Positive GABAB receptor modulators such as GS39783 showed anxiolytic-like ef-fects in several studies while others failed to find such effects. These contradictory findings led us to hypothesize that the anxiolytic-like effects of positive GABAB re-ceptor modulators are dependent on basal anxiety levels of individual animals and/or on the anxiogenic properties of the test paradigm. The present study ad-dresses this hypothesis by testing the effects of intraperitoneally administered GS39783 (10 and 30 mg/kg) on anxiety-like behavior of mice in the light-dark box paradigm. Our findings show that GS39783 had no anxiolytic-like effects on a whole group level. However, after grouping the mice for their basal anxiety levels, GS39783 reduced anxiolytic-like behavior in the animal group with most basal anx-iety. Furthermore, individual GS39783 effects were correlated with individual basal anxiety levels. In a further experiment, the anxiogenic properties of the light-dark box test were increased. Again, GS39783 was not effective on a whole group level. However, GS39783 had anxiolytic-like effects in the most stress-responsive sub-group of mice. In addition, GS39783 effects were correlated with individual stress responsiveness. Last, we also demonstrate that GS39783 brain levels were in a range where GS39783 effects has been observed in vitro. Taken together, our study demonstrates that GS39783 effects are dependent of individuals’ basal anxiety and stress responsiveness. This suggests that anxiety tests should be generally de-signed in a way that individual basal anxiety levels and/or stress responsiveness, as well as individual compound effects can be evaluated.

Background: COVID-19, which occurred at the end of December 2019, has evolved into a global public health threat. COVID-19’s high infectivity and mortality prompt governments and scientific community to respond quickly to the outbreak of the pandemic. The application of personal protective equipment (PPE) is of great significance in overcoming the epidemic situation. Although there were many studies about PPE and COVID-19, there is no study about bibliometric analysis of these studies. This study aims to provide a general overview of studies on PPE and COVID-19. Methods: On October 07, 2021, the Web of Science (WOS) Core Collection database was used to identify documents on PPE and COVID-19. HistCite and VOSviewer softwares were used for citation analysis and visualization mapping. Results: A total of 1462 documents authored by 6993 authors and published in 750 journals were included in the final analysis. The most prolific author was Macintyre CR. The USA was the most productive country with 463 published documents. The leading journal was Plos One. Network visualization map showed that USA was the largest international collaboration network. The keyword “COVID-19” had the strongest total link strengths (TLS) and largest number of occurrences. The New England Journal of Medicine was the leading source with highest TLS. The University of Toronto had the highest number of links and the highest TLS. Conclusions: The bibliometric analysis of PPE and COVID-19 provides an overall perspective, and the appreciation and study of these influential publications are very useful for future research.

Abstract Methotrexate is a vital medication in treating different types of malignancies. There are few reports of successful administration of intravenous methotrexate post adverse reaction by step-up desensitization. We share here, our experience in overcoming methotrexate hypersensitivity though administration of methotrexate by fixed rate infusion in an allergic child who failed a step-up methotrexate desensitization protocol. The outcome of this case suggests an underlying, non IgE mediated mechanism for the adverse reaction.

The evaluation of extinction risk has typically focused on species, although a shift to a focus on ecosystem would appear to be an urgent priority for conservation planning. Here, we investigated how fish extinction modify the functioning of freshwater Amazonian ecosystems. We sampled the fish and environmental conditions of 63 streams in the eastern Amazon, and simulated extinction based on species vulnerability to habitat loss. The simulated extinction of vulnerable species led to a decrease in both the mean body size of the community and functional rarity, and culminated in abrupt losses of ecosystem function after 5% and 10% of extinction at local and regional scales. We provide robust predictions on the modification of the ecosystem following the extinction of fish species, which is a major step towards the development of effective conservation measures that help to prevent the loss of biodiversity and the potentially irreversible modifications of ecosystem function.

Abstract: Introduction & Objectives Antimuscarinic agents represent the cornerstone of pharmacotherapy for Overactive bladder (OAB) but persistence with treatment is often limited by undesirable side effects. The purpose of this review was to evaluate the efficacy and safety of combination therapy of mirabegron 50 mg and solifenacin 5 mg in comparison with 5 mg and 10 mg of solifenacin monotherapy in patients with OAB. Materials & Methods An electronic database search was carried out in Evidence Based Medicine Reviews, Cochrane Library and PubMed using keywords Mirabegron, Solifenacin, Combination, Overactive bladder based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline to include relevant randomized controlled trials (RCT)s. The meta-analysis was performed by Review Manager 5.4 software. Results Out of 907 studies screened, 4 RCTs involving a total of 5339 patients were eligible for analysis. In comparison to Solifenacin 5 and 10 mg monotherapy, combination therapy resulted in significantly more improvement in mean volume voided (MVV) per micturition, frequency of micturitions/24h, number of incontinence epi¬sodes/24h. Compared to Solifenacin 5 mg monotherapy, combination therapy was found to have overall acceptable tolerability profile in terms of treatment-emergent adverse events (TEAEs), dry mouth, constipation. Whereas when compared to Solifenacin 10 mg monotherapy, combination therapy was found to be better tolerated for all studied safety outcomes. Conclusions Combination therapy of mirabegron 50 mg and solifenacin 5 mg leads to significantly greater improvement in OAB symptoms and is better tolerated in comparison with solifenacin 10 monotherapy.

Aim: The study aimed to establish a population pharmacokinetic (PPK) model for Chinese patients with nephrotic syndrome using the patient genotype and Wuzhi capsule dose as the main test factors. Methods: Adult patients with nephrotic syndrome receiving tacrolimus treatment were enrolled. A nonlinear mixed effects model was used to determine the influencing factors of inter-individual tacrolimus metabolism variation and establish a PPK model. To optimize the tacrolimus dosage, 10000 Monte Carlo simulations were performed. Results: The typical population tacrolimus clearance (CL/F) value was 16.9 L/h. Increased Wuzhi capsule and albumin doses both decreased the tacrolimus CL/F. In CYP3A5 homozygous mutation carriers; the CL/F was 39% lower than that of carriers of the wild-type and heterozygous mutation. The tacrolimus CL/F in patients who were co-administered glucocorticoids was 1.23-fold higher than that in the control. According to the patient genotype and combined use of glucocorticoids, 26 combinations of Wuzhi capsule and tacrolimus doses were matched. The Monte Carlo simulation identified the most suitable combination scheme. Conclusion: An improved tacrolimus PPK model for patients with nephrotic syndrome was established and the most suitable combination of Wuzhi capsule and tacrolimus doses was identified, thus facilitating the selection of a more economical and safe administration regimen.

Background: Eosinophils act as a secondary antigen-presenting cell (APC) to stimulate Th cell responses against antigens. IL-25 plays an important role on eosinophil activation in allergic asthma. The role of IL-25 on the classic APC functions of dendritic cells has been elucidated. However, whether IL-25 facilitates eosinophils for antigen presentation is unknown. Objective: To elucidate IL-25 on eosinophils antigen presenting function during allergic asthma and its related mechanism. Methods: Eosinophils from allergic asthma subjects were cultured with IL-25 and HDM to identify the co-stimulator molecules expression. Co-cultures of eosinophils and autologous naïve CD4+ T cells in the same culture system were to explore whether eosinophils had the capacity to promote Th cell differentiation in response to IL-25 engagement. In asthma mouse model, IL-25 -/- mice were exposed to HDM to investigate IL-25 functions on eosinophils during sensitization phase. The impact of IL-25 on the capacity for eosinophil taking up antigens and costimulatory molecules expression was evaluated. Mouse bone marrow derived eosinophils (BmEOS) were co-cultured with naïve CD4+T cells sorted from spleens under HDM and IL-25 stimulation to identify T cell differentiation. Results: IL-25 upregulated HLA-DR, PD-L1 and OX-40L expression on eosinophils from allergic asthma patients. IL-25 and HDM co-sensitized eosinophils promoted Th2 differentiation. In animal model, IL-25 -/- mice experienced restrained allergic pulmonary inflammation and reduced eosinophils chemotaxis during early sensitization phase. In vitro, IL-25 promoted antigen uptake by eosinophils. During BmEOS and naïve CD4+T cells co-culture, IL-25 accreted the proportion of CD4+Th2 cells, which was absent in CD4+T cells culture alone. Conclusion: Our data identify a novel role of IL-25 in enhancing eosinophils antigen presenting capacity to induce Th2 priming in the context of allergic inflammation.

Objectives: This study aimed to assess the impact of COVID-19 on the prevalence of respiratory pathogens among hospitalized children with lower respiratory tract infections (LTRIs) in Shanghai. Methods: Respiratory specimens were collected from children with LTRIs in Children’s Hospital of Fudan University from February 2019 to January 2021 and common respiratory pathogens were detected using multiplex PCR. The data of 13 respiratory pathogens were analyzed and compared between the year of 2020 (from February 2020 to January 2021) and 2019 (from February 2019 to January 2020). Results: A total of 1049 patients were enrolled, including 417 patients in 2019 and 632 patients in 2020. In 2020, 27.53% of patients were tested positive for at least one pathogens, which was significantly lower than that in 2019 (78.66%). The top three pathogens were Mp, ADV and RV in 2019, whereas RV, RSV and PIV were the predominant ones in 2020. The positive rates of Mp, ADV, RV, PIV, InfB, H3N2 and H1N1 were significantly decreased in 2020. RV was the most detectable respiratory pathogen in 2020, and become the most frequent pathogen in all five age groups. PIV had a high prevalence from October to December 2020 which was even higher than that in 2019. InfA was not detected in 2020. Co-infection was significantly less frequent in 2020. Conclusions: The public health interventions aiming to eliminate COVID-19 have great impact on the prevalence of common respiratory pathogens. The prevalence of RV and PIV reminds us a possible resurgence of some pathogens.

A document by Ameer Muhammad. Click on the document to view its contents.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the newest CFTR modulator approved for patients with cystic fibrosis. In randomized controlled trials, ELX/TEZ/IVA showed benefit at 24 weeks in terms of lung function, respiratory symptoms, pulmonary exacerbations and weight. However, long-term clinical benefit of ELX/TEZ/IVA in real-world settings is still being investigated. Methods This retrospective within-groups study examined cystic fibrosis patients receiving care from a single academic health-system specialty pharmacy. Subjects were included who initiated ELX/TEZ/IVA and continued therapy for greater than one year. Retrospective data from the index year prior to ELX/TEZ/IVA initiation and the year following was collected by medical records review. The primary end point was the difference in number of severe cystic fibrosis exacerbations in index year as compared to the year post ELX/TEZ/IVA initiation. Results A total of 76 patients were included in the final analysis. In the post- ELX/TEZ/IVA year, subjects had a significant mean decrease in severe exacerbations (-0.72; 95% CI -0.43, -1.02; p<0.0001). Decreases in severe exacerbations remained significant in subgroups of patients with prior CFTR exposure (-0.56; 95% CI -0.22, -0.91; p =0.002; n=46) and moderate to severe lung disease (-0.98; 95% CI -0.49, -1.45; p = 0.0002; n=41). After one year of ELX/TEZ/IVA therapy, subjects experienced a significant mean absolute increase in ppFEV1 of 6.07% (between-years difference 4.47%; 95% CI 0.58, 8.37; p=0.025) and increase in BMI of 1.46 (between-years difference 1.29; 95% CI 0.65, 1.95; p=0.0002). Conclusion One year of ELX/TEZ/IVA therapy was associated with sustained improvements in clinical status of cystic fibrosis patients.

Adeno-associated viruses (AAV) have attracted significant attention in the field of gene and cell therapy due to highly effective delivery of therapeutic genes into human cells. At present, three AAV-based gene therapy drugs (Glybera, Luxturna and Zolgensma) for the treatment of genetic diseases have been approved by the European Medicines Agency (EMA) and the U.S Food and Drug Administration (FDA) during 2012-2021. In order to make the AAV vector better meet the needs of gene therapy, researchers have carried out a series of optimization and modification on the AAV vectors, which mainly include the modification of the AAV capsid protein, the optimization of the promoter, and Codon optimization for transfer genes. The use of AAV vectors to treat single-gene disorders has become more feasible than ever, but the development of new AAV-based gene therapy drugs still faces many challenges, Such as immunological barriers, large-scale production etc. This article will briefly review the strategies of AAV vectors design and the key challenges in recent years.

Pericardial bands have been rarely reported as a congenital or an acquired defects that can develop after partial pericardiectomy for the treatment of constructive pericarditis in several adult case reports. It can cause an hourglass appearance in ventricular free walls and lead to obstruction in the ventricular outflow or inflow tracts. Here, we present a case of pericardial band, which is considered to be congenital, with an appearance of external compression on the right ventricle in an asymptomatic adolescent girl. The case is presented because there is no similar case in the childhood and adolescent in the literature review.

Clinical image:A 36-year-old woman presented with an asymptomatic eruption of multiple pink umbillicated papules in the left part of trunk and under the umbilical area. There was no history of systemic or skin disease, use of local or systemic immunosuppressive drugs, or suspect sexual contact. She reported similar eruption in her child. Dermatologic examination revealed multiple linear shiny papules in the left part of trunk measuring approximately 4 to 20 mm. (Fig. 1a-b). Dermoscopy revealed a polylobular, pinkish-white, amorphous structure in the centre with a surrounding crown of vessels that did not cross the centre of the lobule (Fig. 2).The diagnosis of MC was evoked. The patient was treated by potassium hydroxide 5% twice resulting in complete healing in 2 weeks.Our case illustrated an atypical presentation of MC in immunocompetent adult. Although recognized nearly 200 years ago, MC still causes a substantial health-care burden and adversely affects quality of life.Clinically it appears like shiny papules with a diameter between 2 and 5 mm. The central umbilication is pathognomonic and its localization concern commonly the face, trunk, and extremities. 1Although easily diagnosed, MC may present as a single lesion or as several small, inflamed lesions of difficult diagnosis. Atypical presentations may occur in immunodepression condition, eczematous or abscessed and sometimes refractory to the usual treatment.2To the best of our knowledge, we report the third case of linear MC. In our patient, the diagnostic was evocated based on the presence of similar case in the family, clinical characteristics of the lesions and confirmed by the typical dermoscopic features.

Castleman disease (CD) is a rare lymphoproliferative disorder, the etiology and pathogenesis of which is not clearly established. It presents more commonly as a localised disease or unicentric CD (UCD), and less often as generalised disease or multricentric CD (MCD). The most common site of UCD is in the thorax; however, UCD is rarely included in the differential diagnosis of an intrathoracic mass due to its rarity. The lesion is highly vascular and often has dense adhesions with adjacent organs, making the surgery a difficult task. We report a case of posterior mediastinal mass located in left paraspinal region which was detected incidentally in a 53-year old female and was subsequently resected successfully via left postero-lateral thoracotomy, and was diagnosed post-operatively on histopathological examination (HPE) as CD, hyaline vascular variant (HVV). We review the relevant clinical, pathological and radiological findings of CD, which may act as clinical pointers for establishing a preoperative diagnosis of CD. Suspecting CD preoperatively would guide the surgeon for appropriate surgical planning and may avoid facing such surprise on the operating table.

Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy. Exposure to certain cytotoxic therapies for ALL is associated with an increased risk of secondary malignancies.We present a rare case of a 6-year-old girl with secondary acute myeloid leukemia (AML) that occurred while the patient was receiving maintenance therapy for ALL approximately 17 months from the time of primary diagnosis. This case indicates that if pediatric patients with ALL receive induction chemotherapy agents used for adults, such as idarubicin and cyclophosphamide, they may have a shorter time to the progression of secondary malignancies.

Stock enhancement and releasing is one of common and effective technique in the wild resource protection and restoration. Nevertheless, missing an effective mark-recapture method makes it hard to evaluate the effect. By the benefit of non-toxic, harmless and long retention time, microchemical marking (i.e. strontium) become an effective means. Here we developed a fin ray strontium marking technique. The larvae, blunt snout bream ( Megalobrama amblycephala Yih, 1955) was marked in the 800 mg L -1 SrCl 2·6H 2O solution for 5 days before a 20-day recovery culture in normal water. The section of dorsal fin rays was extracted to analyze the Sr concentration distribution in the plane by using electron probe microanalysis (EPMA) with accelerating voltage of 15 kV and beam current of 0.36 μA. It showed that the determination condition of 15 kV, 0.36 μA could obtain the obviously visual and accurate distribution map of Sr concentration in the fin rays, with minimum damage. The dynamics of Sr mark in fin ray coped well with that of Sr immersing process of the experimental fish. By the meantime, a 3D mesh image was also used, which was able to reflect more details than the normal 2D mapping result. Non-lethally samplable fin ray can completely replace lethally sampled otolith for accurate evaluation the Sr marking effect by using EPMA with accelerating voltage of 15 kV and beam current of 0.36 μA. The method had immensely practical value in the experimental development of restocking methodologies with the advantages of objectivity, accuracy and visualization.

This paper is devoted to studying the existence of of renormalized solution for an initial boundary problem of a quasilinear parabolic problem with variable exponent and $ L ^{1} $-data of the type \begin{equation*} \left\{ \begin{array}{ll} (b(u))_{t}-\text{div}(\left\vert \nabla u\right\vert ^{p(x)-2}\nabla u)+\lambda \left\vert u\right\vert ^{p(x)-2}u=f(x,t,u) \text{ } & \text{in}\hspace{0.5cm}Q=\Omega \times ]0,T[, \\ u=0 & \text{on}\hspace{0.5cm}\Sigma =\partial \Omega \times ]0,T[, \\ b(u)(t=0)=b(u_{0}) & \text{in}\hspace{0.5cm}\Omega , \\ & \end{array}% \right. \end{equation*}% where $ \lambda>0$ and $ T $ is positive constant. The results of the problem discussed can be applied to a variety of different fields in applied mathematics for example in elastic mechanics, image processing and electro-rheological fluid dynamics, etc.

Calculations of hydration energies are extremely important in physical, chemical and life sciences, and therefore their values need to be accurately determined if these energies were to be used to derive the proper and correct physico-chemical mechanisms. Here, we prove the existence of absolute correlation between ionization and hydration energies for transition-metal cations. The said absolute correlation can be exploited in an unambiguous manner to verify the calculated hydration energies for divalent and trivalent transition metal cations.

In this study, two phages, P69 and KYD2, were isolated from a water sample of the fishing ground. The host of P69 was Nocardia transvalensis, whereas the host of KYD2 was Nocardia carnea. Physiological characteristics and bioinformatics analysis of the isolated phages were performed. The SBR tank was simulated in the laboratory and N. carnea was added for aeration foaming. The feasibility of using phages to control sludge foaming was assessed by measuring turbidity and other water quality indices before and after adding phages and monitoring the changes in the number of hosts and phages in the device by qPCR and other technologies. Using multiple water quality indicators, qPCR, ecological community and other data to prove that P69 has a certain ability to control the sludge foaming event caused by the over-proliferation of N. carnea in the environment. It provides a novel and relatively economical solution for controlling sludge foaming in sewage treatment plants in the future.

Abstract Rationale, aims and objectives During the COVID-19 pandemic, in order to keep schools open and reduce SARS-CoV spreading, it is necessary to identify and isolate early SARS-CoV-2 positive paediatric patients (PP). The aim of this study was to describe the appropriateness of school hot spot (HS) setting for SARS-CoV 2 testing based on open access of PP. Method A cross-sectional study was performed between September 2020 and March 2021 among a sample of 13,283 PP in four different hospital settings. We collected: date of swab execution, type of swab, execution setting of the swab, result of the swab, information about community spread of the virus in the 14 days prior to the swab execution, sex and age. Results In Our sample, females were 45.8%. The swabs executed in all the hospital settings had a lower likelihood of resulting positive compared with the school HS setting. New-borns below 3 months and patients aged between 11 and 13 years old reported a higher probability of a swab tested positive compared to adolescents. Instead, children aged between 3 months and 2 years and aged between 3 years and 5 years were less likely to result positive. Conclusion We found a high prevalence of PP positive to the test for the detection of SARS-CoV-2 at the school hot spot compared with other settings. The open access modality to the nasopharyngeal swab was effective in identifying PP with COVID-19. Public health authorities should implement these testing modality in order to reduce SARS-CoV-2 infections in school settings.

Introduction: While several studies have shown the usefulness and effectiveness of articular and abarticular corticosteroid injections performed by general practitioners, the main limitation that has been identified in expanding the use of these acts in everyday practice lies in a lack of training. Thus, this study aimed to determine the best settings for training courses concerning this subject. Methods: Our study was composed of two parts: the first one consisted in a survey concerning the improvements induced by training courses in the context of continuing medical education on the participants’ skills and degree of confidence, the second part was a review of the published literature about this topic. Results: As expected, every training program analysed through our survey generated improvements in the participants’ confidence in performing articular or abarticular injections. Furthermore, these findings are reflected in an increase in the proportion of such skills that the trainees complete by themselves. These results were reinforced by similar findings raised by the literature review. Moreover, it highlighted that hands-on training courses seemed to be the most efficient and that the use of synthetic models appeared to be a suitable alternative to human bodies or corpses, surrounded by less ethical and logistic concerns. Conclusions: This study supports the expansion of training courses for general practitioners on articular and abarticular injections. It also suggests that they should be based on a hands-on training design, possibly with the use of manikins.

Rationale, aims and objectives: Rasmussen’s encephalitis (RE) is a sporadic and progressive neurological disorder which affects mostly children or young adults. Despite RE is considered a typically childhood disease, it can also affect adulthood. RE patients quality of life (QoL) is bound to worsen because of frequent seizures and due to neurological deficits that cause progressive deterioration but the evaluation of QoL seems to be underestimated in literature. The study aims to explore QoL such as the health conditions of RE young/adult patients that underwent treatment at Fondazione IRCCS Istituto Neurologico Carlo Besta throughout narrative medicine. This would provide an opportunity for healthcare providers to identify the main difficulties and to manage and improve nursing care planning. Method: Audio-recorded, semi-structured interview was performed. During the interview, patients were able to describe their experience throughout the illness narratives. The verbatim transcribed interviews were analyzed according to principles of narrative medicine. Results: We analyzed 13 patients. Overall 11 patients were excluded and two were enrolled in the study. We performed thematic analysis and content analysis of the interviews. It emerged how there are circumstances/factors that influence patients’ lives, such as physical factors, psychological factors, environmental factors, socio-cultural factors and political and economic factors. Conclusion: Narratives of RE patients, allowed us to explore aspects of their lives that are not usually taken into consideration in the daily clinical practice: the need for support, the absence of a social support such as network and the need and the desire to feel and remain active and involved in work and social environment. Adult-onset ER is a very rare disease that significantly interferes with QoL both of patients and caregivers. The attempt to identify all the possible strategies that can facilitate the patient’s adaptation on work and social environment is worth every effort.

This study aimed to investigate the effects of iontophoresis with HA associated to GNPs solution in an epithelial lesion model. Fifty Wistar rats (n=10/group) were randomly assigned to the following groups: epithelial lesion (EL); (EL+MIC); (EL+MIC+HA); (EL+MIC+GNPs); (EL+MIC+HA-GNPs). The animals induced to an epithelial lesion and treatment started 24 hours after injury with microcurrents (300µA) containing gel with HA (0.9%) and/or GNPs (30mg/Kg) in the electrodes (1mL) for seven days. The animals were sacrificed 12 hours after the last treatment application. Results demonstrated a reduction in the levels of pro-inflammatory cytokines (IFNϒ, IL-1β, TNFα, IL6) in the group in which the therapies were combined; an increase in the levels of anti-inflammatory cytokines (IL-4, IL-10) and growth factors (FGF, TGFβ) in EL+MIC+HA and EL+MIC+HA-GNPs groups. As for dichlorofluorescein (DCF) and nitrite levels, decreased in the combined therapy group when compared to the control group, as well as the oxidative damage (carbonyl and sulfhydryl). In antioxidant defense, there was an increase in glutathione (GSH) and a decrease in superoxide dismutase (SOD) in the combination therapy group. Histological analysis showed a reduction in the inflammatory infiltrate in groups treated with MIC and in the combination therapy group. An increase in contraction of the wound area was obtained in all treated groups when compared to the control group, proving that the proposed therapies are effective in the process of epithelial healing. The results of this study demonstrated that the associated therapies favor the tissue repair process more significantly compared to the isolated therapies.

A document by Hailan Wu. Click on the document to view its contents.