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Abstract Background 123I-meta-iodobenzylguanidine (mIBG) has been applied to patients with chronic heart failure (CHF). However, the relationship between 123I-mIBG activity and lethal arrhythmic events (ArE) is not well defined. This study aimed to determine this relationship in Japanese and European cohorts. Results We calculated heart-to-mediastinum (H/M) count ratios and washout rates (WRs) of 827 patients using planar 123I-mIBG imaging. We defined ArEs as sudden cardiac death, arrhythmic death, and potentially lethal events such as sustained ventricular tachycardia, cardiac arrest with resuscitation, and appropriate implantable cardioverter defibrillator (ICD) discharge, either from a single ICD or as part of a cardiac resynchronization therapy device (CRTD). We analyzed the incidence of ArE with respect to H/M ratios, WRs and New York Heart Association (NYHA) functional classes among Japanese (J; n = 581) and European (E; n = 246) cohorts. We also simulated ArE rates versus H/M ratios under specific conditions using a machine-learning model incorporating 13 clinical variables. Consecutive patients with CHF were selected in group J, whereas group E comprised candidates for cardiac electronic devices. Groups J and E mostly comprised patients with NYHA functional classes I/II (95%) and II/III (91%), respectively, and 21% and 72% were respectively implanted with ICD/CRTD devices. The ArE rate increased with lower H/M ratios in group J, but the relationship was bell-shaped, with a high ArE rate within the intermediate H/M range, in group E. This bell-shaped curve was also evident in patients with NYHA classes II/III in the combined J and E groups, particularly in those with a high (> 15%) mIBG WR and with ischemic, but not in those with non-ischemic etiologies. Machine learning-based prediction of ArE risk aligned with these findings, indicating a bell-shaped curve in NYHA class II/III but not in class I. Conclusions The relationship between cardiac 123I-mIBG activity and lethal arrhythmic events is influenced by the background of patients. The bell-shaped relationship in NYHA classes II/III, high WR, and ischemic etiology likely aids in identifying patients at high risk for ArEs.

Summary: Enzymes are crucial for the emergence and sustenance of life on earth. How they became catalytically active during their evolution is still an open question. Two opposite explanations are plausible: acquiring a mechanism in a series of discrete steps or all at once in a single evolutionary event. Here, we use molecular phylogeny, ancestral sequence reconstruction, and biochemical characterization to follow the evolution of a specialized group of flavoprotein monooxygenases, the bacterial Baeyer-Villiger monooxygenases (BVMOs). These enzymes catalyze an intricate chemical reaction relying on three different elements: a reduced nicotinamide cofactor, dioxygen, and a substrate. Characterization of ancestral BVMOs shows that the catalytic mechanism evolved in a series of steps starting from a FAD-binding protein and further acquiring reactivity and specificity toward each of the elements participating in the reaction. Together, the results of our work portray how an intrinsically complex catalytic mechanism emerged during evolution.

Abstract Background Prenatal alcohol exposure (PAE) is a worldwide public health concern. While PAE is known to be associated with low birth weight, little is known about timing and quantity of PAE on fetal growth. This study investigated the association between periconceptional and prenatal alcohol exposure and longitudinal fetal growth, focusing on timing and quantity in a high exposure cohort. Methods The Safe Passage Study was a prospective cohort study, including 1698 pregnant women. Two-dimensional transabdominal ultrasound examinations were performed to measure fetal femur length, abdominal and head circumference, and biparietal diameter, at three time points during pregnancy. Estimated fetal weight and Z-scores of all parameters were calculated. Trimester-specific alcohol exposure was assessed using the Timeline Followback method. To investigate the associations of specific timing of PAE and fetal growth, two models were built. One with alcohol exposure as accumulative parameter over the course of pregnancy and one trimester specific model, in which PAE was separately analyzed. Linear mixed models adjusted for potential confounders were applied with repeated assessments of both alcohol exposure and fetal growth outcomes. Results This study demonstrated that periconceptional and prenatal alcohol exposure were associated with reduced fetal growth. Effect sizes are displayed as estimated differences (ED) in Z-score and corresponding 95% confidence intervals (95% CIs). When investigated as accumulative parameter, PAE was related to a smaller femur length (ED 30 ; − 0.13 (95% CI; − 0.22; − 0.04), ED 36 ; − 0.14 (95% CI; − 0.25; − 0.04)) and a smaller abdominal circumference (ED 36 ; − 0.09 (95% CI; − 0.18; − 0.01)). Periconceptional alcohol exposure was associated with a smaller abdominal circumference (ED 30 ; − 0.14 (95% CI; − 0.25; − 0.02), ED 36 ; − 0.22 (95% CI; − 0.37; − 0.06)) and a smaller estimated fetal weight (ED 36 ; − 0.22 (95% CI; − 0.38; − 0.05)). Second trimester alcohol exposure was associated with a smaller abdominal circumference (ED 30 ; − 0.49 (95% CI; − 0.86; − 0.12), ED 36 ; − 0.70 (95% CI; − 1.22; − 0.17)) and estimated fetal weight (ED 30 ; − 0.54 (95% CI; − 0.94; − 0.14), ED 36 ; − 0.69 (95% CI; − 1.25; − 0.14)). No additional association of binge drinking was found besides the already observed association of PAE and fetal growth. Conclusions This study demonstrated that PAE negatively affects fetal growth, in particular when exposed during the periconception period or in second trimester. Our results indicate that potential negative consequences of PAE are detectable already before birth. Therefore, healthcare providers should actively address and discourage alcohol use during pregnancy.

Abstract Background The negative impact of prenatal alcohol and tobacco exposure (PAE and PTE) on fetal development and birth outcomes are well described, yet pathophysiologic mechanisms are less clear. Our aim was to investigate (1) the associations between quantity, frequency and timing (QFT) of PAE and PTE with blood flow velocities in arteries of the fetal-placental-maternal circulation and (2) the extent to which combined effect of QFT of PAE and/or PTE and Doppler flow velocity waveforms (FWV) predict infant birth weight. Methods The Safe Passage Study is a cohort based in urban Cape Town, South Africa. Recruitment occurred between 2007 and 2015. Information on QFT of PAE and PTE was collected prospectively at up to 4 occasions during pregnancy using a modified Timeline Follow-Back approach. Ultrasound examinations consisted of Doppler flow velocity waveforms of the uterine, umbilical (UA) and fetal middle cerebral arteries for the pulsatility index (PI) at 20–24 and 34–38 weeks. Exclusion criteria included: twin pregnancies, stillbirths, participants exposed to other drugs. The sample was divided into three groups (controls, PAE and PTE) and included 1396 maternal-fetal-dyads assessed during the second trimester; 1398 assessed during the third trimester. Results PTE was associated with higher UA PI values in second and third trimesters (p

Despite the availability of various treatment approaches for patients with posttraumatic stress disorder (PTSD), some patients do not respond to these therapies, and novel treatment approaches are needed. This study investigated the efficacy of mifepristone, a glucocorticoid receptor antagonist, in treatment-resistant PTSD patients. Three patients with PTSD who were resistant to standard psychological and pharmacological treatments were prescribed mifepristone (600–1,200 mg/day) for 1 week. A baseline-controlled single-case design was used, involving a 2-week baseline phase (no intervention), a 1-week intervention phase (mifepristone), and a 2-week postintervention phase. The primary outcome measure, self-reported PTSD symptom severity (PCL-5), was assessed daily, with participants providing their own control condition. Two of the three patients experienced a significant reduction in PTSD symptom severity after the intervention phase and no longer met the diagnostic criteria for PTSD. These positive results were maintained during long-term follow-up. These findings support the potential effectiveness of mifepristone in the treatment of patients with treatment-resistant PTSD. However, our findings must be interpreted with caution, and further studies with larger sample sizes and more rigorous designs are necessary to confirm the promising results.

Neurodevelopment in the first 10 years of life is a critical time window during which milestones that define an individual's functional potential are achieved. Comprehensive multimodal neurodevelopmental monitoring is particularly crucial for socioeconomically disadvantaged, marginalized, historically underserved and underrepresented communities as well as medically underserved areas. Solutions designed for use outside the traditional clinical environment represent an opportunity for addressing such health inequalities. In this work, we present an experimental platform, ANNE EEG, which adds 16-channel cerebral activity monitoring to the existing, USA FDA-cleared ANNE wireless monitoring platform which provides continuous electrocardiography, respiratory rate, pulse oximetry, motion, and temperature measurements. The system features low-cost consumables, real-time control and streaming with widely available mobile devices, and fully wearable operation to allow a child to remain in their naturalistic environment. This multi-center pilot study successfully collected ANNE EEG recordings from 91 neonatal and pediatric patients at academic quaternary pediatric care centers and in LMIC settings. We demonstrate the practicality and feasibility to conduct electroencephalography studies with high levels of accuracy, validated via both quantitative and qualitative metrics, compared against gold standard systems. An overwhelming majority of parents surveyed during studies indicated not only an overall preference for the wireless system, but also that its use would improve their children's physical and emotional health. Our findings demonstrate the potential for the ANNE system to perform multimodal monitoring to screen for a variety of neurologic diseases that have the potential to negatively impact neurodevelopment.

BackgroundAlcohol and tobacco are known teratogens. Historically, more severe prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) have been examined as the principal predictor of neurodevelopmental alterations, with little incorporation of lower doses or ecological contextual factors that can also impact neurodevelopment, such as socioeconomic resources (SER) or adverse childhood experiences (ACEs). Here, a novel analytical approach informed by a socio-ecological perspective was used to examine the associations between SER, PAE and/or PTE, and ACEs, and their effects on neurodevelopment.MethodsN = 313 mother-child dyads were recruited from a prospective birth cohort with maternal report of PAE and PTE, and cross-sectional structural brain neuroimaging of child acquired via 3T scanner at ages 8–11 years. In utero SER was measured by maternal education, household income, and home utility availability. The child’s ACEs were measured by self-report assisted by the researcher. PAE was grouped into early exposure (=12 weeks), and no exposure controls. PTE was grouped into exposed and non-exposed controls.ResultsGreater access to SER during pregnancy was associated with fewer ACEs (maternal education: β = −0.293,p = 0.01; phone access: β = −0.968,p = 0.05). PTE partially mediated the association between SER and ACEs, where greater SER reduced the likelihood of PTE, which was positively associated with ACEs (β = 1.110,p = 0.01). SER was associated with alterations in superior frontal (β = −1336.036, q = 0.046), lateral orbitofrontal (β = −513.865, q = 0.046), caudal anterior cingulate volumes (β = −222.982, q = 0.046), with access to phone negatively associated with all three brain volumes. Access to water was positively associated with superior frontal volume (β=1569.527, q = 0.013). PTE was associated with smaller volumes of lateral orbitofrontal (β = −331.000, q = 0.033) and nucleus accumbens regions (β = −34.800, q = 0.033).ConclusionResearch on neurodevelopment following community-levels of PAE and PTE should more regularly consider the ecological context to accelerate understanding of teratogenic outcomes. Further research is needed to replicate this novel conceptual approach with varying PAE and PTE patterns, to disentangle the interplay between dose, community-level and individual-level risk factors on neurodevelopment.

In recent years, studies have shown that a large number of bacteria secrete multi-flavinylated proteins. The exact roles and properties, of these extracellular flavoproteins that contain multiple covalently anchored FMN cofactors, are still largely unknown. Herein, we describe the biochemical and structural characterization of two multi-FMN-containing covalent flavoproteins, SaFMN3 from Streptomyces azureus and CbFMN4 from Clostridiaceae bacterium. Based on their primary structure, these proteins were predicted to contain three and four covalently tethered FMN cofactors, respectively. The genes encoding SaFMN3 and CbFMN4 were heterologously coexpressed with a flavin transferase (ApbE) in Escherichia coli, and could be purified by affinity chromatography in good yields. Both proteins were found to be soluble and to contain covalently bound FMN molecules. The SaFMN3 protein was studied in more detail and found to display a single redox potential (-184 mV) while harboring three covalently attached flavins. This is in line with the high sequence similarity when the domains of each flavoprotein are compared. The fully reduced form of SaFMN3 is able to use dioxygen as electron acceptor. Single domains from both proteins were expressed, purified and crystallized. The crystal structures were elucidated, which confirmed that the flavin cofactor is covalently attached to a threonine. Comparison of both crystal structures revealed a high similarity, even in the flavin binding pocket. Based on the crystal structure, mutants of the SaFMN3-D2 domain were designed to improve its fluorescence quantum yield by changing the microenvironment of the isoalloxazine moiety of the flavin cofactor. Residues that quench the flavin fluorescence were successfully identified. Our study reveals biochemical details of multi-FMN-containing proteins, contributing to a better understanding of their role in bacteria and providing leads to future utilization of these flavoprotein in biotechnology.

Protein engineering is a powerful and widely applied tool for tailoring enzyme properties to meet application-specific requirements. An attractive group of biocatalysts are PLP-dependent amine transaminases which are capable of converting prochiral ketones to the corresponding chiral amines by asymmetric catalysis. The enzymes often display high enantioselectivity and accept various amine donors. Practical applications of these amine transaminases can be hampered by enzyme instability and by their limited substrate scope. Various strategies to improve robustness of amine transaminases and to redirect their substrate specificity have been explored, including directed evolution, rational design and computation-supported engineering. The approaches used and results obtained are reviewed in this paper, showing that different strategies can be used in a complementary manner and can expand the applicability of amine transaminases in biocatalysis.

Abstract Background Accurate sentinel lymph node (SLN) staging is essential for both prognosis and treatment in patients with breast cancer. However, the preoperative lymphoscintigraphy may fail to visualize the SLN in some patients. The purpose of this retrospective study was to identify risk factors associated with SLN nonvisualization on lymphoscintigraphy. For this single-center retrospective study, all data of lymphoscintigraphy of SLN procedures from March 2011 to April 2021 were collected and reviewed from the Amsterdam UMC database. Results A total of 1886 SLN procedures were included in this study. The SLN nonvisualization rate was 25.1% on lymphoscintigraphy at 4 h post-injection. The SLN nonvisualization rate decreased to 9.4% after reinjection. Multivariable analysis showed that age ≥ 70 years (P

Background: Although antenatal depression and anxiety (e.g., negative antenatal mental health; NAMH) are individually associated with preterm birth (PTB) and infant neurological impairment, few studies account for comorbidity. Understanding how NAMH impacts PTB and infant neurological functioning by either singular (depression or anxiety) or comorbid status, as well as the way in which these effects can be moderated by additional risk or protective factors (traumatic experiences and trait resiliency) can contribute further understanding of NAMH effects on birth outcomes. Methods: The sample included 3042 mother-infant dyads from U.S. and South Africa cohorts of the Safe Passage Study (N = 3042). A four-category NAMH variable was created to categorize depression-only, anxiety-only, comorbid, or no NAMH statuses. Results: There were no NAMH main effects on PTB, however, anxiety-only and comorbid NAMH increased odds of PTB for mothers with higher rates of traumatic life experiences. Anxiety-only and comorbid NAMH were associated with increased odds of newborn neurological impairment, and the effect of comorbid NAMH was stronger for mothers with higher rates of traumatic experiences. Resiliency decreased odds of neurological impairment for mothers who reported depression-only or anxiety-only NAMH. Limitations: Limitations included potential artefacts of two cohorts that differed in rates of almost all variables, a single time point for measuring NAMH, and lack of pregnancy-specific NAMH measures. Conclusions: Especially when compared to mothers with no NAMH, comorbidity or singular-condition NAMH statuses associate with negative birth outcomes in nuanced ways, especially when considering additional contexts that may foster or protect against NAMH.