Revisiting methods for modeling longitudinal and survival data: Framingham Heart Study.

BACKGROUND: Statistical methods for modeling longitudinal and time-to-event data has received much attention in medical research and is becoming increasingly useful. In clinical studies, such as cancer and AIDS, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. More importantly, time-dependent survival models that include the raw longitudinal measurements may lead to biased results. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for the longitudinal data and a survival model is applied to the event outcome. METHODS: In this paper we compare joint maximum likelihood methods, a two-step approach and a time dependent covariate method that link longitudinal data to survival data with emphasis on using longitudinal measures to predict survival. We apply a Bayesian semi-parametric joint method and maximum likelihood joint method that maximizes the joint likelihood of the time-to-event and longitudinal measures. We also implement the Two-Step approach, which estimates random effects separately, and a classic Time Dependent Covariate Model. We use simulation studies to assess bias, accuracy, and coverage probabilities for the estimates of the link parameter that connects the longitudinal measures to survival times. RESULTS: Simulation results demonstrate that the Two-Step approach performed best at estimating the link parameter when variability in the longitudinal measure is low but is somewhat biased downwards when the variability is high. Bayesian semi-parametric and maximum likelihood joint methods yield higher link parameter estimates with low and high variability in the longitudinal measure. The Time Dependent Covariate method resulted in consistent underestimation of the link parameter. We illustrate these methods using data from the Framingham Heart Study in which lipid measurements and Myocardial Infarction data were collected over a period of 26 years. CONCLUSIONS: Traditional methods for modeling longitudinal and survival data, such as the time dependent covariate method, that use the observed longitudinal data, tend to provide downwardly biased estimates. The two-step approach and joint models provide better estimates, although a comparison of these methods may depend on the underlying residual variance.

Dynamical System Modeling of Self-Regulated Systems Undergoing Multiple Excitations: First Order Differential Equation Approach.

This article proposes a dynamical system modeling approach for the analysis of longitudinal data of self-regulated homeostatic systems experiencing multiple excitations. It focuses on the evolution of a signal (e.g., heart rate) before, during, and after excitations taking the system out of its equilibrium (e.g., physical effort during cardiac stress testing). Such approach can be applied to a broad range of outcomes such as physiological processes in medicine and psychosocial processes in social sciences, and it allows to extract simple characteristics of the signal studied. The model is based on a first order linear differential equation with constant coefficients defined by three main parameters corresponding to the initial equilibrium value, the dynamic characteristic time, and the reaction to the excitation. Assuming the presence of interindividual variability (random effects) on these three parameters, we propose a two-step procedure to estimate them. We then compare the results of this analysis to several other estimation procedures in a simulation study that clarifies under which conditions parameters are accurately estimated. Finally, applications of this model are illustrated using cardiology data recorded during effort tests.

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes.

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

Neonatal outcomes of two-step delivery in low-risk pregnancy: A prospective observational study.

AIM: Extraction of the fetal body is typically performed immediately after delivery of the head in Western obstetric care. Reports justifying immediate extraction are few. Two-step delivery entails waiting for the next uterine contraction after delivery of the head. The present study evaluates neonatal asphyxia and respiratory impairment in two-step delivery using the head-to-body delivery interval. METHODS: This prospective observational study performed at a single birth clinic used the data of 262 low-risk pregnant women with two-step delivery. We measured the time interval of head-to-body delivery and correlation analysis and simple linear regression analysis between the head-to-body delivery interval and umbilical artery pH. The women were divided into two groups according to the head-to-body delivery interval: ≤60 or >60 s. The prevalence of neonatal asphyxia and neonatal respiratory impairment was compared between the groups. RESULTS: The mean head-to-body delivery interval was 88.9 ± 71.3 s. The umbilical artery pH tended to decrease with increasing head-to-body delivery interval; however, there was almost no correlation and the decline of pH was only 0.010 for every additional minute. Low Apgar score incidence at 5 min did not differ significantly between the groups. No cases of shoulder dystocia were reported, and tachypnea at 4 h after birth occurred in 3% of the births. CONCLUSIONS: A longer head-to-body delivery interval is not associated with negative outcomes in two-step delivery. We believe that two-step delivery could have some superior outcomes compared with one-step delivery outcomes, particularly as to improving fetal circulation and preventing shoulder dystocia.

Arrhythmic risk stratification in post-myocardial infarction patients with preserved ejection fraction: the PRESERVE EF study.

AIMS: Sudden cardiac death (SCD) annual incidence is 0.6-1% in post-myocardial infarction (MI) patients with left ventricular ejection fraction (LVEF)≥40%. No recommendations for implantable cardioverter-defibrillator (ICD) use exist in this population. METHODS AND RESULTS: We introduced a combined non-invasive/invasive risk stratification approach in post-MI ischaemia-free patients, with LVEF ≥ 40%, in a multicentre, prospective, observational cohort study. Patients with at least one positive electrocardiographic non-invasive risk factor (NIRF): premature ventricular complexes, non-sustained ventricular tachycardia, late potentials, prolonged QTc, increased T-wave alternans, reduced heart rate variability, abnormal deceleration capacity with abnormal turbulence, were referred for programmed ventricular stimulation (PVS), with ICDs offered to those inducible. The primary endpoint was the occurrence of a major arrhythmic event (MAE), namely sustained ventricular tachycardia/fibrillation, appropriate ICD activation or SCD. We screened and included 575 consecutive patients (mean age 57 years, LVEF 50.8%). Of them, 204 (35.5%) had at least one positive NIRF. Forty-one of 152 patients undergoing PVS (27-7.1% of total sample) were inducible. Thirty-seven (90.2%) of them received an ICD. Mean follow-up was 32 months and no SCDs were observed, while 9 ICDs (1.57% of total screened population) were appropriately activated. None patient without NIRFs or with NIRFs but negative PVS met the primary endpoint. The algorithm yielded the following: sensitivity 100%, specificity 93.8%, positive predictive value 22%, and negative predictive value 100%. CONCLUSION: The two-step approach of the PRESERVE EF study detects a subpopulation of post-MI patients with preserved LVEF at risk for MAEs that can be effectively addressed with an ICD. CLINICALTRIALS.GOV IDENTIFIER: NCT02124018.

[Application of two-step approach for tuberculosis infection testing in tuberculosis control in schools].

Latent tuberculosis infection (LTBI) testing and treatment in high risk populations is an important tool for tuberculosis control. In China, tuberculin skin test (TST) has been recommended as a primary testing method for Mycobacterium tuberculosis (MTB) infection in new students and close contacts in schools, which laid a solid foundation for the early case finding and management. However, Due to the influence of multiple factors including BCG vaccination and nontuberculous mycobacteria infection, TST showed limitations in specificity for MTB infection detection. Guidelines issued by other countries showed that using the two-step approach (TST-IGRA) has advantages in improving diagnostic accuracy as compared with using TST alone. From the perspective of precise intervention, two-step approach for MTB infection testing might be a favorable choice for tuberculosis control in schools in China.

Two-step approach for assessing the health effects of environmental chemical mixtures: application to simulated datasets and real data from the Navajo Birth Cohort Study.

BACKGROUND: There is increasing interest in examining the consequences of simultaneous exposures to chemical mixtures. However, a consensus or recommendations on how to appropriately select the statistical approach analyzing the health effects of mixture exposures which best aligns with study goals has not been well established. We recognize the limitations that existing methods have in effectively reducing data dimension and detecting interaction effects when analyzing chemical mixture exposures collected in high dimensional datasets with varying degrees of variable intercorrelations. In this research, we aim to examine the performance of a two-step statistical approach in addressing the analytical challenges of chemical mixture exposures using two simulated data sets, and an existing data set from the Navajo Birth Cohort Study as a representative case study. METHODS: We propose to use a two-step approach: a robust variable selection step using the random forest approach followed by adaptive lasso methods that incorporate both dimensionality reduction and quantification of the degree of association between the chemical exposures and the outcome of interest, including interaction terms. We compared the proposed method with other approaches including (1) single step adaptive lasso; and (2) two-step Classification and regression trees (CART) followed by adaptive lasso method. RESULTS: Utilizing simulated data sets and applying the method to a real-life dataset from the Navajo Birth Cohort Study, we have demonstrated good performance of the proposed two-step approach. Results from the simulation datasets indicated the effectiveness of variable dimension reduction and reliable identification of a parsimonious model compared to other methods: single-step adaptive lasso or two-step CART followed by adaptive lasso method. CONCLUSIONS: Our proposed two-step approach provides a robust way of analyzing the effects of high-throughput chemical mixture exposures on health outcomes by combining the strengths of variable selection and adaptive shrinkage strategies.

A Two-Step Haploidentical Versus a Two-Step Matched Related Allogeneic Myeloablative Peripheral Blood Stem Cell Transplantation.

Haploidentical stem cell transplantation (SCT) offers a transplantation option to patients who lack an HLA-matched donor. We developed a 2-step approach to myeloablative allogeneic hematopoietic stem cell transplantation for patients with haploidentical or matched related (MR) donors. In this approach, the lymphoid and myeloid portions of the graft are administered in 2 separate steps to allow fixed T cell dosing. Cyclophosphamide is used for T cell tolerization. Given a uniform conditioning regimen, graft T cell dose, and graft-versus-host disease (GVHD) prophylaxis strategy, we compared immune reconstitution and clinical outcomes in patients undergoing 2-step haploidentical versus 2-step MR SCT. We retrospectively compared data on patients undergoing a 2-step haploidentical (n = 50) or MR (n = 27) peripheral blood SCT for high-risk hematological malignancies and aplastic anemia. Both groups received myeloablative total body irradiation conditioning. Immune reconstitution data included flow cytometric assessment of T cell subsets at day 28 and 90 after SCT. Both groups showed comparable early immune recovery in all assessed T cell subsets except for the median CD3/CD8 cell count, which was higher in the MR group at day 28 compared with that in the haploidentical group. The 3-year probability of overall survival was 70% in the haploidentical group and 71% in the MR group (P = .81), while the 3-year progression-free survival was 68% in the haploidentical group and 70% in the MR group (P = .97). The 3-year cumulative incidence of nonrelapse mortality was 10% in the haploidentical group and 4% in the MR group (P = .34). The 3-year cumulative incidence of relapse was 21% in the haploidentical group and 27% in the MR group (P = .93). The 100-day cumulative incidence of overall grades II to IV acute GVHD was higher in the haploidentical group compared with that in the MR group (40% versus 8%, P < .001), whereas the grades III and IV acute GVHD was not statistically different between both groups (haploidentical, 6%; MR, 4%; P = .49). The cumulative incidence of cytomegalovirus reactivation was also higher in the haploidentical group compared to the MR group (haploidentical, 68%; MR, 19%; P < .001). There were no deaths from GVHD in either group. Using an identical conditioning regimen, graft T cell dose, and GVHD prophylaxis strategy, comparable early immune recovery and clinical outcomes were observed in the 2-step haploidentical and MR SCT recipients.

Clustered data analysis under miscategorized ordinal outcomes and missing covariates.

The primary objective in this article is to look into the analysis of clustered ordinal model where complete information on one or more covariates cease to occur. In addition, we also focus on the analysis of miscategorized data that occur in many situations as outcomes are often classified into a category that does not truly reflect its actual state. A general model structure is assumed to accommodate the information that is obtained via surrogate variables. The theoretical motivation actually developed while encountering an orthodontic data to investigate the effects of age, sex and food habit on the extent of plaque deposit. The model we propose is quite flexible and is capable of tackling those additional noises like miscategorization and missingness, which occur in the data most frequently. A new two-step approach has been proposed to estimate the parameters of model framed. A rigorous simulation study has also been carried out to justify the validity of the model taken up for analysis. Copyright © 2015 John Wiley & Sons, Ltd.

Laser cellulite treatment and laser-assisted lipoplasty of the thighs and buttocks: Combined modalities for single stage contouring of the lower body.

BACKGROUND AND OBJECTIVES: Cellulite and lipodystrophy are often found together, especially in areas of the buttocks and thighs, causing skin surface irregularities. Each of these conditions is currently treated independently as two separate surgical procedures. In our practice, we developed a novel combined approach for the simultaneous treatment of cellulite and lipodystrophy, as a single stage procedure in the same anatomic area. For the treatment of cellulite, we used the Nd:YAG laser at a wavelength of 1,440-nm, along with an innovative 1,000-micron directional side-firing fiber optic laser system. For the treatment of lipodystrophy, the Nd:YAG laser with a 1,440 nm wavelength, along with a fiber optic laser system was used. The objective of this study is to determine the efficacy and safety of a combined approach for the simultaneous treatment of cellulite and lipodystrophy. STUDY DESIGN, PATIENTS AND METHODS: In 2012, 16 subjects with noticeable cellulite, Grade II and Grade III, accompanied by mild-to-moderate lipodystrophy of the lower body received single treatments of the Nd:YAG laser at a wavelength of 1,440-nm along with the 1,000-micron side-firing fiber optic laser system for simultaneous treatments of both cellulite and lipodystrophy. Patients were assessed at baseline and 3-6 months post-treatment by a modified Nurnberger-Muller scale utilized to quantify the cellulite severity. Additionally, patient satisfaction and a global aesthetic improvement scale were used to measure the improvement in lipodystrophy. RESULTS: Blinded reviewers identified the correct baseline photographs 97% of the time when presented with a set of photographs. The median modified Nurnberger-Muller scale score at baseline was 4.75 ± 1.2 and the average improvement was 2.0 ± 1.2. Global aesthetic improvement scores ranged from 1 to 3 with an average of 1.58 indicating a much-improved overall appearance. Satisfaction was high for both physicians and patients with scores corresponding to extremely satisfied/satisfied. CONCLUSION: Precise, effective delivery of laser energy to the dermal-adipose tissue, as well as the deep adipose lipodystrophy is feasible as a safe modality for the simultaneous treatment of cellulite and lipodystrophy in the buttocks and thighs, as a single stage procedure.

GBAS Ionospheric Anomaly Monitoring Based on a Two-Step Approach.

As one significant component of space environmental weather, the ionosphere has to be monitored using Global Positioning System (GPS) receivers for the Ground-Based Augmentation System (GBAS). This is because an ionospheric anomaly can pose a potential threat for GBAS to support safety-critical services. The traditional code-carrier divergence (CCD) methods, which have been widely used to detect the variants of the ionospheric gradient for GBAS, adopt a linear time-invariant low-pass filter to suppress the effect of high frequency noise on the detection of the ionospheric anomaly. However, there is a counterbalance between response time and estimation accuracy due to the fixed time constants. In order to release the limitation, a two-step approach (TSA) is proposed by integrating the cascaded linear time-invariant low-pass filters with the adaptive Kalman filter to detect the ionospheric gradient anomaly. The performance of the proposed method is tested by using simulated and real-world data, respectively. The simulation results show that the TSA can detect ionospheric gradient anomalies quickly, even when the noise is severer. Compared to the traditional CCD methods, the experiments from real-world GPS data indicate that the average estimation accuracy of the ionospheric gradient improves by more than 31.3%, and the average response time to the ionospheric gradient at a rate of 0.018 m/s improves by more than 59.3%, which demonstrates the ability of TSA to detect a small ionospheric gradient more rapidly.

A Tender Reduced-Intensity Conditioning for the Unfit: A Novel 4 Gy Total Body Irradiation-Based Conditioning Followed by Two-Step Haploidentical Stem Cell Transplant, Results of a Prospective Trial.

Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative treatment for many hematologic malignancies (HM). We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of post-transplant cyclophosphamide (CY). The two-step approach demonstrated safety and efficacy in patients treated with myeloablative and reduced-intensity conditioning. Here, we extended our two-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes. Thirty-four patients with HM were treated. Median age was 68 years old and included a minority population constituting 32%. Eighty-two percent had a hematopoietic cell transplantation comorbidity index score ≥3. Ninety-one percent were haploidentical, and the rest were matched-related donor HSCT. Following administration of fludarabine and 2 Gy total body irradiation (TBI) (13 patients) or 4 Gy TBI (21 patients) conditioning regimen, a fixed dose of 2 × 108/kg CD3+ T cells was given, followed 2 days later by CY, then infusion of CD34-selected stem cells. Overall survival (OS) was 70% at 1 year and 48% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 33% at 3 years. However, the CI of relapse was much lower for patients treated with 4 Gy TBI versus those treated with 2 Gy TBI (11% versus 54%, P = .045), while NRM was similar (23% versus 15%, P = .399). This contributed to a high OS of 64% in patients who received 4 Gy TBI-based conditioning at 3 years, with median OS not reached, although this was not statistically significant (P = .68). The median time to neutrophil and platelet recovery was 12 and 17 days, respectively. The CI of grade II acute graft-versus-host-disease (aGVHD) was 22% and 26% at 100 days and 6 months, respectively. The CI of chronic GVHD (cGVHD) was 7.5% at 3 years. There was no grade III or IV aGVHD, no severe cGVHD, and no deaths attributable to GVHD. In conclusion, the two-step approach HSCT demonstrated a low disease relapse rate and high survival in patients treated with 4 Gy TBI-based conditioning, despite a generally older and more medically compromised patient population.

Harnessing the power of regional baselines for broad-scale genetic stock identification: A multistage, integrated, and cost-effective approach.

In mixed-stock fishery analyses, genetic stock identification (GSI) estimates the contribution of each population to a mixture and is typically conducted at a regional scale using genetic baselines specific to the stocks expected in that region. Often these regional baselines cannot be combined to produce broader geographical baselines due to non-overlapping populations and genetic markers. In cases where the mixture contains stocks spanning across a wide area, a broad-scale baseline is created, but often at the cost of resolution. Here, we introduce a new GSI method to harness the resolution capabilities of baselines developed for regional applications in the analysis of mixtures containing individuals from a broad geographic range. This method employs a multistage framework that allows disparate baselines to be used in a single integrated process that produces estimates along with the propagated errors from each stage. All individuals in the mixture sample are required to be genotyped for all genetic markers in the baselines used by this model, but the baselines do not require overlap in genetic markers or populations representing the broad-scale or regional baselines. We demonstrate the utility of our integrated multistage model using a synthesized data set made up of Chinook salmon, Oncorhynchus tshawytscha, from the North Bering Sea of Alaska. The results show an improved accuracy for estimates using an integrated multistage framework, compared to the conventional framework of using separate hierarchical steps. The integrated multistage framework allows GSI of a wide geographic area without first developing a large scale, high-resolution genetic baseline or dividing a mixture sample into smaller regions beforehand. This approach is more cost-effective than updating range-wide baselines with all regionally important markers.

Chloride and Potassium Assessment Is a Helpful Tool for Differential Diagnosis of Thiazide-Associated Hyponatremia.

CONTEXT: Differential diagnosis of thiazide-associated hyponatremia (TAH) is challenging. Patients can either have volume depletion or a syndrome of inappropriate antidiuresis (SIAD)-like presentation. OBJECTIVE: To evaluate the impact of the simplified apparent strong ion difference in serum (aSID; sodium + potassium - chloride) as well as the urine chloride and potassium score (ChU; chloride - potassium in urine) in the differential diagnosis of TAH, in addition to assessment of fractional uric acid excretion (FUA). METHODS: Post hoc analysis of prospectively collected data from June 2011 to August 2013 from 98 hospitalized patients with TAH < 125 mmol/L enrolled at University Hospital Basel and University Medical Clinic Aarau, Switzerland. Patients were categorized according to treatment response in volume-depleted TAH requiring volume substitution or SIAD-like TAH requiring fluid restriction. We computed sensitivity analyses with ROC curves for positive predictive value (PPV) and negative predictive value (NPV) of aSID, ChU, and FUA in differential diagnosis of TAH. RESULTS: An aSID > 42 mmol/L had a PPV of 79.1% in identifying patients with volume-depleted TAH, whereas a value < 39 mmol/L excluded it with a NPV of 76.5%. In patients for whom aSID was inconclusive, a ChU < 15 mmol/L had a PPV of 100% and a NPV of 83.3%, whereas FUA < 12% had a PPV of 85.7% and a NPV of 64.3% in identifying patients with volume-depleted TAH. CONCLUSION: In patients with TAH, assessment of aSID, potassium, and chloride in urine can help identifying patients with volume-depleted TAH requiring fluid substitution vs patients with SIAD-like TAH requiring fluid restriction.

Factor structure of early numeracy: evaluation of a measurement model in greek-speaking children with intellectual disabilities.

Exploring the individual differences of the longitudinal growth of early numeracy (EN) in young children with Intellectual disabilities (IDs) prerequires the critical stage of exploring and validating the potential factor structure. Despite the fact that Relational Skills (RS), Counting Skills (CS) and Operations (O) are expected to constitute distinct domains of EN, there is not sufficient evidence to support either the above position or the position that they are different means of assessing a general-informal numeracy skill construct. This study was designed to shed light in the field through the evaluation of a measurement model describing the structure of RS, CS and O domains of EN and their interrelation. The sample included N = 155 children with IDs, enrolled in special school classes, mentally aged between 5;02 (y;m) and 6;10 (M = 5.11, SD = 0.974). Confirmatory Factor Analysis indicated a "good fit" of the two-factor model (RS, CS + O) of EN in ID (RMSEA=.029 < 0.08, CFI = 0.98 ≥ 0.90 and SRMR = 0.000 < 0.08). No measurement invariance across gender was reported for the proposed two-factor model of EN. The nested EN models validated full measurement invariance across gender. Finally, educational implications are discussed.

A lncRNA-disease association prediction model based on the two-step PU learning and fully connected neural networks.

Long non-coding RNAs (lncRNAs) have been shown to play a regulatory role in various processes of human diseases. However, lncRNA experiments are inefficient, time-consuming and highly subjective, so that the number of experimentally verified associations between lncRNA and diseases is limited. In the era of big data, numerous machine learning methods have been proposed to predict the potential association between lncRNA and diseases, but the characteristics of the associated data were seldom explored. In these methods, negative samples are randomly selected for model training and the model is prone to learn the potential positive association error, thus affecting the prediction accuracy. In this paper, we proposed a cyclic optimization model of predicting lncRNA-disease associations (COPTLDA in short). In COPTLDA, the two-step training strategy is adopted to search for the samples with the greater probability of being negative examples from unlabeled samples and the determined samples are treated as negative samples, which are combined together with known positive samples to train the model. The searching and training steps are repeated until the best model is obtained as the final prediction model. In order to evaluate the performance of the model, 30% of the known positive samples are used to calculate the model accuracy and 10% of positive samples are used to calculate the recall rate of the model. The sampling strategy used in this paper can improve the accuracy and the AUC value reaches 0.9348. The results of case studies showed that the model could predict the potential associations between lncRNA and malignant tumors such as colorectal cancer, gastric cancer, and breast cancer. The predicted top 20 associated lncRNAs included 10 colorectal cancer lncRNAs, 2 gastric cancer lncRNAs, and 8 breast cancer lncRNAs.

The two-step approach to allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides the only potentially curative option for multiple hematological conditions. However, allogeneic HSCT outcomes rely on an optimal balance of effective immune recovery, minimal graft-versus-host disease (GVHD), and lasting control of disease. The quest to attain this balance has proven challenging over the past few decades. The two-step approach to HSCT was conceptualized and pioneered at Thomas Jefferson University in 2005 and remains the main platform for allografting at our institution. Following administration of the transplant conditioning regimen, patients receive a fixed dose of donor CD3+ cells (HSCT step one-DLI) as the lymphoid portion of the graft on day -6 with the aim of optimizing and controlling T cell dosing. Cyclophosphamide (CY) is administered after the DLI (days -3 and -2) to induce donor-recipient bidirectional tolerance. On day 0, a CD34-selected stem cell graft is given as the myeloid portion of the graft (step two). In this two-step approach, the stem cell graft is infused after CY tolerization, which avoids exposure of the stem cells to an alkylating agent, allowing rapid count recovery. Here, the two-step platform is described with a focus on key results from studies over the past two decades. Finally, this review details lessons learned and current strategies to optimize the graft-versus-tumor effect and limit transplant-related toxicities.

The Two-Step Allogeneic Stem Cell Transplantation Approach Results in Rapid Engraftment and Excellent Outcomes in Patients with Lymphoid Malignancies.

The 2-step graft engineering approach has been the main platform for allogeneic hematopoietic cell transplantation (allo-HCT) at Thomas Jefferson University since 2005. We have previously described separating donor lymphocyte infusion followed by cyclophosphamide for bidirectional tolerization from CD34-selected hematopoietic grafts in haploidentical and matched related donors. Here we analyzed 60 patients with high-risk lymphoid malignancies who underwent a 2-step allo-HCT between 2008 and 2020. The majority of patients received haploidentical stem cell grafts (82%), and 20% of patients received matched related donor stem cell grafts. The patients underwent allo-HCT for diffuse large C cell lymphoma (n = 17; 28%), chronic lymphoblastic leukemia (n = 10; 17%), follicular lymphoma (n = 8; 13%), and Hodgkin lymphoma (n = 7; 12%). Eight patients (13%) had received prior high-dose chemotherapy. Thirty patients (50%) had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, and 20 patients (33%) had a Center for International Blood & Marrow Transplant Research Revised Disease Risk Index of high risk or very high risk. The median patient age was 56 years (range, 24 to 75 years). Neutrophils engrafted at a median of 11 days (range, 9 to 16 days), and platelets engrafted at a median of 16 days (range, 13 to 37 days). With a median follow-up of 6 years, the 3-year probability of overall survival was 62.9% (95% confidence interval [CI], 49.3% to 73.8%), and that of disease-free survival was 60.2% (95% CI, 46.4% to 71.6%). The cumulative incidence of relapse at 3 years was 11.9% (95% CI, 5.2% to 21.6%). The cumulative incidence of nonrelapse mortality at 3 years was 30.1% (95% CI, 1.91% to 42.0%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 1 year was 45% (95% CI, 32.2% to 57.0%), and that of grade III-IV acute GVHD at 1 year was 5% (95% CI, 1.3% to 12.6%). The cumulative incidence of cGVHD at 3 years was 15.2% (95% CI, 7.5% to 25.4%). The 2-step approach achieved excellent outcomes in high-risk lymphoid malignancies, with rapid neutrophil and platelet recovery.

Arrhythmic risk stratification in ischemic, non-ischemic and hypertrophic cardiomyopathy: A two-step multifactorial, electrophysiology study inclusive approach.

Annual arrhythmic sudden cardiac death ranges from 0.6% to 4% in ischemic cardiomyopathy (ICM), 1% to 2% in non-ischemic cardiomyopathy (NICM), and 1% in hypertrophic cardiomyopathy (HCM). Towards a more effective arrhythmic risk stratification (ARS) we hereby present a two-step ARS with the usage of seven non-invasive risk factors: Late potentials presence (≥ 2/3 positive criteria), premature ventricular contractions (≥ 30/h), non-sustained ventricular tachycardia (≥ 1episode/24 h), abnormal heart rate turbulence (onset ≥ 0% and slope ≤ 2.5 ms) and reduced deceleration capacity (≤ 4.5 ms), abnormal T wave alternans (≥ 65µV), decreased heart rate variability (SDNN < 70ms), and prolonged QTc interval (> 440 ms in males and > 450 ms in females) which reflect the arrhythmogenic mechanisms for the selection of the intermediate arrhythmic risk patients in the first step. In the second step, these intermediate-risk patients undergo a programmed ventricular stimulation (PVS) for the detection of inducible, truly high-risk ICM and NICM patients, who will benefit from an implantable cardioverter defibrillator. For HCM patients, we also suggest the incorporation of the PVS either for the low HCM Risk-score patients or for the patients with one traditional risk factor in order to improve the inadequate sensitivity of the former and the low specificity of the latter.

Perinatal outcomes associated with the diagnosis of gestational diabetes: Systematic review and meta-analysis.

OBJECTIVE: To compare perinatal outcomes in pregnant women diagnosed with gestational diabetes using the one-step and the two-step test. METHODS: Meta-analysis of observational studies pregnancies women with gestational diabetes from January 2014 to February 2019. The outcomes studied were induction of labor and delivery, preterm delivery, fetal macrosomia, neonatal hypoglycemia, hyperbilirubinemia, low birth weight, and admission to the neonatal intensive care unit. RESULTS: Eight studies were included with a population of 108,609 pregnancies. Statistical differences were obtained for fetal macrosomia RR0.9 (95%CI0.85-0.97; I20%) and neonatal hypoglycemia RR1.1 (95%CI1.01-1.40; I248.5%). CONCLUSION: Neonatal macrosomia appears to be less present when the one-step diagnostic test is used and neonatal hypoglycemia was lower with the two-step test. Register PROSPERO CRD42020215062.