Protection provided by a commercial modified-live porcine reproductive and respiratory syndrome virus (PRRSV) 1 vaccine (PRRSV1-MLV) against a Japanese PRRSV2 field strain

Background@#Porcine reproductive and respiratory syndrome virus (PRRSV) vaccines do not provide full cross-protection, mainly due to the virus genetic variability. Despite this, vaccines based on modified-live PRRSV (PRRSV-MLV) reduce the disease impact. @*Objectives@#To assess the efficacy of two commercial vaccines—one based on PRRSV1 (PRRSV1-MLV) and another on PRRSV2 (PRRSV2-MLV)—against a Japanese PRRSV2 field strain. @*Methods@#Two groups of three-week-old piglets were vaccinated (G1: PRRSV1-MLV; G2:PRRSV2-MLV) and two were kept as non-vaccinated (INF and CTRL). One month later, G1, G2, and INF were challenged with a PRRSV2 field strain. @*Results@#After the challenge, clinical signs were only observed in INF. Moreover, the highest rectal temperatures and values for the area under the curve (AUC) were observed in INF. Regarding viral detection, both AUC and the proportion of positive samples in blood were higher in INF. In G1, viremic animals never reached 100%. At necropsy (21 d after the challenge), differences for titers among groups were only found in tonsils (G1 < G2 and INF). One animal (belonging to G1) was negative in all tissues. Regarding humoral responses, G1 and G2 seroconverted after vaccination, as detected in the corresponding enzyme-linked immunosorbent assay. Specific neutralizing antibodies (NA) against PRRSV1-MLV were already detected at 14 d after vaccination in G1, showing a significant booster after the challenge, while PRRSV2-MLV NA were detected in G2 at the end of the experiment. @*Conclusions@#Despite genetic differences, PRRSV1-MLV has been demonstrated to confer partial protection against a Japanese PRRSV2 strain, at least as good as PRRSV2-MLV.

Intraoperative Neurovascular Bundle Preservation with Hyaluronic Acid during Radical Brachytherapy for Localized Prostate Cancer: Technique and MicroMosfet In Vivo Dosimetry.

PURPOSE: To evaluate the reduction in the absorbed dose delivered to the neurovascular bundle (NB) in patients with localized prostate cancer treated with only HDR brachytherapy and NB protection with hyaluronic acid (HA) on the side of the prostate to increase the distance from NB to the radioactive sources. METHODS: This is the first published report in the medical literature that studies a new approach to decrease neurovascular bundle toxicity and improve quality of life for patients with prostate cancer treated with radical brachytherapy as monotherapy. Transperineal HA injection on the side of the prostate into the lateral aspect of the prostate fat was used to consistently displace several autonomic fibers and vessels on the lateral wall of the prostate away from radiation sources. RESULTS: When a protection in the form of an HA layer is placed, the reduction effect at the maximum dose is between 46% and 54% (calculated values), which means that the method for protection is highly recommended. The values of the absorbed dose calculated in this project have been compared with the ones given by the treatment planning system. CONCLUSIONS: This newly created space decreases absorbed dose in the NB, calculated with the TPS and measured by microMOSFET due to the thickness of HA.

Corticosteroids in COVID-19: Optimizing Observational Research through Target Trial Emulations

ImportanceCommunication and adoption of modern study design and analytical techniques is of high importance for the improvement of clinical research from observational data. ObjectiveTo compare (1) a modern method for causal inference including a target trial emulation framework and doubly robust estimation to (2) approaches common in the clinical literature such as Cox proportional hazards models. To do this, we estimate the effect of corticosteroids on mortality for moderate-to-severe coronavirus disease 2019 (COVID-19) patients. We use the World Health Organizations (WHO) meta-analysis of corticosteroid randomized controlled trials (RCTs) as a benchmark. DesignRetrospective cohort study using longitudinal electronic health record data for 28 days from time of hospitalization. SettingsMulti-center New York City hospital system. ParticipantsAdult patients hospitalized between March 1-May 15, 2020 with COVID-19 and not on corticosteroids for chronic use. InterventionCorticosteroid exposure defined as >0.5mg/kg methylprednisolone equivalent in a 24-hour period. For target trial emulation, interventions are (1) corticosteroids for six days if and when patient meets criteria for severe hypoxia and (2) no corticosteroids. For approaches common in clinical literature, treatment definitions used for variables in Cox regression models vary by study design (no time frame, one-, and five-days from time of severe hypoxia). Main outcome28-day mortality from time of hospitalization. Results3,298 patients (median age 65 (IQR 53-77), 60% male). 423 receive corticosteroids at any point during hospitalization, 699 die within 28 days of hospitalization. Target trial emulation estimates corticosteroids to reduce 28-day mortality from 32.2% (95% CI 30.9-33.5) to 25.7% (24.5-26.9). This estimate is qualitatively identical to the WHOs RCT meta-analysis odds ratio of 0.66 (0.53-0.82)). Hazard ratios using methods comparable to current corticosteroid research range in size and direction from 0.50 (0.41-0.62) to 1.08 (0.80-1.47). Conclusion and RelevanceClinical research based on observational data can unveil true causal relationships; however, the correctness of these effect estimates requires designing the study and analyzing the data based on principles which are different from the current standard in clinical research. Key PointsO_ST_ABSQuestionC_ST_ABSHow do modern methods for causal inference compare to approaches common in the clinical literature when estimating the effect of corticosteroids on mortality for moderate-to-severe coronavirus disease 2019 (COVID-19) patients? FindingsIn an analysis using retrospective data for 3,298 hospitalized COVID-19 patients, target trial emulation using a doubly robust estimation procedure successfully recovers a randomized controlled trial (RCT) meta-analysis benchmark. In contrast, analytic approaches common in the clinical research literature generally cannot recover the benchmark. MeaningClinical research based on observational data can unveil true causal relations. However, the correctness of these effect estimates requires designing and analyzing the data based on principles which are different from the current standard in clinical research. Widespread communication and adoption of these analytical techniques are of high importance for the improvement of clinical research.

Challenges on optical printing of colloidal nanoparticles.

While colloidal chemistry provides ways to obtain a great variety of nanoparticles with different shapes, sizes, material compositions, and surface functions, their controlled deposition and combination on arbitrary positions of substrates remain a considerable challenge. Over the last ten years, optical printing arose as a versatile method to achieve this purpose for different kinds of nanoparticles. In this article, we review the state of the art of optical printing of single nanoparticles and discuss its strengths, limitations, and future perspectives by focusing on four main challenges: printing accuracy, resolution, selectivity, and nanoparticle photostability.

Risk of Ischemic Stroke in Patients with Covid-19 versus Patients with Influenza

Key PointsO_ST_ABSQuestionC_ST_ABSHow does the risk of acute ischemic stroke compare between patients with Covid-19 and patients with influenza (a respiratory virus previously linked to stroke)? FindingsIn this large retrospective cohort study conducted at two academic hospitals in New York City, patients with emergency department visits and hospitalizations with Covid-19 were approximately seven times as likely to have an acute ischemic stroke as compared to patients with emergency department visits or hospitalizations with influenza. MeaningPatients with Covid-19 are at heightened risk for acute ischemic stroke as compared to patients with influenza. ImportanceCase series without control groups suggest that Covid-19 may cause ischemic stroke, but whether Covid-19 is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection is uncertain. ObjectiveTo compare the rate of ischemic stroke between patients with Covid-19 and patients with influenza, a respiratory viral illness previously linked to stroke. DesignA retrospective cohort study. SettingTwo academic hospitals in New York City. ParticipantsWe included adult patients with emergency department visits or hospitalizations with Covid-19 from March 4, 2020 through May 2, 2020. Our comparison cohort included adult patients with emergency department visits or hospitalizations with influenza A or B from January 1, 2016 through May 31, 2018 (calendar years spanning moderate and severe influenza seasons). ExposuresCovid-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the nasopharynx by polymerase chain reaction, and laboratory-confirmed influenza A or B. Main Outcomes and MeasuresA panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, etiological mechanisms, and outcomes. We used logistic regression to compare the proportion of Covid-19 patients with ischemic stroke versus the proportion among patients with influenza. ResultsAmong 2,132 patients with emergency department visits or hospitalizations with Covid-19, 31 patients (1.5%; 95% confidence interval [CI], 1.0%-2.1%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78) and 58% were men. Stroke was the reason for hospital presentation in 8 (26%) cases. For our comparison cohort, we identified 1,516 patients with influenza, of whom 0.2% (95% CI, 0.0-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was significantly higher with Covid-19 than with influenza infection (odds ratio, 7.5; 95% CI, 2.3-24.9). Conclusions and RelevanceApproximately 1.5% of patients with emergency department visits or hospitalizations with Covid-19 experienced ischemic stroke, a rate 7.5-fold higher than in patients with influenza. Future studies should investigate the thrombotic mechanisms in Covid-19 in order to determine optimal strategies to prevent disabling complications like ischemic stroke.

SARS-CoV-2 amino acid substitutions widely spread in the human population are mainly located in highly conserved segments of the structural proteins

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic offers a unique opportunity to study the introduction and evolution of a pathogen into a completely naive human population. We identified and analysed the amino acid mutations that gained prominence worldwide in the early months of the pandemic. Eight mutations have been identified along the viral genome, mostly located in conserved segments of the structural proteins and showing low variability among coronavirus, which indicated that they might have a functional impact. At the moment of writing this paper, these mutations present a varied success in the SARS-CoV-2 virus population; ranging from a change in the spike protein that becomes absolutely prevalent, two mutations in the nucleocapsid protein showing frequencies around 25%, to a mutation in the matrix protein that nearly fades out after reaching a frequency of 20%.

Improving Precision and Power in Randomized Trials for COVID-19 Treatments Using Covariate Adjustment, for Ordinal or Time to Event Outcomes

SO_SCPLOWUMMARYC_SCPLOWTime is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID-19. There are currently over 400 clinical trials (phase 2 and 3) of treatments for COVID-19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal and time-to-event) that are common in COVID-19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two-arm, randomized trials comparing a hypothetical COVID-19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time-to-event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital, and a Centers for Disease Control and Prevention (CDC) preliminary description of 2449 cases. We found substantial precision gains from using covariate adjustment-equivalent to 9-21% reductions in the required sample size to achieve a desired power-for a variety of estimands (targets of inference) when the trial sample size was at least 200. We provide an R package and practical recommendations for implementing covariate adjustment. The estimators that we consider are robust to model misspecification.

Percutaneous biventricular Impella support in therapy-refractory cardiogenic shock.

INTRODUCTION: Percutaneous mechanical circulatory support systems have increasingly been adopted as a bail out strategy in patients with cardiogenic shock. Since studies showed mostly mixed results, however, the use of support systems remains a case by case decision. CASE: Here, we report on a case of therapy-refractory cardiogenic shock due to acute myocardial infarction treated with percutaneous right and left ventricular assist devices (Impella RP and CP). CONCLUSION: Due to myocardial stunning, even patients with fulminant cardiogenic shock have the potential for full recovery. In the present case, we demonstrate the feasibility of biventricular Impella support in therapy-refractory cardiogenic shock facilitating bridge to recovery.

Accelerated partial breast irradiation in a single 18 Gy fraction with high-dose-rate brachytherapy: preliminary results.

PURPOSE: To evaluate the feasibility of acute and chronic toxicity in patients suitable for accelerated partial breast irradiation (APBI) in a single 18 Gy fraction with multicatheter high-dose-rate (HDR) brachytherapy, as well as cosmetic and oncological outcomes. MATERIAL AND METHODS: Between September 2014 and March 2016, twenty consecutive patients with low-risk invasive and ductal carcinoma in situ were treated with interstitial multicatheter HDR brachytherapy in a single 18 Gy fraction. RESULTS: Median age was 63.5 years (range, 51-79). Acute toxicity was observed in seven patients, while the pain during following days and hematoma were seen in four patients. With a median follow-up of 24 months, late toxicity was found in one patient with fat necrosis g2 and fibrosis g2 in another patient. The overall survival (OS) and locoregional control (LC) was 100%. Disease-free survival (DFS) and distant control was 95%. Good to excellent cosmetic outcomes were noted in 80% of patients and fair in 4 patients (20%). CONCLUSIONS: This is the first report in the medical literature that focuses on feasibility and acute and chronic toxicity, with a median follow-up of 24 months (range, 20-40). The protocol is viable and convenient. However, a longer follow-up is needed to know chronic toxicity and oncologic outcomes.

[High-sensitivity troponin T testing and coronary computed tomography angiography for rapid diagnosis of chest pain in the emergency department]. / Troponina T de alta sensibilidad y angiotomografía computarizada coronaria para el diagnóstico rápido del dolor torácico en el servicio de urgencias.

OBJECTIVES: To determine the probability of finding significant coronary lesions, the time to diagnosis, and the safety of a new diagnostic approach based on high-sensitivity cardiac troponin T (hsTnT) testing followed by coronary computed tomography angiography (CCTA) in patients with chest pain of possible coronary origin. The method was compared with our hospital emergency department's standard practice. MATERIAL AND METHODS: Unblinded randomized controlled trial in a tertiary level university hospital between February 2011 and April 2013. We included emergency patients with chest pain and nondiagnostic electrocardiographic findings. Patients were assigned randomly to the new approach (hsTnT assay, followed by CCTA if the assay findings were negative) or the conventional approach (fourth generation TnT assay and, if negative, followed by an exercise stress test). Invasive coronary angiography was ordered in all patients if the results of either troponin assay, the CCTA, or the stress test were positive. We recorded the results of angiography, time until diagnosis, and all-cause mortality, new myocardial infarction, new unstable angina, or need for revascularization within the next 3 months. RESULTS: Of 102 patients randomized, 7 were excluded; 50 of the remaining 95 patients were assigned to the new strategy, and 45 to the conventional approach. Coronary angiography demonstrated significant lesions in 92.9% of the patients treated with the new strategy and 66.7% of those diagnosed conventionally. A higher percentage of patients were diagnosed within 6 hours with the new approach (20.0% vs 4.4% of conventional-approach patients, P = .023). During the 3 months following diagnosis, 1 death occurred in the intervention group and none in the conventional-approach group. CONCLUSION: The new strategy could accelerate diagnosis and increase the probability of finding significant coronary lesions, but we found no significant differences in adverse events in the 3 months following diagnosis. These findings should be confirmed in studies with larger numbers of patients.

OBJETIVO: Determinar la probabilidad de encontrar lesiones coronarias significativas, el tiempo diagnóstico y la seguridad de una nueva estrategia basada en la utilización de troponina T de alta sensibilidad (TnT-as) seguida de angiotomografía computarizada coronaria (ATCC) en pacientes con dolor torácico de posible origen coronario, en comparación con la atención clínica habitual en un servicio de urgencias (SU). METODO: Ensayo clínico diagnóstico aleatorizado y abierto realizado en un SU de un hospital terciario universitario entre febrero 2011 y abril 2013. Se incluyó a pacientes atendidos por dolor torácico con electrocardiograma no diagnóstico en urgencias. Se asignó de forma aleatorizada a la estrategia nueva (EN) (seriación de TnT-as seguida de ATCC cuando fue negativa) o la estrategia convencional (EC) (seriación de TnT de cuarta generación seguida de ergometría cuando fue negativa). Se indicó coronariografía invasiva si las troponinas, la ATCC o la ergometría fueron positivas. Se registró el resultado de la coronariografía invasiva, el tiempo diagnóstico y la aparición de un evento adverso (muerte por cualquier causa, nuevo infarto de miocardio, nueva angina inestable o necesidad de revascularización) durante los 3 meses de seguimiento. RESULTADOS: De los 102 pacientes aleatorizados se excluyeron 7. Se incluyeron 95 pacientes, 45 asignados a la EC y 50 a la EN. La coronariografía mostró lesiones significativas en un 92,9% de los casos de la EN y en un 66,7% de la EC. La proporción de pacientes diagnosticados en las primeras 6 horas fue mayor en la EN en comparación con la EC (20,0% vs 4,4%; p = 0,023). Durante el periodo de 3 meses de seguimiento, se registró una muerte en la EN y ningún evento en la EC. CONCLUSIONES: La EN podría aportar un diagnóstico más rápido, así como una mayor probabilidad de encontrar lesiones coronarias significativas, sin diferencias en la aparición de eventos adversos en los 3 primeros meses. Estos hallazgos necesitan ser confirmados en futuros estudios con mayor número de pacientes.

Combined measurement of N-terminal pro-B-type natriuretic peptide and highly sensitive cardiac troponin T for diagnosis and monitoring of heart injury in chronic Chagas' disease.

OBJECTIVE: Chronic Chagas disease afflicts millions of patients in Latin America of which 70% remain asymptomatic but 30% develop fatal heart injury. To evaluate the impact of laboratory medicine for diagnosis and guiding of patients with Chagas' heart disease, we measured N-terminal B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). DESIGN AND METHODS: NT-proBNP and cTnT using the highly sensitive assay (hs-cTnT) were measured in 48 asymptomatic Chagas' patients (control group; (-) CM), and in symptomatic patients who suffered from mild/moderate (group (+/++) CM, n=62) or severe cardiomyopathy (group (+++) CM, n=27). RESULTS: Both markers were higher in (+/++) CM and (+++) CM vs. (-) CM and increased in the cardiomyopathy severity. Values of 3 ng/L cTnT and 160 ng/L NT-proBNP were calculated as optimal cut-offs to distinguish (-) CM vs. CM. The NT-proBNP cut-off of 125ng/L, as recommended by international guidelines, was additionally incorporated in the analysis. Cardiomyopathy was most successfully predicted by dual positivity of both markers (positive predictive value=1.0). Negativity of both markers effectively excluded cardiomyopathy (negative predictive value of 0.85). Positivity for at least one of the markers is the best for overall correct classification. CONCLUSIONS: Combined measurement of hs-cTnT and NT-proBNP can be used for diagnosis and monitoring of cardiomyopathy in chronic Chagas' patients. In this way, laboratory medicine increases the pre-test probability of the cardiologic diagnostics, which would reduce its time, cost, and logistical problems.

Time-dependent prediction and evaluation of variable importance using superlearning in high-dimensional clinical data.

BACKGROUND: Prediction of outcome after injury is fraught with uncertainty and statistically beset by misspecified models. Single-time point regression only gives prediction and inference at one time, of dubious value for continuous prediction of ongoing bleeding. New statistical machine learning techniques such as SuperLearner (SL) exist to make superior prediction at iterative time points while evaluating the changing relative importance of each measured variable on an outcome. This then can provide continuously changing prediction of outcome and evaluation of which clinical variables likely drive a particular outcome. METHODS: PROMMTT data were evaluated using both naive (standard stepwise logistic regression) and SL techniques to develop a time-dependent prediction of future mortality within discrete time intervals. We avoided both underfitting and overfitting using cross validation to select an optimal combination of predictors among candidate predictors/machine learning algorithms. SL was also used to produce interval-specific robust measures of variable importance measures (VIM resulting in an ordered list of variables, by time point) that have the strongest impact on future mortality. RESULTS: Nine hundred eighty patients had complete clinical and outcome data and were included in the analysis. The prediction of ongoing transfusion with SL was superior to the naive approach for all time intervals (correlations of cross-validated predictions with the outcome were 0.819, 0.789, 0.792 for time intervals 30-90, 90-180, 180-360, >360 minutes). The estimated VIM of mortality also changed significantly at each time point. CONCLUSION: The SL technique for prediction of outcome from a complex dynamic multivariate data set is superior at each time interval to standard models. In addition, the SL VIM at each time point provides insight into the time-specific drivers of future outcome, patient trajectory, and targets for clinical intervention. Thus, this automated approach mimics clinical practice, changing form and content through time to optimize the accuracy of the prognosis based on the evolving trajectory of the patient.

Population intervention causal effects based on stochastic interventions.

Estimating the causal effect of an intervention on a population typically involves defining parameters in a nonparametric structural equation model (Pearl, 2000, Causality: Models, Reasoning, and Inference) in which the treatment or exposure is deterministically assigned in a static or dynamic way. We define a new causal parameter that takes into account the fact that intervention policies can result in stochastically assigned exposures. The statistical parameter that identifies the causal parameter of interest is established. Inverse probability of treatment weighting (IPTW), augmented IPTW (A-IPTW), and targeted maximum likelihood estimators (TMLE) are developed. A simulation study is performed to demonstrate the properties of these estimators, which include the double robustness of the A-IPTW and the TMLE. An application example using physical activity data is presented.

Cardiac troponin T measured with a highly sensitive assay for diagnosis and monitoring of heart injury in chronic Chagas disease.

CONTEXT: Chronic Chagas disease (15 million patients; annual incidence, 40, 000 patients; annual mortality, 12 ,500 patients) is the most serious parasitic disease in Latin America. Between 10 and 30 years after infection, 30% of patients with Chagas disease develop heart injury, which is the main reason for its high mortality. Consequently, frequent cardiac diagnostics are required for patients with Chagas disease. OBJECTIVE: To minimize time-intensive and cost-intensive diagnostics, such as electrocardiography, echocardiography, and radiologic imaging, we tested the effect of measuring serum cardiac troponin T (cTnT) with a highly sensitive assay. To indicate the pathophysiologic background for cTnT release in Chagas heart injury, inflammation markers, such as C-reactive protein and interleukin 6, were measured in parallel. DESIGN: Serum cTnT was measured in 26 healthy subjects and in 179 patients with chronic Chagas disease who were asymptomatic (indeterminate stage, n  =  86), who were suffering from cardiomyopathy with or without megacolon (n  =  71), or who were suffering from megacolon exclusively (n  =  22). RESULTS: Serum cTnT was significantly higher in patients with cardiomyopathy with or without megacolon than in healthy subjects, asymptomatic subjects, and patients with megacolon, and the cTnT value was correlated with the severity of the cardiomyopathy. The lower limit of detection for the highly sensitive assay (3 ng/L) was best at distinguishing patients with, and without, heart injury. C-reactive protein and interleukin 6 were found to parallel cTnT changes in both the different Chagas groups and the cardiomyopathy groups separated by disease severity. CONCLUSIONS: Highly sensitive cTnT measurement has the potential to contribute to diagnosis and monitoring of heart injury in patients with chronic Chagas disease. The highly sensitive assay of cTnT release seems to be related to Chagas heart disease-specific inflammation.

Assessment of the efficacy of commercial porcine reproductive and respiratory syndrome virus (PRRSV) vaccines based on measurement of serologic response, frequency of gamma-IFN-producing cells and virological parameters of protection upon challenge.

The efficacy of two different types of commercial vaccines against PRRSV (Euro-type) was evaluated based on clinical parameters upon challenge as well as post-challenge virological profiles (viremia and viral load in tissues upon necropsy, measured in both cases by quantitative real time PCR). In an attempt to establish correlates of protective immunity, two commonly proposed parameters predictive of immunity were measured: (1) serologic responses (ELISA and neutralizing antibodies), (2) frequency of gamma interferon-producing cells in peripheral blood mononuclear cell fraction. The vaccines compared consisted of two commercially available products that are regularly marketed in Spain: one modified live virus and one killed vaccine. The efficacy assay was carried out by vaccinating twice 3 weeks apart groups of 5 and-a-half month-old female swine and then challenging them with a European type 1 PRRSV strain (Lelystad). The results obtained indicate that the modified live virus vaccine was the only type of vaccine capable of establishing protective immunity, as measured by viral load in blood and tissues. The killed vaccine, in spite of this product evoking a spontaneous interferon-gamma response and post-challenge titers of virus-neutralizing antibody, evoked no measurable protective immunity. In the case of the modified live vaccine, the protection exhibited did not appear to be based on humoral but rather on cell-mediated immunity.