A document by Narimane Aissaoui. Click on the document to view its contents.

One of the critical aspects of structure-based drug design is to choose important druggable binding sites in the protein's crystallography structures. As experimental processes are costly and time-consuming, computational drug design using machine learning algorithms is recommended. Over recent years, deep learning methods have been utilized in a wide variety of research applications such as binding site prediction. In this study, a new combination of attention blocks in the 3D U-Net model based on semantic segmentation methods is used to improve localization of pocket prediction. The attention blocks are tuned to find which point and channel of features should be emphasized along spatial and channel axes. Our model's performance is evaluated through extensive experiments on several datasets from different sources, and the results are compared to the most recent deep learning-based models. The results indicate the proposed attention model can predict binding sites accurately, i.e. the overlap of the predicted pocket using the proposed method with the true binding site shows statistically significant improvement when compared to other state-of-the-art models. The attention blocks may help the model focus on the target structure by suppressing features in irrelevant regions.

Background: Respiratory syncytial virus (RSV) is becoming increasingly recognized as a serious threat to vulnerable population subgroups. The Epidemiology, Burden, and Cost (EBC) of RSV Infection Study is a retrospective cohort study of adults hospitalized for acute respiratory infection (ARI) designed to estimate the population burden of RSV especially for specific groups such as the elderly, pregnant women and solid organ transplant patients. This paper describes the design and statistical analysis plan for the study. Methods: The study population will consist of residents of Allegheny County, Pennsylvania ≥18 years of age who were hospitalized in Pennsylvania during the period September 1, 2015 to August 31, 2018. Several data sources will be used including U.S. Census, Pennsylvania Health Care Cost Containment Council (PHC4), and the electronic medical record for the health system to which the hospitals belong. The algorithm involves: 1) ARI-associated hospitalizations in PHC4 data; 2) adjustment for ARI hospitalizations among county residents but admitted to hospitals outside the county, and 3) RSV detections from respiratory viral panels (RVPs). Key sensitivity analyses will adjust for undertesting for viruses in the fall and spring quarters. The results will be population-based estimates, stratified by age and risk groups. Conclusion: Adjusting hospitalization data using a multiplier method is a relatively simple means to estimate the impact of RSV in a given area. This algorithm can be applied to other health systems and localities to estimate burden of RSV in adults, as well as burden of other respiratory pathogens.

Objectives: This study analyzed the clinical characteristics and hematologic examination indexes to tell the type of influenza among patients and provide a basis for the early diagnosis and treatment of influenza patients. Methods: We collected demographic characteristics and clinical data from 726 influenza patients and analyzed the impact of different clinical manifestations and hematological tests on the measured values of influenza types. Results: The common clinical manifestations of influenza patients were fever (99.2%), pharyngeal congestion (97.1%) and cough (80.4%), et al. Those with oneset of illness with were 19-49 years of age (OR= 0.335, 95% CI: 0.196-0.573) or had nasal congestion (OR= 0.566, 95% CI: 0.349-0.919) and fever for more than 3 days (OR= 0.368, 95% CI: 0.214-0.632) tend to were diagnosed asprone to have influenza B. While those patients with symptoms of cough (OR=2.119, 95% CI: 1.322-3.389), headache (OR=1.834, 95% CI: 1.157-2.908), muscle pain (OR=1.811, 95% CI: 1.139-2.880), and blood CPR>8mg/L (OR=2.315, 95% CI: 1.501-3.589) were prone to have influenza A. Conclusion: By combining clinical manifestations and laboratory findings, it is possible to initially distinguish the type of influenza, which can provide assistance in the early treatment and prognosis of influenza.

Circulating miRNAs – a potential tool to identify severe asthma risk?M Aref Kyyaly1,2,3, Tilman

Epithelial ovarian carcinoma (EOC) is a malignant tumor with high motility in women. Our previous study found that dysregulated NTPCR was associated with the prognosis of ovarian cancer patients, and thus this present study attempted to explore the potential roles of nucleoside-triphosphatase cancer-related (NTPCR) in disease progression.

Objective: To describe the gross and histological characters of MRKHS patients’ ovaries and assess their ovarian reserve directly for future pregnancy. Design: A prospective case-control study. Setting and population: A prospective case-control study involving 67 MRKH syndrome patients and 17 ovarian biopsies (with age-matched controls), from January 2017 to February 2020. Methods: We observed the gross appearance of 67 Chinese MRKHS patients during laparoscopically assisted neovagina creation surgery. Seventeen ovarian biopsies were obtained and compared with age-matched controls for the histological characters. Twelve biopsy specimens underwent a complete serial section and calculation of the primordial follicular density. Main Outcome Measures: Follicle density, morphology in ovarian cortex biopsies. Results: 5/67 MRKHS patients’ ovaries had abnormal gross appearance, including streak gonads and bilateral porcelain white ovaries. We observed corpus luteum or corpus albicans on 5/8 patients under 20 years old, but none of the controls. None of the biopsies from MRKHS type Ⅱ patients showed corpus luteum or corpus albicans. Two type Ⅰ patients presented with compromised ovarian reserve, and significant increase of atretic follicles and corpus albicans. A significant inverse correlation was observed between primordial follicular density and age in 12 patients aged 16 to 25 years old. Conclusion: The ovaries of MRKHS patients have higher rates of abnormalities regarding gross appearance and histological characters. Tweetable abstract: It is suggested that early preparation for fertility reserve and incorporated as a part of the treatment when reconstructing the neovagina in MRKH syndrome patients due to premature declination of the ovarian reserve.

Intraspecific diet variation is widespread, but the causes and consequences of individual foraging strategies are unclear. Interactions between competition and resources dictate foraging strategies, but classical paradigms like optimal foraging and niche theory offer contrasting predictions for individual consumers. Further, both paradigms assume that individual foraging strategies optimize fitness, yet this prediction is rarely tested. We used over 3,500 stable isotope measurements and six years of capture-mark-recapture data to quantify the relationship between environmental variation, individual foraging, and consumer fitness in four desert rodent species. Consistent with niche theory, we found that individuals contracted their dietary niches and increased specialisation in response to both intraspecific and interspecific competition, but the effect was mediated by resource abundance. However, individual specialists obtained no apparent fitness benefit from dietary niche contractions and exhibited lower survival than generalists. These results suggest diet-mediated fitness consequences can regulate population and community dynamics in stochastic resource environments.

Objective: This study aimed to assess the rotation and torsion in the endocardial, epicardial, and global myocardium using two-dimensional speckle tracking imaging(2D-STI) in patients with rheumatic heart disease who underwent aortic valve replacement (AVR). Methods: This study included 42 AVR patients [(23 F/19 M, aged (62.7±11.2) years] and 25 normal control [(16 F/9 M, aged (63.3±10.5) years]. 2D-STI was performed in five consecutive heart beats, and data were stored for offline analysis using Q-Lab. The peak systolic rotation of the endocardial, epicardial, and global myocardium in the left ventricular basal and apical walls were measured using 2D-STI. The torsion and twisting angles of the sub-endocardial, sub-epicardial, and global myocardium were calculated. Results: Rotation at the left ventricular basal level of the study group was not significantly reduced compared with that in the normal control group. However, at the apical level, rotation was significantly reduced (p=0.03, 0.003, 0.004). The torsion angle of the study group was significantly reduced compared with that of the normal control group (p=0.006, 0.003, 0.003). Furthermore, patients with different left ventricular ejection function after AVR showed differences in torsion of the endocardial, epicardial, and global myocardium. Conclusions: The systolic rotation and twist of the subendocardial, sub-epicardial, and global myocardium in the left ventricle were reduced, whereas those at the basal level remained unchanged. After AVR, old patients have an almost complete recovery of left ventricular rotational motion at the basal level. 2D-STI is a useful non-invasive tool for evaluation of the left ventricular regional function.

ABSTRACT Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymph-adenopathy is characterized as massive, painless, bilateral, symmetric cervical lymphadenopathy, with fever, leucocytosis, elevated sedimentation rate, and hyper-gamma-globulinemia. This paper reports on the case of a 2-year-old child with history of progressive, bilateral cervical lymph-adenopathy associated with fever, generalized weakness. Histo-pathological and immune-histochemistry studies showed predominantly large histiocytes, emperipolesis and S-100 positivity suggestive of RDD. Patient presented with splenic abscess on follow up and managed conservatively. Here we are describing a 2-year old patient of RDD associated with splenic abscess, currently under strict follow-up.

The work aimed to evaluate the effectiveness of the developed distraction system based on the rod external monolateral fixation mechanisms by comparing it with the classical technique of long tubular bones distraction based on the circular multi-axial system. The study included patients with a genetically confirmed diagnosis of achondroplasia. The main group consisted of 14 patients who underwent surgical limb lengthening by the rod monolateral external fixator with a distraction system developed by the authors.). In the majority of patients of the main group the lengthening value close to the planned one as well as the deformation correction was achieved. The fixation period was averagely 83.8±3.7 days, the regenerate length was 8.5±0.6 cm, and the mechanical strength of the distraction regenerate was 10.3±2.18º. The fixation time was significantly lower, and the length of the regenerate was longer compared to that in the control group. The rod external fixator with a control distraction system developed by the authors has small dimensions and low weight of the external supporting elements of high durability. It is reported to provide a good psychological tolerance of the treatment process and significantly outperforms the circular multi-axis system.

Heavy-metal toxicity severely affects agricultural productivity as well as the human health worldwide. Among heavy metals with noticeable noxious effects, mercury (Hg) acts as a potential contaminant, having a crucial impact on natural resources and crop production. Hg-tolerance mechanisms in plants are not very clear. Over the years, proteomics has emerged as a significant tool to explore the plant response and tolerance mechanisms to Hg stress. Proteins are the functional players of cells as they regulate the physiological processes. Hg-induced modulation of proteins has been documented in several plant systems. Identification of key proteins and their roles in Hg tolerance are crucial to produce Hg resistance crops, thus contributing to global food security. Proteomic studies give us a comprehensive idea of protein networks and signalling pathways involved in Hg detoxification. The present review provides an overview of proteomic research about Hg tolerance in the model and non-model plants, offers a broad insight of stress proteins and highlights various proteomic approaches used to identify stress-responsive proteins.

In the first year of its appearance, the 2019 coronavirus disease (COVID-19) has affected more than 120 million individuals and killed 2 million people worldwide. The pandemic has also triggered numerous global initiatives to tackle the newly emerging disease, including the development of SARS-CoV-2 vaccines and the attempt to discover potential pharmacological therapies. Nonetheless, despite the success of SARS-CoV-2 vaccines development, the COVID-19 therapy remains challenging. Several repurposed drugs that were documented to be useful in small clinical trials have been shown to be ineffective in larger studies. Additionally, the pathophysiology of SARS-CoV-2 infection displayed the predominance of cytokine storm in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed. Here, we reviewed the roles of immunomodulation as potential COVID-19 pharmacological modalities based on the existing data and proposed several new immunologic targets to be tested in the foreseeable future.

Determining which patients are at highest risk of acute chest syndrome (ACS) is challenging for pediatric emergency department (PED) providers, resulting in more chest x-rays (CXR), increased radiation exposure, and higher healthcare costs. The objective of this study was to identify significant clinical predictors of ACS to better guide care. In this retrospective review, we included patients diagnosed with sickle cell disease (SCD), aged 2-12 years, who presented to the PED between 2016-2018. We compared patients who were febrile vs. afebrile on presentation, and those diagnosed with ACS vs. those who were not. A total of 424 patients met inclusion criteria, 25% presenting with fever. For febrile patients, 69% received a CXR on presentation vs. 42% of afebrile subjects (p=<0.0001). Overall, 10% of patients were diagnosed with ACS: 13% of febrile presentations vs. 9% of afebrile presentations. Patients diagnosed with ACS were significantly more likely to present with chest pain (p=0.003), tachypnea (p=0.001), hypoxia (p<0.0001), and a history of asthma (p=0.0085). Upon multivariable modeling the only significant predictors were chest pain (OR 3.3, CI 1.5-7.4) and hypoxia (OR 8.4, CI 4-17.9). Current guidelines recommend empiric treatment and a CXR for SCD patients presenting with fever, hypoxia, tachypnea, tachycardia or abnormal respiratory exam. Our data demonstrate that hypoxia and chest pain are significant predictors of ACS. Additionally, data indicated that CXRs were likely performed in excess in febrile patients. Further research is needed, but chest pain and hypoxia may focus the use of CXR on the appropriate patients.

With any \emph{surjective rational map} $f: \p^n \dashrightarrow \p^n$ of the projective space we associate a numerical invariant (\emph{ML degree}) and compute it in terms of a naturally defined vector bundle $E_f \map \p^n$.

Pediatric hematopoietic stem cell transplant patients are highly immune compromised with a significantly increased risk for severe pulmonary infections. In these two case reports, we review the use of plasma microbial cell-free DNA next generation sequencing, also known as the Karius Test (KT), as a non-invasive diagnostic tool. These cases illustrate how the KT can provide early species-level identification of pathogens for patients that are either unable to tolerate sedated bronchoscopy, or those with negative bronchoalveolar lavage due to heavy antibiotic pre-treatment. These two clinical cases illustrate how use of KT can reduce infection-related morbidity and mortality.

Background: Atopic dermatitis (AD) is a common pruritic inflammatory skin disease characterized by impaired epidermal barrier function and dysregulation of T heper-2 (TH2)-biased immune responses. While the lineage of conventional dendritic cells (cDCs) are implicated to play decisive roles in T-cell immune responses, their requirement for the development of AD remains elusive. Therefore, we sought to determine the impact of the constitutive loss of cDCs on the progression of AD-like inflammation. Methods: CD11c-Cre:ROSA26-diphtheria toxin α chain (DTA) transgenic (Tg) mice that constitutively lacked CD11chi cDCs and wild-type (WT) littermates received topical application of a low calcemic analogue of vitamin D3 known as MC903 (calcipotriol) to compare the development of AD-like inflammation and immune responses as well as the colonization of Staphylococcus aureus (S. aureus) in eczematous skin. Results: Unexpectedly, the congenital deficiency of cDCs not only exacerbates the pathogenesis of AD-like inflammation but also elicits immune abnormalities with the increased composition and function of granulocytes and group 2 innate lymphoid cells (ILC2) as well as B cells possibly mediated through the breakdown of the Fms-related tyrosine kinase 3 ligand (Flt3L)-mediated homeostatic feedback loop. Furthermore, the constitutive loss of cDCs accelerates skin colonization of S. aureus, that associated with disease flare. Conclusion: cDCs maintains immune homeostasis to prevent the occurrence of immune abnormalities to maintain the functional skin barrier for mitigating AD flare.

The corrected transposition of great arteries without ventricular septal defect and pulmonary stenosis is rare in the clinic. We reported a case of ccTGA with tricuspid valve regurgitation that lead his exertional angina. Various echocardiographic and CTA methods were useful for its diagnosis. Although the patient didn't choose the surgical treatment, further follow-up was still needed during his conservative treatment procedure.

Over the last two decades, the use of DNA barcodes has transformed our ability to identify and assess life on our planet. Both strengths and weaknesses of the method have been exemplified through thousands of peer-reviewed scientific articles. In the light of novel sequencing approaches, currently capable of generating millions of reads at low cost, we reflect on the questions: what will the future bring for DNA barcoding? Will identification of species using short, standardized fragments of DNA stand the test of time? We present reflected opinions of early career biodiversity researchers in the form of a SWOT-analysis and discuss answers to these questions.

Aims: The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict the waiver of confirmatory clinical trials. Methods: Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments, and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. Results: The drugs categorised as anti-neoplastic agents, use of the cost accounting method in the drug pricing system, ‘orphan’ designation, and Accelerated Approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (P < 0.001). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.754) and specificity (0.785), and high accuracy for newly approved drugs. Conclusion: The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally.

Background: Allergic asthma (AA) in childhood is characterized by a dominance of type 2 immunity and inefficient counter-regulation by type 1 immunity and/or Tregs among other mechanisms. However, a detailed analysis of T cells associated with paediatric AA is still needed. Methods: High-dimensional mass cytometry, algorithmic analysis and manual gating were applied to define the peripheral T-cell signature in treatment-naïve childhood AA. Results: The analysis revealed a changed T-cell profile in children with AA in comparison to healthy controls (HC) consisting of: (i) a lower frequency of memory CD8+ T cells, (ii) an overrepresentation of TIGIT+ICOS+ Th2 cells connected to a more symptomatic disease with allergic comorbidity and eosinophilia, and (iii) an altered Treg compartment. Within Tregs, the naïve/resting fraction was enriched in children with AA vs HC, it associated inversely with memory CD8+ T cells, and was linked to a lung function decline. Moreover, the ratio of TIGIT+ICOS+ Th2 cells to dysbalanced effector (e)Treg clusters significantly associated with eosinophilia. Thus, dysregulated Treg fractions were linked to a lung function and, on the other hand, to eosinophilia via TIGIT+ICOS+Th2 cells. The association of altered Treg clusters with the AA phenotype in ROC analysis underscored the importance of changes in the Treg compartment. Conclusions: Our approach identifies a unique T-cell signature of childhood AA and provides insights for pathophysiological involvement of dysbalanced Tregs, TIGIT+ICOS+ Th2 cells and CD8+ T memory cells. This can be useful for immunomonitoring, immunomodulation and for further studies in childhood AA.

Background Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of life-threatening inflammation caused by an excessive, prolonged, and ineffective immune response. An increasing number of HLH cases is recognized in Poland but the genetic causes of familial HLH (FHL) have not been reported. We investigated the molecular genetics and associated outcomes of Polish pediatric patients who met HLH criteria. Methods We studied 54 patients with HLH, 36 of whom qualified for genetic studies. Twenty-five patients were subjected to direct sequencing of the PRF1, UNC13D, STX11, XIAP and SH2D1A genes. Additionally, 11 patients were subjected to targeted next generation sequencing. In our study group, Results 17 patients (31%) were diagnosed with primary HLH, with biallelic FHL variants identified in 13 (36%) patients whereas hemizygous changes were identified in 4 patients with X-linked lymphoproliferative diseases (XLP). In addition, one patient was diagnosed with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (XMEN) due to a hemizygous MAGT1 variant and another newborn with autoinflammatory syndrome caused by MVK variants. The majority (65%) of FHL patients carried UNC13D pathogenic variants, whereas PRF1 variants only explained two patients. Among 35 secondary HLH patients, EBV was the most common trigger noted in 23 (65%) of the patients. In three patients with secondary HLH, heterozygous variants of FHL genes were found. Conclusions Overall survival for the entire study group was 74% with median of 3,6 years of follow-up. Our results highlight the molecular causes of primary HLH in Poland.

Restrictive cardiomyopathy is rare and usually associated with myocardium amyloidosis, which often involves multiple organs. Here, we describe a rare case of restrictive cardiomyopathy with myocardium amyloidosis. The diagnosis was established using electrocardiogram, transthoracic echocardiography, and confirmed using cardiac magnetic resonance imaging. Nevertheless, no evidence of involvement of the other organs was observed.

Objective To estimate the gestational age-specific serum creatinine (sCr) in pregnancy. Design A population-based prospective cohort study. Settings Anuradhapura district, Sri Lanka Population or sample Study group: Healthy pregnant women with a period of gestation less than 12 weeks and without pre-existing medical conditions. Comparison group: A sample of non-pregnant reproductive age females from a population-based renal screening. Methods Baseline data were compared among pregnant and non-pregnant groups and the pregnant women were followed-up until the end of the second trimester. Main Outcome Measures Gestational period-specific sCr. Results A total of 2,259 pregnant women and 2.012 non-pregnant women were recruited. The mean (SD) sCr of the 2,012 nonpregnant women was 62.8(12.4) μmol/L, with the 97.5th percentile of 89.0 μmol/L. The mean (SD) eGFR was 105.1(27.9) mL/min/1.73 m2. At 4-7, 8-9, 10-12, 24-27 and 28-30 weeks of pregnancy, the mean sCr was 55.1, 52.7, 51.0, 47.2, and 49.3, while the 97.5th percentile for sCr was 72.4, 69.2, 69.3, 63.9, and 66.0 μmol/L, respectively, in the sample of pregnant women. In the first and second trimesters, the average sCr value was 84.7% and 76.4% of that of the nonpregnant group, respectively. The mean eGFR increased up to 129.4 mL/min/1.73 m2 in the 24th week of gestation. The analysis of cohort data clearly confirmed a significant reduction in sCr with advancing pregnancy (p<0 .001). Conclusions This study confirms that the precise normative data needs to be considered in the interpretation of sCr in pregnancy, based on the period of gestation.