Inflammatory Bowel Disease-Associated Arthritis Is Associated with Concomitant Autoimmune and Inflammatory Disorders.

BACKGROUND: Extraintestinal Manifestations (EIMs) are a common and potentially debilitating complication of Inflammatory Bowel Diseases (IBD), sometimes requiring additional treatment beyond those used to control intestinal disease. IBD-associated arthritis (IAA), a form of spondyloarthritis, is associated with several factors including disease location, sex, and IBD type. However, much remains unknown about other clinical factors predicting development of EIMs. Our goal was to identify additional factors associated with IAA. METHODS: Participants in the LOCATION-IBD cohort were included in this analysis. We performed univariate and multivariate analysis of demographics, clinical data, and patient-reported outcomes data. RESULTS: The LOCATION-IBD cohort included 182 participants with (n = 53) and without (n = 110) joint EIMs and with joint pain of unclear etiology (n = 19). In a multivariate analysis comparing those with and without joint EIMs, female sex (OR = 2.5, p = 0.014), the presence of concomitant autoimmune and inflammatory disorders (OR = 2.5, p = 0.038), and Crohn's disease (OR = 2.9, p = 0.026) were associated with the presence of joint EIMs. CONCLUSION: This analysis reveals patients with IAA are more likely to have concomitant autoimmune disorders. Further studies are needed to confirm this association, understand the mechanisms underlying the common pathogenesis of these concurrent disorders, and evaluate their impact on the treatment of IAA.

Artificial intelligence-enhanced electrocardiography derived body mass index as a predictor of future cardiometabolic disease.

The electrocardiogram (ECG) can capture obesity-related cardiac changes. Artificial intelligence-enhanced ECG (AI-ECG) can identify subclinical disease. We trained an AI-ECG model to predict body mass index (BMI) from the ECG alone. Developed from 512,950 12-lead ECGs from the Beth Israel Deaconess Medical Center (BIDMC), a secondary care cohort, and validated on UK Biobank (UKB) (n = 42,386), the model achieved a Pearson correlation coefficient (r) of 0.65 and 0.62, and an R2 of 0.43 and 0.39 in the BIDMC cohort and UK Biobank, respectively for AI-ECG BMI vs. measured BMI. We found delta-BMI, the difference between measured BMI and AI-ECG-predicted BMI (AI-ECG-BMI), to be a biomarker of cardiometabolic health. The top tertile of delta-BMI showed increased risk of future cardiometabolic disease (BIDMC: HR 1.15, p < 0.001; UKB: HR 1.58, p < 0.001) and diabetes mellitus (BIDMC: HR 1.25, p < 0.001; UKB: HR 2.28, p < 0.001) after adjusting for covariates including measured BMI. Significant enhancements in model fit, reclassification and improvements in discriminatory power were observed with the inclusion of delta-BMI in both cohorts. Phenotypic profiling highlighted associations between delta-BMI and cardiometabolic diseases, anthropometric measures of truncal obesity, and pericardial fat mass. Metabolic and proteomic profiling associates delta-BMI positively with valine, lipids in small HDL, syntaxin-3, and carnosine dipeptidase 1, and inversely with glutamine, glycine, colipase, and adiponectin. A genome-wide association study revealed associations with regulators of cardiovascular/metabolic traits, including SCN10A, SCN5A, EXOG and RXRG. In summary, our AI-ECG-BMI model accurately predicts BMI and introduces delta-BMI as a non-invasive biomarker for cardiometabolic risk stratification.

Increased inflammasome protein expression identified in microglia from postmortem brains with schizophrenia.

Schizophrenia (SCZ) is a complex psychiatric disorder that involves an inflammatory response thought to be characterized by microglial activation. The inflammasome complex may play critical roles in the pathomechanism of neuroinflammation but how this relates to SCZ remains unclear. In this study, we performed an immunohistochemical (IHC) analysis to compare the expression of inflammasome proteins in brain tissue from donors with SCZ (n = 16) and non-psychiatric donors (NP; n = 13) isolated from the superior frontal cortex (SFC), superior temporal cortex, and anterior cingulate cortex brain regions. To assess changes in the cell populations that express key inflammasome proteins, we performed IHC analyses of apoptosis-associated speck-like protein containing a CARD (ASC), nod-like receptor protein 3 (NLRP3), and interleukin (IL)-18 to determine if these proteins are expressed in microglia, astrocytes, oligodendrocytes, or neurons. Inflammasome proteins were expressed mainly in microglia from SCZ and NP brains. Increased numbers of microglia were present in the SFC of SCZ brains and exhibited higher inflammasome protein expression of ASC, NLRP3, and IL-18 compared to NPs. These findings suggest that increased inflammasome signaling may contribute to the pathology underlying SCZ.

Biobased short chain fatty acid production - Exploring microbial community dynamics and metabolic networks through kinetic and microbial modeling approaches.

In recent years, there has been growing interest in harnessing anaerobic digestion technology for resource recovery from waste streams. This approach has evolved beyond its traditional role in energy generation to encompass the production of valuable carboxylic acids, especially volatile fatty acids (VFAs) like acetic acid, propionic acid, and butyric acid. VFAs hold great potential for various industries and biobased applications due to their versatile properties. Despite increasing global demand, over 90% of VFAs are currently produced synthetically from petrochemicals. Realizing the potential of large-scale biobased VFA production from waste streams offers significant eco-friendly opportunities but comes with several key challenges. These include low VFA production yields, unstable acid compositions, complex and expensive purification methods, and post-processing needs. Among these, production yield and acid composition stand out as the most critical obstacles impacting economic viability and competitiveness. This paper seeks to offer a comprehensive view of combining complementary modeling approaches, including kinetic and microbial modeling, to understand the workings of microbial communities and metabolic pathways in VFA production, enhance production efficiency, and regulate acid profiles through the integration of omics and bioreactor data.

Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer's disease.

Introduction: Severity and distribution of aggregated tau and neurofibrillary tangles (NFT) are strongly correlated with the clinical presentation of Alzheimer's disease (AD). Clearance of aggregated tau could decrease the rate of NFT formation and delay AD onset. Recent studies implicate corpora amylacea (CA) as a regulator of onset or accumulation of tau pathology. Normally, CA clear brain waste products by amassing cellular debris, which are then extruded into the cerebrospinal fluid to be phagocytosed. The proper functioning of CA may slow progression of AD-associated NFT pathology, and this relationship may be influenced by amount and distribution of phospho-tau (pTau) produced, age, sex, and genetic risk. Objective: The goal of this study was to determine if CA size and number are associated with hippocampal location and local pTau severity while accounting for variations in age, sex, and genetic risk. Methods: Postmortem brain hippocampal tissue sections from 40 AD and 38 unaffected donors were immunohistochemically stained with AT8 (pTau) and counter stained with periodic acid Schiff (PAS). Stained sections of the CA1 and CA3 regions of the hippocampus were analyzed. The percent area occupied (%AO) of CA, pTau, and NFT was calculated. Pairwise comparisons and regression modeling were used to analyze the influence of age, pTau %AO, and genetic risk on %AO by CA in each region, separately in donors with AD and unaffected donors. Results: CA %AO was significantly higher in the CA3 region compared to CA1 in both groups. A significant negative correlation of CA %AO with both pTau %AO and neurofibrillary tangle %AO in the CA3 region of AD brain donors was found. Regression analysis in the CA3 region revealed a significant negative association between CA with both pTau and age. Conclusion: We found an increase of CA in the CA3 region, compared to CA1 region, in AD and unaffected donors. This may suggest that the CA3 region is a hub for waste removal. Additionally, the negative correlation between %AO by CA and NFT in the CA3 region of the hippocampus in donors with AD suggests CA could play a role in AD pathologic progression by influencing tau clearance.

Inpatient education reduces length of outpatient oxygen therapy in bronchopulmonary dysplasia: A quality improvement project.

BACKGROUND: Patients discharged on home oxygen therapy (HOT) for bronchopulmonary dysplasia (BPD) often receive months of this therapy. A previous trial comparing two methods of HOT weaning showed that increased parent involvement in HOT weaning decreased HOT duration. Our outpatient team uses a standard protocol for outpatient HOT weaning, starting at the first clinic visit 4-6 weeks after discharge. AIM: To shorten HOT duration by teaching parents the outpatient HOT weaning process before neonatal intensive care unit (NICU) discharge. METHODS: We launched a quality improvement program in April 2021 for preterm infants with BPD without significant comorbidities who were stable on ≤0.5 L nasal cannula. Eligible infants started the outpatient HOT weaning protocol while inpatient, with education for parents and nurses. The outcome measure was the duration of HOT after discharge. Process measures focused on protocol adherence. Balancing measures included NICU length of stay and appropriateness of parent-directed HOT weaning. RESULTS: During the study period, there were a total of 133 eligible patients discharged on home oxygen, with 75 in the baseline group and 58 in the intervention group. Forty-five (78%) participated in the HOT weaning protocol while inpatient. HOT was reduced from an average of 27 to 12 weeks after May 2021. We observed no change in NICU length of stay or inappropriate HOT weaning. CONCLUSION: Early introduction of HOT weaning with a focus on caregiver education is associated with a decreased duration of HOT.

ExpLOring the role of the intestinal MiCrobiome in InflammATory bowel disease-AssocIated SpONdylarthritis (LOCATION-IBD).

Background: Inflammatory Bowel Disease (IBD)-associated arthritis is a frequent and potentially debilitating complication of IBD, that can affect those with or without active intestinal disease, and is often difficult to treat. The microbiome is known to play a role in IBD development and has been shown to be associated with inflammatory arthritis without concomitant IBD, but its role in IBD-associated arthritis is still unexplored. Further, disease localization is associated with development of IBD-associated arthritis, and stool compositional profiles are predictive of disease localization, yet mucosal location-specific microbiomes have not been well characterized. To address this gap in understanding, we designed a study (LOCATION-IBD) to characterize the mucosa-associated intestinal microbiome and metabolome in IBD-associated arthritis. Methods: Adults with an established diagnosis of IBD undergoing clinical colonoscopy between May of 2021 and February of 2023 were invited to participate in this study; those interested in participation who met inclusion criteria were enrolled. Prior to enrollment, participants were stratified into those with or without IBD-associated arthritis. All participants were interviewed and had clinical and demographic data collected, and 97.8% completed clinical colonoscopy with biopsy collection. Results and conclusion: A total of 182 participants, 53 with confirmed IBD-associated arthritis, were enrolled in this study, resulting in 1151 biopsies obtained for microbiome and metabolome analysis (median 6, mean 6.3 per participant). Clinical and demographic data obtained from the study population will be analyzed with microbiome and metabolome data obtained from biopsies, with the goal of better understanding the mechanisms underpinning the host-microbiome relationship associated the development of IBD-associated arthritis.

Digest: A sex chromosome driver without a sperm deficit.

Meiotic drivers that act during spermatogenesis derive a transmission advantage by disabling sperm that do not carry the driver, often leading to substantially reduced overall sperm number and function. A new study by Bates et al. shows no sperm deficit for a driver in a stalk-eyed fly, in contrast to a related species. This observed sperm compensation is possibly due to secondary testes-expanding mutations linked to the driving genomic locus.

Digest: Mating systems, intragenomic conflict, and speciation.

Conflict over the degree of maternal investment in an offspring can exist between an offspring's maternally inherited and paternally inherited alleles. Such conflict is not expected under self-fertilization. A new study led by Rifkin and Ostevik suggests that divergence in the degree of conflict between closely related outcrossing and selfing species can lead to aberrant early development of hybrids in morning glories. This dynamic represents a potentially powerful driver of reproductive incompatibility and thus speciation.

Digest: Rare male offspring highlight an alternative pathway to obligate asexuality.

Obligate asexuality has arisen many times in eukaryotes, often related to the disrupted function of the core meiotic machinery. For obligately asexual lineages that evolve from facultatively asexual ancestors, there exists another possibility, namely altered regulation of preexisting asexual reproductive processes to produce obligate asexuality. These different pathways leave different signatures in properties of meiosis and recombination that could provide insights into the origin of asexuality. A new study by Molinier et al. (2023) investigates this problem and finds largely typical recombination rates during spermatogenesis of rare, asexually produced sons of obligately asexual Daphnia pulex, suggesting that regulation of reproduction, rather than disruption of meiosis, underpins obligate asexuality in Daphnia.

Opportunities for healthcare digitalization in Europe: Comparative analysis of inequalities in access to medical services.

Digitalization of healthcare systems is a great opportunity to address inequalities in access to healthcare in the European Union. There is an urgent need to build on what we learned from the COVID-19 pandemic, where digital health technologies were integrated swiftly to limit challenges in healthcare delivery. We created a database for the 27 European Union countries from the European Health Interview Survey (EHIS), the Digital Economy and Society Index (DESI), and other Eurostat databases. We performed k-means cluster analysis to group EU countries along two dimensions: inequalities in access to medical services and level of digitalization. We identified five distinct clusters: two clusters with high, two clusters with moderate, and one cluster with low unmet need for healthcare. Regarding digitalization, only one cluster comprising the Nordic countries, Spain and Cyprus exhibit high digital readiness. A cluster comprising the most developed countries in Western Europe represents moderate levels of both unmet need for healthcare and digitalization. For most EU countries, there is still a need to build digital infrastructure for the healthcare industry, which in the long term may increase the number of digital solutions used by both patients and healthcare professionals. Policy makers across the EU need to consider investing in initiatives that would support digital health solutions as an effective means of healthcare provision and healthcare management.

Clinical course and therapeutic trial for a case of congenital secretory diarrhea due to novel GUCY2C variant.

Chronic diarrhea presents a significant challenge for managing nutritional and electrolyte deficiencies, especially in children, given the higher stakes of impacting growth and developmental consequence. Congenital secretory diarrhea (CSD) compounds this further, particularly in the case of the activating variants of the guanylate-cyclase 2C (GUCY2C) gene. GUCY2C encodes for the guanylate-cyclase 2C (GC-C) receptor that activates the downstream cystic fibrosis transmembrane receptor (CFTR) that primarily drives the severity of diarrhea with an unclear extent of influence on other intestinal channels. Thus far, management for CSD primarily consists of mitigating nutritional, electrolyte, and volume deficiencies with no known pathophysiology-driven treatments. For activating variants of GUCY2C, experimental compounds have shown efficacy in vitro for direct inhibition of GC-C but are not currently available for clinical use. However, Crofelemer, a CFTR inhibitory modulator with negligible systemic absorption, can theoretically help to treat this type of CSD. Herein, we describe and characterize the clinical course of a premature male infant with a de novo missense variant of GUCY2C not previously reported and highly consistent with CSD. With multi-disciplinary family-directed decision-making, a treatment for CSD was evaluated for the first time to our knowledge with Crofelemer.

Increasing the versatility of the biphenyl-fused-dioxacyclodecyne class of strained alkynes.

Biphenyl-fused-dioxacyclodecynes are a promising class of strained alkyne for use in Cu-free 'click' reactions. In this paper, a series of functionalised derivatives of this class of reagent, containing fluorescent groups, are described. Studies aimed at understanding and increasing the reactivity of the alkynes are also presented, together with an investigation of the bioconjugation of the reagents with an azide-labelled protein.

Health-Related Quality of Life for Parents of Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: To determine how bronchopulmonary dysplasia (BPD) affects health-related quality of life (HRQL) among infants from NICU hospitalization through 1-year postdischarge. STUDY DESIGN: This was a prospective cohort study of infants with BPD and their parents. Parent HRQL was measured with the PedsQL Family Impact Module before NICU discharge and 3- and 12-months post-discharge. At 12 months, parent-reported child health outcomes included questions from the Test of Respiratory and Asthma Control in Kids, Warner Initial Developmental Evaluation of Adaptive and Functional Skills, and National Survey of Children with Special Health Care Needs. HRQL change over time was assessed by multivariable linear regression. RESULTS: Of 145 dyads, 129 (89%) completed 3-month follow-up, and 113 (78%) completed 12-month follow-up. In the NICU, lower HRQL was associated with earlier gestational age, postnatal corticosteroids, outborn status, and gastrostomy tubes. At 3 months, lower HRQL was associated with readmissions and home oxygen use. At 12 months, lower HRQL was associated with parent-reported difficulty breathing, lower developmental scores, and not playing with other children. At 3 and 12 months, 81% of parents reported similar or improved HRQL compared with the NICU period. Parents reporting infant respiratory symptoms experienced less improvement. CONCLUSIONS: BPD affects parent HRQL over the first year. Most parents report similar or better HRQL after discharge compared with the NICU stay. Less improvement is reported by parents of infants experiencing respiratory symptoms at 12 months. Efforts to improve parent HRQL should target respiratory symptoms and social isolation.

A monomeric StayGold fluorescent protein.

StayGold is an exceptionally bright and stable fluorescent protein that is highly resistant to photobleaching. Despite favorable fluorescence properties, use of StayGold as a fluorescent tag is limited because it forms a natural dimer. Here we report the 1.6 Å structure of StayGold and generate a derivative, mStayGold, that retains the brightness and photostability of the original protein while being fully monomeric.

Did the creeping vole sex chromosomes evolve through a cascade of adaptive responses to a selfish x chromosome?

The creeping vole Microtus oregoni exhibits remarkably transformed sex chromosome biology, with complete chromosome drive/drag, X-Y fusions, sex reversed X complements, biased X inactivation, and X chromosome degradation. Beginning with a selfish X chromosome, I propose a series of adaptations leading to this system, each compensating for deleterious consequences of the preceding adaptation: (1) YY embryonic inviability favored evolution of a selfish feminizing X chromosome; (2) the consequent Y chromosome transmission disadvantage favored X-Y fusion ("XP "); (3) Xist-based silencing of Y-derived XP genes favored a second X-Y fusion ("XM "); (4) X chromosome dosage-related costs in XP XM males favored the evolution of XM loss during spermatogenesis; (5) X chromosomal dosage-related costs in XM 0 females favored the evolution of XM drive during oogenesis; and (6) degradation of the non-recombining XP favored the evolution of biased X chromosome inactivation. I discuss recurrent rodent sex chromosome transformation, and selfish genes as a constructive force in evolution.

The Relevance of Advanced Therapy Medicinal Products in the Field of Transplantation and the Need for Academic Research Access: Overcoming Bottlenecks and Claiming a New Time.

The field of transplantation has witnessed the emergence of Advanced Therapy Medicinal Products (ATMPs) as highly promising solutions to address the challenges associated with organ and tissue transplantation. ATMPs encompass gene therapy, cell therapy, and tissue-engineered products, hold immense potential for breakthroughs in overcoming the obstacles of rejection and the limited availability of donor organs. However, the development and academic research access to ATMPs face significant bottlenecks that hinder progress. This opinion paper emphasizes the importance of addressing bottlenecks in the development and academic research access to ATMPs by implementing several key strategies. These include the establishment of streamlined regulatory processes, securing increased funding for ATMP research, fostering collaborations and partnerships, setting up centralized ATMP facilities, and actively engaging with patient groups. Advocacy at the policy level is essential to provide support for the development and accessibility of ATMPs, thereby driving advancements in transplantation and enhancing patient outcomes. By adopting these strategies, the field of transplantation can pave the way for the introduction of innovative and efficacious ATMP therapies, while simultaneously fostering a nurturing environment for academic research.

Anti-craving medications for alcohol use disorder treatment in the emergency department: A systematic review of direct evidence for SAEM GRACE.

OBJECTIVES: Alcohol-related concerns commonly present to the emergency department (ED), with a subset of individuals experiencing the symptoms of an alcohol use disorder (AUD). As such, examining the efficacy of pharmacological anti-craving treatment for AUD in the ED is of increasing interest. The objective of this systematic review was to evaluate the direct evidence assessing the efficacy of providing anti-craving medications for AUD treatment in the ED. METHODS: A systematic search was conducted according to the patient-intervention-control-outcome question: (P) adults (≥18 years old) presenting to the ED with an AUD (including suspected AUD); (I) anti-craving medications (i.e., naltrexone, acamprosate, gabapentin); (C) no prescription or placebo; (O) reduction of repeat ED visits, engagement in addiction services, reductions in heavy drinking days, reductions in any drinking and amount consumed (or abstinence), and in relapse. Two reviewers independently assessed articles for inclusion and conducted risk of bias assessments for included studies. RESULTS: From 143 potentially relevant articles, 6 met inclusion criteria: 3 clinical trials, and 3 case studies. The clinical trials identified evaluated oral versus extended-release naltrexone, monthly extended-release naltrexone injections, and disulfiram. Both oral and extended-release naltrexone resulted in decreased alcohol consumption. Monthly extended-release naltrexone injections resulted in significant improvements in drinking and quality of life. Although out of scope, the disulfiram studies identified did not result in an improvement in drinking in comparison to no medication. CONCLUSIONS: Overall, there are few studies directly examining the efficacy of anti-craving medications for AUD in the ED, although the limited evidence that exists is supportive of naltrexone pharmacotherapy, particularly extended-release injection formulation. Additional randomized controlled trials are necessary for substantive direct evidence on anti-craving medication initiation in the ED.