Genetically transitional disease: a new concept in genomic medicine.

Traditional classification of genetic diseases as monogenic and polygenic has lagged far behind scientific progress. In this opinion article, we propose and define a new terminology, genetically transitional disease (GTD), referring to cases where a large-effect mutation is necessary, but not sufficient, to cause disease. This leads to a working disease nosology based on gradients of four types of genetic architecture: monogenic, polygenic, GTD, and mixed. We present four scenarios under which GTD may occur; namely, subsets of traditionally Mendelian disease, modifiable Tier 1 monogenic conditions, variable penetrance, and situations where a genetic mutational spectrum produces qualitatively divergent pathologies. The implications of the new nosology in precision medicine are discussed, in which therapeutic options may target the molecular cause or the disease phenotype.

Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.

Regulatory B cells: TIM-1, transplant tolerance, and rejection.

Regulatory B cells (Bregs) ameliorate autoimmune disease and prevent allograft rejection. Conversely, they hinder effective clearance of pathogens and malignancies. Breg activity is mainly attributed to IL-10 expression, but also utilizes additional regulatory mechanisms such as TGF-ß, FasL, IL-35, and TIGIT. Although Bregs are present in various subsets defined by phenotypic markers (including canonical B cell subsets), our understanding of Bregs has been limited by the lack of a broadly inclusive and specific phenotypic or transcriptional marker. TIM-1, a broad marker for Bregs first identified in transplant models, plays a major role in Breg maintenance and induction. Here, we expand on the role of TIM-1+  Bregs in immune tolerance and propose TIM-1 as a unifying marker for Bregs that utilize various inhibitory mechanisms in addition to IL-10. Further, this review provides an in-depth assessment of our understanding of Bregs in transplantation as elucidated in murine models and clinical studies. These studies highlight the major contribution of Bregs in preventing allograft rejection, and their ability to serve as highly predictive biomarkers for clinical transplant outcomes.

Exploring the Inclusion of Person-Centered Care Domains in Stroke Transitions of Care Interventions: A Scientific Statement From the American Heart Association.

BACKGROUND: Health care teams along the stroke recovery continuum have a responsibility to support care transitions and return to the community. Ideally, individualized care will consider patient and family preferences, best available evidence, and health care professional input. Person-centered care can improve patient-practitioner interactions through shared decision-making in which health professionals and institutions are sensitive to those for whom they provide care. However, it is unclear how the concepts of person-centered care have been described in reports of stroke transitional care interventions. METHODS: A secondary analysis of a systematic review and meta-analysis was undertaken. We retrieved all included articles (n=17) and evaluated the extent to which each intervention explicitly addressed 7 domains of person-centered care: alignment of care with patients' values, preferences, and needs; coordination of care; information and education; physical comfort; emotional support; family and friend involvement; and smooth transition and continuity of care. RESULTS: Most of the articles included some aspects of person-centeredness; we found that certain domains were not addressed in the descriptions of transitional care interventions, and no articles mentioned all 7 domains of person-centered care. We identified 3 implications for practice and research: (1) delineating person-centered care components when reporting interventions, (2) elucidating social and cultural factors relevant to the study sample and intervention, and (3) clearly describing the role of family and nonmedical support in the intervention. CONCLUSIONS: There is still room for greater consistency in the reporting of person-centeredness in stroke transitions of care interventions, despite a long-standing definition and conceptualization of person-centered care in academic and clinically focused literature.

Unfolding the dynamics of ecosystems undergoing alternating wet-dry transitional states.

A significant fraction of Earth's ecosystems undergoes periodic wet-dry alternating transitional states. These globally distributed water-driven transitional ecosystems, such as intermittent rivers and coastal shorelines, have traditionally been studied as two distinct entities, whereas they constitute a single, interconnected meta-ecosystem. This has resulted in a poor conceptual and empirical understanding of water-driven transitional ecosystems. Here, we develop a conceptual framework that places the temporal availability of water as the core driver of biodiversity and functional patterns of transitional ecosystems at the global scale. Biological covers (e.g., aquatic biofilms and biocrusts) serve as an excellent model system thriving in both aquatic and terrestrial states, where their succession underscores the intricate interplay between these two states. The duration, frequency, and rate of change of wet-dry cycles impose distinct plausible scenarios where different types of biological covers can occur depending on their desiccation/hydration resistance traits. This implies that the distinct eco-evolutionary potential of biological covers, represented by their trait profiles, would support different functions while maintaining similar multifunctionality levels. By embracing multiple alternating transitional states as interconnected entities, our approach can help to better understand and manage global change impacts on biodiversity and multifunctionality in water-driven transitional ecosystems, while providing new avenues for interdisciplinary studies.

Activation of alveolar epithelial ER stress by ß-coronavirus infection disrupts surfactant homeostasis in mice: implications for COVID-19 respiratory failure.

COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the ß-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were used-mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population (Krt8+ and Cldn4+). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from ß-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure.NEW & NOTEWORTHY COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that ß-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure.

Reliability, validity, and change thresholds of the NCCN/FACT Bladder Symptom Index (NFBlSI-18) in patients with advanced urothelial cancer.

BACKGROUND: The NCCN/FACT Bladder Symptom Index-18 (NFBlSI-18) is a bladder cancer-specific instrument. We aimed to psychometrically evaluate the reliability and validity of NFBlSI-18 and estimate change thresholds for total, disease-related symptoms-physical (DRS-P), DRS-emotional (DRS-E), and function/well-being (F/WB) scales in patients with locally advanced/metastatic urothelial cancer (la/mUC). METHODS: JAVELIN Bladder 100 trial data were analyzed. Anchors to evaluate validity included: 5-level EuroQoL-5D utility index (EQ-5D-5L UI), visual analog scale (VAS), Eastern Cooperative Oncology Group (ECOG) performance status, and number of symptoms. Responsiveness to change was tested by anchoring to time to tumor progression (TTP), best overall response (BOR), and differences in means between ECOG categories to estimate meaningful between-group differences. Meaningful within-group change thresholds were estimated using receiver operating characteristic curve analysis, anchoring to change in EQ-5D-5L UI. Significant within-individual patient change thresholds were estimated with reliable and likely change indexes. RESULTS: Correlations with EQ-5D-5L UI and VAS ranged from 0.53 to 0.73. Standardized effect sizes were >0.20. Compared with patients with TTP of ≥6 months, patients with TTP of >0-2 and 3-5 months had larger declines; results for BOR were similar. Thresholds (points) for meaningful between-group differences were: total, 6-11; DRS-P, 3-6; and DRS-E and F/WB, 1. Thresholds (points) for meaningful within-group worsening were: total, 4; and DRS-P, 3, and for significant individual change they were: total, 3-9; DRS-P, 2-6; DRS-E, 1-3; and F/WB, 2-4. CONCLUSIONS: NFBlSI-18 exhibited evidence of reliability, validity, and responsiveness to assess quality of life in studies of la/mUC, and change thresholds are established for future studies. PLAIN LANGUAGE SUMMARY: The NCCN/FACT Bladder Symptom Index-18 (NFBlSI-18) is a questionnaire used to assess quality of life for people with advanced bladder cancer. People with advanced bladder cancer who took part in the JAVELIN Bladder 100 study completed the NFBlSI-18 when they joined the study and after each treatment with avelumab maintenance or best supportive care. This study showed that NFBlSI-18 is suitable for capturing bladder cancer symptoms and is able to detect important changes in a person's quality of life over time. This study also provides thresholds for changes in NFBlSI-18 scores, which will be useful for future studies.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Adults With Spina Bifida Fare Worse Than Young Adults: A Systemic Vulnerability in Urinary Tract Infection-Related Hospital Care.

PURPOSE: We aim to estimate the odds of UTI-related hospital care in spina bifida (SB) patients aged 18 to 25 years as compared with patients with SB in adolescence (11-17 years) or adulthood (26-35 years). We hypothesize that patients with SB in the typical transitional age, 18 to 25 years, will have higher odds of UTI-related hospital care as compared to adolescent SB patients or adult SB patients. MATERIALS AND METHODS: Using Cerner Real-World Data, we performed a retrospective cohort analysis comparing SB patients to age- and gender-matched controls. SB cases between 2015 and 2021 were identified and compared in 3 cohorts: 11 to 17 years (adolescents), 18 to 25 years (young adults [YA]), and 26 to 35 years (adults). Logistic regression analysis was used to characterize the odds of health care utilization. RESULTS: Of the 5497 patients with SB and 77,466 controls identified, 1839 SB patients (34%) and 3275 controls (4.2%) had at least 1 UTI encounter. UTI-related encounters as a proportion of all encounters significantly increased with age in SB patients (adolescents 8%, YA 12%, adult 15%; P < .0001). Adjusting for race, sex, insurance, and comorbidities, the odds of a UTI-related encounter in YA with SB were significantly higher than for adolescents with SB (adolescent odds ratio = 0.65, 95% CI: 0.57-0.75, P < .001). YA had lower odds of a UTI-related encounter as compared with adults with SB (adult odds ratio = 1.31, 95% CI: 1.16-1.49, P < .001). CONCLUSIONS: YA with SB have higher odds of UTI-related hospital care than adolescents, but lower odds of UTI-related hospital care when compared with adults.

Nine is the New Ten of Apgar Scores: An Observational Retrospective Cohort Study.

Apgar scores of 10 were once common but are now rare. We aggregated scores from US term infants from 1978 to 2021. We found that scores of 10 decreased by logarithmic decay independent of demographic changes. We hypothesize that this trend was driven by improved appreciation of transitional physiology.