of HCV and HBV seropositivity among blood donors at Hyderabad, Pakistan. Material & Methods: Blood donations of 6 months period were studied to determine the prevalence of HBV and HCV seropositivity. During the study period, a total of 2696 blood donors were screened for the presence of Anti-HCV and Hepatitis B surface antigen (HBsAg) using chromatographic immunoassay kit as recommended by the manufacturer. HBV and HCV positivity were the two research variable. As nominal data, these were analyzed as number and percentage. Results: A total of 2696 blood donation were collected during six month period from January 2012 to June 2012. The data revealed that 93 (3.45%) donors were positive for HCV and 49 (1.82) blood donors were positive for HBV. In addition, the prevalence of co-infection of HBV and HCV appeared very low in this study and only two (0.074%) donors were positive for both HCV and HBV. Conclusion: Due to the high prevalence of the two main transfusion-transmitted infections of Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in our setup, it is mandatory to screen all blood donors for both these important infections and to adopt strict measures in selection of blood donors.
Sexual activity by marital status and age: a comparative perspective

Abstract This paper presents an analysis of trends in sexual activity by marital status and age, and their associations with contraceptive use. Understanding levels of, and trends in, sexual activity is important for assessing the needs for family planning services and for analysing commonly used family planning indicators. Data were taken from 220 Demographic and Health Surveys (DHSs) and 62 Multiple Indicator Cluster Surveys (MICSs) to provide insights into sexual activity by marital status and age in a total of 94 countries in different regions of the world. The results show the sensitivity of the indicator with respect to the definition of currently sexually active, based on the timing of last sexual intercourse (during the last 4 weeks, 3 months, or 1 year). Substantial diversity in sexual activity by marital status and age was demonstrated across countries. The proportion of married women reporting recent sexual activity (sexual intercourse during the last 4 weeks) ranged from 50% to 90%. The proportion of unmarried women reporting recent sexual activity did not exceed 50% in any of the 94 countries with available data, but showed substantial regional differences: it appeared to be rare in Asia and extremely varied within Africa, Europe and Latin America and the Caribbean. Among married women, sexual activity did not vary much by age group, while for unmarried women, there was an inverted U-pattern by age, with the youngest age group (15–19 years old) having the lowest proportion sexually active. The proportion of women who reported currently using contraception and reported not being sexually active varied by the contraceptive method used and was overall much greater among unmarried women. The evidence presented in this paper can be used to improve family planning policies and programmes to serve the diverse needs, for example regarding method choice and service provision, of unmarried women.
Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas

Malignant peripheral nerve sheath tumors (MPNST) frequently overexpress eukaryotic initiation factor 4F components, and the eIF4A inhibitor silvestrol potently suppresses MPNST growth. However, silvestrol has suboptimal drug-like properties, including a bulky structure, poor oral bioavailability (<2%), sensitivity to MDR1 efflux, and pulmonary toxicity in dogs. We compared ten silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable with silvestrol. Structure–activity relationship analysis revealed that the dioxanyl ring present in silvestrol was dispensable for, but may enhance, cytotoxicity. Both DDR and Roc arrested MPNST cells at G2–M, increased the sub-G1 population, induced cleavage of caspases and PARP, and elevated the levels of the DNA-damage response marker γH2A. X, while decreasing the expression of AKT and ERK1/2, consistent with translation inhibition. Unlike silvestrol, DDR and Roc were not sensitive to MDR1 inhibition. Pharmacokinetic analysis confirmed that Roc had 50% oral bioavailability. Importantly, Roc, when administered intraperitoneally or orally, showed potent antitumor effects in an orthotopic MPNST mouse model and did not induce pulmonary toxicity in dogs as found with silvestrol. Treated tumors displayed degenerative changes and had more cleaved caspase-3–positive cells, indicative of increased apoptosis. Furthermore, Roc effectively suppressed the growth of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma cells and patient-derived xenografts. Both Roc- and DDR-treated sarcoma cells showed decreased levels of multiple oncogenic kinases, including insulin-like growth factor-1 receptor. The more favorable drug-like properties of DDR and Roc and the potent antitumor activity of Roc suggest that these rocaglamides could become viable treatments for MPNST and other sarcomas.
Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation

Objective To assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state. Methods We studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals. Results The index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis. Conclusion We report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.
Endurance and resistance training mitigate the negative consequences of depression on synaptic plasticity through different molecular mechanisms

Abstract Purpose/aim of the study: To investigate the effect and molecular mechanism of endurance and resistance training on synaptic plasticity in chronic stressed depression rats. Materials and methods: Chronic unpredictable mild stress (CUMS) was used to establish depressive rats model. Healthy male SD rats were randomly divided into 4 groups (control, CUMS, AE, and RT). The animals in AE and RT groups were respectively subjected to continuous treadmill running and intermittent weight-bearing treadmill training for 8 weeks after CUMS. Forced swimming test (FST) was used to evaluate behavior of rats. The flow cytometry was used to detect the hippocampal neuronal apoptosis. LTP in hippocampal CA1 region were analyzed by electrophysiology. The expressions of various mRNA and proteins related to synaptic function were measured using RT-PCR, Western blot or immunohistochemistry in the hippocampus. Results: Results shown that rats exhibited depressive behavior after CUMS stimulation, specifically immobility time was increased and swimming time and climbing time were reduced in rats during FST. After training, AE and RT all attenuated CUMS-induced depressive behavior of rats. AE and RT reduced apoptosis rate of hippocampal neuron and increased PS amplitude and fEPSPs slope after CUMS stimulation. After CUMS stimulation, AE promoted mRNA expressions, including BDNF, mTOR, TrkB, Syn, Syp, CaMKIIβ, and DRD5, and increased protein expressions, including IGF-1, PGC-1α, ERRβ, and FNDC5. While RT promoted mRNA expressions, including IGF-1, mTOR, Akt, Syn, and Syp, and improved protein expressions, including IGF-1, IGF-1R, and p-Akt. Conclusions: In conclusion, AE and RT for 8 weeks improved CUMS-induced depressive behavior, neuron injury and synaptic plasticity through regulating different signaling pathways.