MicroRNA and metabolomics signatures for adrenomyeloneuropathy disease severity

Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro-RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA-seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient\u27s clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease-severity-specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) (r (2) = 0.83, p \u3c 0.00001), dehydroepiandrosterone sulfate (DHEA-S; r (2) = 0.82, p \u3c 0.00001), hypoxanthine (r (2) = 0.82, p \u3c 0.00001), as well as miRNA-432-5p (r (2) = 0.68, p \u3c 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF-1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease-severity-specific mechanisms as a function of disease severity

Golden gaskets: variations on the Sierpi\'nski sieve

We consider the iterated function systems (IFSs) that consist of three general similitudes in the plane with centres at three non-collinear points, and with a common contraction factor \la\in(0,1). As is well known, for \la=1/2 the invariant set, \S_\la, is a fractal called the Sierpi\'nski sieve, and for \la<1/2 it is also a fractal. Our goal is to study \S_\la for this IFS for 1/2<\la<2/3, i.e., when there are "overlaps" in \S_\la as well as "holes". In this introductory paper we show that despite the overlaps (i.e., the Open Set Condition breaking down completely), the attractor can still be a totally self-similar fractal, although this happens only for a very special family of algebraic \la's (so-called "multinacci numbers"). We evaluate \dim_H(\S_\la) for these special values by showing that \S_\la is essentially the attractor for an infinite IFS which does satisfy the Open Set Condition. We also show that the set of points in the attractor with a unique ``address'' is self-similar, and compute its dimension. For ``non-multinacci'' values of \la we show that if \la is close to 2/3, then \S_\la has a nonempty interior and that if \la<1/\sqrt{3} then \S_\la$ has zero Lebesgue measure. Finally we discuss higher-dimensional analogues of the model in question.Comment: 27 pages, 10 figure

Socioeconomic inequalities in health among Swedish adolescents - adding the subjective perspective

Abstract Background Socioeconomic inequalities in adolescent health predict future inequalities in adult health. Subjective measures of socioeconomic status (SES) may contribute with an increased understanding of these inequalities. The aim of this study was to investigate socioeconomic health inequalities using both a subjective and an objective measure of SES among Swedish adolescents. Method Cross-sectional HBSC-data from 2002 to 2014 was used with a total sample of 23,088 adolescents aged 11–15 years. Three measures of self-rated health (dependent variables) were assessed: multiple health complaints, life satisfaction and health perception. SES was measured objectively by the Family Affluence Scale (FAS) and subjectively by “perceived family wealth” (independent variables). The trend for health inequalities was investigated descriptively with independent t-tests and the relationship between independent and dependent variables was investigated with multiple logistic regression analysis. Gender, age and survey year was considered as possible confounders. Results Subjective SES was more strongly related to health outcomes than the objective measure (FAS). Also, the relation between FAS and health was weakened and even reversed (for multiple health complaints) when subjective SES was tested simultaneously in regression models (FAS OR: 1.03, CI: 1.00;1.06 and subjective SES OR: 0.66, CI: 0.63;0.68). Conclusions The level of socioeconomic inequalities in adolescent health varied depending on which measure that was used to define SES. When focusing on adolescents, the subjective appraisals of SES is important to consider because they seem to provide a stronger tool for identifying inequalities in health for this group. This finding is important for policy makers to consider given the persistence of health inequalities in Sweden and other high-income countries

Optimal NHS service delivery to care homes: a realist evaluation of the features and mechanisms that support effective working for the continuing care of older people in residential settings

Background Care homes are the institutional providers of long-term care for older people. The OPTIMAL study argued that it is probable that there are key activities within different models of health-care provision that are important for residents’ health care. Objectives To understand ‘what works, for whom, why and in what circumstances?’. Study questions focused on how different mechanisms within the various models of service delivery act as the ‘active ingredients’ associated with positive health-related outcomes for care home residents. Methods Using realist methods we focused on five outcomes: (1) medication use and review; (2) use of out-of-hours services; (3) hospital admissions, including emergency department attendances and length of hospital stay; (4) resource use; and (5) user satisfaction. Phase 1: interviewed stakeholders and reviewed the evidence to develop an explanatory theory of what supported good health-care provision for further testing in phase 2. Phase 2 developed a minimum data set of resident characteristics and tracked their care for 12 months. We also interviewed residents, family and staff receiving and providing health care to residents. The 12 study care homes were located on the south coast, the Midlands and the east of England. Health-care provision to care homes was distinctive in each site. Findings Phase 1 found that health-care provision to care homes is reactive and inequitable. The realist review argued that incentives or sanctions, agreed protocols, clinical expertise and structured approaches to assessment and care planning could support improved health-related outcomes; however, to achieve change NHS professionals and care home staff needed to work together from the outset to identify, co-design and implement agreed approaches to health care. Phase 2 tested this further and found that, although there were few differences between the sites in residents’ use of resources, the differences in service integration between the NHS and care homes did reflect how these institutions approached activities that supported relational working. Key to this was how much time NHS staff and care home staff had had to learn how to work together and if the work was seen as legitimate, requiring ongoing investment by commissioners and engagement from practitioners. Residents appreciated the general practitioner (GP) input and, when supported by other care home-specific NHS services, GPs reported that it was sustainable and valued work. Access to dementia expertise, ongoing training and support was essential to ensure that both NHS and care home staff were equipped to provide appropriate care. Limitations Findings were constrained by the numbers of residents recruited and retained in phase 2 for the 12 months of data collection. Conclusions NHS services work well with care homes when payments and role specification endorse the importance of this work at an institutional level as well as with individual residents. GP involvement is important but needs additional support from other services to be sustainable. A focus on strategies that promote co-design-based approaches between the NHS and care homes has the potential to improve residents’ access to and experience of health care. Funding The National Institute for Health Research Health Services and Delivery Research programme

Primary peritoneal and ovarian cancers: an epidemiological comparative analysis

We performed case–control analyses using data from the North Carolina Ovarian Cancer Study to determine risk factors that distinguish primary peritoneal cancer (PPC) from epithelial ovarian cancer (EOC). Our risk factor analyses were restricted to invasive serous cancers including 495 EOC cases, 62 PPC cases and 1,086 control women. Logistic regression analyses were used to calculate adjusted odds ratios and 95% confidence intervals for risk factor associations. Although many case–control associations for the invasive serous PPC cases were similar to those of the invasive serous EOC cases, some differences were observed including a twofold increase in risk of invasive serous PPC in women who were ≥35 years at last pregnancy, whereas a decreased risk was observed for invasive serous EOC risk. We could not confirm a previous report of an association between tubal ligation and PPC, a factor consistently associated with a decreased risk of EOC. The difference in the risk factor associations between invasive serous PPC and EOC cancers suggests divergent molecular development of peritoneal and ovarian cancers. A larger study to determine risk factors for invasive serous PPC is warranted

TeV Particle Astrophysics II: Summary comments

A unifying theme of this conference was the use of different approaches to understand astrophysical sources of energetic particles in the TeV range and above. In this summary I review how gamma-ray astronomy, neutrino astronomy and (to some extent) gravitational wave astronomy provide complementary avenues to understanding the origin and role of high-energy particles in energetic astrophysical sources.Comment: 6 pages, 4 figures; Conference summary talk for "TeV Particle Astrophysics II" at University of Wisconsin, Madison, 28-31 August 200

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility

IMPORTANCE: Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. OBJECTIVE: To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. EXPOSURES: Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. MAIN OUTCOMES AND MEASURES: The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. RESULTS: There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer

Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay ( CONCLUSION: Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection