Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants . Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants . Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively. Malaria is responsible for the heaviest burden of all parasitic infections, with an estimated 219 million cases and 435,000 deaths reported worldwide in 2017 46. Many o8–13–The purpose of this meta-analysis was to pool available clinical data to characterize the effect of ARV drug-drug interactions with artemether-lumefantrine and to identify any other significant covariates affecting lumefantrine concentrations. This meta-analysis did not simply collate aggregate results from individual studies but jointly reanalyzed the individual participant data, using a population pharmacokinetic modeling approach. This technique can identify and quantify the different sources of variability in the data, thus separating the random unexplained differences between participants and studies from systematic effects, such as those associated with patient characteristics , drug-drug interactions, and/or disease effects. With an increased and diverse study population and larger variability in treatment scenarios obtained when pooling individual participant data from different studies, it is possible to quantify the extent of drug-drug interactions and other covariates more robustly than in the individual primary studies.A total of 16 artemether-lumefantrine pharmacokinetic studies were identified in a literature review and invited by WorldWide Antimalarial Resistance Network (WWARN) to contribute to the individual patient data (IPD) meta-analysis. Studies addressing the pharmacokinetics of lumefantrine in pregnant women and children were not included, as it was beyond the scope of this meta-analysis. WWARN received and curated data from 11 artemether-lumefantrine pharmacokinetic studies, 9 from Africa and 2 from the United States, but one U.S. study only contributed summary values  and was excluded. Thus, the IPD meta-analysis consisted of 10 clinical studies with 793 nonpregnant adult participants and 6,100 measured lumefantrine concentrations. Out of these, the concentrations in 341 (5.59%) samples were below the lower limit of quantification (LLOQ). All participants were nonpregnant adults treated with artemether-lumefantrine . The distribution of participants and their demographic characteristics across different studies are presented in (i) Structural model and effect of body size. The population pharmacokinetics of lumefantrine was best described with a three-compartment disposition model  with first-order elimination and transit compartment absorption . Final pharmacokinetic parameter estimates are presented in (ii) Drug-drug interactions. Coadministration of lopinavir-ritonavir-based ART increased lumefantrine exposure substantially; the area under the curve (AUC) was nearly 3.4-fold higher due to 50.1% slower clearance  and 67.2% increased bioavailability . Lopinavir-ritonavir-based ART was also found to slow down the rate of absorption by 47.6% . Efavirenz-based ART significantly increased the clearance of lumefantrine by 89.9% , thus resulting in 47% lower AUC. Rifampin-based antituberculosis treatment increased lumefantrine clearance by 142% , thus reducing AUC by 59%. A small number of patients (n = 4) were administered both rifampin and efavirenz, and there was a trend toward an even higher clearance of lumefantrine, but this was not statistically significant and was not retained in the final model. Dolutegravir-based ART did not alter lumefantrine exposure. Discordant trends toward slightly higher or lower exposure in the nevirapine-based ART arms were found in the different studies, but no significant effect was found in the combined data after adjusting for other factors (below).(iii) HIV and malaria disease effects. After adjusting for the substantial drug-drug interactions above (and other effects explained below), the IPD meta-analysis also tested for any malaria and HIV disease effects, but none was identified. The HIV-positive (HIV+) but ART-naive participants from the SEACAT  study showed a trend toward moderately increased clearance of lumefantrine, but the same trend was not found with the HIV+ ART-naive participants in the other studies. As the magnitude of this effect was small and not consistent across studies, it was not retained in the final model. Similarly, no significant consistent difference in pharmacokinetic parameters was found that could be ascribed to malaria infection.(iv) Study and other covariate effects.(a) Diurnal variation. After adjusting for the effects described above, significant differences in drug concentrations remained between the studies and, when data were available, between profiles collected after morning or evening doses. These differences were well captured in the model using categorical covariate effects on relative bioavailability . The highest bioavailability was observed in the InterACT  and the SEACAT studies for the evening doses (with no significant difference between these two studies), and this was chosen as the reference value (fixed to 1) to which the bioavailability of other doses was compared. In the SEACAT studies, the relative bioavailability was 48.6% lower for the first (morning) dose  and 77.2% lower for the consecutive morning doses . The value of relative bioavailability in the Ugandan studies was similar and was found to be 26.9% lower than the reference , while the value was 60.1% lower than the reference  for the 6th (morning) AL dose in the Nigeria study 1. Lumefantrine bioavailability in the U.S. healthy volunteer study was not significantly different from the reference group.(b) Matrix effect. Lumefantrine concentrations in both arms of Nigeria study 2, which was the only study measuring concentrations from whole-blood samples (as opposed to venous plasma samples), were much higher than in all other studies. A scaling factor of 2.28-fold was included to account for this matrix effect , which is consistent with previous reports ( reports .(c) Dosing time. The predose  concentrations in Nigeria study 1 and the U.S. healthy volunteer study were higher and inconsistent with the profile collected after the observed 6th dose. The actual dosing time of the previous (5th) dose was not reported, so it had been imputed to exactly 12 h before the morning dose. We adjusted for this by estimating a delay in the absorption for this specific occasion, ∼4.3 h .(d) Weight-adjusted dose. Finally, a negative trend between bioavailability and milligrams per kilogram of dose was detected in the ART-naive arms of SEACAT, InterACT, and for the AL-only arm of Uganda clinical study 1. However, this trend was not present in the other studies and arms and was not significant in the model when tested overall.(v) Simulations on the attainment of therapeutic day 7 concentrations. The Monte Carlo simulations from the final model . WWARN is a collaborative data-sharing platform which provides an opportunity to share data and results from studies in the field of antimalarial treatment. Participating authors agreed to the WWARN terms of submission  pharmacology publication database to identify relevant antimalarial clinical studies published between 1990 and 2016. The search strategy used key terms “lumefantrine pharmacokinetics” or “lumefantrine concentration,” “clinical study,” and “HIV” or “antiretroviral.” Inclusion criteria permitted data sets of participants treated with at least one dose of artemether-lumefantrine with or at risk of malaria or healthy volunteers who were HIV infected or uninfected and/or treated with antiretroviral(s), and with at least one or more postdose concentrations of lumefantrine (plus desbutyl-lumefantrine) measured. Under the auspices of the WWARN, corresponding authors of relevant studies were invited to participate in this IPD meta-analysis  and the algorithm first-order conditional estimation with eta-epsilon interaction (FOCE-I) . Various2 distributed and thus using a 3.84-point drop as significant at a P value of < 0.05 for the inclusion of a single parameter in a nested model, inspection of diagnostic plots, including visual predictive checks  based on the final model were used to predict the lumefantrine concentrations achieved with the current dosing recommendations in participants of different body weights and cotreated with different concomitant medications. To evaluate the expected effect of the pharmacokinetic differences on the therapeutic outcome, we calculated the probability of target attainment in the various scenarios using the suggested value of lumefantrine day 7 concentrations above 200 ng/ml, which has previously been associated with better cure rates (Monte Carlo simulations (re rates .


Purpose: To report a case of bilateral secondary angle closure in a female using mirtazapine for 6 months.Patient and method: A 55-year-old female was diagnosed with secondary angle closure in both eyes with raised intraocular pressure, and ultrasound biomicroscopic findings suggestive of ciliary body effusion. It was associated with adjoining cyst presumably because of the use of mirtazapine for depression and sleep disturbances.Results: After the planned discontinuation of mirtazapine, the ocular angle opened, the ciliary body edema decreased, and the cyst regressed in size. The intraocular pressure was controlled with topical timolol (0.5%).Conclusion: Patients with risk factors for angle closure should be prescribed antipsychotic drugs with caution. The peripheral laser iridotomy is not indicated in secondary angle closure due to ciliary body effusion. A number of systemic and local medications have a mydriatic effect on the pupil. The common drugs causing angle closure in some anatomically predisposed eyes are anticholinergics, antipsychotics, anticonvulsants, adrenergics, mydriatics, antihistamines and anti-sulfamate derivatives .Mirtazapine, an antipsychotic drug, is a newer drug used for the management of moderate to severe depression worldwide . There iA 55-year-old female presented with a 6-month history of diminution of vision in both eyes with intermittent headache. She had been diagnosed with a depressive illness for which mirtazapine tablets 15 mg/day had been prescribed 6 months earlier. On examination, her best-corrected visual acuity was 6/18 in both eyes. The intraocular pressure measured with Goldmann applanation tonometer was 22 mm Hg and 28 mm Hg in the right and the left eye, respectively, without any anti-glaucoma medications. The slit-lamp examination revealed a shallow anterior chamber in both eyes with Van Herick grade 1. The patient’s posterior segment examination revealed a cup-disk ratio of 0.4 and 0.6 in the right and the left eye, respectively, with healthy neuro-retinal rim.The Zeiss 4-mirror gonioscopy revealed closed angles in both eyes (Shaffer’s grade 0)  and angles were open on gonioscopy (Shaffer’s grade 3) Figure 2 . The cilA number of case reports in the literature have highlighted various antipsychotic drugs which are known to cause angle-closure glaucoma either with pupillary block or non-pupillary block mechanisms  , 5]..5].Mirtazapine acts by enhancing noradrenergic and 5-HT1A-mediated serotonergic neurotransmission by acting as an antagonist at the central a2-adrenergic autoreceptors and heteroreceptors, as well as by post-synaptic blockade of 5-HT2 and 5-HT3 receptors [Various risk factors like shorter axial length increase lens thickness, and shallow anterior chamber increases the chance of angle closure. Peripheral laser iridotomy is indicated only if the mechanism is pupillary block.To the best of our knowledge, there is a single case report of mirtazapine-induced angle closure after single dose of the drug (15 mg/day) . In thatIn our case, the patient was asymptomatic, and only on detailed examination could we find the association between her clinical features and mirtazapine. The ciliary body edema with adjoining cyst suggests some mechanism other than mydriasis might be responsible for angle-closure glaucoma, as discontinuation of the drug resulted in an improvement in the form of open angles on gonioscopy. The pathophysiology remains unclear; an idiosyncratic reaction of some drugs that resulted in ciliary body edema has been reported in the literature .Angle-closure glaucoma induced by these antipsychotic drugs can result in serious or blinding complication if not recognized early. Clinicians should be cautious prescribing these medications to patients, taking into account the risk factors like female sex, hyperopia, and family history of glaucoma.The authors declare that they have no competing interests.The patient has given written consent to publish the case report.


A layered double hydroxide (LDH)-based anticancer delivery system was investigated in terms of crystalline phase, particle size, hydrodynamic radius, zeta potential, etc. through in vitro and in vivo study. Size controlled LDH with anticancer drug methotrexate (MTX) incorporation was successfully prepared through step-by-step hydrothermal reaction and ion-exchange reaction. The MTX-LDH was determined to have a neutral surface charge and strong agglomeration in the neutral aqueous condition due to the surface adsorbed MTX; however, the existence of proteins in the media dramatically reduced agglomeration, resulting in the hydrodynamic radius of MTX-LDH being similar to the primary particle size. The protein fluorescence quenching assay exhibited that MTX readily reduced the fluorescence of proteins, suggesting that the interaction between MTX and proteins was strong. On the other hand, MTX-LDH showed much less binding constant to proteins compared with MTX, implying that the protein interaction of MTX was effectively blocked by the LDH carrier. The in vivo hemolysis assay after intravenous injection of MTX-LDH showed neither significant reduction in red blood cell number nor membrane damage. Furthermore, the morphology of red blood cells in a mouse model did not change upon MTX-LDH injection. Scanning electron microscopy showed that the MTX-LDH particles were attached on the blood cells without serious denaturation of cellular morphology, taking advantage of the cell hitchhiking property. Nanotechnology has affected science and technology in many aspects during the recent decades, and pharmaceutics is one of the most strongly influenced field. Nanomedicine, which consists of nanoimaging, nanomaterials/devices, nano delivery system, therapeutics etc. ,2,3,4,5,Due to the above-mentioned advantages, there have been extensive research studies on LDH-based drug delivery systems utilizing the anticancer drug, methotrexate (MTX). The incorporation of MTX into LDH (MTX-LDH)  and the 2, Ag and nanodiamonds were reported to affect morphological change in blood cells : concentration of quencher, i.e., MTX, LDH or MTX-LDH in this study; KD: dissociation constant = 1/Kb (binding constant); n: Hill parameter related to cooperativity.Q: quenching ratio =  and stored in a citrate coated vial. Three mice without MTX-LDH injection were euthanized and the blood was collected as above for the control group.The animal test was carried out under the guidance of the Institutional Animal Care and Use Committee (IACUC), Yonsei University-Wonju . The MTX-LDH was suspended in saline to obtain a 10 mg/mL concentration, then injected into six respective Balb/c mice utilizing a 31 G sterilized syringe (100 μL). After 0.5 and 6 h, three mice at each time point were euthanized with CO2) of the hemocytometer was determined through counting, which was repeated 5 times.Hemolysis of the mouse with or without administration of MTX-LDH was evaluated by modifying hemolysis assay of ASTM F756, as follows. The blood samples collected from the mouse after 0, 0.5 and 6 h or MTX-LDH were mixed with saline in a 1:1 volume ratio and placed at room temperature for 0.5 h to change hemoglobin to oxyhemoglobin. The samples were then centrifuged at 3000 rpm for 5 min and the absorbance of supernatant at 540 nm was recorded utilizing UV–vis spectroscope . The blood with deionized water instead of saline and the one collected at 0 h were utilized as positive (100% hemolysis) and negative control (0% hemolysis), respectively. The number of viable cells in the collected blood was also counted for quantitative analysis. The collected blood was diluted 200 times with saline and the number of cells in a chamber  and scanning electron microscopy at high magnification  were carried out. The blood samples collected from the mouse model at each time point were located on the slide glass, smeared, fixed with methyl Wright’s stain solution  for 4 min, and stained with Wright’s stain buffered at pH 6.4 for 6 min. The slides were directly subjected to optical microscopy in order to check the morphological change. A piece of slide glass was sputtered with Pt for 20 sec for SEM study .3-LDH exhibited . Thus, we could conclude that the MTX-LDH particles were well-prepared with high homogeneity.As the particle size and homogeneity are important factors regarding the toxicology of nanoparticles, a SEM study was carried out for the MTX-LDH powder and the size distribution was obtained . It was 2/(average)) (1.124 ± 0.07) exhibited that MTX-LDH in neutral aqueous suspension lost its advantageous property of ~100–200 nm particle size.Colloidal properties of MTX-LDH, such as surface charge and hydrodynamic radius, were characterized under neutral aqueous suspension and simulated plasma condition, respectively . As indiHowever, the colloidal properties changed when MTX-LDH existed in the simulated plasma condition. Although the zeta potential  higher than 0.9 for all the tested samples. It is worth taking notice of the binding constant, Kb, values. MTX was determined to have Kb values higher than 100, showing 64.2, 150, and 46.2 for albumin, fibrinogen, and globulin, respectively. On the hand, both MTX-LDH and LDH had Kb values less than 10. The difference in binding constant of MTX-LDH and LDH was less than double, implying that the protein binding nature of MTX-LDH is more similar to LDH than to MTX. This result suggests important features of LDH as a drug delivery carrier: (i) it can take advantage of protein corona in the plasma condition, camouflaging itself from macrophage and preventing aggregation among particles, and (ii) it affects the conformation of plasma protein at the lowest level, excluding unexpected hematotoxicity.The fluorescence quenching behaviors of MTX, LDH, and MTX-LDH were quantitatively analyzed utilizing the Hill equation. The linear fitting results are summarized in The hemolytic effect of intravenously injected MTX-LDH was investigated at the administration times of 0.5 and 6 h, respectively. As shown in 6/μL, which was similar to the previously reported cell count of Balb/c mice [6 and 7.6 × 106/μL, respectively, which were not statistically different values compared with negative control. It should be noted that MTX-LDH exhibited almost no toxicity in blood cells even at high concentration. The potential harmful effect of MTX towards blood cells would be appropriately blocked by LDH encapsulation. It was, therefore, concluded that LDH has an advantageous property as a delivery carrier by reducing the potential hematotoxicity of incorporated drug moiety.In order to cross-confirm the low hematotoxicity of MTX-LDH, we counted the number of red blood cells at each time point B. The reb/c mice ,69. AfteAs we confirmed that MTX-LDH did not induce hemolysis nor acute reduction in the number of blood cells, the morphological change of blood cells upon MTX-LDH injection was investigated for the next step. Optical microscopy is basically utilized to evaluate disorders in red blood cells by observing morphological change. It has been frequently reported that a certain nanoparticle induces echinocyte—abnormal cell membranes characterized by many small thorny projections—or spherocyte, sphere shaped cells rather than bi-concave disc shape . TitaniuInterfacial interaction between MTX-LDH and red blood cells at 6 h of administration was visualized by SEM B. The maIn order to investigate the colloidal properties of the LDH-based drug delivery system in blood conditions, the anticancer drug MTX was incorporated into LDH nanoparticles. According to XRD and FT-IR, it was revealed that the MTX moiety was well-encapsulated by the LDH lattice by electrostatic interaction driven layer-by-layer stacking. The SEM measurement showed that the primary particle size of MTX-LDH was ~120 nm and the size distribution was fairly narrow. MTX-LDH showed an almost neutral surface charge (~4.61 mV) and large aggregate (~4840 nm) in aqueous suspension; however, the particles were well dispersed in the physiological condition with serum, possibly due to the protein corona effect. The protein fluorescence quenching assay revealed that the behavior of MTX-LDH towards plasma protein was between MTX and LDH, while the quantitative analysis of the Hill equation showed that the binding constant of MTX-LDH to protein was closer to LDH alone. This result suggests that the LDH acted efficiently as a delivery capsule. Finally, the hemolysis effect and morphology change of red blood cells upon MTX-LDH treatment were tested in a mouse model. There were neither significant hemolysis nor morphological changes in red blood cells at 10 mg/mL of MTX-LDH injection. Furthermore, the SEM image showed that the MTX-LDH particles were attached on the red blood cells, taking advantage of the cellular hitchhiking effect. It was concluded that the LDH-based delivery system is not only compatible to blood components—blood cells and plasma protein—but also advantageous in systemic circulation.


Within a few months coronavirus disease 2019 (COVID-19) evolved into a pandemic causing millions of cases worldwide, but it remains challenging to diagnose the disease in a timely fashion in the emergency department (ED). In this study we aimed to construct machine-learning (ML) models to predict severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection based on the clinical features of patients visiting an ED during the early COVID-19 pandemic.We retrospectively collected the data of all patients who received reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 at the ED of Baylor Scott & White All Saints Medical Center, Fort Worth, from February 23–May 12, 2020. The variables collected included patient demographics, ED triage data, clinical symptoms, and past medical history. The primary outcome was the confirmed diagnosis of COVID-19 (or SARS-CoV-2 infection) by a positive RT-PCR test result for SARS-CoV-2, and was used as the label for ML tasks. We used univariate analyses for feature selection, and variables with P<0.1 were selected for model construction. Samples were split into training and testing cohorts on a 60:40 ratio chronologically. We tried various ML algorithms to construct the best predictive model, and we evaluated performances with the area under the receiver operating characteristic curve (AUC) in the testing cohort.A total of 580 ED patients were tested for SARS-CoV-2 during the study periods, and 98 (16.9%) were identified as having the SARS-CoV-2 infection based on the RT-PCR results. Univariate analyses selected 21 features for model construction. We assessed three ML methods for performance: of the three methods, random forest outperformed the others with the best AUC result (0.86), followed by gradient boosting (0.83) and extra trees classifier (0.82).This study shows that it is feasible to use ML models as an initial screening tool for identifying patients with SARS-CoV-2 infection. Further validation will be necessary to determine how effectively this prediction model can be used prospectively in clinical practice. Within a few months, coronavirus disease 2019 (COVID-19) evolved into a major pandemic causing millions of cases worldwide.People with COVID-19 may have a wide range of clinical symptoms ranging from mild to severe illness. Since the symptoms of COVID-19 are similar to other viral respiratory illnesses, an emergency approach to COVID-19 should focus on identifying and isolating patients at risk for infection.With the advancement of information technology, researchers and clinicians have also sought to develop artificial intelligence (AI)- or machine learning (ML)-based diagnostic tools for detecting COVID-19, but they are either focused on the patients visiting the local clinic or individuals in the community.We conducted a retrospective cohort study with data retrieved from the electronic health record (EHR) over the study period  at the ED of Baylor Scott & White All Saints Medical Center, a 574-bed university-affiliated tertiary care teaching hospital with approximately 50,000 ED visits annually. This study followed the Standards for Reporting of Diagnostic Accuracy statement: explanation and elaboration.16What do we already know about this issue?Diagnosing coronavirus disease 2019 (COVID-19) in a timely fashion was challenging in the emergency department during the early pandemic.What was the research question?Is machine learning (ML) a feasible method to predict COVID-19 based only on clinical features from patients visiting the ED?What was the major finding of the study?We successfully constructed ML models to predict SARS-CoV-2 infection based on the clinical features alone for ED patients.How does this improve population health?ML has the potential to serve as a screening tool to identify ED patients at risk of SARS-CoV-2 infection.In this study we identified all patients with suspected COVID-19 who were tested for SARS-CoV-2 using RT-PCR technique. Samples for RT-PCR tests were taken from the upper  respiratory tract, and assayed by using the cobas SARS-CoV-2 Test . We included only patients attending the ED. Patients without ED triage data were excluded from the analysis. The decision to perform the RT-PCR test for SARS-CoV-2 was left to the discretion of the emergency physicians or physician assistants who cared for the patient. There was no intervention in this study. This study was institutional review board-approved by the Baylor Scott & White Research Institute.2), duration of symptoms before presentation, travel (to areas with ongoing community transmission of SARS-CoV-2), and contact (in close contact with a confirmed or probable case of COVID-19) histories. Clinical symptoms were manually retrieved from the narrative patient records (including chief complaints and history of present illness) and review of systems recorded by a template with structural format during patient encounters. A total of 36 different clinical symptoms were included for analyses in this study. The primary outcome was the confirmed diagnosis of COVID-19 (or SARS-CoV-2 infection), defined as a positive RT-PCR test result for SARS-CoV-2. The positivity rate for COVID-19 was calculated as the number of positive results divided by the number of tests ordered in patients presenting to the ED.Patient demographics, including age, gender, race, insurance status, weight, height, body mass index (BMI), smoking, and past medical histories (PMH), were obtained from the EHR. We also extracted data on oxygen supplied (yes or no) at ED triage and other ED triage data, including the five-level triage acuity, emergency medical services (EMS) transport (yes or no), Glasgow Coma Scale (GCS) score, body temperature, pulse rate, respiratory rate, oxygen saturation  as listed above. Missing values in variables were retrieved by a research assistant from the patient’s EHR, or replaced with imputed values if no substantial missing rate (<10%) in that specific variable. The binary outcome of SARS-CoV-2 infection was designated as the classification label. We split the dataset into the training and testing cohorts by time of presentation at a ratio of 60:40 to simulate a prospective validation of the derived model. Data were entered and processed with Microsoft Excel 2010  and then analyzed with IBM SPSS Statistics for Windows version 24.0 . We reported results as mean with standard deviation for continuous variables, percentages for categorical variables, and median with interquartile range for time variables.P<0.1 in the training cohort as the input features for constructing the ML models. Supervised ML algorithms using random forest, gradient boosting, and extra trees classifier were employed to construct the prediction models. Models were trained in the training cohort and performances were evaluated in terms of area under the receiver operating characteristic curve (AUC) on the testing cohort. We also reported the classification performances on the testing cohort using accuracy, F1-score, precision , recall (sensitivity), specificity, negative predictive value (NPV), and area under the precision-recall curve, also known as average precision (AP), for each model. All ML analyses were performed using Python 3.8 programming language  with package scikit-learn 0.23.1 installed.17We used univariate analyses  as the feature selection strategy, and we selected variables with We retrieved a total of 598 cases from the EHR system during the targeted study period. After excluding those non-ED patients or patients without ED triage data, we identified 580 cases receiving the RT-PCR testing for SARS-CoV-2. Of them, 98 were confirmed to have the SARS-CoV-2 infection based on the RT-PCR results. The positivity rate of COVID-19 in this cohort was 16.9%. Missing data ranged from a low of 0% for most of the variables to a high of 7.6% for BMI. There were 36 cases (6.2%) with travel history and 110 (19.0%) with contact history. Of the 36 included symptoms, shortness of breath was the most common symptom , followed by fever  and cough . The training cohort consisted of 348 cases presented to our ED from February 23–April 14, 2020, while the testing cohort consisted of 232 cases from April 14–May 12, 2020. The characteristics of the study population are shown in P-value of less than 0.10 from the training cohort, including four demographics ; six triage data ; seven symptoms ; and four PMH .The characteristics and univariate analyses of variables (features) between patients with or without COVID-19 are summarized in 2 as their most important features for the construction of the prediction models.Classification results on the testing cohort for the three different ML models are presented in 2 – are discussed below.In this study, we applied ML techniques to predict SARS-CoV-2 infection from patients who visited the ED during the early months of the COVID-19 pandemic. By using 21 clinical features available at ED encounters, we successfully built ML models capable of classifying the risk of SARS-CoV-2 infection. Instead of using base models like decision tree learning, all of the models we used in this study were ensemble methods, which are ML methods that construct a set of predictive models and combine their outputs into a single prediction to achieve better predictive performance.The spectrum of symptoms caused by COVID-19 ranges from mild to critical; most patients’ symptoms are not severe and they may even be asymptomatic,25In a multicenter study conducted in China, Mei et al developed AI algorithms to combine findings on chest computed tomography (CT) with clinical symptoms, contact history, and laboratory results to diagnose patients with COVID-19.In comparison with either CNN or MLP models in the Mei et al study, our random forest model achieved 0.86 AUC with clinical features alone. This improved AUC may be caused by the increased number of clinical features incorporated in our model as compared to the model developed by Mei et al.2 <95%) achieved more than 80% specificity. Similarly, features selected to construct the ML models in our studies – temperature, BMI, weight, contact history, oxygen saturation, and respiratory rate – were consistently ranked as the top six important variables in predicting COVID-19. It has been reported that people with elevated BMI or body weight may sustain a more serious SARS-CoV-2 infection.In a study conducted by Peyrony et al that included a cohort of 391 patients with 57.5% infected with COVID-19, the most commonly reported symptoms were fever, cough, dyspnea, and myalgia.Our study included 580 patients receiving RT-PCR testing for SARS-CoV-2 during late February and early May 2020, among whom, 98 (16.9%) patients tested positive. The training and testing cohorts were divided chronologically to simulate a prospective study; ie, the performance of the ML models were developed on the basis of the past (training) cohort and evaluated in the future (testing) cohort. The study demonstrated excellent AUC results based on the three ML models we used, with the random forest model achieving the best performance in this analysis (0.86). During this period, the policy for performing RT-PCR testing did not change substantially in our hospital and, therefore, the features between training and testing cohorts were quite similar . AlthougIn addition to AUC, we evaluated the performance of our models by using a series of the available performance measures, including specificity, recall (sensitivity), and precision (or PPV). Precision is a measure of how often the predictions for the positive class are actually true, and the goal of a good ML model is to obtain the right balance of precision and recall . While wThe COVID-19 pandemic has propagated exponentially because of widespread person-to-person transmission and global transportation.Getting safe emergency care during the COVID-19 pandemic is of paramount importance both for the patients seeking help when they feel ill and for the healthcare providers in the ED. With appropriate risk stratification, healthcare personnel may thus have fewer risks of exposure to patients with suspected SARS-CoV-2 infection. As the COVID-19 pandemic persists, an ML-assisted prediction algorithm could help slow transmission and more judiciously allocate our finite healthcare resources. To be used as a diagnostic tool for aiding the identification of patients at risk of COVID-19 infection in the near future, technological feasibility assessment has to be conducted before the full implementation of the decision support tool. This assessment should be based on outlining the design of the resource requirements, and understanding the barriers and obstacles related to both science and logistics.34There are several limitations in this study. First, clinical symptoms were collected retrospectively, which could have been subject to reporting bias. For example, anosmia seemed to be under-reported in our report when compared with other studies.In addition, the fact that we split the dataset into training and testing cohorts by time of presentation may have introduced sampling bias since test availability in the US varied over the study period. Therefore, our proposed model should be proactively updated and adapted to the current patient population. Forth, clinical symptoms were manually retrieved in our study rather than being automatically extracted from the EHR. It is possible that such an approach would be biased in variable selection.Finally, due to the low positivity rate of COVID-19 in our population, our ML model construction suffered from the problem of imbalanced classification.We successfully constructed the ML models to predict COVID-19 with excellent discrimination ability based on the clinical features of initial ED encounters. Implementation of this tool may serve as an initial screening tool for identifying patients at risk of SARS-CoV-2 infection. Further validation will be necessary to determine how effectively this prediction model can be used prospectively in clinical practice.


T-cell replete Haploidentical stem cell transplantation (Haplo-SCT) with Post-transplant cyclophosphamide (PT-Cy) is an emerging therapeutic option for patients with advanced relapsed or refractory lymphoma. The feasibility of this platform is supported by several retrospective studies showing a toxicity profile that is improved relative to umbilical cord blood and mismatched unrelated donor (UD) transplant and comparable to matched unrelated donor transplant. In particular, cumulative incidence of chronic graft-versus-host disease (GVHD) is reduced after Haplo-SCT relative to UD and matched related donor (MRD) transplant thanks to PT-Cy employed as GVHD prophylaxis. This achievement, together with a similar incidence of acute GVHD and disease relapse, results in a promising advantage of Haplo-SCT in terms of relapse-free/GVHD free survival. Unmet needs of the Haplo-SCT platform are represented by the persistence of a not negligible rate of non-relapse mortality, especially due to infections and disease relapse. Future efforts are warranted in order to reduce life-threatening infections and to employ Halo-SCT with PT-Cy as a platform to build new immunotherapeutic strategies. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) represents a potential curative option for patients with refractory or relapsed lymphomas thanks to the immune-mediated graft-versus-lymphoma (GVL) effect. The existence of a GVL effect is supported first by the evidence of a reduced incidence of relapse for patients with Hodgkin (HL) and non-Hodgkin (NHL) lymphoma after Allo-HSCT (ranging between 6% and 29%) relative to autologous transplant (ranging between 35% and 69%) ,2,3,4,5.The development of new drugs for relapsed/refractory lymphomas has challenged the role of allogeneic transplant in this setting. Therapeutic chances comprise monoclonal antibodies , check-pAccording to the recommendations of the European Society for Blood and Marrow Transplantation (EBMT) , Allo-HSTwo large meta-analysis comparing Haplo-SCT relative to other donors’ transplants for patients with any hematologic malignancy have recently been published and comprise most of the published reports since 2013. In the first one, Meybodi et al.  comparedn = 180) and MRD (n = 807) transplants in terms of OS and PFS, while Haplo-SCT was hampered by significantly higher risk of NRM and aGVHD, as reported also in the metanalysis by Meybody and Gagelmann [p < 0.001) but again data on a survival endpoint such as GRFS was unfortunately not available. More recently, Fatobene et al. [p < 0.001) and cGVHD  were lower after Haplo-SCT relative to UCB transplants when the graft source was represented by bone marrow (BM) cells but similar when peripheral blood stem cells (PBSC) were used.There are three main retrospective analyses focusing only on patients with lymphomas that were published by the Center for International Blood and Marrow Transplant Research (CIBMTR) ,28,29. Iagelmann ,26. Consagelmann , Haplo-SEven with the limits of retrospective registry-based studies due to the high heterogeneity in terms of disease subtypes, conditioning regimens and graft sources, all these analysis  stronglyThree main registry-based studies analyzed the outcomes of HL patients after Haplo-SCT and performed a comparison with other donor sources. Relative to UD transplants, Kanate et al.  performeThe CIMBTR report found that Haplo-SCT was endowed by a significantly lower risk (HR: 0.45) of cGVHD relative to MRD transplants. This strikingly different incidence of cGVHD in HL patients translated in a significant improvement in terms of GRFS or extensive cGVHD/relapse free survival (CRFS). These composite endpoints are very useful to evaluate the long-term efficacy of a transplant procedure since they estimate the frequency of patients free of disease and of immunosuppression, thus reflecting potentially cured subjects experiencing a better quality of life. In details, Martinez et al.  found thAnother important and unexpected observation coming both from the EMBT and the CIBMTR studies is that the risk of HL relapse is significantly reduced after Haplo-SCT relative to MRD transplants , patient performance status (Karnofsky) and hematopoietic stem cell transplantation comorbidity index (HCT-CI) (either 0 vs. >0 or <3 vs. ≥3) . In 2013Choice of the better graft source, either bone marrow (BM) or peripheral blood stem cells (PBSC) for patients receiving Haplo-SCT is still matter of debate, with retrospective analysis showing either an increased risk of GVHD ,49 with Choice of the best haploidentical donor may represent another strategy to improve the outcome of Haplo-SCT. In a recent publication from a multicenter retrospective analysis we have shown that choice of a younger haploidentical donor results in lower chance of aGVHD and reduced NRM, while a sibling should be preferable to a parent donor in terms of relapse incidence and PFS and a father donor is better than the mother both for OS and PFS .The impact of the conditioning regimen on the outcome of transplanted patients with HL has been a matter of debate. Sureda et al. , in a prTo summarize, strategies aimed at improving disease control  and reducing transplant related complications such as aGVHD and infections (by choosing the best available donor or a less toxic conditioning regimen and by adopting better strategies to prevent infections and GVHD) are still debated and need to be explore by future randomized clinical trials. Achievement of these targets may result in a significant enhancement of the main outcomes such as OS, PFS and NRM in patients receiving Haplo-SCT.n = 2024) or MUD (n = 437) during the same time interval. Similar to HL retrospective studies, no differences were identified in terms of OS, PFS, NRM and RI (n = 26) vs. UD (n = 28) or MRD (n = 25) transplants and described similar rates of 2-year OS (77% vs. 71% vs. 83%), PFS (65% vs. 68% vs. 80%) and GRFS (65% vs. 54% vs. 66%) among the 3 donor sources  comparing three different RIC-NMA conditioning regimens ranging from a high  to intermediate  to lower (fludarabina/cyclophosphamide with TBI 2 Gy) intensity spectrum. Patients had all NHL and transplants were from a UD, either MRD or MUD. Differently from previous CIBMTR [p < 0.001) and lower OS . This observation is somehow different from a similar comparison in patients with HL [Role of conditioning regimen for NHL patients is still a matter of debate. In our recent report  employins CIBMTR ,71 studis CIBMTR  found th with HL  and is p with HL  in patien = 5). Consistently with HL reports, ORR was interesting (43%) but hampered by a high rate of toxicity due to 48% grade II-IV aGVHD and 29% moderate-severe cGVHD. Interestingly, combination of CPI with DLI resulted in a strikingly higher degree of response (80%). Combinations of DLI with bispecific or trispecific T cell engagers have not been published so far, even if phase I/II trial have been announced in the past [Post-transplant strategies comprise prophylactic DLI or usage of new drugs, such as bispecific antibodies or checkpoint blockades that may rescue donor T-cells from tolerance. Up to date the largest published experience on strategies aimed at improving post-transplant disease control for patients with lymphoma concerns DLI ,10,11,73the past .A recent consensus form the acute leukemia working party of EBMT  has summHaplo-SCT with PT-Cy as GVHD prophylaxis is a promising platform to cure patients with R/R lymphoma when a HLA identical donor, either matched related or matched unrelated, is not available. Moreover, compared with a MUD transplant, Haplo-SCT has important advantages such as better timing to find a donor and increased chances of post-transplant immune-modulation. Improving disease control and reducing NRM are warranted in order to further improve the outcomes of lymphoma patients.


Background: In-hospital mortality in acute myocardial infarction-related cardiogenic shock (AMI-CS) remains high. The only adequately powered randomized trial showed no benefit of routine use of the intra-aortic balloon pump in AMI-CS. We compared individually predicted mortality using CardShock- and IABP-Shock II-scores in AMI-CS patients treated with an Impella microaxial pump, who met the IABP-Shock II-trials inclusion/exclusion criteria, to observed mortality on circulatory support in order to determine whether standardized use of an Impella microaxial flow-pump in AMI-CS is associated with lower than predicted mortality rates and whether timing of implantation or selecting patients based on predicted risk is meaningful.Methods and Results: We analyzed data from 166 consecutive Impella-treated AMI-CS patients meeting the inclusion/exclusion criteria of the IABP-Shock II-trial (age 64 ± 11 years). Thirty-nine percentage of 64 patients had been resuscitated before Impella implantation. Overall 30-day mortality was 42%. Mortality was higher in resuscitated patients  and when Impella was implanted post-PCI . While in both score systems there was no significant difference between predicted and observed overall 30-day mortality, predicted mortality was significantly higher than observed mortality on Impella support only for individuals with highest predicted risk based on CardShock score .Conclusions: Our retrospective analysis suggests that the use of the Impella microaxial pump may be effective in selected cases of high risk patients with AMI-CS.Condensed abstract: Mortality is high in acute myocardial infarction-related cardiogenic shock despite rapid revascularization. Haemodynamic support with an intraortic balloon pump does not reduce mortality. In this retrospective registry including 166 consecutive IABP-Shock II-eligible cardiogenic shock patients in four dedicated shock centers, observed mortality on circulatory support with an Impella was significantly lower than predicted in patients with highest mortality risk. Implantation prior to PCI in acute myocardial infarction-related cardiogenic shock seemed to be associated with lower mortality than implantation post PCI. Cardiogenic shock (CS) may be caused by several conditions, though acute myocardial infarction (AMI) is one of the major contributors . The “ShThere has been renewed interest over the past decade in the use of mechanical circulatory support (MCS) to treat CS with the goal of improving outcomes. Although the intra-aortic balloon pump (IABP) was the most frequently used MCS device, this mode of support failed to improve survival compared to standard medical therapy , 8 and iPrevious randomized clinical trials using Impella microaxial pumps in AMI-CS were underpowered to detect clinically relevant differences in outcome, observed mortality was impacted by high proportions of patients with out-of-hospital cardiac arrest (OHCA), and lacked of standardization of timing of Impella placement , 12. SevWhen retrospective data from Impella-treated patients meeting the entry criteria for the IABP-Shock II study was recently used for a matched pair analysis by many European contributing centers, no benefit of Impella compared to control/IABP was observed . NeverthIn a recent small, single center analysis of patients treated with Impella CP who meet the entry criteria for the IABP-Shock II study from the HAnnover Cardiac Unloading REgistry (HACURE) , mortaliThis was a retrospective, observational analysis that included data from all patients undergoing implantation of an Impella microaxial flow-pump in all four centers who matched the inclusion/exclusion criteria of the IABP-Shock II trial [as described in detail elsewhere ] from JaIn general, all participating centers use algorithms for AMI-CS aiming for rapid detection and treatment of cardiogenic shock. Patients with AMI are taken to the cath labs when in shock and rapid revascularisation and initiation of mechanical circulatory support is used in patients requiring higher amounts of vasopressors and inotropes in conjunction with increased levels of serum lactate as sign of systemic hypoperfusion when LV-EF is impaired. Impella implantation is initiated during the initial cath lab procedure and patients are not taken to ICU for prolonged waiting periods.n = 127) or an Impella 2.5 (n = 39) at four different shock centers in Germany  and Denmark (Odense). By applying the exact definition from IABP-Shock II, patients with OHCA were included if they had return of spontaneous circulation within 30 min. Data from these patients had already been included in local databases from 2013 to early 2017. A 29 patients from Hannover and 67 patients from Odense have been included in recent single center analyses of Impella CP, which covered larger patient populations than the specific ones reported in the present manuscript  and evidence of end organ hypoperfusion as indicated by altered mental status, clammy skin, or elevated lactate (>2 mmol/l) after adequate fluid resuscitation. Individual IABP-Shock II scores were based on: Age >73, history of prior stroke, serum glucose >191 mg/dl, serum creatinine >1.5 mg/dl, blood lactate >5 mmol/L, and TIMI flow <3 after PCI as detailed previously . IndividPatient follow-up was for the period of hospitalization, and vital status was determined from medical records. The follow-up of those patients who were discharged from hospital before 30 days was obtained by documents of primary care physicians or rehabilitation hospitals. In case of discharge from hospital or rehabilitation within 30 days, further follow-up was performed by phone. Vital status was confirmed on all patients so that no patient was lost to follow up .n (%), mean ± standard deviation (SD) for normally distributed variables, or median and interquartile range (IQR) for non-normally distributed variables. Statistical analysis was performed with ANOVA and corrected for multiple comparisons with a Bonferroni correction; Kruskal-Wallis-Test was used for non-parametric tests (Numbers are given as ic tests . Chi-squp < 0.05) were performed. Analysis for correlation and multicollinearities were performed before multivariate regressions analysis. In respect of possible multicollinearities between Card Shock Score and Card Shock Categories, Card Shock Categories were not considered for regressions analysis. Results from regression analyses are expressed as hazard ratios (HR) including 95% confidence interval (CI). Data were analyzed using GraphPad Prism 6.0  and SPSS Statistics 24 (IBM SPSS Statistics 24). A p < 0.05 was considered statistically significant.Univariate Cox proportional hazard regression analyses performed with variables potentially associated with mortality rates were performed to identify factors associated with risk of death. Factors considered included: CardShock score, IABP Shock II score, resuscitation before Impella implantation and Impella implantation prior to PCI. Then, stepwise multivariate Cox regression analyses that included variables that were significantly linked to mortality in the respective univariate analyses  during the early portion of the enrolment period, whereas Impella CP was used in 127 patients (77%) during the latter portion of the enrolment period. Impella CP patients trended to be younger and have a higher rate of pre-Impella cardiac arrest; otherwise, these patients had similar baseline characteristics. Mean support time on Impella was 3 ± 3 days. Clinically meaningful differences between the current cohort and the IABP-Shock II cohort included higher serum lactates and lower ejection fractions.Adverse events are summarized in p = 0.12). However, since both scores use a maximum of 9 points each, but categorize only to three levels, we performed further analyses in each risk category: to gain insights into correlates of mortality, patients were sub-grouped according to low risk , intermediate risk  or high risk  scores ], while observed mortality was only numerically lower using IABP-Shock II-score  due to the much lower number of patients categorized as high risk by IABP-Shock II- compared to CardShock-score).The median CardShock score was 5 which corresponds to a predicted in-hospital mortality of 40%, the median IABP-Shock II score was 3 which corresponds to a 30-day mortality of 49%, while observed 30-day mortality in our cohort was 43%  scores , 2A. ForComparing characteristics of 30-day survivors and non-survivors showed that survivors were younger, had lower admission lactate levels, lower shock score values, and trended to be less often resuscitated. Importantly, there was no difference regarding type of Impella or renal function between survivors and non-survivors .n = 50/98) compared to when Impella was implanted pre-PCI . However, both groups were of similar age , had comparable renal function  and comparable LV function prior to support   .n = 15), survival trended to be better when Impella support was initiated pre-PCI instead of post-PCI.With regard to the interaction between risk scores and timing of PCI, survival was better than predicted in all categories when Impella was placed prior to PCI , 2B. Furn = 32/64) vs. non-resuscitated patients  and had higher admission lactate levels , but similar renal function . The distribution of risk scores was similar for patients with or without prior resuscitation  has been noted in several retrospective analyses to be related to better outcomes –16. In oIn the absence of prospective study results, there are several approaches to using existing registry databases to assess the impact of interventions, each with its own limitations. Recently, the authors contributed the current data to a larger analysis based on an attempted matching of baseline characteristics using patient-level data from the IABP-Shock II-trial . In contKnowing that randomly selecting patients for such an intended matched-pair analysis might not provide an ideal control group, we chose an alternate approach of calculating score-based predicted mortality risk on an individual patient level and compared the average observed event rate with predicted risk. Thereby, all qualifying patients form the registry were included and, by using the validated scores, in essence compared to information from all patients from the IABP-Shock II and CardShock studies. In our analysis we found that a potential benefit of Impella might be observed in very sick CS patients categorized as high-risk by CardShock score. Whether selecting patients for Impella treatment based on CardShock score assessment will help to reduce mortality in AMI-CS, however, has to be tested prospectively. Trying to do a propensity matched statistical study design to create a control population from the IABP-Shock II database, ideally with a greater ratio of control: Impella patients to avoid bias, would have likely resulted in even less patients included in the analysis.More recently, others have used data from larger American databases for cardiac catheterization and acute chest pain treatment . Of 28,3First, the present study utilized data from clinical practice registries, so neither control group nor randomization of treatment were available. Therefore, all results are, at most, hypothesis generating and cannot prove superiority of Impella in AMI-CS. As noted above, an alternate approach could have employed propensity score-matching to select patients from an existing database of patients with known baseline clinical characteristics and risk factors for mortality  to create a control group with characteristics and risk factors similar to those of the current cohort which was subjected to a different treatment strategy. However, assessing heterogeneous patient cohorts such as those encountered in CS would require a much larger database for propensity matching based on all essential parameters such as age, sex, left-ventricular ejection fraction, renal function, admission lactate, prior resuscitation, timing of initiation of support relative to PCI and mechanical ventilation. As also noted, a properly powered prospective randomized controlled trial comparing Impella vs. standard of care in AMI-CS, the DanGer study  is highlIn the absence of randomized trails, the decision whether and which form of MCS to be used is based on institutional and clinical experience. While our data do not support unselected use of circulatory support in AMI-CS, identifying patients deemed at higher risk using scores such as the IABP-Shock II and/or CardShock may help to select patients more likely to benefit from Impella treatment. In our cohort, CardShock score was more predictive of outcomes.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Hannover Medical School. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.AS, NW, RW, and JM designed the study. All authors acquired and analyzed the data. AS, NW, DB, RW, and JM drafted the manuscript. J-TS, AZ, MM, and NJ critically revised the manuscript. All authors agree to be accountable for all aspects of the work ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.AS, NW, DB, RW, and JM have received modest lecture fees, honoraria and research grants from Abiomed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Purpose: The COVID-19 pandemic impacted the sporting and exercise activities of millions of youth. Running is an activity that could be maintained while social distancing restrictions were implemented during the pandemic. If running-related injuries do occur, these restrictions may also influence the access to care or care seeking behavior of this population. Therefore, the purpose of this study was to determine if the social distancing restrictions during the 2020 COVID-19 pandemic influenced training habits, injury, and care seeking behavior in youth long-distance runners.Methods: A customized, open online questionnaire was provided to runners 9–19 years of age who participated in long-distance running activities including team/club cross-country, track and field (distances ≥800 m), road races, or recreational running. Participants responded to questions about demographics, running habits, RRIs, and health care provider visits 6-months before as well as during social distancing restrictions due to COVID-19. Wilcoxon signed rank tests compared differences for ratio data and Chi-square tests were used to compare proportions before and during COVID-19 social distancing restrictions. Statistical significance was set at p ≤ 0.05.Results: A total of 287 youth long-distance runners  participated. Compared to their pre-COVID-19 responses, youth long-distance runners reported lower distances run per week (p < 0.001), fewer runs per week (p < 0.001), fewer hard runs per week (p < 0.001), fewer number of injuries (p < 0.001), and fewer injuries per 1,000 km (p = 0.002) during the COVID-19 social distancing restrictions. A lower proportion of participants reported in-person health care provider visits (p < 0.001) and a lower proportion of visits were made to an athletic trainer during COVID-19 social distancing restrictions compared to prior to COVID-19 (p < 0.001).Conclusion: The COVID-19 pandemic resulted in significant decreases in both training and injuries which were different compared to previous reports in an adult population. Many of the runners who sustained an injury during COVID-19 social distancing restrictions did not seek care, with the most prominent reduction in visits to an athletic trainer. This could impact future injury and chronic pain. On March 11th, 2020, the World Health Organization (WHO) declared Coronavirus Disease 2019 (COVID-19) a pandemic  self-reported weekly running distance, frequency, and intensity would decrease during restrictions, (2) social distancing restrictions would result in fewer injuries, and (3) injured long-distance runners would report more telehealth appointments and fewer in-person appointments with health care providers; athletic trainers would see the greatest reduction in health care encounters.Youth long-distance runners were recruited via emails sent to middle- and high-school athletic directors or coaches across the United States and previous participants in youth long-distance running studies from two institutions. Recruitment materials were initially sent May 2020 through June 2020 with a secondary invitation sent between 10 and 14 days after the initial invitation. The survey link was also shared on various social media platforms and others were encouraged to share the survey. Participants were eligible for study inclusion if they were 9–19 years of age and participated in long-distance running activities including team/club cross-country, track and field (distances ≥800 m), road races, or recreational running. Participants were excluded if their primary sport was not cross-country or track and field and they did not participate in long-distance running activities and/or if they resided outside of the United States. Study procedures were approved by the Institutional Review Boards at the University of Toledo and Cincinnati Children's Hospital Medical Center. Prior to study enrollment, consent was obtained for participants 18 or 19 years of age while parental permission and child assent were obtained for those 9–17 years-old. The participants received no incentives for participating.A customized, open online questionnaire was provided to the participants through a password-protected Qualtrics  or Research Electronic Data Capture  instrument. The Checklist for Reporting Results of Internet E-Surveys (CHERRIES) was used to ensure study quality , average number of runs per week, and average number of higher intensity runs per week  . Injured runners were asked about the type of health care visit they sought . Telehealth visits included remote video or audio calls. Respondents were also asked about the provider specialty that the participant visited for the injury .Incomplete responses were excluded and completed surveys were used for analysis. The IP address was recorded for each response. If duplicate IP addresses were identified, the responses were checked for originality and responses from the same IP address were only used if the responses were clearly different. Weekly running distance was reported in miles and then converted to kilometers (km). The number of injuries for each person were normalized to 1,000 km to reduce the impact that running volume could have on the injury rate.p ≤ 0.05). Wilcoxon signed rank tests compared differences before and during COVID-19 social distancing restrictions for distance run per week, number of runs per week, number of hard runs per week, number of injuries and number of injuries per 1,000 km. For participants that reported ≥1 RRI before and/or during COVID-19 social distancing restrictions, chi-square tests compared differences in proportions of health care providers and visit types before and during COVID-19 social distancing restrictions. Statistical significance was set at p ≤ 0.05.Data analysis was conducted using SPSS statistical software . Data were found to be non-normally distributed , fewer runs per week (p < 0.001), and fewer hard runs per week (p < 0.001) during the COVID-19 social distancing restrictions  met inclusion criteria and were fully completed  and fewer injuries per 1,000 km (p = 0.002) than pre-COVID-19 social distancing restrictions  and a higher proportion of not visiting a health care provider (p < 0.001), while the proportion of telehealth visits did not change  of visits were made to an athletic trainer during COVID-19 social distancing restrictions compared to prior to COVID-19 (56% of visits).COVID-19 social distancing restrictions impacted the proportion of youth long-distance runners seeking care for their injuries compared to pre-COVID-19 behaviors. A lower proportion of participants reported in-person health care provider visits  of their visits were in-person and only a small amount of injuries were not brought to the attention of a health care provider (16.4%). Youth runners significantly reduced their visits to health care providers during the COVID-19 restrictions (41.5%) and were 3.6 times more likely to not visit a health care provider (58.5%) for their injury. Young runners may rely on their parents for transportation or assistance with provider interactions, creating an additional burden to care seeking behaviors. Telehealth appointments are a feasible alternative to in-person appointments (Tenforde et al., The reduction in visits were primarily evident in reported visits to athletic trainers. Injured youth long-distance runners utilized an athletic trainer significantly less for their health care needs during the COVID-19 pandemic. Youth runners sought care from athletic trainers 2.7 times less during this period, though care seeking behavior from other providers did not change. Approximately 76% of high schools employ an athletic trainer (Huggins et al., The primary limitation of the current study is the cross-sectional design of an online survey where recall bias could influence the reporting of training habits and injuries. We attempted to minimize the impact of this bias by limiting the recall period to 6 months prior to COVID-19. Social distancing restrictions also differed in extent and timeline based on state government decisions, leading to likely variability in the stay-at-home orders affecting each participant. This study is also limited in that we only assessed the runners' responses at one time point. Future research should prospectively investigate training habits and injuries in a larger group of youth runners in the season following the COVID-19 restrictions to provide evidence of a long-lasting impact in this running population. Finally, even though we attempted to get a broad sense of the COVID-19 impact on the runners, the responses were weighted more heavily among a few US states which could also have introduced a geographic bias. Future research should attempt to capture a more balanced sampling of responses of youth runners in different regions of the US to better examine any geographic influence. In regard to COVID-19, future research should follow individuals over time to determine the influence of social distancing, reduced running, and reduced care-seeking behavior has on long-term running health and habits.Within the context of these limitations, this study provides novel information about the effects that a large-scale cancellation of a sports season and social distancing restrictions may have on youth long-distance runners. Following social distancing requirements from the COVID-19 pandemic, youth long-distance runners reported significant decreases in both training and injuries, which were different compared to previous reports in an adult population (DeJong et al., The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Toledo Institutional Review Board and Cincinnati Children's Hospital Medical Center Institutional Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.DB-J, MG, JT-H, JL, MR, MP, and KF designed the study, contributed to data collection and analysis, and critically reviewed the manuscript before submission. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


While cytokine storm develops in a minority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, novel treatment approaches are desperately needed for those in whom it does. Tocilizumab, an interleukin-6 receptor antibody, has been utilized for the treatment of cytokine storm in a number of severe inflammatory conditions, including in patients with severe coronavirus disease 2019 (COVID-19). Here, we present the first published case utilizing this therapy in a patient with underlying immunodeficiency. Our patient with aplastic anemia developed cytokine storm due to COVID-19 manifested by fever, severe hypoxia, pulmonary infiltrates, and elevated inflammatory markers. Following treatment with tocilizumab, cytokine storm resolved, and the patient was ultimately safely discharged from the hospital. To date, the novel SARS-CoV-2 has infected more than 4,500,000 people in the United States and more than three times that number worldwide. While a minority of patients develop severe symptoms from COVID-19 requiring hospitalization, treatment options for those who do are limited. There is no currently accepted standard and new approaches are desperately needed.Following the initial reports of COVID-19 from Wuhan, China, Huang et al.  and mortTreatment with tocilizumab, an anti-IL-6 receptor (IL-6R) antibody, has been proposed as a strategy to control cytokine storm associated with COVID-19 , 5. ThisA 72-year-old man with a past medical history of AA, amegakaryocytic thrombocytopenia and chronic kidney disease (CKD) stage 3 presented in April 2020 with high fever, cough, and progressive fatigue.Aplastic anemia had been diagnosed in 2014 and initially responded to therapy with horse anti-thymocyte globulin (ATG), methylprednisolone and cyclosporine A. Nine months later, his disease progressed and he was treated with rabbit ATG, methylprednisolone, and cyclosporine A. In late 2019, his disease progressed primarily as thrombocytopenia due to acquired amegakaryocytic thrombocytopenia (AAT). He received four doses of rituximab in early 2020 for treatment of AAT without response. Bone marrow biopsy performed 2 months prior to presentation was hypocellular with 15–20% bilineage hematopoiesis and near absence of megakaryocytes without evidence of dysplasia or increased blasts. While his diagnosis is most accurately classified as AAT at the time of presentation, he had been consistently pancytopenic for 4 months despite treatment with cyclosporine A and remained dependent on platelet transfusions. Family and psycho-social history were non-contributory.Physical examination at the time of presentation was notable for fever of 103.7F and mild tachycardia (HR 104) with normal oxygen saturation (97%) without supplemental oxygen. He appeared in mild respiratory distress, but pulmonary examination was unremarkable. His initial laboratory studies were notable for severe lymphopenia, which was different from his baseline pancytopenia and elevated C-reactive protein (CRP) and IL-6 as noted in The patient was treated empirically with hydroxychloroquine  for possible COVID-19 in the setting of immunosuppression. Ceftriaxone and azithromycin were added for possible community acquired pneumonia. On admission day 0, SARS-CoV-2 PCR nasal swab came back positive. For the first several days of the hospitalization, the patient had persistent fever (range 100–104F) and intermittently required oxygen up to 2 L/min via nasal cannula to maintain oxygen saturation above 94%.By hospital day 5, he had developed progressive pancytopenia and required near daily transfusion of packed red blood cells and platelets. Due to persistent high fever, and now neutropenia, antibacterial coverage was broadened to cefepime, then meropenem, and antifungal prophylaxis with posaconazole was added. He was also started on tbo-filgrastim and eltrombopag for management of severe neutropenia and thrombocytopenia.On hospital day 9, the patient developed lethargy and hypoxia requiring supplemental oxygen of 6 L/min via nasal cannula and subsequently Venturi mask at 50% FiO2. Repeat chest radiograph demonstrated significant worsening with bilateral pulmonary infiltrates . InflammThe clinical picture was consistent with cytokine storm due to severe COVID-19 and the patient promptly received tocilizumab 5 mg/kg (400 mg) on hospital day 11. The patient received a single dose of methylprednisolone 60 mg IV immediately prior to tocilizumab administration but did not otherwise receive corticosteroid treatment during his admission. The same day, the patient's fever resolved and he developed mild hypothermia (minimum 94.6F). Over the next several days, his temperature normalized, oxygen requirements steadily declined, inflammatory markers decreased and acute renal failure resolved. The patient remained pancytopenic and transfusion dependent. Meropenem was discontinued and he was transitioned to oral levofloxacin prophylaxis due to persistent neutropenia.On hospital day 18, the patient developed mild recurrent fever . The following day, his fever increased significantly to 103.9F and his oxygen requirement increased to 10 L/min. Chest radiograph revealed new pulmonary infiltrates . CefepimBy hospital day 20, the patient had again clinically improved. His blood pressure remained within normal range and his oxygen requirement decreased to 6 L/min by nasal cannula. The exact cause of his brief clinical deterioration was unclear but was presumed to be due to a secondary bacterial pneumonia. Over the subsequent days, he completed a 7-day course of meropenem and vancomycin. He remained afebrile on this treatment and his oxygen requirement slowly normalized. His repeat IL-6 level on day 28 was significantly elevated at 1223.8 pg/mL.The patient was discharged home on hospital day 31. He remained pancytopenic and transfusion dependent at the time of hospital discharge. Notably, his SARS-CoV-2 PCR testing has remained persistently positive as of hospital day 29 . It is unclear whether detectable viral RNA represents persistent infectiousness or whether non-infectious RNA fragments are being detected. Twenty two days after hospital discharge, SARS-CoV-2 PCR was repeated and was negative.Hyperinflammatory syndromes, such as the cytokine storm observed in patients with severe SARS-CoV-2 infection, play a major role in the development of critical illness associated with viral infections. Multiple reports have identified significant increases in inflammatory markers, including IL-6, in patients with severe SARS-CoV-2 infection , 10–12. IL-6 serves many important immunologic and hematopoietic functions, including differentiation of activated B cells to immunoglobulin-producing plasma cells, differentiation of naïve CD4+ T cells to Th17 cells and of CD8+ T cells to cytotoxic T cells, promotion of T follicular helper cell differentiation, inhibition of regulatory T cell (Treg) differentiation and stimulation of acute-phase proteins . In combThe most promising data thus far are from a retrospective analysis of the use of 1–2 doses of tocilizumab in 21 adult patients with severe or critical COVID-19 treated at two centers in China. Following treatment, all patients became afebrile and 70% had decreased oxygen requirements. Nineteen patients (90.5%) had been discharged from the hospital, including two critical patients, after a mean of 13.5 days following treatment with tocilizumab. No patients developed recurrent fever or symptoms of recurrent pneumonia (p = 0.001) and mechanical ventilation  compared to matched controls. No benefit in mortality was seen after weighted analysis  showed that treatment with tocilizumab 8 mg/kg for 1–2 doses was associated with decreased ICU admission . The degree of IL-6 elevation was associated with severity of disease and reduction in IL-6 level was associated with response to immunosuppressive therapy (IST) (p = 0.005) and that an IL-6 level of at least 36.8 pg/mL had 81% sensitivity to distinguish responders from non-responders  . Others sponders . There aBeing a single patient report is a major limitation. However, we felt that it's prudent to report the first use of tocilizumab to treat a cytokine storm induced severe SARSCoV-2 in a patient with underlying immunodeficiency. The findings are consistent with what has been reported in immune competent patients. The rapid clinical improvement and decline of all inflammatory markers suggests that tocilizumab was effective in reversing COVID-19-associated cytokine storm.“I started feeling tired and had no energy even to walk short distances. I had a fever and minor cough. I went to the Emergency Room [sic] at Jefferson [sic], and I tested positive [for SARS-CoV-2] and they admitted me. The first couple of weeks , I slept most of the time. I was either on my back in bed or in a chair. After I started to get better, I was more awake and I became depressed and bored. I looked forward to my daily [physical therapy] visits. It is certainly difficult not having visitors. The doctors and nurses were excellent. The doctors communicated with my wife every day. I simply cannot say enough about the care I received. When released from the hospital, I came directly home and have been receiving nursing care and [physical therapy].My case is complicated by the fact that prior to my hospitalization I required transfusions for aplastic anemia. The medical staff worked diligently to have a procedure for transfusing patients with [COVID-19] as outpatients. They were able to have a procedure set up of which I was the first. The care and attention I received at the infusion center was well-organized and excellent. My improvement is progressing and I am getting better every day.”Until now, treatment of severe COVID-19 with tocilizumab has been tried in patients without pre-existing immune dysfunction. We have reported the first use of this treatment strategy in a patient with underlying immunodeficiency. It is notable that both the symptoms and signs of severe COVID-19 and the result of therapy with tocilizumab is similar to prior reports in patients with presumably normal baseline immune function. More work is desperately needed to better understand the immunological impacts of severe SARS-CoV-2 infection and the risks and benefits of tocilizumab treatment.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.GK and ZF wrote the manuscript. LW, JF-O'H, UG, and AB reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute bronchiolitis caused by respiratory syncytial virus (RSV) has been associated with greater risk of recurrent wheezing and asthma. However, it is unclear whether this association is causal. RSV-specific monoclonal antibodies have been shown to reduce RSV-related hospitalisations in high-risk infants, but the longer-term follow-up has given conflicting evidence for prevention of recurrent wheeze or asthma.We performed a systematic review and meta-analysis to determine whether monoclonal antibody prophylaxis against RSV bronchiolitis reduces the risk of subsequent recurrent wheeze or asthma. If so, this may support the hypothesis of causality.I2 statistic.Studies were identified via an online database search using Embase, MEDLINE, PubMed, Web of Science and the Cochrane Library. Manufacturers of monoclonal antibodies were contacted directly for unpublished data. The intervention of interest was RSV monoclonal antibody prophylaxis, and the primary outcome measure was recurrent wheeze and/or asthma. Studies were screened according to inclusion/exclusion criteria. Included studies were evaluated for quality and assessed for bias independently by 3 reviewers using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) approach. Results were extracted into 2 × 2 outcome tables and a meta-analysis carried out producing forest plots based on relative risk. Heterogeneity was assessed using the p = 0.008). A further sub-group analysis for infants aged 32 to < 36 weeks showed a statistically significant relative risk of 0.35 .The search identified 141 articles, which, after screening, resulted in eight studies , thus including 11,195 infants in the meta-analysis. The overall result demonstrated a non-statistically significant reduction in relative risk of developing recurrent wheeze or asthma . Study quality was generally low with evidence of publication bias and statistical heterogeneity. However, sub-group analysis excluding studies deemed to be ‘very low’ quality showed a relative risk of 0.42 (95% CI 0.22 to 0.80, We did not identify an overall statistically significant benefit. However, our two sub-group analyses did find statistically significant benefits of monoclonal antibody therapy on the risk of recurrent wheeze and asthma. The main limitation of this study is the lack of high-quality randomised controlled trials, highlighting the need for more research in this field.The online version contains supplementary material available at 10.1186/s13643-020-01527-y. Bronchiolitis, an acute lower respiratory tract infection (LRTI), is the most common reason for hospitalisation in young children in many countries including the UK and USA . The majRecurrent wheeze in infancy is common, with one large international study of infants reporting that 45% had at least one wheezing episode, and 20% had three or more . When reAcute bronchiolitis in early life is very strongly associated with an increased risk of asthma development . It has The most common cause of acute bronchiolitis is respiratory syncytial virus (RSV), primarily occurring in infants up to 12 months. RSV-specific monoclonal antibodies provide passive immunity and have shown efficacy in reducing RSV hospitalisations in high-risk infants, such as those born prematurely –15. CurrMonoclonal antibodies are prohibitively expensive and the estimated cost of palivizumab is approximately £3000–£5000 ($3700–$6200 USD) per child . DespiteTo further examine the relationship between RSV bronchiolitis and subsequent development of recurrent wheeze and asthma, we conducted a systematic review and meta-analysis to determine whether monoclonal antibody RSV prophylaxis compared with no prophylaxis, in infants born from early pre-term up to term, reduces the risk of recurrent wheeze or asthma development in later childhood.https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-019-1251-x. Findings are reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) standards  and is accessible at 9i28239 aTable The intervention being investigated was the use of RSV-specific monoclonal antibodies for RSV immunoprophylaxis compared to no RSV prophylaxis or placebo. The only outcome measured was development of subsequent recurrent wheeze and/or asthma as defined by the study authors, including parent-reported wheeze as well as formally doctor-diagnosed wheeze or asthma. Parent-reported wheeze is an important outcome to include as not all infants who wheeze will be assessed by a physician. Other outcomes such as RSV hospitalisation or allergy diagnosis were assessed in some studies; however, these are not a priority for this review.ClinicalTrials.gov’ and ‘BMC Trials’ and the WHO International Clinical Trials Registry, for any potentially suitable studies that may be imminently reported and published. The date last searched was July 2020. Reference lists of included and other relevant papers were hand searched to identify possible additional primary studies.The literature search, using the strategy in Table Studies were independently screened according to inclusion and exclusion criteria by 2 independent reviewers (HG and MS). The screening was a 2-step process, first by title and abstract, and then by full text. A third-party reviewer was involved in the case of any disagreements. Duplicate articles, identified using reference software, were removed.Data were extracted using an adapted form of the ‘Data collection form for Intervention review—RCTs and non-RCTs’ of the Cochrane Collaboration  Additio. Data isStudy validity was evaluated using the Cochrane Risk of Bias table, and overall quality of evidence was evaluated independently by 3 reviewers using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) approach as detailed in our protocol .Using the main outcome of recurrent wheeze (dichotomous—yes/no) and the data from the 2 × 2 outcome tables produced, a meta-analysis was performed using a random effects model, with relative risk as the principal summary measure. Individual studies are represented on a forest plot based on relative risk and 95% confidence intervals. Funnel plots were generated to portray publication bias or possible selective reporting within studies. StatsDirect statistical software was used for the meta-analysis .I2 test, taking an I2 of > 75% as being high heterogeneity.To test for heterogeneity (inconsistency between studies), we used the Sub-group analysis of late pre-term infants was performed to explore the effectiveness of RSV prophylaxis on subsequent recurrent wheeze in this population. Sub-group analysis excluding very low-quality evidence was also carried out, due to the risk of confounding by indication.The search across the main databases generated 141 references. After removal of duplicate papers and full-text screening, eight studies were included in this review Fig. .Fig. 1PIn total, 11,195 infants were included in this review. The gestational age of participants ranged from 24 weeks to full term and the median length of follow-up across the studies was 4 years (range 2 to 6 years). Of the 8 studies, 5 reported a reduction in recurrent wheeze after RSV-specific monoclonal antibody prophylaxis.I2 96.6%; 95% confidence interval [CI] 95.4 to 97.3%).Quality of evidence was variable. The two RCTs were considered as high-quality evidence, with most other studies graded as low-quality evidence. The funnel plot in Fig. p = 0.129).Figure p = 0.008).Two studies  , 38 werep = 0.02) . However, later pre-term infants aged between 32 and 36 weeks gestation also have high RSV hospitalisation rates (3.75% and 9.8%) and immunological differences in lung development . Our preWhile there is an established association between RSV infection and subsequent recurrent wheeze, there is question of whether or not this recurrent wheeze can be called asthma. The MAKI trial  was initially published in 2013 as a 1-year follow-up study; however, in this systematic review, we included the 6-year follow-up data. The original 1-year study found a statistically significant reduction in the proportion of infants with recurrent wheeze in the palivizumab-treated group . In the RSV infection itself causes direct damage to the lungs, particularly in premature infants, for example ciliary destruction, necrosis of epithelial cells, inflammation of the submucosa and bronchiolar plugging from mucous secretions . ConsideFirm conclusions from this systematic review are hindered by the lack of good-quality evidence. Only eight studies were eligible to be included in the review and of these 8, only 2 were considered to be of high quality. The significant statistical heterogeneity between the studies and publication bias found is likely to affect the overall pooled results of this meta-analysis, introducing significant risk of bias. Ideally, more RCTs are needed to investigate the role of monoclonal antibody prophylaxis on the outcome of recurrent wheeze. However, such RCTs in at-risk populations would be difficult given the proven benefit of palivizumab in prevention of severe RSV bronchiolitis in pre-term infants. A further major limitation is the lack of long-term follow-up in the studies included. This meant that our outcome used was recurrent wheezing rather than true asthma. Further studies with longer follow-up are required to address the question of RSV prevention and asthma causation.The main strength of this systematic review and meta-analysis is the thorough literature search, careful study selection with strict inclusion criteria, and comprehensive assessment of bias using the established GRADE approach. Furthermore, the findings of this study are in support of existing evidence for the association between RSV bronchiolitis and recurrent wheeze/asthma.It is still unclear whether administering RSV prophylaxis to pre-term infants reduces the risk of respiratory complications later in childhood. On the basis of pre-specified sub-group analyses excluding low-quality studies, and focusing on late pre-term infants, we conclude that potential long-term benefits cannot be ruled out. This review highlights the need for longer-term high-quality clinical trials investigating RSV prophylaxis on the outcome of asthma, as current evidence is of very limited quality. In particular, there should be a focus on these benefits in late pre-term infants (32–36 weeks).Additional file 1. PRISMA 2009 Checklist.DOCX 19 kb)Additional file 2. Studies excluded based on full text, with full citation and reasoning.