Miracle-dz/UniFAR-FTUs huggingface dataset:
IgIDivA: immunoglobulin intraclonal diversification analysis

Abstract Intraclonal diversification (ID) within the immunoglobulin (IG) genes expressed by B cell clones arises due to ongoing somatic hypermutation (SHM) in a context of continuous interactions with antigen(s). Defining the nature and order of appearance of SHMs in the IG genes can assist in improved understanding of the ID process, shedding light into the ontogeny and evolution of B cell clones in health and disease. Such endeavor is empowered thanks to the introduction of high-throughput sequencing in the study of IG gene repertoires. However, few existing tools allow the identification, quantification and characterization of SHMs related to ID, all of which have limitations in their analysis, highlighting the need for developing a purpose-built tool for the comprehensive analysis of the ID process. In this work, we present the immunoglobulin intraclonal diversification analysis (IgIDivA) tool, a novel methodology for the in-depth qualitative and quantitative analysis of the ID process from high-throughput sequencing data. IgIDivA identifies and characterizes SHMs that occur within the variable domain of the rearranged IG genes and studies in detail the connections between identified SHMs, establishing mutational pathways. Moreover, it combines established and new graph-based metrics for the objective determination of ID level, combined with statistical analysis for the comparison of ID level features for different groups of samples. Of importance, IgIDivA also provides detailed visualizations of ID through the generation of purpose-built graph networks. Beyond the method design, IgIDivA has been also implemented as an R Shiny web application. IgIDivA is freely available at https://bio.tools/igidiva
Sparse kernel models provide optimization of training set design for genomic prediction in multiyear wheat breeding data

The success of genomic selection (GS) in breeding schemes relies on its ability to provide accurate predictions of unobserved lines at early stages. Multigeneration data provides opportunities to increase the training data size and thus, the likelihood of extracting useful information from ancestors to improve prediction accuracy. The genomic best linear unbiased predictions (GBLUPs) are performed by borrowing information through kinship relationships between individuals. Multigeneration data usually becomes heterogeneous with complex family relationship patterns that are increasingly entangled with each generation. Under these conditions, historical data may not be optimal for model training as the accuracy could be compromised. The sparse selection index (SSI) is a method for training set (TRN) optimization, in which training individuals provide predictions to some but not all predicted subjects. We added an additional trimming process to the original SSI (trimmed SSI) to remove less important training individuals for prediction. Using a large multigeneration (8 yr) wheat (Triticum aestivum L.) grain yield dataset (n = 68,836), we found increases in accuracy as more years are included in the TRN, with improvements of ∼0.05 in the GBLUP accuracy when using 5 yr of historical data relative to when using only 1 yr. The SSI method showed a small gain over the GBLUP accuracy but with an important reduction on the TRN size. These reduced TRNs were formed with a similar number of subjects from each training generation. Our results suggest that the SSI provides a more stable ranking of genotypes than the GBLUP as the TRN becomes larger.
Supermicrosurgical Experience pertaining to Replantation of Tamai Zone 1 Fingertip Amputations

Abstract With the advent of supermicrosurgery, the replantation of very distal finger amputations has become possible. The choice between replantation or flap surgeries in the treatment of Tamai Zone I finger amputations continues to be a matter of debate. This study aims to evaluate replantation results in Tamai Zone 1 finger amputations. The demographic characteristics and clinical results of 39 patients undergoing replantation for a Tamai Zone 1 finger amputation between 2018 and 2021 were retrospectively analyzed. The Cold Intolerance Severity Score (CISS), two-point discrimination test (2-PD) and Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) were calculated and recorded after a minimum follow-up period of 6 months. The great majority of patients were males (92.3%, n=36) who had suffered the injuries during work accidents (89.7%, n=35). The socioeconomic status of the patients showed a homogeneous distribution. Replant survival was achieved in 69.2% (n=27) of all fingers. The duration of the surgical procedure in patients who underwent vein repair was significantly longer (p<0.001). However, there was no significant relationship between vein repair and survival rate (p=0.348). This study shows that replantation is a surgical intervention that should be given priority in patients with Tamai Zone 1 amputations. In most cases of unsuccessful replantation, secondary recovery results are also acceptable. Future studies with larger case series are needed.
Hemostasis Proteins in Invasive Meningococcal and Nonmeningococcal Infections: A Prospective Multicenter Study

OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens (Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus, and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012–2016) with community-acquired infections due to meningococci (n = 83), pneumococci (n = 64), S. aureus (n = 50), and GAS (n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019–2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score). Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens (p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70–0.92) for thrombomodulin and 0.78 (95% CI, 0.69–0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.
Telehealth and Remote Interventions for Children With Cerebral Palsy: Scoping Review

Background Remote treatment, or telehealth, has shown promise for children with cerebral palsy (CP) prior to 2020; however, the beginning of the global COVID-19 pandemic limiting access to hospitals for face-to-face treatments has driven the need for telehealth and led to a surge in its development. Due to the recent developments, there has been limited synthesis of the available evidence of telehealth for children with CP. Objective This study aimed to analyze and summarize the existing evidence for telehealth interventions for the treatment of children with CP and identify any areas requiring further research. Methods A scoping review was performed. A systematic search of available literature in MEDLINE and PubMed was performed during July 2021. Inclusion criteria for articles were primary research and systematic reviews that investigated telehealth, included children with CP, were published between 2010-2021, and were written in English. Exclusion criteria were secondary research other than systematic reviews; interventions that did not meet the World Health Organization definition of telehealth; or studies where all participants were aged >18 years, children’s results were not reported separately, or there were no results reported for children with CP. A scoping review was chosen due to the expected heterogeneity of the participants, as well as the expected small sample sizes and inconsistency of measured outcomes; therefore, a narrative reporting of the results was considered appropriate. Results In all, 5 papers were identified, which included the results of 11 studies—2 of the included articles were systematic reviews, which included the results of 3 studies each. These 6 studies, together with 5 primary research articles, were included in this scoping review. The existing evidence is of low methodological quality, primarily consisting of case series. There is some evidence that the requirements of telehealth differ depending on the children’s developmental stage and functional level. Telehealth is reported to reduce caregiver burden. There is mixed evidence on children’s compliance with telehealth. Overall, the results of telehealth interventions for the treatment of children with CP were positive, indicating either comparable or improved results compared with children receiving usual face-to-face care. Conclusions The evidence base is lacking in breadth and methodological quality to provide robust clinical recommendations. Most studies investigated hand function only, indicating the limited scope of existing research. However, this review shows that telehealth has demonstrated potential to improve function for children with CP while making health care services more accessible and reducing caregiver burden. Areas requiring further research include telehealth interventions for the lower limb, postural management, and pain control and the barriers to implementing telehealth.
Locus of control and subjective well-being: Panel evidence from Australia

This paper’s aim is to propose a mediation framework and test whether lifestyle choices and social capital are pathways through which locus of control (LoC) affects subjective well-being. Using longitudinal data for Australia, we find that life satisfaction and mental health are explained by direct and indirect effects of LoC. The direct effect is positive, indicating that individuals with an internal LoC have higher levels of life satisfaction and mental health. We also show that physical activity and social interaction are two pathways linking an internal LoC to higher levels of well-being. Our findings provide new insights into the relationship between LoC and subjective well-being and suggest that, if the aim of policy is to improve well-being, the focus should be on enabling people to develop an internal LoC. This may lead to higher well-being both through the identified channels and, more importantly, through the direct channel of LoC.
Impact of Older Donor Age on Recipient and Graft Survival After LDLT: The US Experience

Background. The impact of selecting older donors for living donor liver transplantation (LDLT) in the United States is incompletely studied, particularly in light of the recent expansion of LDLT nationally. Methods. Adult LDLTs from January 01, 2005 to December 31, 2019 were identified using the United Network for Organ Sharing database. Multivariable Cox models evaluated living donor (LD) age as a predictor of LDLT recipient and graft survival. The impact of increasing donor age on recipient outcomes was compared between LD and deceased donor recipients. Donor postoperative outcomes were evaluated. Results. There were 3539 LDLTs at 65 transplant centers during the study period. Despite the recent expansion of LDLT, the proportion of LDs aged ≥50 y was stable. There were no clinically significant differences in recipient or donor characteristics by LD age group. LD age ≥50 y was associated with an adjusted hazard ratio of 1.49 (P = 0.012) for recipient survival and 1.61 (P < 0.001) for graft survival (vs LDs aged 18–29 y). The negative impact of increasing donor age on graft survival was more profound after LDLT than deceased donor liver transplantation (interaction P = 0.019). There was a possible increased rate of early donor biliary complications for donors >55 y (7.1% versus 3.1% for age <40 y; P = 0.156). Conclusions. Increasing LD age is associated with decreased recipient and graft survival, although older donors still largely yield acceptable outcomes. Donor outcomes were not clearly impacted by increasing age, though this warrants further study.
Temporal auditory processing in people exposed to musical instrument practice

ABSTRACT Purpose To investigate the influence of musical instrument practice on temporal auditory abilities and on the results of cortical potentials related to auditory events (P300) in a group of young musicians compared to individuals without experience in musical practice. Methods This is a prospective cross-sectional observational study. In total, 34 individuals between 18 and 30 years old, of both sexes, took part and were divided in two groups: Group I (GI), composed of musicians (n=16), and Group II (GII), composed of non-musicians (n=18). All participants underwent behavioral evaluation of temporal auditory processing, composed of Duration Pattern Sequence Test (DPS), Pitch Pattern Sequence Test (PPS), Random Gap Detection Test (RGDT) and electrophysiological evaluation – Long Latency Auditory Evoked Potential – P300. GI also answered a specific questionnaire to characterize musical practice. Results We observed statistically significant differences with superior performance of GI compared with GII in all behavioral tests (p<0.001*). The groups’ performance was similar regarding the latency and amplitude parameters analyzed from LLAEP-300 data (p>0.05). Conclusion The findings show a positive influence of musical practice toward the improvement of auditory abilities of temporal ordering and resolution. All participants presented adequate cortical functioning of the central auditory nervous system, without significant differences between musicians and non-musicians when considering P300 amplitude and latency.
Global regulatory factor AaLaeA upregulates the production of antitumor substances in the endophytic fungus Alternaria alstroemeria

The global regulatory factor LaeA has been shown to be involved in the biosynthesis of secondary metabolites in various fungi. In a previous work, we isolated an endophytic fungus from Artemisia annua, and its extract had a significant inhibitory effect on the A549 cancer cell line. Phylogenetic analysis further identified the strain as Alternaria alstroemeria. Overexpression of AalaeA gene resulted in significantly increased antitumor activity of this strain's extract. The 3‐(4, 5‐ dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide assay results showed that the inhibition rate of the AalaeAOE29 mutant extract on A549 cancer cells was significantly higher than that of the WT extract, as the IC50 decreased from 195.0 to 107.4 μg/ml, and the total apoptosis rate was enhanced. Overexpression of the AalaeA gene significantly increased the contents of myricetin, geraniol, ergosterol, and 18 other antitumor compounds as determined by metabolomic analysis. Transcriptomic analysis revealed significant changes in 95 genes in the mutant strain, including polyketide synthases, nonribosomal peptide synthases, cytochrome P450s, glycosyltransferases, acetyl‐CoA acetyltransferases, and others. These results suggested that AaLaeA mediated the antitumor activity of the metabolites in A. alstroemeria by regulating multiple metabolic pathways.
Effect of flight connectivity on the introduction and evolution of the COVID-19 outbreak in Canadian provinces and territories

Abstract Background The COVID-19 pandemic has challenged health services and governments in Canada and around the world. Our research aims to evaluate the effect of domestic and international air travel patterns on the COVID-19 pandemic in Canadian provinces and territories. Methods Air travel data were obtained through licensed access to the ‘BlueDot Intelligence Platform’, BlueDot Inc. Daily provincial and territorial COVID-19 cases for Canada and global figures, including mortality, cases recovered and population data were downloaded from public datasets. The effects of domestic and international air travel and passenger volume on the number of local and non-local infected people in each Canadian province and territory were evaluated with a semi-Markov model. Provinces and territories are grouped into large (>100 000 confirmed COVID-19 cases and >1 000 000 inhabitants) and small jurisdictions (≤100 000 confirmed COVID-19 cases and ≤1 000 000 inhabitants). Results Our results show a clear decline in passenger volumes from March 2020 due to public health policies, interventions and other measures taken to limit or control the spread of COVID-19. As the measures were eased, some provinces and territories saw small increases in passenger volumes, although travel remained below pre-pandemic levels. During the early phase of disease introduction, the burden of illness is determined by the connectivity of jurisdictions. In provinces with a larger population and greater connectivity, the burden of illness is driven by case importation, although local transmission rapidly replaces imported cases as the most important driver of increasing new infections. In smaller jurisdictions, a steep increase in cases is seen after importation, leading to outbreaks within the community. Conclusions Historical travel volumes, combined with data on an emerging infection, are useful to understand the behaviour of an infectious agent in regions of Canada with different connectivity and population size. Historical travel information is important for public health planning and pandemic resource allocation.
Leveraging latent profile analysis to synthesize childhood and adolescent risk factors for suicidal ideation

Person-centered typologies identified with latent profile analysis can clarify patterns of chronic and acute risk factors for suicidal ideation. We derived five profiles of individuals using cognitive, behavioral, and familial factors relating to suicidal ideation risk factors. Participants (n = 1,142) were assessed at age 8 using the Laboratory Temperament Assessment Battery and mother-reported parenting measures and at age 14 using interviews about clinical symptoms and suicidal ideation. The best-fitting model included five profiles: typical, elevated adolescent symptomology, mildly elevated typical, low childhood persistence, and very low childhood persistence/mixed symptoms. Participants in the elevated adolescent symptomology and very low childhood persistence/mixed symptoms profiles were 2.6 and 5.3 times more likely to report suicidal ideation compared with the typical profile. Overall, our results underscore how using a person-centered pattern recognition approach and incorporating facets of childhood behavior may enhance conceptualizations of adolescent suicidal ideation risk.
Excess Mortality Among Solid Organ Transplant Recipients in the United States During the COVID-19 Pandemic

Background. The COVID-19 pandemic is the first sustained respiratory disease pandemic to arise since the start of solid organ transplantation (SOT). Prior studies have demonstrated that SOT recipients are at greater risk for severe complications of infection and are less likely to respond to vaccination. Methods. The Scientific Registry of Transplant Recipients Standard Analysis Files was used to assess the cumulative excess mortality in SOT recipients during the first 20 mo of the pandemic. Results. Compared with excess mortality rates in the US population (25.9 deaths/10 000; confidence interval [CI], 10.9-41.1), the excess mortality per 10 000 was higher in all SOT groups: kidney (188.5; CI, 150.7-225.6), lung (173.6; CI, 17-334.7), heart (123.7; CI, 56-191.4), and liver (105.1; CI, 64.6-146). The higher rates persisted even with attempts to control for population age structure and renal allograft failure. Excess mortality was also higher in Black (236.8; CI, 186.1-287) and Hispanic (256.9; CI, 208.1-305.2) organ recipients compared with other racial and ethnic groups in the Scientific Registry of Transplant Recipients and compared with the Black and Hispanic populations in the United States. Conclusions. Studies of excess mortality provide insight into the health and survival of specialized populations like SOT recipients during major health events like the COVID-19 pandemic.
Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

PURPOSE Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many patients with la/mUC are ineligible. Each enfortumab vedotin and pembrolizumab have shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin. METHODS In this ongoing phase Ib/II, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg once daily on days 1 and 8 and pembrolizumab 200 mg (day 1) intravenously once daily in 3-week cycles. The primary end point was safety. Key secondary end points included confirmed objective response rate, duration of response (DOR), and overall survival (OS). RESULTS Forty-five patients received enfortumab vedotin plus pembrolizumab. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher TRAEs; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a TRAE. The confirmed objective response rate after a median of nine cycles was 73.3% with a complete response rate of 15.6%. The median DOR and median OS were 25.6 months and 26.1 months, respectively. CONCLUSION Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. The median DOR and median OS exceeding 2 years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a phase III study (ClinicalTrials.gov identifier: NCT04223856).