FMR1 allelic complexity in premutation carriers provides no evidence for a correlation with age at amenorrhea.

BACKGROUND: Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian insufficiency (FXPOI). Only 20% of female premutation carriers develop early ovulatory dysfunction, the reason for this incomplete penetrance is unknown. This study validated the mathematical model in premutation alleles, after assigning each allele a score representing allelic complexity. Subsequently, allelic scores were used to investigate the impact of allele complexity on age at amenorrhea for 58 premutation cases (116 alleles) previously published. METHODS: The allelic score was determined using a formula previously described by our group. The impact of each allelic score on age at amenorrhea was analyzed using Pearson's test and a contour plot generated to visualize the effect. RESULTS: Correlation of allelic score revealed two distinct complexity behaviors in premutation alleles. No significant correlation was observed between the allelic score of premutation alleles and age at amenorrhea. The same lack of significant correlation was observed regarding normal-sized alleles, despite a nearly significant trend. CONCLUSIONS: Our results suggest that the use of allelic scores combination have the potential to explain female infertility, namely the development of FXPOI, or ovarian dysfunction, despite the lack of correlation with age at amenorrhea. Such a finding is of great clinical significance for early identification of females at risk of ovulatory dysfunction, enhancement of fertility preservation techniques, and increasing the probability for a successful pregnancy in females with premutations. Additional investigation is necessary to validate this hypothesis.

Intrasubject variability of sustained attention is associated with elevated self-reported attention deficits in women with a fragile X premutation allele.

OBJECTIVE: Women with a fragile X premutation (PM) self-report higher rates of attention difficulties than women without a PM; however, results of studies using objective measures of attention are inconsistent. The present study assessed whether intrasubject variability during a sustained attention task better predicted functional outcomes in women with a PM than the previously published standard reaction time and accuracy variables. METHOD: We analyzed continuous performance test, a computerized measure of sustained attention, and the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale Report (CAARS) data from 273 women with a PM and 175 women without a PM aged 18-50 years. Separate analyses using Pearson correlations and independent t tests were performed on the full range of coefficient of variation (CV) of reaction time scores and the subset of scores that showed higher variability. RESULTS: Performance variability of sustained attention measured by the continuous performance test was associated with functional outcomes measured by the CAARS in women with a PM but not women without a PM. Specifically, the CV in those with higher variability was correlated with two CAARS subscale scores (p = .006). Independent t tests showed significant differences in CV between CAARS scores dichotomized for the presence of subclinical symptoms for two subscales (p ≤ .001-.007). Correlation between the full range of CV scores and the CAARS Inattention/Memory Problems subscale approached significance (p = .012). CONCLUSIONS: Findings highlight the importance of including intrasubject variability in analyzing attention in clinical populations as a more sensitive objective measure associated with reported symptoms and to assist in predicting functional outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gß5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.

Rothia in Nonsmall Cell Lung Cancer is Associated With Worse Survival.

INTRODUCTION: The microbiome is known to play a significant role in cancer biology; however, few studies have elucidated its relationship with Nonsmall Cell Lung Cancer (NSCLC) patient outcomes. We hypothesized that there are specific microorganisms that are closely related with NSCLC patient survival. METHODS: Total of 647 NSCLC (Adenocarcinoma and Squamous Cell Carcinoma combined) patients in The Cancer Genome Atlas (TCGA) were analyzed using the R software. RESULTS: A Volcano Plot was analyzed with the patients divided into Short and Long Survivors by overall survival of 0.9 years, and we found that a bacterium Rothia was significantly abundant in Short Survivors, and Blastococcus, Leptospira, and Haematobacter in Long Survivors, but presence of Rothia alone was associated with overall survival. The age, race, subtype, and sex were not significantly different by the presence of Rothia in NSCLC. Unexpectedly, Rothia-positive NSCLC was associated with less cell proliferation by gene set enrichment analysis, Mki67 expression, proliferation score, with less fraction altered and homologous recombination deficiency, and with high infiltration of stromal cells, indicating favorable oncological characteristics. Further, Rothia-positive tumors were associated with significantly higher infiltration of CD8 T cells, CD4 T cells, Monocytes, and NK cells, and high interferon-gamma response, T-cell receptor richness, cytolytic activity, indicating favorable tumor immune microenvironment. CONCLUSIONS: NSCLC with Rothia was associated with worse survival but also with favorable oncological characteristics such as less cell proliferation and favorable tumor immune microenvironment. We cannot help but speculate that Rothia in NSCLC is associated with mortality unrelated to oncological characteristics.

NIAGADS Alzheimer's GenomicsDB: A resource for exploring Alzheimer's disease genetic and genomic knowledge.

INTRODUCTION: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site Alzheimer's Genomics Database (GenomicsDB) is a public knowledge base of Alzheimer's disease (AD) genetic datasets and genomic annotations. METHODS: GenomicsDB uses a custom systems architecture to adopt and enforce rigorous standards that facilitate harmonization of AD-relevant genome-wide association study summary statistics datasets with functional annotations, including over 230 million annotated variants from the AD Sequencing Project. RESULTS: GenomicsDB generates interactive reports compiled from the harmonized datasets and annotations. These reports contextualize AD-risk associations in a broader functional genomic setting and summarize them in the context of functionally annotated genes and variants. DISCUSSION: Created to make AD-genetics knowledge more accessible to AD researchers, the GenomicsDB is designed to guide users unfamiliar with genetic data in not only exploring but also interpreting this ever-growing volume of data. Scalable and interoperable with other genomics resources using data technology standards, the GenomicsDB can serve as a central hub for research and data analysis on AD and related dementias. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) offers to the public a unique, disease-centric collection of AD-relevant GWAS summary statistics datasets. Interpreting these data is challenging and requires significant bioinformatics expertise to standardize datasets and harmonize them with functional annotations on genome-wide scales. The NIAGADS Alzheimer's GenomicsDB helps overcome these challenges by providing a user-friendly public knowledge base for AD-relevant genetics that shares harmonized, annotated summary statistics datasets from the NIAGADS repository in an interpretable, easily searchable format.

Incidence and outcome of immune checkpoint-induced pneumonitis in oncology patients with history of pulmonary disease.

Background: Immune checkpoint-induced pneumonitis (ICIP) is one of the most fatal adverse events caused by immune checkpoint inhibitors (ICI) and accounts for 35% of anti-PD-[L]1-related deaths. Risk factors including thoracic radiation and use of EGFR tyrosine kinase inhibitors have been identified as contributors to ICIP development. However, there has been very limited information on obstructive pulmonary disease as a risk factor. Objective: The purpose of this study is to evaluate the incidence and management of ICIP in a cohort of patients with pre-existing obstructive pulmonary disease. Methods: This retrospective, descriptive study, includes data from 139 patients between January 1, 2017 and August 31, 2022. Patients included were adult patients 18 years or older, received at least 2 cycles of an immune checkpoint inhibitor, and had a history of an obstructive pulmonary disorder prior to administration. Patients were excluded if they had literature-established risk factors for pneumonitis. Results: The incidence of ICIP was 7.19% (10 out of 139 patients). From a management perspective, 90% of patients had immunotherapy held, 40% received oral steroids, and 70% received intravenous steroids at the time of ICIP identification. After receiving treatment for the initial episode of ICIP, 6 patients restarted immunotherapy and 3 (50%) subsequently experienced a recurrent episode. One patient experienced grade 4 ICIP event and subsequently died from respiratory failure attributed to ICIP. Conclusion: These findings indicate that a pre-existing history of an obstructive pulmonary disorder may be a risk factor for the development of ICIP and subsequent recurrence of ICIP when rechallenged.

Healthcare Experiences of African American Women with the Fragile X Premutation.

This study aims to understand the healthcare experiences of African American women with a fragile X premutation (PM). PM carriers are at risk for fragile X-associated conditions, including primary ovarian insufficiency (FXPOI) and neuropsychiatric disorders (FXAND). There is no racial/ethnic association with carrying a PM, but African American women historically experience barriers receiving quality healthcare in the USA. Obstacles to care may increase mental health conditions like anxiety and depression. Eight African American women with a PM were interviewed to explore disparities in receiving healthcare and to learn about psychosocial experiences during and after their diagnoses. Interviews were transcribed verbatim and independently coded by two researchers. A deductive-inductive approach was used, followed by thematic analysis to determine prominent themes. The average participant age was 52.3 ± 8.60 years, with a mean age at premutation diagnosis of 31 ± 5.95 years. Seven participants had children with FXS. Themes from interviews included healthcare experiences, family dynamics, and emotional/mental health after their diagnosis. Participants reported concerns about not being taken seriously by providers and mistrust of the medical institutions. Within families, participants reported denial, insensitivity, and isolation. Participants reported a high incidence of anxiety and depression. Both are symptoms of FXAND and stresses of systemic racism and sexism. The reported family dynamics around the news of a genetic diagnosis stand apart from other racial cohorts in fragile X research: interventions like family counseling sessions and inclusive support opportunities from national organizations could ease the impacts of a PM for African American women.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Autonomic neuro-cardiac profile of electrical, structural and neuronal remodeling in myocardial infarction-induced heart failure.

Aims: Heart failure is a clinical syndrome typified by abnormal autonomic tone, impaired ventricular function, and increased arrhythmic vulnerability. This study aims to examine electrophysiological, structural and neuronal remodeling following myocardial infarction in a rabbit heart failure model to establish its neuro-cardiac profile. Methods and results: Weight-matched adult male New Zealand White rabbits (3.2 ± 0.1 kg, n = 25) were randomized to have coronary ligation surgeries (HF group, n = 13) or sham procedures (SHM group, n = 12). Transthoracic echocardiography was performed six weeks post-operatively. On week 8, dual-innervated Langendorff-perfused heart preparations were set up for terminal experiments. Seventeen hearts (HF group, n = 10) underwent ex-vivo cardiac MRI. Twenty-two hearts (HF group, n = 7) were examined histologically. Electrical remodeling and abnormal autonomic profile were evident in HF rabbits with exaggerated sympathetic and attenuated vagal effect on ventricular fibrillation threshold, ventricular refractoriness and restitution curves, in addition to increased spatial restitution dispersion. Histologically, there was significant neuronal enlargement at the heart hila and conus arteriosus in HF. Structural remodeling was characterized by quantifiable myocardial scarring, enlarged left ventricles, altered ventricular geometry and impaired contractility. Conclusion: In an infarct-induced rabbit heart failure model, extensive structural, neuronal and electrophysiological remodeling in conjunction with abnormal autonomic profile provide substrates for ventricular arrhythmias.

Re-expression of CA1 and entorhinal activity patterns preserves temporal context memory at long timescales.

Converging, cross-species evidence indicates that memory for time is supported by hippocampal area CA1 and entorhinal cortex. However, limited evidence characterizes how these regions preserve temporal memories over long timescales (e.g., months). At long timescales, memoranda may be encountered in multiple temporal contexts, potentially creating interference. Here, using 7T fMRI, we measured CA1 and entorhinal activity patterns as human participants viewed thousands of natural scene images distributed, and repeated, across many months. We show that memory for an image's original temporal context was predicted by the degree to which CA1/entorhinal activity patterns from the first encounter with an image were re-expressed during re-encounters occurring minutes to months later. Critically, temporal memory signals were dissociable from predictors of recognition confidence, which were carried by distinct medial temporal lobe expressions. These findings suggest that CA1 and entorhinal cortex preserve temporal memories across long timescales by coding for and reinstating temporal context information.

Brain-optimized deep neural network models of human visual areas learn non-hierarchical representations.

Deep neural networks (DNNs) optimized for visual tasks learn representations that align layer depth with the hierarchy of visual areas in the primate brain. One interpretation of this finding is that hierarchical representations are necessary to accurately predict brain activity in the primate visual system. To test this interpretation, we optimized DNNs to directly predict brain activity measured with fMRI in human visual areas V1-V4. We trained a single-branch DNN to predict activity in all four visual areas jointly, and a multi-branch DNN to predict each visual area independently. Although it was possible for the multi-branch DNN to learn hierarchical representations, only the single-branch DNN did so. This result shows that hierarchical representations are not necessary to accurately predict human brain activity in V1-V4, and that DNNs that encode brain-like visual representations may differ widely in their architecture, ranging from strict serial hierarchies to multiple independent branches.

Retrospective study on the efficacy and tolerability of dose modification of PD-1 and PD-L1 inhibitors in hospital-system community outpatient cancer clinics.

BACKGROUND: Anti-programmed cell death (PD)-1 and anti-PD-L1 medications inhibit the PD-1 and PD-L1 interaction and have been shown to be effective in treating several forms of advanced cancers. Since the approval of these agents, standard dosing protocols have been utilized. However, a small population of patients in the community setting has received dose-modified PD-1 and PD-L1 inhibitors secondary to a lack of tolerability. Data from this study suggests possible benefit with different dosing strategies. OBJECTIVES: The purpose of this retrospective study is to assess the efficacy and tolerability in terms of time to progression and adverse effects in patients receiving dose-modified PD-1 and PD-L1 inhibitors in Food and Drug Administration (FDA)-labeled indications. METHODS: This single-institution retrospective chart review was conducted in an outpatient community setting on patients with cancer that received nivolumab, pembrolizumab, durvalumab, or atezolizumab for an FDA indication at one of the Houston Methodist Hospital infusion clinic site between September 1, 2017 and September 30, 2019. Data collection included demographics, adverse effects, dosing, treatment delay, and number of immunotherapy cycles administered per patient. RESULTS: This study included 221 patients, who received either nivolumab (n = 81), pembrolizumab (n = 93), atezolizumab (n = 21), or durvalumab (n = 26). There were 11 patients who experienced a dose reduction and 103 patients who experienced a treatment delay. Of the patients with a treatment delay, the median time to progression was 197 days, and for patients with a dose reduction, the median time to progression was 299 days. CONCLUSION: The results of this study found that the immunotherapy associated adverse effects led to dosing and frequency changes for tolerance with continued therapy. Our data suggests that there could be potential benefits of dose modifications to immunotherapy treatment, but further large studies are needed to assess the efficacy of specific immunotherapy dose modifications on both outcomes and adverse effects.

The diagnostic experience of women with fragile X-associated primary ovarian insufficiency (FXPOI).

PURPOSE: The fragile X premutation occurs when there are 55-200 CGG repeats in the 5' UTR of the FMR1 gene. An estimated 1 in 148 women carry a premutation, with 20-30% of these individuals at risk for fragile X-associated primary ovarian insufficiency (FXPOI). Diagnostic experiences of FXPOI have not previously been included in the literature, limiting insight on experiences surrounding the diagnosis. This study identifies barriers and facilitators to receiving a FXPOI diagnosis and follow-up care, which can inform care and possibly improve quality of life. METHODS: We conducted qualitative interviews with 24 women with FXPOI exploring how FMR1 screening, physician education, and supportive care impacted their experience. Three subgroups were compared: women diagnosed through family history who have biological children, women diagnosed through family history who do not have biological children, and women diagnosed through symptoms of POI. RESULTS: Themes from interviews included hopes for broader clinician awareness of FXPOI, clear guidelines for clinical treatment, and proper fertility workups to expand reproductive options prior to POI onset. Participants also spoke of difficulty finding centralized sources of care. CONCLUSIONS: Our results indicate a lack of optimal care of women with a premutation particularly with respect to FMR1 screening for molecular diagnosis, short- and long-term centralized treatment, and clinical and emotional support. The creation of a "FXPOI health navigator" could serve as a centralized resource for the premutation patient population, assisting in connection to optimal treatment and appropriate referrals, including genetic counseling, mental health resources, advocacy organizations, and better-informed physicians.

Color-biased regions in the ventral visual pathway are food selective.

Color-biased regions have been found between face- and place-selective areas in the ventral visual pathway. To investigate the function of the color-biased regions in a pathway responsible for object recognition, we analyzed the natural scenes dataset (NSD), a large 7T fMRI dataset from 8 participants who each viewed up to 30,000 trials of images of colored natural scenes over more than 30 scanning sessions. In a whole-brain analysis, we correlated the average color saturation of the images with voxel responses, revealing color-biased regions that diverge into two streams, beginning in V4 and extending medially and laterally relative to the fusiform face area in both hemispheres. We drew regions of interest (ROIs) for the two streams and found that the images for each ROI that evoked the largest responses had certain characteristics: they contained food, circular objects, warmer hues, and had higher color saturation. Further analyses showed that food images were the strongest predictor of activity in these regions, implying the existence of medial and lateral ventral food streams (VFSs). We found that color also contributed independently to voxel responses, suggesting that the medial and lateral VFSs use both color and form to represent food. Our findings illustrate how high-resolution datasets such as the NSD can be used to disentangle the multifaceted contributions of many visual features to the neural representations of natural scenes.

Cell type-specific DNA methylome signatures reveal epigenetic mechanisms for neuronal diversity and neurodevelopmental disorder.

DNA methylation plays a critical function in establishing and maintaining cell identity in brain. Disruption of DNA methylation-related processes leads to diverse neurological disorders. However, the role of DNA methylation characteristics in neuronal diversity remains underexplored. Here, we report detailed context-specific DNA methylation maps for GABAergic, glutamatergic (Glu) and Purkinje neurons, together with matched transcriptome profiles. Genome-wide mCH levels are distinguishable, while the mCG levels are similar among the three cell types. Substantial CG-differentially methylated regions (DMRs) are also seen, with Glu neurons experiencing substantial hypomethylation events. The relationship between mCG levels and gene expression displays cell type-specific patterns, while genic CH methylation exhibits a negative effect on transcriptional abundance. We found that cell type-specific CG-DMRs are informative in terms of represented neuronal function. Furthermore, we observed that the identified Glu-specific hypo-DMRs have a high level of consistency with the chromatin accessibility of excitatory neurons and the regions enriched for histone modifications (H3K27ac and H3K4me1) of active enhancers, suggesting their regulatory potential. Hypomethylation regions specific to each cell type are predicted to bind neuron type-specific transcription factors. Finally, we show that the DNA methylation changes in a mouse model of Rett syndrome, a neurodevelopmental disorder caused by the de novo mutations in MECP2, are cell type- and brain region-specific. Our results suggest that cell type-specific DNA methylation signatures are associated with the functional characteristics of the neuronal subtypes. The presented results emphasize the importance of DNA methylation-mediated epigenetic regulation in neuronal diversity and disease.

Expression of expanded GGC repeats within NOTCH2NLC causes behavioral deficits and neurodegeneration in a mouse model of neuronal intranuclear inclusion disease.

GGC repeat expansions within NOTCH2NLC have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here, we established both a transgenic mouse model and a human neural progenitor cells (hNPCs) model. Expression of the NOTCH2NLC with expanded GGC repeats produced widespread intranuclear and perinuclear polyglycine (polyG), polyalanine (polyA), and polyarginine (polyR) inclusions, leading to behavioral deficits and severe neurodegeneration, which faithfully mimicked the clinical and pathological features associated with NIID. Furthermore, conserved alternative splicing events were identified between the NIID mouse and hNPC models, among which was the enrichment of the binding motifs of hnRNPM, an RNA binding protein known as alternative splicing regulator. Expanded NOTCH2NLC-polyG and NOTCH2NLC-polyA could interact with and sequester hnRNPM, while overexpression of hnRNPM could ameliorate the cellular toxicity. These results together suggested that dysfunction of hnRNPM could play an important role in the molecular pathogenesis of NIID.

Multiple traces and altered signal-to-noise in systems consolidation: Evidence from the 7T fMRI Natural Scenes Dataset.

The brain mechanisms of memory consolidation remain elusive. Here, we examine blood-oxygen-level-dependent (BOLD) correlates of image recognition through the scope of multiple influential systems consolidation theories. We utilize the longitudinal Natural Scenes Dataset, a 7-Tesla functional magnetic resonance imaging human study in which ∼135,000 trials of image recognition were conducted over the span of a year among eight subjects. We find that early- and late-stage image recognition associates with both medial temporal lobe (MTL) and visual cortex when evaluating regional activations and a multivariate classifier. Supporting multiple-trace theory (MTT), parts of the MTL activation time course show remarkable fit to a 20-y-old MTT time-dynamical model predicting early trace intensity increases and slight subsequent interference (R2 > 0.90). These findings contrast a simplistic, yet common, view that memory traces are transferred from MTL to cortex. Next, we test the hypothesis that the MTL trace signature of memory consolidation should also reflect synaptic "desaturation," as evidenced by an increased signal-to-noise ratio. We find that the magnitude of relative BOLD enhancement among surviving memories is positively linked to the rate of removal (i.e., forgetting) of competing traces. Moreover, an image-feature and time interaction of MTL and visual cortex functional connectivity suggests that consolidation mechanisms improve the specificity of a distributed trace. These neurobiological effects do not replicate on a shorter timescale (within a session), implicating a prolonged, offline process. While recognition can potentially involve cognitive processes outside of memory retrieval (e.g., re-encoding), our work largely favors MTT and desaturation as perhaps complementary consolidative memory mechanisms.

Paraneoplastic syndromes: A focus on pathophysiology and supportive care.

PURPOSE: This article aims to increase awareness of, outline pathophysiology for, and offer guidance on supportive care strategies for specific endocrine, neurological, and immunological syndromes associated with paraneoplastic syndromes (PNSs). SUMMARY: PNS refers to remote effects that cannot be attributed to the direct or invasive effects of a malignancy. These syndromes are considered clinically important because they may provide early recognition, diagnosis, and management of the malignancy in a timely manner. Many of their presenting symptoms such as ectopic Cushing's syndrome, hypercalcemia of malignancy (HCM), syndrome of inappropriate secretion of antidiuretic hormone (SIADH), neurological dysfunctions, and paraneoplastic autoimmune thrombocytopenia overlap with those of nonneoplastic disorders, yet their pathogenesis and responses to treatments differ. Management of ectopic Cushing's syndrome due to a PNS consists of treatment of the underlying malignancy and its comorbidities. Drug therapies may include ketoconazole, mitotane, metyrapone, somatostatin analogs, and dopamine agonists. Hypercalcemia may be classified into cases with parathyroid hormone (PTH)-dependent causes or PTH-independent causes such as HCM, in which osteoclast inhibitors may be deployed. Treatments of PNS-mediated SIADH include treatment of the underlying malignancy and strategies to increase serum sodium levels. Amifampridine is now considered the first-line agent for paraneoplastic Lambert-Eaton myasthenic syndrome, whereas steroids, intravenous immune globulin, thrombopoietin receptor agonists (eg, romiplostim, eltrombopag, and avatrombopag), fostamatinib, and rituximab may find their niche in treatment of PNS-mediated autoimmune thrombocytopenia. CONCLUSION: Supportive care for PNSs lends opportunities to pharmacists to add quality, value, and safety.

Scalable approaches for functional analyses of whole-genome sequencing non-coding variants.

Non-coding genetic variants outside of protein-coding genome regions play an important role in genetic and epigenetic regulation. It has become increasingly important to understand their roles, as non-coding variants often make up the majority of top findings of genome-wide association studies (GWAS). In addition, the growing popularity of disease-specific whole-genome sequencing (WGS) efforts expands the library of and offers unique opportunities for investigating both common and rare non-coding variants, which are typically not detected in more limited GWAS approaches. However, the sheer size and breadth of WGS data introduce additional challenges to predicting functional impacts in terms of data analysis and interpretation. This review focuses on the recent approaches developed for efficient, at-scale annotation and prioritization of non-coding variants uncovered in WGS analyses. In particular, we review the latest scalable annotation tools, databases and functional genomic resources for interpreting the variant findings from WGS based on both experimental data and in silico predictive annotations. We also review machine learning-based predictive models for variant scoring and prioritization. We conclude with a discussion of future research directions which will enhance the data and tools necessary for the effective functional analyses of variants identified by WGS to improve our understanding of disease etiology.

Descriptive analysis of seizures and comorbidities associated with fragile X syndrome.

BACKGROUND: Fragile X syndrome is characterized by a myriad of physical features, behavioral features, and medical problems. Commonly found behavioral features are hyperactivity, anxiety, socialization difficulties, and ASD. There is also a higher incidence than in the general population of strabismus, otitis media, and mitral valve prolapse. In addition, one of the most common medical problems associated with FXS is an increased risk of seizures. A subset of individuals carrying the full mutation of the FMR1 gene and diagnosed with fragile X syndrome (FXS) are reported to experience seizures, mostly during the first 10 years of their life span. METHODS: As part of a larger project to identify genetic variants that modify the risk of seizures, we collected clinical information from 49 carriers with FXS who experienced seizures and 46 without seizures. We compared seizure type and comorbid conditions based on the source of data as well as family history of seizures. RESULTS: We found that the concordance of seizure types observed by parents and medical specialists varied by type of seizure. The most common comorbid condition among those with seizures was autism spectrum disorder (47% per medical records vs. 33% per parent report compared with 19% among those without seizures per parent report); the frequency of other comorbid conditions did not differ among groups. We found a slightly higher frequency of family members who experienced seizures among the seizure group compared with the nonseizure group. CONCLUSION: This study confirms previously reported features of seizures in FXS, supports additional genetic factors, and highlights the importance of information sources, altogether contributing to a better understanding of seizures in FXS.