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.

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.

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.

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.

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.

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.

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.

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.

Specialty drug coverage varies between health plans' medical and pharmacy benefit policies.

BACKGROUND: In an effort to control drug spending, health plans are increasingly shifting specialty drugs from their medical benefit to the pharmacy benefit. One consequence of this trend is that some health plans have both a medical and a pharmacy coverage policy for the same drug. OBJECTIVE: To examine how frequently health plans issue medical and pharmacy benefit policies for the same specialty drug and to evaluate the concordance between plans' medical and pharmacy policies when plans issue both policy types. METHODS: We identified specialty drug coverage policies from the Tufts Medical Center Specialty Drug Evidence and Coverage Database, which includes policies issued by 17 of the largest US commercial health plans. Policies were current as of August 2020. We determined plans that issued both medical and pharmacy policies. Next, we identified drugs with "medical-pharmacy policy pairs," ie, drugs for which a plan issued both a medical and a pharmacy policy. For these pairs, we compared the plan's policies while accounting for the following coverage criteria: patient subgroups (patients must meet certain clinical criteria), prescriber requirements (a specialist must prescribe the drug), and step therapy protocols (patients must first fail alternative treatments). We considered medical-pharmacy policy pairs to be discordant if coverage criteria differed, eg, the medical policy included a prescriber requirement but the pharmacy policy did not. RESULTS: Eight plans issued separate medical and pharmacy benefit coverage policies for the same specialty drug and indication. Among these 8 plans, we identified 1,619 medical-pharmacy policy pairs. Eighty-six percent of pairs were concordant (1,386/1,619), and 14% were discordant (233/1,619). Discordance was most often due to differences in plans' application of step therapy protocols (184/233), followed by prescriber requirements (52/233) and patient subgroups (25/233). Forty pairs were discordant in multiple ways. Of discordant pairs, medical policies were more restrictive 41% (96/233) of the time; pharmacy policies were more restrictive 54% (125/233) of the time; 5% of the time (12/233), the medical policy was more restrictive in some ways, but the pharmacy policy was more restrictive in others. Overall, plans imposed coverage restrictions in their medical and pharmacy policies with similar frequencies. CONCLUSIONS: Commercial health plans' medical and pharmacy coverage policies for the same specialty drugs tended to be concordant, although we found coverage criteria to be discordant 14% of the time. Medical and pharmacy policies that are inconsistent in their coverage criteria and restrictions complicate, and potentially hinder, patients' access to specialty drugs. DISCLOSURES: Drs Kauf, O'Sullivan, and Strand were employees of Alkermes, Inc., when the study was conducted and may own stock in the company. Mx Levine, Mr Panzer, and Dr Chambers have no conflicts of interest to disclose. This research study was supported by Alkermes, Inc.

Civilian perception of the role of the military in Nigeria's 2014 Ebola outbreak and health-related responses in the North East region.

INTRODUCTION: Civilian-military relations play an important yet under-researched role in low-income and middle-income country epidemic response. One crucial component of civilian-military relations is defining the role of the military. This paper evaluates the role of Nigerian military during the 2014-2016 West African Ebola epidemic. METHODS: Focus groups and key informant interviews were conducted throughout three states in North East region of Nigeria: Borno, Yobe and Adamawa. Participants were identified through mapping of stakeholder involvement in Nigerian epidemic response. English-translated transcripts of each key informant interview and focus group discussion were then coded and key themes were elucidated and analysed. RESULTS: Major themes elucidated include developing inclusive coordination plans between civilian and military entities, facilitating human rights reporting mechanisms and distributing military resources more equitably across geographical catchment areas. The Nigerian Military served numerous functions: 37% (22/59) of respondents indicated 'security/peace' as the military's primary function, while 42% (25/59) cited health services. Variations across geographic settings were also noted: 35% (7/20) of participants in Borno stated the military primarily provided transportation, while 73% (11/15) in Adamawa and 29% (7/24) in Yobe listed health services. CONCLUSIONS: Robust civilian-military relations require an appropriately defined role of the military and clear civilian-military communication. Important considerations to contextualise civilian-military relations include military cultural-linguistic understanding, human rights promotion, and community-based needs assessments; such foci can facilitate the military's understanding of community norms and civilian cooperation with military aims. In turn, more robust civilian-military relations can promote overall epidemic response and reduce the global burden of disease.

Oral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection.

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4+ T cell hyperactivation, and, counterintuitively, enrichment of FOXP3+ T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1ß. Mechanistically, IL-1ß upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. The FOXP3+ T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3+ T cells, and their presence strongly correlates with CD4+ T cell hyper-activation. This suggests that FOXP3+ T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy.

Rare Variants in the DNA Repair Pathway and the Risk of Colorectal Cancer.

BACKGROUND: Inherited susceptibility is an important contributor to colorectal cancer risk, and rare variants in key genes or pathways could account in part for the missing proportion of colorectal cancer heritability. METHODS: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models, adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. RESULTS: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian risk index (BRI) method [summary Bayes factor (BF)BRI = 2604.23]. A rare coding variant in this gene, rs139401613, was the top associated variant (P = 1.01 × 10-6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative BRI (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI = 17852.4), specifically with the nonhomologous end joining (BFiBRI = 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, and ERCC8 as the top associated DNA repair genes (summary BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and rs201642761 being the most likely associated variants in these genes, respectively. CONCLUSIONS: We identified novel variants and genes associated with colorectal cancer risk and provided additional evidence for a role of DNA repair in colorectal cancer tumorigenesis. IMPACT: This study provides new insights into the genetic predisposition to colorectal cancer, which has potential for translation into improved risk prediction.

Recovering from the Ebola crisis: 'Social Reconnection Groups' in a rural Liberian community.

In 2014/2015, International Medical Corps (IMC) operated two Ebola Treatment Units (ETUs) in Liberia and three in Sierra Leone when the Ebola virus disease epidemic killed over 11,000 people across Liberia, Sierra Leone and Guinea. As Ebola cases declined in Liberia, IMC Psychosocial teams transitioned to working in communities highly affected by the epidemic. This article describes IMC's experience with developing and implementing a community-based mental health and psychosocial group intervention in a rural, severely affected Liberian town - Mawah - where 46 out of approximately 800 community members were infected, 39 of whom died. In this paper, we present how the group intervention, named 'Social Reconnection Groups', was developed and implemented. We then discuss intervention strengths, challenges, key lessons learnt and recommendations for how Social Reconnection Groups can be adapted for use in similar settings.

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.

Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

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.

A systematic review of studies of DNA methylation in the context of a weight loss intervention.

AIM: Obesity results from the interaction of genetic and environmental factors, which may involve epigenetic mechanisms such as DNA methylation (DNAm). MATERIALS & METHODS: We have followed the PRISMA protocol to select studies that analyzed DNAm at baseline and end point of a weight loss intervention using either candidate-locus or genome-wide approaches. RESULTS: Six genes displayed weight loss associated DNAm across four out of nine genome-wide studies. Weight loss is associated with significant but small changes in DNAm across the genome, and weight loss outcome is associated with individual differences in baseline DNAm at several genomic locations. CONCLUSION: The identified weight loss associated DNAm markers, especially those showing reproducibility across different studies, warrant validation by further studies with robust design and adequate power.