Increased utilization of the hybrid procedure is not associated with improved early survival for newborns with hypoplastic left heart syndrome: a single-centre experience.

OBJECTIVES: The primary objectives were to examine utilization of the Hybrid versus the Norwood procedure for patients with hypoplastic left heart syndrome or variants and the impact on hospital mortality. The Hybrid procedure was 1st used at our institution in 2004. METHODS: Review of all subjects undergoing the Norwood or Hybrid procedure between 1 January 1984 and 31 December 2022. The study period was divided into 8 eras: era 1, 1984-1988; era 2, 1989-1993; era 3, 1994-1998; era 4, 1999-2003; era 5, 2004-2008; era 6, 2009-2014; era 7, 2015-2018 and era 8, 2019-2022. The primary outcome was in-hospital mortality. Mortality rates were computed using standard binomial proportions with 95% confidence intervals. Rates across eras were compared using an ordered logistic regression model with and adjusted using the Tukey-Kramer post-hoc procedure for multiple comparisons. In the risk-modelling phase, logistic regression models were specified and tested. RESULTS: The Norwood procedure was performed in 1899 subjects, and the Hybrid procedure in 82 subjects. Use of the Hybrid procedure increased in each subsequent era, reaching 30% of subjects in era 8. After adjustment for multiple risk factors, use of the Hybrid procedure was significantly and positively associated with hospital mortality. CONCLUSIONS: Despite the increasing use of the Hybrid procedure, overall mortality for the entire cohort has plateaued. After adjustment for risk factors, use of the Hybrid procedure was significantly and positively associated with mortality compared to the Norwood procedure.

Hereditary haemorrhagic telangiectasia and SMAD4 mutation in a patient with complex single ventricle heart disease.

We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient's staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

Optically Active MXenes in Van der Waals Heterostructures.

The vertical integration of distinct 2D materials in van der Waals (vdW) heterostructures provides the opportunity for interface engineering and modulation of electronic as well as optical properties. However, scarce experimental studies reveal many challenges for vdW heterostructures, hampering the fine-tuning of their electronic and optical functionalities. Optically active MXenes, the most recent member of the 2D family, with excellent hydrophilicity, rich surface chemistry, and intriguing optical properties, are a novel 2D platform for optoelectronics applications. Coupling MXenes with various 2D materials into vdW heterostructures can open new avenues for the exploration of physical phenomena of novel quantum-confined nanostructures and devices. Therefore, the fundamental basis and recent findings in vertical vdW heterostructures composed of MXenes as a primary component and other 2D materials as secondary components are examined. Their robust designs and synthesis approaches that can push the boundaries of light-harvesting, transition, and utilization are discussed, since MXenes provide a unique playground for pursuing an extraordinary optical response or unusual light conversion features/functionalities. The recent findings are finally summarized, and a perspective for the future development of next-generation vdW multifunctional materials enriched by MXenes is provided.

Improved Ionic Transport Using a Novel Semiconductor Co0.6Mn0.4Fe0.4Al1.6O4 and Its Heterostructure with Zinc Oxide for Electrolyte Membrane in LT-CFCs.

Improving the ionic conductivity and slow oxygen reduction electro-catalytic activity of reactions occurring at low operating temperature would do wonders for the widespread use of low-operating temperature ceramic fuel cells (LT-CFCs; 450-550 °C). In this work, we present a novel semiconductor heterostructure composite made of a spinel-like structure of Co0.6Mn0.4Fe0.4Al1.6O4 (CMFA) and ZnO, which functions as an effective electrolyte membrane for solid oxide fuel cells. For enhanced fuel cell performance at sub-optimal temperatures, the CMFA-ZnO heterostructure composite was developed. We have shown that a button-sized SOFC fueled by H2 and ambient air can provide 835 mW/cm2 of power and 2216 mA/cm2 of current at 550 °C, possibly functioning down to 450 °C. In addition, the oxygen vacancy formation energy and activation energy of the CMFA-ZnO heterostructure composite is lower than those of the individual CMFA and ZnO, facilitating ion transit. The improved ionic conduction of the CMFA-ZnO heterostructure composite was investigated using several transmission and spectroscopic measures, including X-ray diffraction, photoelectron, and UV-visible spectroscopy, and density functional theory (DFT) calculations. These findings suggest that the heterostructure approach is practical for LT-SOFCs.

Reintervention for Superior Vena Cava Obstruction After Heart Transplant.

BACKGROUND: Children undergoing orthotopic heart transplant (OHT) may require complex reconstruction of superior vena cava (SVC) anomalies. SVC anatomy and mode of reconstruction are potential risk factors for SVC obstruction. METHODS: A retrospective single-center review was conducted of patients undergoing initial OHT between January 1, 1990, and July 1, 2021. Simple SVC anatomy included a single right SVC to the right atrium or bilateral SVCs with a left SVC to an intact coronary sinus, without prior superior cavopulmonary connection. Presence of anomalous SVC anatomy, superior cavopulmonary connection, or previous atrial switch operation defined complex anatomy. Reconstructive strategies included atrial anastomosis; direct SVC-to-SVC anastomosis; and augmented SVC anastomosis using innominate vein, patch, cavopulmonary connection, or interposition graft. The primary outcome was reintervention for SVC obstruction. RESULTS: Of 288 patients, pretransplant diagnoses included congenital heart disease (n = 155 [54%]), cardiomyopathy (n = 125 [43%]), and other (n = 8 [3%]). Most (n = 208 [72%]) had simple SVC anatomy compared with complex SVC anatomy (80 [28%]). Reintervention for SVC obstruction occurred in 15 of 80 (19%) with complex anatomy and 1 of 208 (0.5%) with simple anatomy (P = .0001). Reintervention was more common when innominate vein or a patch was used (9/25 [36%]) compared with an interposition graft (1/7 [14%]) or direct anastomosis (6/82 [7%]; χ2 = 13.1; P = .001). Most reinterventions occurred within 30 days of OHT (14/16 [88%]). CONCLUSIONS: Patients with complex SVC anatomy have a higher rate of reintervention for SVC obstruction after OHT compared with those with simple SVC anatomy. In cases of complex SVC anatomy, interposition grafts may be associated with less reintervention compared with complex reconstructions using donor tissue.

Representation-Influence Framework (RIF) for analyzing the roles of organized interest groups (OIGs) in environmental governance.

This paper outlines Representation-Influence Framework (RIF) for analyzing the roles of organized interest groups (OIGs) in environmental governance. This framework is created to check OIG claims as representatives of particular groups within society, to capture OIG diversity, including those acting beyond the pursuit of common interests. The development of this framework used two basic OIG roles-the extent of OIGs in representing group interests and exerting political influence on governments. This framework proposes three main categories of OIGs based on their claims as representatives of particular social groups, en route to fulfilling the claims, breaking the claims, and opposing the claims. Finally, this framework is able to present types of OIGs in environmental governance.•RIF is an applicable framework for analyzing the roles of organized interest groups•This framework proposes categories and types of OIGs based on the extent of their role-fulfillment in representing particular groups within society and exerting political influence on governments•This framework captures the actions of OIGs beyond the pursuit of common interests.

C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.

Epidural cerebellar stimulation drives widespread neural synchrony in the intact and stroke perilesional cortex.

BACKGROUND: Cerebellar electrical stimulation has shown promise in improving motor recovery post-stroke in both rodent and human studies. Past studies have used motor evoked potentials (MEPs) to evaluate how cerebellar stimulation modulates ongoing activity in the cortex, but the underlying mechanisms are incompletely understood. Here we used invasive electrophysiological recordings from the intact and stroke-injured rodent primary motor cortex (M1) to assess how epidural cerebellar stimulation modulates neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics. METHODS: We recorded single unit spiking and local field potentials (LFPs) in both the intact and acutely stroke-injured M1 contralateral to the stimulated cerebellum in adult Long-Evans rats under anesthesia. We analyzed changes in the firing rates of single units, the extent of synchronous spiking and power spectral density (PSD) changes in LFPs during and post-stimulation. RESULTS: Our results show that post-stimulation, the firing rates of a majority of M1 neurons changed significantly with respect to their baseline rates. These firing rate changes were diverse in character, as the firing rate of some neurons increased while others decreased. Additionally, these changes started to set in during stimulation. Furthermore, cross-correlation analysis showed a significant increase in coincident firing amongst neuronal pairs. Interestingly, this increase in synchrony was unrelated to the direction of firing rate change. We also found that neuronal ensembles derived through principal component analysis were more active post-stimulation. Lastly, these changes occurred without a significant change in the overall spectral power of LFPs post-stimulation. CONCLUSIONS: Our results show that cerebellar stimulation caused significant, long-lasting changes in the activity patterns of M1 neurons by altering firing rates, boosting neural synchrony and increasing neuronal assemblies' activation strength. Our study provides evidence that cerebellar stimulation can directly modulate cortical dynamics. Since these results are present in the perilesional cortex, our data might also help explain the facilitatory effects of cerebellar stimulation post-stroke.

Computational fluid dynamics modeling aiding surgical planning in a toddler with Parkes Weber syndrome.

Parkes Weber syndrome is a fast-flow and slow-flow vascular anomaly with limb overgrowth that can lead to congestive heart failure and limb ischemia. Current management strategies have focused on symptom management with focal embolization. A pediatric case with early onset heart failure is reported. We discuss the use of computational fluid dynamics (CFD) modeling to guide a surgical management strategy in a toddler with an MAP2K1 mutation.

C9orf72 in myeloid cells suppresses STING-induced inflammation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4-6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72-/- mice show marked early activation of the type I interferon response, and C9orf72-/- myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72-/- immune cells as well as splenomegaly and inflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.

The Biodegradation Role of Saccharomyces cerevisiae against Harmful Effects of Mycotoxin Contaminated Diets on Broiler Performance, Immunity Status, and Carcass characteristics.

A feeding trial (35 days) was carried out to investigate the effect of Saccharomyces cerevisiae cell wall as a mycotoxin biodegradation agent on the performance, feed efficiency, carcass traits, and immunity response against diseases in broilers fed aflatoxin B1 contaminated diets. For this purpose, 200 one day old broilers were randomly allotted into four groups, each with five replicates (10 birds per replicate). Four starter and finisher experimental rations were formulated by using (A) 0, (B) 1.25, (C) 2.5, and (D) 3.75 g kg-1 of Saccharomyces cerevisiae. Experimental diets were contaminated with aflatoxin B1 (100 ppb kg-1 diet). The experimental chicks were kept under standard managerial conditions, and the vaccination program was followed against infectious bursal disease (IBD), infectious bronchitis (IB), and Newcastle disease (ND) diseases. At the end of the feeding trial, carcass, organ weight, and blood samples were collected randomly to determine the carcass traits and antibody titer against ND and IBD viruses. Throughout the experiment, the addition of 3.75 g kg-1 of the Saccharomyces cerevisiae cell wall (Group-D) in feed resulted in the highest weight gain, final weight, feed intake, and the lowest FCR values followed by C group compared with the other groups. All carcass traits were significantly (p > 0.05) improved by increasing the inclusion levels of Saccharomyces cerevisiae in broiler diets. It could be concluded that the broiler diet supplemented with 2.5 or 3.75 g kg-1 of Saccharomyces cerevisiae as a biodegrading agent resulted in improved growth performance, immunity activity and carcass traits, and supplementation with Saccharomyces cerevisiae at these levels can be used effectively in broiler diets without negatively affecting bird health status.

Problem-method fit in forest policy analysis: Empirical pre-orientation for selecting tested or innovative social-qualitative methods.

An array of research methods has been employed for social-qualitative inquiries. However, the selection of specific research methods has rarely been given adequate attention. We mapped out the variety of research methods used in social-qualitative inquiries used in the study of forest policy. Our "problem-method fit" map is based on the usage quantity of a method employed in specific forest policy research themes and contextual analyses. Our map provides a suitable basis for rapid appraisal before deciding appropriate research methods for future studies. While the map provides only an indication of the appropriate methods, it may be supplemented and adapted case-by-case according to the specific needs of the research theme. •We mapped the commonly used research methods in forest policy analysis•The map is "problem-method fit" for specific policy themes and contextual analyses•It can be used as for rapid appraisal when choosing appropriate research methods.

Prevalence of Shigella boydii in Bangladesh: Isolation and Characterization of a Rare Phage MK-13 That Can Robustly Identify Shigellosis Caused by Shigella boydii Type 1.

Shigellosis, caused by Shigella boydii type 1, is understudied and underreported. For 3 years, GEMS study identified 5.4% of all Shigella as S. boydii. We showed the prevalent serotypes of S. boydii in Bangladesh and phage-based diagnosis of S. boydii type 1, a rapid and low-cost approach. Previously typed 793 clinical S. boydii strains were used for serotype distribution. Twenty-eight environmental water samples were collected for isolation of Shigella phages. Forty-eight serotypes of Shigella and other enteric bacteria were used for testing the susceptibility to phage MK-13. Electron microscopy, restriction enzyme analysis, whole genome sequencing (WGS), and annotation were performed for extensive characterization. S. boydii type 1 is the second most prevalent serotype among 20 serotypes of S. boydii in Bangladesh. We isolated a novel phage, MK-13, which specifically lyses S. boydii type 1, but doesn't lyse other 47 serotypes of Shigella or other enteric bacteria tested. The phage belongs to the Myoviridae family and distinct from other phages indicated by electron microscopy and restriction enzyme analysis, respectively. MK-13 genome consists of 158 kbp of circularly permuted double-stranded DNA with G + C content of 49.45%, and encodes 211 open reading frames including four tRNA-coding regions. The genome has 98% identity with previously reported phage, ΦSboM-AG3, reported to have a broader host range infecting most of the S. boydii and other species of Shigella tested. To our knowledge, MK-13 is the first phage reported to be used as a diagnostic marker to detect S. boydii type 1, especially in remote settings with limited laboratory infrastructure.

The bureaucratic politics of conservation in governing land conflict: A typology of capacities.

Recent land management policies around the world have experienced a broader political push to resolve forest and land tenure conflict through agrarian reform policy. As a result, conservation bureaucracies are responding with both formal and informal interventions to acknowledge the role of people in forests. In this methods paper, we provide a closer examination of the ways that conservation bureaucracies apply their political capacity in negotiating forest and land tenure conflicts. Our proposed method measures both the capacity and actions of conservation bureaucracies, combining formal dimensions (such as of legal status, budget availability, and the type of organization unit) with informal dimensions (including ways of gaining authority, donors and funding, and trust). The framing is rooted in theories of bureaucratic politics, and while culled from rich empirical experiences from Indonesia, the proposed method is also applicable in examining bureaucratic politics in other natural resource governance contexts. •We develop a method rooted in bureaucratic politics to measure the capacities of conservation agencies to manage forest land tenure conflict•The proposed typology guides forest and land use policy researchers to incorporate emergent governance issues such as land tenure reform into their assessments of changing conservation bureaucracies•The can be adapted for examination of bureaucratic capacities and actions in other contested natural resource contexts.

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model.

Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin.

Objective: To investigate transplantation of rat Schwann cells or human iPSC-derived neural crest cells and derivatives into models of acquired and inherited peripheral myelin damage. Methods: Primary cultured rat Schwann cells labeled with a fluorescent protein for monitoring at various times after transplantation. Human-induced pluripotent stem cells (iPSCs) were differentiated into neural crest stem cells, and subsequently toward a Schwann cell lineage via two different protocols. Cell types were characterized using flow cytometry, immunocytochemistry, and transcriptomics. Rat Schwann cells and human iPSC derivatives were transplanted into (1) nude rats pretreated with lysolecithin to induce demyelination or (2) a transgenic rat model of dysmyelination due to PMP22 overexpression. Results: Rat Schwann cells transplanted into sciatic nerves with either toxic demyelination or genetic dysmyelination engrafted successfully, and migrated longitudinally for relatively long distances, with more limited axial migration. Transplanted Schwann cells engaged existing axons and displaced dysfunctional Schwann cells to form normal-appearing myelin. Human iPSC-derived neural crest stem cells and their derivatives shared similar engraftment and migration characteristics to rat Schwann cells after transplantation, but did not further differentiate into Schwann cells or form myelin. Interpretation: These results indicate that cultured Schwann cells surgically delivered to peripheral nerve can engraft and form myelin in either acquired or inherited myelin injury, as proof of concept for pursuing cell therapy for diseases of peripheral nerve. However, lack of reliable technology for generating human iPSC-derived Schwann cells for transplantation therapy remains a barrier in the field.

C9orf72 is required for proper macrophage and microglial function in mice.

Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.

C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD.

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.

Lentiviral-induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H.

In human gliomas, the RTK/RAS/PI(3)K signaling pathway is nearly always altered. We present a model of experimental gliomagenesis that elucidates the contributions of genes involved in this pathway (PDGF-B ligand, HRAS-G12V, and AKT). We also examine the effect on gliomagenesis by the potential modifier gene, IDH1-R132H. Injections of lentiviral-encoded oncogenes induce de novo gliomas of varying penetrance, tumor progression, and histological grade depending on the specific oncogenes used. Our model mimics hallmark histological structures of high-grade glioma, such as pseudopalisades, glomeruloid microvascular proliferation, and diffuse tumor invasion. We use our model of gliomagenesis to test the efficacy of an experimental brain tumor gene therapy. Our model allowed us to test the contributions of oncogenes in the RTK/RAS/PI(3)K pathway, and their potential modification by over-expression of mutated IDH1, in glioma development and progression in rats. Our model constitutes a clinically relevant system to study gliomagenesis, the effects of modifier genes, and the efficacy of experimental therapeutics.