The vast volume of data that has been generated as a result of the next-generation sequencing revolution is overwhelming to sift through and interpret. Parsing functional vs. non-functional and benign vs. pathogenic variants continues to be a challenge. Out of three billion bases, the genomes of two given individuals will only differ by about 3 million variants (0.1%). Furthermore, only a small fraction of these are biologically-relevant and, of those that are functional, only a handful actually drive disease pathology. While whole genome and exome sequencing have transformed our collective understanding of the role that genetics plays in disease pathogenesis, there are certain conditions and populations for whom DNA-level data has failed to produce a molecular diagnosis. Patients of non-White race/non-European ancestry are disproportionately affected by “variants of unknown/uncertain significance” (VUS). This limits the scope of precision medicine for minority patients and perpetuates health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret in DNA alone. RNA analysis is capable of illuminating the consequences of VUS thereby allowing for their reclassification as pathogenic vs. benign. Here we review the critical role, going forward, of transcriptome analysis for clarifying VUS in both neoplastic and non-neoplastic diseases.

Prandtl's type integro-differential equations with a different coefficient are investigated. Using the methods of the theory of analytic functions and integral transformations, the singular integro-differential equation is reduced to boundary value problems of the theory of analytic functions. Effective solutions of this equation and the corresponding asymptotic estimates are obtained

The existence of chromatic aberrations such as leucism or albinism is the result of inbreeding in isolated populations of wild local fauna and is associated with environmental stressors. This anomaly may reduce survival rates. There are many cases of leucism in wildlife, but overall, it is considered very rare. In neotropical primates, there have been records of leucism but previously, in howler monkeys was unknown. In this article, we report for the first time leucistic young individuals of Mantled howler monkeys Alouatta palliata, subspecies A. p. aequatorialis in an isolated remanent of tropical dry forest in southwestern Ecuador, namely Cerro Blanco Protective Forest. In total, we found two individuals, we named them Albita (a female) and Japu (a male). We also include a spatial analysis of the covert forest loss between 2000 to 2020. The report of individuals with leucism, may imply inbreeding because of isolated populations. Thus, immediate management strategies must be considered to significantly increase connectivity with other populations of howler monkeys.

Trees and shrubs in suburban forest understories can be subject to chronic herbivory from abundant white-tailed deer. An undocumented consequence of this stress may be shifts in secondary metabolite production associated with defense. We aimed to learn whether plants protected from deer exhibited different metabolomic profiles compared to those exposed to deer. We tested the indigenous species Nyssa sylvatica and Lindera benzoin and the invasive, nonindigenous species Rosa multiflora and Euonymus alatus within a suburban forest understory in New Jersey, USA, in unfenced plots and plots fenced for 5.3 years. We did untargeted metabolomics by sampling leaves from three plants of each species per 6-7 fenced and unfenced plots, conducting chloroform-methanol extractions followed by LC-MS/MS, and conducting statistical analysis on Metaboanalyst. We also scored each species for deer browse frequency over eight years, and compared their heights and percent cover between unfenced and fenced plots. The analysis identified 2,333 metabolites. The global metabolome diverged significantly between fenced and unfenced plots pooled across species, but for individual species only N. sylvatica exhibited a significant fencing effect. Nyssa sylvatica was one of the most browsed species and was the only one with both greater cover and height in fenced plots, suggesting greater susceptibility to deer browsing. The metabolites most responsible for the fenced/unfenced divergence also were affected by the species-fencing combination, with increases in certain species but decreases in others. The most significant metabolites that were upregulated in fenced plants include some involved in defense-related metabolic pathways, e.g. monoterpenoid biosynthesis. Further study of more species in multiple sites is needed to learn how common metabolomic responses to deer are among forest species, how the intensity of deer pressure influences the responses, which types of metabolites are most affected, and if there are ecological consequences at the physiological, population, and/or community levels.

In this work, we consider a thermoelastic laminated beam with structural damping, where the heat flux is given by Green and Naghdi theories. We establish the well-posedness of the system using semigroup theory. Moreover, under the condition of equal wave speeds, we prove an exponential stability result for the considered system. In the case of lack of exponential stability we show that the solution decays polynomially.

Bioprosthetic valve thrombosis is a growing recognized entity, especially with the increasing use of the valve in vale procedures and the advent of new detection technologies (e.g., 4D CT and 4D echocardiography). However, the optimal management strategy in the acute context is not established. This paper presents a case of early thrombosis following the percutaneous tricuspid valve in vale procedure that was successfully managed with thrombolysis.

The distribution and availability of phosphorus (P) fractions in restored cut slope soil aggregates along altitude gradients were studied. We examined soil aggregates total phosphorus (TP), available phosphorus (AP) and phosphorus activation coefficient (PAC), and discovered that there was no significant difference in TP at four altitudes (p> 0.05), but there was a significant difference in AP at 3009 m, 3347 m and 3980 m (p< 0.05). At 3009 m, 3347 m and 3654 m, the AP accumulation in small size aggregates were more advantageous. Overall, PAC dropped steadily as aggregate size increased, as shown by PAC (3654 m)> PAC (3347 m)> PAC (3009 m)> PAC (3980 m) in altitudes. In all particle size soil aggregates, total inorganic phosphorus (TPi) > total organic phosphorus (TPo) > residual phosphorus (R-P) at 3009 m, 3347 m and 3654 m; TPo> TPi> R-P at 3980 m. Through correlation and multiple stepwise regression analysis, we concluded that active NaHCO3-Pi was the main AP source. It was suggested that more attention should be paid to the ratio of small particle size aggregates, so as to increase soil AP storage. At low (3009 m) and high altitude (3980 m), inorganic P fertilizer and P activator were added into soil to improve the activation ability of soil P and the AP supply, so as to promote the healthy development of slope soils ecosystem.

In many cases, understanding species level responses to climate change requires understanding variation among individuals in response to such change. For species with strong symbiotic relationships, such as many coral reef species, genetic variation in symbiont responses to temperature may affect the response to increased ocean temperatures. To assess variation among symbiont genotypes, we examined the population dynamics and physiological responses of genotypes of Breviolum antillogorgium in response to increased temperature. We found broad temperature tolerance across genotypes, with all genotypes showing positive growth at 26, 30, and 32 C. Genotypes differed in the magnitude of the response of growth rate and carrying capacity to increasing temperature, suggesting that natural selection could favor different genotypes at different temperatures. However, the historical temperature at which genotypes were reared was not a good predictor of temperature response, suggesting a lack of adaptation to temperature over hundreds of generations. We found increased photosynthetic rates and decreased respiration rates with increasing temperature, and differences in physiology among genotypes, but found no significant differences in the response of different genotypes to temperature. In species with such broad thermal tolerance, selection experiments on symbionts outside of the host may not yield results sufficient for evolutionary rescue from climate change.

The influence of temperature, stirring speed, and excipients on crystal growth kinetics of mesalazine and allopurinol was investigated through experiment and chemical potential gradient model. The results indicated that the Diffusion-Surface Reaction model (DSR (1,2)) showed good performance in modeling API crystal growth kinetics within the ARDs of 4%. Excipients played a crucial role in inhibiting crystal growth in all the systems. It can not only improve the API solubility, but also reduce the crystal growth rate. By comparing diffusion rate and surface-reaction rate constant within the DSR (1,2) model, it was found that the controlling step of mesalazine crystallization was surface-reaction. Allopurinol crystallization was dominated by both surface-reaction and diffusion. Meanwhile, the crystal growth kinetics of mesalazine and allopurinol were predicted successfully with the ARDs of 2.53% and 4.78%. This work provided a mechanistic understanding of polymer influence on the inhibition of API crystal growth.

In this work, based on mathematical model inspired by transition state theory, the group contribution (GC) method is used to predict the viscosity of DESs. The model is constrained by Eyring rate theory and hard sphere free volume theory. A dataset of 2229 experimental measurements of the viscosity of 183 DESs from literature is used for determining the model parameters and subsequent verification of the model. The rules introduced by this model are simple and easy to understand. The results show that the proposed model is able to predict the DESs viscosity with very high accuracy, i.e., with an average absolute relative deviation of 8.12% over the training set and 8.64% over the test set, using only temperature and composition as inputs. The maximum absolute relative deviation is 34.63%. Therefore, the as-proposed model can be considered a highly reliable tool for predicting DESs viscosity when experimental data are absent.

Background: Studies on age-related differences in clinical and laboratory features on coronavirus disease 2019 (COVID-19) are limited. We aimed to evaluate the demographic, clinical, and laboratory findings of COVID-19 in children younger than six months old and compare them with older children. Methods: A single-center retrospective study, including 209 confirmed COVID-19 cases, was conducted between March 11, 2020, and September 1, 2021. The case group consisted of 47 patients younger than six months old, and the control group consisted of 162 patients older than six months old. Results: The mean age of the case group was 2.77±1.52 months, and the control group was 101.89±65.77 months. Cough was statistically higher in the control group, poor feeding was higher in the case group (P=.043, .010). The underlying disease ratio was statistically higher in the case group; however, the hospitalization rate was higher in the case group (P=.001, .036). The case group had significantly lower median values of the absolute neutrophil count, hemoglobin, and higher median values of white blood cell, absolute lymphocyte count, platelet than the control group (P<.05). C-reactive protein, fibrinogen values were significantly lower, and procalcitonin, D-dimer, troponin T, N‑terminal pro-B-type natriuretic peptide significantly higher in the case group (P<.05). Lymphopenia was more common in the control group, whereas neutropenia was more common in the case group (P= .001, .011). Conclusions: We showed that most children younger than six months old had mild and asymptomatic COVID-19; however, the hospitalization rate was higher, and neutropenia was more common than older children.

The number of diagnoses of mental illness has been increasing for years, especially in the wealthy industrialized nations. What continues to be overlooked is the massive influence of the lobby of the psychotherapeutic "industry", which has long and steadily earned good money from hastily misdiagnosed patients. However, this can be a matter of moderate to severe malpractice. In the meantime, this work has undergone peer review under the auspices of Swabian Research. In some instances, however, the repository in which it is deposited has not implemented this important change in status, and this note is therefore being provided for clarification.

Background. The use of eliciting doses (EDs) for food allergens is necessary to inform individual dietary advice and food allergen risk-management. The Eliciting Dose 01 (ED01) for milk and egg, calculated from populations of allergic subjects undergoing diagnostic Oral Food Challenges (OFCs), are 0.2 mg total protein. The respective Eliciting Dose 05 (ED05) are 2.4 mg for milk and 2.3 mg for egg. As about 70% children allergic to such foods may tolerate them when baked, we sought to verify the EDs of that subpopulation of milk and egg-allergic children. Methods. We retrospectively assessed consecutive diagnostic OFC for fresh milk and egg between January 2018 and December 2020 in a population of baked food-tolerant children. Results. Among 288 children (median age 56 - IQR 36-92.5 months, 67.1% male) included, 87 (30.2%) returned positive OFC results, 38 with milk and 49 with egg. The most conservative ED01 were 0.3 mg total protein (IQR 0.03-2.9) for milk and 14.4 mg total protein (IQR 3.6-56.9) for egg. The respective ED05 were 4.2 (IQR 0.9-19.6) mg for milk and 87.7 (IQR 43-179) mg for egg. Such thresholds are respectively 1.5 (milk ED01), 1.75 (milk ED05), 72 (egg ED01), and 38.35 (egg ED05) times higher than the currently used thresholds. Conclusions The subpopulation of children allergic to milk and egg, but tolerant to baked proteins, displays higher reactivity thresholds than the general population of children allergic to milk and egg. Their risk stratification, in both individual and population terms, should consider this difference. In baked milk-tolerant children, milk causes reactions at lower doses than egg in our group of egg-tolerant children. This could be associated with the relative harmlessness of egg compared to milk in the determinism of fatal anaphylactic reactions in children

Design plays a key role in human culture. A growing body of evidence suggests that most design builds upon human understanding to expand the market. However, few professionals have given attention to unwitting consequences. Drawing from political, economic and social history, this paper argues that design has been instrumental to capitalist ends, thereby forgoing discipline values. The author conducts a case study and explores counterfactual scripting as a way to reflect on alternate presents. Results portray a discursive provotype and a methodology whereby discussion is encouraged. This paper should be of value to future and experienced practitioners interested in technology, critical design and work ethics.

Hybrid coronary revascularization (HCR) consists of left internal thoracic artery (LITA) graft to the left anterior descending (LAD) artery and transcatheter revascularization of the non-LAD stenosis in specific settings to achieve complete coronary revascularization. Technique to perform the LITA to LAD graft has ranged from median sternotomy with cardiopulmonary bypass to robotically assisted totally endoscopic coronary bypass surgery using beating heart revascularization.

We report the case of a 42 years old young patient who was examined in the emergency department for epigastric pain lasting for 3 days. The abdominal tomodensitometry allowed to highlight the presence of an intra peritoneal effusion without pneumopertoneum. The patient underwent an exploratory laparoscopy. There was peritoneal toilet

Rationale, aims, and objectives: Portenoy and Foley’s 1986 landmark study “Chronic use of opioid analgesics in non-malignant pain: report of 38 cases” has been reproached for opening the floodgates of opioid prescribing for chronic non-cancer pain and the attendant harms. This influential article has been cited over 500 times in the scientific literature over the last four decades. This study seeks to understand the impact of Portenoy and Foley’s article on subsequent discussions and research about opioids. Methods: We conducted a multi-method bibliometric analysis of all citations of this article from 1986 through 2019 using quantitative relational and qualitative content analysis to determine how uses and interpretations of this case series and associated prescribing guidance have changed over time, in relationship to the evolution of the North American opioid crises. Results: Using time series analysis, we identified three periods with distinct interpretations and uses of the index study. In the first “exploration” period (1986-1996), the index study was well-received by the scientific community and motivated further study of the effects of opioids. In the second “implementation” period (1997-2003, coinciding with the release of OxyContin®), this study was used as evidence to support widespread prescribing of opioid analgesics, even while it was recognized that long-term effects had not yet been evaluated. The third “reassessment” period (2004-2019) focused on how opioid-related harms had been overlooked, and in many cases these harms were directly attributed to this study. Conclusion: These changes in interpretation demonstrate shifting currents of the use and mobilization of evidence regarding pain and opioids, and how these currents both impact and are impacted by clinical practices and major sociohistorical phenomena such as the opioid crisis. Researchers and clinicians must account for these shifting dynamics when developing and interpreting scientific knowledge, including in the form of clinical practice guidelines.

In the present paper, we study the existence of nontrivial solutions of the following one-dimensional fractional Schr\“{o}dinger equation $$ (-\Delta)^{1/2}u+V(x)u=f(x,u), \ \ x\in \R, $$ where $(-\Delta)^{1/2}$ stands for the $1/2$-Laplacian, $V(x)\in \mathcal{C}(\R, (0,+\infty))$, and $f(x,u):\R\times\R\to \R$ is a continuous function with an exponential critical growth. Comparing with the existing works in the field of exponential-critical-growth fractional Schr\”{o}dinger equations, we encounter some new challenges due to the weaker assumptions on the reaction term $f$. By using some sharp energy estimates, we present a detailed analysis of the energy level, which allows us to establish the existence of nontrivial solutions for a wider class of nonlinear terms. Furthermore, we use the non-Nehari manifold method to establish the existence of Nehari-type ground state solutions of the one-dimensional fractional Schr\”{o}dinger equations.

This paper is devoted to studying the existence of at least one periodic solution for a generalized Basener-Ross model with time-dependent coefficients. The discussion is based on the Man\’asevich-Mawhin continuation theorem and fixed point theorem of cone mapping together with some properties of Green’s function.

Preliminary results of single centre experience with the “release and perfuse technique” during aortic arch surgery.Antonio Piperata1 MD; Nicolas d’Ostrevy1 MD; Olivier Busuttil1 MD; Thomas Modine1 MD, PhD; Giulia Lorenzoni2 PhD; Danila Azzolina2PhD; Dario Gregori2 PhD; Louis Labrousse1 MD, PhD; Mathieu Pernot1MD.1Department of Cardiology and Cardio-Vascular Surgery, Hôpital Cardiologique de Haut-Lévèque, Bordeaux University Hospital, 33604, France2Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, ItalyCorresponding Author : Antonio Piperata,Avenue Magellan,33600, Pessac, FRPhone: +33 771768872E-mail: a.piperata88@gmail.comKey words : aortic arch repair; circulatory arrest; frozen elephant trunk, aortic arch, aortic surgery.Acknowledgments: noneData availability statement: Data cannot be shared for ethical/privacy reasons. The data will be shared on reasonable request to the corresponding author.Funding statement and Conflict of interest disclosure: All authors have no conflicts of interest or financial conflicts to disclose. No funding source was provided for this study.

Atrial fibrillation (AF) is the most common atrial arrhythmia and is subcategorized into numerous clinical phenotypes. Given its heterogeneity, investigations into the genetic mechanisms underlying AF have been pursued in recent decades, with predominant analyses focusing on early onset or lone AF. Linkage analyses, genome wide association studies (GWAS), and single gene analyses have led to the identification of rare and common genetic variants associated with AF risk. Significant overlap with genetic variants implicated in dilated cardiomyopathy syndromes, including truncating variants of the sarcomere protein titin, have been identified through these analyses, in addition to other genes associated with cardiac structure and function. Despite this, widespread utilization of genetic testing in AF remains hindered by the unclear impact of genetic risk identification on clinical outcomes and the high prevalence of variants of unknown significance (VUS). However, genetic testing is a reasonable option for patients with early onset AF and in those with significant family history of arrhythmia. While many knowledge gaps remain, emerging data support genotyping to inform selection of AF therapeutics. In this review we highlight the current understanding of the complex genetic basis of AF and explore the overlap of AF with inherited cardiomyopathy syndromes. We propose a set of criteria for clinical genetic testing in AF patients and outline future steps for the integration of genetics into AF care.

Background: Since the outbreak of the Coronavirus disease 2019 (COVID-19) pandemic, there has been a decline in pediatric emergency department visits. Our aim was to assess the pattern of pediatric foreign body aspiration (FBA) during the first year of the COVID-19, in comparison to the prior years. Methods: In this retrospective multicenter study, we compared the number of children that presented with FBA during the COVID-19 year (March 1st, 2020 to February 28, 2021), to the annual average of the years 2016-2019. We also compared the lockdown periods to the post-lockdown periods and the percentage of missed FBA, proven FBA, and flexible bronchoscopy as the removal procedure. Results: 345 children with FBA from six centers were included, 276 in the pre-COVID-19 years (average 69 per year) and 69 in the COVID-19 year. There was no difference in the prevalence of FBA between the COVID-19 year and any of the prior four years. Examining the lockdown effect, the monthly incidence of FBA dropped from a pre-COVID-19 average of 5.75 cases to 5.1 cases during lockdown periods and increased to 6.3 cases in post-lockdown periods. No difference in the percentage of missed FB or proven FB was observed. There was a significant rise in the usage of flexible bronchoscopy as the removal procedure (Average of 15.4% vs 30.4%, p=0.001) Conclusion: There was no difference in the prevalence of FBA during the COVID-19 year. However, there were fewer cases during lockdown periods, compared to post-lockdown periods, presumably related to better parental supervision.

Pseudoaneurysm of the right ventricular outflow tract(RVOT) is an uncommon yet catastrophic complication after intracardiac repair of Tetralogy of Fallot(TOF). We describe a patient diagnosed with RVOT pseudoaneurysm in the immediate postoperative period after complete repair for TOF with single pulmonary artery. The pseudoaneurysm was repaired successfully. This case is reported to emphasise the importance of a high degree of suspicion of this rare entity in these patients for its early diagnosis and management.

Most organisms belonging to the Saccharomycotina subphylum have high genetic diversity and a vast repertoire of metabolisms and lifestyles, which explains its ecological versatility. The yeast Lachancea cidri is an ideal model for exploring the interplay between genetics, ecological function and evolution. L. cidri is a species that diverged from the Saccharomyces lineage before the whole-genome duplication and exhibits a broad distribution across the South Hemisphere, thus displaying an important ecological success. Here, we applied phylogenomics to investigate the adaptive genetic variation of L. cidri isolates obtained from natural environments in Australia and South America. Our approach revealed the presence of two main lineages according to their geographic distribution (Aus and SoAm). Estimation of the divergence time suggest that South American and Australian lineages diverged near the last glacial maximum event during the Pleistocene (64-8 KYA), consistent with the presence of multiple glacial refugia. Interestingly, we found that the French reference strain belongs to the Australian lineage, with a recent divergence (405-51 YA), likely associated to human movements. Additionally, species delimitation analysis identified different evolutionary units within the South American lineage and, together with parameters like Pi (π) and FST, revealed that Patagonia contains most of the genetic diversity of this species. These results agree with phenotypic characterizations, demonstrating a greater phenotypic diversity in the South American lineage. These findings support the idea of a Pleistocene-dated divergence between South Hemisphere lineages, where the Nothofagus and Araucaria ecological niches likely favored the extensive distribution of L. cidri in Patagonia.