Currently, data on the effects of the novel Coronavirus disease (COVID-19) on hematopoietic stem cell transplant (HSCT) recipients is limited. In this case, an 8-year-old male with IPEX syndrome underwent allogeneic HSCT and was found COVID-19 positive 23 days post-transplant. He was treated with a 10-day course of remdesivir, three doses of tocilizumab, and two units of COVID-19 convalescent plasma (CCP). Initially, inflammatory markers decreased with treatment. However, he experienced primary graft failure, most likely secondary to COVID-19 infection, developed multiple systemic infections, and subsequently died before a second graft infusion could be administered.

Background: Pediatric patients with sickle cell disease (SCD) and moyamoya syndrome (MMS) are at high risk for recurrent cerebrovascular accidents (CVA) despite best conservative management with chronic blood transfusions (CBT). The role of surgical revascularization in this patient population is not clearly defined. We aim to compare the risk of stroke occurrence in patients undergoing conservative treatment to those additionally undergoing surgical revascularization with conservative treatment. Methods: The authors performed a retrospective cohort study of pediatric SCD-MMS patients seen in Jacksonville and Delaware between 2006 and 2018. Patient characteristics and outcomes, including stroke occurrence, were compared between those who underwent conservative treatment and those who underwent surgical revascularization. Results: A total 17 patients diagnosed with SCD-MMS were on CBT, of which 12 (70.6%) were female. The average age at CBT initiation was 7.27 years. Prior to its initiation, 10 patients (83%) in the surgical and 6 (75%) in the conservative group experienced strokes. Twelve patients underwent surgical revascularization on 18 hemispheres (17 indirect, 1 direct) for severe vasculopathy or CVA - this included 2 patients who experienced a stroke while receiving CBT. The degree of vasculopathy was worse in the surgical group. The mean follow-up for conservative and surgical groups were 11.8 and 4.4 years, respectively. Three patients experienced strokes in the conservative group, while no strokes or major complications were observed in the surgical group. Conclusion: Surgical revascularization appears safe and may effectively reduce stroke rates in pediatric patients with SCD-MMS. Larger studies are needed to confirm these findings.

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COVID-19 has now become a global epidemic, prevailing over 213 countries of the world including Pakistan. To date, there have been more than 12000 cases and above 220 deaths reported in Pakistan. The outbreak is caused by a β-coronavirus called SARS-CoV-2, similar in characteristics to the SARS and MERS-CoV. It shows symptoms like pneumonia and may lead to death. Despite lockdown and possible isolation system, it is spreading rapidly. Lack of precautionary measures, specific vaccine and delayed diagnosis may be the major reasons for its spread. Several researches on COVID-19 have described its various features to extend its knowledge in order to help the scientific world in preparation of vaccine. Current review aimed to cover all essential data such as clinical characteristics, pathology, detailed morphology and structure, antigenicity of COVID-19 virus, role of structural proteins in anti-viral drug development and possible treatments being used. This manuscript would be helpful to select the best possible treatment depending on the availability and condition of the patient. Moreover, further research is needed for assistance in designing a virus-specific drug or vaccine.

The SAFT-γ Mie group-contribution equation of state is used to represent the fluid-phase behaviour of aqueous solutions of a variety of linear, branched, and cyclic amines. New group interactions are developed in order to model the mixtures characterised by alkyl primary, secondary, and tertiary amine groups (NH2, NH, N), cyclic secondary and tertiary amine groups (cNH, cN), and cyclohexylamine groups (cCHNH, cCHN). The group-interaction parameters are estimated from appropriate experimental thermodynamic data for pure amines and selected mixtures. The fluid-phase behaviour of these mixtures can then be described over broad ranges of temperature, pressure, and composition. Liquid-liquid equilibria (LLE) bounded by lower critical solution temperatures (LCSTs) have been reported experimentally and are reproduced here with SAFT-γ Mie approach. The main feature of the approach is the ability to represent accurately the experimental data employed in the parameter estimation, a to predict the phase equilibria with the same set of parameters.

Aims: Thrombocytopoenia is a common major side-effect of cytotoxic cancer therapies. A clinically relevant problem is to predict an individual’s thrombotoxicity in the next planned chemotherapy cycle in order to decide on treatment adaptation. To support this task, two dynamical mathematical models of thrombopoiesis under chemotherapy were proposed, a simple semi-mechanistic model and a comprehensive mechanistic model. In this study, we compare the performance of these models. Methods: We consider close-meshed individual time series data of 135 non-Hodgkin’s lymphoma patients treated with six cycles of CHOP/CHOEP chemotherapies. Individual parameter estimates were derived on the basis of these data considering a varying number of cycles per patient. Parsimony assumptions were applied to optimize parameter identifiability. Models are compared by determining deviations of predicted and observed degrees of thrombocytopoenia in the next cycles. Results: The mechanistic model results in superior fits of individual time series data. Moreover, prediction accuracy of future cycle toxicities by the mechanistic model is higher even if it used data of two cycles, while the semi-mechanistic model used data of five cycles for the corresponding calibrations. Conclusions: We successfully established a quantitative and clinically relevant method for comparing prediction performance of biomathematical models of thrombopoiesis under chemotherapy. We showed that the more comprehensive mechanistic model outperforms the semi-mechanistic model. We aim at implementing the mechanistic model into clinical practice to assess its utility in real life clinical decision making

Taxadien-5α-hydroxylase and taxadien-5α-ol O-acetyltransferase catalyse the oxidation of taxadiene to taxadien-5α-ol and subsequent acetylation to taxadien-5α-yl-acetate in the biosynthesis of the blockbuster anti-cancer drug, paclitaxel (Taxol). Despite decades of research, the promiscuous and multispecific CYP725A4 enzyme remains a major bottleneck in microbial biosynthetic pathway development. In this study, an interdisciplinary approach was applied for the construction and optimisation of the early pathway in Saccharomyces cerevisiae, across a range of bioreactor scales. High-throughput microscale optimisation enhanced total oxygenated taxane titre to 39.0±5.7 mg/L and total taxane product titres were comparable at micro and mini-bioreactor scale at 95.4±18.0 and 98.9 mg/L, respectively. The introduction of pH control successfully mitigated a reduction of oxygenated taxane production, enhancing the potential taxadien-5α-ol isomer titre to 19.2 mg/L, comparable to the 23.8±3.7 mg/L achieved at microscale. A combination of bioprocess optimisation and increased GC-MS resolution at 1L bioreactor scale facilitated taxadien-5α-yl-acetate detection with a final titre of 3.7 mg/L. Total oxygenated taxane titres were improved 2.7-fold at this scale to 78 mg/L, the highest reported titre in yeast. Critical parameters affecting the productivity of the engineered strain were identified across a range of scales, providing a foundation for the development of robust integrated bioprocess control systems.

Real-time acoustic emission (AE) monitoring combined with post-test 3D computed tomography (CT) technique was employed to reveal the rock bridge fracturing behaviors of pre-flawed granite. Results show that the structural deterioration of rock bridge is strongly influenced by dynamic loading frequency. The strength, deformation, and fatigue lifetime of the pre-flawed granites are impacted by loading frequency. AE activities in the form of counts and energy increase with increasing loading frequency. In addition, AE spectral frequency analysis reveals six kinds of crack type, and the proportion of high frequency-high amplitude signal decreases, indicating that large-scaled cracks are prone to forming under high dynamic frequency. Moreover, post-test CT scanning visualizes fracturing pattern of rock bridge, a most striking finding is that complex crack network forms under high loading frequency. It is suggested that flaws are easy to be communicated for rock that subjected to low dynamic loading frequency conditions.

Introduction The IL-33 pathway involved in the development of type-2 airway inflammation is activated in allergic asthma patients. According to the “one airway, one disease” concept, the IL-33 pathway should also be activated in the airways of allergic rhinitis patients. Material and methods We compared the levels of IL-33 and its mRNA precursor, in induced sputum of patients suffering from seasonal allergic rhinitis (n=27) with those measured in patients with seasonal allergic asthma (n=23), and in healthy controls (n=17), in and out of the pollen season. Results IL-33 levels were higher in sputum supernatants of allergic rhinitis (median 9.4 pg.ml-1, range 0 – 51.1 pg.ml-1) and asthma patients (5.2 pg.ml-1, range 0 – 45.4 pg.ml-1) when compared to controls (median 0 pg.ml-1, range 0 – 13 pg.ml-1; p<0.001), and the same was observed with qPCR for IL-33. IL-33 levels were similar in patients suffering from allergic rhinitis (median 4.9 pg.ml-1 vs 7.1 pg.ml-1, p=0.256) or allergic asthma patients (median 3.6 pg.ml-1 vs 3.2 pg.ml-1, p=0.61) in and out of pollen seasons. Conclusion IL-33 is detectable in the lower airways of allergic rhinitis patients, to similar levels than in asthma patients, and appears to be independent of natural variation in allergen exposure. Those findings could reflect a silent epithelial dysfunction in the lower airways of allergic rhinitis patients without asthma, further confirming the «one airway, one disease» theory linking asthma and rhinitis.

Background: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n=72) and nasal brushing samples (n=97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and EGEA. Results: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P<0.05) and the same direction of effect in nasal brushes. Conclusion: We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood.

Converting alfalfa (Medicago sativa L.) into cropland (rotation cropland, RC) is a common way of land use to reuse degraded alfalfa pasture. However, it is a big challenge for RC to achieve high productivity and maintain high soil organic carbon (SOC) achieved by previous alfalfa. Here, we conducted a nine-year field experiment, with continuous cropland (CC) under plastic film mulching as reference, to evaluate soil moisture restoration, crop productivity, and SOC in RC also under plastic film mulching, in the case of fertilization and non-fertilization, respectively. SOC and total soil N in the alfalfa pasture before conversion were 12.3% and 7.7% higher, but the available P and inorganic-N were 59.2% and 71.5% lower than in CC, respectively. The crop yield and biomass were not significant between RC and CC following the second year of conversion in both fertilization and without fertilization cases. The SOC and total soil N in RC with fertilization were similar to the previous alfalfa pasture throughout the nine-year experiment, while decreased in RC without fertilization by 8.3% and 7.5% after the nine years. Soil moisture in RC at 0-0.6 m restored to the level of CC only one year after the conversion, and restored from 77.6% and 56.2% of CC to 95.3% and 69.2% at 0.6-2 and 2-5 m through nine-years after conversion. These findings help to dispel the worries about the long-term low production and rapid decline of SOC in RC and support for sustainable high-productivity and high SOC sequestration in dryland farming.

Introduction In different Countries and different Healthcare Systems, GP workload is significantly burdened by a minority of patients seeing their GP a lot more often than their peers (1).Those are patients are generally well-known to their family physician as subjects that make the ”heart sink” and therefore were initially called by O’Dowd “heartsink patients” (2).But when, more precisely, a patient “becomes” a high user or frequent attender ”?Even if the phenomenon is not new, we do not have data to define quantitatively this “entity” and we ignore if the prevalence of FAs as increased over time, or if it hasn’t (3,4).We do not have precise data about the average duration of their GP encounters, which could well differ from the standards 10 minutes, hence likewise affecting the burden on GP time.To describe those patients, we still often reference to a work published in 1988. It is believed that Tom O’Dowd then coined the term ”heartsink”, to describe ”The feeling experienced (by the family doctor) when their names (of patients) appear in the list of the morning appointments. ” (1)Further work has been done to define the reasons behind the frequent GP visits. In 1988, O’Dowd acknowledged that the medical experience was subjective, but perceived that the problem and its solution resided both in the patient.A systematic review from Gill and Sharpe on prevalence, associations and clinical outcomes, and subsequent observations from other Authors, have shown that FAs have high rates of physical illnesses, psychiatric illnesses, social difficulties and emotional distress (3,5).Frequent attendance in General Practice is also considered an indicator of behaviour of inappropriate use of other health services, in particular emergency departments and Secondary Care services (6,7,8).Evidence of the effect of (mainly psychiatric) interventions on the rate of frequency and morbidity ofFAs have shown conflicting results (9,10). In a review of the interventions on FAs, it was found thatthe high frequency can be a sign of a major depressive disorder and that its treatment can improve the depressive symptoms, but there is no evidence that it is thereby possible to influence the use of the services (11).The interpretation of the studies on FAs is hampered by differences in Healthcare Systems and in the definition of FA (12).It has been shown that age and sex are highly associated to the number of GP visits and that the identification of FAs without adjustment by age and sex leads predominantly to the selection of older women (13).After reviewing the literature on high users, Vedsted suggested that the FA should be described as a subject that falls at the top 10% of the practice population stratified by age and gender (4).Vedsted, suggested to arbitrarily fix a threshold in the distribution of the frequency of consultation, such that they are considered FAs all those who go above the percentage or percentile set as threshold.However, this choice is associated with various problems of practicality with one key disadvantage that is of failing to identify a number of variabilities in relation Health Care System, for instances.In this work, we checked the frequency GP encounters, both in office and at patient’s domicile, over the course of 12 months, in both sexes, and in all age bands.We then looked at the number of visits over the course of a year above which such number increases rapidly, isolating a limited group of patients to whom was associated an extremely high number of GP encounters.Doing so, we aimed to clarify if and where the proportional threshold value and the absolute threshold value may converge.We believe that they do converge and that this number can be identified as the most useful threshold value for the definition FA.MethodIn the context of a General Practice medium density urban setting, we collected data on 9651 people registered with 4 different GPs.Unlike most previous studies on FAs, we have not ruled out children and the most elderly.In fact, several studies have only used data from patients aged 15 to 74 years.For all patients registered during the 12 months prior to the audit date, we only counted the GP face to face consultations, either at the Surgery or at home of the patient. We have calculated the contact frequencies of all patients for each combination of age and gender. The top 5% of patients in terms of frequency of yearly encounters has been defined using the concept of proportional threshold.ResultsThe characteristics of the population studied is graphically represented in figure 1, they are the following:Mother population: Patients currently registeredLast Search: 01-mar-2018Relative Date: 01-Mar-2018Population count: 9651Males: 4540Females: 5111

AIM: To analyze the results regarding weight loss and complications with Spatz3® adjustable intragastric balloon (IGB) in Brazil. METHODS: In this randomized prospective study were included patients that were submitted to Spatz3® adjustable IGB treatment between October 2016 to June 2018 in a private clinic in Rio de Janeiro/Brazil. The patients presented a minimum body mass index (BMI) of 27kg/m². Were analyzed the complications of Spatz3® treatment and BMI reduction, percentage of total weight loss (%TWL) and % of excess weight loss (%EWL). RESULTS: 180 patients underwent implant Spatz3® balloon in the period. The patients were randomly separated in one group the Spatz balloon kept the same volume (600 mL) during all the treatment (Control Group), and adjustment group with 250 mL more. The complications were 16.14%. No death or major complications happened in the study. The BMI decreased from 39.51 to 32.84 kg/m² (p<0.0001), body weight decreased from 111.87 to 90.28 kg (p<0.0001) and excess weight diminished from 41.55 to 22.99kg (p<0.0001). The adjustment resulted in a further mean weight loss of 4,35kg (-8 to 17.6kg) and the moment of the procedure was 7.12±1.63 months. The upward adjustment group doesn´t have a higher %TWL, %EWL or a higher BMI reduction when compared to the control group (p=0.4413, p=0,9245, p=0.2729, respectively).CONCLUSION: This study shows that Spatz3® IGB treatment is an effective procedure for weight reduction, without mortality but with higher morbidity rates when compared to tradition IGBs. The upward adjustment efficacy still needs to be confirmed.

Soil degradation in intensive greenhouse vegetable fields is a major agricultural concern since these soils are widely used for food production. Organic materials play essential roles in soil aggregate stability and carbon sequestration. We conducted a 5-year fertilization study in intensively farmed greenhouse vegetable fields to examine the effects of added organic matter on soil aggregate stability, organic carbon fractions and their interrelationships. Four experimental treatments were included: 1) mineral fertilizer only (CK); 2) mineral fertilizer combined with chicken manure (CM); 3) rice husks (RH); and 4) chicken manure plus rice husks (MH). These organic materials applications significantly improved the proportion of > 0.25 mm aggregates while decreasing the ratio of soil < 0.25 mm aggregates. The mean weight diameters of water-stable soil aggregates was increased with organic fertilizer addition and were ranked RH ≈ MH > CM > CK. The organic materials applications treatments had a greater soil organic matter, humic acid and humus than the CK. RH addition significantly increased the proportion of >2 mm aggregates, possibly due to higher humus and polysaccharide carbon content. CM application increased soil Fe-ox content due to soil acidification and increased aliphatic carbon content that in turn increased the proportion of 1-2 mm aggregates. The study indicated a possible advantage for chicken manure and rice husk incorporation for the generation and persistence of stable soil aggregates.

Oleogels prepared from hydrocolloids have recently gained a lot of attention as an alternative for trans and saturated fats. Previously we have demonstrated that the freeze-dried foams prepared using a mixture of 5% faba bean or pea protein concentrates with 0.25% xanthan gum at pH 7 and 9 can hold canola oil 30-40 times their weights (Mohanan, Tang, Nickerson and Ghosh, 2020). However, the oleogels suffered from high oil loss, about 30% oil leaked, which negatively affected the rheological properties of the oleogels. The functionality of the cake baked using the oleogels was poorer compared to a shortening baked cake. The present study explored the addition of a small amount of high-melting monoacylglycerol (MAG) and candelilla wax (CW) on reducing oil loss, improving rheological properties and baking qualities of pulse protein-stabilized oleogels. Different concentrations (0.5-3%) of MAG or CW were dissolved in canola oil at 80 ºC. The hot oil was then added into the freeze-dried protein-polysaccharide foams (pH 7) and quickly transferred to a refrigerator. The crystallized additives reinforced the oleogel network, thereby reducing oil loss while increasing the firmness, cohesiveness, and storage modulus. When model cakes were baked with the oleogels, significant improvement in textural properties was observed with the addition of MAG in the foam-templated oleogels. However, in comparison with shortening-based cakes, oleogel-based cakes still showed a negative effect on hardness, chewiness and cohesiveness.

Research problems in the domains of physical, engineering, biological sciences, often span multiple time and length scales, owing to the complexity of information transfer underlying mechanisms. Multiscale modeling (MSM) and high-performance computing (HPC) have emerged as indispensable tools for tackling such complex problems. We review the foundations, historical developments, and current paradigms in MSM. A paradigm shift in MSM implementations is being fueled by the rapid advances and emerging paradigms in HPC at the dawn of exascale computing. Moreover, amidst the explosion of data science, engineering, and medicine, machine learning (ML) integrated with MSM is poised to enhance the capabilities of standard MSM approaches significantly, particularly in the face of increasing problem complexity. The potential to blend MSM, HPC, and ML presents opportunities for unbound innovation and promises to represent the future of MSM and explainable ML that will likely define the fields in the 21st century.

Remote sensing of specific climatic and biogeographical factors is an effective means of evaluating the desertification status of dryland regions affected by negative human impacts. Here, we identify and analyse land desertification trends in Iran via a combination of three indices of vegetation (NPP—net primary production, NDVI—normalized difference vegetation index, and LAI—leaf area index); and two climate indices (LST—land surface temperature, and P—precipitation) during the period 2001–2015. The Mann-Kendall non-parametric test, the Theil–Sen estimator, and a simple linear regression method were then applied to identify trends and to map regions of Iran that are susceptible to desertification. Our results show that an area of 680,000 km2 (~ 56 %) of Iran is classified with a very high level, indicating that a large fraction of Iran is susceptible to land desertification. We suggest that spatial and temporal trends in the three vegetation indices (NPP, NDVI, and LAI) and the two climate indices (LST and P) are a cost-effective choice for the prediction and management of future environmental trends in the world’s developing regions, and are a step towards achieving land-use sustainability by helping to locate the most degraded areas.

Runoff and erosion can increase after wildfires, but little is known about the effects of wildfire plus post-fire salvage logging, or mitigating these effects. Past research has identified soil compaction and reduced surface cover as controls on runoff and erosion, but the relative contributions of these changes are not clear. Two years after high severity burning by the 2015 Valley Fire in California, replicated rainfall simulations were carried out in four soil conditions across compaction and cover factors: uncompacted/compacted by logging machinery and bare soil/60% wood slash-cover. Runoff after 71 mm of rainfall totaled 27 mm in the uncompacted bare plots and 39 mm in the compacted bare plots. Runoff in the slash-covered plots decreased by 50% and 33% as compared to the uncompacted and compacted bare plots, respectively, although none of the differences in runoff were significant. Rainsplash averaged 30 g for the bare plots, regardless of compaction, and decreased significantly by 70% on slash-covered plots. Sediment yield totaled 460 and 818 g m-2 for the uncompacted and compacted bare plots, respectively, and slash significantly reduced these amounts by 72% and 69%, respectively. Our results showed that post-fire soil erosion in high severity burned unlogged areas was still very high two years after the wildfire. The combination of wildfire and salvage logging doubled soil erosion by increases in both runoff amount and sediment concentration. Antecedent soil moisture (dry or wet) was the dominant factor for runoff, while surface cover was the dominant factor for erosion and sediment delivery. Covering the soil with slash reduced both runoff and erosion, suggesting this treatment would reduce long‐term sediment delivery from burned areas and skid trails. Saturated hydraulic conductivity (Ks) and interrill erodibility (Ki) calculated from these simulations confirmed previous research and will support modeling efforts related to wildfire and post-fire salvage logging.

In this analysis, we observed that human development index (an integrated index of life expectation, education and living standard) correlates with case rate (proportion of confirmed cases among the population) and the fatality rates of COVID-19 in Italy based on data as of May 15, 2020.

Objective: Multi-dose dexamethasone pretreatment prevents postextubation airway obstruction (PEAO), however, its optimal dose in children is not known. We planned to compare effect of 24h pretreatment of low dose (LD) (0.25mg/kg/dose) versus high dose (HD) (0.5mg/kg/dose) dexamethasone for prevention of PEAO. Design: Stratified (for age and intubation duration) randomized open-label non-inferiority trial. Setting: 15-bed Pediatric Intensive Care Unit in a tertiary care teaching hospital of a lower-middle income country. Patients: Children (3mo-12yrs) intubated for ≥48h and planned for first extubation over 26 months (Feb’17 to Mar’19). Children with preexisting upper airway conditions, chronic respiratory diseases, steroid or IVIG therapy in last 7 days, gastrointestinal bleeding, hypertension and hyperglycemia were excluded. Interventions: Low dose (n=144) or high dose (n=143) dexamethasone (q6h) for 6 doses. Extubation was planned after 5th dose. Measurements and Main Results: Patients were monitored for PEAO (Westley’s Croup Score >4) for 24 hours. 238 patients were included in per-protocol analysis. 78 patients (33%) developed PEAO; both groups were similar (LD, 41/121, 34% vs HD, 37/117, 32% p=0.71). Risk difference of LD vs HD touches the non-inferiority margin of 0.12 and hence the overall result is non-significant. Incidence of reintubation was also similar (LD, 10/121, 8.3% vs HD, 9/117, 7.7%; p=0.87). Intubation for more than 7 days was an independent risk factor for development of PEAO. Conclusions: Multi-dose 24-hour pretreatment with low dose dexamethasone is not inferior to high dose in preventing PEAO and reintubation among unselected patients in the studied clinical setting. Multi-centric trials with larger sample size among children at high risk of developing PEAO are needed.

Macrolides and corticosteroid resistant have been reported in mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult even by sensitive antibiotics in severe MPP (SMPP). SMPP children might develop into airway remodeling even bronchiolitis/bronchitis obliterans. There is an urgent need to identify serum biomarkers indicating the progress of MPP and to discover new target drugs for the treatment of SMPP. In this study, we collected serum samples from general MPP (GMPP) and SMPP patients to perform proteomics profiling. Total 130 differentially expressed proteins with 61 up-regulated in GMPP and 69 up-regulated in SMPP were identified. Among these, FCGBP was one of the most altered protein with highest fold change. Biological enrichment analysis indicated an uncontrolled inflammation catastrophe in SMPP. In addition, complement, coagulation cascades, collagen-containing extracellular matrix and platelet degranulation pathway were enriched in both groups. KEGG analysis indicated an enriched platelet activation in SMPP. ELISA was then performed to verify the dynamic serum FCGBP expression level between other GMPP and SMPP patients. FCGBP level in SMPP was significantly higher than that in GMPP. FCGBP level in GMPP exhibited a decreased trend while SMPP showed the opposite trend during the disease course. Our study demonstrates the first proteomics characteristic of GMPP and SMPP and provides FCGBP as a new serum biomarker indicating the progress of SMPP. Further CMap analysis identified 25 drugs target for the treatment of SMPP. Among them, MTOR inhibitor, a macrolide compound and cell proliferation inhibitor, is the most promising drug targeting for the treatment of SMPP.

The accurate determination of the spatial trends on the variability of the gene pool of a species is essential to elucidate the underlying demographic-evolutionary events and, ultimately, to unravel the microevolutionary history of the species or population under examination. In this work, we present a new software tool called GenoCline, which is essentially devised to assist in detecting genetic clines from allele and phenotypic frequency data, and even from genome-wide data. This program package allows identifying the geographic orientation of clinal genetic variation through a system of iterative rotation of a virtual coordinate axis. At the same time, GenoCline can also be used to carry out complementary statistical analyses aimed at clarifying the potential origin of the genetic clines found, among which stand out spatial autocorrelation, isolation by distance, centroid method, multidimensional scaling and Sammon projection. Among the main advantages of this software are those related to ease in data entry and potential interconnection with other programs. Data entry is user-friendly. Genetic frequencies and geographic coordinates can be easily entered in spreadsheet table formatting, while genome-wide data can be imported in Eigensoft format. Genetic frequencies can also be exported in a format compatible with other programs dealing with population genetics and evolutionary biology. All illustrations of results are saved in eps format so that there will be high quality and easily editable vectorial graphs available for the researcher. GenoCline is implemented in Java, so it can be used with different operating systems.

The current pandemic of the novel coronavirus SARS-CoV-2 infection has affected over 6 million humans around the planet. The clinical manifestations of Coronavirus disease 2019 (COVID-19) are diverse, ranging from asymptomatic or mild flu-like symptoms to atypical pneumonia, severe respiratory distress syndrome, systemic inflammation, immune dysregulation and dyscoagulation.Inborn errors of immunity (IEI) are a heterogenous group of more than 430 rare congenital disorders with increased susceptibility to infection, autoimmunity, atopy, hyperinflammation and cancer. Autosomal recessive ARPC1B deficiency is an actinopathy, as are DOCK8 deficiency and the Wiskott-Aldrich Syndrome. Defective actin polymerization affects hematopoietic cells, impairing their migration and immunological synapse1, which results in a combined immune deficiency characterized by leukocytosis, eosinophilia, platelet abnormalities and hypergammaglobulinemia; and clinically, by eczema and food allergy, infections caused by bacteria, fungi and viruses, vasculitis, and bleeding diathesis2.Here, we describe a male infant patient with known ARPC1B deficiency who was hospitalized for COVID-19 pneumonia and improved without requiring intensive care or mechanical ventilation.An 8-month-old infant was brought to the emergency department with high-grade fever. His family history is remarkable for one brother who died as a newborn from intracranial bleeding, and an 11-year-old sister with the same genetic defect who underwent hematopoietic stem-cell transplantation twice without success, and is currently on antimycobacterial treatment, antimicrobial prophylaxis and regular subcutaneous immunoglobulin. The patient was first seen at age 1-month old for eczema and rectal bleeding attributed to cow milk protein allergy. At age 4 months, he developed bronchiolitis caused by respiratory syncytial virus (RSV) and oral candidiasis. Laboratory workup revealed leukocytosis (17,500-33,600/mm3), eosinophilia (5,600-20,100/mm3) and a marginally high (467,000) platelet count; as well as high serum IgG (737 mg/dL) and IgA (165 mg/dL) with normal IgM (37.7 mg/dL). CD8+ T lymphocytes were low at 3% (257 cells) and B cells were elevated at 48% (4,116 cells). Whole exome sequencing identified a homozygous 46 base-pair deletion in exon 8 of ARPC1B(chr7:99,392,784 hg38; p.Glu300fs).Upon his arrival to the emergency department he was febrile with tachycardia and signs of septic shock requiring rapid fluid resuscitation. He showed no respiratory or gastrointestinal signs. He also had a post-traumatic ulcerated lesion under the tongue with dark discoloration, which raised a concern for fungal infection. Intravenous antibiotics (ciprofloxacin) with antifungal coverage were started within the first hour, and a dose of intravenous immunoglobulin (IVIG) at 1g/kg. Blood counts revealed leukocytosis, neutrophilia, and mild eosinophilia without lymphopenia, while platelets were initially found within normal limits. A day later, blood culture had grownPseudomonas aeruginosa .During his second day of hospitalization, the patient persisted febrile, tachycardic and tachypneic, with oxygen desaturation into the low 80s. Chest X-ray showed nonspecific bilateral interstitial opacities in the perihilar regions (Figure 1 ). Real-time Polymerase chain reaction (RT-PCR) for SARS-Cov2 came back positive, and he was then transferred to a COVID-19 isolation area. The potassium hydroxide (KOH) test for oral thrush was negative for yeast cells, after which amphotericin was switched to fluconazole. Supplemental oxygen was discontinued on day 6 of hospitalization, when mild thrombocytopenia and a prolonged thromboplastin time (aPTT) (but normal fibrinogen and ferritin serum levels) were reported. After completing 14 days of antimicrobial treatment, the patient was discharged without ever requiring intensive care unit admission or mechanical ventilation.The behavior of COVID-19 in patients with IEI might help dissect the immune response to SARS-Cov2. A few cases of adults with COVID-19 and predominantly antibody deficiencies have been reported3,4; some of them developed acute respiratory distress syndrome (ARDS), while some had a milder course of illness. Based on what we know, innate immune defects in genes involved in type 1 interferon response (such as IRF7, IRF9, TLR3) are the most likely candidates to result in severe disease and death in patients with flu-like virus infection5. In a few cases of fatal influenza A (H1N1), variants in genes associated with familial hemophagocytic lymphohistiocytosis (FHL) and a decreased cytolytic function of NK cells, were also reported6.Our patient was on monthly supplemental IVIG treatment, and he received an additional dose during his hospital stay. This, and his young age, might have ameliorated the clinical course7. He had a favorable evolution, despite the known susceptibility to viral infection and immune dysregulation in ARPC1B deficient patients1. There were no signs of severe infection, ARDS, hyperinflammation or of “cytokine storm” unleashed by SARS-CoV-2. Despite his having a combined immune deficiency, our patient fully recovered without the need of additional supportive measures other than IVIG, supplemental oxygen and antibiotic treatment directed against the documented bacteremia.Although pediatric cases of COVID-19 are fewer compared to adults, some severe presentations and deaths among children have been reported. The presence of a restricted repertoire of IgG (since infants have no previous exposure to coronaviruses) might play a role in the better outcome seen in pediatric patients. Antibody-dependent enhancement has been implicated in the development of severe COVID-19 in the elderly8. Additionally, lung cells from children and women show a lower expression of membrane-bound ACE-2, which may also be protective against severe pneumonia.Conceivably, some immune defects could protect patients with certain IEIs from mounting a full uncontrolled inflammatory response against SARS-Cov2. The cytoskeleton is a regulator of gene transcription, coupling cell mechanics with the activity of NF-κB. Coronaviruses are thought to alter the cytoskeleton architecture to facilitate viral replication and output9. Thus, ARPC1B deficiency and other actinopathies might limit SARS-CoV-2 replication. Furthermore, Th2 cytokines modulate ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 expression in airway epithelial cells10, and children with allergies (asthma and/or allergic rhinitis) have a lower expression of ACE211. Patients with ARPC1B deficiency often have allergic diseases; their Th2-biased response could help explain the milder presentation seen in our patient. Insights from protective mechanisms in children, with and without certain immune defects, could facilitate the identification of therapeutic targets.Lina Maria Castano-Jaramillo1, MDMarco Antonio Yamazaki-Nakashimada1, MDSelma Cecilia Scheffler Mendoza1, MD, MSJuan Carlos Bustamante-Ogando2, MD, MSSara Elva Espinosa-Padilla2, MD, PhDSaul O. Lugo Reyes2, MD, MS.From the (1) Clinical Immunology Service, and the (2) Immunodeficiencies Research Unit, at the National Institute of Pediatrics, Mexico City, Mexico.Conflict of interests: NoneEthical statement: The patient and his family gave written informed consent for the diagnostic procedures and for publication of the case report.KEY WORDS: Primary immune deficiency, inborn errors of immunity, combined immune deficiency, ARPC1B deficiency, actinopathy, children, COVID-19, SARS-Cov-2, allergy, pneumonia, sepsis.

In this work, for the first time, snail slime from garden snails “Helix Aspersa Müller”, has been used to induce the formation of eco-friendly gold nanoparticles (AuNPs-SS), suitable for biomedical applications. An AuNPs-SS comprehensive investigation was performed observing AuNPs with an average particle size of 14±6 nm, stabilized by a slime snail-based organic layer. Indeed, as recognised in high-resolution MALDI-MS analyses, and corroborated by FESEM, UV-Vis, ATR-FTIR and XPS results, it was possible to assess the main presence of peptides and amino acids as main components of the slime, that, combined with the AuNPs confers them interesting properties. More specifically, we tested, in vitro, the AuNPs-SS safety in human keratinocytes and their potential effect on wound healing as well as their anti-inflammatory properties in Murine Macrophages. Moreover, the AuNPs-SS treatment resulted in a significant increase of the urokinase-type plasminogen activator receptor (uPAR), essential for keratinocyte adhesion, spreading and migration, together with the reduction of LPS-induced IL1-β and IL-6 cytokine levels, and completely abrogated the synthesis of the inducible nitric oxide synthase (iNOS).