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Objective: To quantitatively assess the impact of early versus late surgical intervention on midfacial growth using a mouse model., Methods: A full-thickness mucoperiosteal flap surgery was performed on newborn (P17) mice and on neonatal (P30) mice. High-resolution micro-computed tomographic imaging coupled with histomorphometric analyses was used to assess craniomaxillofacial growth. Histology and immunohistochemical analyses were used to assess cellular and molecular responses postsurgery., Results: Early surgical intervention at P17 resulted in significant midfacial growth arrest, with pronounced maxillary hypoplasia. Histomorphometric analyses revealed significant (P < 0.05) growth disruptions in the mid-palatal suture complex, including premature removal of the cartilaginous growth plate and its replacement by bone. In the suture itself, cell proliferation was significantly reduced (P < 0.05) compared with controls. The same surgical intervention performed in mice at P30 did not lead to significant midfacial growth arrest., Conclusions: Early surgical intervention in a mouse model mirrors the adverse growth outcomes in children undergoing early cleft repair. Molecular and cellular observations accompanying this midfacial growth arrest may inform therapeutic strategies to mitigate midfacial growth disturbances in patients and highlight the need for refined surgical techniques to minimize adverse growth outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

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Introduction: Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. Few studies have investigated changes in brain age longitudinally in MCI and AD. We hypothesized that individuals with MCI and AD would show heightened brain age over time and across the lifespan. We also hypothesized that both MCI and AD would show faster rates of brain aging (higher slopes) over time compared to healthy controls., Methods: We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI) 1 with 3Tesla (3 T) data which totaled 677 scans from 183 participants. This constitutes a secondary data analysis on existing data. We included control participants (healthy controls or HC), individuals with MCI, and individuals with AD. We predicted brain age using a pre-trained model and tested for accuracy. We investigated cross-sectional differences in brain age by group [healthy controls or HC, mild cognitive impairment (MCI), and AD]. We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model., Results: We predicted brain age with a mean absolute error (MAE) < 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change., Discussion: We replicated past studies that showed that MCI and AD had greater brain age than HC. We additionally found that this was true over time, both groups showed higher brain age longitudinally. Contrary to our hypothesis, we found that the MCI, but not the AD group, showed faster rates of brain aging. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). Individuals with MCI may experience higher rates of brain aging than AD and controls. AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ly, Yu, Son, Pascoal, Karim and the Alzheimer’s disease Neuroimaging Initiative.)

Background: Single ventricle palliation may be performed in patients with congenitally corrected transposition of the great arteries due to hypoplasia of 1 ventricle or anatomic complexity rendering biventricular repair unfeasible. There have been only a few small studies of the outcomes of single ventricle palliation in the setting of congenitally corrected transposition of the great arteries., Methods: A multicenter, international, retrospective cohort study of patients with congenitally corrected transposition of the great arteries undergoing single ventricle palliation was conducted in 29 tertiary hospitals in 6 countries from 1990 to 2018., Results: A total of 194 patients with congenitally corrected transposition of the great arteries underwent single ventricle palliation. A functionally univentricular heart was present in 62.4% (121/194). Patients with 2 good-sized ventricles had more laterality defects (50.7% vs 28.1%, P = .002). Fontan completion was achieved in 80.3% (155/194). A tricuspid valve surgery was performed in 9.3% (18/194). Survival was 97.4% (95% CI, 92.1-99.2) at 15 years in the univentricular cohort and 89.8% (95% CI, 78.0-95.5) at 15 years in those with 2 adequate ventricles (P = .05). At last follow-up, 11.5% of patients had heart failure, whereas 6.0% had moderate or greater systemic right ventricle dysfunction and 8.4% exhibited moderate or greater tricuspid regurgitation. In multivariable analysis, aortic coarctation or hypoplasia (hazard ratio, 7.7; P = .005) was associated with mortality., Conclusions: Single ventricle palliation in patients with congenitally corrected transposition of the great arteries is associated with excellent long-term survival and low rates of heart failure and atrioventricular valve failure. In patients who would require complex surgery to achieve a biventricular repair, single ventricle palliation appears to be a good alternative., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: The Quality of Life-Aged Care Consumers (QOL-ACC) is an aged-care-specific preference-based instrument currently being rolled out in residential care across Australia as part of the aged care Quality Indicator program. This study aimed to provide a comprehensive assessment of the feasibility, reliability, and construct validity of the QOL-ACC in a large national sample of older adults receiving aged care services at home., Methods: Older adults receiving in-home aged care services completed a survey including the QOL-ACC, Quality of Care Experience-ACC, adult social care outcome tool, EQ-5D-5L, and 2 global single item measures of health and quality of life. Feasibility was assessed by missing responses (≤5%) and ceiling/floor effects (≤15%). Construct validity was assessed by exploring the relationship between the QOL-ACC and other instruments (convergent validity) and its ability to discriminate varying levels of self-rated health and quality of life (known-group validity)., Results: A total of 802 respondents (mean age, 74.5 ± 6.3 years; 56.0% females) completed the survey. The QOL-ACC had no missing responses, no floor effects, and very low ceiling effect (3.5%) and demonstrated moderate correlation with adult social care outcome tool (r = 0.59, P < .001), EQ-5D-5L (r = 0.65, P < .001), EQ-VAS (r = 0.53, P < .001), and a lower correlation with the QCE-ACC (r = 0.41, P < .001). Respondents with poor self-rated health and quality of life had significantly lower preference-weighted scores on the QOL-ACC., Conclusions: The QOL-ACC demonstrated adequate feasibility, reliability, and construct validity in a large population of older people accessing government-subsidized aged care services at home. Further studies will explore the responsiveness of the QOL-ACC to aged-care-specific interventions both in home and residential aged care settings., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Normothermic machine perfusion (NMP) allows for the assessment and resuscitation of ex-vivo human livers prior to transplantation. Commercially available NMP systems are closed circuits that accumulate metabolic waste and cytokines over time, potentially limiting organ preservation times. Dialysis has been proposed as a method to remove waste and excess fluid from such systems. This study aimed to demonstrate the utility of integrating dialysis into a commercially available system by quantifying solute removal., Methods: A dialysis filter was attached in parallel to a commercially available liver perfusion system. Three livers declined for transplantation were split before undergoing long-term NMP with blood using the modified system. During perfusion, dialysate flow rates were set in the range of 100-600 mL/h for short periods of time. At each flow rate, perfusate and spent dialysate samples were collected and analyzed for solute clearance., Results: The addition of dialysis to a commercial NMP system removed water-soluble waste and helped regulate electrolyte concentrations. Interleukin-6 was successfully removed from the perfusate. Solute clearance was proportional to dialysate flow rate. A guide for our perfusion setup was created for the appropriate selection of dialysis flow rates and duration based on real-time perfusate composition., Conclusions: Dialysis circuits can efficiently remove waste and regulate perfusate composition, and can be easily incorporated to improve the performance of commercially available systems. Quantification of the effect of dialysis on perfusate composition enables refined dialysis control to optimize electrolyte profiles and avoid the over- or under-correction of key solutes., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

We identify a population of Protogenin-positive (PRTG +ve ) MYC high NESTIN low stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL VZ ). Oncogenic transformation of early Prtg +ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG +ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RL VZ , a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTG high compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RL VZ PRTG +ve stem cells inhabiting a specific perivascular niche. Targeting the PRTG high compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB., Competing Interests: Declaration of interests The authors declare no competing interests. A patent related to this work was submitted by University of Pittsburgh (University Docket No. 05700/F&R ref. 48881-0028P01), US 63/275,326, “Molecules that bind to Protogenin polypeptides.”, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman's partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology.

Fitz-Hugh-Curtis (FHCS) is characterized by an inflammation of the hepatic capsule concomitant or following pelvic infection due to Chlamydia trachomatis or Neisseria gonorrhea . It is a rare condition occurring most often in a woman of childbearing age and very rare in male patients. Splenic involvement is also a rare form of abdominal tuberculosis. The association of these two conditions is very uncommon. We report the exceptional case of a 58- year-old HIV-positive male patient, with whom abdominal ultrasound helped diagnose FHCS associated with abdominal tuberculosis invovlving the spleen., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Bile duct regeneration is hypothesized to prevent biliary strictures, a leading cause of morbidity after liver transplantation. Assessing the capacity for biliary regeneration may identify grafts as suitable for transplantation that are currently declined, but this has been unfeasible until now. This study used long-term ex situ normothermic machine perfusion (LT-NMP) to assess biliary regeneration. Human livers that were declined for transplantation were perfused at 36 °C for up to 13.5 days. Bile duct biopsies, bile, and perfusate were collected throughout perfusion, which were examined for features of injury and regeneration. Biliary regeneration was defined as new Ki-67-positive biliary epithelium following severe injury. Ten livers were perfused for a median duration of 7.5 days. Severe bile duct injury occurred in all grafts, and biliary regeneration occurred in 70% of grafts. Traditional biomarkers of biliary viability such as bile glucose improved during perfusion but this was not associated with biliary regeneration (P > .05). In contrast, the maintenance of interleukin-6 and vascular endothelial growth factor-A levels in bile was associated with biliary regeneration (P = .017 for both cytokines). This is the first study to demonstrate biliary regeneration during LT-NMP and identify a cytokine signature in bile as a novel biomarker for biliary regeneration during LT-NMP., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Medical practitioners are entrusted with the pivotal task of making optimal decisions in healthcare delivery. Despite rigorous training, our confidence in reasoning can fail when faced with pressures, uncertainties, urgencies, difficulties, and occasional errors. Day-to-day decisions rely on swift, intuitive cognitive processes known as heuristic or type 1 decision-making, which, while efficient in most scenarios, harbor inherent vulnerabilities leading to systematic errors. Cognitive biases receive limited explicit discussion during our training as junior doctors in the domain of paediatric cardiology. As pediatric cardiologists, we frequently confront emergencies necessitating rapid decision-making, while contending with the pressures of stress, fatigue, an earnest interest in "doing the right thing" and the impact of parental involvement. This article aims to describe cognitive biases in pediatric cardiology, highlighting their influence on therapeutic interventions for congenital heart disease. Whether future pediatric cardiologists or experienced professionals, understanding and actively combating cognitive biases are essential components of our ongoing medical education. Furthermore, it is our responsibility to thoroughly examine our own practices in our unwavering commitment to providing high-quality care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Padovani, Roy, Guerra, Cadeau, Ly, Vasile, Pass and Baruteau.)

The central nervous system coordinates peripheral cellular stress responses, including the unfolded protein response of the mitochondria (UPR MT ); however, the contexts for which this regulatory capability evolved are unknown. UPR MT is up-regulated upon pathogenic infection and in metabolic flux, and the olfactory nervous system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in Caenorhabditis elegans controls the UPR MT cell nonautonomously. We found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of UPR MT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin -mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPR MT transcription factor atfs-1 and fully dependent on mitophagy machinery. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, perhaps in preparation for postprandial metabolic stress or pathogenic infection.

Introduction: Long-term exposure to high-risk human papillomavirus (Hr-HPV) is a well-known necessary condition for development of cervical cancer. The aim of this study is to screen for Hr-HPV using vaginal self-sampling, which is a more effective approach to improve women's adherence and increase screening rates., Methods: This pilot study included a total of 100 Women living with HIV (WLWHIV), recruited from the Center for Listening, Care, Animation, and Counseling of People Living with HIV in Bamako. Hr-HPV genotyping was performed on Self-collected samples using the Cepheid GeneXpert instrument., Results: The median age of WLWHIV was 44 (interquartile range [IQR], 37-50) years. Approximately 92% of the study participants preferred self-sampling at the clinic, and 90% opted to receive result notifications via mobile phone contact. The overall prevalence of Hr-HPV among study participants was 42.6%, and the most frequent Hr-HPV sub-types observed were HPV18/45 (19.1%), HPV31/35/33/52/58 (13.8%), and HPV39/68/56/66 (12.8%), followed by HPV16 (5.3%), and HPV51/59 (5.3%). WLWHIV under 35 years of age had a higher frequency of Hr-HPV compared to their older counterparts, with rates of 30% versus 11.1% (p = 0.03). The duration of antiretroviral treatment showed an inverse association with Hr-HPV negativity, with patients on treatment for 15 (IQR, 10-18) years versus 12 (IQR = 7-14) years for Hr-HPV positive patients (95% CI [1.2-5.8], t = 3.04, p = 0.003). WLWHIV with baseline CD4 T-Cell counts below 200 exhibited a higher frequency of Hr-HPV compared to those with baseline CD4 T-Cell counts above 200 (17.9% versus 1.9%, p = 0.009). However, other demographics and clinical factors, such as marital status, age of sexual debut, parity, education, history of abortion, history of preeclampsia, and cesarean delivery, did not influence the distribution of Hr-HPV genotypes., Conclusion: Our findings indicate that WLWHIV under the age of 35 years old exhibited the highest prevalence of Hr-HPV infection, with HPV18/45 being the most prevalent subtype. Additionally, WLWHIV with baseline CD4 T-Cell counts below 200 showed the highest infection rates., (© 2024. The Author(s).)

Objectives: Body dissatisfaction is often linked to the internalization of Western beauty standards. Existing measures of body dissatisfaction, developed in Western societies, may fail to capture complex variations across ethnicities and cultures. The Negative Physical Self Scale (NPSS) assesses cognitive, affective, perceptual, and behavioural facets of body dissatisfaction. While unique in its consideration of Chinese ideals of body image, the NPSS has recently been translated and validated in a North American sample. The English-translated version of the NPSS has the potential to be an appropriate body dissatisfaction assessment tool for Asian women living in North America. The current study aims to validate the NPSS in an Asian female population living in Canada., Methods: A sample of 899 undergraduate women residing in Canada with self-identified Asian ethnicity completed an online survey consisting of the NPSS and other measures of body dissatisfaction., Results: An initial confirmatory factor analysis indicated that the four-factor structure of the NPSS, previously suggested in a primarily non-Asian North American sample, was a poor fit for the data. A second-order multidimensional model, based on a model proposed during the original development of the NPSS in a Chinese sample, indicated good fit once items were removed due to loadings < .60. High internal consistency between subscales and strong convergent validity with other measures were demonstrated. Notably, the NPSS Body Concern subscale demonstrated high convergence with other popular measures of body dissatisfaction and has the potential for use as a brief measure of body dissatisfaction among North American Asian females in clinical and research settings., Conclusions: The NPSS provides a valid assessment of body dissatisfaction among a sample of Asian women living in Canada, a specific subpopulation that has not been previously investigated. The findings highlight the importance of developing culturally sensitive measures of body dissatisfaction for differing ethnic and cultural groups., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Amin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pulmonary atresia with ventricular septal defect, non-confluent pulmonary arteries, and bilateral arterial duct is a rare and complex CHD. Physiologic ductal closure may lead to life-threatening hypoxia. We present a case of successful bilateral ductal stenting as a bridge to further lower-risk surgical repair.

Background: Ex situ machine perfusion facilitates the assessment of livers prior to transplantation. However, currently available markers of liver function poorly predict long-term graft function. Indocyanine green (ICG) is a liver-specific dye which, although common in vivo, has never been comprehensively evaluated for the assessment of graft quality during ex situ machine perfusion. This study aimed to assess the utility of ICG in the ex situ setting., Methods: Using a customized long-term perfusion system, human livers that were not suitable for transplantation were perfused using a red cell-based perfusate. ICG was delivered into the perfusate on days 0, 1, and 4 to assess ICG clearance (spectrophotometric absorbance at 805 nm) and ICG fluorescence (near-infrared camera)., Results: Sixteen partial livers were perfused for a median duration of 172 h (7.2 days). On day 0, the median ICG perfusate disappearance rate (PDR) was 7.5%/min and the median ICG retention at 15 min was 9.9%. Grafts that survived ≥7 days had a significantly higher median ICG PDR on day 0 (14.5%/min vs. 6.5%/min, p = 0.005) but not on days 1 or 4. ICG perfusion demonstrated that long-surviving grafts had a significantly lower median red-value (89.8 vs. 118.6, p = 0.011) and a significantly lower median blue-value (12.9 vs. 22.6, p = 0.045) than short-surviving grafts., Conclusion: ICG is a novel marker for the assessment of liver function during ex situ normothermic machine perfusion. ICG PDR and quantitative ICG perfusion can distinguish between long- and short-surviving grafts and demonstrate the utility of ICG in the assessment of graft quality prior to transplant., (© 2023 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Objective: This study examined the moderating effect of traumatic brain injury (TBI) history on subjective and objective cognition across multiple cognitive domains., Setting, Participants, and Design: Participants included 242 Vietnam-era veterans with a history of no TBI (n = 86), mild TBI (n = 74), or moderate-to-severe TBI (n = 82) from the observational Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) study., Main Measures: Objective cognition was the outcome and was measured using neuropsychological measures in the domains of memory, attention/executive functioning, and language. Subjective cognition was measured using the memory, divided attention, and language subscales from the Everyday Cognition (ECog) measure. TBI severity status was the moderating variable., Results: Veterans with a history of moderate-to-severe TBI had a stronger negative association between subjective and objective attention relative to participants without a TBI ( P = .002). Although this association did not differ between mild TBI and no TBI history groups ( P = .100), the association between subjective and objective attention for the mild TBI group was intermediate to the no TBI and moderate-to-severe TBI history groups. TBI status did not moderate associations between subjective and objective memory or language., Conclusion: Results highlight the importance of assessing subjective and objective cognition in older veterans and the relevance of attention in the context of TBI history. More work is needed to better understand the intersection of TBI and aging and how these factors may be used to guide individualized assessment and treatment approaches for older veterans., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Objectives: Surgical management of mitral valve disease is challenging in infants <1 year old. We aimed at reviewing the French experience with Melody mitral valve replacement in critically ill infants., Methods: A retrospective cohort study reporting the French experience with Melody mitral valve replacement., Results: Seven symptomatic infants [complete atrioventricular septal defect (n = 4, Down syndrome: n = 3), hammock valve (n = 3)] underwent Melody mitral valve replacement [age: 3 months (28 days to 8 months), weight: 4.3 kg (3.2-6.4 kg)] because of severe mitral valve regurgitation (6) or mixed valve disease (1) and 14 mm (11-16 mm) mitral valve annulus. In 2 patients whose valve was felt irreparable, Melody mitral valve replacement was performed straightaway. The others underwent 2 (1-3) previous attempts of valve repair; 3 were on extracorporeal membrane oxygenation. Melody mitral valve replacement led to competent valve and low gradient [3 mmHg, (1-4 mmHg)]. One patient died 3 days post-implant from extracorporeal membrane oxygenation-related stroke. Of the 6 discharged home patients, 3 (50%) were readmitted for a definite diagnosis (1) or high suspicion (2) of infective endocarditis, of which 2 died. Over the follow-up, 1 underwent balloon expansions of the valve at 9- and 16-months post-implant, and mechanical mitral valve replacement at 2 years; another is currently planned for transcatheter Melody valve dilation., Conclusions: Melody mitral valve replacement may be considered in selected infants with small mitral valve annulus as an alternative to mechanical mitral valve replacement. Our experience highlights a high-risk of late infective endocarditis that deserves further consideration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8- derived variants performed efficiently. This study demonstrates the potential of using normothermic liver perfusion as a model for early-stage testing of liver-focused gene therapies. The results offer preliminary insights that could help inform the development of more effective translational strategies., (© 2024. The Author(s).)

Data on the safety and efficiency of perventricular device closure of complex ventricular septal defects (VSDs) are scarce. We report successful one-stage combined hybrid perventricular and percutaneous closure of the muscular VSDs in a critically ill 4-kg infant, using the new multifunctional occluder., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Annals of Pediatric Cardiology.)

Embryos repair wounds rapidly, with no inflammation or scarring. Embryonic wound healing is driven by the collective movement of the cells around the lesion. The cells adjacent to the wound polarize the cytoskeletal protein actin and the molecular motor non-muscle myosin II, which accumulate at the wound edge forming a supracellular cable around the wound. Adherens junction proteins, including E-cadherin, are internalized from the wound edge and localize to former tricellular junctions at the wound margin, in a process necessary for cytoskeletal polarity. We found that the cells adjacent to wounds in the Drosophila embryonic epidermis polarized Talin, a core component of cell-extracellular matrix (ECM) adhesions, which preferentially accumulated at the wound edge. Integrin knockdown and inhibition of integrin binding delayed wound closure and reduced actin polarization and dynamics around the wound. Additionally, disrupting integrins caused a defect in E-cadherin reinforcement at tricellular junctions along the wound edge, suggesting crosstalk between integrin-based and cadherin-based adhesions. Our results show that cell-ECM adhesion contributes to embryonic wound repair and reveal an interplay between cell-cell and cell-ECM adhesion in the collective cell movements that drive rapid wound healing., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background: Although the mpox global health emergency caused by mpox virus (MPXV) clade IIb.1 has ended, mpox cases are still reported due to low vaccination coverage and waning immunity. COH04S1 is a clinically evaluated, multiantigen COVID-19 vaccine candidate built on a fully synthetic platform of the highly attenuated modified vaccinia Ankara (MVA) vector, representing the only FDA-approved smallpox/mpox vaccine JYNNEOS. Given the potential threat of MPXV resurgence and need for vaccine alternatives, we aimed to assess the capacity COH04S1 and its synthetic MVA (sMVA) backbone to confer MPXV-specific immunity., Methods: We evaluated orthopoxvirus-specific and MPXV cross-reactive immune responses in samples collected during a Phase 1 clinical trial of COH04S1 and in non-human primates (NHP) vaccinated with COH04S1 or its sMVA backbone. MPXV cross-reactive immune responses in COH04S1-vaccinated healthy adults were compared to responses measured in healthy subjects vaccinated with JYNNEOS. Additionally, we evaluated the protective efficacy of COH04S1 and sMVA against mpox in mpox-susceptible CAST/EiJ mice., Results: COH04S1-vaccinated individuals develop robust orthopoxvirus-specific humoral and cellular responses, including cross-reactive antibodies to MPXV-specific virion proteins as well as MPXV cross-neutralizing antibodies in 45% of the subjects. In addition, NHP vaccinated with COH04S1 or sMVA show similar MPXV cross-reactive antibody responses. Moreover, MPXV cross-reactive humoral responses elicited by COH04S1 are comparable to those measured in JYNNEOS-vaccinated subjects. Finally, we show that mice vaccinated with COH04S1 or sMVA are protected from lung infection following challenge with MPXV clade IIb.1., Conclusions: These results demonstrate the capacity of sMVA vaccines to elicit cross-reactive and protective orthopox-specific immunity against MPXV, suggesting that COH04S1 and sMVA could be developed as bivalent or monovalent mpox vaccine alternatives against MPXV., (© 2024. The Author(s).)

Background: Normothermic machine perfusion permits the ex vivo preservation of human livers before transplantation. Long-term perfusion for days-to-weeks provides the opportunity for enhanced pretransplant assessment and potential regeneration of organs. However, this risks microbial contamination and infection of the recipient if the organ is transplanted. An understanding of perfusate microbial contamination is required to inform infection control procedures and antimicrobial prophylaxis for this technology., Methods: We modified a liver perfusion machine for long-term use by adding long-term oxygenators and a dialysis filter. Human livers that were not suitable for transplantation were perfused using a red-cell-based perfusate under aseptic and normothermic conditions (36 °C) with a goal of 14 d. Cephazolin was added to the perfusate for antimicrobial prophylaxis. Perfusate and bile were sampled every 72 h for microbial culture., Results: Eighteen partial human livers (9 left lateral segment grafts and 9 extended right grafts) were perfused using our perfusion system. The median survival was 7.2 d. All organs surviving longer than 7 d (9/18) had negative perfusate cultures at 24 and 48 h. Half of the grafts (9/18) became culture-positive by the end of perfusion. Microbial contaminants included Gram-negative ( Pseudomonas species, Proteus mirabilis, Stenotrophomonas maltophilia ) and Gram-positive bacteria ( Staphylococcus epidermidis , Enterococcus faecalis , and Bacillus species) as well as yeast ( Candida albicans )., Conclusions: Microbial contamination of perfusate is common during long-term perfusion of human livers with both exogenous and endogenous sources. Enhanced infection control practices and review of targeted antimicrobial prophylaxis are likely to be necessary for translation into the clinical arena., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In the United States, more than 19 million people of reproductive age need access to publicly funded hormonal contraception or live in areas where it is not readily available. These include rural areas of the country, commonly known as contraception deserts. Pharmacist prescribing has been proposed to increase access, but little is known about its implementation in such areas., Objective: This study quantified the extent of pharmacists' furnishing (prescribing) of hormonal contraception in California's Central Valley community pharmacies and identified barriers and facilitators to implementation., Methods: The researchers conducted a cross-sectional, mixed methods, observational study by (1) contacting all community pharmacies in the 11 counties of the Central Valley to determine furnishing rates and (2) surveying and interviewing pharmacies that indicated they furnished hormonal contraception., Results: Overall, 13% of pharmacies within the Central Valley reported that they furnished hormonal contraception. Pharmacists reported that barriers to furnishing included costs to patients and the pharmacy, lack of time and staff, lack of training and certifications, limited patient awareness of pharmacists' ability to furnish, pharmacists' limited confidence in furnishing, and patient use of emergency contraception as an alternative to hormonal contraception. Pharmacists reported that patients often sought hormonal contraception from pharmacists owing to ease of accessibility to a pharmacist; some other facilitators included advertising, confidentiality, low cost to patients, and referrals from other providers., Conclusions: Common barriers were identified across pharmacies that furnished hormonal contraception, indicating the need for strategies that reduce these barriers to help expand patient's access to these services and to increase pharmacists' ability and confidence to prescribe., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

(1) Background: Breast cancer is the most prevalent cancer found in women in Mali. The aim of the current study was to determine the association between metabolites circulating in the blood, 25(OH)D and 1,25(OH) 2 D, and vitamin D levels with the risk of breast cancer in Malian women. (2) Methods: We conducted a prospective case-control study from August 2021 to March 2022. Control subjects were matched to cases according to age (within 5 years). The patients' clinical stage was determined by the oncologist according to the tumour-nodes-metastasis (TNM) classification system. (3) Results: We observed no differences in the mean 25(OH)D ( p = 0.221) and 1,25(OH) 2 D ( p = 0.285) between cases and controls. However, our findings indicate a more pronounced inverse association in the first level of plasma 25(OH)D, while the risk function decreases at higher levels. This observation takes strength with 1,25(OH) 2 D by a significant association between the first quartile and breast cancer as a risk factor ( p = 0.03; OR = 71.84; CI: 1.36-3785.34). (4) Conclusions: These outcomes showed a possible association between 25(OH)D and 1,25(OH) 2 D in decreasing the risk of breast cancer.

Background: Managing Canada's immunoglobulin (Ig) product resource allocation is challenging due to increasing demand, high expenditure, and global shortages. Detection of groups with high utilization rates can help with resource planning for Ig products. This study aims to uncover utilization subgroups among the Ig recipients using electronic health records (EHRs)., Methods: The study included all Ig recipients (intravenous or subcutaneous) in Calgary from 2014 to 2020, and their EHR data, including blood inventory, recipient demographics, and laboratory test results, were analyzed. Patient clusters were derived based on patient characteristics and laboratory test data using K-means clustering. Clusters were interpreted using descriptive analyses and visualization techniques., Results: Among 4112 recipients, six clusters were identified. Clusters 1 and 2 comprised 408 (9.9%) and 1272 (30.9%) patients, respectively, contributing to 62.2% and 27.1% of total Ig utilization. Cluster 3 included 1253 (30.5%) patients, with 86.4% of infusions administered in an inpatient setting. Cluster 4, comprising 1034 (25.1%) patients, had a median age of 4 years, while clusters 2-6 were adults with median ages of 46-60. Cluster 5 had 62 (1.5%) patients, with 77.3% infusions occurring in emergency departments. Cluster 6 contained 83 (2.0%) patients receiving subcutaneous Ig treatments., Conclusion: The results identified data-driven segmentations of patients with high Ig utilization rates and patients with high risk for short-term inpatient use. Our report is the first on EHR data-driven clustering of Ig utilization patterns. The findings hold the potential to inform demand forecasting and resource allocation decisions during shortages of Ig products., (© 2023 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Introduction: Histological injury to the biliary tree during organ preservation leads to biliary strictures after liver transplantation. The Bile Duct Injury (BDI) score was developed to assess histological injury and identify the grafts most likely to develop biliary strictures. The BDI score evaluates the bile duct mural stroma, peribiliary vascular plexus (PVP) and deep peribiliary glands (DPGs), which were correlated with post-transplant biliary strictures. However, the BDI score has not been externally validated. The aim of this study was to verify whether the BDI score could predict biliary strictures at our transplant centre., Methods: Brain-dead donor liver grafts transplanted at a single institution from March 2015 to June 2016 were included in this analysis. Bile duct biopsies were collected immediately before transplantation and assessed for bile duct injury by two blinded pathologists. The primary outcome was the development of clinically significant biliary strictures within 24 months post-transplant., Results: Fifty-seven grafts were included in the study which included 16 biliary strictures (28%). Using the BDI score, mural stromal, PVP and DPG injury did not correlate with biliary strictures including Non-Anastomotic Strictures. Severe inflammation (>50 leucocytes per HPF) was the only histological feature inversely correlated with the primary outcome (absent in the biliary stricture group vs. 41% in the no-stricture group, p = 0.001)., Conclusions: The current study highlights limitations of the histological assessment of bile duct injury. Although all grafts had bile duct injury, only inflammation was associated with biliary strictures. The BDI score was unable to predict post-transplant biliary strictures in our patient population.

Obesity, depression and Alzheimer's disease (AD) are three major interrelated modern health conditions with complex relationships. Early-life depression may serve as a risk factor for AD, while late-life depression may be a prodrome of AD. Depression affects approximately 23% of obese individuals, and depression itself raises the risk of obesity by 37%. Mid-life obesity independently increases AD risk, while late-life obesity, particularly metabolically healthy obesity, may offer protection against AD pathology. Chronic inflammation serves as a key mechanism linking obesity, AD, and depression, encompassing systemic inflammation from metabolic disturbances, immune dysregulation through the gut microbiome, and direct interactions with amyloid pathology and neuroinflammation. In this review, we explore the biological mechanisms of neuroinflammation in relation to obesity, AD, and depression. We assess the efficacy of therapeutic interventions targeting neuroinflammation and discuss current and future radiological imaging initiatives for studying neuroinflammation. By comprehending the intricate interplay among depression, obesity, and AD, especially the role of neuroinflammation, we can advance our understanding and develop innovative strategies for prevention and treatment., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR)-T cell patients are immunocompromised, remain at high risk following SARS-CoV-2 infection, and are less likely than immunocompetent individuals to respond to vaccination. As part of the safety lead-in portion of a phase 2 clinical trial in patients post HCT/CAR-T for hematological malignancies (HM), we tested the immunogenicity of the synthetic modified vaccinia Ankara-based COVID-19 vaccine COH04S1 co-expressing spike (S) and nucleocapsid (N) antigens. Thirteen patients were vaccinated 3-12 months post HCT/CAR-T with two to four doses of COH04S1. SARS-CoV-2 antigen-specific humoral and cellular immune responses, including neutralizing antibodies to ancestral virus and variants of concern (VOC), were measured up to six months post vaccination and compared to immune responses in historical cohorts of naïve healthy volunteers (HV) vaccinated with COH04S1 and naïve healthcare workers (HCW) vaccinated with the FDA-approved mRNA vaccine Comirnaty ® (Pfizer, New York, NY, USA). After one or two COH04S1 vaccine doses, HCT/CAR-T recipients showed a significant increase in S- and N-specific binding antibody titers and neutralizing antibodies with potent activity against SARS-CoV-2 ancestral virus and VOC, including the highly immune evasive Omicron XBB.1.5 variant. Furthermore, vaccination with COH04S1 resulted in a significant increase in S- and N-specific T cells, predominantly CD4 + T lymphocytes. Elevated S- and N-specific immune responses continued to persist at six months post vaccination. Furthermore, both humoral and cellular immune responses in COH04S1-vaccinated HCT/CAR-T patients were superior or comparable to those measured in COH04S1-vaccinated HV or Comirnaty ® -vaccinated HCW. These results demonstrate robust stimulation of SARS-CoV-2 S- and N-specific immune responses including cross-reactive neutralizing antibodies by COH04S1 in HM patients post HCT/CAR-T, supporting further testing of COH04S1 in immunocompromised populations.

Current machine perfusion technology permits livers to be preserved ex situ for short periods to assess viability prior to transplant. Long-term normothermic perfusion of livers is an emerging field with tremendous potential for the assessment, recovery, and modification of organs. In this study, we aimed to develop a long-term model of ex situ perfusion including a surgical split and simultaneous perfusion of both partial organs. Human livers declined for transplantation were perfused using a red blood cell-based perfusate under normothermic conditions (36 °C) and then split and simultaneously perfused on separate machines. Ten human livers were split, resulting in 20 partial livers. The median ex situ viability was 125 h, and the median ex situ survival was 165 h. Long-term survival was demonstrated by lactate clearance, bile production, Factor-V production, and storage of adenosine triphosphate. Here, we report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol., (© 2023. Springer Nature Limited.)

Background: The microbiome of the human gut serves a role in a number of physiological processes, but can be altered through effects of age, diet, and disturbances such as antibiotics. Several studies have demonstrated that commonly used antibiotics can have sustained impacts on the diversity and the composition of the gut microbiome. The impact of the two most overused antibiotics, azithromycin, and amoxicillin, in the human microbiome has not been thoroughly described. In this study, we recruited a group of individuals and unrelated controls to decipher the effects of the commonly used antibiotics amoxicillin and azithromycin on their gut microbiomes., Results: We characterized the gut microbiomes by metagenomic sequencing followed by characterization of the resulting microbial communities. We found that there were clear and sustained effects of the antibiotics on the gut microbial community with significant alterations in the representations of Bifidobacterium species in response to azithromycin (macrolide antibiotic). These results were supported by significant increases identified in putative antibiotic resistance genes associated with macrolide resistance. Importantly, we did not identify these trends in the unrelated control individuals. There were no significant changes observed in other members of the microbial community., Conclusions: As we continue to focus on the role that the gut microbiome plays and how disturbances induced by antibiotics might affect our overall health, elucidating members of the community most affected by their use is of critical importance to understanding the impacts of common antibiotics on those who take them. Clinical Trial Registration Number NCT05169255. This trial was retrospectively registered on 23-12-2021., (© 2023. The Author(s).)

Periosteum is a highly vascularized membrane lining the surface of bones. It plays essential roles in bone repair following injury and reconstruction following invasive surgeries. To broaden the use of periosteum, including for augmenting in vitro bone engineering and/or in vivo bone repair, we have developed an ex vivo perfusion bioreactor system to maintain the cellular viability and metabolism of surgically resected periosteal flaps. Each specimen was placed in a 3D printed bioreactor connected to a peristaltic pump designed for the optimal flow rates of tissue perfusate. Nutrients and oxygen were perfused via the periosteal arteries to mimic physiological conditions. Biochemical assays and histological staining indicate component cell viability after perfusion for almost 4 weeks. Our work provides the proof-of-concept of ex vivo periosteum perfusion for long-term tissue preservation, paving the way for innovative bone engineering approaches that use autotransplanted periosteum to enhance in vivo bone repair.

Objective: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of "brain age" analysis on disability in MS using a large, real-world dataset., Methods: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models., Results: MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability., Interpretation: Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Soybean (Glycine max) is a valuable crop in agriculture that has thousands of industrial uses. Soybean roots are the primary site of interaction with soil-borne microbes that form symbiosis to fix nitrogen and pathogens, which makes research involving soybean root genetics of prime importance to improve its agricultural production. The genetic transformation of soybean hairy roots (HRs) is mediated by the Agrobacterium rhizogenes strain NCPPB2659 (K599) and is an efficient tool for studying gene function in soybean roots, taking only 2 months from start to finish. Here, we provide a detailed protocol that outlines the method for overexpressing and silencing a gene of interest in soybean HRs. This methodology includes soybean seed sterilization, infection of cotyledons with K599, and the selection and harvesting of genetically transformed HRs for RNA isolation and, if warranted, metabolite analyses. The throughput of the approach is sufficient to simultaneously study several genes or networks and could determine the optimal engineering strategies prior to committing to long-term stable transformation approaches.

Background: Split liver transplantation permits the transplant of two recipients using a single donor liver. Liver splitting can be performed using the ex-vivo technique (more convenient), or the in-situ technique (shorter cold ischaemic time). We aimed to develop a technique for liver splitting during normothermic machine perfusion which combines the advantages of both techniques and permits graft assessment prior to transplant., Methods: Human livers declined for transplantation were perfused at 36 °C using a modified-commercial perfusion machine. We developed a six-step method to split whole livers into left lateral segment grafts and extended right grafts. Both partial livers were then perfused on separate machines for individual assessment., Results: Using our technique, 10 whole livers were successfully split during normothermic perfusion resulting in 20 partial grafts. Apart from a single graft which failed due to a technical error, all grafts survived for 24-h after splitting. Survival was demonstrated by lactate clearance, bile production and synthesis of coagulation factors., Conclusions: Liver splitting during normothermic machine perfusion has the potential to revolutionise split liver transplantation. We describe a novel technique that reliably achieves two grafts from a single donor liver. This raises the possibility of semi-elective transplantation, and sophisticated graft assessment prior to implant., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Emerging SARS-CoV-2 Omicron subvariants continue to disrupt COVID-19 vaccine efficacy through multiple immune mechanisms including neutralizing antibody evasion. We developed COH04S1, a synthetic modified vaccinia Ankara vector that co-expresses Wuhan-Hu-1-based spike and nucleocapsid antigens. COH04S1 demonstrated efficacy against ancestral virus and Beta and Delta variants in animal models and was safe and immunogenic in a Phase 1 clinical trial. Here, we report efficacy of COH04S1 and analogous Omicron BA.1- and Beta-specific vaccines to protect Syrian hamsters from Omicron subvariants. Despite eliciting strain-specific antibody responses, all three vaccines protect hamsters from weight loss, lower respiratory tract infection, and lung pathology following challenge with Omicron BA.1 or BA.2.12.1. While the BA.1-specifc vaccine affords consistently improved efficacy compared to COH04S1 to protect against homologous challenge with BA.1, all three vaccines confer similar protection against heterologous challenge with BA.2.12.1. These results demonstrate efficacy of COH04S1 and variant-specific derivatives to confer cross-protective immunity against SARS-CoV-2 Omicron subvariants., (© 2023. The Author(s).)

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% ( n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease ( r = -0.23 and -0.20, respectively, P s < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease ( n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy ( P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played <11 years of football ( n = 78), those who played 11 or more years ( n = 128) had lower myelin-associated glycoprotein (mean difference = 46.00, 95% CI [5.32, 86.69]) and proteolipid protein 1 (mean difference = 24.72, 95% CI [2.40, 47.05]). Younger age of first exposure corresponded to lower proteolipid protein 1 (beta = 4.35, 95% CI [0.25, 8.45]). Among brain donors who were aged 50 or older ( n = 144), lower proteolipid protein 1 (beta = -0.02, 95% CI [-0.047, -0.001]) and myelin-associated glycoprotein (beta = -0.01, 95% CI [-0.03, -0.002]) were associated with higher Functional Activities Questionnaire scores. Lower myelin-associated glycoprotein correlated with higher Barratt Impulsiveness Scale-11 scores (beta = -0.02, 95% CI [-0.04, -0.0003]). Results suggest that decreased myelin may represent a late effect of repetitive head impacts that contributes to the manifestation of cognitive symptoms and impulsivity. Clinical-pathological correlation studies with prospective objective clinical assessments are needed to confirm our findings., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Microbial keratitis is the most common cause of infective vision loss. The causative organism varies by region, and most cases require intensive antimicrobial therapy. The purpose of this study was to analyse the causative organisms of microbial keratitis, its presentation and economic burden from a tertiary referral hospital in Australia. A retrospective review of 160 cases of microbial keratitis was performed, over a 5-year period from 2015-2020. A wide variety of costs were considered to determine the economic burden, using standardized data from the Independent Hospital Pricing Authority and the cost of personal income loss. Our study showed the most commonly occurring pathogens were Herpes Simplex (16%), Staphylococcus aureus (15.1%) and Pseudomonas aeruginosa (14.3%). A total of 59.3% of patients were admitted, with a median length of admission of 7 days. Median cost for all presentations of microbial keratitis was AUD 8013 (USD 5447), with costs significantly increasing with admission. The total annual cost of microbial keratitis within Australia is estimated to be AUD 13.58 million (USD 9.23 million). Our findings demonstrate that microbial keratitis represents a significant economic burden for eye-related diseases and the key driving factor for the cost is the length of admission. Minimizing the duration of admission, or opting for outpatient management where appropriate, would significantly reduce the cost of treatment for microbial keratitis.

In the current post-pandemic era, recipients of an allogeneic hematopoietic stem cell transplant (HCT) deserve special attention. In these vulnerable patients, vaccine effectiveness is reduced by post-transplant immune-suppressive therapy; consequently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) is often associated with elevated morbidity and mortality. Characterizing SARS-CoV-2 adaptive immunity transfer from immune donors to HCT recipients in the context of immunosuppression will help identify optimal timing and vaccination strategies that can provide adequate protection to HCT recipients against infection with evolving SARS-CoV-2 variants. We performed a prospective observational study (NCT04666025 at ClinicalTrials.gov) to longitudinally monitor the transfer of SARS-CoV-2-specific antiviral immunity from HCT donors, who were either vaccinated or had a history of COVID-19, to their recipients via T-cell replete graft. Levels, function, and quality of SARS-CoV-2-specific immune responses were longitudinally analyzed up to 6 months post-HCT in 14 matched unrelated donor/recipients and four haploidentical donor/recipient pairs. A markedly skewed donor-derived SARS-CoV-2 CD4 T-cell response was measurable in 15 (83%) recipients. It showed a polarized Th1 functional profile, with the prevalence of central memory phenotype subsets. SARS-CoV-2-specific IFN-γ was detectable throughout the observation period, including early post-transplant (day +30). Functionally experienced SARS-CoV-2 Th1-type T cells promptly expanded in two recipients at the time of post-HCT vaccination and in two others who were infected and survived post-transplant COVID-19 infection. Our data suggest that donor-derived SARS-CoV-2 T-cell responses are functional in immunosuppressed recipients and may play a critical role in post-HCT vaccine response and protection from the fatal disease., Clinical Trial Registration: clinicaltrials.gov, identifier NCT04666025., Competing Interests: CLR received consulting fees and research funding from Helocyte Inc. DJD received consulting fees, patent royalties, research funding, and fees for serving on the advisory board of Helocyte Inc. In addition, DJD has two patents, 8,580,276 and 9,675,689, that are licensed to Helocyte. DJD and FC are co-inventors of the Patent Cooperation Treaty PCT application that covers the development of a COVID-19 vaccine PCT/US2021/032821 licensed to GeoVax Labs Inc. DD receives consulting fees and research support from GeoVax Labs Inc. RN is a consultant for Omeros, Bluebird, Viracor Eurofins, Magenta Therapeutics, Kadmon, and Napajen Pharma; received research funding from Helocyte, Miyarisan Pharmaceutical; and receives travel, accommodations, expenses from Kyowa Hakko Kirin, Alexion Pharmaceuticals. SD is a consultant for Merck, Allovir, and Aseptiscope; an Advisory board for Merck and Aseptiscope; an investigator for Allovir, Merck, Ansun, Gilead, Janssen, Shire/Takeda; and on the speaker’s bureau of Merck, Takeda, and Astellas. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 La Rosa, Chiuppesi, Park, Zhou, Yang, Gendzekhadze, Ly, Li, Kaltcheva, Ortega Francisco, Gutierrez, Ali, Otoukesh, Amanam, Salhotra, Pullarkat, Aldoss, Rosenzweig, Aribi, Stein, Marcucci, Dadwal, Nakamura, Forman, Al Malki and Diamond.)

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin-DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB., (© 2023. The Author(s).)

Biliary complications are a common cause of morbidity after liver transplantation and associated with bile duct injury. To reduce injury, a bile duct flush is performed with high-viscosity preservation solution. It has been suggested that an earlier additional bile duct flush with low-viscosity preservation solution may reduce bile duct injury and biliary complications. This study aimed to investigate whether an earlier additional bile duct flush would reduce bile duct injury or biliary complications., Methods: A randomized trial was conducted using 64 liver grafts from brain dead donors. The control group received a bile duct flush with University of Wisconsin (UW) solution after donor hepatectomy. The intervention group received a bile duct flush using low-viscosity Marshall solution immediately after the onset of cold ischemia and a bile duct flush with University of Wisconsin solution after donor hepatectomy. The primary outcomes were the degree of histological bile duct injury, assessed using the bile duct injury score, and biliary complications within 24 mo of transplant., Results: Bile duct injury scores were not different between the 2 groups. Similar rates of biliary complications occurred in the intervention group (31% [n = 9]) and controls (23% [n = 8]) ( P = 0.573). No difference between groups was observed for anastomotic strictures (24% versus 20%, P = 0.766) or nonanastomotic strictures (7% versus 6%, P = 1.00)., Conclusions: This is the first randomized trial to investigate an additional bile duct flush using low-viscosity preservation solution during organ procurement. The findings from this study suggest that performing an earlier additional bile duct flush with Marshall solution does not prevent biliary complications and bile duct injury., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Glyceollins, isoflavonoid-derived antimicrobial metabolites, are the major phytoalexins in soybean ( Glycine max ). They play essential roles in providing resistance to the soil-borne pathogen Phytophthora sojae and have unconventional anticancer and neuroprotective activities that render them desirable for pharmaceutical development. Our previous studies revealed that the transcription factors GmMYB29A2 and GmNAC42-1 have essential roles in activating glyceollin biosynthesis, yet each cannot activate the transcription of all biosynthesis genes in the absence of a pathogen elicitor treatment. Here, we report that co-overexpressing both transcription factors is also insufficient to activate glyceollin biosynthesis. To understand this insufficiency, we compared the transcriptome profiles of hairy roots overexpressing each transcription factor with glyceollin-synthesizing roots treated with wall glucan elicitor (WGE) from P. sojae . GmMYB29A2 upregulated most of the WGE-regulated genes that encode enzymatic steps spanning from primary metabolism to the last step of glyceollin biosynthesis. By contrast, GmNAC42-1 upregulated glyceollin biosynthesis genes only when overexpressed in the presence of WGE treatment. This is consistent with our recent discovery that, in the absence of WGE, GmNAC42-1 is bound by GmJAZ1 proteins that inhibit its transactivation activity. WGE, and not GmMYB29A2 or GmNAC42-1, upregulated the heat shock family gene GmHSF6-1 , the homolog of Arabidopsis HSFB2a that directly activated the transcription of several glyceollin biosynthesis genes. Our results provide important insights into what biosynthesis genes will need to be upregulated to activate the entire glyceollin biosynthetic pathway.

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in the metabolism of folates and homocysteine, which in turn can affect gene expression and ultimately promote the development of breast cancer. Thus, mutations in the MTHFR gene could influence homocysteine, methionine, and S-adenosylmethionine levels and, indirectly, nucleotide levels. Imbalance in methionine and S-adenosylmethionine synthesis affects protein synthesis and methylation. These changes, which affect gene expression, may ultimately promote the development of breast cancer. We therefore hypothesized that such mutations could also play an important role in the occurrence and pathogenesis of breast cancer in a Malian population. In this study, we used the PCR-RFLP technique to identify the different genotypic profiles of the C677T MTHFR polymorphism in 127 breast cancer women and 160 healthy controls. The genotypic distribution of the C677T polymorphism in breast cancer cases was 88.2% for CC, 11.0% for CT, and 0.8% for TT. Healthy controls showed a similar distribution with 90.6% for CC, 8.8% for CT, and 0.6% for TT. We found no statistical association between the C677T polymorphism and breast cancer risk for the codominant models CT and TT ( p > 0.05). The same trend was observed when the analysis was extended to other genetic models, including dominant ( p  = 0.50), recessive ( p  = 0.87), and additive ( p  = 0.50) models. The C677T polymorphism of MTHFR gene did not influence the risk of breast cancer in the Malian samples., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Brehima Diakite et al.)

Brain PET adds value in diagnosing neurodegenerative disorders, especially frontotemporal dementia (FTD) due to its syndromic presentation that overlaps with a variety of other neurodegenerative and psychiatric disorders. 18F-FDG-PET has improved sensitivity and specificity compared with structural MR imaging, with optimal diagnostic results achieved when both techniques are utilized. PET demonstrates superior sensitivity compared with SPECT for FTD diagnosis that is primarily a supplement to other imaging and clinical evaluations. Tau-PET and amyloid-PET primary use in FTD diagnosis is differentiation from Alzheimer disease, although these methods are limited mainly to research settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Pulmonary autograft reinforcement to prevent dilatation and subsequent neo-aortic valve regurgitation has been reported; however, data on long-term function of the neo-aortic valve after this modified Ross procedure are lacking. Our objective here was to assess long-term outcomes of the modified Ross procedure with autograft reinforcement using the reimplantation technique., Patients: The outcomes of 61 consecutive patients managed using the Dacron-conduit reinforced Ross procedure between 2009 and 2021 were reviewed. Most patients had a unicuspid or bicuspid aortic valve (n = 52; 85%), predominant aortic valve regurgitation (n = 42; 77%), and >30 mm dilatation of the ascending aorta (n = 33; 54%). A prior aortic valve procedure was noted in 47 patients (77%) patients, including 38 (62%) with surgical repair and 9 (15%) with balloon dilatation. The pulmonary autograft was reimplanted within a Dacron conduit with a median diameter of 25.6 mm (range, 20-30 mm) using the David valve-sparing aortic root replacement technique., Results: All patients survived. The median age at surgery was 16.8 years (range, 6-38 years). Neo-aortic valve replacement was required in 3 patients (4.9%; 95% CI, 0.34%- 12.7%) because of infective endocarditis, left ventricular false aneurysm, and leaflet perforation, respectively; the repeat procedure was done early in 2 of these patients (2 of 61; 3%). Six patients required right ventricular outflow conduit replacement, 5 by surgery and 1 percutaneously. The median duration of follow-up was 90 months (range, 10-124 months). The 5- and 10-year rates of reintervention-free survival were 84.3% (95% CI, 74%-95%) and 81.6% (95% CI, 72%-93%), respectively, and 5-year survival without aortic reintervention was 94.5% (95% CI, 88%-100%), with little change at 10 years. No patients experienced deterioration of initial neo-aortic valve function (ie, regurgitation or stenosis)., Conclusions: Autograft reinforcement using the reimplantation technique allowed expansion of Ross procedure indications to all patients requiring aortic valve replacement and prevented neo-aortic root dilatation. Failures were uncommon. Long-term follow-up data showed stable neo-aortic valve function., (© 2023 The Authors.)

Objective: Neonatal cerebral hypoxia-ischemia (HI) results in symptomatic seizures and long-term neurodevelopmental disability. The Rice-Vannucci model of rodent neonatal HI has been used extensively to examine and translate the functional consequences of acute and chronic HI-induced encephalopathy. Yet, longitudinal electrophysiological characterization of this brain injury model has been limited by the size of the neonatal mouse's head and postnatal maternal dependency. We overcome this challenge by employing a novel method of longitudinal single-mouse electroencephalography (EEG) using chronically implanted subcranial electrodes in the term-equivalent mouse pup. We characterize the neurophysiological disturbances occurring during awake and sleep states in the acute and chronic phases following newborn brain injury., Methods: C57BL/6 mice underwent long-term bilateral subcranial EEG and electromyographic electrode placement at postnatal day 9 followed by unilateral carotid cauterization and exposure to 40 minutes of hypoxia the following day. EEG recordings were obtained prior, during, and intermittently after the HI procedure from postnatal day 10 to weaning age. Quantitative EEG and fast Fourier transform analysis were used to evaluate seizures, cortical cerebral dysfunction, and disturbances in vigilance states., Results: We observed neonatal HI-provoked electrographic focal and bilateral seizures during or immediately following global hypoxia and most commonly contralateral to the ischemic injury. Spontaneous chronic seizures were not seen. Injured mice developed long-term asymmetric EEG background attenuation in all frequencies and most prominently during non-rapid eye movement (NREM) sleep. HI mice also showed transient impairments in vigilance state duration and transitions during the first 2 days following injury., Significance: The functional burden of mouse neonatal HI recorded by EEG resembles closely that of the injured human newborn. The use of single-mouse longitudinal EEG in this immature model can advance our understanding of the developmental and pathophysiological mechanisms of neonatal cerebral injury and help translate novel therapeutic strategies against this devastating condition., (© 2022 International League Against Epilepsy.)

We previously developed a novel machine-learning-based brain age model that was sensitive to amyloid. We aimed to independently validate it and to demonstrate its utility using independent clinical data. We recruited 650 participants from South Korean memory clinics to undergo magnetic resonance imaging and clinical assessments. We employed a pretrained brain age model that used data from an independent set of largely Caucasian individuals (n = 757) who had no or relatively low levels of amyloid as confirmed by positron emission tomography (PET). We investigated the association between brain age residual and cognitive decline. We found that our pretrained brain age model was able to reliably estimate brain age (mean absolute error = 5.68 years, r(650) = 0.47, age range = 49-89 year) in the sample with 71 participants with subjective cognitive decline (SCD), 375 with mild cognitive impairment (MCI), and 204 with dementia. Greater brain age was associated with greater amyloid and worse cognitive function [Odds Ratio, (95% Confidence Interval {CI}): 1.28 (1.06-1.55), p = 0.030 for amyloid PET positivity; 2.52 (1.76-3.61), p < 0.001 for dementia]. Baseline brain age residual was predictive of future cognitive worsening even after adjusting for apolipoprotein E e4 and amyloid status [Hazard Ratio, (95% CI): 1.94 (1.33-2.81), p = 0.001 for total 336 follow-up sample; 2.31 (1.44-3.71), p = 0.001 for 284 subsample with baseline Clinical Dementia Rating ≤ 0.5; 2.40 (1.43-4.03), p = 0.001 for 240 subsample with baseline SCD or MCI]. In independent data set, these results replicate our previous findings using this model, which was able to delineate significant differences in brain age according to the diagnostic stages of dementia as well as amyloid deposition status. Brain age models may offer benefits in discriminating and tracking cognitive impairment in older adults., (© 2022. The Author(s).)