Aim: To analyze the effects of CYP3A5 polymorphism on liver function after LT and to characterize the pharmacokinetics of tacrolimus after conversion from a twice-daily regimen to a once-daily extended-release formulation. Methods: A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT 02882113). Results: Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (P=0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (- 42.9% vs. - 26.1%) and dose/kg-adjusted trough level of tacrolimus (- 40.0% vs. - 23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. The absorption of the tacrolimus in the non-expressor group was slower than in the expressors. In line with this observation, the AUC for once-daily tacrolimus correlated with Cmin in the non-expressors and Cmax in the expressors. Conclusions: Determination of CYP3A5 genotype in liver transplant recipients might be helpful in prediction of tacrolimus pharmacokinetics after conversion from a twice-daily regimen to a once-daily formulation.

Strong selection can cause rapid evolutionary change, but temporal fluctuations in the form, direction and intensity of selection can limit net evolutionary change over longer time periods. Fluctuating selection could affect molecular diversity levels and the evolution of plasticity and ecological specialization. Nonetheless, this phenomenon remains understudied, in part because of analytical limitations and the general difficulty of detecting selection that does not occur in a consistent manner. Herein, I fill this analytical gap by presenting an approximate Bayesian computation (ABC) method to detect and quantify fluctuating selection on polygenic traits from population-genomic time-series data. I propose a model for environment-dependent phenotypic selection. The evolutionary genetic consequences of selection are then modeled based on a genotype-phenotype map. Using simulations, I show that the proposed method generates accurate and precise estimates of selection when the generative model for the data is similar to the model assumed by the method. Performance of the method when applied to an evolve-and-resequence study of host adaptation in the cowpea seed beetle (Callosobruchus maculatus) was more idiosyncratic and depended on specific analytical choices. Despite some limitations, these results suggest the proposed method provides a powerful approach to connect causes of (variable) selection to traits and genome-wide patterns of evolution. Documentation and open source computer software (fsabc) implementing this method are available from GitHub (https://github.com/zgompert/fsabc.git).

Coronavirus (CoV) pandemics have become a huge threat to the public health worldwide in the recent decades. Typically, severe acute respiratory syndrome CoV (SARS-CoV) caused SARS pandemic in 2003 and SARS-CoV-2 caused the ongoing COVID-19 pandemic. Both viruses have been reported to originate from bats. Thus, direct or indirect interspecies transmission from bats to humans is required for the viruses to cause pandemics. Receptor utilization is a key factor determining the host range of viruses which is critical to the interspecies transmission. Angiotensin converting enzyme 2 (ACE2) is the receptor of both SARS-CoV and SARS-CoV-2, but only ACE2s of certain animals can be utilized by the viruses. Here, we employed pseudovirus cell-entry assay to evaluate the receptor-utilizing capability of ACE2s of 20 animals by the two viruses and found that SARS-CoV-2 utilized less ACE2s than SARS-CoV, indicating a narrower host range of SARS-CoV-2. Especially, SARS-CoV-2 tended not to use murine or non-mammal ACE2s. Meanwhile, pangolin CoV, another SARS-related coronavirus highly homologous to SARS-CoV-2 in its genome, yet showed similar ACE2 utilization profile with SARS-CoV rather than SARS-CoV-2. To clarify the mechanism underlying the receptor utilization, we compared the amino acid sequences of the 20 ACE2s and found 5 amino acid residues potentially critical for ACE2 utilization, including the N-terminal 20th and 42nd amino acids that may determine the different receptor utilization of SARS-CoV, SARS-CoV-2 and pangolin CoV. Our studies promote the understanding of receptor utilization of pandemic coronaviruses, potentially contributing to the virus tracing, intermediate host screening and epidemic prevention for pathogenic coronaviruses.

Rationale, aims and objectives: Appropriate treatment of paediatric fever in rural areas remains a challenge and may be partly due to inadequate supervision of licensed drug sellers. This study assessed the effectiveness of peer-supervision among drug sellers on appropriate treatment of pneumonia symptoms, uncomplicated malaria and non-bloody diarrhoea among children less than five years of age in the intervention (Luuka) and comparison (Buyende) districts, in East-Central Uganda. Methods: Data on pneumonia symptoms, uncomplicated malaria and non-bloody diarrhoea among children less than five years of age was abstracted from drug shop sick child registers over a 12-month period; six months before and six months after introduction of peer-supervision. Interrupted time series was applied to determine the effectiveness of the peer-supervision intervention on appropriate treatment of pneumonia, uncomplicated malaria and non-bloody diarrhoea among children less than five years of age attending drug shops in East Central Uganda. Results: The proportion of children treated appropriately for pneumonia symptoms was 10.84% (P<0.05, CI = [1.75, 19.9]) higher, for uncomplicated malaria was 1.46% (P = 0.79, CI = [-10.43, 13.36]) higher, and for non-bloody diarrhoea was 4.00% (p <0.05, CI = [-7.95, -0.13]) lower in the intervention district than the comparison district, respectively. Post-intervention trend results showed an increase of 1.21% (p =0.008, CI = [0.36, 2.05]) in the proportion appropriately treated for pneumonia symptoms, no difference in appropriate treatment for uncomplicated malaria, and a reduction of 1% (p <0.06, CI = [-1.95, 0.02]) in the proportion of children appropriately treated for non-bloody diarrhoea, respectively. Conclusions: Peer-supervision increased the proportion of children less than five years of age that received appropriate treatment for pneumonia symptoms but not for uncomplicated malaria and non-bloody diarrhoea. Implementation of community level interventions to improve paediatric fever management should consider including peer-supervision among drug sellers.

Aims In light of the recent safety concerns relating to NSAID use in COVID-19, we sought to evaluate cardiovascular and respiratory complications in patients taking NSAIDs during acute lower respiratory tract infections. Methods We carried out a systematic review and meta-analysis of randomised controlled trials and observational studies. Studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections, were included. Primary outcome was all-cause mortality. Secondary outcomes were cardiovascular, renal and respiratory complications. Results In total, eight studies including two randomised controlled trials, three retrospective and three prospective observational studies enrolling 44140 patients were included. Five of the studies were in patients with pneumonia, two in patients with Influenza, and one in patients with acute bronchitis. There was uncertainty as to the effects on mortality (RR 0.87 [0.63, 1.18]), but pleuro-pulmonary complications were more common with NSAID use (RR 2.62 [1.96, 3.50]). However, all studies exhibited high risks of bias, primarily due to lack of adjustment for confounding variables. Cardiovascular outcomes were not reported by any of the included studies. Conclusion Short-term NSAID use during acute lower respiratory tract infections was associated with more pleuro-pulmonary complications although this may be due to confounding by indication. There remains significant uncertainty on the effects on mortality. Such results should be interpreted cautiously given the very low quality of evidence. Mechanistic and clinical studies addressing the captioned subject are urgently needed, especially in relation to COVID-19.

Background and aim. Classical and paradoxical low-flow, low-gradient aortic stenosis (LFLGAS) are the most challenging aortic stenosis (AS) subtypes. The current therapeutic options are aortic valve replacement (AVR) and conservative management. The matter is controversial because AVR promotes long-term survival, but it is invasive, while no aortic valve replacement (noAVR) in non-invasive, but it is associated with poor prognosis. This meta-analysis aims to investigate the survival rate in patients with LFLGAS undergoing AVR versus noAVR interventions. Methods. A meta-analysis was conducted comparing the outcomes of AVR and noAVR in terms of survival. A meta-regression was carried out to investigate the impact of preserved and reduced left ventricular ejection fraction (LVEF) on survival in both the AVR and noAVR group. Results. The log IRR of survival between AVR group and noAVR group was 0.58 [0.28, 0.87] (p-value = 0.0001), suggesting that survival is significantly better in the AVR group compared to the noAVR group. The meta-regression revealed that low LVEF is related to higher survival rates in the AVR group (p-value = 0.04) when compared to preserved LVEF. LVEF has no impact on survival in the noAVR group (p-value = 0.18). Conclusions. Patients with LFLGAS have better survival in the AVR group rather than in the noAVR group. Reduced LVEF was related to better survival than preserved LVEF in the AVR, and no difference between low and preserved LVEF was found in the noAVR group.

The “coronavirus disease 2019 (COVID-19)” outbreak was first reported in December 2019 (China). Since then, this disease has rapidly spread across the globe and in March 2020 the World Health Organization (WHO) declared the COVID-19 pandemic.1 Since the outbreak was first announced, our journal has extensively focused on the clinical features, outcomes, diagnosis, immunology, and pathogenesis of COVID-19 and its infectious agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We published our first COVID-19 article on 19 February, focusing for the first time on the clinical characteristics of 140 cases of human-to-human coronavirus transmission without any links to the Huanan Wet Market.2 Hypertension and diabetes were mentioned as risk factors and there was no increased prevalence in allergic patients. This early study reported that the main symptoms at hospital admission were fever (91.7%), cough (75.0%), fatigue (75.0%), gastrointestinal symptoms (39.6%), and dyspnea (36.7%). Lymphopenia and eosinopenia were also reported as important signs and biomarkers for monitoring and severity of the patients.2 The prevalent eosinopenia in COVID-19 patients and the possible anti-viral role of eosinophils were further discussed in several following publications inAllergy .3,4 Our second COVID-19 paper brought attention to the wide range of clinical manifestations of this disease, from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia as well as with only diarrhea.5Patients with common allergic diseases did not develop distinct symptoms and severe courses. Cases with pre-existing chronic obstructive pulmonary disease or complicated with a secondary bacterial pneumonia were severe. Another article, timely appearing in our journal, alerted the scientific community that even in experienced hands there was a 14.1% false negative polymerase chain reaction (PCR) diagnosis in COVID-19 cases and were later diagnosed positive after repeated tests.6 A pediatric article was also published extensively analyzing 182 cases and it was reported that children with COVID-19 showed a mild clinical course.7 Patients with pneumonia had a higher proportion of fever and cough and increased inflammatory biomarkers compared to those without pneumonia. There were 43 allergic patients in this series and there was no significant difference between allergic and non-allergic COVID-19 children in disease incidence, clinical features, laboratory, and immunological findings. Allergy was not a risk factor for disease and severity of SARS-CoV-2 infection and did not significantly influence the disease course of COVID-19 in children.7The immunology of COVID-19 was extensively reviewed in two articles from leading experts with a comprehensive discussion of the tip of the iceberg in COVID-19 epidemiology, anti-viral response, antibody response to SARS-CoV-2, acute phase reactants, cytokine storm, and pathogenesis of tissue injury and severity. 8,9Two studies timely reported the role of possible trained immunity in countries with a Bacillus Calmette-Guérin (BCG) vaccination programme and a relatively low COVID-19 prevalence and mortality rate.10,11 In an extensive RNA sequencing analyses of SARS-CoV-2 receptor and their molecular partners revealed that ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA and PPIB), CD26 (DPP4) and related molecules were expressed in both, epithelium and in immune cells.12Allergists, respiratory physicians, pediatricians, and other health care providers treating patients with allergic diseases are frequently in contact with patients potentially infected with SARS-CoV-2. Practical considerations and recommendations given by experts in the field of allergic diseases can provide useful recommendations for clinical daily work. Since the beginning of this current pandemic, our journal has disseminated clinical reports, 2,3,5,6,13 statements on the urgent need for accuracy in designing and reporting clinical trials in COVID-19,14 preventive measures,10,11,15 and Position Statements elaborated by experts in the field in close collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) and its task force “Allergy and Its Impact on Asthma (ARIA) ”.16-28 (keynote information in table 1). A compendium answering 150 frequently encountered questions regarding COVID-19 and allergic diseases has been recently published by experts in their respective area.29 In addition, readers can put further questions regarding this “living ” compendium electronically to the authors and their answers will be available through a new category in the journal’s webpage.30Besides, EAACI in collaboration with ARIA, has provided recommendations on operational plans and practical procedures for ensuring optimal standards in the daily clinical care of patients with allergic diseases, whilst ensuring the safety of patients and healthcare workers.23Table 1: Examples of recently published recommendations, statements and Position Papers of the EAACI

Mahseer (Tor tor) is an important game fish in southern Rajasthan, India, and has recently been listed as an endangered species. The present study aimed to provide robust taxonomic classification of the species by calculating the haplotype gene frequency of Mahseer indigenous to the water bodies of southern Rajasthan. Thirty-two Tor tor samples were collected from eight sites in southern Rajasthan, India. The Cytochrome oxidase I (COI) gene was sequenced from all 32 samples. Haplotype frequencies of the samples collected were measured and phylogenetic analysis was performed. We observed that the Tor tor samples collected from the eight sites could be divided into three haplotypes, hap_1, hap_2, and hap_3. Samples collected from five sites (Chambal river, Rana Pratap Sagar, Bassi dam, Kali Sindh river, and Parwan river) exhibited the same COI haplotype, hap_1. Tor tor hap_2 was found only in samples from Badi lake; samples from Daya dam and Madar tank exhibited only Hap_3, giving a clear idea about phylogeny and group affiliations. This data can be used while repopulating the fish, which will contribute to better ecosystem management.

Dear Editor,we read with great interest the article recently published by Morishima L et al. (1 ). The Authors report an high incidence of Anisakis-specific IgE antiboides in patients with anaphylaxis in two towns in Japan.Worlwide the incidence of Anisakis patients is related to the ingestion of raw fish in seaside places. Herein we present the case of a child who has experienced an anaphylaxis with acute respiratory symptoms and a strange scrotal mass, in Calabria, a region completely surrounded by the sea in Southern Italy.An 8-year-old child italian child referred to our Emergency Department with a clinical complaint characterized by acute respiratory distress and right testicular pain since almost 24 hours, that worsened during the day. The respiratory picture resolved almost immediately with the use of corticosteroids via i.v. The clinical examination showed the presence of a painful testicle-independent swelling of about 1 cm in diameter, between the perineal plane and the scrotum, in the absence of signs of inflammation.The doppler ultrasonography demonstrated the presence of phlogistic area at the level of the right epididymis. We decide for home observation and medical therapy (betamethasone and amoxy-clavulanic acid) with mild improvement in symptoms in the following 3 days.After 4 days the child came back to our attention with an important scrotal lymphadenitis consensual to the previous epididymitis, with erythematous and warm scrotal skin. The intense scrotal pain, as in a clinical picture of acute scrotum, did not allow to visit the boy correctly.A second US showed an independent mass from the testicle of about 1 cm.The laboratory findings were completely negative, including testicular markers for tumour.The formula was; white blood cells 5.800, Neutrophiles 48.9%, Lymphocytes 41.8%, Eosinophils 0.8%. At surgical exploration the testicle was normal and a paratesticular granulomatous mass of about 2 cm in diameter was removed.The section of the anatomical specimen in the operatory room left us speechless.Inside the operating specimen we found … Worms! The histological examination confirmed a case of extra-gastrointestinal anisakiasis.

The expression of Major Histocompatibility Complex (MHC) molecule is essential for homeostasis of the immune system. Tissue-specific expression of MHC-II is regulated at the level of transcription. The master regulator for transcription of the MHC-II gene is CIITA. Homozygous mutations affecting the CIITA gene results in bare lymphocyte syndrome type-II. The clinical manifestations of heterozygous mutations are not well reported. Hence, this case report aims to provide more insight into the clinical features associated with heterozygous mutations of CIITA. We report a 5-year-old child who had presented with recurrent infections in infancy and systemic lupus erythematosus (SLE) in toddler age.

Drought has become one of the major constraints on agricultural development, particularly in areas lacking water. Studying the effects of different water stresses on photosynthesis, growth, yield, water use efficiency (WUE) and water productivity (IWP) of winter wheat will provide scientific irrigation strategies for developing water-saving agriculture. According to the water field capacity, four different water stress levels were set, i.e., 30–40% of water field capacity (severe stress), 40–50% (moderate stress), 50–60% (mild stress) and 60–80% (well-watered), through an automatic irrigation system by controlling the irrigation amount. The results showed that the diurnal and seasonal changes in photosynthetic parameters such as net photosynthetic rate (Pn), intercellular carbon concentration (Ci), stomatal conductance (Gs), and transpiration (E) significantly decreased under moderate and severe stress. The Pn of mild stress only slightly decreased compared to that of well-watered and was even higher after May 16th. As a result, the dry biomass and 1000-grain weight under mild stress increased 2.07% and 1.95% compared with well-watered. Under all water stresses, the heights and straw weights of the winter wheat significantly decreased. It was also found that mild water stress increased the WUE and IWP, which further resulted in the negligible decrease of the fresh weight of the aboveground biomass, dry biomass weight, spike weight, grain weight. Conversely, WUE and IWP significantly decreased under moderate and severe stress, which can affect the growth of winter wheat. So the fresh weight of the aboveground biomass, dry biomass weight, spike weight, grain weight also significantly decreased under moderate and severe stress. Thus, mild stress results in the optimal use of water resources without a significant reduction in yield in the North China Plain. Therefore, mild stress can be considered as a suitable environment for winter wheat growth in arid areas.

Objective To compare the effectiveness and safety of dexamethasone versus betamethasone for preterm birth (registered in PROSPERO CRD42017078006). Search strategy We searched in MEDLINE, EMBASE, Cochrane Library, LILACS, Clinical Trials.gov, International Clinical Trials Registry Platform, reference lists and contacted field experts. Selection criteria, data collection and analysis Randomized controlled trials comparing any corticosteroids against each other or against placebo. Three researchers independently selected, extracted data and assessed the risk of bias of the included studies by using EROS and COVIDENCE software. We performed a pairwise meta-analysis and Bayesian network meta-analysis. Main results We included 45 trials (11227 women, 11878 infants). There was no important difference between corticosteroids in neonatal death (odds ratio[OR] 1.05; 95% confidence interval 0.62-1.84; moderate-certainty evidence[CE]), neurodevelopmental disability (OR 1.03; 0.80-1.33; moderate-CE), intraventricular haemorrhage (OR 1.04; 0.56-1.78); low-CE) and birthweight (+5.29 gr; -49.79 to 58.97; high-CE). Compared with betamethasone, dexamethasone may reduce chorioamnionitis (OR 0.70; 0.45-1.06; moderate-CE), foetal death (OR 0.81; 0.24-2.41; low-CE) while may increase puerperal sepsis (OR 2.04; 0.72-6.06; low-CE) and respiratory distress syndrome (OR 1.34; 0.96-2.11; moderate-CE), however, the confidence interval indicates both beneficial and detrimental effects. Conclusions We found no important difference on neonatal death, neurodevelopmental disability, intraventricular haemorrhage and birthweight between corticosteroids. Compared with betamethasone, dexamethasone may reduce chorioamnionitis and foetal death, but may increase endometritis/puerperal sepsis and respiratory distress syndrome. Further research is warranted to improve the certainty of evidence. Keywords preterm birth, antenatal corticosteroids, dexamethasone, betamethasone, systematic review, network meta-analysis

Introduction, acetamiprid (AMP) is an insecticide that can affect human health as it is easily absorbed through gastrointestinal mucosa inducing erectile dysfunction and reduction of total sperm count. Many research studies had examined the effect of AMP on different body organs while this study was designed to study the underlying mechanisms of AMP associated reproductive toxicity. Material and methods, 40 male albino Wistar rats were divided into four groups. Control (C) group, received vehicle. 40 mg dose (40D), 30 mg dose (30D) and 10 mg dose (10D) groups received 40 mg/kg b.w., 30 mg/kg b.w., 10 mg/kg b.w. of AMP by oral gavage daily for 90 days. Results, sperm counts were significantly decreased in AMP treated groups with an increased count of flattened headed sperms in 40D-group. Plasma and testicular tissue GSH and TAS levels were significantly decreased while MDA and TOS levels were significantly increased after AMP administration in a dose dependent manner while plasma LH, FSH, GnRH and INHB levels were significantly increased. Seminiferous tubules basement membrane showed irregularities in 40D and 30D groups with a decrease in spermatogenic cells number. The testicular proliferative index was decreased associated with an increase in apoptotic index in AMP treated groups. Conclusion, AMP oral administration in a dose 10-40 mg/kg b.w. to male albino Wistar rats was found to possess an oxidative stress and apoptotic impact on the reproductive system which could be reflected on the occupational health precautions.

The microscope drape has been modified recently to provide an additional barrier to airborne transmissions of the SARS-CoV-2 virus. We describe the application of the modified microscope drapes in elective endoscopic sinus surgery and transoral robotic surgery as a standard operating protocol.

Placenta Accreta: Management by Peridural AnesthesiaFrancesco Tarantino,a Giuseppe Calìba Anesthesia and Intensive Care Unit 2, Villa Sofia-Cervello Hospital, PalermobGynecology and Obstetric Unit, Villa Sofia-Cervello Hospital, Palermo, Italy. Person in charge for the Perinatal Medicine and Assistance to the Birth Unit at the ARNAS CIVICO of Palermo, Department of Maternal and Nascent Life HealthCorrespondence : Francesco Tarantino, Anesthesia and Intensive Care Unit 2, Villa Sofia-Cervello Hospital, Viale Strasburgo, 233, 90146 Palermo, Italy. Phone: +393207032427. Email: tarantino.f@virgilio.itRunning title: Peridural Anesthesia in Placenta Accreta surgery

Background: Anosmia and ageusia are acknowledged as pathognomonic symptoms for SARS-CoV-2 infection by now. Smell-and taste disorders were significantly more frequent in COVID- 19 patients than in influenza patients. Disease characteristics show an acute onset and an initial manifestation of anosmia and ageusia. These symptoms have been linked to a neuroinvasive course of disease. Methods: In this study we investigated five consecutive COVID-19 patients with a prolonged course of anosmia and ageusia by conducting a Burghart Screening 12 Test with taste stripes in the late stage of the disease. Those with objectifiable alteration in taste or smell were subjected to MRI with contrast agent to investigate possible involvement of the central nervous system. Results: We found anosmia and ageusia to be mostly objectifiable, but no evidence for neuroinvasiveness could be detected by MRI in the late stage of the disease. Conclusions: Alterations in taste and smell could be objectified in most patients. Nevertheless, no evidence for a neuroinvasive potential could be identified by MRI, at least in the late stage of disease. We encourage medical professionals to conduct specialised examinations and MRIs in the acute stage of disease, which guarantees an optimum patient care.

Background and purpose: Dieckol is a phlorotannin that can be found in seaweeds, particularly in Eisenia bicyclis (brown algae) and is known to have anti-oxidant, anti-inflammatory, and anti-microbial properties. It also possesses anti-thrombotic and pro-fibrinolytic activities; however, the mechanistic aspects of anti-platelet and anti-thrombotic activity are yet to be explored. Experimental approach: We investigated the pharmacological effects of dieckol on the modulation of platelet functions using human, rat, and mice models. Inhibitory effects of dieckol on platelet aggregation were assessed using platelet-rich plasma and washed platelets, followed by measurement of dense granule secretions, fibrinogen binding to integrin αIIbβ3, fibronectin adhesion assay, platelet spreading on immobilized fibrinogen, and clot retraction. Cyclic nucleotide signaling events were evaluated, such as cyclic-AMP production followed by vasodilator-stimulated phosphoprotein (VASP) stimulation. The in vivo anti-thrombotic potential was evaluated in mice using an acute pulmonary thromboembolism model and tail bleeding assay. Key Results: Dieckol markedly inhibited platelet aggregation and granule secretion; furthermore, it down-regulated integrin αIIbβ3–mediated inside-out and outside-in signaling events, including platelet adhesion, spreading, and clot retraction, whereas it upregulated the cAMP–PKA–VASP pathway. Dieckol-treated mice significantly survived the thrombosis than vehicle-treated mice, without affecting hemostasis. Histological examinations of lungs revealed minimum occluded vasculature in dieckol-treated mice. Conclusion and implications: Taken together, dieckol possesses strong anti-platelet and anti-thrombotic properties and is a potential therapeutic drug candidate to treat and prevent platelet-related cardiovascular disorders.

Intestine regeneration in the sea cucumber Apostichopus japonicus is a fascinating biological event and a typical example for studying host-intestinal microbiota interactions. The intestinal microbiota may play important roles in developing intestine promotion, but the underlying mechanism remains unclear. Notably, altered microbiota abundance may be a key marker of the observed ecosystem. To understand the role of the developing intestinal microbiota in intestine regeneration via quantitative data, we developed a germ-free sea cucumber model and analyzed the intestinal microbial differentiation of faster and slower regenerating A. japonicus individuals during intestine regeneration. The results revealed that depletion of the intestinal microbiota resulted in elevated abundance of the potential key players Flavobacteriaceae and Rhodobacterales during intestine regeneration and thus promoted the intestine regeneration rate of A. japonicus. These results first revealed a direct link between intestinal microbial quantity and microbiome features and the intestinal regrowth rate of A. japonicus. Metagenomic analysis revealed that the increased abundance of Flavobacteriaceae elevated the enrichment of genes associated with carbohydrate utilization, whereas the abundant Rhodobacteraceae -enriched genes were associated with polyhydroxybutyrate production. We identified microbiota abundance as a key driver of microbial community alterations, especially beneficial microbiota members, in the developing intestine of A. japonicus. This study provides new insights into the mechanism of host-microbiota interactions related to intestine development, and the understanding of molecular diversity to questions within intestinal ecology.

Background: Although diastolic dysfunction is common among patients treated with cancer therapy, no clear evidence has been shown that it predicts systolic dysfunction. This study evaluated the correlation of longitudinal diastolic strain time (Dst) with the routine echocardiography diastolic parameters and to estimated its role in the early detection of cardiotoxicity among patients with active breast cancer. Methods: Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling all adult patients referred to the cardio-oncology clinic. All patients with breast cancer, planned for Doxorubicin therapy were included. Echocardiography, including Global longitudinal systolic strain (GLS) and Dst, was assessed at baseline before chemotherapy (T1), during Doxorubicin therapy (T2) and after the completion of Doxorubicin therapy (T3). Cardiotoxicity were determined by GLS relative reduction of ≥15%. Dst was assessed as the time measured (ms) of the myocardium lengthening during diastole. =diastolic time (ms) measured. Results: Among 69 patients, 67 (97.1%) were females with a mean age 52±13years. Diastolic strain timeDst measurement was significantly associated with the standard routine diastolic parameters. Significant GLS reduction was observed in 10 (20%) patients at T3 . Both in a univariate and a multivariate analyses the change in Ds basal time from T1 to T2 emerged to be significantly associated with GLS reduction at T3 (p<0.04). Conclusions: Among breast cancer patients, Dst time showed high correlation to standard the routine diastolic echocardiography parameters. Relative reductionChange in Ds basal time emerged associated with clinically significant systolic dysfunction as measured by GLS reduction.

Myocardial non-compaction (NC) is a rare genetically heterogeneous cardiomyopathy which is characterized by excessively prominent ventricular trabeculations with deep intertrabecular recesses. It is commonly believed to be due to an intrauterine arrest of the endomyocardial morphogenesis. Left ventricle (LV) is the usual site of affection, but very rarely right ventricular (RV) or both ventricles may be involved. It can be isolated or associated with other cardiac diseases or neuromuscular disorders. It has a wide spectrum of clinical manifestations that range from asymptomatic status, progressive ventricular dysfunction, arrhythmias and congestive heart failure that have been found to be associated with myocardial fibrosis. Cardiac Magnetic resonance (CMR) is the gold standard non-invasive modality for the diagnosis of cardiomyopathies. In NC cases, late gadolinium enhancement (LGE) of the trabeculated layer or mild fibrosis of the compacted layer was previously described in the literature, however extensive fibrosis in the compacted layer only with no fibrosis at the trabeculated layer was not described before. We report a male patient presented with heart failure symptoms, echocardiogram showed severe LV and RV systolic dysfunction with prominent bi-ventricular trabeculations. CMR confirmed the diagnosis of bi-ventricular non-compaction with peculiar pattern extensive fibrosis of the compacted layer of LV in LGE. To the best of our knowledge, our case is the first case to report extensive fibrosis in the compacted layer only with no fibrosis at the trabeculated layer.

There are views prevalent in the noncovalent chemistry literature that i) the O atom in molecules cannot form a chalcogen bond, and ii) if formed, this bond is very weak. We have shown here that these views are not necessarily true since the attractive energy between the oxygen atom of some molecules and several electron-rich anionic bases examined in a series of 34 ion-molecule complexes varied from the weak (ca –2.30 kcal mol-1) to the ultra-strong (–90.10 kcal mol-1). The [MP2 /aug-cc-pVTZ] binding energies for several of these complexes were found to be comparable to or significantly larger than that of the well-known hydrogen bond complex [FH···F]– (~ 40 kcal mol-1). The nature of the intermolecular interactions was examined using the quantum theory of atoms in molecules, second-order natural bond orbital and symmetric adaptive perturbation theory energy decomposition analyses. It was found that many of these interactions comprise mixed bonding character (ionic and covalent), especially manifest in the moderate to strongly bound complexes. All these can be explained by an n (lone-pair bonding orbital) -> σ* (anti-bonding orbital) donor-acceptor charge transfer delocalization. This study, therefore, demonstrates that the covalently bound oxygen atom in molecules can have a significant ability to act as an unusually strong chalcogen bond donor.

To the editor:Cow’s milk allergy (CMA) is the most common food allergy in children, with a prevalence of 1 to 3% (1). While the vast majority of CMAs clear after five years (2), some children have a persistent and severe disease associated with a risk of life-threatening allergic reactions (3). For those patients, oral immunotherapy (OIT) is now recommended (4); it consists in a tolerance induction by daily ingestion of allergen. However, in the most severe cases which react with a very low quantity of cow’s milk (CM), classic OIT cannot be initiated due to the impossibility of increasing the daily doses of CM. The adjunction of omalizumab, a monoclonal anti-IgE antibody, to OIT (oma-OIT), could be a safe and effective alternative in those cases; however, only a few studies have been published to decisively assess both the safety and efficiency of oma-OIT (5–8). The aim of our study was to evaluate both the effectiveness and safety in an oma-OIT protocol in children with persistent and very severe CMA.In this study performed in Lyon, France, children who initiated an oma-OIT protocol for a persistent and very severe CMA were included. These patients were considered as severely allergic due to failure in initiation of a classic OIT to CM or an history of severe reaction with very small amounts of CM. Initiation of oma-OIT was decided in a concertation meeting of allergist experts in OIT. Briefly, the oma-OIT protocol was performed as following: (1) subcutaneous omalizumab was administrated at a frequency (every 2 or 4 weeks) and a dose that depended on the patient’s weight and total IgE (same dose used as the one recommended for severe asthma); (2) after 16 weeks of omalizumab use alone, OIT was initiated. The induction phase began with the introduction of diluted amounts of CM (first daily dose: 1 mg of CM proteins), followed by introduction of non-diluted doses and daily increases of CM doses until a predefined threshold. Oral food challenges (OFCs) were performed every month or two months at hospital, under the supervision of a medical team trained for the management of high-risk OFCs, in order to establish the cumulative tolerated dose (CTD) and the new threshold to reach by up-dosing. After each OFC, the new threshold was reached at home in one week, and maintained for several weeks, until the next OFC. Allergy tests were usually performed at each OFC (skin prick-test [SPT], specific IgE [sIgE] to CM and CM components and specific IgG4 [sIgG4] to CM, Phadia 250 Thermofisher, Uppsala, Sweden). Additionally, the patients and their parents reported any allergic reactions which occurred at home in a notebook, if applicable. We retrospectively collected the general characteristics of each patient at the initiation of the protocol. We also collected the initial grade and the most severe grade of allergic reactions to CM, using the Ring and Meissmer classification (9), the results of OFCs, the allergy tests and allergic reactions and the use of epinephrine during OFCs and at home. In addition, we collected responses from a satisfaction survey which was completed by the children and their parents after OFC4.In order to evaluate the effectiveness of the initiation of oma-OIT protocol, the primary outcome was the change in the CTD of ingested fresh CM between OFC1 and OFC4. The secondary outcomes were the changes in allergy tests, the occurrence of allergic reactions during OFCs and at home, and the results of the satisfaction survey. Statistical tests were performed using GraphPad Prism version 8.02 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com.Eight children (3 boys and 5 girls, median age of 14.5 years [12-16]) with very severe CMA who received an oma-OIT treatment were included in this study (Table 1). The median administrated dose of omalizumab was 487.5 mg [300-600] every 2 or 4 weeks. The median time between OFC1 and OFC4 was 127 days [84-427] for a total number of 1,342 ingested doses at home. After four OFCs (Table I and Figure S1), the CTD of CM was significantly increased (median CTD1 = 0.96 mg [0.64;15.04] and CTD4 = 160 mg [12.8;480], 167-fold change, p = 0.0078 ). The anti-CM sIgE moderately decreased (sIgE1 = 476.0 kU/L [227.0;2048.0] and sIgE4 = 460.0 kU/L [97.2;1482.0], change -3.4%, p = 0.0391 ) and ratio anti-CM sIgG4/sIgE increased (sIgG4/sIgE1 = 8.6 [1.8;16.2] and sIgG4/sIgE4 = 17.5 [3.3;223.1], change +103.5%,p = 0.0313 ). There were no significant changes in SPT wheal and anti-CM component sIgEs. During the 32 OFCs performed in the 8 children under oma-OIT, 8 allergic reactions occurred in 6 children: 4 were grade 1 and 4 grade 2 according to the Ring and Meissner classification. These children were treated with oral antihistamine; none needed an epinephrine administration. Among the 1,342 ingested doses at home, two doses induced allergic reactions in two children: one grade 2 and one grade 3. The severe reaction was treated by epinephrine at home. Of note, a reactogenic cofactor (physical activity) without adaptation of the protocol was found for this severe reaction. Finally, all the children and their parents were globally very satisfied with the oma-OIT protocol, even if they expressed relative anxiety due to the risk of adverse reactions during the OFCs and the dose intake (Table S1). Interestingly, omalizumab injections were not considered as a constraint by most of the children and their parents (Table S1).Thus, in this cohort of children with very severe CMA, the adjunction of omalizumab to OIT was effective and globally well tolerated, during the first months of the protocol. The main limitations of our study are the absence of a control group (placebo or no treatment), the limited size of our cohort, and the duration of follow-up. These are preliminary results and they need to be confirmed. Moreover, our patients were more severe than those included in previous studies, in terms of initial CTD and sIgE (5–8). Thus, this preliminary study encourages continuation of further oma-OIT protocols in cohorts of patients with very severe CMA.

Background: Pulmonary veins reconnection due to insufficient lesions is an important cause of recurrence of atrial fibrillation (AF). High power ablation (HPA) with shorter duration or guided by Ablation index (AI) seen to increase efficacy and safety. This analysis aimed to evaluate the clinical benefits of HPA in patients with AF. Methods: The Medline, PubMed, Embase, and the Cochrane Library databases were searched for studies comparing HPA and conventional power ablation (CPA). Results: A total of nine trials with 2297 patients were included in the analysis. Pooled analyses demonstrated that HPA showed a benefit of first-pass pulmonary vein isolation (PVI) and acute PVs reconnection [risk ratio (RR): 1.27; 95% confidence interval (CI): 1.18–1.37, P < 0.001] and (RR: 0.52; 95% CI: 0.30–0.88, P = 0.01). HPA could reduce recurrence of atrial arrhythmias (RR: 0.71; 95% CI: 0.53–0.97, P = 0.03). Additionally, HPA was more beneficial in terms of procedural time [Weighted Mean Difference, (WMD): −41.19; 95% CI, −56.01 to −26.36, P < 0.001], ablation time (WMD: −19.45; 95% CI: −23.11 to −15.78, P < 0.001), and fluoroscopy time (WMD: −3.10; 95% CI: −5.52 to −0.68, P < 0.001) compared with the CPA approach. Moreover, HPA was associated with low complications (RR: 0.60; 95% CI: 0.36–0.99, P = 0.05). Conclusion: The HPA was a safe and effective approach for treating AF with clear advantages of procedural features. It was also associated with higher first-pass PVI, fewer acute PVs reconnection, recurrence of atrial arrhythmias and complications compared with the CPA approach.

Vanessa Yee Jueen Tan MBBS (S’pore), MRCS (Glasgow), MMed (ORL) Department of Otorhinolaryngology – Head and Neck Surgery Singapore General HospitalEdward Zhiyong Zhang MBBS (S’pore), MRCS (Glasgow), MMed (ORL), MCI, FAMS (ORL) Department of Otolaryngology – Head and Neck Surgery Sengkang General HospitalDan Daniel PhD Institute of Materials Research and EngineeringAnton Sadovoy PhD Institute of Materials Research and EngineeringNeville Wei Yang Teo MBBS (S’pore), MRCS (Glasglow), MMed (ORL) Department of Otorhinolaryngology – Head and Neck Surgery Singapore General HospitalKimberley Liqin Kiong MBBS (S’pore), MRCS (Edinburgh), MMed (ORL), FAMS (ORL) Department of Otorhinolaryngology – Head and Neck Surgery Singapore General HospitalSong Tar Toh MBBS (S’pore), MRCS (Edin), MMed (ORL), MMed (Sleep Med), FAMS (ORL) Department of Otorhinolaryngology – Head and Neck Surgery Singapore General HospitalHeng Wai Yuen MBBS (S’pore), MRCS (Edinburgh), MMed (ORL), DOHNS (England), GDFM Ear Nose Throat, Head and Neck Surgery Changi General HospitalCorresponding author: Vanessa Yee Jueen Tan vanessa.tan.y.j@singhealth.com.sg