Miracle-dz/UniFAR-FTUs huggingface dataset:
Competing against COVID-19: have we forgotten about student-athletes’ mental health?

INTRODUCTION Since the onset of the COVID-19 pandemic, athletes have expressed significant grief and frustration, attributed to alterations in routine, limited or modified training and the postponement of sporting events across the globe. 2 The additional strain from the removal of team support networks, which are often crucial components for stress management, can result in significant mental and physical health consequences, including low mood, sleep disruption, worsening diet and deconditioning. There is a current lack of attention on the unique mental health needs of studentathletes (ie, athletes who participate in secondary or postsecondary school sport programmes during their academic studies) during the COVID-19 pandemic, leading to a limited response from sporting organisations and academic institutions in addressing athletespecific concerns. Accordingly, the purpose of this editorial is to suggest directions for future research and provide recommendations to ensure the mental health needs of studentathletes are met during this period of extraordinary disruption and uncertainty.
Investigation of a Tumor Location-Specific Therapeutic Strategy for Intrahepatic Cholangiocarcinoma

Objective: An optimal therapeutic strategy for intrahepatic cholangiocarcinoma (ICC) has not yet been determined. Herein we focused on intrahepatic tumor location and retrospectively analyzed tumor characteristics depending on location to elucidate a location-specific therapeutic strategy for ICC. Methods: Sixty-five ICC patients were divided into three groups based on the distance between the innermost portion of the tumor and portal vein branches observed on preoperative imaging: peripheral, intermediate and central ICC. Results: Median disease-specific survival (DSS) of the peripheral ICC was not reached, whereas median DSS was 32.9 months in intermediate ICC and 25.2 months in central ICC (p <0.05). Vascular invasion was observed in all groups (56-92%). Bile duct invasion to the first branch of the hepatic duct was more commonly observed in central ICC (43%) compared with the peripheral and intermediate ICC (0-8%). Lymph node metastasis was not observed in peripheral ICC, whereas it was frequently observed in intermediate and central ICC (39-44%). A Cox regression analysis revealed sufficient RDI (≥58.3%) of adjuvant chemotherapy (AC) significantly increased the length of DSS (HR: 0.205). Based on these data, we have proposed a location-specific therapeutic strategy as follows: peripheral ICC requires anatomical resection without lymphadenectomy; intermediate ICC requires anatomical resection with lymphadenectomy and sufficient doses of AC; and central ICC requires anatomical resection with extrahepatic bile duct resection, caudate lobectomy, lymphadenectomy, and sufficient doses of AC. Conclusion: We propose an intrahepatic tumor location-specific therapeutic strategy for ICC. This information could contribute to the appropriate therapeutic management of patients with ICC.
Altered Renal Pathology in an Autoimmune Disease Mouse Model After Induction of Diabetes Mellitus

Abstract Diabetes mellitus (DM) is a predisposing factor for renal disorder progression and is referred to as diabetic kidney disease (DKD). However, there are no reports of DKD with an underlying autoimmune disorder. In this study, we compared the pathophysiological changes caused by DM induction after streptozotocin (STZ) injection in comparison with that in a control group receiving citrate buffer (CB) in the autoimmune disease model mice “BXSB/MpJ-Yaa” (Yaa) and the wild-type strain BXSB/MpJ. Both strains showed hyperglycemia after 12 weeks of STZ injection. Interestingly, the Yaa group developed membranous and proliferative glomerulonephritis, which tended to be milder glomerular lesions in the STZ group than in the CB group, as indicated by a decreased mesangial area and ameliorated albuminuria. Statistically, the indices for hyperglycemia and autoimmune abnormalities were negatively and positively correlated with the histopathological parameters for mesangial matrix production and glomerular proliferative lesions, respectively. STZ treatment induced renal tubular anisonucleosis and dilations in both strains, and they were more severe in Yaa. Significantly decreased cellular infiltration was observed in the Yaa group compared to the CB group. Thus, in DKD related to autoimmune nephritis, hyperglycemia modifies its pathology by decreasing the mesangial area and interstitial inflammation and aggravating renal tubular injury.
Effects of parathyroidectomy on plasma PTH fragments and heart rate variability in stage 5 chronic kidney disease patients

Abstract Introduction Circulating intact parathyroid hormone (iPTH) levels include full-length (1-84) PTH and long C-PTH fragments, but primarily (7-84) PTH, which have been reported to have antagonistic effects on the bones and kidneys. However, their effects on the cardiovascular system remain unclear. In this study, the relationships between the plasma PTH fragments levels and heart rate variability (HRV) in stage 5 chronic kidney disease (CKD5) patients are explored. Furthermore, the effects of parathyroidectomy (PTX) on the above indices are investigated. Methods In this cross-sectional study, 164 healthy controls and 354 CKD5 patients, including 208 secondary hyperparathyroidism (SHPT) subgroup with PTX, were enrolled. Circulating (7-84) PTH levels were calculated by subtracting plasma (1-84) PTH levels from iPTH levels. The HRV parameters were measured using a 24-hour Holter. Results The baseline levels of plasma iPTH, (1-84) PTH, and (7-84) PTH in the CKD5 patients were 930.40 (160.65, 1792.50) pg/mL, 448.60 (99.62, 850.45) pg/mL, and 468.20 (54.22, 922.55) pg/mL, respectively. In the CKD5 patients, plasma (1-84) PTH levels were independently correlated with the standard deviation of the normal-to-normal R-R intervals (SDNN) and the standard deviation of the five-minute average of the normal R-R intervals (SDANN). With a median follow up time of 6.50 months after PTX in the SHPT patients (n = 30), improved SDNN and SDANN markers were related with decreased (1-84) PTH levels. Furthermore, an improved SDNN was related with decreased (7-84) PTH levels. Conclusions The CKD5 patients’ baseline (1-84) PTH levels were correlated with the SDNN and SDANN. After PTX, an improved SDNN was related with decreased (1-84) PTH and (7-84) PTH levels, while improved SDANN was related with decreased (1-84) PTH levels. No antagonistic effects of (1-84) PTH and (7-84) PTH on HRV were found in the CKD5 patients.
Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real‐world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single‐nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18–0.98, P = 0.044) and 1236T‐2677T‐3435T (rs1128503‐rs2032582‐rs1045642) haplotype (HR 0.44, 95% CI, 0.20–0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C‐2677G‐3435C (HR 2.55, 95% CI, 1.03–6.36, P = 0.044) and 1236T‐2677G‐3435C (HR 5.88, 95% CI, 2.35–14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482‐2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16–0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.
Deep learning of resting-state electroencephalogram signals for three-class classification of Alzheimer’s disease, mild cognitive impairment and healthy ageing

Objective. This study aimed to produce a novel deep learning (DL) model for the classification of subjects with Alzheimer’s disease (AD), mild cognitive impairment (MCI) subjects and healthy ageing (HA) subjects using resting-state scalp electroencephalogram (EEG) signals. Approach. The raw EEG data were pre-processed to remove unwanted artefacts and sources of noise. The data were then processed with the continuous wavelet transform, using the Morse mother wavelet, to create time-frequency graphs with a wavelet coefficient scale range of 0–600. The graphs were combined into tiled topographical maps governed by the 10–20 system orientation for scalp electrodes. The application of this processing pipeline was used on a data set of resting-state EEG samples from age-matched groups of 52 AD subjects (82.3 ± 4.7 years of age), 37 MCI subjects (78.4 ± 5.1 years of age) and 52 HA subjects (79.6 ± 6.0 years of age). This resulted in the formation of a data set of 16197 topographical images. This image data set was then split into training, validation and test images and used as input to an AlexNet DL model. This model was comprised of five hidden convolutional layers and optimised for various parameters such as learning rate, learning rate schedule, optimiser, and batch size. Main results. The performance was assessed by a tenfold cross-validation strategy, which produced an average accuracy result of 98.9 ± 0.4% for the three-class classification of AD vs MCI vs HA. The results showed minimal overfitting and bias between classes, further indicating the strength of the model produced. Significance. These results provide significant improvement for this classification task compared to previous studies in this field and suggest that DL could contribute to the diagnosis of AD from EEG recordings.
Regulation of cerebral blood flow by arterial PCO2 independent of metabolic acidosis at 5050 m

We investigated the influence of arterial PCO2 (PaCO2) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3−). Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO3−] (i.e. buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H+]/pH were consistent with the altered relationship between PaCO2 and [H+]/pH following ACZ at high altitude (i.e. leftward x‐intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH.
A practical method for evaluating the in vivo efficacy of EVA-71 vaccine using a hSCARB2 knock-in mouse model

ABSTRACT Hand-foot-and-mouth disease is a contagious disease common among children under 5 years old worldwide. It is caused by strains of enterovirus, especially EV-A71, which can lead to severe disease. Vaccines are the only way to fight this disease. Accordingly, it is necessary to establish an efficient and accurate methodology to evaluate vaccine efficacy in vivo. Here, we established a practical method using a hSCARB2 knock-in mouse model, which was susceptible to EV-A71 infection at 5–6 weeks of age, to directly determine the efficacy of vaccines. Unlike traditional approaches, one-week-old hSCARB2 mice were immunized twice with a licensed vaccine, with an interval of a week. The titre of antibodies was measured after 1 week. Mice at 4 weeks of age were challenged with EV-A71 intraperitoneally and intracranially, respectively. The unimmunized hSCARB2 mice displayed systemic clinical symptoms and succumbed to the disease at a rate of approximately 50%. High viral loads were detected in the lungs, brain, and muscles, accompanied by clear pathological changes. The expression of IL-1β, IL-13, IL-17, and TNF-α was significantly upregulated. By contrast, the immunized group was practically normal and indistinguishable from the control mice. These results indicate that the hSCARB2 knock-in mouse is susceptible to infection in adulthood, and the in vivo efficacy of EV-A71 vaccine could be directly evaluated in this mouse model. The method developed here may be used in the development of new vaccines against HFMD or quality control of licensed vaccines.
“Student-as-educator” development programs to promote a sustainable educational workforce for the future

Ugo Caramori , Eliana Amaral, Jacqueline Teixeira Caramori, Maria Helena Senger, Sandra H. C. Tibiriç a, Vera L ucia Garcia, Daniel Fernandes Mello de Oliveira and Henry de Holanda Campos University of Campinas (UNICAMP), Campinas, Brazil; S~ao Paulo State University (UNESP), Botucatu, Brazil; Pontifical Catholic University of S~ao Paulo (PUC-SP), Sorocaba, Brazil; Federal University of Juiz de Fora (UFJF), Juiz de Fora, Brazil; Max Planck University (UNIMAX), Sao Paulo, Brazil; Federal University of Rio Grande do Norte (UFRN), Natal, Brazil; Federal University of Cear a (UFC), Fortaleza, Brazil
Mortality among workers at the Los Alamos National Laboratory, 1943–2017

Abstract Background During World War II (WWII), the Manhattan Engineering District established a secret laboratory in the mountains of northern New Mexico. The mission was to design, construct and test the first atomic weapon, nicknamed ‘The Gadget’ that was detonated at the TRINITY site in Alamogordo, NM. After WWII, nuclear weapons research continued, and the laboratory became the Los Alamos National Laboratory (LANL). Materials and methods The mortality experience of 26,328 workers first employed between 1943 and 1980 at LANL was determined through 2017. Included were 6157 contract workers employed by the ZIA Company. Organ dose estimates for each worker considered all sources of exposure, notably photons, neutrons, tritium, 238Pu and 239Pu. Vital status determination included searches within the National Death Index, Social Security Administration and New Mexico State Mortality Files. Standardized Mortality Ratios (SMR) and Cox regression models were used in the analyses. Results Most workers (55%) were hired before 1960, 38% had a college degree, 25% were female, 81% white, 13% Hispanic and 60% had died. Vital status was complete, with only 0.1% lost to follow-up. The mean dose to the lung for the 17,053 workers monitored for radiation was 28.6 weighted-mGy (maximum 16.8 weighted-Gy) assuming a Dose Weighting Factor of 20 for alpha particle dose to lung. The Excess Relative Risk (ERR) at 100 weighted-mGy was 0.01 (95%CI −0.02, 0.03; n = 839) for lung cancer. The ERR at 100 mGy was −0.43 (95%CI −1.11, 0.24; n = 160) for leukemia other than chronic lymphocytic leukemia (CLL), −0.06 (95%CI −0.16, 0.04; n = 3043) for ischemic heart disease (IHD), and 0.29 (95%CI 0.02, 0.55; n = 106) for esophageal cancer. Among the 6499 workers with measurable intakes of plutonium, an increase in bone cancer (SMR 2.44; 95%CI 0.98, 5.03; n = 7) was related to dose. The SMR for berylliosis was significantly high, based on 4 deaths. SMRs for Hispanic workers were significantly high for cancers of the stomach and liver, cirrhosis of the liver, nonmalignant kidney disease and diabetes, but the excesses were not related to radiation dose. Conclusions There was little evidence that radiation increased the risk of lung cancer or leukemia. Esophageal cancer was associated with radiation, and plutonium intakes were linked to an increase of bone cancer. IHD was not associated with radiation dose. More precise evaluations will await the pooled analysis of workers with similar exposures such as at Rocky Flats, Savannah River and Hanford.
Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models. The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Taken together, M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344.
Novel pH sensitive composite hydrogel based on functionalized chitosan/clay for the controlled release of a calcium channel blocker

The concept of novel drug delivery systems aims at achieving systematically improved therapeutic success for drugs including those that have limited use because of toxicity, uneven distribution pattern, stability and formulation of difficulties. The paper reveals the potential uses of novel hybrids of oleic acid-g-chitosan and montmorillonite (OA-g-CS/MMT) in controlled drug delivery applications. A calcium channel blocker is a chemical that disrupts the movement of calcium (Ca2+) through calcium channels. The calcium channel blocker used for the present investigation is diltiazem hydrochloride, which forms a class three antianginal drug, and a class IV antiarrhythmic. The drug-loaded novel composites have been prepared by solvent casting and freeze drying of the grafted polymer solution. Drug release was monitored by changing time, percentage of drug loading and pH of the medium. It was observed that the release was much more pronounced in the basic medium than in the acidic medium. The maximum release of drug from OA-g-CS/MMT in both gastric and intestinal fluids was observed within a time period of 12 h.
Low dose gamma irradiation pretreatment modulates the sensitivity of CNS to subsequent mixed gamma and neutron irradiation of the mouse head

ABSTRACТ Purpose: To explore if the total body γ-irradiation at a dose of 0.1 Gy 7 days prior to acute mixed γ, n-irradiation of the head at the dose of 1 Gy can reduce the harmful effects of neutron irradiation on the hippocampal functions, neuroinflammation and neurogenesis. Materials and methods: Mice were exposed to γ-radiation alone, mixed γ,n-radiation or combined γ-rays and γ,n-radiation 7 days after γ-irradiation. Two months post-irradiation, mice were tested in Open Field and in the Morris water maze. The content of microglia, astrocytes, proliferating cells and cytokines TGF-β, TNF-α, IL-1β, GFAP levels, hippocampal BDNF, NT-3, NT-4, NGF mRNA expression were evaluated. Results: Two months after combined irradiation, we observed impaired hippocampus-dependent cognition, which was not detected in mice exposed to γ,n-irradiation. Combined exposure and γ,n-irradiation led to a significant increase in the level of activated microglia and astrocytes in the brains. The level of pro- and anti-inflammatory cytokines in the brain and hippocampal neurotrophine's genes changed differenly after the combined exposure and γ,n-irradiation. The quantity of DCX-positive cells was reduced after γ,n-irradiation exposer alone, but increased after combined irradiation. Conclusions: Our results indicate radio-adaptive responses in brains of mice that were exposed to low-dose gamma irradiation 7 days prior to acute 1 Gy γ,n-irradiation.
Two decades of digital interventions for anxiety disorders: a systematic review and meta-analysis of treatment effectiveness

Abstract Background Digital interventions for anxiety disorders are a promising solution to address barriers to evidence-based treatment access. Precise and powerful estimates of digital intervention effectiveness for anxiety disorders are necessary for further adoption in practice. The present systematic review and meta-analysis examined the effectiveness of digital interventions across all anxiety disorders and specific to each disorder v. wait-list and care-as-usual controls. Methods A systematic search of bibliographic databases identified 15 030 abstracts from inception to 1 January 2020. Forty-seven randomized controlled trials (53 comparisons; 4958 participants) contributed to the meta-analysis. Subgroup analyses were conducted by an anxiety disorder, risk of bias, treatment support, recruitment, location and treatment adherence. Results A large, pooled effect size of g = 0.80 [95% Confidence Interval: 0.68–0.93] was found in favor of digital interventions. Moderate to large pooled effect sizes favoring digital interventions were found for generalized anxiety disorder (g = 0.62), mixed anxiety samples (g = 0.68), panic disorder with or without agoraphobia (g = 1.08) and social anxiety disorder (g = 0.76) subgroups. No subgroups were significantly different or related to the pooled effect size. Notably, the effects of guided interventions (g = 0.84) and unguided interventions (g = 0.64) were not significantly different. Supplemental analysis comparing digital and face-to-face interventions (9 comparisons; 683 participants) found no significant difference in effect [g = 0.14 favoring digital interventions; Confidence Interval: −0.01 to 0.30]. Conclusion The precise and powerful estimates found further justify the application of digital interventions for anxiety disorders in place of wait-list or usual care.
Effect of pre-harvest application of calcium on flesh firmness and cell-wall composition of apples - influence of fruit size

SummaryApples, cv. Golden Delicious were subjected to ten preharvest sprays of 1.2% CaCl2 at weekly intervals. At the beginning of the climacteric stage, the fruits were harvested and sorted to small (4–5 cm dia.) and average (6–7.5 cm dia.) sizes, and stored at ambient conditions (25°C). The firmness of small fruits was higher than average ones. Application of CaCl2 resulted in higher flesh firmness at the time of harvest in average fruits but showed no significant changes in small ones. However, after three weeks of storage, both average and small fruits were showing better retention of firmness by CaCl2 treatment. Thus, preharvest treatment of CaCl2 may not necessarily always lead to firmer fruits at the time of harvest but may result in better retention of firmness during storage. The results are discussed in relation to cell-wall yield, β-D-galactosidase activity, total, free, ionically associated and covalently bound pectins, and hemicellulose contents. The differences in behaviour of average and sm.