Background: Although FoxP3+ regulatory T (Treg) cells constitute a highly heterogeneous population, with different regulatory potential depending on the context, distinct subsets or phenotypes remain poorly defined. This hampers the development of immunotherapy for allergic and autoimmune disorders. This study aimed at characterizing distinct FoxP3+ Treg subpopulations involved in the suppression of Th2-mediated allergic inflammation in the lung. Methods: We used an established mouse model of allergic airway disease based on ovalbumin sensitization and challenge to analyze FoxP3+ Tregs during the induction and resolution of inflammation, and identify markers that distinguish their most suppressive phenotypes. We also developed a new knock-in mouse model (Foxp3creCd103dtr) enabling the specific ablation of CD103+FoxP3+ Tregs for functional studies. Results: We found that during resolution of allergic airway inflammation in mice >50% of FoxP3+ Treg cells expressed the integrin CD103 which marks FoxP3+ Treg cells of high IL-10 production, increased expression of immunoregulatory molecules such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for Th2-mediated inflammatory responses. CD103+FoxP3+ Tregs were essential for keeping allergic inflammation under control as their specific depletion in Foxp3creCd103dtr mice lead to severe alveocapillary damage and eosinophilic pneumonia, markedly reducing the lifespan of the experimental animals. Conversely, adoptive transfer of CD103+FoxP3+ Tregs effectively treated disease, attenuating Th2 responses and allergic inflammation in an IL-10-dependent manner. Conclusion: Our study identifies a novel regulatory T cell population, defined by CD103 expression, programmed to prevent exuberant type 2 inflammation and keep homeostasis in the respiratory tract under control. This has important therapeutic implications.

Objectives: This study investigated the relationship between viral load and the incidence and recovery of olfactory and gustatory dysfunction (OD and GD), incidence of respiratory and gastrointestinal symptoms in COVID-19 patients. Design: A Retrospective Cohort Study. Setting and Participants: In total 599 outpatients’ cases polymerase chain reaction (PCR)–confirmed COVID-19-positive patients in Golestan province were included in the study. Main Outcome Measures: The incidence of OD, GD, their severity and the time of recovery was determined. The association of these variables with cycle threshold (CT) values of SARS-CoV-2 polymerase chain reaction was assessed. Results: The mean age of patients was 38.27 ± 13.62 years. The incidence of general symptoms included myalgia 70.1%, headache 51.8%, fever 47.7%, and dyspnea 21.4%. 41.9% of patients had gastrointestinal symptoms, including abdominal pain 26.5%, diarrhea 25.2%, nausea 20.5%, and vomiting 12.9%. 12.2% of patients had comorbidity. The trimester recovery rates of OD and GD were 93.94% and 94.74%, respectively. The mean recovery time of OD and GD was 14.56±13.37 and 13.8±3.77 days, respectively. The mean CT value in all patients was 27.45±4.55. There were significant associations between CT value with headache (P=0.04), GD (P=0.002) and OD (P=0.001). Conclusions: The intensity and the recovery of OD and GD in Covid-19 patients may be affected by initial viral load. Unlike to respiratory and gastrointestinal symptoms, the OD and GD were associated with lower viral load. Therefore, it may be recommended to use these clinical symptoms as an indicator in the initial screening of patients during pandemics.

Background Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Methods Prospective study evaluating children aged under 16 years reporting DHRs to beta-lactams. Reactions were classified as immediate and nonimmediate reactions. The work-up included sIgE, skin testing and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for nonimmediate ones. Results Of the 510 included children, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among nonimmediate reactions (11,4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6–7 days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. Conclusions There were few confirmed cases of either type of reaction. Skin testing proved less valuable in nonimmediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have nonimmediate reactions, while clavulanic acid-selectivity was exclusive to the nonimmediate typology. Over half the cases with DPTs required 6-7 days of treatment for DHR confirmation.

Objective: The aim of this study was to ascertain the relationship between Bethesda category and molecular mutation of thyroid nodules in patients undergoing thyroidectomy. Design: A retrospective cohort of patients who underwent thyroidectomy following needle biopsy and molecular profile testing was performed. Setting: Two tertiary care academic hospitals. Participants: Consecutive patients with a dominant thyroid nodule who underwent both USFNA and molecular profile testing followed by thyroidectomy were included in the study. Main Outcome and Measures: The main outcome was postoperative diagnosis of thyroid cancer and aggressivity of disease based on histopathological variants, nodal metastasis or extra-thyroidal extension. Associations between Bethesda category, molecular mutation and postoperative pathology was assessed using descriptive analysis and Chi-square testing. Results: 451 patients were included. 95.9% (93/97) of patients with a BRAFV600E mutation had a Bethesda category V or VI (P<0.001), and all had confirmed thyroid cancer on postoperative pathology. Those with H, K or N RAS or EIF1AX mutations, gene expression profiling (GEP) or copy number alterations showed an association with Bethesda categories III and IV (P≤0.01). Those with no identified molecular mutation had a lower incidence of aggressive thyroid cancer compared to those with an identified mutation (12.6% vs 44.3%, P<0.01). Conclusion: BRAFV600E mutations were associated with thyroid cancer subtypes known to be more aggressive. These findings may help thyroid specialists better identify aggressive thyroid nodules associated with indeterminate Bethesda categories.

A document by Shannon Gabbard. Click on the document to view its contents.

The presence of pigmented and partially pigmented skin lesions of non-univocal interpretation should always trigger a cautious approach. Albeit the diagnosis of malignant melanoma should remain our main concern, other more common skin conditions, namely basal cells carcinoma, should be taken into consideration in the diagnostic process and management plan. The following case highlights how, sometimes, the diagnosis of partially pigmented basal cells carcinoma may not appear to be immediately evident and the opportunity to deal with non-surgical approach missed. Case report 50-year-old man of Caucasian origin, phototype III in Fitzpatrick scale, initially presenting with a 6-month history of pigmented, inflamed, flat skin lesion at the base of the neck. The lesion had been noticed in the summer months due to the itching and occasional burning it caused (figure 1). Physical examination revealed a 7 mm x 8 mm superficial skin lesion, partially pigmented, not well defined, slightly hyperkeratotic, against a background with several lentigo and nevi. No particular concerns were raised by dermoscopy, or dermatoscopy, and the patient was reassured, even though a small white clod was noted.

Knowledge about artificial soil nutrient of cut-slopes associated with slope aspect and landslide attributes is vital for understanding cut-slopes environmental ecosystem and establishing sustainable artificial soil management practices. Our study focuses on cut-slopes recovered by slope protect technology in alpine region, where slope aspect (east-, south-, west-, and north-facing slope) and landslide (non- and landslide) are dominant environment factors. Integrated matter-element model and path analysis were adopted to investigate the effects of slope aspect and landslide on the selected soil properties: pH, soil organic matter (SOM), alkali-hydrolysable nitrogen (AN), total phosphorus (TP), available phosphorus (AP), and available potassium (AK). Both slope aspect and landslide had no significant effect on artificial soil pH (p > 0.05). Statistically significant differences were found for artificial SOM, AN, TP, AP, and AK between the slope aspect and landslide (p < 0.05). SOM, nitrogen (N), and potassium (K) were limiting factors for artificial soil nutrients on all slope aspect under landslide. N was a limiting factor for artificial soil nutrients on all slope aspect under non-landslide. K was a limiting factor for artificial soil nutrients on all slope aspect under non-landslide, except for non-landslide-north-facing slope, while SOM was a limiting factor for artificial soil nutrients on non-landslide-north-facing slope. Landslide and slope aspect had a highly significant positive correlation with AN and AK, but negative correlation with AP. Therefore, it is necessary to formulate different artificial soil management measures for different slope aspect and landslide to achieve the most effective slope ecological restoration.

A 36-year-old male with non-lesional refractory frontal-lobe epilepsy, diagnosed at 16 years of age, and with a history of four hospitalizations for refractory status epilepticus and admitted to the intensive care unit with focal seizures in the right upper limb, impaired consciousness, and recurrent progression to bilateral tonic-clonic seizures.

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a logistic regression models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]) and did not show any significant difference when compared with FTY The risk of the progression of MS specific disability was not significantly different for any matched cohorts. Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Pulmonary sarcomatoid carcinoma; non-small cell lung cancer; EGFR mutation; MET amplification; crizotinib/gefitinib

Pseudoaneurysm of the ascending aorta is a rare complication of cardiac surgery occurring in less than 0.5% of cases. Deep sternal wound infections (DSWI) increase the likelihood of aortic pseudoaneurysm. An ascending aortic pseudoaneurysm has high morbidity and the mortality rate has ranged from 29%-46% in the medical literature. We report a complex patient who underwent an AVR at an outside hospital complicated by DSWI requiring pectoral flap coverage. Months later, he was transferred to our institution with acute swelling of his sternum, diagnosed as massive aortic pseudoaneurysm originating from the cannulation site.

Abstract: Because of chronic and progressive nature of disease congestive heart failure become standart therapies. Peritoneal dialysis (PD) has been reported as a long-term maintenance treatment of refracter congestive heart failure (RCHF).In this study, we aimed to evaluate the outcome of patients with RCHF, treated with PD in our center. Patients and methods: Twenty-four incident PD patients with RCHF and chronic kidney disease stage IV. The CAPD programme consisted of 2–3 exchanges daily and one exchange nightly. In follow-up period clinical and echocardiographic biochemical findings and requirement of hospitalization were recorded. Results: Fifteen patients (66.7%) were male and mean age was 62,75 years. The etiology of congestive heart failure were hypertensive cardiomyopathy (5), ischemic coronary artery disease (12), diabetes mellitus (6), dilated cardiomyopathy (1). Under the PD treatment the average daily urine volume and ultrafiltration of the patients were 800-1000 ml and 1000-15000 ml respectively. Ten patients were followed for 24 months, eight patients were followed for 12 months. During the follow up period, there were regression in class of heart failure of NYHA (class IV to class II in 18 patients) , decrease in the body weights and an increase of serum sodium levels in all patients. Only 2 patients were hospitalised for cardiovascular disase in 2 years. During the follow-up period, 1 patient was transferred to hemodialysis due to peritonitis. In conclusion; in patients with resistant congestive heart failure and non-dialysis chronic renal failure PD in addition to standard treatment, may be safe treatment choice.

Sepsis causes multi-organ dysfunction and is a major cause of death in intensive care units, but there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti-inflammatory, anticoagulant and immune modulatory actions, so is a potential treatment for sepsis. Recent clinical trials of high-doses of intravenous vitamin C (6-16 g/day) had variable effects. Since much higher doses are without side-effects in cancer and burns patients, we studied the effects of a mega-dose of intravenous sodium ascorbate (150 g/40 kg) in a clinically relevant ovine model of sepsis. This treatment dramatically improved the clinical state and over 3-7-h improved cardiovascular, pulmonary, hepatic and renal function and reduced body temperature. In a critically ill COVID-19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. Clinical trials are testing the effectiveness of mega-dose vitamin C in septic patients.

During valvular surgery, abnormal coronary distribution, especially if unidentified by preoperative exams, may put coronary arteries at risk of damage. In this case report, we describe the approach to an anomalous right coronary artery during aortic valve replacement.

The efficient construction of γ-chirogenic amines has been realized via asymmetric hydrogenation of γ-branched N-phthaloyl allylamines by using a bisphosphine-Rh catalyst bearing a large bite angle. The desired products possessing different types of γ-substituents were obtained in quantitative yields and with excellent enantioselectivities (up to >99.9% ee). This protocol provided a practical method for the preparation of γ-chirogenic amine derivatives such as the famous antidepressant drug Fluoxetine (up to 50000 S/C). The mechanism calculation shows a weak interaction-promoted activation mode which is completely different from the traditional coordination-promoted activation mode in the Rh-catalyzed hydrogenation.

The European sardine (Sardina pilchardus, Walbaum 1792) is indisputably a commercially important species. Previous studies using uneven sampling or a limited number of makers have presented sometimes conflicting evidence for the genetic structure of S. pilchardus populations.  Here we show that whole genome data from 108 individuals from 16 sampling areas across 5,000 Km of the species’ distribution range (from the Eastern Mediterranean to the archipelago of Azores) supports at least three genetic clusters. One includes individuals from Azores and Madeira, with evidence of substructure separating these two archipelagos in the Atlantic. Another cluster broadly corresponds to the center of the distribution including the sampling sites around Iberia, separated by the Almeria-Oran front from the third cluster that includes all of the Mediterranean samples, except those from the Alboran Sea. Individuals from the Canary Islands appear as belonging to the same ancestral group as those from the Mediterranean. This suggests at least two important geographical barriers to gene flow, even though these do not seem complete, with many individuals from around Iberia and the Mediterranean showing some patterns compatible with admixture with other genetic clusters. Genomic regions corresponding to the top outliers of genetic differentiation are located in areas of low recombination indicative that genetic architecture also has a role in shaping population structure. These regions include genes related to otolith formation, a calcium carbonate structure in the inner ear previously used to distinguish S. pilchardus populations.  Our results provide a baseline for further characterization of physical and genetic barriers that divide European sardine populations, and information for transnational stock management of this highly exploited species towards sustainable fisheries.

In this paper, we address the global asymptotic synchronization (GAS) problem of the Master-Slave fractional order multi-linked memristive neural networks (FOMMNNs). Firstly, we propose the FOMMNNs which incorporate the fractional calculus into multi-linked memristive neural networks (MMNNs) for the first time. Then, by utilizing the fractional differential inclusions and set-valued mapping theories, the addressed FOMMNNs with discontinuous state switching at the right-hand side and time-varying delays are converted into the continuous FOMMNNs. Under the frameworks of fractional Caputo derivative and fractional Fillipov solution, by the way of building up appropriate Lyapunov functionals and utilizing some synchronous analysis technology, several sufficient criteria ensuring that the Master-Slave FOMMNNs can realize global asymptotic synchronization (GAS) under two different state-feedback controllers are obtained.

Pelvic arteriovenous malformations (pAVMs) are rare lesions that sometimes pose diagnostic challenges. We report on a 50-year-old woman with a pAVM presenting with only abdominal distension and bloating. The diagnostic tool was color Doppler transvaginal ultrasonography. Surgical excision of the AVM was performed, and there was no subsequent recurrence.

We present in this report case of a-19-year-old teenager who had presented in her near term, infected with COVID-19 and delivered in rural part of Nepal. She is probably one of the first COVID-19 infected case in this country to be delivered normally.

A document by Indrani Roy. Click on the document to view its contents.

A document by Giuseppe Maltese. Click on the document to view its contents.

Using simulations for scientific discovery requires that the software used in the simulations undergoes a rigorous design and development process similar to that of the lab instruments in the experimental sciences. To devise a good design methodology it is critical to understand the requirements, constraints and challenges. This article describes insights from the long-term stewardship of a multiphysics multicomponent software, FLASH, that was designed more than 20 years ago for astrophysics, now serves multiple communities, and has been successful in adapting to the changing world of high-performance computing.

Background: Foramen ovale is a residual cavity in the developing heart in the fetus. At present, the standard methods for the diagnosis of PFO-right-to-left-shunting (PFO-RLS) include transesophageal echocardiography (TEE), contrast-transcranial Doppler echocardiography (C-TCD), and contrast-transthoracic echocardiography (C-TTE), each of them having its advantages and disadvantages.However, there are no data allowing the comparison of these three methods. Methods: We systematically reviewed all published studies on patients with cryptogenic cerebral ischemia. The sensitivity, specificity, and other indexes of C-TCD and C-TTE in the diagnosis of PFO-RLS were calculated using the Stata 16.0 software. The area under the summary receiver operating curve（SROC) was calculated. Results: Twenty-five 25 controlled studies involving a total of 2282 patients were analyzed. There was considerable heterogeneity between C-TCD and C-TTE sensitivity and specificity among the studies. The combined sensitivity and specificity of C-TCD and C-TTE were 0.95 (95%CI, 0.93-0.97) and 0.86(95%CI, 0.78-0.91), and 0.88 (95%CI, 0.69-0.96) and 0.99 (95%CI, 0.67-1.00). The positive likelihood ratio and negative likelihood ratio of C-TCD and C-TTE were 6.81 (95%CI, 4.42-10.48) and 0.05 (95%CI, 0.03-0.08), and 82.31(95%CI, 2.03-3341.00) and 0.12 (95%CI, 0.04-0.34). The areas under the SROC for C-TCD and C-TTE were 0.97 (95%CI, 0.95–0.98) and 0.98 (95%CI, 0.96–0.99), respectively, and were not significantly different by the Z test (z=-0.17, p=0.86). Conclusion: C-TCD and C-TTE have advantages in diagnosing PFO-RTL. The combination of C-TCD and C-TTE improves the detection rate and reduces the misdiagnosis rate. Key words: patent foramen ovale, cryptogenic cerebral ischemia, contrast-transthoracic echocardiography, contrast-transthoracic echocardiography

Background: Functional mitral regurgitation (FMR) is common in patients with myocardial infarction or dilated cardiomyopathies, and portends a poor prognosis despite guideline-directed medical therapy. Surgical or transcatheter mitral repair for FMR from recent randomized clinical trials showed disappointing or conflicting results. Aims: To provide an update on the role of surgical repair in the management of FMR. Materials & Methods: A literature search was conducted utilizing PubMed, Ovid, Web of Science, Embase and Cochrane Library. The search terms included secondary/functional mitral regurgitation, ischemic mitral regurgitation, mitral repair, mitral replacement, mitral annuloplasty, transcatheter mitral repair, and percutaneous mitral repair. Randomized clinical trials over the past decade were the particular focus of this current review. Results: Recent data underlined the complexity and poor prognosis of FMR. Guideline-directed medical therapy and cardiac resynchronization, when indicated, should always be applied. Accurate assessment of the interplay between ventricular geometry and mitral valve function is essential to differentiate proportionate FMR from the disproportionate subgroup, which could be helpful in selecting appropriate transcatheter intervention strategies. Surgical repair, most commonly performed with an undersized ring annuloplasty, remains controversial. Adjunctive valvular or subvalvular repair techniques are evolving and may produce improved results in selected FMR patients. Conclusion: FMR resulted from complex valve-ventricular interaction and remodeling. Distinguishing proportionate FMR from disproportionate FMR is important in exploring their underlying mechanisms and to guide medical treatment with surgical or transcatheter interventions. Further studies are warranted to confirm the clinical benefit of appropriate surgical repair in selected FMR patients.