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Cardiovascular disease remains a major contributor to maternal morbidity and mortality in the United States. Cardio Obstetrics is a nascent field for which most cardiovascular clinicians have not received any formal training. This has resulted in knowledge and care gaps. In this review we provide principles to guide the care for the evaluation and management of pregnancy capable individuals, which should be considered the standard knowledge for all clinicians., Competing Interests: Declaration of competing interest No conflict, (Copyright © 2024. Published by Elsevier Inc.)

Volatile organic compounds (VOCs) are harmful chemicals that are found in minute quantities in the atmosphere and are emitted from a variety of industrial and biological processes. They can be harmful to breathe or serve as biomarkers for disease detection. Therefore, capture and detection of VOCs is important. Here, we have examined if the Zr-based UiO-66 metal-organic framework (MOF) can be used to capture butanone─a well-known VOC. Toward that end, we have performed Born-Oppenheimer ab initio molecular dynamics (AIMD) at 300 and 500 K to probe the energetics and molecular interactions between butanone [CH 3 C(O)CH 2 CH 3 ] and open-cage Zr-UiO-66. Such interactions were systematically interrogated using three MOF structures: defective MOF with a missing 1,4-benzene-dicarboxylate linker and two H 2 O; pristine MOF with two H 2 O; and pristine dry MOF. These structures were loaded with one and four molecules of butanone to examine the effect of concentration as well. One-molecule loading interacted favorably with the defective structure at 300 K, only. In comparison, interactions with four-molecule loading were energetically favorable for all conditions. Persistent hydrogen bonds between the O atom of butanone, H 2 O, and μ 3 -OH hydroxyl attachments at Zr nodes substantially contributed to the intermolecular interactions. At higher loadings, butanone also showed a pronounced tendency to diffuse into the adjoining cages of Zr-UiO-66. The effect of such movement on interaction energies was rationalized using simple statistical mechanics-based models of interacting and noninteracting gases. Broadly, we learn that the presence of prior moisture within the interstitial cages of Zr-UiO-66 significantly impacts the adsorption behavior of butanone.

Calcium (Ca 2+ ) dysregulation is a hallmark feature of cardiovascular disease. Intracellular Ca 2+ regulation is essential for proper heart function and is controlled by the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2a). Another-regulin (ALN) is a newly discovered cardiomyocyte-expressed SERCA2a inhibitor, suggesting cardiomyocyte Ca 2+ -handling is more complex than previously appreciated. To study the role of ALN in cardiomyocytes, we generated ALN null mice (knockout, KO) and found that cardiomyocytes from these animals displayed enhanced Ca 2+ cycling and contractility compared to wildtype (WT) mice, indicating enhanced SERCA2a activity. In vitro and in vivo studies show that ALN is post-translationally modified via phosphorylation on Serine 19 (S19), suggesting this contributes to its ability to regulate SERCA2a. Immunoprecipitation and FRET analysis of ALN-WT, phospho-deficient ALN (S19A), or phosphomimetic ALN (S19D) revealed that S19 phosphorylation alters the SERCA2a-ALN interaction, leading to relief of its inhibitory effects. Adeno-associated virus mediated delivery of ALN-WT or phospho-mutant ALN-S19A/D in ALN KO mice showed that cardiomyocyte-specific expression of phospho-deficient ALN-S19A resulted in increased SERCA2a inhibition characterized by reduced rates of cytoplasmic Ca 2+ clearance compared to ALN-WT and ALN-S19D expressing cells, further supporting a role for this phosphorylation event in controlling SERCA2a-regulation by ALN. Levels of ALN phosphorylation were markedly increased in cardiomyocytes in response to Gα q agonists (angiotensin II, endothelin-1, phenylephrine) and Gα q -mediated phosphorylation of ALN translated to increased Ca 2+ cycling in cardiomyocytes from WT but not ALN KO mice. Collectively, these results indicate that ALN uniquely regulates Ca 2+ handling in cardiomyocytes via integration of neuroendocrine signaling with SERCA2a activity., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Hindbrain herniation (HH) is a clinical prerequisite for prenatal repair of myelomeningocele/myeloschisis; however, a subset of patients lack HH on initial fetal imaging and may ultimately progress to exhibit herniation on subsequent prenatal or postnatal imaging. The authors sought to explore the cohort of patients without HH at the time of initial fetal consultation for myelomeningocele/myeloschisis repair to define their clinical characteristics and outcome., Methods: From July 2016 to July 2022, patients evaluated at the Children's Hospital of Philadelphia Center for Fetal Diagnosis and Treatment for myelomeningocele/myeloschisis were classified into two cohorts: those with and those without HH. The diagnosis of HH was obtained from prenatal and postnatal MRI. The osseous lesion level, prenatal sac volume, and prenatal ventricular size was obtained from fetal ultrasound. The fronto-occipital horn ratio was measured on the first postnatal ultrasound. Ambulation status was obtained from postnatal evaluation in the spina bifida clinic., Results: A total of 176 patients with prenatal HH had postnatal follow-up, of whom 95 (54%) had HH resolution and 81 (46%) had herniation persistence. Of 73 patients without prenatal HH, 9 (12%) had herniation on subsequent prenatal imaging while 64 (88%) had no herniation on prenatal imaging. Of these 64 patients, 11 (17%) had postnatal HH, 32 (50%) had no postnatal herniation, and 21 (33%) were lost to follow-up or the pregnancy was terminated. For patients without HH throughout, the sac volume was larger (9 cm3) than those who had herniation progression or initial herniation; however, the rate of talipes was not significantly different among the groups. The majority of patients were also ambulators (with assistive devices or independent), and the atrial diameter was also < 10 mm for most patients. Overall, 53% of those with initial HH compared with 35% with progression of herniation required CSF diversion, while only 25% of those without herniation required diversion., Conclusions: This study demonstrates the natural history of HH in patients with a prenatal diagnosis of myelomeningocele/myeloschisis. The majority of patients without any herniation had larger sac sizes but not higher rates of talipes and smaller ventricles and were ambulatory. These findings improve the ability to guide families during prenatal consultation.

Background: Although clinical evidence supports rapid institution of guideline-directed medical therapy (GDMT) for heart failure (HF), in actual practice, there remain large gaps in adherence to guideline recommendations. Recent data support safety and efficacy of rapid GDMT implementation; however, rapid GDMT deployment within a general cardiology environment remains unexplored., Objectives: The purpose of this study was to evaluate the efficacy and safety of a GDMT clinic within a general cardiology practice relative to usual care, the impact on prescription of GDMT, HF symptoms, N-terminal pro-B-type natriuretic peptide concentrations and echocardiographic parameters of remodeling., Methods: Individuals with HF with an abnormal ejection fraction (<50%) referred to the GDMT clinic underwent rapid GDMT titration with close monitoring of clinical data. Rates of GDMT prescription were compared with a matched reference group. Patients underwent echocardiography at baseline and after GDMT clinic completion., Results: A total of 114 persons were treated in GDMT clinic. The mean age was 67.6 ± 14.6 years, and 32 (28%) were women. Among those referred, 100 (87.7%) had no contraindications for 4-drug GDMT. From baseline to clinic completion (median 15.8 weeks [Q1-Q3: 10.7-23.0 weeks]), patients without medication contraindications experienced significant increases in 4-drug GDMT use (from 21% to 88%; P < 0.001); of 4-drug GDMT recipients, 92% received angiotensin receptor neprilysin inhibitor. GDMT clinic participants achieved higher medication doses than those in usual care, with greater achievement of ≥50% target dose of angiotensin receptor neprilysin inhibitor (52% vs 8%), beta-blocker (78% vs 6.2%), mineralocorticoid receptor antagonist (98% vs 15.6%), and sodium-glucose cotransporter 2 inhibitors (92% vs 6.2%). Target doses of all 4 drugs were reached in nearly 1 in 4 participants. HF symptoms improved (94% to 75% NYHA functional class II/III; P < 0.001) and N-terminal pro-B-type natriuretic peptide concentration decreased (median 587 to 534 ng/L; P = 0.03) despite loop diuretic reduction. Additionally, we observed an absolute 6% LVEF increase (from 37% [Q1-Q3: 31%-41%] to 43% [Q1-Q3: 38%-53%]; P < 0.001) and substantial decrease in moderate or severe mitral regurgitation. GDMT titration was well-tolerated., Conclusions: Rapid GDMT implementation via an outpatient GDMT clinic was effective, safe, and associated with improvement in key clinical parameters. The more widespread role of GDMT clinics to improve HF care warrants further study., Competing Interests: Funding Support and Author Disclosures Data analysis supported by an unrestricted grant from Novartis Pharmaceuticals Corporation. Dr Cohen has a board position with Kento Health Inc. Dr Khairnar is an employee of Novartis Pharmaceuticals Corporation. Dr Williamson was an employee of Novartis Pharmaceuticals Corporation at the time that this study was conducted and the analyses were completed. Dr Scott has received research support from the REBIRTH study and HOPE registries; and has received consulting income from Mediflix. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Corcept Therapeutics, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Eli Lilly, Lexicon, Merck, Novo Nordisk, Otsuka, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Fonarow has consulted for Abbott Laboratories, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson and Johnson, Medtronic, Merck, Novartis, and Pfizer. Dr Januzzi has a board position with Imbria Pharmaceuticals; has received grant support from Abbott, Applied Therapeutics, AstraZeneca, Bristol Myers Squibb, and Novartis Pharmaceuticals, has received consulting income from Abbott Diagnostics, Beckman-Coulter, Jana Care, Janssen, Novartis, Prevencio, Quidel, and Roche Diagnostics; and serves on clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Medtronic, Pfizer, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral blood DNA., Objective: To examine whether somatic post-zygotic mutations of known HI genes are responsible for disease in children with diazoxide-unresponsive HI requiring surgery with histology not classified as focal or Localized Islet Nuclear Enlargement (LINE), and without detectable mutations by standard genetic testing of peripheral blood DNA., Methods: Next-generation sequencing (NGS) was performed on specimens of pancreas from 10 children with diazoxide-unresponsive HI., Results: Four unique GCK mutations were identified at low levels of mosaicism ranging from 4.4-10.1% in pancreatic DNA from five of these 10 children. The GCK mutations were not detectable in peripheral blood DNA by NGS in three cases from which peripheral blood DNA was available for testing. All four GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse-HI in four of the five cases with mosaic GCK mutations. In one of these, hypomethylation of IC2 on chromosome 11p was identified in pancreatic and peripheral blood DNA. Histology of the fifth case revealed minor islet abnormalities suggestive of Beckwith Wiedemann Spectrum (BWSp) although molecular analysis for 11pUPD was negative in pancreas., Conclusion: These results indicate that post-zygotic somatic GCK mutations are responsible for some cases of non-focal diazoxide-unresponsive hyperinsulinism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Data on near- and long-term clinical outcomes are critical for the care of all maternal-fetal patients presenting to a fetal center. This is especially important since physiologic and neurodevelopmental attributes do not manifest until later childhood when multilevel (e.g., individual, family, policy) factors have a direct influence on health outcomes. Electronic health records (EHRs) create opportunity for efficient data collection. However, documentation structures are not designed for acquisition of key attributes, and changes over time and between-clinician differences can affect resultant output. Therefore, EHR derived datasets have limited ability to accurately characterize the clinical presentation and care trajectory of patients with congenital anomalies. In addition, in most systems, the fetus lacks a digital identity and requires relinking fetal attributes documented in the maternal chart to those from the pediatric EHR. This conundrum amplifies in the setting of multiple gestation, returning maternal patients, and pregnancies with fetal demise. Moreover, current data capture systems result in incomplete abstraction of variables that may confound, mediate, or moderate critical associations. Our objective was to develop and implement a prospective data capture platform to transform EHR data into an analytic-grade database for multipurpose use., Methods: A unified platform for longitudinal follow-up of maternal-child dyads cared for at our fetal center, named the Clinical Outcomes Data Archive (CODA), was constructed. CODA was designed using a data dictionary based on multidisciplinary and interprofessional expert input, a relational identity for each patient, fetus, and pregnancy, and a process by which EHR-sourced and chart-abstracted data are validated by a well-trained team. Descriptive analyses were performed for data acquired between July 2022 and July 2023, and a comparison of studies before and after implementation of CODA is presented., Conclusion: 5,394,106 data points were validated for 7,662 patients across 12 conditions. 2% of data points were found to be unreliable or undocumented. 91% of data points were sourced from the EHR. Eighty-five percent of condition-specific variables required manual chart abstraction. The study conducted with CODA was able to contribute to 18 other studies. CODA successfully merges EHR-sourced and manually abstracted documentation for longitudinal study of the maternal-child dyad., (© 2024 S. Karger AG, Basel.)

Mutation analysis provides confirmation of a clinical and radiological diagnosis of thanatophoric dysplasia types I and II (TD I and II). We developed a single multiplexed PCR and a single-nucleotide extension (SNE) assay to identify 14 common mutations causing 99% of TD I and TD II, including the challenging three adjacent mutations in the stop codon of exon 18 of the FGFR3 gene. The assay design also provides a solution for resolving SNE PCR product sizing using performance optimized polymer-7. The assay was validated using 37 previously characterized, de-identified patient samples representing the nine wild-types and 10 of 14 mutant genotypes. Four artificial templates were synthesized to mimic four TD I mutations not represented in the available patient samples. Fragment size and fluorophore channel for each SNE product from 10 samples and the four artificial templates were used to define bins and panels for analysis with GeneMarker version 3.0 and GeneMapper version 6.0 software. Allele calls (bin placement within the panels) were verified using the remaining 27 previously characterized samples. This TD I and II PCR and SNE assay is a robust multiplexed assay, streamlined, to identify 14 mutations in one single reaction. This assay has a shorter turnaround time in comparison to traditional Sanger or next-generation sequencing., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine whether bisphosphonates and NF-κB ligand (RANKL) inhibitors delay coronary artery calcification (CAC)., Design: A systematic review was conducted., Data Sources: MEDLINE, EMBASE and CENTRAL., Eligibility Criteria: Longitudinal studies investigating CAC progression in adults (>18 years) taking either a bisphosphonate or denosumab compared with those who did not., Data Extraction and Synthesis: Study and participant characteristics, and primary outcome ( ∆ CAC from baseline to follow-up) were extracted. The Risk Of Bias In Non-Randomised Studies-of Interventions (ROBINS-I) and Risk-of-Bias Tool for Randomised Trials (RoB2) tools were used to assess the risk of bias for observational and randomised controlled trials (RCTs), respectively. Outcome measures were reported., Results: Four observational studies and one RCT (n=377) were included. Three studies solely reported the effect of bisphosphonates on ∆ CAC; one study (n=56) demonstrated a statistically significant CAC reduction in the intervention group (-372 mm 3 /year) compared with control (+159 mm 3 /year) (p<0.01). One study (n=14) demonstrated a difference in ∆ CAC between intervention (+880 mm 3 /year) versus control (+2220 mm 3 /year), however, no p value comparing groups was reported. One study (n=115) found no statistically significant difference between intervention and control.One study (n=42) exclusively investigated the effect of RANKL on ∆ CAC; there was a statistically significant reduction in CAC at 6-month follow-up between intervention (-133±124 modified Agatston unit (AU)) and control (+188±72 modified AU), p=0.03.One study (n=150) compared both bisphosphonates and denosumab to control and found no statistically significant difference between either intervention group and control over 24 months. Meta-analysis was not performed due to limited, heterogeneous studies., Conclusions: There is insufficient evidence supporting the correlation between bisphosphonate or RANKL inhibitor use and CAC progression. Further research is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Insulinomas are rare insulin-secreting tumors that most commonly affect adults. A 26-month-old child presented to her local emergency department with severe hypoglycemia. Initial workup was consistent with hyperinsulinemic hypoglycemia. Over the course of 10 months, multiple therapies for hyperinsulinism (HI) were trialed without significant benefit. Genetic testing for genes associated with HI was negative. At age 35 months, the patient was transferred to our center for further treatment. She underwent several imaging tests that revealed a lesion on her pancreas concerning for an insulinoma. The patient underwent surgical intervention to enucleate the lesion. Histopathological review of the specimen confirmed a benign, well-circumscribed insulinoma. A postoperative fasting test proved the patient was cured and she was discharged without the need for further glucose monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Congenital pulmonary airway malformations (CPAM), intra- and extralobar bronchopulmonary sequestrations (iBPS/eBPS), CPAM-BPS hybrid lesions (HL), congenital lobar emphysema (CLE), bronchial atresia (BA), and foregut duplication cysts (FDC), collectively referred to as congenital thoracic lesions (CTL), are mostly solitary. Patients with multiple CTL are rare, and reports on such cases are scarce. To address this dearth, we analyzed a large multifocal CTL patient cohort., Methods: Retrospective chart review of patients born between September 1, 2013, and March 31, 2023, who underwent surgery for a CTL at our tertiary center. Patients with radiological and surgical diagnosis of multifocal CTL, defined as ≥2 CTL present in more than one lobe were included to record pre-, peri-, and postnatal patient characteristics., Results: Among 701 CTL patients, 74 (10.5%) had multiple CTL. CTL multifocality was prenatally recognized correctly in 8 (12.9%) patients. Most multiple CTL were right-sided, unilateral multilobar lesions (n = 33, 44%). Bilateral CTL were found in 9 (12.1%) patients. CPAM-CPAM lesions were the most prevalent CTL types (n = 36, 49%). Genetic syndromes were confirmed in 3 (4%) and additional congenital anomalies in 9 (12.9%) patients, 5 of those had multiple congenital anomalies. Of 49 (65%) patients with multilobar CTL, 25 (51%) underwent bilobectomy and 24 (49%) lung-sparing surgery. Length of stay was similar. Mortality was 5.4%., Conclusion: We report on the largest patient cohort with multiple CTL to date. Multiple CTL occurred in 1/10 patients with CTL, and only 12.9% were recognized prenatally. Lung-sparing surgery can be considered. Multiple additional congenital anomalies and genetic syndromes may be more common and genetic testing should be considered. Overall, outcomes in this patient population are favorable., (© 2024 S. Karger AG, Basel.)

Objective: The American Thyroid Association (ATA) Pediatric Guidelines recommend selective, prophylactic central neck dissection (pCND) for patients with papillary thyroid carcinoma (PTC) based on tumor focality, tumor size, and the surgeon's experience. With the expansion of pre-surgical somatic oncogene testing and continued controversy over the benefits of pCND, oncogenic alteration data may provide an opportunity to stratify pCND. This study compared lymph node (LN) involvement in pediatric patients with PTC between tumors with low- and high-invasive-associated alterations to explore the potential utility of preoperative oncogenic alterations in the stratification of pCND., Methods: This is retrospective cohort study of pediatric patients who underwent somatic oncogene testing post thyroidectomy for PTC between July 2003 and July 2022., Results: Of 192 eligible PTC patients with postoperative somatic oncogene data, 19 tumors harbored somatic alterations associated with low-invasive disease (19/192, 10%), and 128 tumors harbored a BRAFV600E alteration (45/192, 23%) or an oncogenic fusion (83/192, 43%). Tumors with low-invasive alterations were less likely to present malignant preoperative cytology (2/18, 11%) than those with high-invasive alterations (97/124, 78%; P < 0.001). Twelve patients with low-invasive alterations had LNs dissected from the central neck (12/19, 63%) compared to 127 patients (127/128, 99%) with high-invasive alterations. LN metastasis was identified in two patients with low-invasive alterations (2/19, 11%) compared to 107 patients with high-invasive alterations (107/128, 84%; P < 0.001)., Conclusion: Pediatric patients with low-invasive somatic oncogenic alterations are at low risk for metastasis to central neck LNs. Our findings suggest that preoperative knowledge of somatic oncogene alterations provides objective data to stratify pediatric patients who may not benefit from pCND.

Purpose: Historically, the presence of gray matter heterotopia was a concern for adverse postnatal neurocognitive status in patients undergoing fetal closure of open spinal dysraphism. The purpose of this study was to evaluate neurodevelopmental outcomes and the onset of seizures during early childhood in patients with a prenatal diagnosis of myelomeningocele/myeloschisis (MMC) and periventricular nodular heterotopia (PVNH)., Methods: All patients evaluated at the Center for Fetal Diagnosis and Treatment with a diagnosis of MMC between June 2016 to March 2023 were identified. PVNH was determined from prenatal and/or postnatal MRI. The Bayley Scales of Infant and Toddler Development (edition III or IV) were used for neurodevelopmental assessments. Patients were screened for seizures/epilepsy., Results: Of 497 patients evaluated with a prenatal diagnosis of MMC, 99 were found to have PVNH on prenatal MRI, of which 35 had confirmed PVNH on postnatal imaging. From the 497 patients, 398 initially did not exhibit heterotopia on prenatal MRI, but 47 of these then had confirmed postnatal PVNH. The presence of PVNH was not a significant risk factor for postnatal seizures in early childhood. The average neurodevelopmental scores were not significantly different among heterotopia groups for cognitive, language, and motor domains., Conclusion: The presence of PVNH in patients with a prenatal diagnosis of MMC does not indicate an increased risk for neurodevelopmental delay at 1 year of age. We did not demonstrate an association with seizures/epilepsy. These findings can aid clinicians in prenatal consultation regarding fetal repair of open spinal dysraphism. Long-term follow-up is required to discern the true association between PVNH seen on prenatal imaging and postnatal seizures/epilepsy and neurodevelopmental outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We present a compelling case of an elderly male with a complex medical history who presented with sepsis secondary to a urinary tract infection. During admission, changes in his abdominal exam prompted imaging studies, which revealed a grade IV splenic laceration with a giant splenic artery pseudoaneurysm containing a suspected arteriovenous fistula component. Multidisciplinary discussion was had regarding patient management which resulted in the decision to perform an emergent splenectomy. Learning points from this case underscore the crucial role of interdisciplinary collaboration in the treatment of this pathology. Additionally, we discuss the decision-making process to support surgical intervention in the absence of clear guidelines in this exceedingly rare condition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [ 18 F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[ 18 F]fluoro-2-deoxytrehalose ([ 18 F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [ 18 F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [ 18 F]FDT from the most globally-abundant organic 18 F-containing molecule, [ 18 F]FDG. The full, pre-clinical validation of both production method and [ 18 F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [ 18 F]FDT directly from the widely-available clinical reagent [ 18 F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer., (© 2024. The Author(s).)

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [ 18 F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [ 3 H]OXD-2115, and in silico models were used to predict brain uptake. [ 18 F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies., (© 2024. The Author(s).)

Competing Interests: NSC has received payment or honoraria for presentations for Research to Practice.

Background: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk., Methods: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging., Results: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (β, -0.67 [95% CI, -1.21 to -0.13]; P =0.016), lower stress myocardial blood flow (β, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P =0.001), and higher stress coronary vascular resistance (β, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P =0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery ( P =0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow ( r =0.71; P <0.001), independent of hemodynamics., Conclusions: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease., Competing Interests: Disclosures M.C. Honigberg reports consulting fees from CRISPR Therapeutics and Comanche Biopharma, the advisory board service for Miga Health, and grant support from Genentech. J.M. Brown reports consulting fees from Bayer AG and AstraZeneca. B.N. Weber reports advisory board service for Novo Nordisk, Horizon Therapeutics, Kinsika Pharmaceuticals, and Aegpha. E.S. Lau reports previous advisory board service for Astellas Pharma. P. Natarajan reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, equity in Preciseli and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals and is a scientific co-founder of TenSixteen Bio, all unrelated to the present work. N.M. Hamburg reports consulting fees from Merck, Boston Scientific, and Novo Nordisk, all unrelated to the present work. M.F. Di Carli reports grant support from Gilead Sciences, in-kind research support from Amgen, and consulting fees from Sanofi, MedTrace Pharma, and Vale Health. The other authors report no conflicts.

Sarcopenia burdens the older population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are lacking. The glucocorticoid prednisone remodels muscle metabolism on the basis of frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone administration rescued muscle quality in aged 24-month-old mice to a level comparable to that seen in young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and its cofactor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed myocyte-specific Lipin1 as a nonredundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes for the coordinated rescue of energy and mass in sarcopenia.

The analysis of low-abundance protein molecules in human serum is reported based on counting of the individual affinity-captured analyte on a solid sensor surface, yielding a readout format similar to digital assays. In this approach, a sandwich immunoassay with rolling circle amplification (RCA) is used for single molecule detection (SMD) through associating the target analyte with spatially distinct bright spots observed by fluorescence microscopy. The unspecific interaction of the target analyte and other immunoassay constituents with the sensor surface is of particular interest in this work, as it ultimately limits the performance of this assay. It is minimized by the design of the respective biointerface and thiol self-assembled monolayer with oligoethylene (OEG) head groups, and a poly[oligo(ethylene glycol) methacrylate] (pHOEGMA) antifouling polymer brush was used for the immobilization of the capture antibody (cAb) on the sensor surface. The assay relying on fluorescent postlabeling of long single-stranded DNA that are grafted from the detection antibody (dAb) by RCA was established with the help of combined surface plasmon resonance and surface plasmon-enhanced fluorescence monitoring of reaction kinetics. These techniques were employed for in situ measurements of conjugating of cAb to the sensor surface, tagging of short single-stranded DNA to dAb, affinity capture of the target analyte from the analyzed liquid sample, and the fluorescence readout of the RCA product. Through mitigation of adsorption of nontarget molecules on the sensor surface by tailoring of the antifouling biointerface, optimizing conjugation chemistry, and by implementing weak Coulombic repelling between dAb and the sensor surface, the limit of detection (LOD) of the assay was substantially improved. For the chosen interleukin-6 biomarker, SMD assay with LOD at a concentration of 4.3 fM was achieved for model (spiked) samples, and validation of the ability of detection of standard human serum samples is demonstrated.

Prompted by the increasing public focus on environmental policy and the continuous inability of States to reach environmental targets agreed upon in the context of the United Nations and the European Union, we explore the development of discourses within the Danish public agenda regarding nature management 2016-2021. This is done through a mixed-methods framework of discourse analysis and structural topic modeling based on documents from the Danish Parliament's Environmental committee 2016-2021, estimating topic prevalence, and analyzing the discourses within each topic, resulting in a qualitative overview of 21 identified topics and their associated discourses and an overview of how the different topic proportions changed over time. A shift in the public agenda was found: a change from discussions about untouched forest focused on trade-offs between timber extraction and biodiversity, to a discussion about different understandings of animal welfare in the context of large grazers in nature national parks in Denmark., (© 2023. The Author(s).)

Maternal mortality is a major public health crisis in the United States. Cardiovascular disease (CVD) is a leading cause of maternal mortality and morbidity. Labor and delivery is a vulnerable time for pregnant individuals with CVD but there is significant heterogeneity in the management of labor and delivery in high-risk patients due in part to paucity of high-quality randomized data. The authors have convened a multidisciplinary panel of cardio-obstetrics experts including cardiologists, obstetricians and maternal fetal medicine physicians, critical care physicians, and anesthesiologists to provide a practical approach to the management of labor and delivery in high-risk individuals with CVD. This expert panel will review key elements of management from mode, timing, and location of delivery to use of invasive monitoring, cardiac devices, and mechanical circulatory support., Competing Interests: Dr Lau is supported by the 10.13039/100000002NIH (K23-HL159243) and the 10.13039/100000968American Heart Association (853922). Dr Briller is supported by the REBIRTH trial. Dr Malhamé is supported by a 10.13039/501100020951Fonds de recherche du Québec – Santé Career award. Dr Quesada is supported by the 10.13039/100000002NIH (K23-HL151867). Dr Meng is supported by the 10.13039/100005831Foundation for Anesthesia Education and Research. Dr Scott is supported by the HOPE registry and the REBIRTH trial. Dr Lau has previously consulted for Roche Diagnostics and Astellas Pharma. Dr Mattina is a paid consultant for Zoll Medical. Dr Harrington is a paid consultant for AllWays Health Partners and Quidelortho. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: We evaluated the impact of delivery at a comprehensive fetal care center co-located in a pediatric hospital on extracorporeal membrane oxygenation (ECMO) exposure and survivorship of children with CDH., Methods: This retrospective study includes maternal-fetal dyads with a prenatal diagnosis of isolated CDH who received any prenatal care at a single fetal center between February 2006 and March 2021. The principal variables included: (1) delivery setting (children born in the pediatric hospital ["inborn"] vs. children who were delivered elsewhere ["outborn"]), (2) exposure to ECMO (yes vs. no), and (3) survival-at-discharge from birth hospitalization (yes vs. no). Multivariable logistic regression was used to evaluate the association between delivery setting and ECMO cannulation, and whether delivery setting moderates the association between exposure to ECMO and survival-at-discharge., Results: Among 418 maternal-fetal dyads, 77.0% of children were inborn and 32.0% of children were exposed to ECMO during their index hospitalization. Inborn children had more severe prenatal prognostic indicators but had a 57% lower odds of extracorporeal than outborn children. In multivariable logistic regression, delivery setting moderated the association between exposure to ECMO and survival-at-discharge. Although there was no statistically significant difference in mortality between inborn and outborn children who were not exposed to ECMO, inborn children exposed to ECMO had a 6.86 (1.98, 23.74) increased odds of death and outborn children exposed to ECMO had a 17.71 (4.69, 66.87) increased odds of death when both were compared to non-cannulated outborn children., Conclusions: Comprehensive fetal care with delivery co-located in a pediatric hospital was associated with decreased exposure to ECMO and a survivorship advantage among children with CDH who required extracorporeal support., Level of Evidence: Level III., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Micrognathic neonates are at risk for upper airway obstruction, and many require intubation in the delivery room. Ex-utero intrapartum treatment is one technique for managing airway obstruction but poses substantial maternal risks. Procedure requiring a second team in the operating room is an alternative approach to secure the obstructed airway while minimizing maternal risk. The aim of this study was to describe the patient characteristics, airway management, and outcomes for micrognathic neonates and their mothers undergoing a procedure requiring a second team in the operating room at a single quaternary care children's hospital., Methods: This was a retrospective descriptive study. Subjects had prenatally diagnosed micrognathia and underwent procedure requiring a second team in the operating room between 2009 and 2021. Collected data included infant characteristics, delivery room airway management, critical events, and medications. Follow-up data included genetic testing and subsequent procedures within 90 days. Maternal data included type of anesthetic, blood loss, and incidence of transfusion., Results: Fourteen deliveries were performed via procedure requiring a second team in the operating room during the study period. 85.7% were male, and 50% had a genetic syndrome. Spontaneous respiratory efforts were observed in 93%. Twelve patients (85.7%) required an endotracheal tube or tracheostomy. Management approaches varied. Medications were primarily a combination of atropine, ketamine, and dexmedetomidine. Oxygen desaturation was common, and three patients experienced bradycardia. There were no periprocedural deaths. Follow-up at 90 days revealed that 78% of patients underwent at least one additional procedure, and one patient died due to an unrelated cause. All mothers underwent cesarean deliveries under neuraxial anesthesia. Median blood loss was 700 mL [IQR 700 mL, 800 mL]. Only one mother required a blood transfusion for pre-procedural placental abruption., Discussion: Procedure requiring a second team in the operating room is a safe and effective approach to manage airway obstruction in micrognathic neonates while minimizing maternal morbidity., Conclusions: Though shown to be safe and effective, more data are needed to support the use of procedure requiring a second team in the operating room as an alternative to ex-utero intrapartum treatment for micrognathia outside of highly specialized maternal-fetal centers., (© 2023 John Wiley & Sons Ltd.)

Importance: Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease., Objective: To identify proteins in the circulation associated with HDPs., Design, Setting, and Participants: Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease-related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins' dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP-related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease-related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023., Exposures: Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs)., Main Outcomes and Measures: Gestational hypertension and preeclampsia., Results: Genetic association data for cardiovascular disease-related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro-brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP-related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins., Conclusions and Relevance: Study findings suggest genetic associations of 4 cardiovascular disease-related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.

Engineered carbon molecular sieves (CMSs) with tapered pores, high surface area, and high total pore volume were investigated for their CO 2 , CH 4 , water, and acetone adsorption properties at 288.15, 298.15, 308.15 K, and pressures of <1 bar. The results were compared with BPL carbon. The samples exhibited higher adsorption capacity for CO 2 compared to BPL carbon, with Carboxen 1005 being the highest due to the presence of ultramicropores (pores smaller than 0.8 nm). Similar observations were made for CH 4 except at 288.15 K. Although the CMSs exhibited higher hydrophobicity than BPL carbon, the latter had the highest acetone uptake for all investigated temperatures due to its higher oxygen content, which facilitates stronger interactions with polar VOC molecules. Heats of adsorption were calculated using the Clausius-Clapeyron equation after fitting the isotherms with the dual-site Langmuir-Freundlich model, and results largely corroborated the order of adsorption capacities of CO 2 , CH 4 , and water on the carbon materials., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Molybdenum disulfide (MoS 2 ) is a 2D material widely used as a dry lubricant. However, exposure to water and oxygen is known to reduce its effectiveness, and therefore an understanding of the uptake of water is important information for mitigating these effects. Here we use grand canonical Monte Carlo simulations to rigorously study water adsorption on MoS 2 surfaces and edges with different concentrations of defects under realistic atmospheric conditions ( i.e. various temperatures and humidity levels). We find that the amount of water adsorbed depends strongly on the number of defects. Simulations indicate that defect sites are generally saturated with water even at low ppm levels of humidity. Water binds strongly to S vacancies on interlamellar surfaces, but generally only one water molecule can fit on each of these sites. Defects on surfaces or edges of lamellae also strongly attract water molecules that then nucleate small clusters of water bonded via hydrogen bonding. We demonstrate that water preferentially binds to surface defects, but once those are saturated at a critical humidity level of about 500-1000 ppm water, water binds to edge sites where it negatively impacts the tribological performance of MoS 2 ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The application of microfluidic devices as next-generation cell and tissue culture systems has increased impressively in the last decades. With that, a plethora of materials as well as fabrication methods for these devices have emerged. Here, we describe the rapid prototyping of microfluidic devices, using micromilling and vapour-assisted thermal bonding of polymethyl methacrylate (PMMA), to create a spheroid-on-a-chip culture system. Surface roughness of the micromilled structures was assessed using scanning electron microscopy (SEM) and atomic force microscopy (AFM), showing that the fabrication procedure can impact the surface quality of micromilled substrates with milling tracks that can be readily observed in micromilled channels. A roughness of approximately 153 nm was created. Chloroform vapour-assisted bonding was used for simultaneous surface smoothing and bonding. A 30-s treatment with chloroform-vapour was able to reduce the surface roughness and smooth it to approximately 39 nm roughness. Subsequent bonding of multilayer PMMA-based microfluidic chips created a durable assembly, as shown by tensile testing. MDA-MB-231 breast cancer cells were cultured as multicellular tumour spheroids in the device and their characteristics evaluated using immunofluorescence staining. Spheroids could be successfully maintained for at least three weeks. They consisted of a characteristic hypoxic core, along with expression of the quiescence marker, p27 kip1 . This core was surrounded by a ring of Ki67-positive, proliferative cells. Overall, the method described represents a versatile approach to generate microfluidic devices compatible with biological applications., (© 2024. The Author(s).)

Maternal Cardiovascular Health Post-DobbsPregnancy is associated with increasing morbidity and mortality in the United States. In the post-Dobbs era, many pregnant patients at highest risk no longer have access to abortion, which has been a crucial component of standard medical care.

Introduction: Randomized controlled trials found that fetoscopic endoluminal tracheal occlusion (FETO) resulted in increased fetal lung volume and improved survival for infants with isolated, severe left-sided congenital diaphragmatic hernia (CDH). The delivery room resuscitation of these infants is particularly unique, and the specific delivery room events are largely unknown. The objective of this study was to compare the delivery room resuscitation of infants treated with FETO to standard of care (SOC) and describe lessons learned., Methods: Retrospective single-center cohort study of infants treated with FETO compared to infants who met FETO criteria during the same period but who received SOC., Results: FETO infants were more likely to be born prematurely with 8/12 infants born &lt;35 weeks gestational age compared to 3/35 SOC infants. There were 5 infants who required emergent balloon removal (2 ex utero intrapartum treatment and 3 tracheoscopic removal on placental bypass with delayed cord clamping) and 7 with prenatal balloon removal. Surfactant was administered in 6/12 FETO (50%) infants compared to 2/35 (6%) in the SOC group. Extracorporeal membrane oxygenation use was lower at 25% and survival was higher at 92% compared to 60% and 71% in the SOC infants, respectively., Conclusion: The delivery room resuscitation of infants treated with FETO requires thoughtful preparation with an experienced multidisciplinary team. Given increased survival, FETO should be offered to infants with severe isolated left-sided CDH, but only in high-volume centers with the experience and capability of removing the balloon, emergently if needed. The neonatal clinical team must be skilled in managing the unique postnatal physiology inherent to FETO where effective interdisciplinary teamwork is essential. Empiric and immediate surfactant administration should be considered in all FETO infants to lavage thick airway secretions, particularly those delivered &lt;48 h after balloon removal., (© 2024 S. Karger AG, Basel.)

Background: Executive function, adaptive function, and behavioral outcomes in congenital diaphragmatic hernia (CDH) survivors have not been well studied., Aim: To evaluate executive and neurobehavioral dysfunction in preschool and early school-aged children with CDH., Study Design: Retrospective cohort study., Subjects: All eligible CDH survivors ages 3 to 7 years enrolled in our follow-up program between February 2020 and February 2021., Outcome Measures: The Behavior Rating Inventory of Executive Function (BRIEF), the Adaptive Behavior Assessment System, 2nd Edition (ABAS-II), and the Child Behavior Checklist (CBCL) were used to assess functional and behavioral outcomes. Summary scores were compared to standard population norms., Results: A total of 100 patients were enrolled during the study period. Of those, 73 parents completed at least one of the questionnaires, resulting in completion of the BRIEF, ABAS-II, and CBCL for 63, 68, and 63 patients, respectively. Preschool children had normal executive function (BRIEF-P) while global executive composite (P = 0.012) and the emotional regulation index (P = 0.010) for school age patients (BRIEF-2) were worse. CDH survivors had favorable adaptive functioning (ABAS-II). Mean CBCL scores for preschool attention problems (P = 0.018), school age attention problems (P = 0.001), and attention deficits hyperactivity problems (P = 0.027) were significantly worse. Prematurity, surrogate markers of disease severity, non-white race, and public insurance status were associated with worse neurobehavioral dysfunction in bivariable analysis., Conclusions: The majority of preschool and school age CDH survivors have age-appropriate executive, adaptive and behavioral functioning. CDH survivors, however, have lower executive function and attention scores compared with the general population., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for differentiated thyroid cancer (DTC) in CCS post-RT remains controversial. We assessed the outcome of thyroid ultrasound (US) surveillance in CCS exposed to RT., Methods: 306 CCS were surveilled with thyroid US between 2002-2021. Surveillance was dependent on age at the time of primary diagnosis, interval from receipt of RT, and individual provider. Thyroid US, clinicopathologic features, and outcomes were described. Cutpoints of CCS RT age associated with varying risk of nodule presentation were explored. The selected cutpoints were used to define age categories, which were then used to compare thyroid nodule-related outcomes. Risk factors for thyroid nodule(s) were evaluated using multivariate logistic regression (odds ratio [OR] [95% confidence interval])., Results: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (45%) and/or RT to craniospinal (44%), chest (11%), and neck regions (6%). About 49% (n = 150) of patients had thyroid nodule(s). Forty-four patients underwent surgery, and 28 had DTC: 19 with American Thyroid Association (ATA) low-risk classification, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Age cutpoint analyses identified cutpoints 3 and 10; hence, ≤3, &gt;3 to ≤10, and &gt;10 years were used. Of the 9 patients with intermediate- or high-risk disease, 8 were ≤10 years and 1 was &gt;10 years at the time of RT. Female sex (OR = 1.62 [1.13-2.12] p = 0.054) and greater interval between RT and first US (OR = 1.10 [1.04-1.16] p = 0.001) were independent risk factors for nodule presentation., Conclusions: Thyroid US surveillance may be beneficial for CCS exposed to RT at younger ages (≤10 years) for earlier detection of DTC, prior to developing advanced metastatic disease., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge., Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer's disease where multiple levels of tau positivity are used to stage participants., Methods: 18F-flortaucipir scans from 301 non-demented participants were processed and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging., Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints., Conclusions: When using 18F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework.

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response., Article Highlights: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis., (© 2023 by the American Diabetes Association.)

Introduction: Fetuses with large lung lesions including congenital cystic adenomatoid malformations (CCAMs) are at risk for cardiopulmonary compromise. Prenatal maternal betamethasone and cyst drainage for micro- and macrocystic lesions respectively have improved outcomes yet some lesions remain large and require resection before birth (open fetal surgery, OFS), at delivery via an Ex Utero Intrapartum Treatment (EXIT), or immediately post cesarean section (section-to-resection, STR). We sought to compare prenatal characteristics and outcomes in fetuses undergoing OFS, EXIT, or STR to inform decision-making and prenatal counseling., Methods: A single institution retrospective review was conducted evaluating patients undergoing OFS, EXIT, or STR for prenatally diagnosed lung lesions from 2000 to 2021. Specimens were reviewed by an anatomic pathologist. Lesions were divided into "CCAMs" (the largest pathology group) and "all lung lesions" since pathologic diagnosis is not possible during prenatal evaluation when care decisions are made. Prenatal variables included initial, greatest, and final CCAM volume-ratio (CVR), betamethasone use/frequency, cyst drainage, and the presence of hydrops. Outcomes included survival, ECMO utilization, NICU length of stay (LOS), postnatal nitric oxide use, and ventilator days., Results: Sixty-nine percent (59 of 85 patients) of lung lesions undergoing resection were CCAMs. Among patients with pathologic diagnosis of CCAM, the initial, largest, and final CVRs were greatest in OFS followed by EXIT and STR patients. Similarly, the incidence of hydrops was significantly greater and the rate of hydrops resolution was lower in the OFS group. Although the rate of cyst drainage did not differ between groups, maternal betamethasone use varied significantly (OFS 60.0%, EXIT 100.0%, STR 74.3%; p = 0.0378). Notably, all OFS took place prior to 2014. There was no difference in survival, ventilator days, nitric oxide, NICU LOS, or ECMO between groups. In multiple variable logistic modeling, determinants of survival to NICU discharge among patients undergoing resection with a pathologic diagnosis of CCAM included initial CVR <3.5 and need for <3 maternal betamethasone doses., Conclusion: For CCAMs that remain large despite maternal betamethasone or cyst drainage, surgical resection via OFS, EXIT, or STR are viable options with favorable and comparable survival between groups. In the modern era there has been a shift from OFS and EXIT procedures to STR for fetuses with persistently large lung lesions. This shift has been fueled by the increased use of maternal betamethasone and introduction of a Special Delivery Unit during the study period and the appreciation of similar fetal and neonatal outcomes for STR vs. EXIT and OFS with reduced maternal morbidity associated with a STR. Accordingly, efforts to optimize multidisciplinary perinatal care for fetuses with large lung lesions are important to inform patient selection criteria and promote STR as the preferred surgical approach in the modern era., Level of Evidence: Level IV., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca 2+ uniporter (MCU) and Ca 2+ levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca 2+ influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca 2+ influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight. In contrast, mice lacking Mcub in skeletal muscle showed increased pyruvate dehydrogenase activity, increased muscle malonyl coenzyme A (CoA), reduced fatty acid utilization, glucose intolerance, and increased adiposity. Mechanistically, pyruvate dehydrogenase kinase 4 (PDK4) overexpression in muscle of Mcub-deleted mice abolished altered substrate preference. Thus, MCUb is an inducible control point in regulating skeletal muscle mitochondrial Ca 2+ levels and substrate utilization that impacts total metabolic balance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Context: The American Thyroid Association (ATA) Pediatric Guidelines recommend patients not receive radioactive iodine therapy (RAIT) for differentiated thyroid cancer (DTC) confined to the thyroid. Since publication, there is ongoing concern whether withholding RAIT will result in a lower rate of remission., Objective: This study explores whether ATA low-risk patients treated with and without RAIT achieved similar remission rates., Methods: Medical records of patients <19 years old diagnosed with DTC and treated with total thyroidectomy between 2010 and 2020 were reviewed. Multivariate logistic regression was performed to evaluate factors influencing RAIT administration and remission rate., Results: Ninety-five patients with ATA low-risk DTC were analyzed: 53% (50/95) and 47% (45/95) were treated with and without RAIT, respectively. RAIT was used to treat 82% of patients before 2015 compared with 33% of patients after 2015 (P < .01). No significant difference in 1-year remission rate was found between patients treated with and without RAIT, 70% (35/50) vs 69% (31/45), respectively. With longer surveillance, remission rates increased to 82% and 76% for patients treated with and without RAIT, respectively. Median follow-up was 5.8 years (IQR 4.3-7.9, range 0.9-10.9) and 3.6 years (IQR 2.7-6.6; range 0.9-9.3) for both cohorts. No risk factors for persistent or indeterminate disease status were found, including RAIT administration, N1a disease, and surgery after 2015., Conclusion: Withholding RAIT for pediatric patients with ATA low-risk DTC avoids exposure to radiation and does not have a negative impact on remission rates. Dynamic risk stratification at 1-year after initial treatment is a suitable time point to assess the impact of withholding RAIT for these patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either 18 F-flortaucipir or 18 F-MK-6240 PET scans. Methods: 18 F-flortaucipir ( n = 798) and 18 F-MK-6240 ( n = 216) scans were processed and sampled to obtain regional SUV ratios. Subsamples of the cohorts were based on participant diagnosis, age, amyloid-β status (positive or negative), and neurodegeneration status (positive or negative), creating older-adult (age ≥ 55 y) cognitively unimpaired (amyloid-β-negative, neurodegeneration-negative) and cognitively impaired (mild cognitive impairment/Alzheimer disease, amyloid-β-positive, neurodegeneration-positive) groups, and then were further subsampled via matching to reduce significant differences in diagnostic prevalence, age, and Mini-Mental State Examination score. We used the biostatistical estimation of tau threshold hallmarks (BETTH) algorithm to determine sensitivity and specificity in 6 composite regions. Results: Parametric double receiver operating characteristic analysis yielded the greatest joint sensitivity in 5 of the 6 regions, whereas hierarchic clustering, gaussian mixture modeling, and k-means clustering all yielded perfect joint specificity (2.00) in all regions. Conclusion: When 18 F-flortaucipir and 18 F-MK-6240 are used, Alzheimer disease-related tau status is best assessed using 2 thresholds, a sensitivity one based on parametric double receiver operating characteristic analysis and a specificity one based on gaussian mixture modeling, delimiting an uncertainty zone indicating participants who may require further evaluation., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Exposure to pathogens in public transport systems is a common means of spreading infection, mainly by inhaling aerosol or droplets from infected individuals. Such particles also contaminate surfaces, creating a potential surface-transmission pathway., Methods: A fast acoustic biosensor with an antifouling nano-coating was introduced to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on exposed surfaces in the Prague Public Transport System. Samples were measured directly without pre-treatment. Results with the sensor gave excellent agreement with parallel quantitative reverse-transcription polymerase chain reaction (qRT-PCR) measurements on 482 surface samples taken from actively used trams, buses, metro trains and platforms between 7 and 9 April 2021, in the middle of the lineage Alpha SARS-CoV-2 epidemic wave when 1 in 240 people were COVID-19 positive in Prague., Results: Only ten of the 482 surface swabs produced positive results and none of them contained virus particles capable of replication, indicating that positive samples contained inactive virus particles and/or fragments. Measurements of the rate of decay of SARS-CoV-2 on frequently touched surface materials showed that the virus did not remain viable longer than 1-4 h. The rate of inactivation was the fastest on rubber handrails in metro escalators and the slowest on hard-plastic seats, window glasses and stainless-steel grab rails. As a result of this study, Prague Public Transport Systems revised their cleaning protocols and the lengths of parking times during the pandemic., Conclusions: Our findings suggest that surface transmission played no or negligible role in spreading SARS-CoV-2 in Prague. The results also demonstrate the potential of the new biosensor to serve as a complementary screening tool in epidemic monitoring and prognosis., (© International Society of Travel Medicine 2023. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)