Pregnant, or potentially pregnant women have historically been excluded from clinical trials of new medications. However, it is increasingly recognised that it is imperative to generate evidence from the population in whom the drugs are likely to be used in order to inform safe, evidence-based shared clinical decision making. Reluctance by researchers and regulators to perform such studies often relates to concerns about risk, particularly to the fetus. However, this must be offset against the risk of untreated disease or using a drug in pregnancy where safety, efficacy and dosing information are not known. This review summarises the historical perspective, the ethical and legal frameworks which inform the conduct of such research, then highlights examples of innovative practice which have enabled high quality, ethical research to proceed to inform the evidence-based use of medication in pregnancy.

1. The COVID-19 pandemic has highlighted the importance of efficient sampling strategies and statistical methods for monitoring infection prevalence, both in humans and reservoir hosts. Pooled testing can be an efficient tool for learning pathogen prevalence in a population. Typically pooled testing requires a second phase follow up procedure to identify infected individuals, but when the goal is solely to learn prevalence in a population, such as a reservoir host, there are more efficient methods for allocating the second phase samples. 2. To estimate pathogen prevalence in a population, this manuscript presents an approach for data integration with two-phased testing of pooled samples that allows more efficient estimation of prevalence with less samples than traditional methods. The first phase uses pooled samples to estimate the population prevalence and inform efficient strategies for the second phase. To combine information from both phases, we introduce a Bayesian data integration procedure that combines pooled samples with individual samples for joint inferences about the population prevalence. 3. Data integration procedures result in more efficient estimation of prevalence than traditional procedures that only use individual samples or a single phase of pooled sampling. 4. The manuscript presents guidance on implementing the first phase and second phase sampling plans using data integration. Such methods can be used to assess the risk of pathogen spillover from reservoir hosts to humans, or to track pathogens such as SARS-CoV-2 in populations.

How much troponin leak is too much before CABG?Clancy W. Mullan, MD and Arnar Geirsson, MDDivision of Cardiac SurgeryDepartment of SurgeryYale School of Medicine330 Cedar Street, BB204New Haven, CT 06511Acute myocardial infarction (MI) is a well-recognized risk factor for worse outcomes after coronary artery bypass grafting (CABG), and the proportion of patients undergoing CABG after MI appears to be increasing over time(1). With nearly a third of patients undergoing CABG having presented with MI, the question has been asked repeatedly of whether the degree of troponin leak correlates to post-operative outcomes, with conflicting results through the years(2, 3). In this edition of theJournal of Cardiac Surgery , Dr. Hess and colleagues present a compelling argument against the use of the degree of troponinemia in predicting major outcomes of surgical revascularization after non-ST elevation MI (NSTEMI). Principally, the authors demonstrate that neither troponin I leak above median nor increasing troponinemia independently predict mortality or major adverse cardiac or cerebrovascular events (MACCE). Secondarily, they find that multivariable adjustment obviates the association of peak troponin level with prolonged ventilation, prolonged intensive care unit stay, and prolonged hospital stay.With these data, the reader must ask: does there exist a residual argument for delaying surgical revascularization? A key observation in the present study is that nearly the entire cohort underwent urgent, rather than emergent or elective, revascularization. In the context of this relatively large cohort, this suggests a degree of stability to the “average” NSTEMI patient. Furthermore, given that the time from peak troponin to revascularization did not differ between the low- and high-risk cohorts and that time from peak troponin to surgery was not associated with post-operative mortality or MACCE, the data reported argue that patients can afford to wait for optimization prior to proceeding to surgery, certainly a controversial topic with a notable lack of society-level guidance that the authors appropriately address in their discussion. While the 2014 American Heart Association/American College of Cardiology guidelines for management of patients with NSTEMI provides some guidance on timing of surgical revascularization in relation to P2Y12 antiplatelet agent administration, no recommendations are provided on when to proceed with CABG otherwise. The authors findings seemingly fit directly on the middle of the debate’s metaphorical fence; however, interpretation of this is challenging given a lack of information such as time from presentation to peak troponin level, from presentation to coronary catheterization, or from catheterization to surgery.What should, then, dictate when to take a patient with NSTEMI to the operating room? There is no straightforward answer to this question, but, generally, these patients should proceed to surgery soon enough to prevent progression from a non-transmural to a transmural injury but late enough to avoids the bleeding risk of potent P2Y12 inhibitor loads (4, 5). While emergent revascularization is likely not warranted in the absence of arrythmias or evidence of continued ischemia, urgent revascularization within 24 hours should be encouraged barring prohibitive bleeding risk from an antiplatelet agent load. Interestingly, the authors did not find intra-aortic balloon pump (IABP) placement to be associated with post-operative mortality hazard, suggesting that IABPs were not especially targeted to unstable patients in their population. However, pre-operative inotrope requirement was associated with increased post-operative mortality, supporting an argument that NSTEMI patients, like their STEMI counterparts, with cardiogenic shock represent a particularly vulnerable population that should be revascularized with greater urgency. Where coronary anatomy demands surgical revascularization and cardiac surgical resources are not available, medical optimization followed by prompt referral to a surgical center is key.The tenacity with which the authors undertook the principal analyses of the manuscript should be commended. Hess et al. present a thorough and convincing argument that a patient’s risk from NSTEMI is likely fixed and dictated by the overall clinical picture rather than dependent on the degree of troponinemia and that the peak troponin level should not dictate clinical decisions.References1. Alkhouli M, Alqahtani F, Kalra A et al. Trends in characteristics and outcomes of hospital inpatients undergoing coronary revascularization in the united states, 2003-2016. JAMA Network Open 2020;3(2):e1921326-e1921326.2. Beller JP, Hawkins RB, Mehaffey JH et al. Does preoperative troponin level impact outcomes after coronary artery bypass grafting? The Annals of thoracic surgery 2018;106(1):46-51.3. Thielmann M, Massoudy P, Neuhäuser M et al. Prognostic value of preoperative cardiac troponin i in patients undergoing emergency coronary artery bypass surgery with non-st-elevation or st-elevation acute coronary syndromes. Circulation 2006;114(1 Suppl):I448-453.4. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 aha/acc guideline for the management of patients with non-st-elevation acute coronary syndromes: A report of the american college of cardiology/american heart association task force on practice guidelines. Circulation 2014;130(25):e344-426.5. Hillis LD, Smith PK, Anderson JL et al. 2011 accf/aha guideline for coronary artery bypass graft surgery. Journal of the American College of Cardiology 2011;58(24):e123-e210.

Many organisms can reproduce both asexually and sexually. For cyclical parthenogens, periods of asexual reproduction are punctuated by bouts of sexual reproduction, and the shift from asexual to sexual reproduction has large impacts on fitness and population dynamics. We studied populations of Daphnia dentifera to determine the amount of investment in sexual reproduction as well as the factors associated with variation in investment in sex. To do so, we tracked host density, infections by nine different parasites, and sexual reproduction in 15 lake populations of D. dentifera for three years. Sexual reproduction was seasonal, with male and ephippial female production beginning as early as late September and generally increasing through November. However, there was substantial variation in the prevalence of sexual individuals across populations, with some populations remaining entirely asexual throughout the study period and others shifting almost entirely to sexual females and males. We found strong relationships between density, prevalence of infection, parasite species richness, and sexual reproduction in these populations. However, strong collinearity between density, parasitism, and sexual reproduction means that further work will be required to disentangle the causal mechanisms underlying these relationships.

Plant-plant interactions can vary depending on the severity of the environment. Positive interactions, such as facilitation, are important in early life stages while negative interactions, such as competition, predominate in later stages. Through succession, plant-plant interactions often change from facilitative to competitive. In northern temperate rainforests, gap dynamics result in tree falls that facilitate tree regeneration (nurse logs) as well as bryophyte succession. While the importance of nurse logs for tree seedlings is known, how the interactions of bryophyte communities and tree seedlings vary through succession of the log remains unclear. We examined the relationships of tree seedlings, bryophyte community composition, bryophyte depth, and percent canopy cover in 166 plots on nurse logs and the forest floor in the Hoh rainforest in Washington, USA. Tree seedling density was highest on young logs with early-colonizing bryophyte species (e.g., Rhizomnium glabrescens), and lowest on decayed logs with Hylocomium splendens, a long-lived moss that reaches depths >20 cm. As a result, bryophyte depth increased with nurse log decay and was negatively associated with tree seedling density. Tree seedling density was 4.6x higher on nurse logs than on the forest floor, which was likely due to competitive exclusion by H. splendens. Nurse logs had 17 species of bryophytes while the forest floor had six, indicating that nurse logs contribute to maintaining bryophyte diversity. Nurse logs are essential for forest dynamics as they enable both tree seedlings and smaller bryophyte species to avoid competition with the dominant forest floor bryophyte, H. splendens. Given that H. splendens has a global distribution and is often dominant in forested systems across the northern hemisphere, it is likely a widespread driver of plant community structure. Our findings indicate that plant-plant interactions shift with succession on nurse logs from facilitative to competitive and, thus, influence forest community structure and dynamics.

Background: A series of repeated questionnaire surveys among 8- and 9-year-old schoolchildren in the city of Patras, Greece, demonstrated a continuous rise in the prevalence of wheeze/asthma from 1978 to 2003, with a plateau between 2003 and 2008. We further investigated wheeze/asthma trends within the same environment during the last decade. Methods: Two further identical cross-sectional surveys were conducted in 2013 (N=2554) and 2018 (N=2648). Physician-diagnosed wheeze and asthma were analysed separately and in relation to their occurrence (recent-onset: solely within the last two years; non-current: prior to the last two years; persistent: both before and within the last two years). In addition, in 2018, spirometry was performed in participants reporting relevant symptoms and in a random sample of healthy controls. Results: The prevalence of current wheeze/asthma declined from 6.9% in 2008 to 5.2% in 2013 and 4.3% in 2018. The persistent and non-current wheeze/asthma groups (both including children with symptoms at preschool age) followed this overall trend, while the prevalence of recent-onset wheeze/asthma remained unchanged. Persistent and non-current wheezers were also more frequently diagnosed with asthma, in contrast to those with recent-onset wheeze. Children with recent-onset wheeze/asthma and a considerable fraction of those with persistent symptoms had lower lung function. Conclusions: The prevalence of childhood wheeze/asthma has declined significantly during the last decade in Greece. Our analysis suggests that the reversing trend is most likely attributed to changing asthma perceptions among physicians and/or parents, especially in the case of preschool children with troublesome respiratory symptoms.

The promotion of responsible and sustainable trade in biological resources is widely proposed as one solution to mitigate currently high levels of global biodiversity loss. Various molecular identification methods have been proposed as appropriate tools for monitoring global supply chains of commercialized animals and plants. We demonstrate the efficacy of target capture genomic barcoding in identifying and establishing the geographic origin of samples traded as Anacyclus pyrethrum, a medicinal plant assessed as globally vulnerable in the IUCN Red List. Samples collected from national and international supply chains were identified through target capture sequencing of 443 low-copy nuclear makers and compared to results derived from genome skimming of plastome, standard plastid barcoding regions and ITS. Both target capture and genome skimming provided approximately 3.4 million reads per sample, but target capture largely outperformed standard plant DNA barcodes and entire plastid genome sequences. Despite the difficulty of distinguishing among closely related species and infraspecific taxa of Anacyclus using conventional taxonomic methods, we succeeded in identifying 89 of 110 analysed samples to subspecies level without ambiguity through target capture. Furthermore, we were able to discern the geographical origin of Anacyclus samples collected in Moroccan, Indian and Sri Lankan markets, differentiating between plant materials originally harvested from diverse populations in Algeria and Morocco. With a recent drop in the cost of analysing samples, target capture offers the potential to routinely identify commercialized plant species and determine their geographic origin. It promises to play an important role in monitoring and regulation of plant species in trade, supporting biodiversity conservation efforts, and in ensuring that plant products are unadulterated, contributing to consumer protection.

Background: It is unclear if asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. Methods: All patients testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. Results: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4·15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1·12 [95% CI 0·86, 1·45], p=0·40). Among SARS-CoV-2 positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared to non-allergic asthma (OR 0·52 (0·28, 0·91), p=0·026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared to patients with mild or asymptomatic disease, independent of asthma status (p=0.0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms. Conclusions: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.

A document by Emma Magavern. Click on the document to view its contents.

We present the first documented case of a 69 year-old female with history of sickle cell anemia with hereditary persistence of fetal hemoglobin that presented due to joint pains and COVID-19 infection. The red blood cell exchange transfusion may play an important factor in preventing intubations and longer hospital stays.

The COVID-19 pandemic has raised concern of viral transmission during otolaryngological procedures by means of droplets/saliva. The use of PPE and isolation settings are mandatory during surgery. This paper describes the development of the STAPID setting to reduce salivary spread during a sialendoscopy-assisted transfacial removal of a parotid stone.

1. Environmental soundscapes are increasingly being used as descriptors of ecosystem health and vocal animal biodiversity. Soundscape data can quickly become very expensive and difficult to manage, so data compression or temporal down-sampling are sometimes employed to reduce data storage and transmission costs. These parameters vary widely between experiments, with the consequences of this variation remaining mostly unknown. 2. We analyse field recordings from North-Eastern Borneo across a gradient of historical land-use. We quantify the impact of experimental parameters (mp3 compression, recording length and temporal subsetting) on soundscape descriptors (Analytical Indices and a convolutional neural net derived AudioSet Fingerprint). Both descriptor types were tested for their robustness to parameter alteration and their usability in a landscape classification task. 3. We find that compression and frame size both drive considerable variation in calculated index values. However, we find that the effects of this varaiation and temporal subsetting on the performance of classification models is minor: performance is much more strongly determined by acoustic index choice, with Audioset fingerprinting offering substantial (12-16%) increases in all of classifier accuracy, precision and recall. 4. We advise using the AudioSet Fingerprint in soundscape analysis, demonstrating its superior and consistent performance even on small pools of data. If data storage is a bottleneck to a study, we recommend Variable Bit Rate encoded compression (quality=0, 23% file size) to reduce file size without affecting most Analytical Index values. The AudioSet Fingerprint can be confidently compressed further to a Constant Bit Rate encoding of 64kb/s (8% file size) without any detectable effect. These recommendations balance the efficient use of restricted data storage against the comparability of results between different studies.

Background: Medulloblastoma is the most common malignant brain tumor in children. We aim to determine the survival in children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 to 2013 in Peru, a low-middle income country at the time of this analysis. We also describe the barriers and factors influencing outcomes. Methods: Between 1997-2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Two groups of treatment were identified 1997 – 2008 and 2009 – 2013. Event-free (EFS) and overall survival (OS) were obtained using Kaplan-Meier method and prognostic factors by univariate analysis (log-rank test). A survey was created to identify factors that may have influenced outcome. Results: Eighty-nine patients were included; median age was 8.1 years (range: 2.9-13.9 years). Surgical resection was complete in 39 patients. The five-year OS was 63% (95% CI: 53 – 74%) while EFS was 59% (95% CI: 49 – 71%). The variables adversely affecting survival were: anaplastic histology [compared to desmoplastic; OS: HR=3.5, p=0.03; EFS: HR=3.4, p=0.03], metastasis [OS: HR=3.4, p=0.01; EFS: HR=4.4, p=0.003], and treatment post-2008 [OS: HR=2.5, p=0.01; EFS: HR=2.5; p=0.01]. Conclusions: Outcomes for Medulloblastoma at INEN are low compared with high- income countries (HIC). Univariate analysis demonstrated that histological sub-type, metastasis at diagnosis, and treatment post-2008 all negatively affected outcomes in our study. The importance of multidisciplinary teamwork in the care of children with pediatric brain tumors as well as partnerships with loco-regional groups and colleagues in HIC is vastly beneficial.

This study compares the U.S. National Water Model (NWM) reanalysis snow outputs to observed snow water equivalent (SWE) and snow-covered area fraction (SCAF) at SNOTEL sites across the Western U.S. SWE was obtained from SNOTEL sites, while SCAF was obtained from MODIS observations at a nominal 500 m grid scale. Retrospective NWM results were at a 1000 m grid scale. We compared results for SNOTEL sites to gridded NWM and MODIS outputs for the grid cells encompassing each SNOTEL site. Differences between modeled and observed SWE were attributed to both model errors, as well as errors in inputs, notably precipitation and temperature. The NWM generally under-predicted SWE, partly due to precipitation input differences. There was also a slight general bias for model input temperature to be cooler than observed, counter to the direction expected to lead to under-modeling of SWE. There was also under-modeling of SWE for a subset of sites where precipitation inputs were good. Furthermore, the NWM generally tends to melt snow early. There was considerable variability between modeled and observed SCAF as well as the binary comparison of snow cover presence that hampered useful interpretation of SCAF comparisons. This is in part due to the shortcomings associated with both model SCAF parameterization and MODIS observations, particularly in vegetated regions. However, when SCAF was aggregated across all sites and years, modeled SCAF tended to be more than observed using MODIS. These differences are regional with generally better SWE and SCAF results in the Central Basin and Range and differences tending to become larger the further away regions are from this region. These findings identify areas where predictions from the NWM involving snow may be better or worse, and suggest opportunities for research directed towards model improvements.

Background. Whether small airway dysfunction (SAD), which is prevalent in asthma, helps to characterize wheezing phenotypes is undetermined. The objective was to assess whether SAD parameters obtained from impedance measurement and asthma probability are linked. Methods. One hundred and thirty-nine preschool children (mean age 4.7 years, 68% boys) suffering from recurrent wheeze underwent impulse oscillometry that allowed calculating peripheral resistance and compliance of the respiratory system (markers of SAD) using the extended RIC model (central and peripheral Resistance, Inertance and peripheral Compliance of the respiratory system). Children were classified using the probability-based approach of GINA guidelines (few, some, most having asthma). A principal component analysis (PCA) that determined the dimensions of wheezing disease evaluated the links between SAD and asthma probability. Results. Forty-seven children belonged to the few, 28 to the some and 64 to the most having asthma groups. Whereas their anthropometrics and measured parameters were similar, the most having asthma group exhibited the lowest mean value of airway inertance after bronchodilator probably due to airway inhomogeneities. PCA characterized nine independent dimensions including a peripheral resistance (constituted by baseline peripheral resistance, AX, R5-20Hz, X5Hz), a central resistance (baseline central resistance, R20Hz) and an airway size dimension (post-bronchodilator inertance and central resistance). PCA showed that the SAD markers were independent from clinical dimensions (control and asthma probability were two other dimensions) and did not help to define wheezing phenotypes. Conclusions. Lung function parameters obtained from impulse oscillometry and asthma probability were belonging to independent dimensions of the wheezing disease.

Geographic parthenogenesis (GP), a phenomenon where parthenogens and their close sexual relatives inhabit distinct geographic areas, has been considered an interesting topic to understand the adaptation to marginal habitats and the role of hybridization in evolution. Reports of GP from land and freshwater are numerous, however, this occurrence has been rarely reported on from the sea. Brown algae are mostly marine and are thought to include numerous obligate parthenogens; still, little is known about the distribution, origin, and evolution of parthenogens in this group. Here we report a novel pattern of GP in the isogamous brown alga Scytosiphon lomentaria. Sex ratio investigation demonstrated that, in Japan, sexual populations grew in the coast along warm ocean currents, whereas female-dominant parthenogenetic populations grew mainly in the coast along a cold ocean current. In the two localities where sexual and parthenogenetic populations were parapatric, parthenogens grew in more wave-exposed areas than sexuals. Population genetic and phylogenetic analyses, including those based on genome-wide single nucleotide polymorphism data, suggested that: (1) parthenogens evolved at least twice in S. lomentaria, (2) parthenogens did not originate from inter-species hybridization, (3) new parthenogenetic lineages have arisen from hybridizations between parthenogens and sexuals, and (4) parthenogens have a wider distribution than sexuals. We also showed that the production of sex pheromones, which attract male gametes, has been independently suppressed/lost in two parthenogenetic lineages. This parallel suppression/loss of the sexual trait may represent the direct origin of parthenogens, or the regressive evolution of a useless trait under asexuality.

Background: Transvenous implantable cardiac defibrillators (TV ICD) provide life-saving therapy for millions of patients worldwide. However, they are susceptible to several potential short- and long- term complications including cardiac perforation and pneumothorax, lead dislodgement, venous obstruction, and infection. The extravascular ICD (EV ICD) system’s novel design and substernal implant approach avoids the risks associated with TV ICDs while still providing pacing features and similar generator size to TV ICDs. Study Design: The EV ICD pivotal study is a prospective, multi-center, single-arm, non-randomized, pre-market clinical study designed to examine the safety and acute efficacy of the system. This study will enroll up to 400 patients with a Class I or IIa indication for implantation of an ICD. Implanted subjects will be followed up to approximately 3.5 years, depending on when the patient is enrolled. Objective: The clinical trial is designed to demonstrate safety and effectiveness of the EV ICD system in human use. The safety endpoint is freedom from major complications, while the efficacy endpoint is defibrillation success. Both endpoints will be assessed against prespecified criteria. Additionally, this study will evaluate antitachycardia pacing (ATP) performance, electrical performance, extracardiac pacing sensation, asystole pacing, appropriate and inappropriate shocks, as well as a summary of adverse events. Conclusion: The EV ICD pivotal study is designed to provide clear evidence addressing the safety and efficacy performance of the EV ICD System.

Enzymatic detachment of cells might damage important features of cells and could affect subsequent function of cells in various applications. Therefore, non-enzymatic cell detachment using thermosensitive polymer matrix is necessary for maintaining cell quality after harvesting. In this study, we synthesized thermosensitive PNIPAm-co-AAc-b-PS and PNIPAm-co-AAm-b-PS copolymers and LCST was tuned near to body temperature. Then, polymer solutions (5% w/v, 10% w/v, and 20% w/v) were spin coated to prepare films for cell adhesion and thermal-induced cell detachment. The apha-step analysis and SEM image of the films suggested that the thickness of the films depends on the molecular weight and concentration which ranged from 206 nm to 1330 nm for PNIPAm-co-AAc-b-PS and 97.5 nm to 497 nm for PNIPAm-co-AAm-b-PS. The contact angles of the films verified that the polymer surface was moderately hydrophilic at 37°C. From cell attachment and detachment studies, RAW264.7 cells, were convincingly proliferated on the films to a confluent of >80 % within 48 days. However, relatively more cells were grown on PNIPAm-co-AAm-b-PS (5%w/v) films and thermal-induced cell detachment was more abundant in this formulation. As a result, commercial cytodex 3 microcarrier was coated with PNIPAm-co-AAm-b-PS (5%w/v) and interestingly enhanced cell detachment with preserved potential of recovery was observed at low temperature during 3D culturing. Thus, surface modification of microcarriers with PNIPAm-co-AAm-b-PS could be vital strategy for non-enzymatic cell dissociation and able to achieve adequate number of cells with maximum cell viability, and functionality for various cell-based applications. Keywords: surface coated microcarriers; thermosensitive polymer; non-enzymatic cell detachment