The Health Benefits, Costs, and Cost-Effectiveness of Ultraorphan Drugs.

OBJECTIVES: To examine ultraorphan drugs in terms of incremental health, costs, and cost-effectiveness compared with more prevalent disease drugs. METHODS: We identified Food and Drug Administration drug approvals from 1999 to 2019. For drugs approved for multiple indications, we considered each drug-indication pair separately. Utilizing Food and Drug Administration's orphan drug designation and US disease prevalence, we categorized drug-indication pairs as: ultraorphan (<10 000 patients), "other" orphan (≥10 000 and <200 000), and nonorphan (≥200 000). We searched the PubMed database for cost-effectiveness analyses and comparative effectiveness studies. We excluded manufacturer-funded studies. We extracted estimates of incremental health gains in terms of quality-adjusted life-years (QALYs) and incremental costs associated with drug-indication pairs compared with the standard of care at the time of their approval. We compared QALY gains, added costs, and incremental cost-effectiveness ratios (ICERs) using the Kruskal-Wallis, Mann-Whitney U (MWU), and Kolmogorov-Smirnov (KS) tests. RESULTS: Median incremental QALYs, costs, and ICERs differed across nonorphan, "other" orphan, and ultraorphan categories (Kruskal-Wallis P < .01). Compared with nonorphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.050, MWU P < .01, KS P < .01), larger costs ($172 231 vs $3360, MWU P < .01, KS P < .01), and larger ICERs ($1 216 184/QALY vs $114 061/QALY, MWU P < .01, KS P <.01). Compared with "other" orphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.310, MWU P =.65, KS P =.32), larger costs ($172 231 vs $69 308, MWU P = .03, KS P = .03), and larger ICERs ($1 216 184/QALY vs $223 472/QALY, MWU P <.01, KS P <.01). CONCLUSIONS: Novel ultraorphan drugs typically offer larger incremental health gains than drugs for more prevalent diseases, but because of their substantial added costs, are typically less cost-effective.

Overcoming barriers to implementation: mapping implementation strategies in four hospital in home programs within the Veterans Health Administration.

The Hospital at Home model, called Hospital-in-Home (HIH) in the Department of Veterans Affairs, delivers coordinated, high-value care aligned with older adult and caregiver preferences. Documenting implementation barriers and corresponding strategies to overcome them can address challenges to widespread adoption. To evaluate HIH implementation barriers and identify strategies to address them, we conducted interviews with 8 HIH staff at 4 hospitals between 2010 and 2013. We utilized qualitative directed content analysis guided by the Consolidated Framework for Implementation Research (CFIR) and mapped identified barriers to possible strategies using the CFIR-Expert Recommendations for Implementing Change (ERIC) Matching Tool. We identified 11 barriers spanning 5 CFIR domains. Three implementation strategies - identifying and preparing champions, conducting educational meetings, and capturing and sharing local knowledge - achieved high expert endorsement for each barrier. A mix of strategies targeting resources, organizational readiness and fit, and leadership engagement should be considered to support the sustainability and spread of HIH.

Genome-wide association study of circulating folate one-carbon metabolites.

Experimental, observational, and clinical trials support a critical role of folate one-carbon metabolism (FOCM) in colorectal cancer (CRC) development. In this report, we focus on understanding the relationship between common genetic variants and metabolites of FOCM. We conducted a genome-wide association study of FOCM biomarkers among 1,788 unaffected (without CRC) individuals of European ancestry from the Colon Cancer Family Registry. Twelve metabolites, including 5-methyltetrahydrofolate, vitamin B2 (flavin mononucleotide and riboflavin), vitamin B6 (4-pyridoxic acid, pyridoxal, and pyridoxamine), total homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, and creatinine were measured from plasma using liquid chromatography-mass spectrometry (LC-MS) or LC-MS/MS. For each individual biomarker, we estimated genotype array-specific associations followed by a fixed-effect meta-analysis. We identified the variant rs35976024 (at 2p11.2 and intronic of ATOH8) associated with total homocysteine (p = 4.9 × 10-8 ). We found a group of six highly correlated variants on chromosome 15q14 associated with cystathionine (all p < 5 × 10-8 ), with the most significant variant rs28391580 (p = 2.8 × 10-8 ). Two variants (rs139435405 and rs149119426) on chromosome 14q13 showed significant (p < 5 × 10-8 ) associations with S-adenosylhomocysteine. These three biomarkers with significant associations are closely involved in homocysteine metabolism. Furthermore, when assessing the principal components (PCs) derived from seven individual biomarkers, we identified the variant rs12665366 (at 6p25.3 and intronic of EXOC2) associated with the first PC (p = 2.3 × 10-8 ). Our data suggest that common genetic variants may play an important role in FOCM, particularly in homocysteine metabolism.

Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease.

Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn's disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease.

Feasibility of Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests in systemic lupus erythematosus outpatients.

Objective The aims of this study were to assess the feasibility of administering Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests (CATs) to outpatients with systemic lupus erythematosus (SLE). Methods Adults with SLE were recruited during routine outpatient visits at an SLE Center of Excellence. Participants completed 14 PROMIS CATs and provided feedback on their experience. Differences in socio-demographic and clinical characteristics between participants and non-participants were evaluated. Results A total of 204 (86%) of 238 socioeconomically and racially diverse SLE patients completed PROMIS CATs. There were no significant differences between participants and non-participants. Time constraints were cited most frequently as reasons for non-participation. More than 75% of individuals submitted positive comments, including approval of the content and format of questions, and the survey's promotion of self-reflection. A minority of participants cited challenges, most often related to question phrasing (8%) and technical difficulties (6%). Conclusions The administration of PROMIS CATs was feasible and positively received in a diverse cohort of SLE outpatients. Neither socio-demographic nor disease characteristics were significant barriers to successful completion of PROMIS CATs. PROMIS CATs have great potential for efficiently measuring important patient-centered outcomes in routine clinical care of a wide range of SLE patients.

The association between physical activity and cognition in men with and without HIV infection.

OBJECTIVES: HIV-associated neurocognitive disorders are highly prevalent, and physical activity (PA) is a modifiable behaviour that may affect neurocognitive function. Our objective was to determine the association between PA and neurocognitive function and the effect of HIV on this association. METHODS: PA was assessed in the Multicenter AIDS Cohort Study with the International Physical Activity Questionnaire. A neuropsychological test battery assessed global impairment and domain-specific impairment (executive function, speed of processing, working memory, learning, memory, and motor function) every 2 years. Semiannually, the Symbol Digit Modalities Test and Trail Making Test Parts A and B were performed. Adjusted logistic regression models were used to assess the PA-neurocognitive function association. Using longitudinal data, we also assessed the PA category-decline of neurocognitive function association with multivariate simple regression. RESULTS: Of 601 men, 44% were HIV-infected. Low, moderate, and high PA was reported in 27%, 25%, and 48% of the HIV-infected men vs. 19%, 32% and 49% of the HIV-uninfected men, respectively. High PA was associated with lower odds of impairment of learning, memory, and motor function [odds ratio (OR) ranging from 0.52 to 0.57; P < 0.05 for all]. The high PA-global impairment association OR was 0.63 [95% confidence interval (CI) 0.39, 1.02]. Among HIV-infected men only, across multiple domains, the high PA-impairment association was even more pronounced (OR from 0.27 to 0.49). Baseline high/moderate PA was not associated with decline of any domain score over time. HIV infection was marginally associated with a higher speed of decline in motor function. CONCLUSIONS: A protective effect of high PA on impairment in neurocognitive domains was observed cross-sectionally. Longitudinal PA measurements are needed to elucidate the PA-neurocognitive function relationship over time.

Team-based model for non-operating room airway management: validation using a simulation-based study.

BACKGROUND: Non-operating room (non-OR) airway management has previously been identified as an area of concern because it carries a significant risk for complications. One reason for this could be attributed to the independent practice of residents in these situations. The aim of the present study was to ascertain whether differences in performance exist between residents working alone vs with a resident partner when encountering simulated non-OR airway management scenarios. METHODS: Thirty-six anaesthesia residents were randomized into two groups. Each group experienced three separate scenarios (two scenarios initially and then a third 6 weeks later). The scenarios consisted of one control scenario and two critical event scenarios [i.e. asystole during laryngoscopy and pulseless electrical activity (PEA) upon post-intubation institution of positive pressure ventilation]. One group experienced the simulated non-OR scenarios alone (Solo group). The other group consisted of resident pairs, participating in the same three scenarios (Team group). RESULTS: Although the time to intubation did not differ between the Solo and Team groups, there were several differences in performance. The Team group received better overall performance ratings for the asystole (8.5 vs 5.5 out of 10; P<0.001) and PEA (8.5 vs 5.8 out of 10; P<0.001) scenarios. The Team group was also able to recognize asystole and PEA conditions faster than the Solo group [10.1 vs 23.5 s (P<0.001) and 13.3 vs 36.0 s (P<0.001), respectively]. CONCLUSIONS: Residents who performed a simulated intubation with a second trained provider had better overall performance than those who practised independently. The residents who practised in a group were also faster to diagnose serious complications, including peri-intubation asystole and PEA. Given these data, it is reasonable that training programmes consider performing all non-OR airway management with a team-based method.

Learning through simulated independent practice leads to better future performance in a simulated crisis than learning through simulated supervised practice.

BACKGROUND: Anaesthetists may fail to recognize and manage certain rare intraoperative events. Simulation has been shown to be an effective educational adjunct to typical operating room-based education to train for these events. It is yet unclear, however, why simulation has any benefit. We hypothesize that learners who are allowed to manage a scenario independently and allowed to fail, thus causing simulated morbidity, will consequently perform better when re-exposed to a similar scenario. METHODS: Using a randomized, controlled, observer-blinded design, 24 first-year residents were exposed to an oxygen pipeline contamination scenario, either where patient harm occurred (independent group, n=12) or where a simulated attending anaesthetist intervened to prevent harm (supervised group, n=12). Residents were brought back 6 months later and exposed to a different scenario (pipeline contamination) with the same end point. Participants' proper treatment, time to diagnosis, and non-technical skills (measured using the Anaesthetists' Non-Technical Skills Checklist, ANTS) were measured. RESULTS: No participants provided proper treatment in the initial exposure. In the repeat encounter 6 months later, 67% in the independent group vs 17% in the supervised group resumed adequate oxygen delivery (P=0.013). The independent group also had better ANTS scores [median (interquartile range): 42.3 (31.5-53.1) vs 31.3 (21.6-41), P=0.015]. There was no difference in time to treatment if proper management was provided [602 (490-820) vs 610 (420-800) s, P=0.79]. CONCLUSIONS: Allowing residents to practise independently in the simulation laboratory, and subsequently, allowing them to fail, can be an important part of simulation-based learning. This is not feasible in real clinical practice but appears to have improved resident performance in this study. The purposeful use of independent practice and its potentially negative outcomes thus sets simulation-based learning apart from traditional operating room learning.

Assisted reproductive technology in SLE and APS.

Assisted reproductive technology (ART) procedures, which include in vitro fertilization (IVF), are performed frequently and may be considered for patients with systemic lupus erythematosus and antiphospholipid syndrome. These procedures do not appear to increase the risk of disease flare or thrombosis in these patients. In addition, the presence of antiphospholipid antibodies (aPL) does not independently predict the outcome of IVF pregnancies. As with pregnancies that are achieved naturally, candidates for ART should have quiescent disease for at least 6 months prior to attempting pregnancy for the best possible outcome for mother and child.

The efficacy and safety of bazedoxifene in postmenopausal women by baseline kidney function status.

INTRODUCTION: Two global, double-blind, placebo- and active-controlled, phase-3 studies (2-year prevention (n = 1583) and 3-year treatment (n = 7492)) have shown that bazedoxifene (BZA) is safe and effective for prevention and treatment of postmenopausal osteoporosis. OBJECTIVE: To evaluate the efficacy/safety of BZA according to baseline kidney function. METHODS: Data for the BZA 20- and 40-mg and placebo groups from both studies were integrated for assessment of bone turnover markers (BTMs), bone mineral density (BMD), and fracture incidence (treatment study only). Safety was assessed using integrated data for the BZA, placebo, and raloxifene 60-mg groups from both studies. Baseline glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease Study equation; among subjects with baseline GFR, renal function categories were defined by GFR (ml/min per 1.73 m(2)): normal (GFR ≥ 90; n = 1982), mild impairment (60 ≤ GFR < 90; n = 6032), or moderate/severe impairment (GFR < 60; n = 723). RESULTS: Demographics were similar across treatment groups and within GFR subgroups. Across GFR subgroups, BZA 20 and 40 mg reduced BTM levels and improved lumbar spine and total hip BMD versus placebo. At month 24, there were significant treatment-by-GFR (p = 0.003) and treatment-by-serum creatinine (p = 0.034) interactions for the increase in lumbar spine BMD versus placebo. Fracture incidence was lower with BZA than placebo across all GFR categories, with no treatment-by-GFR interaction. There were no significant differences among treatment groups in incidences of overall, serious, or renal-related adverse events across GFR subgroups. CONCLUSIONS: Mild to moderate kidney impairment did not affect the efficacy and safety of BZA in postmenopausal women.

Are Drug Novelty Characteristics Associated With Greater Health Benefits?

OBJECTIVE: The aim of this study was to examine the association between characteristics of novel drugs and incremental health gains relative to standard of care, in terms of quality-adjusted life-years (QALYs). METHODS: This study's unit of analysis is the drug-indication pair. For pairs approved by the US FDA from 1999 to 2018, we quantified incremental health gains using QALYs from the published literature and characterized each pair's novelty in terms of a series of six binary (yes/no) characteristics of novel drugs given special consideration by Health Technology Assessment agencies: Novel mechanism of action, Indicated for a rare disease, Indicated for a pediatric population, Treats a serious condition, Offers meaningful improvement over available therapies, and Potential to address unmet clinical needs. We analyzed measures of bivariate association (Mann-Whitney U and Kolmogorov-Smirnov tests) and multivariable regression, accounting for the influence of multiple novelty characteristics simultaneously. RESULTS: Our sample of 146 drugs represents 21% of drugs approved the FDA in the time period (1999-2018). Median and mean QALY gains for 'novel' drug-indication pairs exceeded corresponding QALY gains for non-novel drug-indication pairs. For most comparisons, the bivariate relationships between QALY gains and novelty characteristics were significant at p < 0.05 except for novel mechanism of action (Kolmogorov-Smirnov test) and pediatric indication (both bivariate tests). Multivariable models revealed an independent association between novelty characteristics and QALY gain except for unmet clinical need and indicated for a rare disease. CONCLUSIONS: Drugs with novelty characteristics conferred larger health gains than drugs without these characteristics in bivariate analysis, multivariable models, or both. Future research should examine other aspects of drug novelty, such as patient and health system costs and equitable access.

Medicare, Medicaid, and dual enrollment for adults with intellectual and developmental disabilities.

OBJECTIVE: Given high rates of un- and underemployment among disabled people, adults with intellectual and developmental disabilities rely on Medicaid, Medicare, or both to pay for healthcare. Many disabled adults are Medicare eligible before the age of 65 but little is known as to why some receive Medicare services while others do not. We described the duration of Medicare enrollment for adults with intellectual and developmental disabilities in 2019 and then compared demographics by enrollment type (Medicare-only, Medicaid-only, dual-enrolled). Additionally, we examined the percent in each enrollment type by state, and differences in enrollment type for those with Down syndrome. DATA SOURCES AND STUDY SETTING: 2019 Medicare and Medicaid claims data for all adults (≥18 years) in the US with claim codes for intellectual disability, Down syndrome, or autism at any time between 2011 and 2019. STUDY DESIGN: Administrative claims cohort. DATA COLLECTION AND ABSTRACTION METHODS: Data were from the Transformed Medicaid Statistical Information System Analytic Files and Medicare Beneficiary Summary files. PRINCIPLE FINDINGS: In 2019, Medicare insured 582,868 adults with identified intellectual disability, autism, or Down syndrome. Of 582,868 Medicare beneficiaries, 149,172 were Medicare only and 433,396 were dual-enrolled. Most Medicare enrollees were enrolled as child dependents (61.5%) Medicaid-only enrollees (N = 819,256) were less likely to be white non-Hispanic (58.5% white non-Hispanic vs. 72.9% white non-Hispanic in dual-enrolled), more likely to be Hispanic (19.6% Hispanic vs. 9.2% Hispanic in dual-enrolled) and were younger (mean 34.2 years vs. 50.5 years dual-enrolled). CONCLUSION: There is heterogeneity in public insurance enrollment which is associated with state and disability type. Action is needed to ensure all are insured in the program that works for their healthcare needs.

Care partner evaluation of the behaviors in the Cohen-Mansfield Agitation Inventory.

Introduction: Agitation is a common symptom in patients with Alzheimer's dementia. But agitation can be a heterogeneous symptom, encompassing a diverse array of behaviors exhibited by patients. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale that is used to systematically assess the frequency and severity of agitation in older adults as rated by a primary caregiver. The CMAI was originally designed for use by professional care givers in institutional care settings. Alzheimer's dementia, however, is associated with a significant burden on family members, who provide the majority of care, and other informal care partners. Methods: Our qualitative study aimed to assess the accuracy and applicability of the CMAI according to the needs and perceptions of non-professional care partners. Specifically, we wanted to determine if the behaviors included in the instrument reflect: (a) the care partner's experience with agitation in Alzheimer's dementia patients, (b) how the behaviors and their frequency are related to the perception of agitation severity, and (c) what changes in agitation behaviors are meaningful to care partners. We interviewed 30 care partners for patients with Alzheimer's dementia in the United States. Results: The care partners confirmed all behaviors listed in the CMAI as relevant. The behaviors reflect a spectrum of severity, with aggressive behaviors considered more severe than non-aggressive behaviors and physical behaviors generally considered more severe than verbal behaviors. Any reduction or increase in the frequency of a behavior was meaningful to care partners. Generally, a change from physical to verbal behaviors and aggressive to non-aggressive was considered a meaningful improvement while a change from verbal to physical and non-aggressive to aggressive was considered a meaningful worsening. Discussion: The CMAI appropriately captures relevant behaviors of agitation in Alzheimer's dementia and provides insight into the relative improvement or worsening of agitation symptoms.

Inequities in medicaid home- and community-based services waiver enrollment among people with intellectual and/or developmental disabilities: A nationwide claims-based analysis.

BACKGROUND: States use Medicaid 1915(c) waiver programs to enable access to home- and community-based services for people with intellectual and/or developmental disabilities (I/DD). However, enrollment rates and potential inequities are not well documented, impeding efforts to improve care access and quality for waiver program enrollees, especially for racially minoritized beneficiaries experiencing compounded barriers to services and supports. OBJECTIVE: To characterize year-by-year 1915(c) waiver program enrollment among Medicaid-enrolled adults with I/DD from 2016 to 2019 and to analyze population-level inequities by type of I/DD and racial/ethnic group. METHODS: Our data source was 2016-2019 Medicaid Transformed Medicaid Statistical Information System Analytic Files Demographic and Eligibility files for beneficiaries with Down syndrome, autism, and intellectual disability. We used generalized estimating equation linear models to estimate the associations of type of I/DD and racial/ethnic group with the probability of 1915(c) waiver program enrollment and reported (1) unadjusted estimates and (2) estimates adjusted for demographics with state and year fixed effects. RESULTS: From 2016 to 2019, across all types of I/DD and racial/ethnic groups, unadjusted 1915(c) waiver program enrollment rates ranged from 40 to 60 % nationwide. We found modest growth in 1915(c) I/DD waiver program enrollment but persistent inequities over time. Compared to beneficiaries with intellectual disabilities, beneficiaries with autism were less likely to enroll while beneficiaries with Down syndrome were more likely. While some racial/ethnic groups had higher unadjusted mean enrollment, after adjustment, racially minoritized beneficiaries were 3.66-12.0 percentage points less likely to enroll compared to white non-Hispanic beneficiaries. CONCLUSIONS: Given extensive waiting lists for 1915(c) waiver programs, Medicaid programs should evaluate existing enrollment and authorization processes and consider alternative HCBS program authorities.

T staging esophageal tumors with x rays.

With histopathology results typically taking several days, the ability to stage tumors during interventions could provide a step change in various cancer interventions. X-ray technology has advanced significantly in recent years with the introduction of phase-based imaging methods. These have been adapted for use in standard labs rather than specialized facilities such as synchrotrons, and approaches that enable fast 3D scans with conventional x-ray sources have been developed. This opens the possibility to produce 3D images with enhanced soft tissue contrast at a level of detail comparable to histopathology, in times sufficiently short to be compatible with use during surgical interventions. In this paper we discuss the application of one such approach to human esophagi obtained from esophagectomy interventions. We demonstrate that the image quality is sufficiently high to enable tumor T staging based on the x-ray datasets alone. Alongside detection of involved margins with potentially life-saving implications, staging tumors intra-operatively has the potential to change patient pathways, facilitating optimization of therapeutic interventions during the procedure itself. Besides a prospective intra-operative use, the availability of high-quality 3D images of entire esophageal tumors can support histopathological characterization, from enabling "right slice first time" approaches to understanding the histopathology in the full 3D context of the surrounding tumor environment.

Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation.

RSV lower respiratory tract infections (LRTI) are among the most common diseases necessitating hospital admission in children. In addition to causing acute respiratory failure, RSV infections are associated with sequelae such as secondary bacterial infections and reactive airway disease. One characteristic host response observed in severe RSV-induced LRTI and/or subsequent development of asthma is increased expression of interleukin (IL)-10. However, contradictory results have been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease. We aimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the host response to RSV LRTI. In this study, we used a lung-specific, inducible IL-10 over-expression (OE) transgenic mouse model to address this question. Our results showed that the presence of IL-10 at the time of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but also late inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression]. While this result appears contradictory to some clinical observations where elevated IL-10 levels are observed in asthmatic patients, we also found that delaying IL-10 OE until the late immune response to RSV infection, additive effects rather than inhibitory effects were observed. Importantly, in non-infected, IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-related chemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) and regulated upon activation normal T cell expressed and secreted (RANTES)] expression. We identified a subset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source of IL-10-induced IL-13 production. Therefore, the augmented pathological responses observed in our 'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone. Taken together, our study indicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timing of when elevated IL-10 is expressed in the lung.

Gain of function mutations in p53.

We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS-2 cells). Also, mutant human p53 alleles, unlike the wild-type p53 protein, could also enhance the expression of a test gene regulated by the multi-drug resistance enhancer-promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.

The transcriptome of Arabidopsis thaliana during systemic acquired resistance.

Infected plants undergo transcriptional reprogramming during initiation of both local defence and systemic acquired resistance (SAR). We monitored gene-expression changes in Arabidopsis thaliana under 14 different SAR-inducing or SAR-repressing conditions using a DNA microarray representing approximately 25-30% of all A. thaliana genes. We derived groups of genes with common regulation patterns, or regulons. The regulon containing PR-1, a reliable marker gene for SAR in A. thaliana, contains known PR genes and novel genes likely to function during SAR and disease resistance. We identified a common promoter element in genes of this regulon that binds members of a plant-specific transcription factor family. Our results extend expression profiling to definition of regulatory networks and gene discovery in plants.

Association of Loneliness with Cognitive Functions.

INTRODUCTION: Observational studies suggest psychosocial factors such as social support and loneliness are associated with vulnerability for cognitive decline in older adults. However, because of racial/ethnic homogeneity in prior studies focused on identifying these associations in predominantly White cohorts, less is known about the generalizability of these putative psychosocial mechanisms in a diverse population. Thus, we evaluated whether lower levels of loneliness were associated with better cognitive performance in our sample. METHODS: We conducted a cross-sectional study using 541 participants from (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) Dementia Cohort. Participants' self-reported loneliness as exposure. Cognitive performance is measured using a neuropsychological battery as the outcome. Raw scores were converted into Z scores, and global cognitive function was created. Generalized estimated equation and robust regression analysis). RESULTS: Better global cognitive function is associated with a lower level of loneliness at (ß = -0.0131, 95 % CI -0.1990, -0.0071) after adjustment for age, gender, and education. Lower levels of loneliness were associated with varying cognitive domains after adjustment for age, gender, and education; and persisted after additional adjustments of vascular risk factors. CONCLUSIONS: Self-reported lower loneliness was associated with higher levels of cognitive performance in a rural South African cohort of Black older adults. Although these findings and the potential of reverse causality need to be further validated, our results suggest that an intervention study may be merited to assess whether reducing loneliness lessens vulnerability to cognitive decline.

Medicaid Enrollment and Service Use Among Adults With Down Syndrome.

Importance: Down syndrome is the leading genetic cause of intellectual disability and automatically qualifies individuals for Social Security Insurance. Therefore, Medicaid is the major health insurance provider for a population at high risk for dementia, obesity, and premature mortality. Despite the importance of Medicaid for adults with Down syndrome, little is known about how this population uses Medicaid. Objective: To describe enrollment in, health care use in, and cost to Medicaid for adults with Down syndrome compared with adults with intellectual disability and a random sample of adults enrolled in Medicaid. Design, Setting, and Participants: In this cohort study, the data are from a claims cohort of adults aged 18 years or older enrolled in Medicaid at any point between January 1, 2011, and December 31, 2019. Participants were enrollees with 1 or more inpatient claim or 2 or more other claims with an International Classification of Diseases, Ninth Revision code or an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code for Down syndrome or intellectual disability as well as a random sample of those without developmental disability. Analyses were conducted from June 2022 to February 2023. Main Outcomes and Measures: Data were linked across 2 data reporting systems. Main outcomes were enrollee demographic characteristics, enrollment characteristics, cost, and service use. Results: This cohort study included 123 024 individuals with Down syndrome (820 273 person-years of coverage; mean [SD] age, 35 [14.7] years; median age, 33 years [IQR, 21-48 years]; 51.6% men; 14.1% Black individuals; 16.7% Hispanic individuals; and 74.6% White individuals), 1 182 246 individuals with intellectual disability (mean [SD] age, 37.1 [16.8] years; median age, 33 years [IQR, 22-50 years]; 56.5% men; 22.0% Black individuals; 11.7% Hispanic individuals; and 69.5% White individuals), and 3 176 371 individuals with no developmental disabilities (mean [SD] age, 38 [18.6] years; median age, 33 years [IQR, 21-52 years]; 43.8% men; 23.7% Black individuals; 20.7% Hispanic individuals; and 61.3% White individuals). Median enrollment in Medicaid for a person with Down syndrome was 8.0 years (IQR, 5.0-9.0 years; mean [SD], 6.6 [2.6] years). Costs were higher for the Down syndrome group (median, $26 278 per person-year [IQR, $11 145-$55 928 per person-year]) relative to the group with no developmental disabilities (median, $6173 per person-year [IQR, $868-$58 390 per person-year]). Asian, Black, Hispanic, Native American, and Pacific Islander adults with Down syndrome had fewer costs and claims per person-year compared with White adults with Down syndrome. Conclusion and Relevance: This cohort study of individuals with Down syndrome enrolled in Medicaid found consistent enrollment and high use of health care in a population with high health care needs. Results were similar comparing individuals with Down syndrome and those with intellectual disability, with both groups differing from a sample of Medicaid enrollees with no developmental disabilities. Medicaid data are a useful tool for understanding the health and well-being of individuals with Down syndrome.