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Individuals within the criminal justice system are at greater risk of substance use–related morbidity and mortality and have substantial healthcare needs. In this quasi-experimental study, we assessed utilization patterns of Massachusetts Medicaid Program (MassHealth) services and associated expenditures among drug court probationers compared to a propensity score–matched sample of traditional court probationers. Risk of reoffending, employment status, age, and living arrangement data were used to calculate propensity scores and match probationers between the two court types, producing a final sample of 271 in each court (N=542). Utilization of services and associated expenditures were analyzed using a two-part model to address the skewed distribution of the data and to control for residual differences after matching from the perspective of the payer (i.e., MassHealth). The largest categories of MassHealth spending were prescription pharmaceuticals, hospital inpatient visits, and physician visits. In the unadjusted analysis, drug court probationers exhibited greater MassHealth services utilization and expenditures than traditional court probationers. However, drug courts enrolled more females, more people at higher risk of reoffending, and more people with opioid use disorders. After controlling for differences between the two court types, the difference in MassHealth services utilization and associated expenditures did not reach statistical significance. Drug court probationers were more likely to engage with healthcare services but did not incur significantly greater expenditures than traditional court probationers after controlling for differences between the samples.

Abstract Background In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. Methods and results Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. Conclusions Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine‐C(5))‐methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients. Moreover, we demonstrate that overexpression of NSUN5 increases protein synthesis in GBM cells. NSUN5 knockdown decreased protein synthesis, cell proliferation, sphere formation, migration, and resistance to temozolomide in GBM cell lines. NSUN5 knockdown also decreased the number and size of GBM neurospheres in vitro. As a corollary, mice harboring U251 tumors wherein NSUN5 was knocked down survived longer than mice harboring control tumors. Taken together, our results suggest that NSUN5 plays a protumorigenic role in GBM by enabling the enhanced protein synthesis requisite for tumor progression. Accordingly, NSUN5 may be a hitherto unappreciated target for the treatment of GBM.

Abstract Background For more than 20 years, and despite the development of new social networks, health forums have remained a privileged place for people to discuss health issues. This study investigates the motivations of participants to post a message on a French online health forum (called 'Doctissimo') (Forum Santé - Doctissimo, 2022). Method Between January 1, 2017 and December 31, 2019, all the first messages recorded on the health forum doctissimo ( www.forum.doctissimo.fr ) were selected in their initial format by a crawler. The transcripts were imported into the qualitative analysis software Nvivo. Two researchers coded the data until a theoretical saturation was obtained. Results We identified four categories of motivation: 1) 'Questioning' allows the exchange of mainly medical information, or sharing of feedback on experiences with the disease: 1722 codes, 44.8%, 2) Worry, need for reassurance: 1066 codes, 27.7% about symptoms or anticipatory anxiety, 3) 'Expressing oneself' mainly allows a catharsis and thus an emotional release, especially negative, but also to share a personal experience: 764 codes 19.9%, 4) Community spirit is a central element to create an emotional support group for psychological support, exchange ideas, meet people in similar situations: 291 codes, 7.6%. The relationship with a health professional when mentioned is generally marked by doubts 39.5%, confusion, or lack of information and the need for additional elements 64.6% or reassurance 60%. The relationship and the obstacles to a medical consultation are described in relation to the use of the forum: immediate availability, anonymity, absence of taboo and community spirit. Conclusion The use of information sources offered by the Internet is a way to ask questions, to be reassured, to express oneself or to be confirmed by the community in the hypothesis emitted by a health professional. Patients are looking for an immediate answer, they come to the community for reassurance, they feel free and legitimate.

Summary: The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery, but whether these molecular programs generate oscillations of membrane properties is unclear. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-h oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium currents that reduce excitability during the Light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the Light phase by removing G-protein regulation. These results reveal that circadian transcriptional machinery regulates intrinsic excitability by coordinated regulation of ion channels by G-protein signaling, highlighting a potential novel mechanism of cell-autonomous oscillations.

ABSTRACT Worldwide, extended-spectrum β-lactamase (ESBL) rates are increasing at an alarming level with increasing rates of health care exposures, international travel, and antibiotic usage. In this study, we investigated whether enhanced social isolation, travel restrictions, and the reduced use of antibiotics in Ontario, Canada during coronavirus disease 2019 (COVID-19) pandemic had an impact on ESBL rates in urine cultures collected from the community and long-term-care (LTC) facilities across the province. Data from a total of 8.6 million urine cultures performed at LifeLabs Ontario from 2016 to 2021 were utilized for analysis. ESBL-producing Escherichia coli (ESBL Escherichia coli) and ESBL Klebsiella pneumoniae were identified using standard operating procedures. Data trends were estimated by interrupted time series (ITS) regression analysis. Among 2.3 million positive urine cultures, 48.9% and 7.2% grew E. coli and K. pneumoniae, of which 5.8% and 3.3% produced ESBLs, respectively. While the overall rate of ESBL isolation was higher in the pandemic period than in the prepandemic period, by ITS regression analysis of the monthly rates of ESBL isolation, decreasing trends were noted for ESBL E. coli in both the community and LTC facilities and for ESBL K. pneumoniae in the community. The ESBL K. pneumoniae rates in LTC facilities continued to increase throughout the COVID-19 period. By subgroup analysis for different genders, age groups, and local health integration network (LHIN) units, similar trends were seen in most cases (P

Host behavioural changes are among the most apparent effects of infection. 'Sickness behaviour' can involve a variety of symptoms, including anorexia, depression, and changed activity levels. Here, using a real-time tracking and behavioural profiling platform, we show that in Drosophila melanogaster, several systemic bacterial infections cause significant increases in physical activity, and that the extent of this activity increase is a predictor of survival time in some lethal infections. Using multiple bacteria and D. melanogaster immune and activity mutants, we show that increased activity is driven by at least two different mechanisms. Increased activity after infection with Micrococcus luteus, a Gram-positive bacterium rapidly cleared by the immune response, strictly requires the Toll ligand spätzle. In contrast, increased activity after infection with Francisella novicida, a Gram-negative bacterium that cannot be cleared by the immune response, is entirely independent of both Toll and the parallel IMD pathway. The existence of multiple signalling mechanisms by which bacterial infections drive increases in physical activity implies that this effect may be an important aspect of the host response.

Abstract Background Autosomal‐recessive renal tubular dysgenesis (AR‐RTD) is a rare genetic disorder caused by defects in the renin‐angiotensin system that manifests as fetal anuria leading to oligohydramnios and Potter sequence. Although the most common outcome is neonatal death from renal failure, pulmonary hypoplasia, and/or refractory arterial hypotension; several cases have been reported that describe survival past the neonatal period. Methods Herein, we report the first family with biallelic ACE variants and more than one affected child surviving past the neonatal period, as well as provide a review of the previously reported 18 cases with better outcomes. Results While both siblings with identical compound heterozygous ACE variants have received different treatments, neither required renal replacement therapy. We show that both vasopressin and fludrocortisone in the neonatal period may provide survival advantages, though outcomes may also be dependent on the type of gene variant, as well as other factors. Conclusion While AR‐RTD is most often a lethal disease in the neonatal period, it is not universally so. A better understanding of the factors affecting survival will help to guide prognostication and medical decision‐making.

Aim: Transient hypothyroxinemia of prematurity (THOP) has been associated with suboptimal neurodevelopment. We aimed to assess neurodevelopment in very preterm infants with treated and untreated THOP., Methods: This study was a multicentre, cohort study, based on prospectively collected data in four French level III neonatal intensive care units. Infants born before 32 weeks of gestation between 2009 and 2020 who underwent a thyroid function test were included. THOP was defined as low free thyroxine and unelevated thyroid stimulating hormone. Infants were classified as no THOP, treated THOP, and untreated THOP. The primary outcome was suboptimal neurodevelopment at 2 years of age evaluated by clinical examination., Results: Three hundred and seventy-three infants (54% male) born at a median gestational age of 28 weeks of gestation were included. There was no significant difference in neurodevelopment at 2 years of age when comparing the no THOP to the THOP group (Odds Ratio (OR) 1.4, 95% confident Interval (CI) 0.8-2.3) nor when comparing the treated with the untreated THOP group (OR 0.8, 95% CI 0.3-1.9). Results remained unchanged after adjusting for confounding factors., Conclusion: In very preterm infants treated THOP was not associated with improved neurodevelopment compared to untreated THOP. Numerous biases could have limited treatment effect., (© 2025 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Although Mg-Li dual metal-ion batteries are proposed as a superior system that unite safety of Mg-batteries and performance of Li-ion based systems, its practical implantation is limited due to the lack of reliable high-performance cathodes. Herein, we report a high-performance Mg-Li dual metal-ion battery system based on highly pseudocapacitive hierarchical TiO 2 -B nanosheet assembled spheres (NS) cathode. This 2D cathode displayed exceptional pseudocapacitance (a maximum of 93%) specific capacity (303 mAh g -1 at 25 mA g -1 ), rate performance (210 mAh g -1 at 1 A g -1 ), consistent cycling (retain ∼100% capacity for 3000 cycles at 1 A g -1 ), Coulombic efficiency (nearly 100%) and fast-charging (∼12.1 min). These properties are remarkably dominant to the existing Mg-Li dual metal-ion battery cathodes. Spectroscopic and microscopic mechanistic studies confirmed negligible structural changes during charge-discharge cycles of the TiO 2 -B nanosheet assembled spheres electrodes. Exceptional electrochemical properties of the 2D electrode is ascribed to remarkable pseudocapacitive Mg-Li dual metal-ion diffusion via the numerous nanointerfaces of TiO 2 -B caused by its hierarchical microstrucrure. Large surface area, nanosheet morphology, mesoporous structure and ultrathin nature also acted as secondary factors facilitating improved electrode-electrolyte contact. Demonstrated approach of pseudocapacitive type Mg-Li dual metal-ion intercalation through hierarchical nanointerfaces may be further utilized for the designing of numerous top-notch electrode materials for futuristic Mg-Li dual metal-ion batteries., (© 2025 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Introduction: We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks., Methods: Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment., Results: In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause., Conclusions: Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification., (© The Author(s) 2025. Published by Oxford University Press.)

Alnus glutinosa , able to establish symbiosis with mutualistic bacteria of the genus Frankia , is one of the main species in European riparian environments, where it performs numerous biological and socio-economic functions. However, riparian ecosystems face a growing threat from Phytophthora alni , a highly aggressive waterborne pathogen causing severe dieback in A. glutinosa . To date, the tripartite interaction between the host plant, the symbiont Frankia and the pathogen remains unexplored but is critical for understanding how pathogen-induced stress influences the nodule molecular machinery and so on the host-symbiont metabolism. In the present study, we aimed to explore for the first time how P. alni affects the overall molecular processes of Alnus glutinosa - Frankia nodules, with a special focus on unraveling the spatial expression of defense mechanisms within these tissues. We conducted a laboratory experiment based on P. alni infection of young A. glutinosa seedlings nodulated with Frankia alni ACN14a, non-infected or infected with the pathogen P. alni . Multi-omics analyses were carried out on nodules (N) and associated roots (AR) of the same plant in order to underline the impact on the nodule molecular processes (i.e. N/AR markers) when the host plant is infected compared to non-infected plants. Our results revealed that P. alni infection modified the molecular nodule processes and induced reprograming of defense-related markers by a shift in associated roots to the detriment of nodules. These findings suggest that A. glutinosa reinforces locally its immune responses in roots but moderates this activation in nodule to preserve its Frankia symbiont.

Background: Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the FGD1 gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients., Methods: Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in FGD1 , through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders., Results: This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations., Conclusion: A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of FGD1 variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: The total burden of migraine includes not only the episodes with headache pain but extends throughout the interictal periods. Interictal symptoms and associated psychological responses may profoundly impact well-being and drive treatment-seeking behavior., Methods: A cross-sectional online survey was conducted with participants aged ≥ 18 years, 250 with episodic migraine (EM) and 250 with chronic migraine (CM), having ≥ 4 monthly migraine headache days. All were naïve to galcanezumab or began ≤ 6 months before survey completion. The study evaluated factors associated with the Migraine Interictal Burden Scale (MIBS-4), including social determinants of health and well-being. Multiple linear regression, logistic regression, and random forests (RF) were used to explore predictors of MIBS-4., Results: The majority of participants (90%) were female with a mean (standard deviation) age of 40.6 (± 12.0) years and 18.1 (± 12.7) years since the first migraine episode. Sociodemographically, the EM and CM groups were similar. Common comorbidities were anxiety disorder (45%) and depression (44%). Migraine family history was reported in 59% of participants. MIBS-4 was correlated with a number of diverse variables, including well-being, anxiety sensitivity, income, aura symptoms, and the worst migraine pain in the year before starting galcanezumab. Linear and logistic regression identified years since the first symptom, worst migraine attack pain, premonitory symptoms, and income as significant predictors. RF explained more of the variance than multiple linear regression and introduced additional concepts to the prediction of MIBS, identifying well-being (WHO-5 total score), the WHO-5 item "cheerful and in good spirits," worry about exercise, and fear of missing social obligations as significant predictors. Socioeconomic status and income were also critical explanatory variables for interictal burden (IIB) based on regression modeling and RF. Still, income was the only variable significantly associated with IIB across regression and RF methods., Conclusions: Interictal burden should be considered in the medical care of people with migraine. This additional burden is holistic, with psychosocial and socioeconomic elements in addition to residual symptoms. It is essential to consider this when assessing the impact of IIB., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by an institutional review board and conformed with International Conference on Harmonization guidelines and was conducted in accordance with the World Medical Association Declaration of Helsinki and applicable local data protection laws. Consent for publication: Not applicable. Competing interests: Elizabeth Seng: research funding from the National Institutes of Health, Veterans Health Administration, Cystic Fibrosis Foundation, and the American Heart Association, as well as fees for consulting from GlaxoSmithKline, Theranica, and Abbvie. Christian Lampl: consulting fees and honoraria for lectures/ presentations from AbbVie/Allergan, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva. Principal investigator in clinical trials as the for Eli Lilly. Past-president of the European Headache Federation and associate editor for The Journal of Headache and Pain. Lars Viktrup and Margaret Hoyt are employees of Eli Lilly and Company and may own Lilly stock. Maurice Vincent was an employee of Eli Lilly and Company at the time the study was conducted and may own Lilly stock. William R. Lenderking, Mary Kate Ladd, and Karen Malley are employees of Evidera., (© 2024. The Author(s).)

Introduction: Migraine is under-diagnosed and under-treated. Many people with migraine do not seek medical care, and those who do may initially receive a different diagnosis and/or be dissatisfied with provided care on their journey before treatment with a CGRP-mAb (calcitonin-gene-related-peptide monoclonal antibody)., Methods: This is a cross-sectional, self-reported, online survey of subjects in Lilly's Emgality ® Patient Support Program in 2022. Questionnaires collected insights into subjects' prior experiences with migraine and interactions with healthcare professionals before receiving CGRP-mAbs., Results: Of the 250 participants with episodic and 250 with chronic migraine, 90% were female and white with a mean age of 26.2 years (± 11.9) at diagnosis and 40.6 (± 12.0) years at survey enrollment. Many participants (71%) suspected they had migraine before diagnosis, with 31% reluctant to seek help. Of these, approximately one-third were unaware of treatment, did not think that a physician could do anything more for migraine, would not take them seriously, or were reluctant due to a previous unhelpful experience. Participants mainly received information from friends/family (47%) or the internet (28%). Participants initially sought treatment due to an increase in migraine frequency (77%), attacks interfering with work or school (75%), or increased pain intensity (74%). Subjects saw a mean of 4.1 (± 4.3) healthcare providers before migraine diagnosis, and 20% of participants previously received a different diagnosis. Participants reported migraine causes included stress/anxiety/depression (42%), hormonal changes (30%), nutrition (20%), and weather (16%). Acute treatment of migraine included prescription (82%) and over-the-counter (50%) medications, changes in nutrition (62%), adjusting fluid intake (56%), and relaxation techniques (55%). Preventive medications included anticonvulsants (61%), antidepressants (44%), blood pressure-lowering medications (43%), and botulinum toxin A injections (17%). Most discontinuations were due to lack of efficacy or side effects., Conclusion: People with migraine describe reluctance in seeking health care, and misunderstandings seem common especially in the beginning of their migraine journey. Graphical abstract available for this article., (© 2024. The Author(s).)

Despite major instrumental developments over the last decade, endodontic files are still not infallible. It is well known that NiTi rotary files can break without any visible sign of deformation. Instrument breakage under combined flexion-torsion loading is still common in clinical practice. Unfortunately, breakage of this type of instrument mainly occurs in narrow canals, through pinching in the apical region. When such an incident occurs, the endodontist must adopt a debris retrieval strategy that is both stressful and not guaranteed success. This study proposes a new method for experimental damage detection leading to the fracture of Ni-Ti shape memory alloy endodontic files. It is based on the acoustic emission (AE) technique and mechanical parameters measured in real-time and image analysis. It has been shown that the AE results correlate with the damage observations and torque and force measurements recorded during the tests. Having carried out numerous root canal treatment on resin blocks, it appears that this new detection and analysis technique can be used to analyze and anticipate the first signs of damage leading to endodontic file failure. The technological development of such a method, at the level of the engine itself, associated with the act in service procedure, would constitute a revolution in the field of endodontics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeanne Davril reports equipment, drugs, or supplies was provided by Micro-Mega SA. Marin Vincent has patent #FR3127686 issued to Marin Vincent. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glutathione synthetase deficiency is a rare inborn metabolic disease usually caused by biallelic variants in GSS. Clinical severity varies from isolated hemolytic anemia, sometimes associated with chronic metabolic acidosis and 5-oxoprolinuria, to severe neurological phenotypes with neonatal lethality. Here we report on two fetal siblings from two pregnancies with glutathione synthetase deficiency exhibiting similar multiple congenital anomalies associating phocomelia, cleft palate, intra-uterine growth retardation, genito-urinary malformations, and congenital heart defect. Genome sequencing showed that both fetuses were compound heterozygous for two GSS variants: the previously reported pathogenic missense substitution NM&#95;000178.4 c.800G>A p.(Arg267Gln), and a 2.4 kb intragenic deletion NC&#95;000020.11:g.34944530&#95;34946833del. RNA-seq on brain tissue revealed the out-of-frame deletion of the exon 3 and an almost monoallelic expression of the missense variant (88%), suggesting degradation of the deletion-harboring allele by nonsense-mediated mRNA decay. 5-oxoproline (pyroglutamic acid) levels in amniotic fluid were elevated, suggesting an alteration of the gamma-glutamyl cycle, and corroborating the pathogenicity of the two GSS variants. Only one case of glutathione synthetase deficiency with limb malformations has previously been reported, in a newborn homozygous for the c.800G>A variant. Thus, our data allow us to discuss a potential phenotypic extension of glutathione synthetase deficiency, with a possible involvement of the c.800G>A variant., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Late postnatal steroids are given to premature infants who cannot be weaned from ventilation because of the possible development of bronchopulmonary dysplasia (BPD). At that time, some infants still have a patent ductus arteriosus (PDA). In our experience, the use of betamethasone (BTM) seems to reduce the need for surgical/endovascular treatment of PDA. We evaluated herein the impact of oral BTM on PDA in extremely preterm infants with BPD. Extremely preterm infants (GA < 29 weeks) with PDA and treated with BTM to facilitate extubation/avoid reintubation were included in this retrospective, single-centre study. BTM was administered orally at 0.3 mg/kg/day for 3 days, 0.15 mg/kg/day the following 2 days, and 0.05 mg/kg/day on the last day. An echocardiography was performed before and after BTM treatment. The 51 infants included were born at a median [IQR] GA of 25.7 [25.0-26.7] weeks. At the time of BTM treatment (28 [26-30] days), 94.1% (48/51) were on invasive ventilation, and most (44/48, 91.7%) were extubated after BTM treatment. At that time, nearly all infants had a closed or non-haemodynamically significant PDA (50/51, 98.0%). None required surgical or endovascular treatment after BTM. Adverse effects included transient moderate hypertension (68.6%), transient hyperglycaemia (15.7%), and transient slowing of postnatal weight gain during BTM treatment., Conclusion: In extremely preterm infants with a severe respiratory condition at 3 weeks of life, oral BTM treatment can help wean invasive ventilation and is associated with PDA closure. It could reduce the need for surgical or endovascular treatment that are associated with serious adverse effects. Trial registration: Clinicaltrials.gov NCT05987202., What Is Known: • Patent ductus arteriosus and bronchopulmonary dysplasia are two most frequent complications of extreme prematurity. • Betamethasone is one of the corticosteroids used to help wean invasive ventilation in infants at risk for bronchopulmonary dysplasia., What Is New: • In extremely preterm infants still ventilated after 3 weeks of life and suffering from patent ductus arteriosus, treatment with oral betamethasone facilitated ventilatory weaning • Oral betamethasone treatment was associated with patent ductus arteriosus closure in almost all infants., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. Based on the breeding of 8 founder strains with extreme genetic diversity, the Jackson laboratory diversity outbred population can capture the impact of genetic heterogeneity in like fashion to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for post-transfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid Quantitative Trait Loci (QTL) mapped >400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase Steap3, a transcriptional target to p53. Steap3 regulated post-transfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation and in vitro hemolysis in 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (FADS1/2, EPHX2, LPCAT3, SLC22A16, G6PD, ELOVL, PLA2G6) associated with lower levels of oxylipins. These polymorphisms were prevalent in donors of African descent and were linked to allele frequency of hemolysis-linked polymorphisms for Steap3 or p53. These genetic variants were also associated with lower hemoglobin increments in thousands of single-unit transfusion recipients from the vein-to-vein database., (Copyright © 2024 American Society of Hematology.)