Background When considering adherence to antiretroviral therapy (ART) for HIV, many different cut-points are used. The primary goals of this study were to identify a level of self-reported medication ...adherence that best distinguished HIV viral suppression from non-suppression, and to compare the ability of a single-item and a 3-item adherence questionnaire to predict HIV viral suppression. Methods This cross-sectional analysis included 380 persons with HIV (PWH) from the Florida Cohort study who completed a self-reported ART adherence measure within 30-days of having an HIV viral load test. We used Receiver Operating Characteristic (ROC) curve analyses and ROCContrast to compare the ability of a single-item and a 3-item self-reported adherence measure to predict HIV viral suppression (defined as less than or equai to 200 copies/mL). We used the Youden index and chi square statistics to assess specific cut-points, and repeated the analysis with a different definition of HIV viral suppression (less than or equai to 1000 copies/mL). Results The mean percent adherence was 92.4% using the single-item score and 90.4% using the 3-item score; 81.6% had viral suppression. The areas under the curve for the single-item and 3-item adherence measures were generally poor overall and not significantly different from each other (0.589 and 0.580, p = 0.67). The Youden index identified cut-points of 93% and 89% as maximizing the sensitivity and specificity for the single-item and 3-item measures, respectively, whereas a cut-point of 80% on the single-item measure was best able to discriminate those with viral suppression (58% vs. 84%, p < 0.001). Results were similar with viral suppression defined as less than or equai to 1000 copies/mL. Conclusions In this sample of PWH, a single question on medication adherence was as good as a 3-item questionnaire in predicting HIV viral suppression, although neither had good discriminatory ability. A cut-point close to 90% adherence maximized sensitivity and specificity, although viral suppression was very similar for nearly all measures above 80%. Keywords: HIV, Viral suppression, Self-reported, Adherence, ART
Imprinted genes have been posited to have important roles in human brain development and cognition, but their effects in nonclinical populations have yet to be investigated. Single-nucleotide ...polymorphisms (SNPs) of the imprinted gene LRRTM1 have previously been associated with schizophrenia risk and with handedness in individuals with dyslexia. We tested the hypothesis that genetic variation (SNPs) and epigenetic variation (methylation) in this gene are associated with schizotypy and handedness in a nonclinical population. Risk alleles of the three schizophrenia-linked SNPs were associated with significantly and substantially higher levels of total schizotypy. Variation in SNP genotypes was not associated with handedness, but levels of methylation in a block of CpG sites in the putative LRRTM1 promoter region were associated with more-mixed handedness. These findings provide evidence of continuity between schizophrenia and schizotypy with regard to the psychological effects of allelic variation in this imprinted gene, and show that epigenetic variation in an imprinted gene mediates the development and expression of human handedness.
•Imagination was hypothesized as high in psychotic disorders and low in autism.•We conducted a comprehensive narrative review that supported this hypothesis.•A meta-analysis demonstrated a strong ...male bias to imagination deficits in autism.•Higher schizophrenia genetic risk score was associated with higher imagination.
Complex human social cognition has evolved in concert with risks for psychiatric disorders. Recently, autism and psychotic-affective conditions (mainly schizophrenia, bipolar disorder, and depression) have been posited as psychological ‘opposites’ with regard to social-cognitive phenotypes. Imagination, considered as ‘forming new ideas, mental images, or concepts’, represents a central facet of human social evolution and cognition. Previous studies have documented reduced imagination in autism, and increased imagination in association with psychotic-affective conditions, yet these sets of findings have yet to be considered together, or evaluated in the context of the diametric model. We first review studies of the components, manifestations, and neural correlates of imagination in autism and psychotic-affective conditions. Next, we use data on dimensional autism in healthy populations to test the hypotheses that: (1) imagination represents the facet of autism that best accounts for its strongly male-biased sex ratio, and (2) higher genetic risk of schizophrenia is associated with higher imagination, in accordance with the predictions of the diametric model. The first hypothesis was supported by a systematic review and meta-analysis showing that Imagination exhibits the strongest male bias of all Autism Quotient (AQ) subscales, in non-clinical populations. The second hypothesis was supported, for males, by associations between schizophrenia genetic risk scores, derived from a set of single-nucleotide polymorphisms, and the AQ Imagination subscale. Considered together, these findings indicate that imagination, especially social imagination as embodied in the default mode human brain network, mediates risk and diametric dimensional phenotypes of autism and psychotic-affective conditions.
Inborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as 'atypical CP'. A significant proportion is ...amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage.
We performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists.
We identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology (e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects (e.g. emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4-5 (n = 6); Level 5 (n = 8). Thirty-eight (57%) of the treatable IEMs mimicking CP can be identified by ready available metabolic screening tests in blood or urine, while the remaining IEMs require more specific and sometimes invasive tests.
Limited by the rare nature of IEMs and incomplete information in the literature, we conclude that (1) A surprisingly large number of IEMs can present with CP symptoms, as 'CP mimics', (2) although individually rare, a large proportion of these diseases are treatable such that neurological damage can either be reversed or prevented, (3) clinician awareness of treatable CP mimics is important for appropriate screening, diagnosis, and early intervention, and (4) systematic studies are required to elucidate the collective frequency of treatable IEMs in CP.
We report a case of sudden unexplained death in a young asymptomatic woman in whom postmortem genetic testing after a negative autopsy identified a homozygous pathogenic mutation in SLC22A5 which ...leads clinically to primary carnitine deficiency (PCD). Her brother was subsequently diagnosed clinically with short QT syndrome, received an implantable defibrillator, and was then found to carry the same pathogenic homozygous mutation and critically low levels of carnitine. His QT interval improved with the use of carnitine supplementation, highlighting the close relationship between electrophysiology and biochemistry, and the importance of postmortem genetic testing in the clinical management of surviving relatives.
Nous décrivons le cas de mort subite inexpliquée d’une jeune femme asymptomatique chez qui les analyses génétiques post-mortem effectuées après une autopsie négative ont révélé une mutation homozygote pathogène du gène SLC22A5 entraînant sur le plan clinique un déficit primaire en carnitine (DPC). Son frère, chez qui un diagnostic clinique de syndrome du QT court a été posé ultérieurement, a reçu un défibrillateur implantable. On a alors constaté qu’il était porteur de la même mutation homozygote pathogène et qu’il présentait des concentrations de carnitine dangereusement faibles. La prise de supplément de carnitine a donné lieu à une amélioration de l’intervalle QT chez le patient, ce qui met en lumière la relation étroite qui existe entre l’électrophysiologie et la biochimie, de même que l’importance des analyses génétiques post-mortem dans la prise en charge clinique des proches survivants.
Chromosome folding has profound impacts on gene regulation, whose evolutionary consequences are far from being understood. Here we explore the relationship between 3D chromatin remodelling in mouse ...germ cells and evolutionary changes in genome structure. Using a comprehensive integrative computational analysis, we (i) reconstruct seven ancestral rodent genomes analysing whole-genome sequences of 14 species representatives of the major phylogroups, (ii) detect lineage-specific chromosome rearrangements and (iii) identify the dynamics of the structural and epigenetic properties of evolutionary breakpoint regions (EBRs) throughout mouse spermatogenesis. Our results show that EBRs are devoid of programmed meiotic DNA double-strand breaks (DSBs) and meiotic cohesins in primary spermatocytes, but are associated in post-meiotic cells with sites of DNA damage and functional long-range interaction regions that recapitulate ancestral chromosomal configurations. Overall, we propose a model that integrates evolutionary genome reshuffling with DNA damage response mechanisms and the dynamic spatial genome organisation of germ cells.
Episodic ataxia associated with a de novo SCN2A mutation Leach, Emma L., MSc; van Karnebeek, Clara D.M., MD, PhD, FCCMG; Townsend, Katelin N., MSc ...
European journal of paediatric neurology,
09/2016, Letnik:
20, Številka:
5
Journal Article
Recenzirano
Abstract Introduction Episodic ataxia (EA) is characterized by paroxysmal attacks of ataxia interspersed by asymptomatic periods. Dominant mutations or copy number variants in CACNA1A are a ...well-known cause of EA. Clinical presentation This boy presented clinical features of episodic ataxia, and also showed cerebellar atrophy, hypotonia, autism and global developmental delay at age 4 years. Acetazolamide prevented further episodes of ataxia, dystonia and encephalopathy. Extensive biochemical and genetic tests were unrevealing; whole exome sequencing found a previously unreported variant in SCN2A , proven to be de novo and predicted to be protein-damaging. Conclusion Considered alongside previous reports of episodic ataxia in SCN2A mutation-positive patients, our case further illustrates the genetic heterogeneity of episodic ataxia. In addition, this case suggests that acetazolamide may be an effective treatment for some aspects of the phenotype in a broader range of channelopathy-related conditions.
BackgroundMetastatic uveal melanoma(mUM), a rare cancer with poor prognosis, has a historical 1-yr overall survival (OS) rate of 52%. Tebentafusp, a bispecific (gp100 x CD3) ImmTAC, is approved for ...adult HLA-A*02:01+ patients (pts) with unresectable or mUM. In the primary analysis of the Ph3 IMCgp100–202 study in previously untreated mUM NCT03070392, tebentafusp significantly improved OS compared to investigator’s choice (IC) HR 0.51. We explored molecular features in tumor biopsies and serum as predictors of long OS (≥3 years) on tebentafusp in the Ph3 study.MethodsIn this randomized, open-label, Ph3 trial, 1L HLA-A*02:01+ mUM pts were randomized 2:1 to receive tebentafusp or IC, stratified by LDH. Primary endpoint was OS. This analysis is based on OS Nov 2022 data cutoff. Serum cytokines were measured using a multiplex panel of 11 immune markers in 226 patients on tebentafusp and 76 on IC. Tumor biopsies were available from 176 pts on tebentafusp and 72 on IC. Biopsies were analyzed by immunohistochemistry using antibodies to gp100, CD3 and CD163 and assessed by a pathologist or quantified using digital image analysis. Sera (N=202) collected at baseline and week 9 on tebentafusp were analyzed for ctDNA using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX.Results378 pts were randomized to tebentafusp (245) or IC, including pembrolizumab (77), ipilimumab (11) or dacarbazine (7). After a median follow-up of 22 months, the estimated 3-year OS on tebentafusp was 27% (95% CI 22–34) vs IC of 13% (95% CI 7–23).At baseline, gp100 expression in the tumor was not associated with long OS in the tebentafusp arm. Lower CD163:CD3 ratio in tumor biopsies or lower serum levels of IL6, IL10, CXCL10, CXCL11, MCP1 cytokines were associated with long OS on tebentafusp but not IC. Combination of low tumor CD163:CD3 ratio and low serum IL10 levels was most strongly associated with long OS (table 1). This subset also had long OS in the Ph2 IMCgp100–102 study enrolling 2L+ treated mUM patients (3 yr OS 46% (95% C.I. 28–74)).In the tebentafusp arm, 13/18 (72%) ctDNA evaluable pts with survival ≥3 years cleared their ctDNA at week 9 after initiation of tebentafusp, and 5/18 pts had ≥50% reduction in ctDNA.ConclusionsA low immunosuppressive tumor microenvironment, low serum levels of inflammatory cytokines and ctDNA reduction by week 9 are associated with OS ≥3 years on tebentafusp in previously untreated mUM.Trial RegistrationNCT03070392: A Phase II Randomized, Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 Compared With Investigator Choice in HLA-A*0201 Positive Patients With Previously Untreated Advanced Uveal MelanomaEthics ApprovalInstitutional review board approval was obtained and all participants gave informed consent prior to enrolement.Abstract 30 Table 1
•Schizophrenia risk alleles do not reliably predict measures of schizotypy.•Higher summed genetic risk is correlated with lower mental rotation skill in males.•Lack of linear, genetic continuity ...between clinical and healthy populations.
Schizophrenia risk alleles are expected to mediate effects on cognitive task performance, and aspects of personality including schizotypy, in nonclinical populations. We investigated how 32 of the best-validated schizophrenia risk alleles, singly and as summed genetic risk, were related to measures of schizotypal personality and measures of two aspects of cognitive performance, verbal skills (vocabulary) and visual-spatial skills (mental rotation), in healthy individuals. Summed genetic risk score was not associated with levels of total schizotypy or its three main subscales. Similarly, genotypic variation at none of the individual risk loci was related to cognitive performance measures, after correction for multiple tests. Higher overall genetic risk score was, however, associated with lower performance on the mental rotation test in males, with a broad set of loci contributing to this effect. These results imply that there is a lack of linear, genetically-based continuity connecting schizotypal cognition with the expression of schizophrenia itself, and indicate that, for males, higher genetic risk of schizophrenia exerts negative effects on visual-spatial skills, as measured by mental rotation.
BackgroundImmTAC molecules are bispecific fusion proteins consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target cells. Tebentafusp, a ...gp100-directed ImmTAC, has demonstrated survival benefit in metastatic uveal melanoma 1. We previously reported that a tumor microenvironment with a high immunosuppressive CD163+ tumor-associated macrophage (TAM): CD3 T cell ratio was associated with reduced benefit from tebentafusp 2. Here, we explored whether IL-2 could potentiate T cells to overcome inhibition of ImmTAC-mediated killing by TAM-like M2 macrophages.MethodsTumor biopsies from a Phase 2 trial of metastatic uveal melanoma HLA-A*02:01+ patients treated with tebentafusp (NCT02570308) were used to quantify CD163+ TAMs and CD3+ T cells by immunohistochemistry (N=107) and to measure gene expression by bulk RNAseq (N=70). Pro-inflammatory M1 and TAM-like M2 macrophages were generated in vitro from healthy donors (N=5) and their effect on ImmTAC-mediated T cell activation and tumor killing was assessed against THP-1 tumor cells. T cells were untreated or pre-treated for 4 days with commercially sourced IL-2 or IL-15.ResultsIn vitro, ImmTAC-mediated T cell killing of tumor cells was reduced by 85±5% in the presence of TAM-like M2 but not M1 macrophages. Consistent with this finding, below median CD163:CD3 ratio was associated with greater tumor shrinkage (TS) (odds ratio OR=2.9, p=0.014) and longer overall survival (OS) (hazard ratio HR=0.4, p=0.001) in tebentafusp-treated patients. We next explored in vitro whether the T cell activating cytokines IL-2 and IL-15 could overcome TAM-mediated inhibition of T cell redirection by ImmTAC. At clinically relevant doses, IL-2 but not IL-15 treatment resulted in dose dependent restoration of ImmTAC-mediated T cell killing of tumor cells in the presence of TAM-like M2 macrophages—60% and 83% restoration of killing at 50 and 150 U/ml of IL-2, respectively. Consistent with this observation, increased expression of IL2RB (HR 0.3, p<0.001) and IL2RG (HR 0.4, p=0.002), but not IL2RA (HR 0.8, p=0.5) in tumors was associated with longer OS on tebentafusp.ConclusionsLow CD163+ TAM to CD3 T cell ratio and high IL2RB/G expression in tumors at baseline were associated with longer OS and greater TS in tebentafusp-treated metastatic uveal melanoma patients in a Phase 2 trial. In vitro, TAM-like M2 macrophages suppressed ImmTAC-mediated T cell killing of tumor cells, an effect abrogated by IL-2. These observations provide strong rationale for combining IL-2 biased to IL2RB/G with ImmTAC molecules to enhance benefit in tumors with high levels of TAMs.Trial RegistrationNCT02570308ReferencesPiperno-Neumann S, Hassel JC, Rutkowski P et al. Abstract CT002: Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first line metastatic uveal melanoma. Cancer Res. 2021; 81 (13 Supplement) CT002.Hassel JC, Benlahrech A, Stanhope S, et al. Abstract 1673: Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp. Cancer Res. 2021; 81 (13 Supplement) 1673.Ethics ApprovalThe Oxford A REC approved protocol 13/SC/0226 was used to obtain written consent for all blood donations and was fully approved by the National Research Ethics Committee South Central.
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