Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort.

BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING: 83 enrolling sites. PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests. RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE: National Institutes of Health.

Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC.

Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI-based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection. SIGNIFICANCE: Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC.

"Fast but not so furious": A condensed step-up dosing schedule of teclistamab for relapsed/refractory multiple myeloma.

Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific T-cell engager approved for relapsed-refractory multiple myeloma (RRMM). Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) are well-documented treatment -related adverse events of teclistamab. The prescribing information recommends step-up dosing on days 1, 4, and 7 with 48-72 h of inpatient observation after each dose to monitor for CRS. This leads to a more than weeklong hospital stay, adding to the cost of therapy, resource utilization, and patient inconvenience. Here, we present a single center retrospective analysis addressing the safety and utility of a condensed step-up dosing schedule for teclistamab. All patients who were treated with teclistamab from November 2022 to August 2023 at the Medical University of South Carolina were included in the analysis. Patients received subcutaneous (SC) teclistamab with step-up doses (0.06 and 0.3 mg/kg) separated by either 2 or 3 (48-72 h) before the administration of the first full (1.5 mg/kg) dose (days 1, 3, and 5 'condensed' schedule or days 1, 4, and 7 'standard' schedule, respectively). All patients were hospitalized for the two step-up doses and first full dose of teclistamab and received pre-medications prior to each dose. Patients could be discharged after a minimum of 24 h following the full dose, if they did not have any CRS or ICANS. Relevant data regarding incidence, severity, and onset of CRS was collected. Statistical analysis was completed to assess the probability of fever with the first full dose of teclistamab based on incidence of fever with previous doses. A total of 25 patients were included in the analysis. Twenty-eight percent (7/25) of patients underwent the standard step up while the remaining 72% (18/25) underwent a condensed step up of teclistamab. More than half (53%, 13/25) of the patients experienced CRS during step up dosing. Grades 1 and 2 CRS occurred in 48% (12/25) and 4% (1/25) patients, respectively. Of the 13 patients that experienced CRS, 30% (4/13) fevered with the first dose, 84% (11/13) fevered with the second dose, and one patient developed fever after the third dose. The negative predictive value of being 'fever free' after doses 1 and 2 and remaining 'fever free' throughout hospitalization was 0.92. The median length of hospital stay among the 1, 3, and 5 step up group was 6 days (6-25) and 70% (14/20) of patients were discharged from the hospital within 7 days of treatment initiation. This report demonstrates the utility of a condensed step-up schedule for teclistamab initiation. The schedule was found to be safe and reduced hospital length of stay. These results should prompt consideration of shorter hospital stays for patients who do not experience CRS and raise the possibility of outpatient administration with close observation.

Early Dysglycemia Is Detectable Using Continuous Glucose Monitoring in Very Young Children at Risk of Type 1 Diabetes.

OBJECTIVE: Continuous glucose monitoring (CGM) can detect early dysglycemia in older children and adults with presymptomatic type 1 diabetes (T1D) and predict risk of progression to clinical onset. However, CGM data for very young children at greatest risk of disease progression are lacking. This study aimed to investigate the use of CGM data measured in children being longitudinally observed in the Australian Environmental Determinants of Islet Autoimmunity (ENDIA) study from birth to age 10 years. RESEARCH DESIGN AND METHODS: Between January 2021 and June 2023, 31 ENDIA children with persistent multiple islet autoimmunity (PM Ab+) and 24 age-matched controls underwent CGM assessment alongside standard clinical monitoring. The CGM metrics of glucose SD (SDSGL), coefficient of variation (CEV), mean sensor glucose (SGL), and percentage of time >7.8 mmol/L (140 mg/dL) were determined and examined for between-group differences. RESULTS: The mean (SD) ages of PM Ab+ and Ab- children were 4.4 (1.8) and 4.7 (1.9) years, respectively. Eighty-six percent of eligible PM Ab+ children consented to CGM wear, achieving a median (quartile 1 [Q1], Q3) sensor wear period of 12.5 (9.0, 15.0) days. PM Ab+ children had higher median (Q1, Q3) SDSGL (1.1 [0.9, 1.3] vs. 0.9 [0.8, 1.0] mmol/L; P < 0.001) and CEV (17.3% [16.0, 20.9] vs. 14.7% [12.9, 16.6]; P < 0.001). Percentage of time >7.8 mmol/L was greater in PM Ab+ children (median [Q1, Q3] 8.0% [4.4, 13.0] compared with 3.3% [1.4, 5.3] in Ab- children; P = 0.005). Mean SGL did not differ significantly between groups (P = 0.10). CONCLUSIONS: CGM is feasible and well tolerated in very young children at risk of T1D. Very young PM Ab+ children have increased SDSGL, CEV, and percentage of time >7.8 mmol/L, consistent with prior studies involving older participants.

Modeling Nursing Home Harms From COVID-19 Staff Furlough Policies.

Importance: Current guidance to furlough health care staff with mild COVID-19 illness may prevent the spread of COVID-19 but may worsen nursing home staffing shortages as well as health outcomes that are unrelated to COVID-19. Objective: To compare COVID-19-related with non-COVID-19-related harms associated with allowing staff who are mildly ill with COVID-19 to work while masked. Design, Setting, and Participants: This modeling study, conducted from November 2023 to June 2024, used an agent-based model representing a 100-bed nursing home and its residents, staff, and their interactions; care tasks; and resident and staff health outcomes to simulate the impact of different COVID-19 furlough policies over 1 postpandemic year. Exposures: Simulating increasing proportions of staff who are mildly ill and are allowed to work while wearing N95 respirators under various vaccination coverage, SARS-CoV-2 transmissibility and severity, and masking adherence. Main Outcomes and Measures: The main outcomes were staff and resident COVID-19 cases, staff furlough days, missed care tasks, nursing home resident hospitalizations (related and unrelated to COVID-19), deaths, and costs. Results: In the absence of SARS-CoV-2 infection in the study's 100-bed agent-based model, nursing home understaffing resulted in an annual mean (SD) 93.7 (0.7) missed care tasks daily (22.1%), 38.0 (7.6) resident hospitalizations (5.2%), 4.6 (2.2) deaths (0.6%), and 39.7 (19.8) quality-adjusted life years lost from non-COVID-19-related harms, costing $1 071 950 ($217 200) from the Centers for Medicare & Medicaid Services (CMS) perspective and $1 112 800 ($225 450) from the societal perspective. Under the SARS-CoV-2 Omicron variant conditions from 2023 to 2024, furloughing all staff who tested positive for SARS-CoV-2 was associated with a mean (SD) 326.5 (69.1) annual furlough days and 649.5 (95% CI, 593.4-705.6) additional missed care tasks, resulting in 4.3 (95% CI, 2.9-5.9) non-COVID-19-related resident hospitalizations and 0.7 (95% CI, 0.2-1.1) deaths, costing an additional $247 090 (95% CI, $203 160-$291 020) from the CMS perspective and $405 250 (95% CI, $358 550-$451 950) from the societal perspective. Allowing 75% of staff who were mildly ill to work while masked was associated with 5 additional staff and 5 additional resident COVID-19 cases without added COVID-19-related hospitalizations but mitigated staffing shortages, with 475.9 additional care tasks being performed annually, 3.5 fewer non-COVID-19-related hospitalizations, and 0.4 fewer non-COVID-19-related deaths. Allowing staff who were mildly ill to work ultimately saved an annual mean $85 470 (95% CI, $41 210-$129 730) from the CMS perspective and $134 450 (95% CI, $86 370-$182 540) from the societal perspective. These results were robust to increased vaccination coverage, increased nursing home transmission, increased importation of COVID-19 from the community, and failure to mask while working ill. Conclusion and Relevance: In this modeling study of staff COVID-19 furlough policies, allowing nursing home staff to work with mild COVID-19 illness was associated with fewer resident harms from staffing shortages and missed care tasks than harms from increased COVID-19 transmission, ultimately saving substantial direct medical and societal costs.

Risk factors associated with piglet pre-weaning mortality in a Midwestern U.S. swine production system from 2020 to 2022.

Piglet pre-weaning mortality (PWM) is a significant issue in the U.S. swine industry, causing economic losses and raising sustainability and animal welfare concerns. This study conducted a multivariable analysis to identify factors associated with PWM in a Midwestern U.S. swine production system. Weekly data from 47 sow farms (7207 weaning weeks) were captured from January 2020 to December 2022. Initially, 29 variables regarding farm infrastructure, productivity parameters, health status, and interventions were selected for univariate analysis to assess their association with PWM. The initial multivariable analysis included the variables with P < 0.20 in the univariate analyses. A backward stepwise model selection was conducted by excluding variables with P > 0.05, and the final multivariable model consisted of 19 significant risk factors and 6 interaction terms. The overall average PWM for the study population was 14.02 %. Yearly variations in PWM were observed, with the highest recorded in 2020 (16.61 %) and the lowest in 2021 (15.78 %). Cohorts with a pond water source, lower farrowing rate (71.9 %), higher farrowing parity (5.1), shorter gestation length (116.2 days), and using oxytocin during farrowing had increased PWM. The higher productivity parameters such as mummies rate, stillborn rate, and average total born, the higher the PWM was. Additionally, health status and intervention-related factors were associated with PWM, where higher PWM rates were observed in herds facing porcine reproductive and respiratory syndrome virus (PRRSV) outbreaks, porcine epidemic diarrhea virus (PEDV) positive, the weeks before and during feed medication, and weeks without using Rotavirus vaccine or Rotavirus feedback. Altogether, these results corroborate that PWM is a multifactorial problem, and a better understanding of the risk factors is essential in developing strategies to improve survival rates. Therefore, this study identified the major risk factors associated with PWM for groups of pigs raised under field conditions, and the results underscore the significance of data analysis in comprehending the unique challenges and opportunities inherent to each system.

Cure models, survival probabilities, and solid organ transplantation for patients with colorectal cancer.

A previous cancer diagnosis can preclude patients from consideration for solid organ transplantation. Statistical models may improve candidate selection. We fitted statistical cure models and estimated five-year cancer-specific survival (5yCSS) for colorectal cancer patients in the United States using registry data. The median cure probability at cancer diagnosis for patients in the general population was 0.67. Among 956 colorectal cancer patients who underwent solid organ transplantation, the median time since diagnosis was 6.3 years and the median 5yCSS at transplantation was 0.96. Patients with a 5yCSS below 0.90 had increased posttransplant cancer-specific mortality (hazard ratio 3.31, 95% confidence interval 1.52-7.21). Compared with recently published guidelines, our models suggested shorter wait times for some groups of colorectal cancer patients (e.g., stage IIA cancers) and longer wait times for others (stages IIB, IIIB, IIIC, IV). In conclusion, colorectal cancer patients undergoing solid organ transplantation had excellent prognoses, reflecting selection incorporating existing guidelines and clinical judgement. Nonetheless, 5yCSS probabilities estimated from cure models offer additional prognostic information for patients considered for transplantation and identify situations where current guidelines might be revised. We developed a web-based tool for clinicians to calculate 5yCSS probabilities for use in transplant evaluation for individual colorectal cancer patients (https://dceg.cancer.gov/tools/risk-assessment/calculator-of-colorectal-cancer-survival-probability).

Use of an electronic documentation module to improve surgical debriefing effectiveness.

BACKGROUND: Effective communication in the operating room is crucial for patient safety and optimal outcomes. Structured debriefing communication tools can improve team coordination and address recurring safety concerns. During the unique circumstances of the COVID-19 pandemic, this study evaluated an approach to documentation and loop closure that functioned under constrained hospital resources, a loss of capacity for face-to-face provider training and loop closure, and periods of performing only urgent and emergent surgery for which some debriefing elements, like patient disposition and equipment needs, are more dynamic. METHODS: Employing a longitudinal repeated-measures design, this quality improvement study used a newly integrated module within the electronic health record system to document debriefings, which were linked to surveys assessing perceptions of the debriefing process. Data were collected from 56 operating rooms in 3 separate hospital towers during a 3-year period ending December 2023, encompassing 4 reiterative Plan-Do-Study-Act cycles. RESULTS: The study recorded 49,426 surgical debriefings. The overall incidence of debriefing increased 111% during the study period, reaching 88% during the third and final year of the project. Compared with 193 preintervention surveys, 129 postintervention surveys demonstrated increased incidence of perceiving debriefings as very or extremely effective (52% vs 38%, P = .02), greater frequency of discussing whether equipment issues occurred (87% vs 75%, P = .008), and greater frequency of loop closure (46% vs 34%, P = .03) and leadership (Chair or Program Director of Quality) involvement in loop closure activities (14% vs 3%, P = .008) addressing issues identified during debriefs. CONCLUSION: Despite challenges associated with implementation during a viral pandemic, the intervention was associated with increased incidence and perceived effectiveness of documented surgical debriefings, greater frequency of downstream loop closure, and positive impacts on team communication.

A proteome-wide analysis unveils a core Epstein-Barr virus antibody signature of classic Hodgkin lymphoma across ethnically diverse populations.

Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.

Epigenome-wide association study of fluoride exposure during early adolescence and DNA methylation among U.S. children.

Exposure to fluoride in early childhood has been associated with altered cognition, intelligence, attention, and neurobehavior. Fluoride-related neurodevelopment effects have been shown to vary by sex and very little is known about the mechanistic processes involved. There is limited research on how fluoride exposure impacts the epigenome, potentially leading to changes in DNA methylation of specific genes regulating key developmental processes. In the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), urine samples were analyzed using a microdiffusion method to determine childhood urinary fluoride adjusted for specific gravity (CUFsg) concentrations. Whole blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip 850 k Array. In a cross-sectional analysis, we interrogated epigenome-wide DNA methylation at 775,141 CpG loci across the methylome in relation to CUFsg concentrations in 272 early adolescents at age 12 years. Among all participants, higher concentrations of CUF were associated with differential methylation of one CpG (p < 6 × 10-8) located in the gene body of GBF1 (cg25435255). Among females, higher concentrations of CUFsg were associated with differential methylation of 7 CpGs; only three CpGs were differentially methylated among males with no overlap of significant CpGs observed among females. Secondary analyses revealed several differentially methylated regions (DMRs) and CpG loci mapping to genes with key roles in psychiatric outcomes, social interaction, and cognition, as well as immunologic and metabolic phenotypes. While fluoride exposure may impact the epigenome during early adolescence, the functional consequences of these changes are unclear warranting further investigation.

Infection prevention and control studies for care of patients with suspected or confirmed filovirus disease in healthcare settings, with focus on Ebola and Marburg: an integrative review.

Objective: To review evidence pertaining to methods for preventing healthcare-associated filovirus infections (including the survivability of filoviruses in clinical environments and the chlorine concentration required for effective disinfection), and to assess protocols for determining the risk of health worker (HW) exposures to filoviruses. Design: Integrative review. Data sources: PubMed, Embase, Google Scholar, internet-based sources of international health organisations (eg, WHO, CDC), references of the included literature and grey literature. Study selection: Laboratory science, clinical research and real-world observational studies identified through comprehensive search strings that pertained to Ebola disease and Marburg disease and the three research objectives. Methods: Using the framework of population, intervention or exposure, outcomes, study types and report characteristics, reviewers extracted data and critically appraised the evidence using predefined data extraction forms and summary tables. The extraction forms, summary tables and critical appraisals varied based on the included literature; we used both the QUIPS Risk-of-Bias tool when possible and an internally developed instrument to systematically extract and review the evidence from observational and experimental studies. Evidence was then synthesised and summarised to create summary recommendations. Results: Thirty-six studies (including duplicates across research questions) were included in our reviews. All studies that related to the review questions were either (1) descriptive, real-world studies (ie, environmental audits of various surfaces in operational Ebola Treatment Units) or (2) controlled, laboratory studies (ie, experimental studies on the survivability of ebolaviruses in controlled conditions), presenting a range of concerns pertaining to bias and external validity. Our reviews of viral survivability evidence revealed significant disconnections between laboratory-based and real-world findings. However, there is greater viral persistence in liquid than dried body fluids, with the possible exception of blood, and ebolaviruses can survive for significant periods of time in dried substrate. Evidence suggests that 0.5% hypochlorite solution should be used for disinfection activity. Spills should be cleaned with covering and soaking for 15 min. Existing literature suggests that within a well-resourced clinical environment with trained, foreign HWs and established protocols, transmission of ebolaviruses as an occupational risk is a rare event. Despite the high rates of HW infections within public African healthcare settings, no evidence with low risk of bias exists to assess the risk of various occupational exposures given that all high-quality studies were conducted on foreign Ebola clinicians who had low overall rates of infection. This review underscores the critical need for better-quality evidence to inform best practices to ensure HW safety during filovirus disease epidemics.

Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection.

The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [18F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the postacute COVID-19 group, which included those with and without continuing symptoms, was higher compared with prepandemic controls in many regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. T cell activation in the spinal cord and gut wall was associated with the presence of LC symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms specifically. Increased T cell activation in these tissues was also observed in many individuals without LC. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization of SARS-CoV-2 RNA and immunohistochemical studies in a subset of five participants with LC symptoms. We identified intracellular SARS-CoV-2 single-stranded spike protein-encoding RNA in rectosigmoid lamina propria tissue in all five participants and double-stranded spike protein-encoding RNA in three participants up to 676 days after initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations.

Controlled Study of Metabolic Syndrome Among Offspring of Parents With Bipolar Disorder.

Objectives: Bipolar disorder (BD) is highly heritable and associated with increased rates of metabolic syndrome (MetS). However, little is known about MetS in offspring of parents with BD. We therefore examined this topic in the Pittsburgh Bipolar Offspring Study cohort.Methods: Participants included 199 parents (n = 116 BD, diagnosed using DSM-IV; n = 83 non-BD) and 330 offspring (mean age 19.9 ± 5.3 years), including 198 high-risk offspring of parents with BD (n = 80 affected with a mood disorder) and 132 control offspring. We defined MetS and its components using International Diabetes Federation (IDF) guidelines (primary) and National Cholesterol Education Program (NCEP) guidelines (secondary). Multivariable analyses controlled for age and socioeconomic status in offspring. Sensitivity analyses controlled for psychotropic medications.Results: There was higher prevalence of MetS in parents with BD as compared to controls. NCEP-defined MetS was significantly more prevalent among affected high-risk offspring (16.3%) and controls (15.2%) vs unaffected high-risk offspring (6.0%; χ2 = 6.54, P = .04). There was greater mean number of MetS components (IDF: 1.7 ± 1.1; NCEP: 1.4 ± 1.0) among affected high-risk offspring vs unaffected high-risk offspring (IDF: 1.2 ± 1.0; NCEP: 1.0 ± 1.0) and controls (IDF: 1.3 ± 1.2; NCEP: 1.1 ± 1.1; IDF: H[2] = 10.26, P = .006; NCEP: H[2] = 9.18, P = .01). Most findings became nonsignificant in multivariable analyses. Some between-group results became nonsignificant after controlling for second-generation antipsychotics.Conclusions: This preliminary study found increased risk of MetS among affected high-risk offspring, which may be attributable to socioeconomic status. Prospective studies may determine timing of MetS onset in relation to mood disorder onset, and the role of socioeconomic status in moderating this association.

Environmental Determinants of Islet Autoimmunity (ENDIA) longitudinal prospective pregnancy to childhood cohort study of Australian children at risk of type 1 diabetes: parental demographics and birth information.

INTRODUCTION: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS: The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS: This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment. TRIAL REGISTRATION NUMBER: ACTRN12613000794707.

Effects of ondansetron on symptoms during a gastric emptying study and enteral lipid challenge and on daily symptoms in diabetic gastroenteropathy.

BACKGROUND: This study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]). METHODS: We performed a randomized, double-blinded, placebo-controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed. KEY RESULTS: Of 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024). CONCLUSIONS & INFERENCES: Ondansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

Rare but diverse off-target and somatic mutations found in field and greenhouse grown trees expressing CRISPR/Cas9.

Introduction: CRISPR gene editing, while highly efficient in creating desired mutations, also has the potential to cause off-target mutations. This risk is especially high in clonally propagated plants, where editing reagents may remain in the genome for long periods of time or in perpetuity. We studied a diverse population of Populus and Eucalyptus trees that had CRISPR/Cas9-containing transgenes that targeted one or two types of floral development genes, homologs of LEAFY and AGAMOUS. Methods: Using a targeted sequence approach, we studied approximately 20,000 genomic sites with degenerate sequence homology of up to five base pairs relative to guide RNA (gRNA) target sites. We analyzed those sites in 96 individual tree samples that represented 37 independent insertion events containing one or multiples of six unique gRNAs. Results: We found low rates of off-target mutations, with rates of 1.2 × 10-9 in poplar and 3.1 × 10-10 in eucalypts, respectively, comparable to that expected due to sexual reproduction. The rates of mutation were highly idiosyncratic among sites and not predicted by sequence similarity to the target sites; a subset of two gRNAs showed off-target editing of four unique genomic sites with up to five mismatches relative to the true target sites, reaching fixation in some gene insertion events and clonal ramets. The location of off-target mutations relative to the PAM site were essentially identical to that seen with on-target CRISPR mutations. Discussion: The low rates observed support many other studies in plants that suggest that the rates of off-target mutagenesis from CRISPR/Cas9 transgenes are negligible; our study extends this conclusion to trees and other long-lived plants where CRISPR/Cas9 transgenes were present in the genome for approximately four years.