Microdeletions and gross deletions are important causes (~20%) of human inherited disease. Their genomic locations are strongly influenced by the local DNA sequence environment. Yet no systematic study has examined the generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions from the Human Gene Mutation Database (HGMD) that together form a continuum of germline deletions ranging in size from 1 bp to 28,394,429 bp. We analyzed the sequence within 1-kb of the breakpoint junctions and found the frequencies of non-B DNA-forming repeats, GC content, and the presence of seven of 78 specific sequence motifs in the vicinity of pathogenic deletions correlated with deletion length for deletions of length ≤30 bp. Furthermore, we found the repeats of DR, GQ, and STR appear to be important for the formation of longer deletions (>30 bp) but not for the formation of shorter deletions (≤30 bp) and significantly (Chi-square test P-value < 2E-16) more microhomologies were identified in flanking short deletions than long deletions (length >30 bp). We provide evidence to support a functional distinction between microdeletions and gross deletions. A deletion length cut-off of 25-30 bp may serve as an objective means to functionally distinguish microdeletions from gross deletions.

Runs of long homozygous stretches (ROH) are considered to be the result of consanguinity and usually contain recessive deleterious disease causing mutations (Szpiech et al., 2013). Several algorithms have been developed to detect ROHs. Here, we developed a simple, alternative strategy by examining X chromosome non-pseudoautosomal region to detect the ROHs from next generation sequencing data utilizing the genotype probabilities and the Hidden Markov Model algorithm as a tool, namely ROHMM. It is implemented purely in java and contains both command-line and a graphical user interface. We tested ROHMM on simulated data as well as real population data from 1000G Project and a clinical sample. Our results have shown that ROHMM can perform robustly producing highly accurate homozygosity estimations under all conditions thereby meeting and even exceeding the performance of its natural competitors.

The dilution effect was originally proposed to describe the negative effect of increased host diversity on parasite abundance; with greater host diversity, parasite levels per host are predicted to be lower due to a higher probability of dispersing parasites encountering non-competent hosts. Dilution effects could also occur in many mutualisms if dispersing symbionts encounter hosts that vary in their competency. The introduction of non-native hosts can change community competency of a local group of host species. Crayfish introductions are occurring world-wide and these introductions are likely disrupting native crayfish-symbiont systems. Branchiobdellidan symbionts declined on native Cambarus crayfish occurring in the presence and absence of non-native Faxonius crayfish in the New River, USA. We performed an experiment investigating the effect of host density (1 vs 2 native hosts) and host diversity (1 native host and 1 introduced host) on branchiobdellidan abundance. The introduced F. cristavarius is a non-competent host for these worms. Six C. ingens were stocked on a C. chasmodactylus in each treatment and worm numbers were followed over 34 days. Worm numbers decreased over time on C. chasmodactylus alone and in the treatment in which a C. chasmodactylus was paired with an F. cristavarius. Worm numbers remained highest in the 2 C. chasmodactylus treatment . There was no significant effect of host diversity on worm reproduction. Crayfish invasions may have negative effects on mutualistic symbionts depending on the competence of introduced hosts. Loss of native symbionts is one of the potential hidden, negative effects of invasions on native freshwater diversity.

Plant competition experiments commonly suggest that larger species have an advantage, especially in light acquisition. However, within crowded natural vegetation, where competition evidently impacts fitness, most resident species are relatively small. It remains unclear, therefore, whether the size-advantage observed in controlled experiments is realized in habitats under intensive competition. We tested for evidence of a size-advantage in competition for light in an old-field plant community composed of herbaceous perennial species. We investigated whether larger species contributed to reduced light penetration (i.e., greater shading), and examined the impact of shade on smaller species by testing whether their abundance and richness were lower in plots with less light penetration. Light penetration in plots ranged from 0.3-72.4%. Plots with greater mean species height had significantly lower light penetration. Plots with lower light penetration had significantly lower small species abundance and richness. However, the impact of shade on small species abundance and richness was relatively small (R2 values between 8% and 15%) and depended on how we defined “small species”. Significant effects were more common when analyses focused on individuals that reached reproduction; focusing on only flowering plants can clarify patterns. Our results confirm that light penetration in herbaceous vegetation can be comparable to levels seen in forests, that plots with taller species cast more shade, and that smaller species are less abundant and diverse in plots where light penetration is low. However, variation in mean plot height explained less than 10% of variation in light penetration, and light penetration explained 5-15% of variation in small species abundance and richness. Coupled with the fact that reproductive small species were present even within the most heavily shaded plots, our results suggest that any advantage in light competition by large species is limited. One explanation is that some small species in these communities are shade tolerant.

In the present paper the representation, in different domains, of analytic functions by complex conformable fractional derivative bases (CCFDB) and complex conformable fractional integral bases (CCFIB) in Frechet space are investigated . Theorems are proved to show that such representation is possible in closed disks, open disks, open regions surrounding closed disks, at the origin and for all entire functions. Also, some results concerning the growth order and type of CCFDB and CCFIB are determined. Moreover the T-property of CCFDB and CCFIB are dis- cussed. The obtained results recover some known results when alpha = 1. Finally, some applications to the CCFDB and CCFIB of Bernoulli, Euler, Bessel and Chebyshev polynomials have been studied.

The performance of advanced controllers depends on the selection of several tuning parameters that can affect the closed-loop control performance and constraint satisfaction in highly nonlinear and nonconvex ways. There has been a significant interest in auto-tuning of complex control structures using Bayesian optimization (BO). However, an open challenge is how to deal with uncertainties in the closed-loop system that cannot be attributed to a lumped, small-scale noise term. This paper develops an adversarially robust BO (ARBO) method that is suited to auto-tuning problems with significant time-invariant uncertainties in a plant simulator. ARBO uses a Gaussian process model that jointly describes the effect of the tuning parameters and uncertainties on the closed-loop performance. ARBO uses an alternating confidence-bound procedure to simultaneously select the next candidate tuning and uncertainty realizations, implying only one expensive closed-loop simulation is needed at each iteration. The advantages of ARBO are demonstrated on two case studies.

The aim of the present paper is to describe and discuss how recent theories about translation, bridging medical and humanistic understandings of knowledge translation, in the medical humanities (Kristeva et al 2018) can bring about a new understanding of health literacy in the context of patient education. We argue that knowledge translation must be understood as a simultaneous interrogation of the patient’s and the health care providers co-construction of new and shared meanings that can create realities with medical consequences. To illustrate our points, we will describe the case of Jim, a kidney transplant recipient who received standard patient education, but lost the graft (the new kidney). If we apply Kristeva’s view onto this context, graft function is not merely a biology but a complex bio-cultural fact. In this perspective, graft function is seen as a phenomenon that embraces translation between health as a biomedical phenomenon and healing as lived experience, and that opens for shared meaning -making processes between the patient and the health care provider. In Jim’s case this means that we need to rethink the approach to patient education in a way that encourage the patient’s idiosyncratic way of thinking and experiencing – and transform health information into a means for sustaining Jim’s particular life – not life ‘in general’. The patient education program did not take into consideration the singularities of Jim’s biographical temporality, with its changes in everyday life, priorities, attitudes and values. The arguments are generic and could be applied to other contexts.

Scoring docking solutions is a difficult task, and many methods have been developed for this purpose. In docking, only a handful of the hundreds of thousands of models generated by docking algorithms are acceptable, causing difficulties when developing scoring functions. Today’s best scoring functions can significantly increase the number of top-ranked models but still fails for most targets. Here, we examine the possibility of utilising predicted residues on a protein-protein interface to score docking models generated during the scan stage of a docking algorithm. Many methods have been developed to infer the portions of a protein surface that interact with another protein, but most have not been benchmarked using docking algorithms. Different interface prediction methods are systematically tested for scoring >300.000 low-resolution rigid-body template free docking decoys. Overall we find that BIPSPI is the best method to identify interface amino acids and score docking solutions. Further, using BIPSPI provides better docking results than state of the art scoring functions, with >12% of first ranked docking models being acceptable. Additional experiments indicated precision as a high-importance metric when estimating interface prediction quality, focusing on docking constraints production. We also discussed several limitations for the adoption of interface predictions as constraints in a docking protocol.

BACKGROUND: Postoperative pericardial adhesions have been associated with increased morbidity, mortality, and surgical difficulty. Barriers exist to limit adhesion formation, yet little is known about their use in cardiac surgery. The study presented here provides the first major systematic review of adhesion barriers in cardiac surgery. METHODS: Scopus and PubMed were assessed on November 20, 2020. Inclusion criteria were clinical studies on human subjects, and exclusion criteria were studies not published in English and case reports. Risk of bias was evaluated with the Cochrane Risk of Bias Tool. Barrier safety and efficacy data were assessed with Excel and GraphPad Prism 5. RESULTS: 25 studies were identified with a total of 13 barriers and 2,928 patients. Polytetrafluoroethylene (PTFE) was the most frequently evaluated barrier (13 studies, 67% of patients) with an infection rate of 1.14%, bleeding event rate of 0.75%, mortality rate of 1.22%, adhesion formation rate of 37.31%, and standardized tenacity score of 26.50. Several barriers had improved safety and efficacy. In particular, Cova CARD had an infection rate of 0.00%, a bleeding event rate of 0.00%, and a tenacity score of 15.00. CONCLUSIONS: Overall, the data varied considerably in terms of study design and reporting bias. The amount of data was also limited for the non-PTFE studies. PTFE has historically been effective in preventing adhesions. More recent barriers may be superior, yet the current data is non-confirmatory. No ideal adhesion barrier currently exists, and future barriers must focus on the requirements unique to operating in and around the heart.

Objective: Vaginal birth after caesarean (VBAC) has been suggested to be associated with an increased risk of obstetric anal sphincter injury (compared with primiparous women who birth vaginally). However, prior studies have been small, or used outdated methodology. We set out to validate whether the risk of obstetric anal sphincter injury among women having their first VBAC is greater than that among primiparous women having a vaginal birth. Design: State-wide retrospective cohort study. Setting: Victoria, Australia. Population: All births (455,000) between 2009-2014. Methods: The risk of severe perineal injury between first vaginal birth and first vaginal birth after previous caesarean section was compared, after adjustment for potential confounding variables. Covariates were examined using logistic regression for categorical data and Wilcoxon rank-sum test for continuous data. Missing data were handled using multiple imputation; the analysis was performed using regression adjustment and Stata v16 multiple imputation and teffects suites. Results: Women having a VBAC (n=5,429) were significantly more likely than primiparous women (n=123,353) to sustain a 3rd or 4th degree tear during vaginal birth (7.1 vs 5.7%, p<0.001). After adjustment for mode of birth, body mass index, maternal age, infant birthweight, episiotomy and epidural, there was a 21% increased risk of severe perineal injury (relative risk 1.21 (95%CI 1.07 – 1.38)). Conclusions: Women having their first vaginal birth after caesarean section have a significant increased risk of sustaining a 3rd or 4th degree tear, compared with primiparous women having a vaginal birth. Patient counselling and professional guidelines should reflect this increased risk.

A document by Irtiza Sheikh. Click on the document to view its contents.

Ever since the adoption of the newest heart allocation system in the Fall of 2018, clinicians have grappled with the safest method of utilizing temporary mechanical circulatory support to get patients successfully to transplantation. In unique patients that do not have a durable left ventricular assist device as a therapeutic option and have not had a full work-up for transplantation consideration, the establishment of ambulatory extracorporeal membrane oxygenation is an attractive solution.

Background and Purpose Refractory status epilepticus is a clinical emergency associated with high mortality and morbidity. Increasing evidence suggests neuroinflammatory pathways contribute to the development of drug-refractoriness during status epilepticus. The ATP-gated P2X7 receptor (P2X7R) has been described as potential link between inflammation and increased hyperexcitability. The aim of the present study was to determine the contribution of the P2X7R to drug-refractory status epilepticus and its therapeutic potential. Experimental Approach Status epilepticus was induced via a unilateral microinjection of kainic acid into the amygdala in adult mice. Severity of status epilepticus was compared in animals overexpressing or knock-out in the P2X7R, after inflammatory priming by the pre-injection of bacterial lipopolysaccharide (LPS) and in mice treated with P2X7R-targeting and anti-inflammatory drugs. Key Results P2X7R overexpressing mice were unresponsive to several anticonvulsants (lorazepam, midazolam, phenytoin and carbamazepine) during status epilepticus. P2X7R expression was increased in microglia during drug-refractory status epilepticus, P2X7R overexpression led to a pro-inflammatory phenotype in microglia during status epilepticus and the anti-inflammatory drug minocycline restored normal responsiveness to anticonvulsants in P2X7R overexpressing mice. Pre-treatment of wildtype mice with LPS increased P2X7R levels in the brain and promoted the development of pharmaco-resistant status epilepticus, which was overcome by either a genetic deletion of the P2X7R or the administration of the P2X7R antagonists AFC-5128 or ITH15004. Conclusion and Implications Our results demonstrate that P2X7R-induced pro-inflammatory effects contribute to resistance to pharmacotherapy during status epilepticus and suggest therapies targeting the P2X7R as novel adjunctive treatments for drug-refractory status epilepticus.

Comparing genome scans among species is a powerful approach for investigating the patterns left by evolutionary processes. In particular, this offers a way to detect candidate genes that drive convergent evolution. We compared genome scan results to investigate if patterns of genetic diversity and divergence are shared among divergent species within the stickleback order (Gasterosteiformes): the threespine stickleback (Gasterosteus aculeatus), ninespine stickleback (Pungitius pungitus) and tubesnout (Aulorhynchus flavidus). Populations were sampled from the southern and northern edges of each species’ range, to identify patterns associated with latitudinal changes in genetic diversity. Weak correlations in genetic diversity (FST and expected heterozygosity) and three different patterns in the genomic landscape were found among these species. Additionally, no candidate genes for convergent evolution were detected. This is a counterexample to the growing number of studies that have shown overlapping genetic patterns, demonstrating that genome scan comparisons can be noisy due to the effects of several interacting evolutionary forces.

Myoclonus-Dystonia is a neuropsychiatric disorder with autosomal dominant mode of inheritance with variable severity and incomplete penetrance. Pathogenic variants in SGCE are the most frequent genetic cause of M-D with maternal imprinting. Herein we report a new deleterious variant based on protein modeling analysis (c.662G> T) inherited in moroccan family.

ABSTRACT The involvement of Medical Technology (MedTech) corporations in the provision of surgical care remains a topic of debate. This relationship is especially relevant in cardiac and aortic surgery as the use of grafts, stents, prostheses, and other devices is an integral component of most procedures. Many argue that the involvement of device representatives in cardiac surgical cases is valuable – they are often experts on their product and are able to contribute their expertise in challenging cases. Yet, the potential for MedTech corporations to influence surgeons’ clinical decision-making introduces a conflict-of-interest and calls into question what the ‘best practice’ for sales reps should be. The influence of MedTech corporations over policymaking bodies in the US, UK, and Europe also represents a major issue for transparency and is equally deserving of evaluation.

This paper aims to investigate the ecological role of Merlucicius merluccius, Linnaeus, 1758, in the southern and central Tyrrhenian Sea (GSA 10, Resolution GFCM/33/2009/2 General Fisheries Commission for the Mediterranean), analysing ontogenetic diet shift, geographical variations on prey composition and feeding habits. A sample of 734 hake specimens between 6 cm and 73 cm of total length (TL) were collected in 2018. To value the ontogenetic shifts in prey composition, five size-classes were created from the sample and for each class were calculated quantitative feeding indices. The cluster and MDS analysis, based on the % IRI, resulted in three trophic groups of hake size classes. The most abundant preys for small hake (size class I) were the Euphausiids, Stylocheiron longicorne and Mysidacea, while for hake with size over 10.5 cm of TL were crustaceans and fish. Engraulis encrasicolus was the most abundant prey fish for hake, followed by Boops boops and Myctophids. The mesopelagic fauna had a relevant role in the European hake diet in the southern zone. The high presence of Euphausiids, Mysids, Myctophidae and Sternoptychidae in the gut content of juvenile hakes (6-23 cm) showed the importance of organic matter and energy flowed from the mesopelagic environment to the epipelagic. Important is also the presence of decapod crustaceans in hake with size over 36 cm TL considering that our study area includes an important Gulf for the fishing of decapod crustacea.

The disjunct temperate rainforests of the Pacific Northwest of North America (PNW) are characterized by late-successional dominant tree species western redcedar (Thuja plicata) and western hemlock (Tsuga heterophylla). The demographics of these species, along with the PNW rainforest ecosystem in its entirety, have been heavily impacted by the geological and climatic changes the PNW has experienced over the last 5 million years, including mountain orogeny and repeated Pleistocene glaciations. These environmental events have ultimately shaped the history of these species, with inland segments potentially being extirpated during the Pleistocene glaciation. Here, we collect genomic data for both species across their ranges in order to develop multiple demographic models, each reflecting a different hypothesis on how the ecosystem dominant species may have responded to dramatic climatic change. Results indicate that inland and coastal populations in both species diverged an estimated ~2.5 million years ago and experienced a decrease in population size during glaciation, with a subsequent population expansion. Importantly, we found evidence for gene-flow between coastal and inland populations during the mid-Holocene. It is likely that intermittent migration in these species has prevented allopatric speciation. In conclusion, the combination of genomic data and population demographic inference procedures involving machine learning establish that populations of the ecosystem dominants Thuja plicata and Tsuga heterophylla persisted in refugia located in both the coastal and inland regions, with populations expanding and contracting in response to glacial cycles with occasional gene-flow.