Evidence For Subgroups Research Articles

Emerging drugs for the treatment of adrenocortical carcinoma

ABSTRACT Introduction: Adrenocortical cancer (ACC) is a rare and aggressive disease with a median survival of 14–17 months and 5-year survival of around 20% for advanced disease. Emerging evidence of sub-groups of ACC with specific molecular drivers indicate ACC may be amenable to inhibition of receptor tyrosine kinases involved in growth and angiogenic signaling. A significant subset of patients may also be responsive to immune strategies. Areas covered: This review outlines approaches of targeting upregulated growth pathways including Insulin-like Growth Factor, Vascular Endothelial Growth Factor, Fibroblast Growth Factor and Epidermal Growth Factor Receptor in ACC. Data of immune checkpoint blockade with nivolumab, ipilimumab, pembrolizumab and avelumab is explored in detail. Genomic studies indicate that up to 40% of ACC are driven by dysregulated WNT and glucocorticoid signaling, special focus is placed on emerging drugs in these pathways. Expert opinion: Progress in the treatment of ACC has faced challenges stemming from the rarity of the disease. Given recent advances in the understanding of the molecular pathogenesis of ACC, a window of opportunity has now opened to make significant progress in developing therapeutic options that target key pathways such as excessive glucocorticoid signaling, WNT signaling, cell cycle and immune checkpoints.

The historical phonology of Paunaka (Arawakan)

Abstract This paper applies the comparative method to unravel the historical development of the segmental phonology of Paunaka, an Arawakan language of Bolivia. Although the Paunaka vowel system features a single back rounded vowel, it is rather simple to show that it derives from a system with two back rounded qualities *u and *o, but that the former segment shifted to a high central unrounded vowel ɨ. The language has lost *r unconditionally, implying that Paunaka items with r are probable loanwords. Paunaka underewent a spirantization of *ts, thus merging this affricate with the fricative *s. Although Paunaka shares a coronalization of *k > s with Proto-Mojeño, most of the phonological developments that affected Paunaka are either recurrent in the Arawakan language family or only superficially similar to developments in related languages, and thus provide little weight as evidence for subgrouping. An Appendix is also included, with 105 etymologies matching Paunaka lexical and grammatical morphemes with their cognates in Proto-Mojeño, the two extant Mojeño dialects (Ignaciano and Trinitario) and Terena.

Evidence of subgroups in smokers as revealed in clinical measures and evaluated by neuroimaging data: a preliminary study

To date, fractionation of the nicotine addiction phenotype has been limited to that based primarily on characteristics of cigarette use, although it is widely appreciated that a variety of individual factors are associated with tobacco use disorder. Identifying subtypes of tobacco use disorder based on such factors may lead to better understanding of potential treatment targets, individualize treatments and improve outcomes. In this preliminary study, to identify potential subgroups, we applied hierarchical clustering to a broad range of assessments measuring personality, IQ and psychiatric symptoms, as well as various environmental and experiential characteristics from 102 otherwise healthy cigarette smokers. The identified subgroups were further compared on various resting-state fMRI measures from a subset (N=65) of individuals who also underwent resting-state fMRI scanning. The clustering dendrogram indicated that smokers can be divided into three subgroups. Each subgroup had unique clinical assessment characteristics. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus. Regression analyses showed that amplitude of low frequency fluctuations in the supplementary motor area/middle cingulate cortex differed between groups and were negatively correlated with the Toronto Alexithymia Scale subscale Difficulty Describing Feelings.

A Qualitative Exploration of Adult Baby/Diaper Lover Behavior From an Online Community Sample

This study examined qualitative data on 1,795 male, 139 female, and 78 transgender members of the adult baby/diaper lover (ABDL) online community. Using grounded theory, the analyses examined a description of ABDL practices, explored evidence of subgroups within the ABDL community, and examined the degree to which ABDL behavior involves sexual motivations. Overall, the data suggest there is a fair amount of diversity within the ABDL community. Most participants enjoy wearing diapers or engaging in age regression (as babies or children), and the importance of incontinence may vary. ABDL practices can reflect bondage play for some individuals and a way to cope with medical problems for others. Overall, there is modest evidence of more than two ABDL subgroups. Although a large number of individuals do not see their ABDL practices as sexual in nature, there is a clear contingent that describes sexual motivations. For some, sex during ABDL activity violates conceptions of baby play. Nonsexual motivations include a desire to relax or be carefree as well as a desire to be nurtured. Some diaper lovers and adult babies have the same goals but achieve them in different ways. ABDL practices may be as diverse as seemingly typical sexual behaviors.

Understanding definitions of minimally verbal across instruments: evidence for subgroups within minimally verbal children and adolescents with autism spectrum disorder.

Minimally verbal (MV) children with autism spectrum disorder (ASD) are often assumed to be profoundly cognitively impaired and excluded from analyses due to challenges completing standardized testing protocols. A literature aimed at increasing understanding of this subgroup is emerging; however, the many methods used to define MV status make it difficult to compare studies. Understanding how different instruments and definitions used to identify MV children affect sample composition is critical to advance research on this understudied clinical population. The MV status of 1,470 school-aged children was defined using five instruments commonly used in ASD research. MV sample composition was compared across instruments. Analyses examined the proportion of overlap across MV subgroups and the extent to which child characteristics varied across MV subgroups defined using different definitions or combinations of measures. A total of 257 children were classified as MV on at least one instrument. Proportion of overlap between definitions ranged from 3% to 100%. The stringency of definition (i.e. few-to-no vs. some words) was associated with differences in cognitive and adaptive functioning; more stringent definitions yielded greater consistency of MV status across instruments. Cognitive abilities ranged from profoundly impaired to average intelligence; 16% had NVIQ≥70. Approximately half exhibited verbal skills commensurate with nonverbal cognitive ability, whereas half had verbal abilities significantly lower than their estimated NVIQ. Future studies of MV children must carefully consider the methods used to identify their sample, acknowledging that definitions including children with 'some words' may yield larger samples with a wider range of language and cognitive abilities. Broadly defined MV samples may be particularly important to delineate factors interfering with language development in the subgroup of children whose expressive impairments are considerably below their estimated nonverbal cognitive abilities.

Engagement in risk behaviors among adolescents who misuse prescription drugs: evidence for subgroups of misusers

Background: This study examines whether there is variation in selected risk behavior engagement (multiple sexual partners, binge drinking, vandalism, self-harm and suicide ideation) among groups of high school students who report misusing prescription drugs.Methods: Data were taken from the Minnesota Student Survey. Participants (n = 64 997) were categorized into four groups: non-drug users; prescription-only users; prescription and marijuana (cannabis) users; and prescription and other illicit drug users. Risk behavior engagement was compared across groups using general linear modeling.Results: Significant variation in externalizing risk behaviors (number of sexual partners, binge drinking, vandalism) was found, with greater variation among females. Variation was also found for internalizing risk behaviors (self-harm and suicide ideation), though the differences between drug use groups were less drastic.Conclusions: Distinct subgroups exist among adolescents who misuse prescription drugs. Researchers should consider these differences when assessing analytic strategies; those who work directly with adolescents who misuse prescriptions should consider these differences when designing interventions.

Status and influence in virtual communities: an examination of interactions between followers of a video blog

It is important for organisations to understand why their customers participate in virtual communities, the groups in which they participate, and the interactions that occur. This information can offer insight into how social media might be used to build brands and strengthen marketing communications programs. Although groups are comprised of members who strive to belong, individuals also have a fundamental need to distinguish themselves from others. Using blog entries submitted over a nine-week period by followers of a Ustream.tv live broadcast of Shiba Inu puppies, the research examines motives for participation, and identifies sources of differentiation within the group and their relationship to status and attempts to influence others. Evidence of subgroups is found, and comments posted by members suggest the potential for influence in messages that are not company-initiated.

The role of fairness and benefit distribution in community-based Payment for Environmental Services interventions: A case study from Menabe, Madagascar

Community-based conservation interventions can only be successful in the long term if their aims and activities are accepted by local people. A key determinant of acceptability is the perceived fairness of the distribution of the costs and benefits of the intervention. We examined the opportunities and challenges posed by benefit distribution in community-based Payment for Environmental Services (PES) interventions through a case study from Menabe, Madagascar. The intervention appears to be an overall success, with individuals reporting high levels of perceived fairness of payment distribution and a high proportion of individuals expressing overall net benefit. Nevertheless, a lack of adequate benefits accruing to those individuals facing high agricultural opportunity costs and evidence of sub-groups in the community reaping excessive benefits was noted across communities, and instances of poor governance were observed as a barrier to success in some communities. We present solutions to address these key challenges in the design and implementation of community-based PES interventions.

Self‐reported proficiency in Māori language among those of Māori descent in New Zealand

In a national survey in New Zealand (N = 12 992), participants of Māori descent (N = 2936) reported their proficiency in speaking, reading, and writing Māori and in understanding spoken Māori. Only 6–10% reported that they could cope “very well” in these areas while 36–52% reported their proficiency as “no more than a few words or phrases”. There was no evidence of subgroups of Māori with divergent proficiency across oral language or literacy. Six latent classes were fitted but these appeared to lie along a continuum, and analysis employing item response theory (IRT) and factor analysis confirmed this. A simple sum of scores across the four areas correlated very highly with the IRT factor score (r = 0.97). High proficiency was more common among older Māori and females, in the Midland region (lowest in the South), and for those with sole‐Māori ethnicity, followed by multi‐ethnic Māori (seldom seen in those of Māori descent but not ethnicity).

Functional defecation disorder as a clinical subgroup of chronic constipation: Analysis of symptoms and physiological parameters

Objective. Patients with functional constipation can be classified according to symptoms and physiological parameters as either having a disorder of defecation or having normal defecation. It is hypothesized that the disordered defecation, where it exists, is a causative factor of the constipation. However, the utility of this classification has yet to be proven in terms of predicting response to therapy. The definitions are non-specific and based on tests that are done in an artificial setting and with derived normal ranges. It is therefore possible that the symptoms and physiological parameters of a defecatory disorder may occur as a continuous spectrum in these patients, rather than defining a discrete entity or subtype. The aim of this study was to use cluster analysis and factor analysis of defecatory symptoms and physiological parameters to look for evidence of subgroups in patients with functional constipation. Material and methods. Consecutive patients presenting to a specialist constipation clinic and satisfying the inclusion criteria were assessed to determine the severity of defecatory symptoms, and underwent isotope defecating proctography and the Sitzmark transit study. Assessments were made contemporaneously and results of any test not performed within 6 weeks of the initial assessment were excluded. Principle components analysis and cluster analysis were performed to look for evidence of subgroups. Relationships between evacuatory symptoms, index parameters, and test results were explored. The detailed and unselected nature of the analyses produced hundreds of test results, and statistically significant results were critically evaluated in this context. Results. A total of 116 patients were studied (age range 18–73 years, mean 40.5 years). Based on the results of the transit study and proctography, 38% of patients showed evidence of slow transit constipation, 20% FDD (functional defecation disorder), 29% both, and 12% neither. Principle components analysis did not demonstrate an obvious dimension reduction for the variables tested. Cluster analysis (over 150 solutions tested) failed to show evidence of clustering. There were no useful predictive relationships between evacuatory symptoms, index parameters and test results. Conclusions. We used multiple statistical analyses to look for clustering and predictive relationships between clinical and physiological parameters in consecutive patients with functional constipation and found no evidence of the existence of a subgroup of patients with a defecatory disorder. This may be due to weaknesses in the study design, poor validity of the assessments performed, or that defecatory features do not identify a distinct pathophysiological entity, but rather are manifested variably as a continuous spectrum.

Patterns of decline and evidence of subgroups in patients with Alzheimer's disease taking galantamine for up to 48 months

Lacking long-term placebo-controlled trials of cholinesterase inhibitors (ChEIs) in Alzheimer's disease, how decline is modeled is crucial to interpreting the effects of long-term, open-label use. We aimed to: 1) understand changes in cognition and function in people taking galantamine; (2) identify treatment subgroups. This is an open-label long-term extension (up to 48 months) of two placebo-controlled clinical trials from Europe and Canada. At baseline, 240 patients with mild-moderate Alzheimer's disease at baseline had received galantamine continuously for 36 months. The trajectory of scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Disability Assessment for Dementia (DAD) was modeled over 48 months. Goodness of fit was compared using normalized residuals and by calculating correlation coefficients between observed and fitted data. Iterative K-means clustering identified subgroups. Of 240 patients, 51 (21%) withdrew between months 36-48 (nine died and 12 with adverse events). The mean ADAS-Cog worsened from 22.6 (mean)+/-8.6 (SD) at baseline to 31.3+/-3.1, with similar changes in the DAD. The logistic function fit better (ADAS-Cog norm of residuals=2.05, r=0.993; DAD=2.21, r=0.998) than the commonly used Stern equation (ADAS-Cog=4.22, r=0.944; DAD=7.51, r=0.986). K-means clustering identified three stable groups; least decline (n=82), persistent progression (n=75), and an intermediate group (n=82). Initial conditions were important: the mean ADAS-Cog score for those with least decline was 15+/-8, better than both the intermediate group (20+/-9) and persistent progressors (30+/-10; p<0.001). Alzheimer's disease patients show variable long-term decline that is best modeled as a logistic function, not as linear decline. Over 48 months, about one-third of patients showed little decline, while one-third showed important decline.

Investigating prophylactic botulinum toxin type A for chronic headache disorders

There is an increasing number of studies on botulinum toxin A in the treatment of idiopathic and symptomatic headache; however, many studies can hardly be compared with each other because of different end points and different trial designs. For the prophylactic treatment of tension-type headache, migraine and cervicogenic headache, no sufficient positive evidence for a successful treatment can be obtained from the randomised, double-blind and placebo-controlled trials performed so far. For the treatment of chronic daily headache (including medication-overuse headache), there is inconsistent positive evidence for subgroups (e.g., patients without other prophylactic treatment). This means that most of the double-blind and placebo-controlled studies do not confirm the assumption that botulinum toxin A is efficacious in the treatment of idiopathic headache disorders; however, it is possible that some subgroups of patients with chronic migraine benefit from a long-term treatment for ≥ 6 months.

A 4‐year epidemiological study of typical and atypical eating disorders: preliminary evidence for subgroups of atypical eating disorders with different natural outcomes

AbstractBackgroundsWe designed a two‐step prospective study aiming to detect cases with full and atypical eating disorders (EDs) in a population of female high‐school students (first step) and to assess their natural outcome after a 4‐year time period (second step).MethodsIn the first step, we screened female students in their first year of high school by means of the EDI‐2 and GHQ‐28 questionnaires. Those students identified as being at risk for an ED underwent a psychiatric interview. In the second step, 4 years later, we tested schoolgirls in their last year of high school by adopting the same procedure as the first step.Results140 subjects participated in both steps. In the first step, we identified one subject with full‐blown bulimia nervosa (BN), one with partial‐syndrome BN, two with subclinical BN and eight with subclinical anorexia nervosa (AN). At the reassessment 4 years later, none of the girls had received any form of help. The full‐blown BN case, the partial‐syndrome BN case and one of the subclinical AN cases persisted unchanged; one of the subclinical BN cases shifted to subclinical AN; the remaining subclinical cases remitted spontaneously. Moreover, we identified 12 new cases of EDs.ConclusionsPresent findings provide the first evidence that subclinical AN and subclinical BN represent unstable states that can spontaneously remit over time. Copyright © 2004 John Wiley &amp; Sons, Ltd and Eating Disorders Association.

Genetic analysis of glioblastoma multiforme provides evidence for subgroups within the grade

We analyzed 72 primary and 25 recurrent glioblastoma multiforme (GBM) samples for DNA sequence copy number abnormalities (CNAs) by comparative genomic hybridization (CGH). The number of aberrations per tumor ranged from 2 to 23 in primary GBM and 5 to 25 in recurrent GBM. There were 26 chromosome regions with CNAs in more than 20% of tumors. 7q22-36 was the most common gain and 10q25-26 was the most common loss; each occurred in more than 70% of tumors. Of 27 amplification sites, epidermal growth factor receptor (EGFR) was the most common; it was observed in 25% of primary GBMs. Statistical analysis based on pairwise correlation of CNAs indicated that there is more than one class of primary GBM.

Genetic analysis of glioblastoma multiforme provides evidence for subgroups within the grade

We analyzed 72 primary and 25 recurrent glioblastoma multiforme (GBM) samples for DNA sequence copy number abnormalities (CNAs) by comparative genomic hybridization (CGH). The number of aberrations per tumor ranged from 2 to 23 in primary GBM and 5 to 25 in recurrent GBM. There were 26 chromosome regions with CNAs in more than 20% of tumors. 7q22-36 was the most common gain and 10q25-26 was the most common loss; each occurred in more than 70% of tumors. Of 27 amplification sites, epidermal growth factor receptor (EGFR) was the most common; it was observed in 25% of primary GBMs. Statistical analysis based on pairwise correlation of CNAs indicated that there is more than one class of primary GBM. Genes Chromosomes Cancer 21:195–206, 1998. © 1998 Wiley-Liss, Inc.

Relation of neuropsychological and magnetic resonance findings in amyotrophic lateral sclerosis: evidence for subgroups.

The relationship between neuropsychological impairments and changes in cranial MR images was investigated in a group of 74 consecutive patients with the sporadic form of amyotrophic lateral sclerosis (ALS). Neuropsychological tests included measures of frontal lobe function, memory, intelligence, and attention. Compared with a control group, a significant impairment of the ALS group emerged for the areas of visual attention, inhibition of response alternatives, visual memory, and word generation. These neuropsychological impairments did not show a relation to clinical status of the patients. Likewise, MR parameters derived by computer assisted planimetric analysis showed a ventricular enlargement and parenchymal atrophy in the ALS group compared with age-matched controls. When ALS patients were assigned to two subgroups differing on the basis of the neuropsychological tests by cluster-analysis the cluster with the significant impairment also showed a pronounced change for the MR-parameters while the subgroup showed essentially normal neuropsychological performance. This pattern suggests that subgroups of ALS with differential impairment of neuropsychological functions can be defined.

Relation of neuropsychological and magnetic resonance findings in amyotrophic lateral sclerosis: evidence for subgroups

The relationship between neuropsychological impairments and changes in cranial MR images was investigated in a group of 74 consecutive patients with the sporadic form of amyotrophic lateral sclerosis (ALS). Neuropsychological tests included measures of frontal lobe function, memory, intelligence, and attention. Compared with a control group, a significant impairment of the ALS group emerged for the areas of visual attention, inhibition of response alternatives, visual memory, and word generation. These neuropsychological impairments did not show a relation to clinical status of the patients. Likewise, MR parameters derived by computer assisted planimetric analysis showed a ventricular enlargement and parenchymal atrophy in the ALS group compared with age-matched controls. When ALS patients were assigned to two subgroups differing on the basis of the neuropsychological tests by cluster-analysis the cluster with the significant impairment also showed a pronounced change for the MR-parameters while the subgroup showed essentially normal neuropsychological performance. This pattern suggests that subgroups of ALS with differential impairment of neuropsychological functions can be defined.

Longitudinal study of basal cortisol levels in healthy elderly subjects: Evidence for subgroups

A group of 51 healthy elderly volunteer subjects participated in a 3- to 6-year longitudinal study of basal cortisol levels. Once per year basal cortisol levels were examined using hourly sampling over a 24-h period. Analyses of three cortisol measures (last measure obtained, mean cortisol levels across years, and the cortisol slope) revealed that the slope of the regression line measuring cortisol levels at each year was the most predictive measure of cortisol secretion over the years in this elderly population. Cortisol levels were shown to increase with years in one subgroup, to decrease in another, and to remain stable in a third. The age of the subjects was not related to either cortisol levels or to the pattern of change in cortisol secretion over years. Free and total cortisol levels were highly correlated and the groups did not differ with regard to plasma corticosteroid binding globulin. No group differences were observed for weight, height, body mass index, pulse, blood pressure and glucose. However, significant group differences were reported for plasma triglycerides levels as well as high density lipoproteins levels. Positive correlations were reported between the obsession/compulsion subscale of the SCL-90 questionnaire and the cortisol slope of subjects. Finally, previously reported group differences in neuropsychological performance are summarized. Thus, there exists considerable variation in hypothalamo-pituitary-adrenal function amongst aged humans. These results are consistent with recent animal studies showing the existence of subpopulations of aged rats which differ in hypothalamo-pituitary-adrenal activity and cognitive efficiency.

Characteristics of familial aggregation in early-onset Alzheimer's disease: evidence of subgroups.

Characteristics of familial aggregation of Alzheimer's Disease were studied in 92 families ascertained through a clinically diagnosed proband with an onset below age 60 years. In each family data were systematically collected on the sibships of the proband, of his father, and of his mother. A total of 926 relatives were included and 81% of the living relatives (i.e., 251 individuals) were directly examined. The estimated cumulative risk among first degree relatives was equal to 35% by age 89 years (95% confidence interval 22 to 47%). This result does not support the hypothesis that an autosomal dominant gene, fully penetrant by age 90 years, is segregating within all these pedigrees. Despite the fact that all probands were selected for an onset before age 60 years it was shown that two types of families could be delineated with respect to age at onset among affected relatives: all secondary cases with an onset below age 60 years were contributed by a particular group of families (type 1 families), whereas all secondary cases with an onset after age 60 years were contributed by another group of families (type 2 families). Although genetic interpretation of these findings is not straightforward, they support the hypothesis of etiologic heterogeneity in the determination of early-onset Alzheimer's disease.