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Critically injured children and teens often present to adult trauma centers or nontrauma facilities prior to transfer to a pediatric trauma center. For pediatric patients wanting transfer to the intensive care unit (ICU), there is little data to guide which can be safely transferred directly to the unit, and which should be evaluated first in the trauma bay.We used our institutional trauma registry to evaluate transferred trauma patients over a three year period. We compared time to imaging, time to operating room, and overall mortality between the group evaluated first in the emergency room and those transferred directly to the ICU.When adjusted for other variables, there was no increased mortality in those transferred directly to the ICU. While there was a higher nonadjusted mortality in those transferred to the ICU (13% versus 3.7%), these nonsurvivors had a lower GCS (3 versus 13), higher Pediatric Risk of Mortality scores, and a high rate of severe head trauma. There was no significant delay in ordered imaging or procedures.In patients, who have been assessed at another institution prior to transfer to the pediatric ICU, transfer directly to the ICU, bypassing the emergency department, does not delay interventions and does not appear to worsen outcomes.

IntroductionIn attempts to quell the spread of COVID-19, shelter-in-place orders were employed in most states. Increased time at home, in combination with parents potentially balancing childcare and work-from-home duties, may have had unintended consequences on pediatric falls from windows. We aimed to investigate rates of falls from windows among children during the first 6mo of the COVID-19 pandemic.MethodsPatients

Due to significant advances in instrumentation, many previously specialized techniques have become “routine” in user facilities. However, detailed knowledge held by experts has often not been relayed to general users, so they often rely on entry-level information, basic principles, and comparison with literature results for data analysis. As a result, major errors in the data analysis of multiple surface and material analysis techniques, including in x-ray photoelectron spectroscopy (XPS), have been appearing in the scientific literature. Representative examples of serious errors in XPS data analysis are shown in this work. We suggest that surface and material analysis, and perhaps even science in general, are in a state of “pre-crisis.” We use two (logistic) models from population biology to suggest that bad analyses self-correct if they remain below a critical number. However, beyond a threshold, the literature can become useless because of the perpetuation of faulty analyses and concomitant loss of its self-correcting ability. XPS is used by scientists in many communities because of the power of the technique and high-quality instrumentation that is commercially available. Those who make new surfaces and materials face unique challenges because of the large number of surface and material analytical techniques that are often needed to characterize their materials. Graduate students and post-docs are often provided with only minimal instruction on using surface and material characterization methods. High fees for instruments may affect both the quality and the quantity of the data people collect. The Prisoner's Dilemma is a model from game theory that describes situations with reward structures that encourage uncooperative behavior and lead to suboptimal outcomes. However, the outcomes of Prisoner's Dilemma are not inevitable—their consequences change if their reward structures change. The current system does not appear to incentivize detailed learning of surface and material characterization techniques and careful material characterization. Prisoner's dilemmas appear to lead to other undesirable consequences in science. The concerns raised in this work suggest that many manuscripts are incompletely reviewed at present. The different stakeholders in this problem, including authors, research advisers, subject matter experts, reviewers, scientists who notice examples of faulty data analysis, editors, journals and publishers, funding agencies, scientific societies, leaders at universities and research centers, and instrument vendors, can improve the current situation. This work provides specific recommendations for each of these stakeholders. For example, we believe that authors are primarily responsible for the correctness of their work, not reviewers or editors; we question the wisdom of listing the names of the editor and reviewers on a paper; we are grateful for the significant contributions that have been made by subject matter experts to produce standards and tutorial information; the high cost of instrument time at some institutions may limit student access and result in suboptimal analyses; staff scientists often need to be better recognized for their intellectual contributions to studies; publishers may wish to allow selective reviewing of specific sections of papers related to material characterization; the reviewing at some open access journals may be inadequate; while it had its shortcomings, the pre-open access model of publishing incentivized the production and publication of high-quality work; audits of the products (scientific papers) of funding agencies may be necessary; collaboration needs to be encouraged to a greater extent at some institutions; and instrument vendors should not suggest to potential customers that surface characterization, e.g., by XPS, is trivial or simple.

A detailed study of iminyl radical cyclizations of

It is a pleasure to comment on the paper by Katsikopoulos et al. (2021), where they present a provocative and stimulating viewpoint in which they argue that simple forecasting rules based on heuristics frequently outperform big data models and should be used as a benchmark when testing big data models. I argue that it is important not to conflate simplicity with adaptability, and that there is a role for big data models in forecasting.

Objective We analyze the number of recorded cases and deaths of COVID-19 in many parts of the world, with the aim to understand the complexities of the data, and produce regular forecasts. Methods The SARS-CoV-2 virus that causes COVID-19 has affected societies in all corners of the globe but with vastly differing experiences across countries. Health-care and economic systems vary significantly across countries, as do policy responses, including testing, intermittent lockdowns, quarantine, contact tracing, mask wearing, and social distancing. Despite these challenges, the reported data can be used in many ways to help inform policy. We describe how to decompose the reported time series of confirmed cases and deaths into a trend, seasonal, and irregular component using machine learning methods. Results This decomposition enables statistical computation of measures of the mortality ratio and reproduction number for any country, and we conduct a counterfactual exercise assuming that the United States had a summer outcome in 2020 similar to that of the European Union. The decomposition is also used to produce forecasts of cases and deaths, and we undertake a forecast comparison which highlights the importance of seasonality in the data and the difficulties of forecasting too far into the future. Conclusion Our adaptive data-based methods and purely statistical forecasts provide a useful complement to the output from epidemiological models.

T cells show tremendous efficacy as cellular therapeutics. However, obtaining primary T cells from human donors is expensive and variable. Pluripotent stem cells (PSCs) have the potential to provide a renewable source of T cells, but differentiating PSCs into hematopoietic progenitors with T cell potential remains an important challenge. Here, we report an efficient serum- and feeder-free system for differentiating human PSCs into hematopoietic progenitors and T cells. This fully defined approach allowed us to study the impact of individual proteins on blood emergence and differentiation. Providing DLL4 and VCAM1 during the endothelial-to-hematopoietic transition enhanced downstream progenitor T cell output by ~80-fold. These two proteins synergized to activate notch signaling in nascent hematopoietic stem and progenitor cells, and VCAM1 additionally promoted an inflammatory transcriptional program. We also established optimized medium formulations that enabled efficient and chemically defined maturation of functional CD8αβ+, CD4−, CD3+, TCRαβ+T cells with a diverse TCR repertoire.

ObjectiveTelerehabilitation for individuals with vision impairment aims to maintain maximum physical and/or psychological functioning through remote service delivery. This review aims to describe the type of telerehabilitation services available to people with vision impairment and summarise evidence on health-related outcomes, well-being and cost-effectiveness.DesignScoping review.Data sourcesCINAHL Plus, MEDLINE, PsycARTICLES, PsychINFO, Embase, PubMed, HMIC and Ovid Emcare were searched, without date restrictions up to 24 May 2021. Charity and government websites, conference proceedings and clinical trial databases were also examined.Eligibility criteriaEligible studies evaluated benefits of telerehabilitation services for adults with vision impairment. Studies were excluded if they were not available in English, or focused on distance learning of visually impaired students.Data extraction and synthesisTwo independent reviewers screened articles and extracted data. A risk of bias analysis was performed.Outcome measuresMeasures of benefit included performance-based assessment, patient-reported outcomes and cost-effectiveness.ResultsOf 4472 articles, 10 eligible studies were included. Outcomes addressed patient satisfaction (n=4;33.3%), quality-of-life, activities of daily living and well-being (n=4;33.3%), objective visual function (n=2;16.6%) and knowledge relating to ocular symptoms (n=1;8.3%). Two studies addressed multiple outcomes. Cost-effectiveness was addressed in one article (8.3%). Patients were generally satisfied with their experiences, which had a range of positive benefits on functional and quality-of-life outcomes in areas relating to daily activities (eg, reading, making phone calls). Telerehabilitation allowed patients to undertake vision optimisation training to prevent vision deterioration. Grey literature indicated that there are no completed clinical trials relating to low vision telerehabilitation. Charity services had implemented digital skills training to help beneficiaries communicate remotely.ConclusionWhile acceptability of telerehabilitation was mostly high, limited real-world data are available which raises questions around the long-term desirability of this approach. Further trials are needed to evaluate telerehabilitation using a robust set of outcome measures.PROSPERO registration numberCRD42021254825.

Three new bulky cycloalkyl α,β-dehydroamino acids (ΔAAs) have been designed and synthesized. Each residue enhances the rigidity of model peptides and their stability to proteolysis, with larger ring sizes exhibiting greater effects. Peptides containing bulky cycloalkyl ΔAAs are inert to conjugate addition by a nucleophilic thiol. The results suggest that these residues will be effective tools for improving the proteolytic stability of bioactive peptides.

O-Phenyloximes tethered to alkenes undergo 5-exo-trig iminyl radical cyclizations upon microwave irradiation. Trapping of the resulting cyclic radicals results in C-C, C-N, C-O, C-S, or C-X bond formation. Allylic sulfides undergo a tandem cyclization-thiyl radical β-elimination, affording terminal alkenes. The cyclizations exhibit a broad scope, and in some cases they are highly diastereoselective. The pyrroline adducts are versatile intermediates that can be transformed into a range of different species.

Economic forecasting is difficult, largely because of the many sources of nonstationarity influencing observational time series. Forecasting competitions aim to improve the practice of economic forecasting by providing very large data sets on which the efficacy of forecasting methods can be evaluated. We consider the general principles that seem to be the foundation for successful forecasting, and show how these are relevant for methods that did well in the M4 competition. We establish some general properties of the M4 data set, which we use to improve the basic benchmark methods, as well as the Card method that we created for our submission to that competition. A data generation process is proposed that captures the salient features of the annual data in M4.

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its β-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer. Alkene isomerization was negligible during this process. These methods enabled a highly convergent and efficient synthetic route to the natural product.

There has been growing recognition of the impact of COVID-19 and the restrictions implemented to contain the virus on mental health. This study provides a preliminary assessment of the longitudinal impact on state anxiety in individuals with disabilities and a subsample of individuals with visual impairment (VI). Two surveys were conducted in April–May 2020 (T1) and March 2021 (T2) to explore state anxiety (State-Trait Anxiety Inventory). Participants who consented to being re-contacted were invited to take part in T2. A total of 160 participants completed T1 and T2. There were no significant group differences in median anxiety at T1; however, at T2 anxiety was significantly higher in those with disabilities and there was a trend towards being higher in participants with VI compared to those with no disabilities. While not statistically significant within any of the three subgroups, state anxiety decreased slightly in those with no disabilities. The absence of a disability affecting mobility, experiencing loneliness, and poorer sleep quality predicted state anxiety at both timepoints. While anxiety appeared to decrease in individuals with no disabilities, it remained comparatively stable, and higher in those with disabilities. Loneliness and poor sleep may need to be addressed to alleviate feelings of anxiety.

Research has shown that visual impairment may impact daily functioning, health, and well-being negatively for adults of all ages. Ex-service personnel (‘veterans’) too may be at risk of poor health and well-being outcomes associated with post-military life, and this may be exacerbated by the presence of visual impairment. Despite this, research considering the experience of blind veterans has been limited and has not yet assessed well-being for these individuals across a broad spectrum of life domains. Rather, it has highlighted poor mental health and psychological well-being in working-age visually impaired veterans. However, the experiences of older visually impaired veterans (who make up the majority of visually impaired veterans in the United Kingdom) have been poorly represented in the literature. This pilot study aimed to provide a preliminary assessment of holistic well-being in an adult sample of 97 UK blind veterans, predominantly composed of older age veterans (majority over 80 years). Cross-sectional well-being data were collected using a validated measure of well-being (the Well-Being Inventory [WBI]). Results suggest that members of Blind Veterans UK are functioning well and are satisfied across four life domains (vocation, finances, health, and social relationships). Lower health satisfaction was identified, particularly in blind veterans with comorbid mental health conditions. Results are discussed in relation to the older age of the sample, the limitations of face-to-face survey administration, and the applicability of the WBI finance domain in this age cohort. Recommendations are made for future research in this population.

Objectives Examine the outcomes of pediatric burn patients requiring extracorporeal membrane oxygenation to determine whether extracorporeal membrane oxygenation should be considered in this special population. Design Retrospective cohort study. Setting All extracorporeal membrane oxygenation centers reporting to the Extracorporeal Life Support Organization. Subjects Pediatric patients (birth to younger than 18 yr) who were supported with extracorporeal membrane oxygenation with a burn diagnosis between 1990 and 2016. Interventions None. Measurements and main results A total of 113 patients were identified from the registry by inclusion criteria. Patients cannulated for respiratory failure had the highest survival (55.7%, n = 97) compared to those supported for cardiac failure (33.3%, n = 6) or extracorporeal cardiopulmonary resuscitation (30%, n = 10). Patients supported on venovenous extracorporeal membrane oxygenation for respiratory failure had the best overall survival at 62.2% (n = 37). Important for the burn population, rates of surgical site bleeding were similar to other surgical patients placed on extracorporeal membrane oxygenation at 22.1%. Cardiac arrest prior to cannulation was associated with increased hospital mortality (odds ratio, 3.41; 95% CI, 0.16-1.01; p = 0.048). Following cannulation, complications including the need for inotropes (odds ratio, 2.64; 95% CI, 1.24-5.65; p = 0.011), presence of gastrointestinal hemorrhage (p = 0.049), and hyperglycemia (glucose > 240 mg/dL) (odds ratio, 3.42; 95% CI, 1.13-10.38; p = 0.024) were associated with increased mortality. Of patients with documented burn percentage of total body surface area (n = 19), survival was 70% when less than 60% total body surface area was involved. Conclusions Extracorporeal membrane oxygenation could be considered as an additional level of support for the pediatric burn population, especially in the setting of respiratory failure. Additional studies are necessary to determine the optimal timing of cannulation and other patient characteristics that may impact outcomes.

Perihematomal edema (PHE) growth in intracranial hemorrhage (ICH) is a biomarker for worse outcomes. Although the management of PHE is potentially beneficial for ICH patients, there is currently no proven clinical therapy that both reduces PHE and improves outcomes in this population. To examine the safety and tolerability of conivaptan, a non-peptide vasopressin (AVP) receptor antagonist, for the management of PHE in ICH patients. We performed a single-center, open-label, phase I study in seven patients with ICH at risk for developing PHE. Conivaptan (20 mg) was administered every 12 h for 2 days, along with the standard ICH management. Electrolyte levels, renal and cardiac function, and vital signs were monitored throughout treatment. Neurological status, ICH, and PHE volumes were assessed at study baseline, 24 h, 72 h, and 7 days from the first conivaptan administration, as well as at the 3-month follow-up. Conivaptan was well tolerated in our patients. We observed the expected increase in sodium levels following conivaptan administration (p = 0.01), with no change in cardiac or renal function. All patients survived to follow-up, and adverse event rates were comparable with those of the neurocritical care unit overall. These data indicate that conivaptan can be safely administered to ICH patients and support further clinical investigation into the efficacy of this drug for ICH treatment. clinicaltrials.gov; NCT03000283, 22 December 2016.

Shared features of economic and climate time series imply that tools for empirically modeling nonstationary economic outcomes are also appropriate for studying many aspects of observational climate-change data. Greenhouse gas emissions, such as carbon dioxide, nitrous oxide, and methane, are a major cause of climate change as they cumulate in the atmosphere and reradiate the sun’s energy. As these emissions are currently mainly due to economic activity, economic and climate time series have commonalities, including considerable inertia, stochastic trends, and distributional shifts, and hence the same econometric modeling approaches can be applied to analyze both phenomena. Moreover, both disciplines lack complete knowledge of their respective data-generating processes (DGPs), so model search retaining viable theory but allowing for shifting distributions is important. Reliable modeling of both climate and economic-related time series requires finding an unknown DGP (or close approximation thereto) to represent multivariate evolving processes subject to abrupt shifts. Consequently, to ensure that DGP is nested within a much larger set of candidate determinants, model formulations to search over should comprise all potentially relevant variables, their dynamics, indicators for perturbing outliers, shifts, trend breaks, and nonlinear functions, while retaining well-established theoretical insights. Econometric modeling of climate-change data requires a sufficiently general model selection approach to handle all these aspects. Machine learning with multipath block searches commencing from very general specifications, usually with more candidate explanatory variables than observations, to discover well-specified and undominated models of the nonstationary processes under analysis, offers a rigorous route to analyzing such complex data. To do so requires applying appropriate indicator saturation estimators (ISEs), a class that includes impulse indicators for outliers, step indicators for location shifts, multiplicative indicators for parameter changes, and trend indicators for trend breaks. All ISEs entail more candidate variables than observations, often by a large margin when implementing combinations, yet can detect the impacts of shifts and policy interventions to avoid nonconstant parameters in models, as well as improve forecasts. To characterize nonstationary observational data, one must handle all substantively relevant features jointly: A failure to do so leads to nonconstant and mis-specified models and hence incorrect theory evaluation and policy analyses.

Forecasting has always been at the forefront of decision making and planning. The uncertainty that surrounds the future is both exciting and challenging, with individuals and organisations seeking to minimise risks and maximise utilities. The large number of forecasting applications calls for a diverse set of forecasting methods to tackle real-life challenges. This article provides a non-systematic review of the theory and the practice of forecasting. We provide an overview of a wide range of theoretical, state-of-the-art models, methods, principles, and approaches to prepare, produce, organise, and evaluate forecasts. We then demonstrate how such theoretical concepts are applied in a variety of real-life contexts. We do not claim that this review is an exhaustive list of methods and applications. However, we wish that our encyclopedic presentation will offer a point of reference for the rich work that has been undertaken over the last decades, with some key insights for the future of forecasting theory and practice. Given its encyclopedic nature, the intended mode of reading is non-linear. We offer cross-references to allow the readers to navigate through the various topics. We complement the theoretical concepts and applications covered by large lists of free or open-source software implementations and publicly-available databases. Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)001 Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)307403/2019-0 CA19130 ECO2017-87245-R SBPLY/19/180501/000151 info:eu-repo/semantics/publishedVersion

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the inflammatory and angiogenic endothelial cell neoplasm, Kaposi’s sarcoma (KS). We previously demonstrated that expression of the KSHV protein, Kaposin B (KapB), promoted inflammation via the disassembly of cytoplasmic ribonucleoprotein granules called processing bodies (PBs). Processing bodies (PBs) modify gene expression by silencing or degrading labile messenger RNAs (mRNAs) including many transcripts that encode inflammatory or angiogenic proteins that are associated with KS disease. Although our work implicated PB disassembly as one of the causes of inflammation during KSHV infection, the precise mechanism used by KapB to elicit PB disassembly was unclear. Here we reveal a new connection between the degradative process of autophagy and PB disassembly. We show that both latent KSHV infection and KapB expression enhanced autophagic flux via the phosphorylation of the autophagy regulatory protein, Beclin 1. KapB was necessary for this effect, as infection with a recombinant virus that does not express the KapB protein did not induce Beclin 1 phosphorylation or autophagic flux. Moreover, we reveal that PB disassembly mediated by KSHV or KapB depended on canonical autophagy genes and the selective autophagy receptor NDP52/CALCOCO2 and that the PB scaffolding protein, Pat1b, co-immunoprecipitated with NDP52. These studies reveal a new role for autophagy and the selective autophagy receptor NDP52 in promoting PB turnover and the concomitant synthesis of inflammatory molecules during KSHV infection.Author SummaryKaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of the inflammatory, endothelial cell cancer, Kaposi’s Sarcoma (KS). KSHV induces a pro-tumourigenic inflammatory environment which aids in the establishment and maintenance of the KS lesion. Processing bodies (PBs) are cellular structures that dampen inflammatory gene expression by suppression or decay of their cognate RNA molecules. We previously showed that the viral protein KapB caused PB disappearance during KSHV infection, identifying a new pathway used by KSHV to elicit inflammation. Now, we show that KSHV and KapB hijack the cellular degradative process of autophagy to promote PB disassembly and increase inflammatory gene expression. This places autophagy as central to the regulation of inflammation by KSHV and illustrates another remarkable strategy used by these viruses to create a tumourigenic microenvironment.

T cells are key mediators of the adaptive immune response and show tremendous efficacy as cellular therapeutics. However, obtaining primary T cells from human donors is expensive and variable. Pluripotent stem cells (PSCs) have the potential to serve as a consistent and renewable source of T cells, but differentiating PSCs into hematopoietic progenitors with T cell potential remains a significant challenge. Here, we developed an efficient serum- and feeder-free protocol for differentiating human PSCs into hematopoietic progenitors and T cells. This defined method allowed us to study the impact of individual recombinant proteins on blood emergence and lineage potential. We demonstrate that the presence of DLL4 and VCAM1 during the endothelial-to-hematopoietic transition (EHT) enhances downstream progenitor T cell output by >80-fold. Using single cell transcriptomics, we showed that these two proteins synergise to drive strong notch signalling in nascent hematopoietic stem and progenitor cells and that VCAM1 additionally drives a pro-inflammatory transcriptional program. Finally, we applied this differentiation method to study the impact of cytokine concentration dynamics on T cell maturation. We established optimised media formulations that enabled efficient and chemically defined differentiation of CD8αβ+, CD4-, CD3+, TCRαβ+ T cells from PSCs.

Processing bodies (PBs) are ribonucleoprotein granules important for cytokine mRNA decay that are targeted for disassembly by many viruses. Kaposi’s sarcoma-associated herpesvirus is the etiological agent of the inflammatory endothelial cancer, Kaposi’s sarcoma, and a PB-regulating virus. The virus encodes kaposin B (KapB), which induces actin stress fibers (SFs) and cell spindling as well as PB disassembly. We now show that KapB-mediated PB disassembly requires actin rearrangements, RhoA effectors, and the mechanoresponsive transcription activator, YAP. Moreover, ectopic expression of active YAP or exposure of ECs to mechanical forces caused PB disassembly in the absence of KapB. We propose that the viral protein KapB activates a mechanoresponsive signaling axis and links changes in cell shape and cytoskeletal structures to enhanced inflammatory molecule expression using PB disassembly. Our work implies that cytoskeletal changes in other pathologies may similarly impact the inflammatory environment.

BackgroundThe COVID-19 pandemic has resulted in delays in presentation for other urgent medical conditions, including pediatric appendicitis. Several single-center studies have reported worse outcomes, but no state-level data is available. We aimed to determine the statewide effect of the COVID-19 pandemic on the presentation and management of pediatric appendicitis patients.Materials and methodsPatients < 18 years old with acute appendicitis at four tertiary pediatric hospitals in California between March 19, 2020 to September 19, 2020 (COVID-era) were compared to a pre-COVID cohort (March 19, 2019 to September 19, 2019). The primary outcome was the rate of perforated appendicitis. Secondary outcomes were symptom duration prior to presentation, and rates of non-operative management.ResultsRates of perforated appendicitis were unchanged (40.4% of 592 patients pre-COVID versus 42.1% of 606 patients COVID-era, P=0.17). The median symptom duration was 2 days in both cohorts (P=0.90). Computed tomography (CT) use rose from 39.8% pre-COVID to 49.4% during COVID (P=0.002). Non-operative management increased during the pandemic (8.8% pre-COVID versus 16.2% COVID-era, P < 0.0001). Hospital length of stay (LOS) was longer (2 days pre-COVID versus 3 days during COVID, P < 0.0001).ConclusionsPediatric perforated appendicitis rates did not rise during the first six months of the COVID-19 pandemic in California in this multicenter study, and there were no delays in presentation noted. There was a higher rate of CT scans, non-operative management, and longer hospital lengths of stay.

Simplified full-length analogs of yaku'amide A were designed with the aid of computations and then synthesized. The analog that was predicted to most closely resemble the structure of the natural product mimicked its anticancer activity.