Aims: Lopinavir (LPV) and ritonavir (RTV) is using as combination therapy for combating COVID-19 in considerable proportion of patients. However, the potential clinically significant life-threatening drug-drug interactions (DDIs) of this combination antiviral therapy used in the treatment of COVID-19 patients is not systematically reviewed. It was aimed to identify severe DDI pairs of LPV/RTV from international resources predicted to cause life-threatening adverse drug reactions (ADRs) and cross-compared between the resources. Methods: Severe DDI pairs predicted to cause life-threatening ADRs were identified from the FDA and Liverpool COVID-19 prescribing information of LPV/RTV. Results: In total, 62 severe DDI pairs were identified from the FDA and Liverpool COVID-19 drug interactions resources predicted to cause life-threatening ADRs in patients with COVID-19. Of these, seven unique DDI pairs were identified from the FDA only whereas 45 unique DDI pairs were identified from the Liverpool COVID-19 drug interactions resource. Of interest, only 10 DDI pairs were recognized by both of these drug interaction resources. Conclusion: Clinicians should not entirely rely on any individual DDI resource for checking life threatening ADRs of LPV/RTV in patients with COVID-19 since there were discrepancies in enlisting contraindicated drugs.

Background and aim: Small ubiquitin–like modifier (SUMO)-specific protease (SENP)3 is a protease molecule that responds to reactive oxygen species (ROS) with high sensitivity. However, the role of ROS and SENP3 in the formation of nasal polyps (NPs) remains unclear. This study aimed to explore how SENP3 influenced the outcome of chronic rhinosinusitis (CRS) by altering macrophage function, that is, the formation of NPs. Methods: The alternative activation of macrophage (M2) was detected with CD68+CD206+ in humans and CD206+ in mice. The nasal mucosa of patients with CRS was tested using flow cytometry (CD68, CD80, and CD206) and triple-color immunofluorescence staining (CD68, CD206, and SENP3). The bone marrow–derived macrophages from SENP3 knockout and control mice were stimulated with interleukin (IL)-4 and IL-13 to analyze alternative macrophage polarization in vitro. An animal model of allergic rhinitis was constructed using SENP3 knockout mice. CD206 was detected by immunofluorescence staining. The thickening of eosinophil-infiltrated mucosa was detected by Luna staining. Results: The number of CD68+ CD206+ M2 increased in the nasal mucosa of patients with CRS with NP (CRSwNP) compared with patients with CRS without NP (CRSsNP), but with no significant difference between the groups. SENP3 knockout increased the polarization of F4/80+CD206+M2. Meanwhile, the number of CD206+M2 significantly increased in the allergic rhinitis model constructed using SENP3 knockout mice and controls, with a more obvious proliferation of the nasal mucosa. Conclusion： The downregulation of the expression of macrophage SENP3 in the nasal mucosa in chronic sinusitis promoted the formation of NPs.

We present an unusual combination of lesions in an eight months old child diagnosed with Tetralogy of Fallot (TOF), Anomalous origin of Right Pulmonary artery (AORPA) and anomalous coronary artery (ACA) crossing the pulmonary annulus. The association of AOPA and TOF is extremely rare with an incidence of 0.4%. (1) The incidence of anomalous coronary artery in TOF is 10.3%. (3) However a combination of all three lesions poses challenges to surgical repair and has not been previously reported.

Double clefts of both the anterior and posterior leaflets are extremely rare. A 21-year-old female with mitral valve regurgitation was admitted to our institute, and real-time three-dimensional transesophageal echocardiography revealed a cleft in the posterior mitral valve leaflet and an additional partial cleft in the anterior leaflet. Totally-endoscopic mitral valve plasty using surgical robot with direct suturing of both clefts, and annuloplasty were performed successfully. This is the first report of robotic totally-endoscopic mitral valve plasty for mitral regurgitation due to double clefts of the anterior and posterior mitral valve.

A 52-year-old man presented to our institution with a one year history of intermittent, progressive chest tightness with activity. He underwent stress test which was positive. Coronary angiography revealed a long segment myocardial bridge of the left anterior descending artery (LAD). Initially, he was trialed on maximal medical therapy, however, symptoms continued. As a result, he was brought to the operating room for unroofing of the myocardial bridge with excellent clinical and radiographic outcome. The diagnosis, medical, and surgical management of myocardial bridge is complicated. Long-term data surrounding best options for management is scarce.

We reported a patient presenting with tuberous sclerosis complex. Next-generation sequencing showing a frameshift mutation in TSC2 gene confirmed the clinical diagnosis. The study contributed to raise medical awareness on tuberous sclerosis complex in Vietnam that could lead to future approval of its diagnostics and treatment.

Objective: A globus sensation is one of the most common complaints in otolaryngological practice. Patients with no associated abnormalities detected during the usual examinations performed in ENT clinics, are being diagnosed with globus sensation. Cervical ultrasonography is usually not performed in ENT clinics; however, it is useful in screening diseases of the subcutaneous tissue/organs, whose detection is not possible with the routine ENT examinations. The purpose of our study was to elucidate whether cervical ultrasound examination identifies abnormalities in patients with globus sensation. Design: A single-centre retrospective cohort study. Cervical ultrasonographic examinations were performed on patients with globus sensation from January 2013 to September 2017. Setting: Department of Otolaryngology of Tottori university hospital, a tertiary care centre Participants: The subjects were 74 patients (42 women and 32 men) experiencing globus sensation with no abnormality detected on general otolaryngological examination (including laryngoscopy). The mean age was 58.4 years. Main outcomes: The primary outcome measure was the percentage of patients with globus sensation who have structural abnormalities detected by cervical ultrasonography. Results: Ultrasonography detected structural abnormalities in 60.8% of the patients with globus sensation: thyroid disorders in 41 patients, including: 35 patients with thyroid nodules, 4 patients with Hashimoto’s disease, 1 patient with Grave’s disease, and 1 patient with subacute thyroiditis; Sjögren syndrome in 2 patients; and cervical lipoma in 1 patient. Furthermore, 2 patients with thyroid disorders had concomitant oesophageal cancer. Conclusions: Cervical ultrasonography identified thyroid disorders in patients with globus sensation, despite the normal ENT status. Therefore, it would be appropriate to adopt cervical ultrasonography as a routine examination at ENT clinics for patients with globus sensation.

A document by Phuong Vo. Click on the document to view its contents.

There are a significant number of symptomatic aortic stenosis (AS) patients not referred to the traditional methods for some complexity conditions. We described a case of a 61-year-old female with severe symptomatic AS, calcific small aortic annulus (16.6 mm), narrow porcelain ascending aorta (aortic root 14.6 mm, internal diameter 14.0 mm), chronic renal insufficiency and a history of previous sternotomy for mechanical mitral valve replacement (MVR) and coronary artery bypass grafting (CABG) who underwent aortic valve bypass (AVB) with favorable results. AVB has been proposed as a complementary to surgery operation of aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) in high-risk AS patients.

In up to 10 % of patients with hypertrophic cardiomyopathy, the disease is caused by genetic disorders including metabolic diseases. Sometimes clinical workup may be confusing. To our knowledge, this is the first report of false positive results of scintigraphy indicating cardiac amyloidosis in a patient with Danon disease.

Studies indicate that cannabis (marijuana) is the most frequently used recreational substance (after tobacco and alcohol) in pregnancy despite being under-reported. The prevalence is expected to increase with the recent wave of interest in medicinal and recreational cannabis use, resulting in the reconsideration of its classification in terms of clinical and legal risks, in the backdrop of campaigns for its decriminalisation and legalisation gradually sweeping the world. This paper reviews the likely impact on the ethics of the use of cannabis in pregnancy, and implications for obstetricians, midwives, general practitioners, psychiatrists, and other clinicians managing such patients.

Rivers support some of Earth’s richest biodiversity and provide essential ecosystem services to society, but only if they flow. In Europe, attempts to quantify river connectivity have been hampered by the absence of a harmonised barrier database. We assembled ~630,000 unique barrier records from 36 European countries and surveyed 2,715 km of 147 rivers to reveal a ~61% underestimation of barrier numbers. We estimate there are at least 1.2 million instream barriers (mean density = 0.74 barriers/km), 72% of which are low-head (<2m) structures, making Europe the world’s most fragmented river landscape. The highest barrier densities occur in the heavily modified rivers of Central Europe, and the lowest in the most remote, sparsely populated alpine areas. Barrier density was predicted by agricultural pressure, road density, extent of surface water, and elevation. Relatively unfragmented rivers are still found in the Balkans, Scandinavia, the Baltic states, and parts of southern Europe, but these require urgent protection from new dam developments. Our findings can inform the implementation of the EU Biodiversity Strategy, which aims to reconnect 25,000 km of Europe’s rivers by 2030, but achieving this will require a paradigm shift in river restoration that recognises the impacts caused by small barriers.

Polymorphisms in the granulocyte colony-stimulating factor receptor gene (GCSFR, CSF3R) have been reported to be associated with peripheral blood stem cell enrichment and hematological diseases. The aim of our study was to investigate the effects of donor CSF3R allelic polymorphisms on the outcomes of allogeneic stem cell transplantation. A total of 273 patients who were diagnosed with hematological diseases and treated with allogeneic hematopoietic stem cell transplantation(allo-HSCT) were enrolled in this study. Single-nucleotide polymorphisms in CSF3R were genotyped by targeted next-generation sequencing. There were six types of CSF3R genotypes with percentages over 1%. LFS and OS analyses showed that recipients receiving grafts from healthy donors with an rs3917980 G/G or A/G genotype had higher LFS rates than those receiving grafts from donors carrying an rs22754272 T/C genotype and the double negative group (p=.036) Univariate analysis showed that donor CSF3R with the rs2275472 T/C genotype was associated with higher transplantation-related mortality(TRM) rates (HR=3.77, 95% CI: 1.416-9.631, p=.004) and higher rates of leukemia-free survival(LFS) (HR=2.523; 95% CI: 1.032-6.13, p=.026). In addition, donor CSF3R with the rs3917980G/G or A/G genotype was associated with better overall survival(OS) rates (HR=0.512, 95% CI: 0.244-1.017, p=.047). Our findings demonstrate the important prognostic value of genetic variations in donor CSF3R to predict clinical outcomes in patients undergoing allo-HSCT.

Background: Post-traumatic stress disorder (PTSD) affects approximately 3% of women in the postnatal period, but less is known about risk factors for PTSD than for other postnatal mental illnesses. Objectives: To analyse literature surrounding the impact of mode of birth on postnatal PTSD. Search Strategy: Five databases were systematically searched (1990-2019). Selection Criteria: Studies investigating the link between mode of birth and postnatal PTSD in high income countries. Data Collection and Analysis: Quantitative and qualitative data were collected and synthesised. Meta-analysis was performed with four of the studies, and the rest were analysed narratively. Main Results: Twelve quantitative and two qualitative studies were included in the review. Most found a significant relationship between mode of birth and maternal PTSD symptoms. Meta-analysis found caesarean section was more associated with PTSD than vaginal delivery (VD) (p=0.005), emergency caesarean section (EmCS) more than elective caesarean section (ElCS) (p<0.001), instrumental vaginal delivery (IVD) more than spontaneous vaginal delivery (SVD) (p<0.001) and EmCS more than VD (P<0.001). Women who developed PTSD after EmCS felt less in control and less supported than those who did not develop it after the same procedure. Request for repeat ElCS appeared more common among women with pre-existing postnatal PTSD, but this may subsequently leave them feeling dissatisfied and their fears of childbirth unresolved. Conclusions: Modes of birth involving emergency intervention may be risk factors for the development of postnatal PTSD. Ensuring that women feel supported and in control during emergency obstetric interventions may mediate against this risk.

The COVID-19 pandemic has presented the NHS with unprecedented challenges following the declaration of “global pandemic” by the WHO.1 In response to this crisis, reconfiguration of services and resource allocation were undertaken across all levels with a view to provide effective supportive and emergency care as well as minimise risk of exposure to the infection in hospitals.1

Objective: Universal screening has been proposed as a strategy to identify asymptomatic individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mitigate transmission. We aimed to investigate the rate of positive tests among pregnant women attending routine antenatal care. Design: Cross-sectional prevalence study. Setting: Antenatal clinic at three maternity hospitals (one tertiary referral hospital and two secondary maternities) in Melbourne, Australia. Population: Asymptomatic pregnant women attending routine antenatal care and pregnant women undergoing testing with symptoms of possible coronavirus disease. Methods: SARS-CoV-2 testing was offered to all pregnant women attending face-to-face antenatal visits and to those attending the hospital with symptoms of possible coronavirus disease, between 6th and 19th of May 2020. Testing was performed by multiplex-tandem polymerase chain reaction (PCR) on combined oropharyngeal and nasopharyngeal swabs. Main Outcome Measures: Proportion of positive SARS-CoV-2 tests. Results: SARS-CoV-2 testing was performed in 350 women, of whom 19 had symptoms of possible COVID-19. The median maternal age was 32 years (IQR 28 to 35 years), and the median gestational age at testing was 33 weeks and four days (IQR 28 weeks to 36 weeks and two days). All 350 tests returned negative results (p̂ = 0%, 95% CI 0 to 0.86%). Conclusion: The rate of asymptomatic coronavirus infection among pregnant women in Australia during the study period was negligible, which reflected reassuringly low levels of community transmission.

Background and Purpose: Bone marrow-derived mesenchymal stem cells (BMSCs) are potential in promoting bone regeneration for their multipotential differentiation capacity. Our previous study showed that carbon monoxide releasing molecule-3 (CORM-3) promoted the osteogenic differentiation of rat BMSCs. However, the mechanism was not clearly understood. MicroRNAs (miRNAs) play a critical role in regulating the osteogenic differentiation of BMSCs. We therefore investigated the role of miR-195-5p in CORM-3-induced osteogenic differentiation. Experimental Approach: The rat BMSCs were transfected with miR-195-5p mimics, miR-195-5p inhibitor, pcDNA3.1-Wnt3a, Wnt3a siRNA or their corresponding controls. The rat BMSCs osteogenic differentiation was assessed by quantitative real-time polymerase chain reaction, Western blot and alizarin red staining. In addition, dual luciferase assay was used for the verification of targeting relationship between miR-195-5p and Wnt3a. Key Results: miR-195-5p was down-regulated during the CORM-3-induced osteogenic differentiation of rat BMSCs. Overexpression of miR-195-5p inhibited CORM-3-induced osteogenic differentiation of rat BMSCs, evidenced by significantly decreased mRNA and protein expressions of runt-related transcription factor 2 and osteopontin, and matrix mineralization demonstrated. Whereas, inhibition of miR-195-5p expression enhanced osteogenic differentiation. miR-195-5p directly targeted Wnt3a. Overexpression of Wnt3a increased CORM-3-induced osteogenic differentiation of rat BMSCs, the opposite effect was observed in Wnt3a-deficient cells. Moreover, the inhibitory effect of miR-195-5p overexpression on CORM-3-induced osteogenic differentiation was rescued by Wnt3a overexpression. Conclusion and Implications: These results demonstrated that miR-195-5p may negatively regulate CORM-3-induced osteogenic differentiation of rat BMSCs by targeting Wnt3a, which provided insight into new mechanism of CORM-3, and theoretical basis for bone regeneration.

To what extend that biochar addition promotes organic carbon increase in saline-sodic soils, however, remains poorly understood. Here, we evaluated soil organic carbon (SOC) contents change before and after biochar addition, and deciphered which driving factor or process govern SOC change with biochar application. There was a limited increase in SOC, about by +1.16%~+12.8%, even biochar was applied at the rate of 10% of bulk soil weight. However, soil dissolved organic carbon (DOC) increased significantly by up to 67%. About half SOC was stored in small macroaggregates (250-2000 μm, CPOC), and SOC in silt and clay-sized particles (<53 μm) decreased obviously with biochar addition. Microorganism biomass, represented by phospholipid fatty acid, increased with biochar amendment, of which actinomycetes, fungi, protozoon, and bacteria with straight-chain saturated fatty acids (OB) increased remarkably. DOC was governed by ACT and soil N:P ratio, while SOC mostly depended on CPOC. Biochar addition aggravated nitrogen limitation in saline-sodic soils, and the roles of microorganisms on regulating SOC greatly depended on nitrogen bioavailability. Biochar amendment had greatly changed interactions between environmental factors and SOC in saline-sodic soils. The effects of nutrients on soil carbon changed to strongly negative from strongly positive after and before biochar addition, meanwhile, aggregation was the only factor with positive effects on soil carbon change. How to mitigate nutrient limitation and improve soil aggregation process should be considered in priority when biochar was used to increase SOC in saline-sodic soils.

This article describes the training activities carried out under the auspices of the U.S. Department of Energy’s (DOE) Exascale Computing Project (ECP). While some of these activities are specific to members of ECP, others can be beneficial to the community at large. We report on training opportunities and resources that the broad computational science community can tap into. We seek to increase awareness about these resources, which we expect to go beyond ECP’s scope and life cycle.

Resistance (host capacity to reduce parasite burden) and tolerance (host capacity to reduce impact on its health for a given parasite burden) manifest two different lines of defence. Tolerance can be independent from resistance, traded-off against it, or the two can be positively correlated because of redundancy in underlying (immune) processes. We here tested whether this coupling between tolerance and resistance could differ upon infection with closely related parasite species. We tested this in experimental infections with two parasite species of genus Eimeria. We measured proxies for resistance (the (inverse of) number of parasite transmission stages (oocysts) per gram of feces at the day of maximal shedding) and tolerance (the slope of maximum relative weight loss compared to day of infection on number of oocysts per gram of feces at the day of maximal shedding for each host strain) in four inbred mouse strains and four groups of F1 hybrids belonging to two mouse subspecies, Mus musculus domesticus and M. m. musculus. We found a negative correlation between resistance and tolerance against E. falciformis, while the two are uncoupled against E. ferrisi. We conclude that resistance and tolerance against the first parasite species might be traded off, but evolve more independently in different mouse genotypes against the latter. We argue that evolution of the host immune defences can be studied largely irrespective of parasite isolates if resistance-tolerance coupling is absent or weak (E. ferrisi) but host-parasite coevolution is more likely observable and best studied in a system with negatively correlated tolerance and resistance (E. falciformis).

Chronic Eosinophilic Pneumonia (CEP) is a rare idiopathic eosinophilic lung disease characterized by a triad of pulmonary symptoms, radiographic findings and peripheral and/or lung eosinophilia. CEP is usually treated with oral corticosteroids however, treatment durations commonly exceed 12 months, relapses occur in ½ of patients and adverse effects of steroid use are common. We report a case of an 11-year-old female with corticosteroid refractory CEP who experienced clinical remission after initiation of dupilumab, a monoclonal antibody therapy approved for eosinophilic or steroid dependent asthma that inhibits IL-4 and IL-13. This case demonstrates the potential role of biologic agents in CEP.

We read the letter to the editor “B-lines score: artifacts as a sign of neonatal specific disease?” by Quarato et al. and we are pleased by the interest aroused by our article “Neonatal lung ultrasonography score after surfactant in preterm infants: A prospective observational study” published on your journal. This study included preterm neonates with respiratory distress syndrome (RDS), requiring non-invasive ventilation and surfactant. The aim of our citated study was to asses changes of a validated neonatal lung ultrasonography score (nLUS) after surfactant treatment. Our data demonstrate a lowering of the nLUS 2h and 12h after surfactant treatment. In their letter to the editor Quarato et al. expressed criticism about the nLUS score validation and about the utility of the Lung Ultrasound (LUS) as a diagnostic tool. They conclude that “LUS can be used only for diagnosing minimal pleural effusion and, at least, as complementary imaging, in addiction to chest radiographs (CR), for monitoring the reduction of subpleural pneumonitic consolidations under therapy”. Our citated study hasn’t focused on validation of the nLUS score or on LUS as a diagnostic tool for neonatal RDS, so we don’t get how Quarato’s concerns can be addressed to our paper. Nevertheless, finding the debate about nLUS or LUS in the neonatal field an occasion to promote an improving in the care of the preterm babies, we will discuss objections raised in Quadrato’s work, point by point.

Objectives: To evaluate the risk factors of recurrent pulmonary exacerbation and poor prognosis in children with idiopathic pulmonary hemosiderosis (IPH).  Methods: In this multicenter study, 54 patinets with diagnosis of IPH included. Medical records were retrospectively reviewed from three tertiary care hospitals between 1979 and 2019. Also, current information and the long-term progress of patients was determined by contacting the families by telephone. Results: A total of 54 children were included. The median age of onset of symptoms was 4.5 ± 3.8 years. The median time from onset to diagnosis was 0.9 years ± 2.2. The mean number of recurrent episodes per child in the recurrence-positive group was 3.55 (1-15). Univariate analysis demonstrated that patients presenting with hypoxia or requiring transfusion at the time of presentation had significantly more recurrence episodes (P=0.002). Multivariate analysis showed that the presence of hypoxia at the time of initial presentation was a significant independent predictor of recurrent episodes (P=0.027). The median follow-up was 3.3 ± 4.8 years (0.75 months-27 years). There was a significant relationship between the presence of hypoxia, transfusion history, ANA positivity, and elevated transaminases at the time of initial evaluation and treatment response. Conclusions: The present study provides important information on the clinical course and outcome of pediatric IPH, and substantial information regarding factors that affect recurrent exacerbations and prognosis. Demonstrating of hypoxia as an independent risk factor in recurrence episodes could be guide physicians in the planning of treatment strategies.

Fatigue crack growth thresholds ΔKth given in the WRC Bulletin, IIW and BS 7910 are constant values at negative stress ratios. However, the definitions of ΔKth at negative stress ratios are different: Kmax according to the WRC Bulletin and IIW, and Kmax - Kmin according to BS 7910, where Kmax is the maximum and Kmin is the minimum stress intensity factors. From fatigue crack growth tests conducted on ferritic steels and aluminium alloys in air at ambient temperatures, the thresholds expressed by Kmax - Kmin are variable values at negative stress ratios; that is, the threshold increases with decreasing stress ratio. The thresholds expressed by Kmax are also variables. Kmax decreases with decreasing stress ratio. The thresholds at negative stress ratios are not constant; they are affected by compression stress. Therefore, the thresholds given by the WRC Bulletin and IIW are slightly unconservative. The threshold given by BS 7910 is considerably conservative. A suitable definition of the threshold at negative stress ratios for application in flaw evaluation procedures is the variable threshold ΔKth expressed by Kmax - Kmin.