Impact of social network composition on cognitive decline: Digital Dementia Registry Bavaria (digiDEM Bayern).

BACKGROUND: Currently, there is no curative treatment for dementia. The implementation of preventive measures is of great importance. Therefore, it is necessary to identify and address individual and modifiable risk factors. Social isolation, defined through social networks, is a factor that may influence the onset and progression of the disease. The networks of older people are mostly composed of either family or friends. The aim of this study is to examine the influence of social isolation and network composition on cognition over the course of 12 months in people with cognitive impairment. METHODS: Data basis is the multicentre, prospective, longitudinal register study 'Digital Dementia Registery Bavaria-digiDEM Bayern'. The degree of social isolation was assessed using the Lubben Social Network Scale- Revised (LSNS-R) and the degree of cognitive impairment using the Mini Mental State Examination (MMSE), conducted at baseline and after 12 months. Data were analysed using pre-post ANCOVA, adjusted for baseline MMSE, age, gender, education, living situation and Barthel-Index. RESULTS: 106 subjects (78.9 ± 8.2 years; 66% female) were included in the analysis. The mean MMSE score at baseline was 24.3 (SD = 3.6). Within the friendship subscore, risk for social isolation was highly prevalent (42.5%). Though, there was no difference between individuals with higher/ lower risk of social isolation within the friendship-network after adjusting for common risk factors in cognitive decline over time, F (1,98) = .046, p = .831, partial η2 = .000. CONCLUSION: The results of this study showed that the risk of social isolation from friends is very high among people with cognitive impairment. However, social isolation does not appear to have a bearing influence on the course of cognition. Nevertheless, it is important for people with cognitive impairment to promote and maintain close social contacts with friends.

Have a little heart (or not): highly minimized skeletal muscle regulatory cassettes with low or no activity in heart.

Adeno-associated virus (AAV)-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression in the heart may also play a role. Thus, certain muscle disorders may require a modulated level of therapeutic expression in the heart, while others may not require any cardiac expression at all. Additionally, the size of some cargos requires regulatory cassettes to be small enough that large cDNAs and other therapeutic payloads can be accommodated. Thus, we have performed enhancer/promoter optimization to develop highly minimized regulatory cassettes that are active in skeletal muscles, with either low or no detectable activity in cardiac muscle. Our no-heart (NH) cassette is active in most skeletal muscles, but exhibits only very low activity in extensor digitorum longus (EDL), soleus, and diaphragm, and no activity in heart. By contrast, our have-a-little-heart (HLH) cassette displays high activity in most skeletal muscles, comparable to the ~800-bp CK8 cassette, with increased activity in EDL, soleus, and diaphragm, and low activity in heart. Due to their small size, these cassettes can be used in therapeutic strategies with both flexible (e.g., antisense) and stringent (e.g., CRISPR/Cas or bicistronic) size limitations. Thus, our new cassettes may be useful for gene therapies of muscle disorders in which the need for low or almost no expression in cardiac muscle would outweigh the need for high levels of therapeutic product in certain skeletal muscles.

A standardized approach to evaluate effectiveness of aerobic exercise training interventions in cardiovascular disease at the individual level.

BACKGROUND: Reliable change indices can determine pre-post intervention changes at an individual level that are greater than chance or practice effect. We applied previously developed minimal meaningful change (MMCRCI) scores for oxygen uptake (V̇O2) values associated with estimated lactate threshold (θLT), respiratory compensation point (RCP), and peak oxygen uptake (V̇O2peak) to evaluate the effectiveness of exercise training in cardiovascular disease patients. METHODS: 303 patients (65 ± 11 yrs.; 27% female) that completed a symptom-limited cardiopulmonary exercise test (CPET) before and after 6-months of guideline-recommended exercise training were assessed to determine absolute and relative V̇O2 at θLT, RCP, and V̇O2peak. Using MMCRCI ∆V̇O2 scores of ±3.9 mL·kg-1·min-1, ±4.0 mL·kg-1·min-1, and ± 3.6 mL·kg-1·min-1 for θLT, RCP, and V̇O2peak, respectively, patients were classified as "positive" (ΔθLT, ΔRCP, and/or ΔV̇O2peak ≥ +MMCRCI), "non-" (between ±MMCRCI), or "negative" responders (≤ -MMCRCI). RESULTS: Mean RCP (n = 86) and V̇O2peak (n = 303) increased (p < 0.05) from 19.4 ± 3.6 mL·kg-1·min-1 and 18.0 ± 6.3 mL·kg-1·min-1 to 20.1 ± 3.8 mL·kg-1·min-1 and 19.2 ± 7.0 mL·kg-1·min-1 at exit, respectively, whereas θLT (n = 140) did not change (15.5 ± 3.4 mL·kg-1·min-1 versus 15.7 ± 3.8 mL·kg-1·min-1, p = 0.324). For changes in θLT, 6% were classified as "positive" responders, 90% as "non-responders", and 4% as "negative" responders. For RCP, 10% exhibited "positive" changes, 87% were "non-responders", and 2% were "negative" responders. For ΔV̇O2peak, 57 patients (19%) were classified as "positive" responders, 229 (76%) as "non-responders", and 17 (6%) as "negative" responders. CONCLUSION: Most patients that completed the exercise training program did not achieve reliable improvements greater than that of chance or practice at an individual level in θLT, RCP and V̇O2peak.

Sacral nerve stimulation leads to long-term improvement in fecal incontinence and quality of life for children with functional and organic defecation disorders.

BACKGROUND: Our objective was to evaluate long-term outcomes of sacral nerve stimulation (SNS) for children with functional and organic defecation disorders. METHODS: We performed a prospective study of children <21 years of age who started SNS treatment between 2012 and 2018. We recorded demographics, medical history, and diagnostic testing. We obtained measures of symptom severity and quality of life at baseline and follow up at 1, 6, 12, 24, 36, 48, and ≥60 months. Successful response was defined as bowel movements >2 times/week and fecal incontinence (FI) <1 time/week. Families were contacted to administer the Glasgow Children's Benefit Inventory and to evaluate patient satisfaction. KEY RESULTS: We included 65 patients (59% female, median age at SNS 14 years, range 9-21) with median follow-up of 32 months. Thirty patients had functional constipation (FC), 15 had non-retentive FI (NRFI), and 16 had an anorectal malformation (ARM). The percentage with FI <1 time/week improved from 30% at baseline to 64% at 1 year (p < 0.001) and 77% at most recent follow-up (p < 0.001). Patients with FC, NRFI, and ARM had sustained improvement in FI (p = 0.02, p < 0.001, p = 0.02). Patients also reported fewer hard stools (p = 0.001). Bowel movement frequency did not improve after SNS. At most recent follow-up, 77% of patients with a functional disorder and 50% with an organic disorder had responded (p = 0.03). Nearly all families reported benefit. CONCLUSIONS AND INFERENCES: SNS led to sustained improvement in FI regardless of underlying etiology, but children with functional disorders were more likely to respond than those with organic disorders.

Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications.

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.

Deep learning-based image quality assessment: impact on detection accuracy of prostate cancer extraprostatic extension on MRI.

OBJECTIVE: To assess impact of image quality on prostate cancer extraprostatic extension (EPE) detection on MRI using a deep learning-based AI algorithm. MATERIALS AND METHODS: This retrospective, single institution study included patients who were imaged with mpMRI and subsequently underwent radical prostatectomy from June 2007 to August 2022. One genitourinary radiologist prospectively evaluated each patient using the NCI EPE grading system. Each T2WI was classified as low- or high-quality by a previously developed AI algorithm. Fisher's exact tests were performed to compare EPE detection metrics between low- and high-quality images. Univariable and multivariable analyses were conducted to assess the predictive value of image quality for pathological EPE. RESULTS: A total of 773 consecutive patients (median age 61 [IQR 56-67] years) were evaluated. At radical prostatectomy, 23% (180/773) of patients had EPE at pathology, and 41% (131/318) of positive EPE calls on mpMRI were confirmed to have EPE. The AI algorithm classified 36% (280/773) of T2WIs as low-quality and 64% (493/773) as high-quality. For EPE grade ≥ 1, high-quality T2WI significantly improved specificity for EPE detection (72% [95% CI 67-76%] vs. 63% [95% CI 56-69%], P = 0.03), but did not significantly affect sensitivity (72% [95% CI 62-80%] vs. 75% [95% CI 63-85%]), positive predictive value (44% [95% CI 39-49%] vs. 38% [95% CI 32-43%]), or negative predictive value (89% [95% CI 86-92%] vs. 89% [95% CI 85-93%]). Sensitivity, specificity, PPV, and NPV for EPE grades ≥ 2 and ≥ 3 did not show significant differences attributable to imaging quality. For NCI EPE grade 1, high-quality images (OR 3.05, 95% CI 1.54-5.86; P < 0.001) demonstrated a stronger association with pathologic EPE than low-quality images (OR 1.76, 95% CI 0.63-4.24; P = 0.24). CONCLUSION: Our study successfully employed a deep learning-based AI algorithm to classify image quality of prostate MRI and demonstrated that better quality T2WI was associated with more accurate prediction of EPE at final pathology.

Tirbanibulin decreases cell proliferation and downregulates protein expression of oncogenic pathways in human papillomavirus containing HeLa cells.

Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). Topical tirbanibulin has clinically resolved HPV-57 ( +) squamous cell carcinoma (SCC), HPV-16 ( +) vulvar high-grade squamous intraepithelial lesion, epidermodysplasia verruciformis, and condyloma. We examined how tirbanibulin might affect HPV oncoprotein expression and affect other cellular pathways involved in cell proliferation and transformation. We treated the HeLa cell line, containing integrated HPV-18, with increasing doses of tirbanibulin to determine the effects on cell proliferation. Immunoblotting was performed with antibodies against the Src canonical pathway, HPV 18 E6 and E7 transcription regulation, apoptosis, and invasion and metastasis pathways. Cell proliferation assays with tirbanibulin determined the half-maximal inhibitory concentration (IC50) of HeLa cells to be 31.49 nmol/L. Increasing concentrations of tirbanibulin downregulates the protein expression of Src (p < 0.001), phospho-Src (p < 0.001), Ras (p < 0.01), c-Raf (p < 0.001), ERK1 (p < 0.001), phospho-ERK1 (p < 0.001), phospho-ERK2 (p < 0.01), phospho-Mnk1 (p < 0.001), eIF4E (p < 0.01), phospho-eIF4E (p < 0.001), E6 (p < 0.01), E7 (p < 0.01), Rb (p < 0.01), phospho-Rb (p < 0.001), MDM2 (p < 0.01), E2F1 (p < 0.001), phospho-FAK (p < 0.001), phospho-p130 Cas (p < 0.001), Mcl-1 (p < 0.01), and Bcl-2 (p < 0.001), but upregulates cPARP (p < 0.001), and cPARP/fPARP (p < 0.001). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.

Tirbanibulin is Promising Novel Therapy for Human Papillomavirus (HPV)-associated Diseases.Tirbanibulin 1% ointment is an approved synthetic topical ointment for treating actinic keratoses (AK), a precancer of skin cancer. Topical tirbanibulin has previously been reported to clinically resolve human papillomavirus (HPV)-( +) diseases.In this study, we examine how tirbanibulin may affect the HPV and pathways associated with cancer.We treated the HeLa cell line to determine the effects on HPV cell proliferation. Increasing the concentration of tirbanibulin statistically significantly affected numerous cellular pathways often associated with cancer.These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins and thereby kill cancer cells.

Natural selection drives emergent genetic homogeneity in a century-scale experiment with barley.

Direct observation is central to our understanding of adaptation, but evolution is rarely documented in a large, multicellular organism for more than a few generations. In this study, we observed evolution across a century-scale competition experiment, barley composite cross II (CCII). CCII was founded in 1929 in Davis, California, with thousands of genotypes, but we found that natural selection has massively reduced genetic diversity, leading to a single lineage constituting most of the population by generation 50. Selection favored alleles originating from climates similar to that of Davis and targeted loci contributing to reproductive development, including the barley diversification loci Vrs1, HvCEN, Ppd-H1, and Vrn-H2. Our findings point to selection as the predominant force shaping genomic variation in one of the world's oldest biological experiments.

Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs.

TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.

From Rhetoric to Action: Justice, Equity, Diversity, and Inclusion in Coordinated Specialty Care for Early Psychosis.

Attention to inclusivity and equity in health research and clinical practice has grown in recent years; however, coordinated specialty care (CSC) for early psychosis lags in efforts to improve equity despite evidence of ongoing disparities and inequities in CSC care. This Open Forum argues that marginalization and disparities in early psychosis research and clinical care are interrelated, and the authors provide suggestions for paths forward. Commitment to equity and justice demands recentering the perspectives of those most affected by early psychosis services and investing in the integration of historically excluded perspectives across all aspects of practice, policy, and research.

Visualization, Quantification, and Statistical Evaluation of Dynamics for DNA-Binding Proteins in Bacteria by Single-Molecule Tracking.

All DNA-binding proteins in vivo exist as a population of freely diffusing molecules and of DNA-bound molecules. The molecules bound to DNA can be split into specifically/tightly and nonspecifically bound proteins. Single-molecule tracking (SMT) is a method allowing to visualize protein dynamics in living cells, revealing their behavior in terms of mode of motion, diffusion coefficient/speed, change of dwell times, and unveiling preferred subcellular sites of dwelling. Bleaching-type SMT or fluorescent protein-tagged SMT involves rapid laser-induced bleaching of most fluorophore-labeled molecules. The remaining single fluorescent proteins are then continuously tracked. The trajectories of several fluorescent molecules per cell for a population of cells are analyzed and combined to permit a robust analysis of average behavior of single molecules in live cells, including analyses of protein dynamics in mutant cells or cells exposed to changes in environmental conditions.In this chapter, we describe the preparation of Bacillus subtilis cells, the recording of movies of those cells expressing a monomeric variant of a yellow fluorescent protein (mNeonGreen) fused to a protein of choice, and the subsequent curation of the movie data including the statistical analysis of the protein dynamics. We present a short overview of the analysis program SMTracker 2.0, highlighting its ability to analyze SMT data by non-expert scientists.

Optical genome mapping with genome sequencing identifies subtelomeric Xq28 deletion and inserted 7p22.3 duplication in a male with multisystem developmental disorder.

We report a 17-year-old male with supravalvular stenosis, initial failure to thrive and delayed early development, short stature, acromelia, dysmorphic facial features, hypertelorism, macrocephaly, syringomyelia, hypertension, and anxiety disorder. Fluorescent in situ hybridization (FISH), chromosomal microarray analysis (CMA), and exome sequencing (ES) were nondiagnostic. Combined optical genome mapping (OGM) and genome sequencing (GS) showed a complex rearrangement including an X chromosome with a 22.5 kb deletion in band Xq28 replaced by a 61.4 kb insertion of duplicated chromosome 7p22.3 material. The deletion removes the distal 3' untranslated region (UTR) of FUNDC2, the entire CMC4 and MTCP1, and the first five exons of BRCC3. Transcriptome analysis revealed absent expression of CMC4 and MTCP1 and BRCC3 with normal transcript level of FUNDC2. The inserted duplication includes only one known gene: UNCX. Similar overlapping Xq28 deletions have been reported to be associated with Moyamoya disease (MMD), short stature, hypergonadotropic hypogonadism (HH), and facial dysmorphism. Although he has short stature, our patient does not have signs of Moyamoya arteriopathy or hypogonadism. The structurally abnormal X chromosome was present in his mother, but not in his unaffected brother, maternal uncle, or maternal grandparents. We propose that the combination of his absent Xq28 and duplicated 7p22.3 genomic material is responsible for his phenotype. This case highlights the potential of combined OGM and GS for detecting complex structural variants compared with standard of care genetic testing such as CMA and ES.

Efficacy, drug sustainability, and safety of ustekinumab treatment in Crohn's disease patients over three years.

Long-term data on ustekinumab in real-life Crohn's disease patients are still missing, though randomized controlled trials demonstrated it as a favorable therapeutic option. We aimed to evaluate ustekinumab's clinical efficacy, drug sustainability, and safety in a prospective, nationwide, multicenter Crohn's disease patient cohort with a three-year follow-up. Crohn's disease patients on ustekinumab treatment were consecutively enrolled from 9 Hungarian Inflammatory Bowel Disease centers between January 2019 and May 2020. Patient and disease characteristics, treatment history, clinical disease activity (Harvey Bradshaw Index (HBI)), biomarkers, and endoscopic activity (Simple Endoscopic Score for Crohn's Disease (SES-CD)) were collected for three-years' time. A total of 148 patients were included with an overall 48.9% of complex behavior of the Crohn's disease and 97.2% of previous anti-TNF exposure. The pre-induction remission rates were 12.2% (HBI), and 5.1% (SES-CD). Clinical remission rates (HBI) were 52.2%, 55.6%, and 50.9%, whereas criteria of an endoscopic remission were fulfilled in 14.3%, 27.5%, and 35.3% of the subjects at the end of the first, second, and third year, respectively. Dose intensification was high with 84.0% of the patients on an 8-weekly and 29.9% on a 4-weekly regimen at the end of year 3. Drug sustainability was 76.9% during the follow-up period with no serious adverse events observed. Ustekinumab in the long-term is an effective, sustainable, and safe therapeutic option for Crohn's disease patients with severe disease phenotype and high previous anti-TNF biological failure, requiring frequent dose intensifications.

Neuroinflammation and Lysosomal Abnormalities Characterise the Essential Role for Oxidation Resistance 1 in the Developing and Adult Cerebellum.

Loss-of-function mutations in the TLDc family of proteins cause a range of severe childhood-onset neurological disorders with common clinical features that include cerebellar neurodegeneration, ataxia and epilepsy. Of these proteins, oxidation resistance 1 (OXR1) has been implicated in multiple cellular pathways related to antioxidant function, transcriptional regulation and cellular survival; yet how this relates to the specific neuropathological features in disease remains unclear. Here, we investigate a range of loss-of-function mouse model systems and reveal that constitutive deletion of Oxr1 leads to a rapid and striking neuroinflammatory response prior to neurodegeneration that is associated with lysosomal pathology. We go on to show that neuroinflammation and cell death in Oxr1 knockouts can be completely rescued by the neuronal expression of Oxr1, suggesting that the phenotype is driven by the cell-intrinsic defects of neuronal cells lacking the gene. Next, we generate a ubiquitous, adult inducible knockout of Oxr1 that surprisingly displays rapid-onset ataxia and cerebellar neurodegeneration, establishing for the first time that the distinctive pathology associated with the loss of Oxr1 occurs irrespective of developmental stage. Finally, we describe two new homozygous human pathogenic variants in OXR1 that cause neurodevelopmental delay, including a novel stop-gain mutation. We also compare functionally two missense human pathogenic mutations in OXR1, including one newly described here, that cause different clinical phenotypes but demonstrate partially retained neuroprotective activity against oxidative stress. Together, these data highlight the essential role of Oxr1 in modulating neuroinflammatory and lysosomal pathways in the mammalian brain and support the hypothesis that OXR1 protein dosage may be critical for pathological outcomes in disease.

The Sociodemographic Biases in Machine Learning Algorithms: A Biomedical Informatics Perspective.

Artificial intelligence models represented in machine learning algorithms are promising tools for risk assessment used to guide clinical and other health care decisions. Machine learning algorithms, however, may house biases that propagate stereotypes, inequities, and discrimination that contribute to socioeconomic health care disparities. The biases include those related to some sociodemographic characteristics such as race, ethnicity, gender, age, insurance, and socioeconomic status from the use of erroneous electronic health record data. Additionally, there is concern that training data and algorithmic biases in large language models pose potential drawbacks. These biases affect the lives and livelihoods of a significant percentage of the population in the United States and globally. The social and economic consequences of the associated backlash cannot be underestimated. Here, we outline some of the sociodemographic, training data, and algorithmic biases that undermine sound health care risk assessment and medical decision-making that should be addressed in the health care system. We present a perspective and overview of these biases by gender, race, ethnicity, age, historically marginalized communities, algorithmic bias, biased evaluations, implicit bias, selection/sampling bias, socioeconomic status biases, biased data distributions, cultural biases and insurance status bias, conformation bias, information bias and anchoring biases and make recommendations to improve large language model training data, including de-biasing techniques such as counterfactual role-reversed sentences during knowledge distillation, fine-tuning, prefix attachment at training time, the use of toxicity classifiers, retrieval augmented generation and algorithmic modification to mitigate the biases moving forward.

Efficacy of Vonoprazan vs. Intravenous Proton Pump Inhibitor in Prevention of Re-Bleeding of High-Risk Peptic Ulcers: A Randomized Controlled Pilot Study.

Background: Proton pump inhibitor (PPI) therapy is well-established for its effectiveness in reducing re-bleeding in high-risk peptic ulcer patients following endoscopic hemostasis. Vonoprazan (VPZ) has demonstrated the capacity to achieve gastric pH levels exceeding 4, comparable to PPIs. This study aims to evaluate the comparative efficacy of intravenous PPI infusion versus VPZ in preventing re-bleeding after endoscopic hemostasis in patients with high-risk peptic ulcers. Methods: A randomized, double-blind, controlled, and double-dummy design was employed. Patients with peptic ulcer bleeding (Forrest class IA/IB or IIA/IIB) who underwent endoscopic hemostasis were randomly assigned to either the PPI group or the VPZ group. Re-bleeding rates at 3, 7, and 30 days, the number of blood transfusions required, length of hospitalization, and ulcer healing rate at 56 days were assessed. Results: A total of 44 eligible patients were enrolled, including 20 patients (PPI group, n = 11; VPZ group, n = 9) with high-risk peptic ulcers. The mean age was 66 years, with 70% being male. Re-bleeding within 72 h occurred in 9.1% of the PPI group versus 0% in the VPZ group (p = 1.000). There was no significant difference in re-bleeding rates within 7 days and 30 days (18.2% vs. 11.1%, p = 1.000). Additionally, the ulcer healing rate did not significantly differ between the groups (87.5% vs. 77.8%). Conclusions: This pilot study demonstrates comparable efficacy between oral vonoprazan and continuous PPI infusion in preventing recurrent bleeding events among high-risk peptic ulcer patients following successful endoscopic hemostasis.

Significance of retrograde flow with antegrade continence enemas in children with fecal incontinence and constipation.

BACKGROUND: For children with constipation and fecal incontinence treated with antegrade continence enemas (ACE), a fluoroscopic study with contrast administered via appendicostomy/cecostomy can define the anatomy of the colon and simulate the flush to investigate associated symptoms or inadequate response. These studies can at times show retrograde flow into the small intestine. Our objective was to investigate the significance of this finding. METHODS: We reviewed studies at our institution with contrast administered via appendicostomy/cecostomy in children treated with ACE, identifying those demonstrating retrograde flow of contrast. We recorded demographics, medical history, interventions, and outcomes. RESULTS: We identified 162 studies (52% male, median age 10.7 years) with contrast via appendicostomy (76%) or cecostomy (24%). Diagnoses included anorectal malformation (38%), spinal cord anomaly (26%), functional constipation (24%), colonic dysmotility (18%), and Hirschsprung disease (12%). Fifty-nine (36%) studies showed retrograde flow: 28/59 children (48%) were not responding adequately and 21/59 (36%) had symptoms with ACE. Children with retrograde flow were more likely to have symptoms with ACE than those without (36% vs. 15%, p < 0.01). Fourteen children underwent interventions for this finding, including administering flushes more distally (4/8 responded), changing positioning of the child during flush administration, (1/2 responded), and slowing administration (1/1 responded). Retrograde flow was associated with younger age (p < 0.01), not sex or underlying diagnosis. CONCLUSION: Identifying retrograde flow during studies with contrast administered via appendicostomy/cecostomy can be useful for children with a poor response or symptoms associated with ACE, as adjustments to the mechanics of the flush can alleviate those symptoms. LEVEL OF EVIDENCE: Prognostic study, Level III.

Lung Donation and Transplant Recipient Outcomes at Independent vs Hospital-Based Donor Care Units.

Importance: Centralizing deceased organ donor management and organ recovery into donor care units (DCUs) may mitigate the critical organ shortage by positively impacting donation and recipient outcomes. Objective: To compare donation and lung transplant outcomes between 2 common DCU models: independent (outside of acute-care hospitals) and hospital-based. Design, Setting, and Participants: This is a retrospective cohort study of Organ Procurement and Transplantation Network deceased donor registry and lung transplant recipient files from 21 US donor service areas with an operating DCU. Characteristics and lung donation rates among deceased donors cared for in independent vs hospital-based DCUs were compared. Eligible participants included deceased organ donors (aged 16 years and older) after brain death, who underwent organ recovery procedures between April 26, 2017, and June 30, 2022, and patients who received lung transplants from those donors. Data analysis was conducted from May 2023 to March 2024. Exposure: Organ recovery in an independent DCU (vs hospital-based DCU). Main Outcome and Measures: The primary outcome was duration of transplanted lung survival (through December 31, 2023) among recipients of lung(s) transplanted from cohort donors. A Cox proportional hazards model stratified by transplant year and program, adjusting for donor and recipient characteristics was used to compare graft survival. Results: Of 10 856 donors in the starting sample (mean [SD] age, 42.8 [15.2] years; 6625 male [61.0%] and 4231 female [39.0%]), 5149 (primary comparison group) underwent recovery procedures in DCUs including 1466 (28.4%) in 11 hospital-based DCUs and 3683 (71.5%) in 10 independent DCUs. Unadjusted lung donation rates were higher in DCUs than local hospitals, but lower in hospital-based vs independent DCUs (418 donors [28.5%] vs 1233 donors [33.5%]; P < .001). Among 1657 transplant recipients, 1250 (74.5%) received lung(s) from independent DCUs. Median (range) duration of follow-up after transplant was 734 (0-2292) days. Grafts recovered from independent DCUs had shorter restricted mean (SE) survival times than grafts from hospital-based DCUs (1548 [27] days vs 1665 [50] days; P = .04). After adjustment, graft failure remained higher among lungs recovered from independent DCUs than hospital-based DCUs (hazard ratio, 1.85; 95% CI, 1.28-2.65). Conclusions and Relevance: In this retrospective analysis of national donor and transplant recipient data, although lung donation rates were higher from deceased organ donors after brain death cared for in independent DCUs, lungs recovered from donors in hospital-based DCUs survived longer. These findings suggest that further work is necessary to understand which factors (eg, donor transfer, management, or lung evaluation and acceptance practices) differ between DCU models and may contribute to these differences.