Miracle-dz/UniFAR-FTUs huggingface dataset:
Leukocyte Telomere Length and Bladder Cancer Risk: A Large Case–Control Study and Mendelian Randomization Analysis

Background: Leukocyte telomere length (LTL) has been associated with risk of several cancers. The association between LTL and bladder cancer is still inconsistent. Methods: In this large case–control study consisting of 2,011 patients with bladder cancer and 2,259 healthy controls of European ancestry, we investigated the associations of real-time qPCR-measured LTL (a retrospective case–control study) and genetically predicted LTL [a Mendelian randomization (MR) study] with bladder cancer risk. Genotypes from 10 LTL-associated SNPs were used as instrumental variables to predict LTL. We used an individual level data–based weighted genetic risk score (GRS) and a summary statistics–based inverse‐variance weighting (IVW) method in MR analyses. Results: The qPCR-measured LTL was shorter in cases with muscle-invasive bladder cancer (MIBC) than those with non–muscle-invasive bladder cancer [NMIBC; ratio of telomere repeats copy number to single gene copy number (T/S): 1.19 ± 0.34 vs. 1.23 ± 0.36, P = 0.081]. Multivariable logistic regression analyses showed long qPCR-measured LTL was associated with a reduced risk of MIBC. In MR analyses, genetically predicted LTL was weakly associated with bladder cancer risk in both the GRS analysis [OR = 1.13, per SD increase; 95% confidence interval (CI), 0.73–1.75; P = 0.595] and the IVW analysis (OR = 1.14 per SD increase; 95% CI, 0.75–1.74; P = 0.543). Conclusions: There was no strong evidence supporting an association between LTL and bladder cancer risk in European Americans. Impact: This is the largest study of LTL and bladder cancer risk. The study showed that LTL does not play an important role in bladder cancer etiology.
Adverse events associated with potential drugs for COVID-19: a case study from real-world data

Abstract The coronavirus disease 2019 (COVID-19) has resulted as a global pandemic. The World Health Organization announced the most promising drugs in SOLIDARITY for the global trial, and several other drugs are under investigation through ongoing clinical trials to prove the effectiveness and safety of potential therapeutics. Here, we depicted the safety profile of these drugs and investigated their associated adverse events (AEs). We observed the associated AEs in different organs/systems, especially in skin and subcutaneous tissue, immune system and musculoskeletal and connective tissue. Furthermore, we observed strong bias of AEs in different groups of sex and age. Our study provides knowledge of the toxicity of potential COVID-19 drugs. While these drugs hold promise to fight the global pandemic, healthcare providers should pay attention to AEs to maximize the treatment benefit while minimizing toxicity.
Novel Therapeutic Approaches and Treatment Targets for Psoriatic Arthritis.

BACKGROUND Psoriatic arthritis (PsA) is the most common extracutaneous manifestation of psoriasis. This chronic inflammatory arthritis is burdened with significant morbidity, leading to irreversible joint damage and disability. In recent years, a deeper understating of its pathogenesis has led to the development of several new drugs targeting different pathways. OBJECTIVES This review aims to highlight the clinical efficacy and safety of the novel agents that have become recently available for the treatment of PsA, as well as new promising therapeutic targets that are being evaluated in clinical trials. METHODS For the purpose of this narrative review, we searched in the MEDLINE and ClinicalTrials.gov databases. RESULTS After the introduction of the first biologic drugs targeting tumor necrosis factor (TNF), several other drugs with different targets have been developed, including anti-interleukin (IL) 12/23p40, anti-IL17 and, more recently, anti-IL23p19 agents. CONCLUSIONS We summarize data supporting the efficacy of different agents in the major domains of PsA, as well as their safety issues. Finally, we present the current pipeline, including several novel non-biological small molecules, such as Janus kinase (JAK) inhibitors, that are currently being evaluated in clinical trials. DISCUSSION The availability of newer therapeutic agents has substantially changed the treatment strategy for PsA. In the future, a personalized treatment approach will probably achieve a better control of disease manifestations.
Overexpression of VEGF165 is associated with poor prognosis of cervical cancer

Cervical cancer is a major health hazard to Indian women. Human papillomavirus (HPV) infection is an established risk factor for cervical carcinogenesis. However, understanding the cervical cancer biology beyond HPV infection is very crucial to predict aggressive behavior, prognosis, treatment response and survival. In the present study, we explored the role of vascular endothelial growth factor A (VEGFA) isoforms, VEGFC and VEGFD in cervical cancer progression and its association with HPV 16 and 18 infections.
Epidemiological Correlates of PCR Cycle Threshold Values in the Detection of SARS-CoV-2

Abstract Background Detection of SARS-CoV-2 infection has principally been performed through the use of real-time reverse-transcription PCR (rRT-PCR) testing. Results of such tests can be reported as cycle threshold (Ct) values, which may provide semi-quantitative or indirect measurements of viral load. Previous reports have examined temporal trends in Ct values over the course of a SARS-CoV-2 infection. Methods Using testing data collected during a prospective household transmission investigation of outpatient and mild COVID-19 cases, we examined the relationship between Ct values of the viral RNA N1 target and demographic, clinical, and epidemiological characteristics collected through participant interviews and daily symptom diaries. Results We found Ct values are lowest (corresponding to higher viral RNA concentration) soon after symptom onset and are significantly correlated with time elapsed since onset (p<0.001); within 7 days after symptom onset, the median Ct value was 26.5 compared with a median Ct value of 35.0 occurring 21 days after onset. Ct values were significantly lower among participants under 18 years of age (p=0.01) and those reporting upper respiratory symptoms at the time of sample collection (p=0.001) and were higher among participants reporting no symptoms (p=0.05). Conclusions These results emphasize the importance of early testing for SARS-CoV-2 among individuals with symptoms of respiratory illness and allows cases to be identified and isolated when their viral shedding may be highest.
Effects of Music Therapy on Patients with Dementia—A Systematic Review

Dementia is an increasingly common syndrome and while pharmacotherapy is available, its potential benefit is limited, especially in non-cognitive outcomes. Non-pharmacotherapy such as music therapy is potentially associated with improved outcomes. We assessed the effects of music therapy on patients with dementia to evaluate its potential benefits on dementia. Two independent reviewers searched MEDLINE, EMBASE, CINAHL, CENTRAL, and ClinicalTrials.gov databases for clinical trials, using the keywords “music therapy” and “dementia”. Study outcomes included cognitive function, behavioral and psychological symptoms of dementia (BPSD), and quality of life. A total of 82 studies were included, of which 43 were interventional clinical trials, and 39 were systematic reviews or meta-analyses. Significant improvements in verbal fluency occurred after music therapy, with significant reductions in anxiety, depression, and apathy. There were no significant improvements in cognition or daily functioning, and the results on quality of life and agitation were ambiguous. Limitations of studies included low patient numbers, lack of standardized music therapy, and high heterogeneity in outcomes. More large-scale clinical trials would allow for clearer conclusions on the benefits of music therapy in patients with dementia.
Optimal treatments for hepato-pancreato-biliary trauma in severely injured patients: a narrative scoping review.

SUMMARY Hepato-pancreato-biliary (HPB) injuries can be extremely challenging to manage. This scoping review (8438 citations) offers a number of recommendations. If diagnosis and therapy are rapid, patients with major hepatic injuries who present in physiologic extremis have high survival rates despite prolonged hospital stays. Nonoperative management of major liver injuries, as diagnosed using computed tomography, is typically successful. Adjuncts (e.g., angioembolization, laparoscopic washouts, biliary stents) are essential in managing high-grade injuries. Injury to the extrahepatic biliary tree is rare. Cholecystectomy is indicated for all gallbladder trauma. Full-thickness common bile duct injuries require a hepaticojejunostomy, although damage control remains closed suction drainage. Injuries to the pancreatic head often involve concurrent trauma to regional vasculature. Damage control necessitates drainage after stopping hemorrhage. Injury to the left pancreas commonly requires a distal pancreatectomy. Outcomes for high-grade pancreatic and liver injuries are improved by involving an HPB team. Complications are multidisciplinary and should be managed without delay.
Root xylem embolisms: implications for water flow to the shoot in single-rooted maize plants

The recent measurements of high percentage embolized vessels in a sample of maize axile roots during the day raised the question whether such interruptions to water flow could occur in plants that had only a single water-supplying root. Zea mays L. plants were grown in the field on a root system developed entirely from the single primary root. The formation of vessel embolisms in this root was monitored by cryo-scanning electron microscopy. Vessels were sap-filled at dawn, but 60% of late metaxylem (LMX) vessels were embolized by 0830 h. This high percentage persisted until early afternoon, then declined to reach 30% by 1800 h. Leaf balance pressures rose from about 0.3 MPa at dawn to a peak mean of 1.2 MPa at 1300 h, then declined to 0.5 MPa by 1800 h. Peak embolism in LMX vessels was reached in the early morning at balance pressures of 0.7–0.8 MPa. Some refilled in the afternoon while balance pressures were 0.5–0.7 MPa. The six to eight LMX vessels at the root base would deliver most of the transpiration stream to the shoot. Our finding that up to 60% were embolized during the day, while the plants continue to transpire, suggests that the mean flow velocity in the vessels is higher than the value of 270 m h–1 estimated recently by others for completely full vessels in the mesocotyl of single-rooted corn plants.
Risk factors for amyotrophic lateral sclerosis: A regional United States case‐control study

Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and environmental exposures are thought to play a causal role. To learn more about sporadic ALS etiology, we recruited n = 188 ALS patients from northern New England and Ohio and matched controls 2:1 from the general population of the same regions. Questionnaires evaluated the association between a variety of lifestyle, behavioral (ie, hobbies and activities), and occupational factors and the risk of ALS, including the duration of time between exposure and ALS onset, and exposure frequency. Head trauma was associated with increased ALS risk (adjusted odds ratio [OR] 1.60 95% confidence interval [CI] 1.04‐2.45), with significantly greater effects for injuries occurring 10 or more years prior to symptom onset (P = .037). ALS risk was increased for those reporting severe electrical burns (adjusted OR 2.86, 95% CI 1.37‐6.03), with odds ratios highest for burns after age 30 (OR 3.14), and for burns 10 or more years prior to symptom onset (OR 3.09). Hobbies involving lead were the most strongly associated with ALS risk (adjusted OR 2.92, 95% CI 1.45‐5.91). Exposures to lead 20 or more years prior to diagnosis had larger effect sizes compared to those occurring more recently. Holding a job in mechanics, painting, or construction was associated with ALS. The identification of these specific environmental factors associated with ALS highlight the need for future prospective and laboratory studies to assess causality, biological mechanisms, and find prevention or treatment opportunities.
Galium sect. Leiogalium (Rubiaceae) in the Bulgarian flora

The work contains the results from the investigation of morphological variation, chromosome numbers and ploidy levels, distribution, phytogeographic and phylogenetic relationships of the species of genus Galium sect. Leiogalium, occuring on the territory of Bulgaria. The section includes 18 species and two non-nominal subspecies. Morphologically, phytogeographically and supposedly phylogenetically related species are divided into five species groups. The species are cross-pollinated entomophilous plants, which reproduce sexually and vegetatively by underground runners.The mesophilous species with white flowers, G. album, G. intermedium, G. lucidum, G. pashale, and G. procurrens, are pollinated chiefly by flies of Syrphidae, Muscidae and Larvivoridae. The xerophilous G. aegeum, G. mirum, G. asparagifolium, G. flavescens, G. rhodopeum with pale yellowish to greenish corolla are visited mostly by small coleopterans of the genera Strangalia, Agriotes, Mordelis, etc. Six species are Balkan endemics: G. mirum, G. macedonicum, G. rigidifolium, G. rhodopeum, G. aegeum and G. procurrens. Galium velenovskyi is a local endemic, restricted in its occurence to the calcareous slopes of E Rhodopi Mts. The chromosome numbers and the ploidy levels of 18 species and two subspecies studied in 95 populations are reported in the article. Eight species are diploid, nine are tetraploid, and one is hexaploid, all with x = 11, the most common and probably original basic chromosome number in the genus. G. ×pomeranicum (G. album × G. verum) is polyploid with 2n = 44.
Gaining ecological information about Bayesian foragers through their behaviour. II. A field test with woodpeckers

The lesser spotted woodpecker Dendrocopos minor is a territorial species with its food resources distributed in patches, i.e. insect larvae in dead branches of trees. The species is threatened in Northern Europe, and therefore it is of interest to identify factors responsible for its decline. We hypothesise that (a) foraging behaviour is maximising fitness, (b) the woodpeckers, through their foraging behaviour, reveal their own opinion about their territory or their individual quality, and (c) that an inter-territorial comparison of behaviour and reproduction shows which factor is responsible for the breeding success of the woodpeckers. We collected data on giving-up density of prey (GUD) and patch residence time (PRT) during branch visits about one month before egg laying. The data was collected from a natural breeding population in southern Sweden, 1993-1996. A positive correlation between GUD and PRT within individuals is diagnostic for a Bayesian forager exploiting a clumped distribution of prey. This correlation was found in 22 of 28 investigated individuals. Average GUD of the breeding individuals was positively related to breeding success, i.e. there was a significant negative correlation between average GUD and commencement of egg laying, and a significant positive correlation between average GUD and number of fledglings. For the number of eggs laid there was a weak (not significant) positive relation with average GUD. Average GUD was not influenced by the age or sex of the individuals. Neither did these individual quality measures influence the relations between average GUD and reproductive success. Average GUD and average PRT of individuals was positively correlated. In concert, these results suggest that differences in average prey density across territories prior to breeding is the factor explaining most of the variation in breeding success of the lesser spotted woodpeckers in the studied population.
Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.
Compulsivity is linked to reduced adolescent development of goal-directed control and frontostriatal functional connectivity

Significance Goal-directed behavior is impaired in disorders of compulsivity. Here, we characterize the developmental trajectory of model-based control and show a progressive strengthening from adolescence to early adulthood. We found that the presence of compulsivity traits impacts on this trajectory as well as on the degree of remodeling in functional connectivity within frontostriatal circuits. These findings have implications for understanding the interplay between compulsivity, the developmental trajectory of model-based planning, and functional connectivity in frontostriatal circuits. A characteristic of adaptive behavior is its goal-directed nature. An ability to act in a goal-directed manner is progressively refined during development, but this refinement can be impacted by the emergence of psychiatric disorders. Disorders of compulsivity have been framed computationally as a deficit in model-based control, and have been linked also to abnormal frontostriatal connectivity. However, the developmental trajectory of model-based control, including an interplay between its maturation and an emergence of compulsivity, has not been characterized. Availing of a large sample of healthy adolescents (n = 569) aged 14 to 24 y, we show behaviorally that over the course of adolescence there is a within-person increase in model-based control, and this is more pronounced in younger participants. Using a bivariate latent change score model, we provide evidence that the presence of higher compulsivity traits is associated with an atypical profile of this developmental maturation in model-based control. Resting-state fMRI data from a subset of the behaviorally assessed subjects (n = 230) revealed that compulsivity is associated with a less pronounced change of within-subject developmental remodeling of functional connectivity, specifically between the striatum and a frontoparietal network. Thus, in an otherwise clinically healthy population sample, in early development, individual differences in compulsivity are linked to the developmental trajectory of model-based control and a remodeling of frontostriatal connectivity.
The FcγRIIa–Syk Axis Controls Human Dendritic Cell Activation and T Cell Response Induced by Infliximab Aggregates

Key Points Infliximab aggregates induce dendritic cell maturation and CD4 T cell activation. Aggregate-induced immune response is mediated via the FcγRIIa–Syk axis. Visual Abstract The development of anti-drug Abs in response to biological products (BP) is a major drawback in the treatment of patients. Factors related to the patient, the treatment, and the product can influence BP immunogenicity. Among these factors, BP aggregates have been suggested to promote immunogenicity by acting as danger signals recognized by dendritic cells (DC) facilitating the establishment of an anti-BP CD4 T cell–dependent adaptive immune response leading to anti-drug Abs production. To date, little is known on the mechanism supporting the effect of aggregates on DCs and consequently on the T cell response. The aim of this work was to identify key signaling pathways involved in BP aggregate DC activation and T cell response. We generated aggregates by submitting infliximab (IFX), an immunogenic anti–TNF-α chimeric Ab, to heat stress. Our results showed that IFX aggregates were able to induce human monocyte-derived DC (moDC) maturation in a concentration-dependent manner. Aggregate-treated moDCs enhanced allogeneic T cell proliferation and IL-5, IL-9, and IL-13 production compared with native Ab-treated moDCs. We then investigated the implication of FcγRIIa and spleen tyrosine kinase (Syk) in DC activation and showed that they were both strongly implicated in moDC maturation induced by IFX aggregates. Indeed, we found that neutralization of FcγRIIa inhibited DC activation, and consequently, Syk inhibition led to a decrease in T cell proliferation and cytokine production in response to IFX aggregates. Taken together, our results bring new insight, to our knowledge, on how protein aggregates could induce DC and T cell activation via the FcγRIIa–Syk signaling pathway.
Demographically adjusted norms for the Trail Making Test in native Spanish speakers: Results from the neuropsychological norms for the US-Mexico border region in Spanish (NP-NUMBRS) project

Abstract Objective Despite the wide use of the Trail Making Test (TMT), there is a lack of normative data for Spanish speakers living in the USA. Here we describe the development of regional norms for the TMT for native Spanish speakers residing in the Southwest Mexico-Border Region of the USA. Method Participants were 252 healthy native Spanish speakers, 58% women, from ages 19 to 60, and ranging in education from 0 to 20 years, recruited in San Diego, CA and Tucson, AZ. All completed the TMT in Spanish along with a comprehensive neuropsychological test battery as part of their participation in the Neuropsychological Norms for the US–Mexico Border Region in Spanish (NP-NUMBRS) project. Univariable and interactive effects of demographics on test performance were examined. T-scores were calculated using fractional polynomial equations to account for linear and any non-linear effects of age, education, and sex. Results Older age and lower education were associated with worse scores on both TMT A and B. No sex differences were found. The newly derived T-scores showed no association with demographic variables and displayed the expected 16% rates of impairment using a −1 SD cut point based on a normal distribution. By comparison, published norms for English-speaking non-Hispanic Whites applied to the current data yielded significantly higher impairment for both TMT A and B with more comparable rates using non-Hispanic African Americans norms. Conclusions Population-specific, demographically adjusted regional norms improve the utility and diagnostic accuracy of the TMT for use with native Spanish speakers in the US-Mexico Border region.