The evolutionary histories of alpine species are often directly associated with responses to glaciation. Deep divergence among populations and complex patterns of genetic variation have been inferred as consequences of persistence within glacier boundaries (i.e. on nunataks), while shallow divergence and limited genetic variation is assumed to result from expansion from large refugia at the edge of ice shields (i.e. massifs de refuge). However, for some species, dependence on specific microhabitats could profoundly influence their spatial and demographic response to glaciation, and such a simple dichotomy may obscure the localization of actual refugia. In this study, we use the Nebria ingens complex (Coleoptera: Carabidae), a water-affiliated ground beetle lineage, to test how drainage basins are linked to their observed population structure. By analyzing mitochondrial COI gene sequences and genome-wide single nucleotide polymorphisms, we find that the major drainage systems of the Sierra Nevada Mountains in California best explain the population structure of the N. ingens complex. In addition, we find that an intermediate morphotype within the N. ingens complex is the product of historical hybridization of N. riversi and N. ingens in the San Joaquin basin during glaciation. This study highlights the importance of considering ecological preferences in how species respond to climate fluctuations and provides an explanation for discordances that are often observed in comparative phylogeographic studies.

This paper begs an ontological question about the nature of health and challenges some underpinning assumptions in western healthcare. In its analysis, the structure of health, in its various statuses, is framed as a complex adaptive system made up of dynamically interacting subsystems that include the physiological, psychological, spiritual, social, cultural, and more, realms. Furthermore, openness in complex systems such as health, is necessary for the exchange of energy, information, and resources. Yet, within healthcare much effort is invested in constraining systems’ behaviours, whether they be systems of knowledge, states of health, models of care, and more. This paper draws on the complexity sciences and Levinasian philosophy to explicate the essential role of system openness in individual and population health, and the viability of healthcare systems. It highlights holism to be ‘not whole-ism’, and system openness to be, not just a reality, but a critical feature of viability. Hence requisite openness is advocated as essential to efficacious and ethical healthcare practice and strategy, and vital for good quality health.

The skin is a unique immune organ that constitutes a complex network of physical, chemical, and microbiological barriers against external insults. Keratinocytes are the most abundant cell type in the epidermis. These cells form the physical skin barrier and represent the first line of the host defense system by sensing pathogens via innate immune receptors, initiating antimicrobial responses and producing various cytokines, chemokines and antimicrobial peptides, which are important events in immunity. A damaged epidermal barrier in atopic dermatitis allows the penetration of potential allergens and pathogens to activate keratinocytes. Among the dysregulation of immune responses in atopic dermatitis, activated keratinocytes play a role in several biological processes that contribute to the pathogenesis of atopic dermatitis. In this review, we summarize the current understanding of the innate immune functions of keratinocytes in the pathogenesis of atopic dermatitis, with a special emphasis on skin-derived antimicrobial peptides and atopic dermatitis-related cytokines and chemokines in keratinocytes. An improved understanding of the innate immunity mediated by keratinocytes can provide helpful insight into the pathophysiological processes of atopic dermatitis and support new therapeutic efforts.

Numerous studies have investigated bacterial community structure in grassland ecosystems and bacterial community responses to human management at various spatial and temporal scales; however, research on soil bacterial community assembly dynamics in the course of grassland degradation is limited. Here, the authors investigate the response and assembly processes of bacterial communities adopted in two grasslands with different degrees of degradation. Stochastic processes dominated bacterial community assembly processes in response to grassland degradation, with the bacterial diversity decreasing; however, functional gene diversity increased. Furthermore, different phyla exhibited distinct response strategies: Proteobacteria and Bacteroidetes, as r-strategists, exhibited positive responses, with increases in diversity, abundance, and niche width with an increase in grassland degradation, enhancing biodiversity and productivity; other phyla (mainly Acidobacteria) exhibited greater phylogenetic dispersion and functional redundancy, and less niche overlap, highlighting the role of K-strategy in improving community resource-use efficiency in response to resource loss in degraded grasslands. The transition from K- to r- strategy in bacterial communities following grassland degradation could help communities adapt to environmental disturbance in the form of nutrient loss. The results of the present study enhance our understanding of how nutrient loss in natural grassland ecosystems leads to shifts in bacterial community composition and assembly processes mediated by different response strategies of different phyla.

Introduction: Remote monitoring (RM) has profoundly transformed the standard of care for patients with cardiac electronic implantable devices. It provides easy access to valuable information about arrhythmic events, acute decompensation manifestations and device-related issues without the need of continuous in-person visits. Methods: Starting March 1st, 332 patients were introduced to a RM program during the Italian lockdown in order to limit the risk of in-hospital exposure to Severe Acute Respiratory Syndrome Coronavirus-2. Patients were categorized in two groups based on the modality of RM delivery [home (n=229) vs office (n= 103) delivered]. The study aimed at assessing the efficacy of the new follow-up protocol, reported as the mean RM Activation Time (AT) and the need for technical support for its activation. Patients’ acceptance and anxiety status was also quantified by means of the Home Monitoring Acceptance and Satisfaction Questionnaire and the Generalized Anxiety Disorder 7-item scale. Results: AT time was <48 hours in 93% of patients and 7% of them required further technical support. Despite a higher number of trans-telephonic technical support in home-delivered RM group, AT was comparable between groups (1.33±0.83 days in home-delivered vs 1.28±0.81 days in office-delivered patients; p=0.60). Twenty-eight (2.5%) urgent/emergent in-person examinations were planned. High degree of patient’s satisfaction was reached in both groups while anxiety status was higher in office-delivered group. Conclusions: RM was effective, safe and well tolerated by patients during the Italian lockdown. Our findings confirm the efficacy of this approach to reduce in-hospital visits, guaranteeing patients’ safety and quality of care.

COVID 19 has created one of the world’s worst pandemics and is associated with various life-threatening complications, such as Cytomegalovirus (CMV) co-infection. We present a life-threatening CMV viremia co-infection in a none-immunocompromised COVID 19 patient to highlight our management approach and a comprehensive literature review.

On Time Surgery Start: Is Standardization The Answer?Olufunke Folasade Dada MD, Tanaya Sparkle M.B.B.S.University of Toledo Medical Center, Anesthesiology Department,3000 Arlington Avenue, Toledo, Ohio, USACorresponding Author: Dr. Tanaya Sparkle, M.B.B.S.Address for correspondence:University of Toledo Medical Center, Anesthesiology Department,3000 Arlington Avenue, Toledo, Ohio - 43614E-mail: [email protected]: 419-383-3531

Respiratory syncytial virus (RSV) hospitalizations disappeared in 2020. Now, with southern hemisphere 2021 winter behind us, RSV has returned. Despite it is difficult to weigh the impact of pandemic mitigation measures on common respiratory virus circulation, it appears that acute respiratory infections in children are returning to their usual epidemiology.

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity that occurs in immunocompetent but susceptible patients with asthma and/or cystic fibrosis (CF). In children, ABPA remains mostly undiagnosed, resulting in one of the most common causes of poorly controlled asthma and highly significant morbidity in children with CF. Currently, no specific diagnostic criteria of ABPA for children are available. Corticosteroids and itraconazole are the mainstays of therapy, althoughthere is a lack of randomized clinical trials regarding their usefulness for ABPA in children. Several monoclonal antibodies, such asomalizumab and mepolizumab, may be potential therapies for refractory ABPA in pediatric patients; however, further data are required to clarify the optimal dose and duration of therapy as a routine treatment approach.

The current COVID-19 pandemic has forced the global higher education community to rapidly adapt to partially- or fully-online course offerings. For field- or lab-based courses in ecological curricula, this presents unique challenges. Fortunately, a diverse set of active learning techniques exist, and these techniques translate well to online settings. However, limited guidance and resources exist for developing, implementing, and evaluating active learning assignments that fulfil specific objectives of ecology-focused courses. To address these informational gaps, we (1) identify broad learning objectives across a variety of ecology-focused courses, (2) provide examples, based on our collective online teaching experience, of active learning activities that are relevant to the identified ecological learning goals, and (3) provide guidelines for successful implementation of active learning assignments in online courses. Using The Wildlife Society’s list of online higher education ecology-focused courses as a guide, we obtained syllabi from 45 ecology-focused courses, comprising a total of 321 course-specific learning objectives. We classified all course-specific learning objectives into at least one of five categories: (1) Identification, (2) Application of Concepts/Hypotheses/Theories, (3) Management of Natural Resources, (4) Development of Professional Skills, or (5) Evaluation of Concepts/Practices. We then provided two examples of active learning activities for each of the five categories, along with guidance on their implementation in online settings. We suggest that, when based on sound pedagogy, active learning techniques can enhance the online student’s experience by activating ecological knowledge; moreover, active learning techniques should also be incorporated into in-person offerings once the current COVID-19 crisis has abated.

Rendu Osler's disease is a genetic disease characterized by mucocutaneous and visceral telangiectasias. Rendu Osler's disease was discovered during hypoxemia during an outbreak of SARS-Cov2.This was a 36-year-old woman with exertional dyspnea and severe hypoxemia revealing pulmonary arteriovenous malformations on chest CT scan.

Background and Purpose Neonatal seizures are a clinical emergency. Current anti-seizure medications, however, fail to resolve seizures in ~50% of infants. The P2X7 receptor (P2X7R) is an important driver of inflammation and evidence suggest P2X7R contributing to seizures and epilepsy in adults. To date, however, no genetic proof has been provided to determine the contribution of the P2X7R to neonatal seizures, its effects on inflammatory signalling during neonatal seizures and the therapeutic potential of P2X7R-based treatments on long-lasting brain excitability. Experimental Approach Neonatal seizures were induced via global hypoxia in 7 day-old mouse pups (P7). The role of P2X7Rs during seizures was analyzed in P2X7R overexpressing and knock-out mice. Treatment of wild-type mice post-hypoxia with the P2X7R antagonist JNJ-47965567 was used to determine the effects of the P2X7R on long-lasting brain hyperexcitability. Cell type-specific P2X7R expression was analyzed via P2X7R-EGFP reporter mice. RNA sequencing was used to monitor P2X7R-dependent hippocampal down-stream signalling. Key Results P2X7R deletion reduced seizure severity whereas P2X7R overexpression exacerbated seizure severity and reduced responsiveness to anti-seizure medication. P2X7R deficiency let to an anti-inflammatory phenotype in microglia and treatment of mice with a P2X7R antagonist reduced long-lasting brain hyperexcitability. RNA sequencing identified several pathways altered in P2X7R knock-out mice after neonatal hypoxia including a down-regulation of genes implicated in inflammation and glutamatergic signalling. Conclusion and Implications Treatments based on targeting the P2X7R may represent a novel therapeutic strategy for neonatal seizures with P2X7Rs contributing to the generation of neonatal seizures, driving inflammatory processes and long-term hyperexcitability states.

Dear Editor,Thank you for the opportunity to respond to Dr Sahu’s letter1. We would like to thank Dr Sahu and his team for their valuable points and ourselves recognise and acknowledge the gaps in our early commentary2 which reflected on the early practice at our hospital, with an aim to help fellow obstetricians with the management of COVID-19 at the start of the outbreak. Since then, more literature has been published providing us with greater knowledge regarding this new infection. Guidance from the Royal College of Obstetricians and Gynaecologists (RCOG)3 and International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG)4 amongst others help us streamline management of COVID-19 in pregnant patients.Both guidelines concur that radiographic investigations should be performed in pregnant patients – protecting the fetus by using a radiation shield over the gravid uterus. Chest CT has high sensitivity up to 97% for diagnosis of COVID-19 and may be considered as primary tool for COVID-19 detection.Both guidelines recommend the use of antenatal corticosteroids (ANC) for the usual indications but cautions use in critically ill women with COVID-19 infection as it may worsen their clinical condition. Importantly, urgent deliveries should not be delayed for the administration of ANC.Li et al5 compared clinical characteristics, maternal and neonatal outcomes of pregnant women with and without COVID-19. They found that COVID-19 infection generally causes mild respiratory symptoms in pregnant women, with no deaths or severe respiratory complications requiring critical care. They observed a higher rate of preterm deliveries in confirmed cases (33.3%) compared to control groups (¬5%). This study included two patients who had vaginal deliveries prior to COVID-19 diagnosis. Their newborns did not show any respiratory symptoms.New reports of SARS-COV-2 IgM in infants6 at birth suggest possibility of vertical transmission although COVID-19 infection in newborns is more commonly likely due to neonatal transmission.During breastfeeding, the main risk for infants lies in their close contact with mothers and transmission of infective respiratory droplets. Infected mothers wishing to breastfeed should do so with precautions such as wearing surgical masks, practising good hand hygiene and thorough cleaning of equipment after use. While the decision for separation of mother and baby has serious consequences on bonding and mental health, we continue to advise separation of baby from mothers infected with COVID-19 due to risk of neonatal transmission.Current data suggests that the adverse effects of COVID-19 in pregnancy are less severe than those of SARS-CoV and MERS-CoV. All presently reported patients were diagnosed in the third trimester and the potential effects of COVID-19 infections in the first and second trimesters remain to be investigated.As Dr Sahu mentioned, comparative studies are scarce. Establishment of international registries will improve our understanding of COVID-19 in pregnancy. Meanwhile, we shall continue to support one another and work together in the fight against this pandemic.We would like to thank the all departments from the Division of Obstetrics and Gynaecology, Infectious Diseases Department and all staff in KK Womens’ and Children’s Hospital for leading the COVID-19 fight locally.Monica Shi Qi Chua1, Jill Cheng Sim Lee2, Suzanna Sulaiman1, Hak Koon Tan31Department of Obstetrics and Gynaecology,2Department of Urogynaecology,3Division of Obstetrics and GynaecologyKK Women’s and Children’s Hospital, Singapore

Background and purpose: Increasing evidence has shown that human cholestasis is closely related to hepatic macrophage accumulation and activation. Research has indicated that peroxisome proliferator-activated receptor-g (PPARg) activation exerts liver protection in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARg agonists, such as troglitazone and rosiglitazone, have significant side effects that impede their clinical application in the treatment of CLD. In this study, we found that tectorigenin (TEC) can alleviate intrahepatic cholestasis in mice by activating PPARg. Experimental approach: Wild-type mice received intragastric administration of a-naphthylisothiocyanate (ANIT) or were fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to establish an experimental intrahepatic cholestasis model and TEC intervention simultaneously, followed by determination of intrahepatic cholestasis and the involved mechanisms. In addition, PPARg deficient mice were administered ANIT and/or TEC to determine whether TEC exerts its liver protection effect by activating PPARg. Key results: Our results demonstrated that TEC intervention alleviated intrahepatic cholestasis by inhibiting hepatic macrophage recruitment and activation as well as promoting the expression of bile transporters through activating PPARg. Furthermore, our results show that TEC increased bile salt export pump (Bsep) expression through enhanced PPARg binding to the Bsep promoter. We also demonstrated that PPARg deficiency blocked the hepatocyte protective effect of TEC during cholestasis. Conclusions and implications: In conclusion, TEC reduced hepatic macrophage recruitment and activation, and enhanced bile acid export by activating PPARg. Taken together, our results suggest that TEC is a potential drug for the prevention of CLD.

Background: H1-antihistamines (AHs) are widely used for the treatment of allergic diseases, being one of the most commonly prescribed classes of medications in Pediatrics. Newer-generation AHs are associated with fewer adverse effects compared to first-generation. However, their relative harms in the pediatric population still need scrutiny. Methods: We performed a systematic review of randomized controlled trials (RCTs) which included comparisons of safety parameters between an orally administered newer-generation AH with another AH (first- or second- generation), montelukast or placebo in children aged≤12 years. We searched MEDLINE and CENTRAL, independently extracted data on study population, interventions, adverse events (AEs) and treatment discontinuations, and assessed the methodological quality of the included RCTs using the Cochrane’s risk of bias tool. Results: Fourty-five RCTs published between 1989 and 2017 met eligibility criteria. The majority of RCTs included school-aged children with allergic rhinitis and had a follow-up period of up to a month. Four RCTs reported serious AEs in patients receiving a newer-generation AH, but only two patients experienced a possibly drug-related serious AE. The occurrence of AEs, drug-related AEs and treatment discontinuations due to AEs varied between RCTs. Most AEs reported were of mild intensity. Indirect evidence indicates that cetirizine is more sedating than the other newer-generation AHs. Conclusion: Our findings confirm that newer-generation AHs have a favorable safety and tolerability profile. However, we could not draw firm conclusions regarding the comparative safety profile of the newer-generation AHs due to the paucity of head-to-head RCTs, variation in definitions and reporting of AEs, and short follow-up duration.

Silent RSV in infants with SARS‑CoV‑2 infection: a case seriesAntonietta Giannattasio, MD, PhD1, Marco Maglione, MD, PhD1, Carolina D’Anna, MD1, Stefania Muzzica, MD1,Francesca Angrisani, MD1, Sabrina Acierno, MD1, Alessandro Perrella2, MD, PhD2, Vincenzo Tipo, MD11Santobono-Pausilipon Children’s Hospital, Pediatric Emergency and Short Stay Unit, Naples, Italy2Cardarelli Hospital, Infectious Disease-Health Policy Direction, Naples, Italy

The authors present an revolutionary study aiming to evaluate the effect of alterations in potassium concentrations in transfused packed red blood cells (PRBC) on neonate and infant potassium levels after congenital cardiac surgery. By establishing a strict protocol which restricts the rate of transfusion, the age of the transfused PRBC, and not transfusing a PRBC with a potassium level above 15 mmol/L, they accomplished to suggest a safe and easy way for preventing transfusion associated hyperkalemia.

Staircase testing is a standard method for evaluating the fatigue strength of components. However, staircase testing assumes a normal distribution, while components can display bimodal behavior due to flaws in material, or issues during the manufacturing process. Three unique step loading data sets on different production crankshafts provide evidence that step loading reliably identifies material or manufacturing issues, that lower a component’s fatigue strength. Staircase testing has an 87% or greater chance of overestimating the component’s fatigue strength, which in turn overestimates the component’s expected reliability. For example, a component with a 99.9% reliability, based on staircase testing would only have a 74% reliability based on step loading. If a component contains an undetectable manufacturing defect, staircase testing has a 99% chance of overestimating the component’s fatigue strength. Step loading reliably improves the estimation of a component’s fatigue strength distribution while providing insights into a component’s defect tolerance.