COVID-19 as an Acute Inflammatory Disease.

The 2019 coronavirus disease (COVID-19) pandemic caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis for the infrastructure sectors, including economic, political, healthcare, education, and research systems. Although over 90% of infected individuals are asymptomatic or manifest noncritical symptoms and will recover from the infection, those individuals presenting with critical symptoms are in urgent need of effective treatment options. Emerging data related to mechanism of severity and potential therapies for patients presenting with severe symptoms are scattered and therefore require a comprehensive analysis to focus research on developing effective therapeutics. A critical literature review suggests that the severity of SARS-CoV-2 infection is associated with dysregulation of inflammatory immune responses, which in turn inhibits the development of protective immunity to the infection. Therefore, the use of therapeutics that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy.

Complete genome sequence and construction of an infectious full-length cDNA clone of a cucumber vein yellowing virus (CVYV) isolate from Portugal.

Cucumber vein yellowing virus (CVYV) is a member of the genus Ipomovirus in the family Potyviridae. In the National Center for Biotechnology Information (NCBI) database, three complete genome sequences of CVYV isolates from Spain (NC_006941), Israel (KT276369), and Jordan (JF460793) are available. In this study, we report the complete sequence of an isolate of CVYV from Portugal (DSMZ PV-0776) along with the construction of an infectious full-length cDNA clone via Gibson assembly. The sequence of CVYV Portugal shows the closest relationship to a CVYV isolate from Spain (genome, 99.7% identity; polyprotein, 99.7% identity). The CVYV full-length cDNA clone was introduced by electroporation into Rhizobium radiobacter and infiltrated into the cotyledons of Cucumis sativus plantlets, resulting in symptoms resembling those of the wild-type virus. Transmission of the infectious CVYV full-length clone by the whitefly Bemisia tabaci was confirmed. This first report confirming the infectivity of a CVYV cDNA clone provides the opportunity to study gene functions in a consistent genomic background.

Complete genome sequence of a German isolate of spartina mottle virus supports its classification as a member of the proposed genus "Sparmovirus" within the family Potyviridae.

Spartina mottle virus (SpMV), an unassigned member of the family Potyviridae, has been known since 1980, when it was first described in England and Wales in symptomatic plants of the genus Spartina. In infected cells, flexuous particles and pinwheel inclusion bodies were found that resemble those of potyvirids. To date, the NCBI database contains only two partial sequences of a German (Nessmersiel) and an Italian (Assisi) isolate, suggesting that SpMV could be the first member of a new genus, called "Sparmovirus", in the family Potyviridae. In this study, the first complete genome sequence of the German SpMV isolate (SpMV Ger) was determined. The genome of SpMV is a single-stranded, monopartite, polyadenylated RNA consisting of 9376 nucleotides. Sequence analysis revealed a genome organization similar to that of classical potyviruses, including many conserved features. In phylogenetic analysis, SpMV could not be assigned to any of the known genera, but it showed the closest relationship to rymoviruses and common reed chlorotic stripe virus (CRCSV, unassigned). Sequence comparisons confirmed that a new genus should be established containing SpMV, CRCSV, and three Bermuda grass mosaic virus isolates, which are considered divergent strains of SpMV.

Goal-setting and attainment in prolonged disorders of consciousness - development of a structured approach.

Aims: To develop a structured goal-set for use in programs for the assessment and management of prolonged disorders of consciousness (PDOC).Methods: A retrospective analysis of goals from a consecutive cohort of patients (n = 162) admitted to a specialist in-patient PDOC program in the UK from 2007 to 2018. Overall goal attainment was examined with Goal Attainment Scaling (GAS) using the GAS-Light method. Rates of individual goal-setting and achievement were examined for both standardized objectives (n = 2959) and personalized goals (n = 661). Goal statements from the personalized goals were independently reviewed and mapped to the domains of the existing structured objective set to identify any missing goal areas.Results: Mean outcome GAS T-scores were 47.2 (95% CI: 46.7, 47.6) and 47.7 (95% CI: 46.7, 48.8), respectively, for the standardized and personally set goals. These were closely correlated (r = 0.482, p < .001) with no significant difference between them. Analysis of goal achievement within each domain identified goals that were/were not likely to be achieved. An initial structured set of 20 standardized objectives in 12 domains was expanded and re-organized to produce a final-structured goal-set of 36 objectives in 18 domains.Conclusions: Developed through real-life clinical practice, this first published structured goal-set for PDOC programs now requires testing in other services/settings.

Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire.

MALT1 (mucosa-associated lymphoid tissue lymphoma-translocation gene 1) is an intracellular signaling protein that activates NFκB and is crucial for both the adaptive and innate immune responses. Only 6 patients with immune deficiencies secondary to inherited mutations in the MALT1 gene have been described. PURPOSE: To provide clinical and immunological insights from 2 patients diagnosed with MALT1 immunodeficiency syndrome due to a novel MALT1 mutation. METHODS: Two cousins with suspected combined immunodeficiency underwent immunological and genetic work-up, including lymphocyte phenotyping, lymphocyte activation by mitogen stimulation, and next-generation sequencing (NGS) of T cell receptor gamma chain (TRG) repertoire. Whole exome sequencing was performed to identify the underlying genetic defect. RESULTS: Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity. Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells. A normal proliferative response was induced by phytohemagglutinin and IL-2 but was diminished with anti-CD3. TRG repertoire was diverse with a clonal expansion pattern. Genetic analysis identified a novel autosomal recessive homozygous c.1799T>A; p. I600N missense mutation in MALT1. MALT1 protein expression was markedly reduced, and in vitro IL-2 production and NFκB signaling pathway were significantly impaired. CONCLUSIONS: Two patients harboring a novel MALT1 mutation presented with signs of immune deficiency and dysregulation and were found to have an abnormal T cell receptor repertoire. These findings reinforce the link between MALT1 deficiency and combined immunodeficiency. Early diagnosis is crucial, and curative treatment by hematopoietic stem cell transplantation may be warranted.

Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

Risk factors of infected sternal wounds versus sterile wound dehiscence.

BACKGROUND: Sterile sternal dehiscence (SSD) and sternal wound infections (SWIs) are two complications of median sternotomy with high rates of morbidity. Sternal wound complications also carry significant economic burden, almost tripling patients' hospital costs and are considered a nonreimbursable "never event" for Medicare. Historically, SDD and SWI have been recognized as discrete entities, but nonetheless continue to be categorized as a singular complication in literature. The purpose of this study was to determine specific patient demographic and perioperative predictors of SSD and SWI. MATERIALS AND METHODS: An institutional review board-approved, retrospective study of 8098 consecutive patients who underwent cardiac surgery at Columbia University Medical Center between January 2008 and December 2013 was conducted. Patients were categorized into three groups: no sternal wound complication, SSD, or SWI. Statistical analysis was performed using univariate and multivariate logistic regression analysis. RESULTS: Of 8098 patients, there were 73 patients (0.9%) with SSD and 40 (0.5%) with SWI who required plastic surgical consultation, debridement, and flap closure. In univariate analysis of SSD, positive predictors (i.e., "risk" factors) were age >42 years, prior surgery this admission, ≥2 arterial conduits, internal mammary artery (IMA) grafting with or without previous IMA grafting, body mass index (BMI) >30 (obese), CHF, diabetes requiring medication, respiratory failure, and unplanned cardiac reoperation; negative predictors (i.e., "protective" factors) were no arterial conduits and extubation within 24 h. In univariate analysis of SWI, positive predictors were IMA grafting with or without previous IMA grafting, postoperative hematocrit urgent/emergent surgical priority, BMI >30 (obese), cardiac ejection fraction <40%, and respiratory failure; negative predictors were no arterial conduits and elective surgical priority. In multivariate regression, BMI >30, diabetes requiring medication, and respiratory failure were determined to be significant positive predictors of SSD, and IMA grafting with or without prior IMA grafting and respiratory failure were significant positive predictors for SWI; no significant negative predictors were identified. CONCLUSIONS: This study found that SSD and SWI have many common significant predictors consistent with findings that increased BMI, use of IMA grafts, poor cardiac reserve, and postoperative respiratory failure confer increased risk of sternal wound complications. Additionally, this study also found that there were predictors unique to each entity supporting that SSD and SWI may be related but are not a singular entity. Recognition and prevention of significant positive and negative predictors of SSD and SWI may be valuable in preoperative counseling, operative planning, and postoperative management. Although sternal wound complications can be successfully managed by plastic surgical intervention, preventing the development of median sternotomy complications may curb costs incurred by both patients and health care systems.

Increased prevalence and geographic spread of the cardiopulmonary nematode Angiostrongylus vasorum in fox populations in Great Britain.

The nematode Angiostrongylus vasorum is becoming more widely recorded globally, and is of increasing concern as a cause of disease in dogs. Apparent geographic spread is difficult to confirm due to a lack of standardized disease recording systems, increasing awareness among veterinary clinicians, and recent improvements in diagnostic technologies. This study examines the hypothesis that A. vasorum has spread in recent years by repeating the methods of a previous survey of the fox population. The hearts and lungs of 442 foxes from across Great Britain were collected and examined by dissection and flushing of the pulmonary circulation and microscopic inspection of tracheal scrapes. Sampling and parasite extraction methods were identical to an earlier survey in 2005 to ensure comparability. Prevalence of A. vasorum was 18·3% (exact binomial confidence bounds 14·9-22·3), compared with 7·3% previously (5·3-9·9, n = 546), and had increased significantly in most regions, e.g. 7·4% in the Northern UK (previously zero) and 50·8% in the south-east (previously 23·2%). Other nematodes identified were Crenosoma vulpis (prevalence 10·8%, CI 8·1-14·2) and Eucoleus aerophilus (31·6%, CI 27·3-36·2). These data support the proposal that A. vasorum has increased in prevalence and has spread geographically in Great Britain.

Transmission of methicillin-resistant Staphylococcus aureus via deceased donor liver transplantation confirmed by whole genome sequencing.

Donor-derived bacterial infection is a recognized complication of solid organ transplantation (SOT). The present report describes the clinical details and successful outcome in a liver transplant recipient despite transmission of methicillin-resistant Staphylococcus aureus (MRSA) from a deceased donor with MRSA endocarditis and bacteremia. We further describe whole genome sequencing (WGS) and complete de novo assembly of the donor and recipient MRSA isolate genomes, which confirms that both isolates are genetically 100% identical. We propose that similar application of WGS techniques to future investigations of donor bacterial transmission would strengthen the definition of proven bacterial transmission in SOT, particularly in the presence of highly clonal bacteria such as MRSA. WGS will further improve our understanding of the epidemiology of bacterial transmission in SOT and the risk of adverse patient outcomes when it occurs.

Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine.

BACKGROUND: Allergen-specific immunotherapy (SIT) faces problems related to side effects and limited efficacy. Direct administration of allergen extracts into lymph nodes induces increased specific IgG production and T-cell responses using significantly lower allergen doses. METHODS: In this study, mechanisms of immune regulation by MAT vaccines in vitro and in allergen-SIT of cat-allergic rhinitis patients, who received 3 inguinal intra-lymph node injections of MAT-Fel d 1 vaccine, were investigated in PBMC and cell cultures for specific T-cell proliferation, Fel d 1-tetramer-specific responses, and multiple immune regulatory molecules. RESULTS: MAT-Fel d 1 vaccine was efficiently internalized by antigen-presenting cells. This was followed by precaspase 1 cleavage to caspase 1 and secretion of IL-1ß, indicating inflammasome activation. Mat-Fel d 1 induced specific T-cell proliferation and an IL-10- and IFN-γ-dominated T-cell responses with decreased Th2 cytokines at 100 times lower doses than Fel d 1. Induction of immune tolerance by MAT-Fel d 1-ILIT involved multiple mechanisms of immune suppression. Early Fel d 1-specific T-cell activation was followed by full T-cell unresponsiveness to allergen after 1 year in the MAT-Fel d 1 group, characterized by increased allergen-specific T regulatory cells, decreased circulating Fel d 1 tetramer-positive cells, increased IL-10 and FOXP3 expression, and change in the HR2/HR1 ratio toward HR2. CONCLUSIONS: This study demonstrates the induction of allergen tolerance after 3 intra-lymph node injections of MAT-Fel d 1 vaccine, mediated by increased cellular internalization of the allergen, activation of inflammasome, and generation of allergen-specific peripheral T-cell tolerance.

Occupational handling of nickel nanoparticles: a case report.

A 26-year-old female chemist formulated polymers and coatings usually using silver ink particles. When she later began working with nickel nanoparticle powder weighed out and handled on a lab bench with no protective measures, she developed throat irritation, nasal congestion, "post nasal drip," facial flushing, and new skin reactions to her earrings and belt buckle which were temporally related to working with the nanoparticles. Subsequently she was found to have a positive reaction to nickel on the T.R.U.E. patch test, and a normal range FEV1 that increased by 16% post bronchodilator. It was difficult returning her to work even in other parts of the building due to recurrence of symptoms. This incident triggered the company to make plans for better control measures for working with nickel nanoparticles. In conclusion, a worker developed nickel sensitization when working with nanoparticle nickel powder in a setting without any special respiratory protection or control measures.

A critical appraisal of analyzing nasal provocation test results in allergen immunotherapy trials.

BACKGROUND: The statistical analysis of nasal provocation tests is very complex. We compared the conventional analysis with the maximally selected test statistics and the hierarchical ordered logistic model. METHODS: We re-analyzed data from a trial with 112 patients suffering from grass pollen allergy. The patients had been randomized to receive either intralymphatic immunotherapy (ILIT) or subcutaneous immunotherapy (SCIT). RESULTS: The conventional analysis indicated that the logarithmized ratio between the pre- and the post-treatment threshold concentration was significantly lower for ILIT than for SCIT. The maximally selected test statistics was used to test different threshold symptom scores that would imply positive clinical symptoms at the given allergen concentration. A threshold score of 3 maximised the difference in improvement between the ILIT and the SCIT groups. The hierarchical ordered logistic model does not take threshold allergen concentrations as the basis for analysis, but the single scores measured at each concentration. This approach simultaneously considers the treatment effect (ILIT versus SCIT), the time effect (pre- versus post-treatment), and the dose effect (different allergen concentrations). The hierarchical ordered logistic model revealed that the clinical improvement was greater after ILIT than after SCIT. CONCLUSION: As the choice of method can affect the outcome, guidelines for analysis are highly needed.

Deconstructing wisdom through a cultural lens: Folk understandings of wisdom and its ontology in the Philippines and Sri Lanka.

In many contemporary societies, misinformation, epistemic arrogance, and intergroup conflict pose serious threats to social cohesion and well-being. Wisdom may offer a potential antidote to these problems, with a recently identified Common Wisdom Model (CWM) suggesting that wisdom involves epistemic virtues such as intellectual humility, openness to change, and perspective-taking. However, it is unclear whether these virtues are central for folk concepts of wisdom in non-Western contexts. We explored this question by conducting focus group discussions with 174 participants from the Philippines and Sri Lanka, two countries facing socio-political and economic challenges. We found that epistemic themes were common in both countries, but more so when participants were asked to define wisdom in general terms rather than to describe how it is acquired or expressed in daily lives. Moreover, epistemic themes were more prevalent among Filipino than Sri Lankan participants, especially when the questions posed were abstract rather than concrete. We discuss how these findings relate to the CWM and the socio-cultural contexts of the two countries, and suggest that a question format should be considered in cross-cultural research on wisdom.

Slip to π Ru: structural distortions due to metal-iminoxolene π bonding.

Both pseudo-octahedral and pseudo-square pyramidal bis-iminoxolene complexes trans-(Diso)2RuCl2 and trans-(Diso)2Ru(PPh3) are structurally distorted, with the ruthenium atom slipping off the twofold axis of the idealized coordination polyhedra. These distortions take place because they allow or enhance π interactions between ruthenium and the iminoxolene π orbitals.

Repeated deep-inspiration breath-hold CT scans at planning underestimate the actual motion between breath-holds at treatment for lung cancer and lymphoma patients.

PURPOSE/OBJECTIVE: Deep-inspiration breath-hold (DIBH) during radiotherapy may reduce dose to the lungs and heart compared to treatment in free breathing. However, intra-fractional target shifts between several breath-holds may decrease target coverage. We compared target shifts between four DIBHs at the planning-CT session with those measured on CBCT-scans obtained pre- and post-DIBH treatments. MATERIAL/METHODS: Twenty-nine lung cancer and nine lymphoma patients were treated in DIBH. An external gating block was used as surrogate for the DIBH-level with a window of 2 mm. Four DIBH CT-scans were acquired: one for planning (CTDIBH3) and three additional (CTDIBH1,2,4) to assess the intra-DIBH target shifts at scanning by registration to CTDIBH3. During treatment, pre-treatment (CBCTpre) and post-treatment (CBCTpost) scans were acquired. For each pair of CBCTpre/post, the target intra-DIBH shift was determined. For lung cancer, tumour (GTV-Tlung) and lymph nodes (GTV-Nlung) were analysed separately. Group mean (GM), systematic and random errors, and GM for the absolute maximum shifts (GMmax) were calculated for the shifts between CTDIBH1,2,3,4 and between CBCTpre/post. RESULTS: For GTV-Tlung, GMmax was larger at CBCT than CT in all directions. GMmax in cranio-caudal direction was 3.3 mm (CT)and 6.1 mm (CBCT). The standard deviations of the shifts in the left-right and cranio-caudal directions were larger at CBCT than CT. For GTV-Nlung and CTVlymphoma, no difference was found in GMmax or SD. CONCLUSION: Intra-DIBH shifts at planning-CT session are generally smaller than intra-DIBH shifts observed at CBCTpre/post and therefore underestimate the intra-fractional DIBH uncertainty during treatment. Lung tumours show larger intra-fractional variations than lymph nodes and lymphoma targets.

Maternal Bean Consumption during Pregnancy: Distribution and Nutritional Outcomes.

(1) Background: Due to their high nutritional value, we aimed to characterize the frequency and amount of maternal consumption of beans during pregnancy and their associations with diet quality and nutrient intake. (2) Methods: We conducted a secondary data analysis of US pregnant women (n = 1444) from the Infant Feeding Practices Study II, a longitudinal study that followed mother-infant pairs from late pregnancy to 1 year postpartum. Maternal bean intake (food types [dried beans, chili, and bean soup], frequency, serving size, and amount), diet quality (Healthy Eating Index [HEI]), and nutrient intake were estimated with a Food Frequency Questionnaire taken in the third trimester of pregnancy. Associations of bean consumption with diet quality and nutrient intake were examined with analysis of variance, Fisher's least significant difference tests, correlation coefficients, and coefficients of determination. (3) Results: In general, maternal bean consumption was low during pregnancy: 0.31 cups/week of dried beans, 0.37 cups/week of chili, and 0.10 cups/week of bean soup. Maternal bean consumption varied by socio-demographics and geographic regions. In comparison with those who never consumed dried beans, mothers who ate dried beans ≥ 1 time per week had a higher mean HEI score (67.5 vs. 63.6), intake of total fiber (24.4 vs. 17.4 g/day), and protein (93.4 vs. 79.9 g/day), but a lower percentage of energy from added sugar (12.6 vs. 15.2%). Higher dried bean consumption had weak-to-moderate correlations with intake of total fiber (correlation coefficient, 0.320), insoluble fiber (0.316), soluble fiber (0.310), and folate (0.286). Similar but less extensive correlations were observed for chili and bean soup consumption. (4) Conclusions: In this US cohort of pregnant women, bean consumption was low. Increased intake of beans (≥1 time per week) may improve maternal diet quality during pregnancy.

Amyloid Goiter Secondary to Behcet's Disease: A Case Report and Literature Review.

Amyloid deposition in the thyroid gland is a common presentation, yet amyloid goiter remains relatively rare. Proper differentiation of this condition from other goiter types and malignancies is essential. Although amyloid extensively invades the thyroid gland, patients are usually euthyroid, and many different presentations may occur. We report a case of a 42-year-old male patient who was diagnosed with secondary amyloidosis due to Behcet's disease. He presented with clinical manifestations of hyperthyroidism and systemic amyloidosis complicated by chronic kidney disease, which is the first case of such an entity to be reported in Palestine.