Developmental and epileptic encephalopathies are a group of devastating disorders where an underlying, usually genetic, cause leads to brain developmental impairment which can be further aggravated by superimposed, abundant epileptiform activity. Compared to other epilepsies, DEE show much greater locus heterogeneity and de novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause. Here, in a young girl with early-onset refractory epilepsy, severe disability and progressive cerebral and cerebellar atrophy, trio-based whole exome sequencing analysis uncovered a de novo missense variant in CHRM1. No additional CHRM1 variants were found by WES reanalysis in a cohort of 102 patients with EIEE/DEE nor any matches were produced upon sharing the novel variants in the Matchmaker Exchange platform. Biochemical analyses proved that this variant caused a reduction in protein levels and an impaired cellular trafficking. In addition, the mutated receptor showed defective activation of intracellular signalling pathways. Our data strengthen the concept that brain reduced muscarinic signalling lowers seizure threshold and severely impairs neurodevelopment.

Nowadays the prescription of off-label in psychiatric practice is very common, exclusively in the pregnant women, pediatric and geriatric groups due to the lack of available standards and alternatives, that elevate the safety issue in the vulnerable groups. This observational study performed in a Tertiary Care Teaching Hospital for six months prospectively and retrospectively. It involved 549 patients with a mean age of 37.13 ± 12.62 years (range 9–81 years) and male: female ratio was 1:1.3, showing a higher incidence of the female population as compared to previous Indian studies which reported a higher population of males. We found approximately 1550 drugs prescriptions in which the 44% were antipsychotic and antidepressants. The indication of drugs was found to be 560 in numbers, in which 31.5% of drugs prescription not found any distinguish indication. Amitriptyline 19.51% was the most commonly prescribed drug followed by the Escitalopram 17.0%, Clonazepam 12.1%, Fluoxetine 11.2%, Sertraline 6.5%, etc. Also the various adverse effect association recorded with this prescribing pattern. The off-label prescription was ascertaining with the application of drug package insert (US-FDA) and National formulary of India 2011 and 2016 was used as a reference basis to ascertain the off-label prescribing. Wide variability was noticed in prescribing practices among clinicians, however it is not limited to psychiatric only. The conclusion of the study underlined a prerequisite accountability of healthcare professional on the way to safe medication practices through a lot of scientific evidence for the risks and benefits profiling of off-label medication

Mini-commentary on BJOG-19-1883.R1: A core outcome set for pre-eclampsia research: An international consensus development study

Although increasing evidence demonstrates the association between intestinal dysbiosis and pancreatic diseases, such as chronic pancreatitis and pancreatic cancer, it remains largely unknown whether intestinal dysbiosis is involved in the immunopathogenesis of autoimmune pancreatitis (AIP). Recently, we found that intestinal dysbiosis mediates experimental AIP via the activation of plasmacytoid dendritic cells (pDCs), which can produce IFN-α and IL-33. However, candidate pathobionts for type 1 AIP have not been identified. In this study, we tried to identify pathobionts associated with type 1 AIP. Fecal samples were obtained from type 1 AIP patients before and after prednisolone (PSL) treatment and subjected to 16S ribosomal RNA sequencing to evaluate the composition of intestinal bacteria. Induction of remission by PSL was associated with the complete disappearance of Klebsiella species from feces, in two of the three analyzed patients with type 1 AIP. To assess the pathogenicity of Klebsiella species, mild experimental AIP was induced in MRL/MpJ mice by repeated injections of 10 μg of polyinosinic-polycytidylic acid (poly (I:C)) in combination with oral administration of heat-killed Klebsiella pneumoniae. The AIP pathology score was significantly higher in MRL/MpJ mice that received both oral administration of heat-killed K. pneumoniae and intraperitoneal injections of poly (I:C) than in those administered with either agent alone. Pancreatic accumulation of pDCs capable of producing large amounts of IFN-α and IL-33 was also significantly higher in mice that received both treatments. These data suggest that intestinal colonization by K. pneumoniae may play a pathogenic role in AIP.

Unilateral pulmonary artery discontinuity (UPAD) is a rare malformation which is associated with other intracardiac abnormalities. Cases accompanied by other cardiac abnormalities are often missed on prenatal echocardiography. We reported our case which was prenatally diagnosed as pulmonary atresia with ventricular septal defect (PAVSD) and left pulmonary artery (LPA) discontinuity.

Cardiac malignant tumours are extremely seldom in clinic, especially primary cardiac lymphomas. Due to the complexity of tumor, cardiac malignant tumours are characterized by multiple clinical and imaging manifestations. Consequently, cardiac malignant tumours may be easily misdiagnosed or neglected before histopathologic examinations. In this case, we reported a patient presented with intermittent bradyarrhythmia and was diagnosed as myxoma by imaging examinations, but he was eventually confirmed as primary cardiac lymphoma. This case highlights that diagnosis for cardiac myxoma should be caution even with sufficient imaging data.

Background Coronavirus disease 2019(Covid-19) Personal Protective Equipment (PPE) has been reported to effect communication in healthcare settings. We sought to identify those challenges experimentally. Method Bamford-Kowal-Bench speech discrimination in noise performance of healthcare workers was tested under simulated background noise conditions from a variety of hospital environments. Candidates were assessed for speech intelligibility with and without PPE both at normal speech and raised voice. Results There was a significant difference in speech discrimination scores between normal and PPE wearing subjects in theatre simulated background noise levels (70dB). Conclusion PPE wearing can impact communication and efforts should be made to remind staff about this burden and seek alternative communication paradigms, particularly in theatre environments.

Objective: To reduce mesh use for prolapse repair, practice has shifted towards traditional native tissue. Combining native tissue repair with sufficient apical repair could allow effective treatment. Pectopexy showed in a randomized trial focusing on combining traditional native tissue repair with pectopexy or sacrocolpopexy no association with new risks for patients. The short follow-up of this international multicenter study is presented in this article. Design, Setting, and Population: Eleven clinics and 13 surgeons in four European counties participated in the study. All surgeons committed to using a strict standard for pectopexy, using a pre-tailored mesh (PVDF PRP 3×15 Dynamesh solely for apical repair. Methode: Data were independently collected for 14 months on a secured server; 501 surgeries were documented and evaluated and 264 (52.7%) patients returned for physical examination for follow-up. Main Outcome and Results: The mean follow-up time was 15 months, and the overall success rate for apical repair was 96.9%. A satisfaction score was positively rated in 95.5% of the patients. A positive general recommendation was provided by 95.1% of the patients. Pelvic pressure was reduced in 95.2%, pain was reduced in 98.0%, and urgency was reduced in 86.0%.No major de novo problems occurred in the follow-up. Conclusion: Clinical routine pectopexy and concomitant surgery, mainly using native tissue approaches, resulted in high satisfaction rates and good clinical findings. The procedure can also be recommended for general use by general uro-gynecological practitioners with experience in laparoscopy. Funding: FEG Textieltechnik; Aachen Keywords: prolapse; pelvic floor; laparoscopy; native tissue, pectopexy

Background: Infective endocarditis (IE) remains an expressive health problem with high morbimortali-ty rates. Despite its importance, epidemiological and microbiological data remain scarce, especially in developing countries. Aim: This study aims to describe IE epidemiological, clinical, and microbiological profile in a tertiary university center in South America, and to identify in-hospital mortality rate and predictors. Methods: Observational, retrospective study of 167 patients, who fulfilled modified Duke’s criteria during a six-year enrollment period, from January 2010 to December 2015. Primary outcome was de-fined as in-hospital mortality analyzed according to treatment received (clinical vs. surgical). Multivari-ate analysis identified mortality predictors. Results: Median age was 60years (Q1-Q3 50-71), and 66% were male. Echocardiogram demonstrated vegetations in 90.4%. An infective agent was identified in 76.6%, being Staphylococcus aureus (19%), Enterococcus (12%), Coagulase-negative staphylococci (10%), and Streptococcus viridans (9.6%) the most prevalent. Overall in-hospital mortality was 41.9%, varying from 49.4% to 34.1%, in clinical and surgical patients, respectively (p=0.047). On multivariate analysis, diabetes mellitus (OR 2.5), previous structural heart disease (OR 3.1), and mitral valve infection (OR 2.1) were all-cause death predictors. Surgical treatment was the only variable related to better outcome (OR 0.45; 95%IC 0.2-0.9). Conclusion: This study presents IE profile and all-cause mortality in a large patient’s cohort, compris-ing a 6-years’ time window, a rare initiative in developing countries. Elderly and male patients predom-inated, while Staphylococcus aureus was the main microbiological agent. Patients conservatively treated presented higher mortality than surgically managed ones. Epidemiological studies from developing countries are essential to increase IE understanding.

Mast flowering (or masting) is synchronous highly variable flowering among years in populations of perennial plants. Despite having widespread consequences for seed consumers, endangered fauna and human health, masting is hard to predict because the underlying mechanism regulating masting is poorly understood. Observational studies show links to various weather patterns in different plant species, but the molecular mechanism(s) underpinning the regulation of masting is still not fully explained. We studied floral induction in Celmisia lyallii (Asteraceae), a mast flowering herbaceous alpine perennial, comparing gene expression in flowering and non-flowering plants. Differential expression analysis showed elevated expression of ClSOC1 and ClmiR172 (promoters of flowering) in leaves of plants that subsequently flowered, in contrast to elevated expression of ClAFT and ClTOE1 (repressors of flowering) in leaves of plants that did not flower. The warm summer temperatures that promoted flowering led to differential regulation of age and hormonal pathway genes, including ClmiR172 and ClGA20ox2/8, known to repress the expression of floral repressors and permit flowering. Upregulated expression of epigenetic modifiers of floral promoters also suggests that plants may maintain a novel ‘summer memory’ across the years to induce flowering. These results provide a mechanistic understanding of floral induction in masting plants and evidence of their ability to imprint various environmental cues to synchronise flowering. This should allow better prediction of masting events under climate change, thereby assisting conservation programs for the protection of endangered fauna.

This study investigated the fretting fatigue behavior and mechanism of 35CrMoA steel of different contact stresses under diamond and square loading paths in the form of curved surface contact. The results show that multiple crack sources will initiate on the subsurface of the specimen under the combined effect of contact stress and cyclic stress. Under low contact stress, only one crack source dominates, causing the instantaneous fracture zone to be biased to the other side of the main crack source. Under high contact stress, the crack sources in both fretting zones play a dominant role, making the shape of the instantaneous fracture zone into a nearly circular shape with better symmetry; At the beginning of the fretting fatigue, cracks only propagate in the cross-section where they form. When they propagate to a certain depth, a component that propagates in the longitudinal direction will be generated.

Non-indigenous Daphnia ‘pulex’ have been found in many lakes in New Zealand (NZ) in the past 20 years, suggesting a recent invasion. However, very little is known about the origin of invasive D. ‘pulex’, whether they are D. pulex or D. pulicaria, and whether they are obligately asexual clones or cyclical parthenogens. Furthermore, the source and time of arrival of the invasive genotype(s) are unclear. We address these questions by genomic sequencing Daphnia populations from 13 lakes on the South Island and one on the North Island, NZ. Based on ~24,000 monomorphic species-specific markers, the invasive Daphnia on the South Island were found to be D. pulicaria, while those on the North Island are D. pulex/ pulicaria hybrids. Both the South and North Island Daphnia are phylogenetically clustered with North American D. pulicaria/pulex, thereby suggesting their North American origins. We further found that the South Island Daphnia populations are fixed heterozygotes for nearly all bi-allelic sites in the nuclear genome and contain identical mitochondrial genomes, suggesting the origin and proliferation from a single founder clone, which we experimentally verified to be an obligate asexual. Estimates from molecular data imply a colonization time for the South Island populations of ~ 60 years ago, with a likely invasion route associated with the introduction of salmonids from North America. Key words： Daphnia pulex; Daphnia pulicaria; invasion; obligately asexual; hybridization

The coronavirus disease 2019 (COVID-19) pandemic has become a major public health crisis. The diagnostic and containment efforts for the disease have presented significant challenges for the global healthcare community. In this brief report, we provide perspective on the potential use of salivary specimens for detection and serial monitoring of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), based on current literature. Oral healthcare providers are at an elevated risk of exposure to COVID-19 due to their proximity to nasopharynx of patients, and the practice involving the use of aerosol-generating equipment. Here we summarize the general guidelines for oral healthcare specialists for prevention of nosocomial transmission of COVID-19, and provide specific recommendations for clinical care management.

Background: The relative resistance of children to severe course of novel coronavirus infection remains unclear. We hypothesized that there might be a link between this phenomenon and observation from our previous studies, concerning an inhibitory or cytotoxic effect of children exhaled breath condensate (EBC) on endothelial cell cultures. Since we could not find any data on similar effect caused by EBC from adults, the aim of our study was to evaluate and compare the biological activity of EBC from adults and children in an experimental in vitro model. Furthermore, in order to identify a putative agent responsible for these properties of children EBC, we attempted to analyse the composition of selected EBC samples. Methods: The influence of EBC samples on metabolic activity of endothelial cell line C-166 was assessed using colorimetric tetrazolium salt reduction assay (MTT assay). Selected EBC samples were fractionated using size exclusion chromatography and subjected to mass spectrometry analysis. Results: Exhaled breath condensates from healthy children, but not from adults, revealed a cytotoxic effect on in vitro cell cultures. This effect was most significant in condensate fraction, which contained a prominent 4.8 kDa peak in the mass spectra. Conclusion: Breath condensates from healthy children contain the factor, which reveals inhibitory/cytotoxic effect on endothelial cell cultures. Although physiological role of this agent remains unclear, its identification may potentially be useful in ongoing research on SARS-CoV-2/COVID-19.

A document by Cristina Quecchia. Click on the document to view its contents.

Background: Serum or cord blood soluble Fas ligand (FasL) has been related to asthma, allergic rhinitis, and atopic dermatitis in cross-sectional and short-term follow-up studies. However, the association of cord blood soluble FasL with long-term allergic outcomes has seldom been investigated. Thus, this study investigated the relationship between cord blood soluble FasL and long-term allergic outcomes in a follow-up birth cohort. Methods: The Prediction of Allergies in Taiwanese Children birth cohort study recruited healthy newborns upon delivery. At birth, blood was collected from the umbilical cords of these children, and the cord blood soluble Fas ligand levels were measured. At the age of seven years, the allergic outcome of each child was diagnosed by pediatric allergists and pulmonologists. Tests were conducted to measure the specific immunoglobulin E, fractional exhaled nitric oxide (FeNO), and pulmonary function levels of each child. Results:Cord blood soluble FasL levels were higher in 7-year-old children with allergic rhinitis (Odds ratio [OR] = 2.41, p = .012) and expiratory airway obstruction (the highest forced expiratory volume in 1 second/ forced vital capacity < 90%, OR = 2.11, p = .022). The FeNO and Dermatophagoides pteronyssinus-specific immunoglobulin E levels of 7-year-old children were positively correlated with cord blood soluble FasL levels (p = .006 and .02, respectively). Conclusion: In this birth cohort, the cord blood soluble FasL levels were associated with allergic rhinitis, obstructive-type lung function, FeNO, and house dust mite sensitization in 7-year-old children. The cord blood soluble FasL level might be used as a predictor for allergic diseases in children who are 7 years old.

In late December 2019, a novel coronavirus disease (COVID-19) emerged and rapidly spread in China. Some of the pets were abandoned due to the poor economic situation, being quarantined in exotic areas or the death of their owners; these were usually adopted by an animal sanctuary. However, an extreme phenomenon of abandoning pets during the outbreak of the COVID-19. We analyzed the reasons and serious consequences of this improper behavior and gave our suggestions. We appeal for the careful protection of the pets. These innocent animals should be taken care of.

In this study, we obtain the solutions of some interesting problems by Sumudu transform. We investigate the economic models based on market equilibrium with constant proportional Caputo derivative. We prove the efficiency of the Sumudu transform by some applications.

Mycobacterium bovis is the main causative agent of bovine tuberculosis (BTB) in cattle and it is also responsible for a proportion of human TB cases. The annual cost of BTB worldwide is estimated at US$3 billion. Zebu cattle are considered to be more resistant to some infectious diseases than Holstein-Friesian (HF) cattle, including BTB. However, epidemiological studies do not necessarily take into account usage differences of the two types of cattle. It could be argued that HF cattle suffer greater metabolic stress due to their mainly dairy use, whereas Zebu cattle are mainly used for beef production. However, in experiments comparing Zebu and European cattle, the number of animals has been too small to draw statistically robust conclusions on the differences in the level of resistance between these breeds of cattle. Here, we used a recently developed vaccination-and-BCG challenge model to compare the ability of naïve and vaccinated Zebu and HF cattle to control/kill mycobacteria. Young male cattle of both breeds with similar ages were housed in the same accommodation for the duration of the experiment; after correcting for multiple comparison, we found that there was a trend for vaccinated HF cattle to have lower cfu numbers than non-vaccinated HF cattle (ρ = 0.057). No such trend was observed between vaccinated and non-vaccinated Zebu cattle (ρ = 0.560); similarly, no difference was observed between naïve HF and Zebu (ρ = 0.862) cattle. In contrast, evaluation of antigen-specific IFNγ secretion indicated that Zebu and HF cattle differed in their response to mycobacteria. Thus, under the conditions used in this work, the data indicate that there are no differences between Zebu and HF cattle. Further experiments, using larger numbers of animals may be required to determine whether Zebu and HF cattle differ in their susceptibility to infection with M. bovis.

Nodular fasciitis (NF) is a rare benign, rapidly growing, self- limiting condition rarely affecting head and neck district. Following a short Literature review, the authors report a rare case of maxillary Nodular Fasciitis in an elderly, pointing out that in selected cases direct surgery could avoid misdiagnosis, delays and overtreatment.

Emerging or re-emerging zoonotic diseases are the main issue in global health and affect the well-being of nations. COVVID-19 originated from a wet market where wild animals are sold and rapidly outbreak across worldwide. Analysis outlined bats are key host, so COVID-19 is a zoonotic disease and crossed from animals into humans. Wildlife migration among world protected areas and disease transmission has caused an increased risk of emerging or re-emerging of zoonotic diseases such as COVID-19. Transboundary animal diseases (TDAs) make the health approach more crucial as these diseases cause many problems. Hence, the prevention and control of zoonotic diseases are critical. In this paper, we addressed world protect areas management, wildlife migration, and preventive and control measures aspects on zoonotic diseases such as COVID-19 that have already been globally recommended. South American and African countries due to higher coverage of protected areas in human development regions; and Asian and South American countries due to lack of protected area management assessment are more prone to transmit COVID-19 by wildlife migrations. World Health Organization should pay attention to the determined countries for more practical health care plans in protected area communities and settlement especially in facing with wildlife species.

Background: While bioavailability of oral voriconazole is known to be >90%, several reports have observed much lower oral bioavailability. The aim of the present study was to assess the oral bioavailability of voriconazole in clinical use by evaluating the change in serum voriconazole concentration in patients who received intravenous-to-oral switch therapy with the same dose of voriconazole. Methods: A single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous-to-oral switch therapy with the same dose of voriconazole between January 1, 2011 and December 31, 2018 were enrolled in the present study. We evaluated changes in serum voriconazole concentration before and after switch therapy. Results: Voriconazole trough concentrations significantly decreased following oral compared to intravenous treatment (2.5 ± 1.5 µg/mL vs 3.3 ± 2.0 µg/mL, P = 0.021). The median change rate of serum concentration by switching the route of administration was 82.7%, with wide inter-individual variability (range 27.2–333.3%). Further, young age (OR 1.04, 95% CI 0.99–1.08, P = 0.090) and low blood urea nitrogen (OR 1.11, 95% CI 0.99–1.24, P = 0.070) were found to be close to significant factors associated with decreased serum concentration. Conclusions: Switching from intravenous to oral treatment resulted in a significant decline in voriconazole trough concentrations with wide inter-individual variability. Therefore, measurement of serum concentration for dose adjustment should be performed after switching to the oral form.

The health crisis due to coronavirus disease 2019 (COVID-19) shocks the world with more than million infections and casualties. COVID-19 could present from mild illness to multi-organ involvement, especially acute respiratory distress syndrome. Cardiac injury and arrhythmias including atrial fibrillation (AF) are not uncommon in COVID-19. COVID-19 is highly contagious, and the therapy against the virus remains premature and largely unknown. These make the management of AF patients during pandemic particularly challenging. We here describe possible pathophysiology link between COVID-19 and AF, and therapeutic considerations for AF patients during this pandemic.

Objective: Optimal antithrombotic therapy following left atrial appendage closure (LAAC) with the Watchman occluder (Boston Scientific) remains uncertain. This study aimed to investigate the efficacy and safety of a 3-month dual antiplatelet therapy (DAPT) after LAAC. Methods: This was a post hoc analysis of a prospective study of patients who underwent successful LAAC with Watchman devices at the REGIOMED Hospitals of Coburg and Lichtenfels (Germany). Those treated from 11/2016 to 05/2018 received DAPT for 3 months (DAPT group); those from 02/2012 to 04/2017 received 45-day anticoagulant+aspirin followed by 4.5-month DAPT (ACT group). The primary efficacy outcome and safety outcome were analyzed. The net clinical benefit and bleeding events 1 year after treatment, and their independent risk factors were also explored. Results: There were 220 and 304 patients in the DAPT and ACT groups. The primary efficacy outcome were 9.5% vs. 6.3% [hazard ratio (HR), 1.58; 95% confidence interval (CI), 0.84-2.97; P=0.14]; the primary safety outcome were 4.5% vs. 5.9% (HR, 0.80; 95% CI, 0.38-1.69; P=0.57); the net clinical benefit were 13.6% vs. 11.8% (HR, 1.23; 95% CI, 0.75-2.02; P=0.39) over 1 year in DAPT and ACT groups, respectively. Age ≥75 years (HR, 2.08; 95%CI, 1.13-3.84; P=0.02) was identified as an independent predictor for the net clinical benefit. ACT (HR, 1.97; 95%CI, 1.12-3.50; P=0.02) was independently associated with bleeding events after procedure. Conclusions: In patients who underwent LAAC using the Watchman occluder, 3-month DAPT is associated with fewer bleeding events compared with ACT regimen.