The epidemiology and risk factors for postnatal complications among postpartum women and newborns in southwestern Uganda: A prospective cohort study.

Sub-Saharan Africa accounts for two-thirds of the global burden of maternal and newborn deaths. Adverse outcomes among postpartum women and newborns occurring in the first six weeks of life are often related, though data co-examining patients are limited. This study is an exploratory analysis describing the epidemiology of postnatal complications among postpartum women and newborns following facility birth and discharge in Mbarara, Uganda. This single-site prospective cohort observational study enrolled postpartum women following facility-based delivery. To capture health information about both the postpartum women and newborns, data was collected and categorized according to domains within the continuum of care including (1) social and demographic, (2) pregnancy history and antenatal care, (3) delivery, (4) maternal discharge, and (5) newborn discharge. The primary outcomes were readmission and mortality within the six-week postnatal period as defined by the WHO. Multivariable logistic regression was used to identify risk factors. Among 2930 discharged dyads, 2.8% and 9.0% of women and newborns received three or more postnatal visits respectively. Readmission and deaths occurred among 108(3.6%) and 25(0.8%) newborns and in 80(2.7%) and 0(0%) women, respectively. Readmissions were related to sepsis/infection in 70(88%) women and 68(63%) newborns. Adjusted analysis found that caesarean delivery (OR:2.91; 95%CI:1.5-6.04), longer travel time to the facility (OR:1.54; 95%CI:1.24-1.91) and higher maternal heart rate at discharge (OR:1.02; 95%CI:1.00-1.01) were significantly associated with maternal readmission. Discharge taken on all patients including maternal haemoglobin (per g/dL) (OR:0.90; 95%CI:0.82-0.99), maternal symptoms (OR:1.76; 95%CI:1.02-2.91), newborn temperature (OR:1.66; 95%CI:1.28-2.13) and newborn heart rate at (OR:1.94; 95%CI:1.19-3.09) were risk factors among newborns. Readmission and death following delivery and discharge from healthcare facilities is still a problem in settings with low rates of postnatal care visits for both women and newborns. Strategies to identify vulnerable dyads and provide better access to follow-up care, are urgently required.

Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: A meta-analysis of 60 randomized controlled trials.

BACKGROUND AND AIMS: Individuals with or at high risk of cardiovascular disease (CVD) often receive long-term treatment with low-density lipoprotein cholesterol (LDL-C) lowering therapies, but whether the effects of LDL-C reduction remain stable over time is uncertain. This study aimed to establish the course of the effects of LDL-C reduction on cardiovascular risk over time. METHODS: Randomized controlled trials (RCTs) of LDL-C lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). The primary analyses were restricted to statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, with other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the hazard ratio (HR) for major vascular events (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization, or stroke) per 1 mmol/L LDL-C reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the HR for major vascular events per 1 mmol/L LDL-C reduction. Additionally, treatment-by-time interactions were evaluated in an individual participant data meta-analysis of six atorvastatin trials. RESULTS: A total of 60 RCTs were identified (408,959 participants, 51,425 major vascular events). The HR for major vascular events per 1 mmol/L LDL-C reduction was 0.78 (95 % confidence interval [CI] 0.75-0.81). Follow-up duration was not associated with a change in the HR for major vascular events (HR for change per year 0.994; 95 % CI 0.970-1.020; p = 0.66). The HR attenuated with increasing age in primary prevention (HR for change per 5 years 1.097; 95 % CI 1.031-1.168; p = 0.003), but not secondary prevention (HR for change per 5 years 0.987; 95 % CI 0.936-1.040; p = 0.63). Consistent results were found for statin trials only, and all trials combined. In the individual participant data meta-analysis (31,310 participants, 6734 major vascular events), the HR for major vascular events did not significantly change over follow-up time (HR for change per year 0.983; 95 % CI 0.943-1.025; p = 0.42), or age (HR for change per 5 years 1.022; 95 % CI 0.990-1.055; p = 0.18). CONCLUSIONS: Based on available RCT data with limited follow-up duration, the relative treatment effects of LDL-C reduction are stable over time in secondary prevention, but may attenuate with higher age in primary prevention.

Initial Experience with the Eclipse Double-Lumen Balloon Catheter for Embolization of Cranial Vascular Malformations.

BACKGROUND: Double lumen balloon catheters (DLBCs) have emerged as a potential alternative to single lumen balloon catheters for endovascular embolization of arteriovenous malformations (AVMs) and dural arteriovenous fistulas (dAVFs). This study describes our preliminary experience with the Eclipse 2L DLBC in treating AVMs and dAVFs. METHODS: Patients who underwent embolization of cranial dAVFs or AVMs at our institution from August 2021 to March 2024 were included. Spinal vascular malformations were excluded. Descriptive statistics were used to analyze procedural outcomes, technical nuances, and postoperative outcomes on follow-up. RESULTS: Twenty-five patients who underwent 38 embolization procedures (15 AVMs and 23 dAVFs) met criteria for inclusion in this study. The mean age of the cohort was 52.44 (standard deviation = 17.26), and 48% of the overall cohort (n = 13) was female. The average procedure times for AVMs and dAVFs were 80.4 minutes and 96.73 minutes, respectively. There was 1 instance of catheter entrapment. Two patients in the AVM cohort experienced mortality, and 1 experienced postoperative rupture. CONCLUSIONS: Our preliminary experience using the Eclipse 2L balloon catheter for Onyx embolization reported procedural outcomes comparable to other DLBCs despite relatively higher procedure times and radiation doses. Further long-term studies on its efficacy as primary modality in treating AVMs and dAVFs are encouraged.

May Measurement Month 2021: an analysis of blood pressure screening results from a suburban community in the Democratic Republic of the Congo.

Hypertension remains the most powerful contributor to the global morbidity and mortality. May Measurement Month (MMM), a worldwide screening campaign initiated by the International Society of Hypertension (ISH), is organized annually to increase awareness of high blood pressure (BP). We screened 20 913 adult (≥18 years) residents of suburb hamlets of Mbujimayi (mean age 35.1 ± 15.1 years; Black ethnicity: 98.8%; women: 29.6%; diabetes: 1.6%; alcohol drinkers: 16.8% and smokers: 6.7%, previous myocardial infarction: 1.4%; stroke: 0.8%; taking aspirin: 3.2%; taking statins: 1.9%). Three sitting BP readings were taken, and hypertension was defined as a systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or being on antihypertensive medication. Half of the participants had never had their BP checked, whilst 4.2% of respondents had participated in the MMM19 campaign. 0.9% and 1.7% reported COVID-19 vaccination and positive test, respectively. After multiple imputation of missing BP readings, 14.0% of respondents had hypertension of which 35.8% were aware, 28.0% were on antihypertensive medication and 14.1% had controlled BP. Of those on antihypertensive medication, 40.4% were on monotherapy, 37.2% adhered to taking their medication regularly, and 50.4% had controlled BP (<140/90 mmHg). In regression analyses adjusted for age, sex, and antihypertensive treatment, smoking was associated with lower systolic BP, having more years of education was associated with higher systolic and diastolic BP, and physical activity was associated with lower systolic and diastolic BP. This campaign contributes somewhat to reducing the 'black hole' on the prevalence of hypertension in DRC pending systematic countrywide BP screening.

Extended Length of Stay After Mechanical Thrombectomy for Stroke: A Single-Center Analysis of 703 Patients.

BACKGROUND AND OBJECTIVES: Mechanical thrombectomy (MT) is crucial for improving functional outcomes for acute ischemic stroke. Length of stay (LOS) is a reimbursement metric implemented to incentivize value-based care. Our study aims to identify predictors of LOS in patients undergoing MT at a high-volume center in the United States. METHODS: This was a retrospective study of patients who underwent MT at a single institution from 2017 to 2023. Patients who experienced mortality during their course of hospital stay were excluded from this study. Extended LOS (eLOS) was defined as the upper quartile (≥75th) of the median duration of hospital stay. Univariate and multivariate analyses were performed, with P values < .05 denoting statistical significance. RESULTS: Seven hundred three patients met criteria for inclusion. The median age of the cohort was 72 years (IQR: 61-82), and 57.2% was female. The median LOS was 6, IQR: 4-10. A total of 28.9% of the cohort (n = 203) patients experienced eLOS. The multivariate regression model identified age (odds ratio [OR]: 0.98, 95% CI: 0.97-0.99), diabetes mellitus (OR: 1.68, 95% CI: 1.15-2.44), and hemorrhagic transformation of stroke (OR: 2.89, 95% CI: 0.39-0.90) as predictors of eLOS, whereas antiplatelet use before admission (OR: 0.55, 95% CI: 0.34-0.89) and higher baseline modified Rankin Scale before stroke were associated with lower odds (OR: 0.59 [0.39-0.90]; P < .05) of eLOS. CONCLUSION: By identifying predictors of eLOS, we provide a foundation for targeted interventions aimed at optimizing post-thrombectomy care pathways and improving patient outcomes. The implications of our study extend beyond clinical practice, offering insights into healthcare resource utilization, reimbursement strategies, and value-based care initiatives.

Predictors of Extended Length of Stay After Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND: Despite their asymptomatic occurrence, unruptured intracranial aneurysms (UIAs) account for a significant proportion of hospital charges and healthcare resource utilization in the United States. Hospital length of stay (LOS) is a reimbursement metric utilized to incentivize value-based care. Our study identifies predictors of extended LOS (eLOS) after elective treatment of UIAs. METHODS: This was a retrospective study of 525 patients who underwent elective treatment of an UIA at a single institution. Data were collected with regard to demographics, clinical presentation, treatment characteristics, and postoperative outcomes. The primary outcome, eLOS, was defined as hospital stay in the upper quartile of the median (≥75th percentile). Univariate and multivariate analyses were performed to identify factors predictive of eLOS in this cohort. RESULTS: The average age of the cohort was 61.40, standard deviation=11.41. 77.3% of the cohort was female. The median duration of LOS was 2 days (interquartile range: 1-5). 11.6% experienced eLOS (≥5 days). Multivariate logistic regression identified age (OR: 1.04, 95% confidence interval [CI]: 1.01-1.07), coexistent vascular pathology (OR: 21.33, 95% CI: 8.06-56.39), open surgery (OR: 3.93, 95% CI: 1.85-8.34), and postoperative stroke (OR: 11.72, 95% CI: 3.18-43.18) as independent predictors of eLOS. CONCLUSIONS: Our study identified predictors of eLOS that could help promote risk stratification prior to treatment of UIAs. Future research that identifies predictors of long-term outcomes based on treatment modality could help identify ways to improve healthcare resource utilization in this cohort.

The impact of the Woven EndoBridge device on the treatment of anterior circulation wide-neck bifurcation aneurysms: a single-center experience.

OBJECTIVE: The paucity of literature comparing Woven EndoBridge (WEB) embolization to microsurgical clipping for anterior circulation wide-neck bifurcation aneurysms (WNBAs) underscores the need for further investigation into the optimal management of this patient subpopulation. The objective of this study was to compare the rate of endovascular and microsurgical treatment of WNBAs before and after the introduction of the WEB device. In addition, the authors performed a comparison of demographics, aneurysm characteristics, and treatment outcomes in patients before and after the introduction of the WEB device. METHODS: This study was a retrospective review of the usage rate of different treatment modalities for WNBAs before and after the WEB device was approved by the US FDA on September 27, 2018. RESULTS: The study cohort comprised 235 patients with anterior circulation WNBAs treated at the authors' institution, including 127 aneurysms treated pre-WEB and 108 treated post-WEB. Generally, the rate of endovascular treatment of anterior circulation WNBAs was significantly higher post-WEB (86.1% vs 46.5%, p < 0.001), while the rate of clipping was significantly lower (13.9% vs 53.5%, p < 0.001). During follow-up, the rate of adequate aneurysm occlusion (Raymond-Roy occlusion classification [RROC] grades 1 and 2) was nonsignificantly higher in the post-WEB cohort (83.9% vs 78.5%, p = 0.34), while the rate of RROC grade 3 was nonsignificantly higher in the pre-WEB cohort (21.5% vs 16.1%, p = 0.34). Additionally, and although nonsignificant, the rates of recurrence (pre-WEB 25.3% vs post-WEB 14.9%, p = 0.12) and retreatment (pre-WEB 22.8% vs post-WEB 14.9%, p = 0.22) were higher in the pre-WEB cohort. Recurrence was assessed before retreatment. CONCLUSIONS: After the introduction of the WEB device, the rate of endovascular treatment of WNBAs increased while the rate of microsurgical clipping decreased. It is essential for neurointerventionalists to become familiar with the indications, advantages, and shortcomings of all these different techniques to be able to match the right patient with the right technique to produce the best outcome.

The Era of Radial-Specific Catheters: A Multicenter Comparison of the Armadillo and RIST Catheters in Transradial Procedures.

BACKGROUND AND OBJECTIVES: As the radial approach is gaining popularity in neurointervention, new radial-specific catheters are being manufactured while taking into consideration the smaller size of the radial artery, different trajectories of angles into the great vessels from the arm, and subsequent force vectors. We compared outcomes of transradial procedures performed using the Armadillo catheter (Q'Apel Medical Inc.) and the RIST radial guide catheter (Medtronic). METHODS: This is a retrospective multicenter study comparing outcomes of transradial neuroendovascular procedures using the Armadillo and RIST catheters at 2 institutions between 2021 and 2024. RESULTS: The study comprised 206 patients, 96 of whom underwent procedures using the Armadillo and 110 using the RIST. Age and sex were comparable across cohorts. In most procedures, 1 target vessel was catheterized (Armadillo: 94.8% vs 89.1%, P = .29) with no significant difference between cohorts. The use of an intermediate catheter was minimal in both cohorts (Armadillo 5.2% vs RIST: 2.7%, P = .36), and the median number of major vessel catheterization did not significantly differ between cohorts (Armadillo: 1 [1-4] vs RIST: 1 [0-6], P = .21). Failure to catheterize the target vessel was encountered in 1 case in each cohort (Armadillo: 1.0% vs RIST: 0.9%, P = .18), and the rate did not significantly differ between cohorts. Similarly, the rate of conversion to femoral access was comparable between cohorts (Armadillo: 2.1% vs RIST: 1.8%, P = .55). There was no significant difference in access site complications (Armadillo: 1% vs RIST: 2.8%, P = .55) or neurological complications (Armadillo: 3.1% vs RIST: 5.5%, P = .42) between cohorts. CONCLUSION: No significant difference in successful catheterization of target vessels, procedure duration, triaxial system use, complication rates, or the need for transfemoral cross-over was observed between both catheters. Both devices offer high and comparable rates of technical success and low morbidity rates.

Integration of QTL and transcriptome approaches for the identification of genes involved in tomato response to nitrogen deficiency.

Optimising plant nitrogen (N) usage and inhibiting N leaching loss in the soil-crop system is crucial to maintaining crop yield and reducing environmental pollution. This study aimed at identifying quantitative trait loci (QTLs) and differentially expressed genes (DEGs) between two N treatments in order to list candidate genes related to nitrogen-related contrasting traits in tomato varieties. We characterised a genetic diversity core-collection (CC) and a multi-parental advanced generation intercross (MAGIC) tomato population grown in greenhouse under two nitrogen levels and assessed several N-related traits and mapped QTLs. Transcriptome response under the two N conditions was also investigated through RNA sequencing of fruit and leaves in four parents of the MAGIC population. Significant differences in response to N input reduction were observed at the phenotypic level for biomass and N-related traits. Twenty-seven (27) QTLs were detected for three target traits (Leaf N content, leaf Nitrogen Balance Index and petiole NO3- content), ten and six at low and high N condition, respectively; while 19 QTLs were identified for plasticity traits. At the transcriptome level, 4,752 and 2,405 DEGs were detected between the two N conditions in leaves and fruits, respectively, among which 3,628 (50.6%) in leaves and 1,717 (71.4%) in fruit were genotype specific. When considering all the genotypes, 1,677 DEGs were shared between organs or tissues. Finally, we integrated DEGs and QTLs analyses to identify the most promising candidate genes. The results highlighted a complex genetic architecture of N homeostasis in tomato and novel putative genes useful for breeding tomato varieties requiring less N input.

Assessment of affective dysregulation in children: development and evaluation of a semi-structured interview for parents and for children.

BACKGROUND: Children with affective dysregulation (AD) show an excessive reactivity to emotionally positive or negative stimuli, typically manifesting in chronic irritability, severe temper tantrums, and sudden mood swings. AD shows a large overlap with externalizing and internalizing disorders. Given its transdiagnostic nature, AD cannot be reliably and validly captured only by diagnostic categories such as disruptive mood dysregulation disorder (DMDD). Therefore, this study aimed to evaluate two semi-structured clinical interviews-one for parents and one for children. METHODS: Both interviews were developed based on existing measures that capture particular aspects of AD. We analyzed internal consistencies and interrater agreement to evaluate their reliability. Furthermore, we analyzed factor loadings in an exploratory factor analysis, differences in interview scores between children with and without co-occurring internalizing and externalizing disorders, and associations with other measures of AD and of AD-related constructs. The evaluation was performed in a screened community sample of children aged 8-12 years (n = 445). Interrater reliability was additionally analyzed in an outpatient sample of children aged 8-12 years (n = 27). RESULTS: Overall, internal consistency was acceptable to good. In both samples, we found moderate to excellent interrater reliability on a dimensional level. Interrater agreement for the dichotomous diagnosis DMDD was substantial to perfect. In the exploratory factor analysis, almost all factor loadings were acceptable. Children with a diagnosis of disruptive disorder, attention-deficit/hyperactivity disorder, or any disorder (disruptive disorder, attention-deficit/hyperactivity disorder, and depressive disorder) showed higher scores on the DADYS interviews than children without these disorders. The correlation analyses revealed the strongest associations with other measures of AD and measures of AD-specific functional impairment. Moreover, we found moderate to very large associations with internalizing and externalizing symptoms and moderate to large associations with emotion regulation strategies and health-related quality of life. CONCLUSIONS: The analyses of internal consistency and interrater agreement support the reliability of both clinical interviews. Furthermore, exploratory factor analysis, discriminant analyses, and correlation analyses support the interviews' factorial, discriminant, concurrent, convergent, and divergent validity. The interviews might thus contribute to the reliable and valid identification of children with AD and the assessment of treatment responses. TRIAL REGISTRATION: ADOPT Online: German Clinical Trials Register (DRKS) DRKS00014963. Registered 27 June 2018.

C-Terminal Decarboxylation of Proline-Derived Building Blocks for Protein-Binding Peptides.

Using a set of conformationally restricted Proline-derived Modules (ProMs), our group has recently succeeded in developing inhibitors for the enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain, which is a key mediator of cell migration and plays an important role in tumor metastasis. While these (formally) pentapeptidic compounds show nanomolecular binding affinities towards EVH1, their drug-like properties and cell permeability need to be further optimized before they can be clinically tested as therapeutic agents against metastasis. In this study, we sought to improve these properties by removing the C-terminal carboxylic acid function of our peptoids, either by late-stage decarboxylation or by direct synthesis. For late-stage decarboxylation of ProM-like systems, a method for reductive halo decarboxylation was optimized and applied to several proline-derived substrates. In this way, a series of new decarboxy ProMs suitable as building blocks for decarboxy EVH1 inhibitors were obtained. In addition, we incorporated decarboxy-ProM-1 into the pentapeptide-like compound Ac[2ClF][ProM-2][Decarb-ProM-1], which showed similar affinity towards EVH1 as the methyl ester derivative (Ac[2Cl-F][ProM-2][ProM1]OMe). However, despite better calculated drug-like properties, this compound did not inhibit chemotaxis in a cellular assay.

Clinical-Hematological Changes and Predictors of Severity in Acute Food Protein-Induced Enterocolitis Syndrome Reactions at Oral Food Challenge: A Multicenter Observational Study.

BACKGROUND: Oral food challenge (OFC) is the criterion standard for diagnosis of acute food protein-induced enterocolitis syndrome (FPIES). No diagnostic/prognostic biomarkers are available, and OFC assessment criteria are not validated. OBJECTIVE: To assess clinical-hematological changes and predictors of severity of FPIES reactions at OFC. METHODS: This was an observational multicenter prospective study. Children aged 0 to 18 years diagnosed with acute FPIES were recruited at follow-up OFC in 12 tertiary centers in Spain and Italy. OFC outcomes (as positive/negative/inconclusive and mild/moderate/severe) were assessed on the basis of published "2017 FPIES Consensus" criteria. Clinical characteristics were recorded, and full blood cell count was done at baseline, reaction onset, and 4 hours later. Regression analysis was performed to assess predictors of severe reactions at OFC. RESULTS: A total of 81 children had positive OFC (mild in 11% [9 of 81], moderate in 61% [49 of 81], and severe in 28% [23 of 81]). Increase in neutrophils and reduction in eosinophils, basophils, and lymphocytes were observed (P < .05). OFC was inconclusive in 19 cases despite objective signs or neutrophilia. Regression analysis showed that a 2-day OFC protocol where only 25% of an age-appropriate portion is given on day 1 (not sex, age, culprit food, cumulative dose, and previous reaction severity) was associated with reduced odds of severe reaction compared with giving multiple doses in a single day. CONCLUSIONS: Distinct hematological changes may help support FPIES diagnosis. Current OFC assessment criteria may not capture the broad spectrum of acute FPIES presentations. This 2-day protocol may be associated with a reduced risk of severe reactions. Future work should aim to develop safer OFC and non-OFC diagnostics for FPIES.

Bordetella pertussis infection following relaxation of COVID-19 non-pharmaceutical interventions in 2021-2023 in Vancouver metropolitan area, British Columbia, Canada.

BACKGROUND: We recently reported a near disappearance of B. pertussis and a decline in anti-B. pertussis antibodies during the peak implementation of Coronavirus disease 2019 (COVID-19) non-pharmaceutical interventions (NPI) in 2021 in British Columbia (BC), Canada. During 2021-2023, incidence of reported B. pertussis cases remained low in BC at < 1/100,000 population. This study determined how serological evidence of B. pertussis changed after the gradual relaxation of NPI between 2021-2023. METHODS: Randomly selected blood samples from school staff 25-51 years old (n = 65) were collected yearly between 2021-2023 in the Vancouver metropolitan area, BC, Canada, and tested for anti-pertussis toxin (PT) IgG levels. Serological evidence of B. pertussis infection (thereafter "seroconversion") was defined as a quantifiable anti-PT IgG levels in subjects with anti-PT IgG levels below lower limit of quantification in the preceding year or a > 4-fold increase in anti-PT IgG levels between two subsequent years. Samples were also tested for anti-diphtheria toxoid (DT) IgG, and similar seroconversion criteria were applied to exclude seroconversion due to vaccination with tetanus-diphtheria-acellular-pertussis (Tdap). RESULTS: Three subjects met seroconversion criteria for anti-PT IgG between 2021 and 2022 and 9 between 2022 and 2023, yielding a seroconversion rate of 4.6 /100 person-years and 14.9/100 person-years, P = 0.127, respectively. None of the subjects met the criteria for vaccination with Tdap. The geometric mean concentration of anti-PT IgG showed a statistically significant decrease in 2022 compared with 2021, 4.8 IU/mL IU/ml (95 % confidence interval [CI], 3.8-5.9) vs. 6.4 IU/ml (95 % CI, 4.9-8.2; p = 0.001), followed by a statistically significant increase in 2023 compared with 2022 6.5 IU/ml (95 % CI, 4.9-8.5) vs. 4.8 IU/ml (95 % CI, 3.8-5.9; p = 0.0006), respectively. DISCUSSION: Serological evidence of B. pertussis increased between 2022 and 2023 despite low reported cases, which suggests that B. pertussis circulation resumed after relaxing of COVID-19 NPI.

Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes.

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

HLA reduction of human T cells facilitates generation of immunologically multicompatible cellular products.

ABSTRACT: Adoptive cellular therapies have shown enormous potential but are complicated by personalization. Because of HLA mismatch, rejection of transferred T cells frequently occurs, compromising the T-cell graft's functionality. This obstacle has led to the development of HLA knock-out (KO) T cells as universal donor cells. Whether such editing directly affects T-cell functionality remains poorly understood. In addition, HLA KO T cells are susceptible to missing self-recognition through natural killer (NK) cells and lack of canonical HLA class I expression may represent a safety hazard. Engineering of noncanonical HLA molecules could counteract NK-cell recognition, but further complicates the generation of cell products. Here, we show that HLA KO does not alter T-cell functionality in vitro and in vivo. Although HLA KO abrogates allogeneic T-cell responses, it elicits NK-cell recognition. To circumvent this problem, we demonstrate that selective editing of individual HLA class I molecules in primary human T cells is possible. Such HLA reduction not only inhibits T-cell alloreactivity and NK-cell recognition simultaneously, but also preserves the T-cell graft's canonical HLA class I expression. In the presence of allogeneic T cells and NK cells, T cells with remaining expression of a single, matched HLA class I allele show improved functionality in vivo in comparison with conventional allogeneic T cells. Since reduction to only a few, most frequent HLA haplotypes would already be compatible with large shares of patient populations, this approach significantly extends the toolbox to generate broadly applicable cellular products.

Early-Life Adversities Are Associated With Lower Expected Value Signaling in the Adult Brain.

BACKGROUND: Early adverse experiences are assumed to affect fundamental processes of reward learning and decision making. However, computational neuroimaging studies investigating these circuits in the context of adversity are sparse and limited to studies conducted in adolescent samples, leaving the long-term effects unexplored. METHODS: Using data from a longitudinal birth cohort study (n = 156; 87 female), we investigated associations between adversities and computational markers of reward learning (i.e., expected value, prediction errors). At age 33 years, all participants completed a functional magnetic resonance imaging-based passive avoidance task. Psychopathology measures were collected at the time of functional magnetic resonance imaging investigation and during the COVID-19 pandemic. We applied a principal component analysis to capture common variations across 7 adversity measures. The resulting adversity factors (factor 1: postnatal psychosocial adversities and prenatal maternal smoking; factor 2: prenatal maternal stress and obstetric adversity; factor 3: lower maternal stimulation) were linked with psychopathology and neural responses in the core reward network using multiple regression analysis. RESULTS: We found that the adversity dimension primarily informed by lower maternal stimulation was linked to lower expected value representation in the right putamen, right nucleus accumbens, and anterior cingulate cortex. Expected value encoding in the right nucleus accumbens further mediated the relationship between this adversity dimension and psychopathology and predicted higher withdrawn symptoms during the COVID-19 pandemic. CONCLUSIONS: Our results suggested that early adverse experiences in caregiver context might have a long-term disruptive effect on reward learning in reward-related brain regions, which can be associated with suboptimal decision making and thereby may increase the vulnerability of developing psychopathology.

Prediction models for post-discharge mortality among under-five children with suspected sepsis in Uganda: A multicohort analysis.

In many low-income countries, over five percent of hospitalized children die following hospital discharge. The lack of available tools to identify those at risk of post-discharge mortality has limited the ability to make progress towards improving outcomes. We aimed to develop algorithms designed to predict post-discharge mortality among children admitted with suspected sepsis. Four prospective cohort studies of children in two age groups (0-6 and 6-60 months) were conducted between 2012-2021 in six Ugandan hospitals. Prediction models were derived for six-months post-discharge mortality, based on candidate predictors collected at admission, each with a maximum of eight variables, and internally validated using 10-fold cross-validation. 8,810 children were enrolled: 470 (5.3%) died in hospital; 257 (7.7%) and 233 (4.8%) post-discharge deaths occurred in the 0-6-month and 6-60-month age groups, respectively. The primary models had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95%CI 0.74-0.80) for 0-6-month-olds and 0.75 (95%CI 0.72-0.79) for 6-60-month-olds; mean AUROCs among the 10 cross-validation folds were 0.75 and 0.73, respectively. Calibration across risk strata was good: Brier scores were 0.07 and 0.04, respectively. The most important variables included anthropometry and oxygen saturation. Additional variables included: illness duration, jaundice-age interaction, and a bulging fontanelle among 0-6-month-olds; and prior admissions, coma score, temperature, age-respiratory rate interaction, and HIV status among 6-60-month-olds. Simple prediction models at admission with suspected sepsis can identify children at risk of post-discharge mortality. Further external validation is recommended for different contexts. Models can be digitally integrated into existing processes to improve peri-discharge care as children transition from the hospital to the community.

Effects of icosapent ethyl according to baseline residual risk in patients with atherosclerotic cardiovascular disease: results from REDUCE-IT.

BACKGROUND AND AIMS: Icosapent ethyl lowers triglycerides and significantly reduces major adverse cardiovascular events (MACE), though treatment effects may vary between individuals. This study aimed to determine the relative and absolute effects of icosapent ethyl on MACE according to baseline CVD risk in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: Participants from REDUCE-IT with ASCVD were included (n = 5,785). The primary outcome was 3-point MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Baseline 5-year risk of MACE was estimated using the ESC guideline-recommended SMART2 risk score. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models including a treatment-by-risk interaction. Next, treatment effects were assessed stratified by quartiles of baseline risk. RESULTS: During a median follow-up of 4.8 years (interquartile range 3.2-5.3), MACE occurred in 361 vs 489 patients in the icosapent ethyl vs placebo group (95% confidence interval [CI]); hazard ratio (HR) 0.72 (0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%), number needed to treat (NNT) 23 (16-38), 5-year Kaplan-Meier estimated cumulative incidence reduction (CIR) 5.7% (3.5-7.9%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96) respectively (p for treatment-by-risk interaction = 0.106). The ARR (95% CI) increased across risk quartiles, i.e. was 3.9% (1.0-6.8%), 4.3% (1.2-7.3%), 5.1% (1.4-8.7%), and 5.6% (1.3-10.0%) respectively. This translates to NNTs (95% CI) of 26 (15-98), 24 (14-84), 20 (11-70), and 18 (10-77). The 5-year CIR (95% CI) was 4.8% (1.3-8.2%), 5.0% (1.3-8.7%), 6.1% (1.7-10.5%), and 7.7% (2.3-13.2%) respectively. Consistent results were obtained for 5-point MACE, additionally including coronary revascularization and unstable angina. CONCLUSIONS: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE irrespective of baseline CVD risk, though absolute benefits are largest for patients at the highest risk.