Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study.

Direct-acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo-controlled, phase III C-EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty-nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once-daily, fixed-dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate-treatment group (ITG) or deferred-treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow-up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, ß-thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. CONCLUSION: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017;66:736-745).

Lipid-Mediated Regulation of Embedded Receptor Kinases via Parallel Allosteric Relays.

Membrane-anchored receptors are essential cellular signaling elements for stimulus sensing, propagation, and transmission inside cells. However, the contributions of lipid interactions to the function and dynamics of embedded receptor kinases have not been described in detail. In this study, we used amide hydrogen/deuterium exchange mass spectrometry, a sensitive biophysical approach, to probe the dynamics of a membrane-embedded receptor kinase, EnvZ, together with functional assays to describe the role of lipids in receptor kinase function. Our results reveal that lipids play an important role in regulating receptor function through interactions with transmembrane segments, as well as through peripheral interactions with nonembedded domains. Specifically, the lipid membrane allosterically modulates the activity of the embedded kinase by altering the dynamics of a glycine-rich motif that is critical for phosphotransfer from ATP. This allostery in EnvZ is independent of membrane composition and involves direct interactions with transmembrane and periplasmic segments, as well as peripheral interactions with nonembedded domains of the protein. In the absence of the membrane-spanning regions, lipid allostery is propagated entirely through peripheral interactions. Whereas lipid allostery impacts the phosphotransferase function of the kinase, extracellular stimulus recognition is mediated via a four-helix bundle subdomain located in the cytoplasm, which functions as the osmosensing core through osmolality-dependent helical stabilization. Our findings emphasize the functional modularity in a membrane-embedded kinase, separated into membrane association, phosphotransferase function, and stimulus recognition. These components are integrated through long-range communication relays, with lipids playing an essential role in regulation.

Engineering a Novel Porin OmpGF Via Strand Replacement from Computational Analysis of Sequence Motif.

ß-Barrelmembrane proteins (ßMPs) form barrel-shaped pores in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. Because of the robustness of their barrel structures, ßMPs have great potential as nanosensors for single-molecule detection. However, natural ßMPs currently employed have inflexible biophysical properties and are limited in their pore geometry, hindering their applications in sensing molecules of different sizes and properties. Computational engineering has the promise to generate ßMPs with desired properties. Here we report a method for engineering novel ßMPs based on the discovery of sequence motifs that predominantly interact with the cell membrane and appear in more than 75% of transmembrane strands. By replacing ß1-ß6 strands of the protein OmpF that lack these motifs with ß1-ß6 strands of OmpG enriched with these motifs and computational verification of increased stability of its transmembrane section, we engineered a novel ßMP called OmpGF. OmpGF is predicted to form a monomer with a stable transmembrane region. Experimental validations showed that OmpGF could refold in vitro with a predominant ß-sheet structure, as confirmed by circular dichroism. Evidence of OmpGF membrane insertion was provided by intrinsic tryptophan fluorescence spectroscopy, and its pore-forming property was determined by a dye-leakage assay. Furthermore, single-channel conductance measurements confirmed that OmpGF function as a monomer and exhibits increased conductance than OmpG and OmpF. These results demonstrated that a novel and functional ßMP can be successfully engineered through strand replacement based on sequence motif analysis and stability calculation.

The inner membrane histidine kinase EnvZ senses osmolality via helix-coil transitions in the cytoplasm.

Two-component systems mediate bacterial signal transduction, employing a membrane sensor kinase and a cytoplasmic response regulator (RR). Environmental sensing is typically coupled to gene regulation. Understanding how input stimuli activate kinase autophosphorylation remains obscure. The EnvZ/OmpR system regulates expression of outer membrane proteins in response to osmotic stress. To identify EnvZ conformational changes associated with osmosensing, we used HDXMS to probe the effects of osmolytes (NaCl, sucrose) on the cytoplasmic domain of EnvZ (EnvZ(c)). Increasing osmolality decreased deuterium exchange localized to the four-helix bundle containing the autophosphorylation site (His(243)). EnvZ(c) exists as an ensemble of multiple conformations and osmolytes favoured increased helicity. High osmolality increased autophosphorylation of His(243), suggesting that these two events are linked. In-vivo analysis showed that the cytoplasmic domain of EnvZ was sufficient for osmosensing, transmembrane domains were not required. Our results challenge existing claims of robustness in EnvZ/OmpR and support a model where osmolytes promote intrahelical H-bonding enhancing helix stabilization, increasing autophosphorylation and downstream signalling. The model provides a conserved mechanism for signalling proteins that respond to diverse physical and mechanical stimuli.

Mental Illness in Assisted Living: Challenges for Quality of Life and Care.

An unknown number of mentally ill elders in the U.S. receive care in assisted living [AL], along with persons facing physical or cognitive challenges. While dementia is familiar in AL, our data indicate that neither staff nor residents are prepared to work or live with the mentally ill. Challenges are created for professionals, since these residents bring diverse needs. Daily inter-resident interactions are also disrupted or stressful. Qualitative data describe the impacts on quality of resident life as well as care and management dilemmas identified within five assisted living settings having varying presence of mental illness among residents.

Safety, tolerability, and immunogenicity of an adult pneumococcal conjugate vaccine, V116 (STRIDE-3): a randomised, double-blind, active comparator controlled, international phase 3 trial.

BACKGROUND: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. METHODS: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). FINDINGS: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. INTERPRETATION: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. FUNDING: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

A phase 3 study of safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by 23-valent pneumococcal polysaccharide vaccine, in children with HIV.

OBJECTIVES: To evaluate the safety and immunogenicity of V114 [15-valent pneumococcal conjugate vaccine (PCV) containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F, 22F, 23F, 33F], followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later, in children with HIV. DESIGN: This phase 3 study (NCT03921424) randomized participants 6-17 years of age with HIV (CD4 + T-cell count ≥200 cells/µl, plasma HIV RNA <50 000 copies/ml) to receive V114 or 13-valent PCV (PCV13) in a double-blind manner on Day 1, followed by PPSV23 at Week 8. METHODS: Adverse events (AEs), pneumococcal serotype-specific immunoglobulin G (IgG), and opsonophagocytic activity (OPA) were evaluated 30 days after each vaccination. RESULTS: The proportion of participants experiencing at least one AE post-PCV was 78.8% in the V114 group ( n  = 203) and 69.6% in the PCV13 group ( n  = 204); respective proportions post-PPSV23 were 75.4% ( n  = 203) and 77.2% ( n  = 202). There were no vaccine-related serious AEs. IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally comparable between V114 and PCV13 for shared serotypes at Day 30, and were higher for V114 compared with PCV13 for the additional V114 serotypes 22F and 33F. Approximately 30 days after PPSV23, IgG GMCs and OPA GMTs were generally comparable between the V114 and PCV13 groups for all 15 serotypes in V114. CONCLUSIONS: In children with HIV, a sequential administration of V114 followed 8 weeks later with PPSV23 is well tolerated and induces immune responses for all 15 pneumococcal serotypes included in V114.

Paradigms in the gerontology classroom: connections and challenges to learning.

The article explores paradigms for approaching course content to be studied in the classroom. These paradigms, or global views about what is of interest or importance and ways of knowing, relate to key questions in gerontology, such as what is the relevant domain/content to be studied, what is the central level of analysis or action, what are appropriate ways to gain knowledge, and how do we best address the challenges related to aging? For interdisciplinary gerontology programs, the discussion of paradigms raises the question of whether learning effectiveness and student satisfaction may suffer when the students are unaware of their own budding gerontological paradigms or when an instructor's paradigm remains unarticulated or differs from those of students. This article discusses selected paradigms inherent within gerontology education/training programs and their diverse foci, two emerging paradigms of gerontology, and potential steps to clarify these paradigms in the classroom.

A phase 3 trial of safety, tolerability, and immunogenicity of V114, 15-valent pneumococcal conjugate vaccine, compared with 13-valent pneumococcal conjugate vaccine in adults 50 years of age and older (PNEU-AGE).

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have greatly reduced the incidence of pneumococcal disease, yet unmet medical need remains due to increased disease caused by non-vaccine serotypes (STs). V114 (VAXNEUVANCETM, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) is a 15-valent PCV containing 13 serotypes in licensed PCV13 and 2 additional serotypes (22F, 33F) which significantly contribute to pneumococcal disease burden. This phase 3 trial compared safety, tolerability, and immunogenicity of V114 to PCV13 in adults ≥50 years of age. METHODS: Adults were randomized 1:1 to receive a single dose of V114 or PCV13; randomization was stratified by age (50-64 years, 65-74 years, and ≥75 years). Adverse events (AEs) were collected following vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were measured prior to and 30 days after vaccination (Day 30). Primary objectives included assessing noninferiority of V114 to PCV13 for the 13 shared serotypes and superiority of V114 to PCV13 for the two unique serotypes. Superiority of V114 to PCV13 for shared serotype 3 was assessed as a secondary objective. RESULTS: Overall, 1,202 participants were vaccinated (V114 N = 602, PCV13 N = 600). The most commonly reported AEs across both groups were injection-site pain, fatigue, and myalgia. V114 met noninferiority criteria compared to PCV13 for the 13 shared serotypes (using a 2-fold non-inferiority margin for the ratio of OPA geometric mean titers [GMTs] [V114/PCV13] at Day 30) and met superiority for the 2 unique serotypes (using a 2-fold super-superiority margin for the ratio of OPA GMTs [V114/PCV13] at Day 30 and a 0.10 super-superiority margin for the difference in proportions of participants with ≥4-fold rise from prevaccination to Day 30). V114 met superiority criteria compared to PCV13 for serotype 3 (based on a super-superiority margin of 1.2 for the ratio of the OPA GMTs [V114/PCV13] and a superiority margin of 0 for the difference in proportions of participants with ≥4-fold rise). [NCT03950622, EudraCT#2018-004316-22, Japic-CTI#194845].

Disulfide disruption reverses mucus dysfunction in allergic airway disease.

Airway mucus is essential for lung defense, but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes. Current asthma treatments have minimal effects on mucus, and the lack of therapeutic options stems from a poor understanding of mucus function and dysfunction at a molecular level and in vivo. Biophysical properties of mucus are controlled by mucin glycoproteins that polymerize covalently via disulfide bonds. Once secreted, mucin glycopolymers can aggregate, form plugs, and block airflow. Here we show that reducing mucin disulfide bonds disrupts mucus in human asthmatics and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice, inhaled mucolytic treatment loosens mucus mesh, enhances mucociliary clearance, and abolishes airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal is directly related to reduced mucus plugging. These findings establish grounds for developing treatments to inhibit effects of mucus hypersecretion in asthma.

Gender and informal caregiving in CCRCs: primary caregivers or support networks?

Relatively little research has been conducted on caregiving or kin support patterns among residents of newer forms of senior housing. The current research investigates variation in reported current or potential supporters by gender, age, and marital status among 687 residents of four continuing care retirement communities. Women and men tended to identify different configurations of social support, with the gender difference partially attributable to marital status (i.e., higher rates of widowhood among women). Age 75-84 was nonlinearly associated with more reported supporters, suggesting a shift in types of supporters by age. Unmarried persons more often identified friends and "others" in terms of support, in lieu of spousal support.

Back to the Future for Influenza Preimmunity-Looking Back at Influenza Virus History to Infer the Outcome of Future Infections.

The influenza virus-host interaction is a classic arms race. The recurrent and evolving nature of the influenza virus family allows a single host to be infected several times. Locked in co-evolution, recurrent influenza virus infection elicits continual refinement of the host immune system. Here we give historical context of circulating influenza viruses to understand how the individual immune history is mirrored by the history of influenza virus circulation. Original Antigenic Sin was first proposed as the negative influence of the host's first influenza virus infection on the next and Imprinting modernizes Antigenic Sin incorporating both positive and negative outcomes. Building on imprinting, we refer to preimmunity as the continual refinement of the host immune system with each influenza virus infection. We discuss imprinting and the interplay of influenza virus homology, vaccination, and host age establishing preimmunity. We outline host signatures and outcomes of tandem infection according to the sequence of virus and classify these relationships as monosubtypic homologous, monosubtypic heterologous, heterosubtypic, or heterotypic sequential infections. Finally, the preimmunity knowledge gaps are highlighted for future investigation. Understanding the effects of antigenic variable recurrent influenza virus infection on immune refinement will advance vaccination strategies, as well as pandemic preparedness.

Engineering an Osmosensor by Pivotal Histidine Positioning within Disordered Helices.

Histidine kinases (HKs) funnel diverse environmental stimuli into a single autophosphorylation event at a conserved histidine residue. The HK EnvZ is a global sensor of osmolality and cellular acid pH. In previous studies, we discovered that osmosensing in EnvZ was mediated through osmolyte-induced stabilization of the partially disordered helical backbone spanning the conserved histidine autophosphorylation site (His243). Here, we describe how backbone stabilization leads to changes in the microenvironment of His243, resulting in enhanced autophosphorylation through relief of inhibition and repositioning of critical side chains and imidazole rotamerization. The conserved His-Asp/Glu dyad within the partially structured helix is equally geared to respond to acid pH, an alternative environmental stimulus in bacteria. This high-resolution "double-clamp" switch model proposes that a His-Asp/Glu dyad functions as an integrative node for regulating autophosphorylation in HKs. Because the His-Asp/Glu dyad is highly conserved in HKs, this study provides a universal model for describing HK function.

Prevention Starts With Awareness: Adoptive Adolescents at High Risk for Suicidal Behavior.

Adolescents are at higher risk for suicide attempts than other age groups. Suicide is now the second leading cause of death in the United States for ages 12 to 18; moreover, the risk of suicide is significantly higher for adoptive teens. In fact, adoptive teenagers have a four times higher rate of suicide attempts than biological children, perhaps due to the underlying nature of adoption, which can involve a pervasive sense of grief and loss for the adoptee. Unresolved anger and sadness from feelings of abandonment-especially when transitioning to adolescence-can cause a seemingly functional child to dissociate through self-harm and eventually demonstrate suicidal behavior. Little evidence-based research exists on the risk factors for adoptive teens who resort to suicidal behavior. Thus, it is vitally important for school nurses to understand the emotional stressors that adolescent adoptees face throughout life to help identify teens at risk for suicide. School districts and registered nurses are well positioned to address this critical health issue through education, assessment, and intervention.

Non-canonical activation of OmpR drives acid and osmotic stress responses in single bacterial cells.

Unlike eukaryotes, bacteria undergo large changes in osmolality and cytoplasmic pH. It has been described that during acid stress, bacteria internal pH promptly acidifies, followed by recovery. Here, using pH imaging in single living cells, we show that following acid stress, bacteria maintain an acidic cytoplasm and the osmotic stress transcription factor OmpR is required for acidification. The activation of this response is non-canonical, involving a regulatory mechanism requiring the OmpR cognate kinase EnvZ, but not OmpR phosphorylation. Single cell analysis further identifies an intracellular pH threshold ~6.5. Acid stress reduces the internal pH below this threshold, increasing OmpR dimerization and DNA binding. During osmotic stress, the internal pH is above the threshold, triggering distinct OmpR-related pathways. Preventing intracellular acidification of Salmonella renders it avirulent, suggesting that acid stress pathways represent a potential therapeutic target. These results further emphasize the advantages of single cell analysis over studies of population averages.

TGF-ß activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-ß signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-ß blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-ß is regulated at the level of activation, but how TGF-ß is activated in this disease is unknown. Here we show TGF-ß activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-ß activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-ß could thus be a therapeutic approach in TGF-ß-dependent vascular diseases.

Hierarchical modeling and other spatial analyses in prostate cancer incidence data.

BACKGROUND: State central cancer registries are often asked to respond to questions about the spatial distribution of cancer cases. Spatial analysis methods and technology are evolving rapidly, and can be a considerable challenge to registries that do not have staff with training in this area. The purpose of this article is to describe a general methodological approach that potentially might be a starting point for many cancer registry spatial analyses at the county level. METHODS: Prostate cancer incident cases (N=31,159) from the Louisiana Tumor Registry from 1988 to 1999 were used for illustrative purposes. To explore spatio-temporal patterns, analyses focused on four time periods, each 3 years in length: 1998-1990, 1991-1993, 1994-1996, and 1997-1999. For each time period, race-specific (white and black), direct age-adjusted incidence rates and indirect standardized incidence ratios (SIRs) were calculated, smoothed using Bayesian methods, and assessed for evidence of spatial autocorrelation using global and local Moran's I. Hierarchical generalized linear models (HGLM) were fitted to identify significant covariates. Clusters of elevated and lower rates were identified using a spatial scan statistic (SaTScan). RESULTS: Temporal trends in SIRs in both race groups were consistent with the introduction of prostate specific antigen (PSA) testing in Louisiana during the late 1980s and early 1990s, but possibly with a lag in black males. Clusters of lower than expected values were observed for white males in the central (p=0.001) and southeastern coastal areas (p=0.001), and to a greater extent for black males in the central (p=0.001), southwestern and southeastern coastal parishes (p=0.001). CONCLUSIONS: Mapping disease occurrence by time period is an effective way to explore spatio-temporal patterns. HGLM models and software are available to control for covariates and for unstructured and spatially structured variability that may confound spatial variability patterns.

Stigma and Discontinuity in Multilevel Senior Housing's Continuum of Care.

PURPOSE OF THE STUDY: This article presents data from 2 qualitative studies, confirming what gerontologists observed 30 years ago. Multilevel senior housing residents experience stigma and distress in an environment where people are grouped by levels of functioning. DESIGN AND METHODS: Qualitative, interview-based (N = 367) studies were conducted in senior housing settings offering multiple levels of care (N = 7). Analyses involved revisiting coded narrative data, ethnographers' field-based knowledge, and identification of pattern saturation. RESULTS: Residents and places reflecting the highest levels of care are stigmatized in a context where people are monitored for health changes and required to relocate. Consequently, residents self-isolate, develop a diminished sense of self, and hide health and cognitive conditions out of fear of relocation. IMPLICATIONS: Developers, operators, staff, and potential residents need to recognize the personal and social challenges typically experienced even in within-site relocation. It is important to rethink the predominant model of senior housing that requires residents with changing needs to move and adapt to the setting.