Endoscopic assessment of the J pouch in ulcerative colitis: A narrative review.

Patients with ulcerative colitis sometimes need a total colectomy with ileal pouch-anal anastomosis due to medically refractory disease or colitis-associated neoplasia. Up to 50% of patients with ulcerative colitis postoperatively develop pouchitis and the rate of chronic inflammatory pouch conditions requiring pouch excision or diverting ileostomy is reported to be 10%. In order to diagnose and monitor pouchitis, pouchoscopy is essential to assess endoscopic inflammatory findings of the J pouch and to survey neoplasia development, particularly in the remnant distal rectum. However, endoscopic protocols for the evaluation of the pouch may not be standardized worldwide and the reliability of existing disease activity indices for pouchitis has been questioned due to the lack of validation. Recently, reliable endoscopic scoring systems based on an observation of the anatomical location of the J pouch were reported and a significant association between the distribution pattern of endoscopic inflammation (i.e., endoscopic phenotype) and pouch outcomes was also uncovered. In this review, we discuss how to survey the J pouch using pouchoscopy, endoscopic indices for pouchitis disease activity, endoscopic phenotypes and classification, and the pathological mechanisms of pouchitis phenotype in patients with ulcerative colitis.

Stem Cell-Based Acellular Therapy: Insight into Biogenesis, Bioengineering and Therapeutic Applications of Exosomes.

The vast regenerative potential of stem cells has laid the foundation for stem cell-based therapies. However, certain challenges limit the application of cell-based therapies. The therapeutic use of cell-free therapy can avoid limitations associated with cell-based therapies. Acellular stem cell-based therapies rely on the use of biological factors released by stem cells, including growth factors and extracellular vesicles such as exosomes. Due to their comparable regenerative potential, acellular therapies may provide a feasible and scalable alternative to stem cell-based therapies. Exosomes are small vesicles secreted by various types of cells, including stem cells. Exosomes contain parent cell-derived nucleic acids, proteins, lipids, and other bioactive molecules. They play an important role in intra-cellular communication and influence the biological characteristics of cells. Exosomes inherit the properties of their parent cells; therefore, stem cell-derived exosomes are of particular interest for applications of regenerative medicine. In comparison to stem cell-based therapy, exosome therapy offers several benefits, such as easy transport and storage, no risk of immunological rejection, and few ethical dilemmas. Unlike stem cells, exosomes can be lyophilized and stored off-the-shelf, making acellular therapies standardized and more accessible while reducing overall treatment costs. Exosome-based acellular treatments are therefore readily available for applications in patients at the time of care. The current review discusses the use of exosomes as an acellular therapy. The review explores the molecular mechanism of exosome biogenesis, various methods for exosome isolation, and characterization. In addition, the latest advancements in bioengineering techniques to enhance exosome potential for acellular therapies have been discussed. The challenges in the use of exosomes as well as their diverse applications for the diagnosis and treatment of diseases have been reviewed in detail.

Validation and performance of the sleep inertia questionnaire in central disorders of hypersomnolence.

BACKGROUND: Optimal measurement tools for problematic sleep inertia, common in some central disorders of hypersomnolence (CDH), have not yet been determined. We evaluated the performance of the Sleep Inertia Questionnaire (SIQ) in CDH, and how well it distinguished hypersomnolent groups from controls, and IH (idiopathic hypersomnia) from narcolepsy type 1 (NT1). METHODS: This prospective, bi-centric study included 63 control, 84 IH, 16 NT1, 18 narcolepsy type 2 (NT2), and 88 subjective excessive daytime sleepiness (sEDS) participants, using ICSD-3 criteria. 126 (47.2 %) participants were on any medication at the time of SIQ completion. We assessed construct validity of SIQ scores, and sleep inertia duration (SID), and compared them across diagnoses, controlling for age and center. We derived cutpoints to distinguish hypersomnolent patients from controls and IH from NT1. Sensitivity analyses for depression, chronotype, and medication were performed. RESULTS: The SIQ sum and composite score were significantly lower in controls than in other groups (p < 0.0001), demonstrating outstanding ability to distinguish patients from controls (AUCs 0.92), without differences among hypersomnolent groups. SID (AUC 0.76) was significantly shorter in controls than in all hypersomnolent groups except NT1, and was shorter in NT1 than in IH or sEDS. Optimal SIQ sum cutpoint was 42 (J = 0.71) for patients versus controls. Optimal SID cutpoint in distinguishing IH from NT1 was 25 min (J = 0.39). CONCLUSION: The SIQ has excellent ability to distinguish hypersomnolent patients from healthy controls, after controlling for depression, eveningness, and medication. SID is best at distinguishing IH from NT1.

Deployment expectations of multi-gigatonne scale carbon removal could have adverse impacts on Asia's energy-water-land nexus.

Existing studies indicate that future global carbon dioxide (CO2) removal (CDR) efforts could largely be concentrated in Asia. However, there is limited understanding of how individual Asian countries and regions will respond to varying and uncertain scales of future CDR concerning their energy-land-water system. We address this gap by modeling various levels of CDR-reliant pathways under climate change ambitions in Asia. We find that high CDR reliance leads to residual fossil fuel and industry emissions of about 8 Gigatonnes CO2yr-1 (GtCO2yr-1) by 2050, compared to less than 1 GtCO2yr-1 under moderate-to-low CDR reliance. Moreover, expectations of multi-gigatonne CDR could delay the achievement of domestic net zero CO2 emissions for several Asian countries and regions, and lead to higher land allocation and fertilizer demand for bioenergy crop cultivation. Here, we show that Asian countries and regions should prioritize emission reduction strategies while capitalizing on the advantages of carbon removal when it is most viable.

Quantifying Replication Slippage Error in Cryptosporidium Metabarcoding Studies.

Genetic variation in Cryptosporidium, a common protozoan gut parasite in humans, is often based on marker genes containing trinucleotide repeats, which differentiate subtypes and track outbreaks. However, repeat regions have high replication slippage rates, making it difficult to discern biological diversity from error. Here, we synthesized Cryptosporidium DNA in clonal plasmid vectors, amplified them in different mock community ratios, and sequenced them using next-generation sequencing to determine the rate of replication slippage with dada2. Our results indicate that slippage rates increase with the length of the repeat region and can contribute to error rates of up to 20%.

Impact of infectious diseases on wild bovidae populations in Thailand: insights from population modelling and disease dynamics.

The wildlife and livestock interface is vital for wildlife conservation and habitat management. Infectious diseases maintained by domestic species may impact threatened species such as Asian bovids, as they share natural resources and habitats. To predict the population impact of infectious diseases with different traits, we used stochastic mathematical models to simulate the population dynamics over 100 years for 100 times in a model gaur (Bos gaurus) population with and without disease. We simulated repeated introductions from a reservoir, such as domestic cattle. We selected six bovine infectious diseases; anthrax, bovine tuberculosis, haemorrhagic septicaemia, lumpy skin disease, foot and mouth disease and brucellosis, all of which have caused outbreaks in wildlife populations. From a starting population of 300, the disease-free population increased by an average of 228% over 100 years. Brucellosis with frequency-dependent transmission showed the highest average population declines (-97%), with population extinction occurring 16% of the time. Foot and mouth disease with frequency-dependent transmission showed the lowest impact, with an average population increase of 200%. Overall, acute infections with very high or low fatality had the lowest impact, whereas chronic infections produced the greatest population decline. These results may help disease management and surveillance strategies support wildlife conservation.

Impact of Age of Heart Transplant Program on Patient Survival and Post-Transplant Outcomes.

BACKGROUND: The relationship between age of a heart transplant (HT) program and outcomes has not been explored. METHODS: We performed a retrospective cohort analysis of the United Network for Organ Sharing database of all adult HTs between 2009 and 2019. For each patient, we created a variable that corresponded to program age: new (<5), developing (≥5 but <10) and established (≥10) years. RESULTS: Of 20 997 HTs, 822 were at new, 908 at developing, and 19 267 at established programs. Patients at new programs were significantly more likely to have history of cigarette smoking, ischemic cardiomyopathy, and prior sternotomy. These programs were less likely to accept organs from older donors and those with a history of hypertension or cigarette use. As compared to patients at new programs, transplant patients at established programs had less frequent rates of treated rejection during the index hospitalization (HR 0.43 [95% CI, 0.36-0.53] p < 0.001) and at 1 year (HR 0.58 [95% CI, 0.49-0.70], p < 0.001), less frequently required pacemaker implantations (HR 0.50 [95% CI, 0.36-0.69], p < 0.001), and less frequently required dialysis (HR 0.66 [95% CI, 0.53-0.82], p < 0.001). However, there were no significant differences in short- or long-term survival between the groups (log-rank p = 0.24). CONCLUSION: Patient and donor selection differed between new, developing, and established HT programs but had equivalent survival. New programs had increased likelihood of treated rejection, pacemaker implantation, and need for dialysis. Standardized post-transplant practices may help to minimize this variation and ensure optimal outcomes for all patients.

Antibiotic pharmacokinetics in infected pleural effusions.

Pleural infection is usually treated with empirical broad-spectrum antibiotics, but limited data exist on their penetrance into the infected pleural space. We performed a pharmacokinetic study analysing the concentration of five intravenous antibiotics across 146 separate time points in 35 patients (amoxicillin, metronidazole, piperacillin-tazobactam, clindamycin and cotrimoxazole). All antibiotics tested, apart from co-trimoxazole, reach pleural fluid levels equivalent to levels within the blood and well above the relevant minimum inhibitory concentrations. The results demonstrate that concerns about the penetration of commonly used antibiotics, apart from co-trimoxazole, into the infected pleural space are unfounded.

Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children.

Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.

Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome.

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

Maternal gestational diabetes mellitus associates with altered gut microbiome composition and head circumference abnormalities in male offspring.

The impact of gestational diabetes mellitus (GDM) on maternal or infant microbiome trajectory remains poorly understood. Utilizing large-scale longitudinal fecal samples from 264 mother-baby dyads, we present the gut microbiome trajectory of the mothers throughout pregnancy and infants during the first year of life. GDM mothers had a distinct microbiome diversity and composition during the gestation period. GDM leaves fingerprints on the infant's gut microbiome, which are confounded by delivery mode. Further, Clostridium species positively correlate with a larger head circumference at month 12 in male offspring but not females. The gut microbiome of GDM mothers with male fetuses displays depleted gut-brain modules, including acetate synthesis I and degradation and glutamate synthesis II. The gut microbiome of female infants of GDM mothers has higher histamine degradation and dopamine degradation. Together, our integrative analysis indicates that GDM affects maternal and infant gut composition, which is associated with sexually dimorphic infant head growth.

Universal Measurement-Based Quantum Computation in a One-Dimensional Architecture Enabled by Dual-Unitary Circuits.

A powerful tool emerging from the study of many-body quantum dynamics is that of dual-unitary circuits, which are unitary even when read "sideways," i.e., along the spatial direction. Here, we show that this provides the ideal framework to understand and expand on the notion of measurement-based quantum computation (MBQC). In particular, applying a dual-unitary circuit to a many-body state followed by appropriate measurements effectively implements quantum computation in the spatial direction. We show how the dual-unitary dynamics generated by the dynamics of the paradigmatic one-dimensional kicked Ising chain with certain parameter choices generate resource states for universal deterministic MBQC. Specifically, after k time steps, equivalent to a depth-k quantum circuit, we obtain a resource state for universal MBQC on ∼3k/4 encoded qubits. Our protocol allows generic quantum circuits to be "rotated" in space-time and gives new ways to exchange between resources like qubit number and coherence time in quantum computers. Beyond the practical advantages, we also interpret the dual-unitary evolution as generating an infinite sequence of new symmetry-protected topological phases with spatially modulated symmetries, which gives a vast generalization of the well-studied one-dimensional cluster state and shows that our protocol is robust to symmetry-respecting deformations.

Clinical Utility of the Molecular Microscope Diagnostic System in a Real-World Transplant Cohort: Moving Towards a New Paradigm.

Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx ) of biopsy specimens in heart transplant (HT ) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis.

Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

Advocating for the inclusion of kidney health outcomes in neonatal research: best practice recommendations by the Neonatal Kidney Collaborative.

Acute kidney injury (AKI) occurs in nearly 30% of sick neonates. Chronic kidney disease (CKD) can be detected in certain populations of sick neonates as early as 2 years. AKI is often part of a multisystem syndrome that negatively impacts developing organs resulting in short- and long-term pulmonary, neurodevelopmental, and cardiovascular morbidities. It is critical to incorporate kidney-related data into neonatal clinical trials in a uniform manner to better understand how neonatal AKI or CKD could affect an outcome of interest. Here, we provide expert opinion recommendations and rationales to support the inclusion of short- and long-term neonatal kidney outcomes using a tiered approach based on study design: (1) observational studies (prospective or retrospective) limited to data available within a center's standard practice, (2) observational studies involving prospective data collection where prespecified kidney outcomes are included in the design, (3) interventional studies with non-nephrotoxic agents, and (4) interventional studies with known nephrotoxic agents. We also provide recommendations for biospecimen collection to facilitate ancillary kidney specific research initiatives. This approach balances the costs of AKI and CKD ascertainment with knowledge gained. We advocate that kidney outcomes be included routinely in neonatal clinical study design. Consistent incorporation of kidney outcomes across studies will increase our knowledge of neonatal morbidity.

An evaluation of the outcomes associated with peritoneal catheter use in neonates undergoing cardiac surgery: A multicenter study.

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score-matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.