The HSCT procedure (II): Conditioning, hematopoietic stem cell infusion, supportive care, and monitoring.

Autologous hematopoietic stem cell transplantation (aHSCT) is a complex process, designed to replace the blood and lymphoid systems of a patient with hematopoietic stem cells (HSCs) that have been previously collected and cryopreserved, derived from the same patient. The rationale of aHSCT in neurologic diseases is to eliminate self-reacting cell clones and induce self-tolerance through a profound renewal of the immune system. The steps analyzed in this chapter are conditioning, HSCs infusion, supportive care, and monitoring. Before transplantation, ablation of the hemato-lymphopoietic system is achieved with chemotherapy; this stage is known as the conditioning regimen. The EBMT guidelines support the use of "intermediate intensity" regimens, either cyclophosphamide 200mg/kg or BEAM (bis-chloroethyl-nitrosourea, etoposide, cytarabine, and melphalan), in combination with serotherapy that consists of rabbit antithymocyte globulin (ATG) in most protocols. The infusion of HSC is performed through a central intravenous line, after being thawed at 37°C using either a water bath or a heat bath; in this phase, the prevention and management of infusion-related adverse events are crucial. The supportive care consists mainly of infection prophylaxis and treatment, administration of blood product transfusions, and nutritional and electrolyte support. The monitoring phase is focused on hematologic recovery and monitoring for early and late complications of aHSCT.

Event-related potentials of familiar monosyllabic words with unexpected lexical tones: A picture-word study of Mandarin-speaking preschoolers with and without a history of late talking.

This study examined how Mandarin-speaking preschoolers with and without a history of late talking (LT) process familiar monosyllabic words with unexpected lexical tones, focusing on both phonological and semantic violations. This study initially enrolled 64 Mandarin-speaking toddlers: 31 with a history of LT (mean age: 27.67 months) and 33 without a history of LT (non-LT) (mean age: 27.85 months). Event-related potentials were recorded at the age of 4 years during a picture-word mismatch task (LT mean age: 51.36 months; non-LT mean age: 51.20 months); in this task, the participants were presented with auditory words either matching (Tone 3) or mismatching with images in terms of their lexical tones; the mismatches encompassed acoustically dissimilar (Tone 1) and similar (Tone 2) mismatches. A significant difference in the phonological mapping negativity (PMN) responses to Tones 1 and 3 was observed only in the non-LT group. However, differences in the N400 responses to Tones 1 and 3 remained consistent across both groups. In addition, greater differences in the PMN responses between Tones 1 and 3 were associated with higher language proficiency during the preschool period. The PMN response serves as an indicator of neural correlates in lexical tone processing, reflecting challenges encountered by preschoolers with a history of LT when processing the lexical tones of familiar words. Furthermore, the PMN response was correlated with concurrent language abilities. These findings indicate the importance of early tonal perception development for Mandarin speakers with a history of LT. RESEARCH HIGHLIGHTS: Preschoolers with a history of late talking (LT), similar to preschoolers without such a history, can establish word expectations and detect the lexical tone violation in real time. However, those with a history of LT require additional time to process acoustic cues and differentiate between word semantics based on lexical tone information. The phonological mapping negativity response serves as an indicator of neural correlates in lexical tone processing, reflecting challenges encountered by preschoolers with a history of LT when processing the lexical tones of familiar words. The present findings indicate the importance of early intervention for Mandarin speakers with a history of LT, with an emphasis on lexical tone processing from toddlerhood.

Sjogren's syndrome due to immune checkpoint inhibitors (ICIs): Insights from a single-institution series and systematic review of the literature.

INTRODUCTION: Careful adverse event assessment and management are important when prescribing immune checkpoint inhibitors (ICIs) to cancer patients. Iatrogenic Sjogren's syndrome is a relatively rare immune-related adverse event (irAEs) that affects the moisture-producing glands. METHODS: We describe a series of four patients who developed Sjogren's syndrome while being treated with ICIs at a community cancer center in Southern California, USA (1/1/2017-12/31/2023). Patient, drug and disease-related data were collected by retrospective chart review. A systematic search of the PubMed database was performed to identify similar cases in the literature (1/1/2016-12/31//2023). RESULTS: Of 224 cancer patients at our center treated with ICIs, four (1.8%) developed iatrogenic Sjogren's syndrome. All of our patients were male; three received PD-1 inhibitors (nivolumab, pembrolizumab) and one received the PD-L1 inhibitor atezolizumab. The median time to development of Sjogren's syndrome was 24 weeks (range, 8-36 weeks); dry mouth symptoms were more prominent than dry eye symptoms. None of the patients had elevated SS-A, SS-B or antinuclear antibodies. One patient developed multiple tooth cavities and had several extractions, due to severe xerostomia. Management of all patients was primarily symptomatic. Two cases were irreversible; one was reversible and the 4th case is undermined as he is still on ICI therapy. Our systematic review of the literature identified 80 cases in five articles. Incidence of xerostomia was twice of that of xerophthalmia. The male/female ratio was 1.5:1. SS-A, SS-B, or antinuclear antibodies were found in only 9% of patients. Steroids were reported to have had only a limited role in management. CONCLUSIONS: The incidence of Sjogren's syndrome due to ICIs in our center was 1.8%. Details of clinical course and management in these patients are presented. Caring for patients with ICI-related Sjogren's syndrome is facilitated by a multidisciplinary effort including oncologists, otolaryngologists, dentists, ophthalmologists and rheumatologists. Expanding the knowledge base pertaining to iatrogenic Sjogren's syndrome in patients on ICIs will be helpful in promoting early detection and treatment, and improving outcomes.

When we fail to live up to our own standards: the relationship between self-discrepancy and moral injury.

BACKGROUND: Moral injury is a potentially debilitating outcome of exposure to events involving transgressions against an individual's moral code. It is often observed in the context of PTSD; however, treatments that do not differentiate the two are often ineffective for moral injury, suggesting different mechanisms contribute to the conditions. The most widely accepted model of moral injury proposes an important role for self-discrepancy processes in generating and maintaining event-related distress, but this has yet to be examined. METHODS: This study recruited 172 adults online who had been exposed to a potentially morally injurious event in the previous 5 years. Participants completed measures of event-related distress, PTSD, depression, and anxiety, as well as a self-discrepancy task involving subjective representations of their ideal, ought, and feared selves. RESULTS: Multiple regression analyses found a small but significant relationship between self-discrepancy and event-related distress, with higher levels of ought self-discrepancy independently predicting higher event-related distress scores. CONCLUSIONS: This study provides the first empirical evidence of the relationship between self-discrepancy and moral injury. We identified the ought self as a domain of self-discrepancy salient to moral injury, further differentiating moral injury from PTSD.

A multimedia dataset for object-centric business process mining in IT asset management.

This manuscript introduces a multimedia business process dataset provided by a German research institute. The dataset was systematically collected in a laboratory environment that reflects the workspace of IT staff managing IT Asset Management (ITAM) processes. It encompasses data from 121 process instances across six basic processes, captured using 37 video recordings from two camera perspectives, motion tracking, environmental sensors, an ITAM system trace, and event log data from user interactions. The data is made available in its raw state and processed form. The object-centric event log format (OCEL) provides discrete business process events from system activities. Event data from reality is supplied as raw video files and logs from environmental sensors. The video files were also manually labelled with identifiable business process activities and their associated entities. This multimedia dataset has been designed as a resource for developing, training, and evaluating process mining techniques based on unstructured data. Consequently, the dataset design emphasizes the traceability of activities and entities across the multimedia data sources.

Statistical approaches for component-wise censored composite endpoints.

Composite endpoints defined as the time to the earliest of two or more events are often used as primary endpoints in clinical trials. Component-wise censoring arises when different components of the composite endpoint are censored differently. We focus on a composite of death and a non-fatal event where death time is right censored and the non-fatal event time is interval censored because the event can only be detected during study visits. Such data are most often analysed using methods for right censored data, treating the time the non-fatal event was first detected as the time it occurred. This can lead to bias, particularly when the time between assessments is long. We describe several approaches for estimating the event-free survival curve and the effect of treatment on event-free survival via the hazard ratio that are specifically designed to handle component-wise censoring. We apply the methods to a randomized study of breastfeeding versus formula feeding for infants of mothers infected with human immunodeficiency virus.

Acute toxicity of hypofractionated radiotherapy for Japanese breast cancer patients after surgery: a single center prospective observational study (HyPORT-BC).

BACKGROUND: This single center prospective observational study was conducted to evaluate the acute toxicity of hypo-fractionated radiotherapy for Japanese breast cancer patients after surgery. METHODS: This study recruited patients who were scheduled for moderately hypo-fractionated radiotherapy including supraclavicular lymph node area (Cohort M) or ultra-hypo-fractionated radiotherapy for the conserved breast (Cohort U) as postoperative treatment for breast cancer. Radiotherapy plans were generated using automated planning system. Irradiation of 42.5 Gy/16 fractions (Cohort M) or 26 Gy/5 fractions (Cohort U) was delivered, and boost irradiation of 10 Gy/5 fractions was added as needed. The primary endpoint was the proportion of grade ≥ 2 acute adverse events within 90 days. The toxicities were evaluated using CTCAE ver 5.0. RESULTS: Between January 2023 and December 2023, 123 patients (81 in Cohort M and 42 in Cohort U) were enrolled. All the included patients were Japanese and completed their planned radiotherapy and were also able to be evaluated for acute adverse events. Grade 1/2/3-5 acute adverse events were observed in 67/12/0 for Cohort M and 31/4/0 for Cohort U. The proportion of grade ≥ 2 acute adverse events within 90 days was 15% (95% confidence interval 8-24%) for Cohort M and 10% (95% confidence interval 3-23%) for Cohort U. CONCLUSIONS: The proportion of acute toxicity of hypo-fractionated radiotherapy for Japanese breast cancer patients after surgery was shown to be acceptable in this study.

Effects of mixed land use on urban stormwater quality under different rainfall event types.

The joint effect of mixed land uses and rainfall event types was studied using a two-year field monitoring program in four urban catchments in Calgary, Alberta, Canada. Event mean concentration (EMC) and event pollutant load (EPL) were employed to evaluate the total suspended sediment (TSS), nitrogen and phosphorus. The correlation analysis showed that most nitrogen and phosphorus components (except for NO2-/NO3- and TDP) predominantly exist in particulate form in the study areas. The correlation for EPL was notably stronger than EMC, which can be attributed to varying rainfall characteristics. The differences in EMCs and EPLs of TSS, nitrogen and phosphorus across catchments indicated that the complexity and spatial distribution of mixed land use can influence the generation and transportation of pollutants in urban runoff. The impacts of rainfall characteristics on stormwater quality are integrated rather than driven by a single rainfall characteristic. Brief but intense events tended to elevate TSS, nitrogen and phosphorus concentrations, especially in complex land-use catchments. Events with long antecedent dry days and short duration also resulted in increased pollutant concentrations, while events with long duration and low intensity could result in higher EPLs. The effect of mixed land use on water quality can vary depending on rainfall event types. Seasonal variations were found in EMC and EPL of TSS, nitrogen and phosphorus, with higher values in the spring and summer than the fall. Seasonal variations are mainly influenced by rainfall conditions, temperature and anthropogenic activities (e.g. lawn fertilization and de-icing with sands). MLR considering rainfall characteristics is an effective method for predicting stormwater quality within a single catchment. Considering complexity and spatial distribution of mixed land use can improve the accuracy of the harmonized MLR model. This research provided insights into understanding the complexities introduced by mixed land use and rainfall event types in urban stormwater quality.

Signal mining and gender differences analysis of adverse events in NMIBC treatment with gemcitabine and BCG bladder instillation based on the FAERS database.

OBJECTIVE: To explore safety differences and perform a gender-based analysis of adverse events related to gemcitabine and Bacillus Calmette-Guérin (BCG) vaccine using the U.S. FDA Adverse Event Reporting System (FAERS) database. METHODS: Using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods, adverse events associated with gemcitabine and BCG were mined from FAERS database reports spanning from Q1 2004 to Q3 2023. RESULTS: The study extracted 37,855 reports with gemcitabine and 5,455 reports with BCG as the primary suspected drugs. Adverse events were more prevalent in males (male-to-female ratio: gemcitabine 1.10, BCG 4.25). Differences in high-frequency adverse events among the top 20 signals were detected for both drugs. Both drugs affected similar organ systems, including potential pulmonary, ocular, and renal toxicity, with gemcitabine showing a broader range of adverse events. Gender analysis revealed fewer adverse reactions to gemcitabine in females, while males had fewer adverse reactions to BCG. CONCLUSION: Differences in high-frequency adverse events between gemcitabine and BCG, including some not listed on drug labels, were observed. Both drugs affect similar organ systems, with gemcitabine showing a broader range of adverse events. Gender differences in adverse events were notable.

Impacts of the Chengdu 2021 world university games on NO2 pollution: Implications for urban vehicle electrification promotion.

Emissions of nitrogen oxides (NOx) are a dominant contributor to ambient nitrogen dioxide (NO2) concentrations, but the quantitative relationship between them at an intracity scale remains elusive. The Chengdu 2021 FISU World University Games (July 22 to August 10, 2023) was the first world-class multisport event in China after the COVID-19 pandemic which led to a substantial decline in NOx emissions in Chengdu. This study evaluated the impact of variations in NOx emissions on NO2 concentrations at a fine spatiotemporal scale by leveraging this event-driven experiment. Based on ground-based and satellite observations, we developed a data-driven approach to estimate full-coverage hourly NO2 concentrations at 1 km resolution. Then, a random-forest-based meteorological normalization method was applied to decouple the impact of meteorological conditions on NO2 concentrations for every grid cell, the resulting data were then compared with the timely bottom-up NOx emissions. The SHapley-Additive-exPlanation (SHAP) method was employed to delineate the individual contributions of meteorological factors and various emission sources to the changes in NO2 concentrations. According to the full-coverage meteorologically normalized NO2 concentrations, a decrease in NOx emissions and favorable meteorological conditions accounted for 80 % and 20 % of the NO2 reduction, respectively, across Chengdu city during the control period. Within the strict control zone, a 30 % decrease in the meteorologically normalized NO2 concentrations was observed during the control period. The normalized NO2 concentrations demonstrated a strong correlation with NOx emissions (R = 0.96). Based on the SHAP analysis, traffic emissions accounted for 73 % of the reduction in NO2 concentrations, underscoring the significance of traffic control measures in improving air quality in urban areas. This study provides insights into the relationship between NO2 concentrations and NOx emissions using real-world data, which implies the substantial benefits of vehicle electrification for sustainable urban development.

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.

BACKGROUND: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. METHODS: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. RESULTS: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. CONCLUSIONS: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.

Implications of anemia in patients undergoing PCI with Impella-support: insights from the PROTECT III study.

Background: Anemia is prevalent among patients with cardiovascular disease and is associated with adverse outcomes. However, data regarding the impact of anemia in high-risk percutaneous coronary intervention (HRPCI) are limited. Objectives: This study aimed to evaluate the impact of anemia in patients undergoing Impella-supported HRPCI in the PROTECT III study. Methods: Patients undergoing Impella-supported HRPCI in the multicenter PROTECT III study were assessed for anemia based on baseline hemoglobin levels according to World Health Organization criteria. Patients were stratified into three groups, namely, no anemia, mild anemia, and moderate or severe anemia. Major adverse cardiovascular and cerebrovascular events (MACCE: all-cause death, myocardial infarction, stroke/transient ischemic attack, and repeat revascularization) at 30 and 90 days, and major bleeding events were compared across groups. Results: Of 1,071 patients with baseline hemoglobin data, 37.9% had no anemia, 43.4% had mild anemia, and 18.7% had moderate or severe anemia. Anemic patients were older and more likely to have comorbidities. Anemia was associated with higher MACCE rates at 30 days (moderate to severe, 12.3%; mild, 9.8%; no anemia, 5.4%; p = 0.02) and at 90 days (moderate to severe, 18.7%; mild, 14.6%; none, 8.3%; p = 0.004). These differences persisted after adjustment for potential confounders at 30 and 90 days, and sensitivity analysis excluding dialysis showed similar results. Major bleeding at 30 days was also higher in anemic patients (5.5% vs. 1.2%, p = 0.002). Conclusion: Baseline anemia in Impella-supported HRPCI is common and independently associated with MACCE and major bleeding, emphasizing its significance as a prognostic factor. Specific management strategies to reduce anemia-associated MACCE risk after HRPCI should be examined. Clinical Trial Information Trial Name: The Global cVAD Study (cVAD)ClinicalTrial.gov Identifier: NCT04136392URL: https://clinicaltrials.gov/ct2/show/NCT04136392?term=cvad&draw=2&rank=2.

Vonoprazan-associated Clostridioides difficile infection: an analysis of the Japanese Adverse Drug Event Report and the FDA Adverse Event Reporting System.

Background: Prolonged or excessive use of acid suppressants may increase the risk of Clostridioides difficile infection (CDI) by altering the intestinal microecosystem. Vonoprazan, a novel potassium-competitive acid blocker, exhibits a faster and more sustained acid-suppressive effect than proton pump inhibitors (PPIs). Therefore, vonoprazan may have a greater impact on the gut microbiota, potentially resulting in CDI. Objectives: This study aimed to explore the potential relationship between acid suppressants and CDI by the Japan Adverse Drug Event Report (JADER) and the FDA Adverse Event Reporting System (FAERS) databases. Design: A retrospective analysis of the JADER and FAERS databases was examined by disproportionality analysis. Methods: We performed signal detection analyses of CDI induced by vonoprazan and PPIs using the JADER and FAERS databases. The association between acid suppressants and CDI was calculated using the reporting odds ratio (ROR) and corresponding 95% confidence interval (95% CI). When the lower limit of the 95% CI is exceeded by 1, the association is considered statistically significant. Results: In the JADER database, the ROR (95% CI) for vonoprazan and PPIs based on suspect drug reports was 15.84 (12.23-20.50) and 2.51 (1.92-3.28), respectively. In the FAERS database, the ROR (95% CI) for vonoprazan and PPIs based on primary and secondary suspect drug reports was 11.50 (6.36-20.82) and 1.42 (1.34-1.51), respectively. Subgroup analysis showed that elderly patients aged 60 years and older were more strongly associated with CDI. The ROR (95% CI) for vonoprazan and PPIs in patients aged 60 years and older in the JADER database was 15.35 (11.59-20.33) and 1.65 (1.14-2.39), respectively. Similarly, the ROR (95% CI) for vonoprazan and PPIs in the FAERS database was 12.56 (6.26-25.20) and 1.43 (1.31-1.57), respectively. Excluding the effect of Helicobacter pylori (H. pylori) infection, the use of acid suppressants was still associated with CDI. Conclusion: While signal detection analysis based on the JADER and FAERS databases could not establish causality, our study demonstrated that both vonoprazan and PPIs were significantly associated with CDI. Vonoprazan showed a stronger association with CDI in both databases.

Introduction: Vonoprazan is a new type of acid suppressant, which has a stronger effect on acid inhibition than traditional proton pump inhibitors (PPIs). Vonoprazan may have a greater impact on the gut microbiota, which may increase the risk of Clostridioides difficile infection (CDI). The FDA created the FDA Adverse Event Reporting System (FAERS) database to support the post-market surveillance program. The PMDA created the Japan Adverse Drug Reaction Event Report (JADER) database to specifically collect adverse reaction reports in Japan. To further understand the potential relationship between acid suppressants and CDI, this study was analyzed using the JADER and FAERS databases. Methods: This study analyzed cases of CDI reported after the use of acid suppressants in the JADER and FAERS databases. Results: The analysis revealed that vonoprazan and PPIs are significantly associated with CDI in both databases. Notably, vonoprazan exhibited a stronger association compared to PPIs. Subgroup analysis indicated that this association was more pronounced in elderly patients aged 60 years and older. Additionally, excluding the influence of Helicobacter pylori (H. pylori) did not diminish the association between acid suppressants and CDI. Conclusion: Although signal detection analysis based on the JADER and FAERS databases could not establish causality, the results showed that both vonoprazan and PPIs were significantly associated with CDI. Vonoprazan was also more strongly associated with CDI than PPIs, which could be a potential safety concern, and further clinical studies are needed to confirm this finding.

Vonoprazan and Clostridioides difficile infection risk.

Successful Lorlatinib Rechallenge After Severe Drug-Induced Psychosis in ALK-Positive Metastatic NSCLC: A Case Report.

Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system-active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.

A time-to-event modelling of sputum conversion within two months after antituberculosis initiation among drug-susceptible smear positive pulmonary tuberculosis patients: Implementation of internal and external validation.

Delayed sputum conversion has been associated with a higher risk of treatment failure or relapse among drug susceptible smear-positive pulmonary tuberculosis patients. Several contributing factors have been identified in many studies, but the results varied across regions and countries. Therefore, the current study aimed to develop a predictive model that explained the factors affecting time to sputum conversion within two months after initiating antituberculosis agents among Malaysian with drug-susceptible smear-positive pulmonary tuberculosis patients. Retrospective data of pulmonary tuberculosis patients followed up at a tertiary hospital in the Northern region of Malaysia from 2013 until 2018 were collected and analysed. Nonlinear mixed-effect modelling software (NONMEM 7.3.0) was used to develop parametric survival models. The final model was further validated using Kaplan-Meier-visual predictive check (KM-VPC) approach, kernel-based hazard rate estimation method and sampling-importance resampling (SIR) method. A total of 224 patients were included in the study, with 34.4 % (77/224) of the patients remained positive at the end of 2 months of the intensive phase. Gompertz hazard function best described the data. The hazard of sputum conversion decreased by 39 % and 33 % for moderate and advanced lesions as compared to minimal baseline of chest X-ray severity, respectively (adjusted hazard ratio (aHR), 0.61; 95 % confidence intervals (95 % CI), (0.44-0.84) and 0.67, 95 % CI (0.53-0.84)). Meanwhile, the hazard also decreased by 59 % (aHR, 0.41; 95 % CI, (0.23-0.73)) and 48 % (aHR, 0.52; 95 % CI, (0.35-0.79)) between active and former drug abusers as compared to non-drug abuser, respectively. The successful development of the internally and externally validated final model allows a better estimation of the time to sputum conversion and provides a better understanding of the relationship with its predictors.

The Complex Pattern Mismatch Negativity as a Potential Indicator of Psychosis Across all Phases of Illness: A Meta-Analysis.

Over the past decade, there has been extensive research on the mismatch negativity (MMN) and its promise as a biomarker of illness in people with schizophrenia (SZ). Nevertheless, when attempting to assess the early stages of illness progression, the utility of MMN has been inconsistent. Recently, researchers have been investigating a more advanced MMN paradigm (the complex MMN [cMMN]) which is believed to index higher-order cognitive processing and has been suggested to be a more effective indicator of the early phases of SZ. The cMMN is defined as a paradigm that relies on alterations within a pre-established pattern of stimuli. In this meta-analysis, we investigated cMMN deficits in individuals with SZ, including an analysis involving those in the first 5 years of illness. Our search also included individuals with bipolar disorder who experience psychosis; however, no related papers were found and thus, no findings are reported. Our findings indicate a small/moderate effect (d = 0.47), suggesting that individuals with SZ exhibit reduced cMMN amplitudes compared to individuals without SZ. Interestingly, this effect seems to be more pronounced in individuals within the first 5 years of their illness (d = 0.58), suggesting that cMMN might be a more sensitive biomarker in the early phases of SZ compared to traditional paradigms.

Using multistate models with clinical trial data for a deeper understanding of complex disease processes.

A clinical trial represents a large commitment from all individuals involved and a huge financial obligation given its high cost; therefore, it is wise to make the most of all collected data by learning as much as possible. A multistate model is a generalized framework to describe longitudinal events; multistate hazards models can treat multiple intermediate/final clinical endpoints as outcomes and estimate the impact of covariates simultaneously. Proportional hazards models are fitted (one per transition), which can be used to calculate the absolute risks, that is, the probability of being in a state at a given time, the expected number of visits to a state, and the expected amount of time spent in a state. Three publicly available clinical trial datasets, colon, myeloid, and rhDNase, in the survival package in R were used to showcase the utility of multistate hazards models. In the colon dataset, a very well-known and well-used dataset, we found that the levamisole+fluorouracil treatment extended time in the recurrence-free state more than it extended overall survival, which resulted in less time in the recurrence state, an example of the classic "compression of morbidity." In the myeloid dataset, we found that complete response (CR) is durable, patients who received treatment B have longer sojourn time in CR than patients who received treatment A, while the mutation status does not impact the transition rate to CR but is highly influential on the sojourn time in CR. We also found that more patients in treatment A received transplants without CR, and more patients in treatment B received transplants after CR. In addition, the mutation status is highly influential on the CR to transplant transition rate. The observations that we made on these three datasets would not be possible without multistate models. We want to encourage readers to spend more time to look deeper into clinical trial data. It has a lot more to offer than a simple yes/no answer if only we, the statisticians, are willing to look for it.

Reproductive resilience of growth and nitrogen uptake underpins yield improvement in winter wheat with forced delay of sowing.

Winter wheat production is influenced by climate extremes worldwide. Heavy precipitation induced delay of sowing generates limited photothermal resources for wheat early growth. However, how wheat build resilience from stunted seedling growth has not been fully explored. Here, a twelve-year farmers' survey of wheat yield was recorded and four-year field experiments of wheat grown in normal and late-sowing were performed under zero nitrogen (N0) and optimum nitrogen (Opt.N) supply. Wheat growth and N uptake were measured at both vegetative and reproductive stages alongside photothermal resource-use efficiency. Farmers' survey showed 10.4 % yield losses due to delayed sowing compared to the normal. However, four-year field trials revealed that the combination of increasing seeding rates and Opt.N application recovered grain yield of sowing-delayed wheat and even increased by 13.2 % compared to plants in the normal seasons. Although delayed sowing substantially suppressed seedling growth and tillering before winter dormancy, the Opt.N application increased spring tillers by 2.4-fold which were productive at maturity. Further, plant growth and N uptake from jointing to anthesis of sowing-delayed wheat were accelerated by Opt.N, but not by N0 treatment. Delayed sowing significantly shortened the duration of lag phase of grain filling by 3.5 days and by 183 growing degree days compared with the normal, which initiated the linear and fast filling earlier. Increased leaf photosynthesis by 27.4 % during grain filling further supported the fast recovery of grain filling in the sowing-delayed wheat. Concomitantly, the physiological N-use efficiency increased by 46.7 % during grain filling and by 41.5 % at maturity by enhancing N availability and seeding rates, and photothermal resource-use efficiency increased by 1.3- to 1.7-fold for wheat with delayed vs. normal sowing. Overall, these findings highlight the integrated management of nutrient and cultivation to mitigate the impacts of climate extremes on crop productivity through building plant reproductive resilience.

Association between cardiac time intervals and incident heart failure after acute coronary syndrome.

BACKGROUND: Cardiac time intervals are sensitive markers of myocardial dysfunction that predispose to heart failure (HF). We aimed to investigate the association between cardiac time intervals and HF in patients with acute coronary syndrome (ACS). METHODS: This study included 386 ACS patients treated with percutaneous coronary intervention (PCI). Patients underwent an echocardiography examination a median of two days after PCI. Cardiac time intervals including isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and systolic ejection time (ET), and myocardial performance index (MPI) were obtained by tissue Doppler echocardiography. The outcome was incident HF. RESULTS: During follow-up (median 4.3, IQR:1.0-6.7 years), 140 (36%) developed HF. In unadjusted analyses, IVRT was not associated with HF (HR 1.02 (0.95-1.10), p = 0.61, per 10ms increase), and neither was IVCT (HR 0.07 (0.95-1.22), p = 0.26, per 10ms increase). Increasing MPI was associated with a higher risk of HF (HR 1.20 (1.08-1.34), P = 0.001, per 0.1 increase), and so was decreasing ET (HR 1.13 (1.07-1.18), P < 0.001 per 10ms decrease). After multivariable adjustment for cardiovascular risk factors, MPI (HR 1.13 (1.01-1.27), P = 0.034) and ET (HR 1.09 (1.01-1.17), P = 0.025) remained significantly associated with incident HF. LVEF modified the association between ET and HF (p for interaction = 0.002), such that ET was associated with HF in patients with LVEF ≥ 36% (HR = 1.15 (1.06-1.24), P = 0.001, per 10ms decrease). CONCLUSION: In patients admitted with ACS, shortened ET and higher MPI were independently associated with an increased risk of incident HF. Additionally, ET was associated with incident HF in patients with LVEF above 36%.