Well-validated Tools Research Articles

Chemotherapy-induced peripheral neuropathy: where are we now?

Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge, with increasing impact as oncological treatments, using potentially neurotoxic chemotherapy, improve cancer cure and survival. Acute CIPN occurs during chemotherapy, sometimes requiring dose reduction or cessation, impacting on survival. Around 30% of patients will still have CIPN a year, or more, after finishing chemotherapy. Accurate assessment is essential to improve knowledge around prevalence and incidence of CIPN. Consensus is needed to standardize assessment and diagnosis, with use of well-validated tools, such as the EORTC-CIPN 20. Detailed phenotyping of the clinical syndrome moves toward a precision medicine approach, to individualize treatment. Understanding significant risk factors and pre-existing vulnerability may be used to improve strategies for CIPN prevention, or to use targeted treatment for established CIPN. No preventive therapies have shown significant clinical efficacy, although there are promising novel agents such as histone deacetylase 6 (HDAC6) inhibitors, currently in early phase clinical trials for cancer treatment. Drug repurposing, eg, metformin, may offer an alternative therapeutic avenue. Established treatment for painful CIPN is limited. Following recommendations for general neuropathic pain is logical, but evidence for agents such as gabapentinoids and amitriptyline is weak. The only agent currently recommended by the American Society of Clinical Oncology is duloxetine. Mechanisms are complex with changes in ion channels (sodium, potassium, and calcium), transient receptor potential channels, mitochondrial dysfunction, and immune cell interactions. Improved understanding is essential to advance CIPN management. On a positive note, there are many potential sites for modulation, with novel analgesic approaches.

The Support for New Mums Project: A protocol for a pilot randomized controlled trial designed to test a postnatal psychoeducation smartphone application.

To report a pilot trial protocol for testing the effectiveness of the Support for New Mums smartphone application in a cohort of first-time mothers. A pilot/feasibility randomized controlled trial using a two-group pre-test and repeated post-test design. This protocol follows the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines. The Intervention group will receive access to the smartphone application for 6weeks post birth. Both Intervention and control groups will receive standardized institutional postnatal care services. Trial funding was gained from respective grant sponsors in May and November 2016. The Support for New Mums smartphone application could be a novel method for addressing the gap in provision of postpartum care services providing psychoeducation and improving maternal parental self-efficacy for Australian childbearing women. Australian New Zealand Clinical Trials Registry ACTRN12618001580268.

Validation of the SymptoMScreen with performance-based or clinician-assessed outcomes

Background: People with multiple sclerosis (MS) experience symptoms in multiple domains. High-quality patient-reported outcomes (PROs) that assess multiple domains can aid healthcare providers in assessing these symptoms and may support remote disease monitoring. The “SymptoMScreen” PRO correlates with other PROs in MS; however, whether the SymptoMScreen or its component domains are associated with performance-based or clinician-assessed outcomes is unknown. Objectives: To validate SymptoMScreen and its domains against performance-based, clinician-assessed measures or other well-validated diagnostic tools. Methods: We recruited participants with MS from a large tertiary care center. At routine clinic visits participants completed the MS performance test (MSPT), which is an iPad-based application that objectively assesses walking speed, manual dexterity, processing speed, and low contrast letter acuity. Expanded Disability Status Scale (EDSS) scores were assessed in a subset. Participants also completed an online SymptoMScreen following clinic visits. We assessed criterion and construct validity by calculating Spearman rank correlations between the 12 SymptoMScreen domains and respective clinical outcomes. We evaluated test-retest reliability using intra-class correlation coefficients [ICC], and internal consistency reliability using Cronbach's alpha. Results: The 102 participants were predominantly female (78%), of average age [standard deviation]: 47.6 [12.3] years, with an average disease duration: 13.1 [10.0] years); 60 participants completed the SymptoMScreen and EDSS. Composite SymptoMScreen scores were associated with EDSS (r = 0.71; 95% CI 0.54, 0.83). For individual domains, strong correlations were observed between mobility scores and walking speed (r = 0.63; 95% CI: 0.48, 0.75) and hand function scores with manual dexterity (r = 0.52; 95% CI: 0.36, 0.65). More moderate correlations were detected for the cognition domain with processing speed (r=-0.37; 95% CI: -0.53, -0.18) and for the visual function domain with low contrast letter acuity at 2.5% contrast (r=-0.33; 95% CI -0.54, -0.08). Both test-retest and internal consistency reliability measures for overall SymptoMScreen scores were high (ICC: 0.88; 95% CI: 0.80, 0.93; Cronbach's alpha: 0.93; 95% CI: 0.90, 96). Conclusions: The SymptoMScreen is practical outcome measure whose subscales may provide a valid assessment of corresponding performance-based and clinician-assessed measures among people with MS with mild-to-moderate disability.

Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging.

To characterize the adaptive behavior profile of children with neurofibromatosis type 1 (NF1) and determine its relationship to neuropsychological functioning and non-neoplastic T2-weighted hyperintense brain lesions on brain magnetic resonance imaging (MRI). In this cross-sectional study, we retrospectively reviewed neuropsychological reports from 104 children with NF1 (56 males, 48 females; mean age 10y 4mo; standard deviation [SD] 3y 4mo; range 3y 5mo-17y 6mo), and extracted data from a range of cognitive and behavioral measures, including the Adaptive Behavior Assessment System (ABAS). Brain MRI was retrospectively reviewed in 42 individuals. Adaptive Behavior Assessment System scores were continuously distributed and pathologically shifted by 0.79 to 1.26SD across Conceptual, Social, and Practical domains, and 46.5% of individuals had a composite score in the borderline or impaired range. Impairment in adaptive functioning was correlated with deficits in executive function (r=-9.543, p<0.001), externalizing problems (r=-0.366, p<0.001), and attention (r=-9.467, p=0.001). Cluster analysis revealed three distinct phenotypic subgroups, one of which exhibited normal cognitive ability, but impaired adaptive functioning, with persistent deficits in executive function, behavioral problems, and attention-deficit/hyperactivity disorder symptomatology. There was no relationship between ABAS scores and the number or location of unidentified bright objects. Adaptive functioning deficits are common among children with NF1 and are associated with impairment in other cognitive/behavioral domains, independent of general cognitive ability. Deficits in adaptive behavior are common in children with neurofibromatosis type 1 (NF1). Poor adaptive functioning is associated with impairments in executive function, externalizing behaviors, and attention, regardless of cognitive ability. The presence or location of unidentified bright objects do not predict adaptive behavior skills in children with NF1.

Improved Nutrition Status in Patients With Advanced Heart Failure Implanted With a Left Ventricular Assist Device.

Left ventricular assist device (LVAD) implantation for advanced heart failure is known to improve survival, functional capacity, and quality of life. Most patients implanted with LVADs suffer from moderate to severe malnutrition and deconditioning due to their advanced disease. The Mini Nutritional Assessment (MNA) and the short form of the survey (MNA-SF) are 2 well-validated clinical tools, previously used to assess patient nutrition status in numerous conditions. Earlier work has demonstrated that low nutrition scores can independently predict mortality in the LVAD population. This study explored changes in MNA scores and other clinical markers following LVAD. This retrospective study included 74 patients implanted with LVADs between 2012 and 2017. MNA or MNA-SF along with other clinical data and nutrition indices were assessed during the preoperative workup and reassessed on average 423.9days post LVAD. Paired-samples t-tests were used to evaluate any changes. Despite an average body mass index of 30.8, 28.3% of patients were classified by MNA as malnourished, and 58.5% were considered at risk prior to LVAD implantation. Post LVAD implantation, MNA scores improved from an average of 19.2-23.0 (P<0.001), with now only 3.8% classified as malnourished and 45.3% classified as at risk. MNA-SF and prognostic nutritional index also improved significantly. This study indicates that LVAD implantation is associated with a long-term improvement in nutrition status when compared with the preoperative heart failure state.

Chapter 19 - Delirium in the critically ill patient

Delirium is an acute and transient brain dysfunction that is characterized by disturbances in consciousness, affecting both its content (i.e., attention) and level (i.e., arousal). It affects as many as 50% of those admitted to an intensive care unit (ICU). Once believed to be an inconsequential outcome of critical illness, it is now recognized that delirium is harmful in both the short- and long-term. Despite occurring frequently in critically ill patients, delirium often goes unrecognized. Well-validated delirium screening tools, designed for use in the ICU, should be used to reliably detect delirium. The first step in delirium treatment is to identify and address potentially modifiable risk factors. Multiple trials have shown that benzodiazepines are a risk factor for delirium in a dose-dependent manner. Sedation with nonbenzodiazepine-based strategies are an effective means by which to reduce delirium. Nonpharmacologic strategies such as those which seek to reduce sensory impairment, sleep deprivation, and immobility are effective. Pharmacologic treatment with antipsychotics, though commonly used, is not supported by findings from placebo-controlled trials. Recent data support from multiple trials support the use of the "ABCDEF bundle" as a means by which to reduce delirium.

A systematic review of tools used to screen and assess for externalising behaviour symptoms in low and middle income settings.

Mental health issues, often manifested as behavioural difficulties, in children are estimated to be high in low and middle-income countries (LMIC) settings. There is a paucity of definitive data due to a lack of well-validated tools to use across settings. This review aims to provide evidence on what tools are used and which have been adapted and validated in LMIC settings. We performed a systematic review to identify tools used to assess or screen externalising behaviour problems in children and adolescents in LMIC and assess their cultural adaptations. We searched for studies measuring externalising behaviour in children from 0 to 19 years published up to September 2018. Articles were assessed to identify tools used and analysed using the Ecological Validity Framework. We identified 82 articles from over 50 LMICs who had studied externalising behaviour in children. Twenty-seven tools were identified, with a predominance of studies using tools from the USA and Europe. Most studies did not describe an adaptation and evaluation process, with only one study following recommended criteria. New tools were identified which both screen and assess externalising behaviour which have not yet been utilised across settings. Although tools from the USA and Europe are often utilised to screen and assess for externalising behaviour problems in children in LMICs, the conceptual frameworks behind the use of these tools in other cultural contexts are not always carefully examined. In order to have valid data across cultures, we should aim to adapt and validate tools before use. Provision of processes to validate tools across LMIC settings would be beneficial.

The State of Assessment in Human-Animal Interaction Research

Abstract There is a growing body of research in human-animal interaction (HAI), but the field is often criticized for its lack of methodological rigor and heterogeneous outcome assessment. In addition, there is a scarcity of valid and reliable assessment tools specific to measuring constructs directly related to HAI. As the field continues to develop, there is a critical need for the consistent use of standardized, well-validated, and appropriate assessment tools. The goal of this paper is to provide an overview of the state of assessment in HAI while identifying current needs for method standardization, development, or refinement. Specifically, we review in detail the use of (1) questionnaires, (2) physiological measures, and (3) behavior assessment tools in the field of HAI while offering examples of successful application, describing methodological limitations, and providing recommendations for use in HAI research.

Interventional Pulmonology: The Role of Simulation Training and Competency-Based Evaluation.

Medical education and training are becoming more complex endeavors as technological and research advancements lead to new tools and methods to care for patients. In recent years, there has been a paradigm shift in medical education to competency-based assessments. Another important recent development in medical education has been the increasing use of simulation-based learning for procedural training. Interventional pulmonology (IP) is a relatively young and rapidly evolving procedural-based subspecialty. There are several well-validated competency-based assessment tools available to measure training adequacy in many of the most commonly performed procedures in IP. These tools have been shown to improve learning curves and training outcomes. The extent of how widely these tools are being used in clinical and educational spheres, however, remains unclear. Moreover, several commonly performed procedures in IP have no or limited validation tools currently available. Standardized training using simulation has also been shown to lead to positive training outcomes as compared with more traditional training models. However, widespread adoption of simulators has been limited due to the cost and availability.

Validity of a two-item screen for early psychosis

Well-validated screening tools have been developed to identify people at high risk for psychosis, but these are rarely used outside of specialty clinics or research settings. The development of extremely brief and simple screening tools could increase dissemination, especially in settings with low buy-in such as those with low base rates of psychosis and/or time constraints. We sought to identify such a brief measure by modeling participant responses to three psychosis screening questionnaires (Prime Screen; Prodromal Questionnaire-Brief; Youth Psychosis At Risk Questionnaire) in a sample of 139 help-seeking individuals and 335 college students (age range: 12–25). Two screening questions with especially strong information characteristics were identified: "Do you see things that others can't or don't see?" and "Have you ever felt that someone was playing with your mind?" (Alternative two-item screens with similarly strong properties were also identified and validated using uncertainty quantified through Bayesian modeling.) The resulting measure was validated against clinician ratings of psychosis. The screen performed with a sensitivity of 53% and specificity 98% for clinically significant hallucinations or delusions, and sensitivity of 32% and specificity 99% for identifying people in an early phase of psychosis (clinical high risk or first episode psychosis).

Implementation of a Routine Health Literacy Assessment at an Academic Medical Center.

Limited health literacy is a common but often unrecognized problem associated with poor health outcomes. Well-validated screening tools are available to identify and provide the opportunity to intervene for at-risk patients in a resource-efficient manner. This is a multimethod study describing the implementation of a hospital-wide routine health literacy assessment at an academic medical center initiated by nurses in April 2014 and applied to all adult inpatients. Results were documented in the electronic health record, which then generated care plans and alerts for patients who screened positive. A nursing survey showed good ease of use and adequate patient acceptance of the screening process. Six months after hospital-wide implementation, retrospective chart abstraction of 1,455 patients showed that 84% were screened. We conclude that a routine health literacy assessment can be feasibly and successfully implemented into the nursing workflow and electronic health record of a major academic medical center.

Psychometric Properties and Clinical Utility of the Specific Phobia Questionnaire in an Anxiety Disorders Sample

Despite an abundance of self-report measures that screen for the presence of specific phobias, there is a lack of comprehensive, well-validated screening tools for identifying a wide range of fears based on DSM-5 specific phobia types. The current paper reports on the psychometric properties and clinical utility of the Specific Phobia Questionnaire (SPQ), a new screening tool for assessing fear of a broad range of phobic stimuli, and the extent to which fear interferes with daily life. An exploratory factor analysis revealed five factors with internal consistency (Cronbach’s α) ranging from .64–.92. The SPQ also demonstrated good convergent and discriminant validity with measures of worry, depression, and other specific phobias, and good test-retest reliability. Results also suggest that SPQ scores are useful for discriminating individuals with specific phobias from those without specific phobias, and for identifying specific phobia types. Overall, preliminary results suggest that the SPQ can serve as a useful tool in both research and clinical settings, and inform intervention and prevention efforts.

Assessment of the Prodromal Questionnaire–Brief Child Version for Measurement of Self-reported Psychoticlike Experiences in Childhood

Childhood psychoticlike experiences (PLEs) are associated with greater odds of a diagnosis of a psychotic disorder during adulthood. However, no known, well-validated self-report tools have been designed to measure childhood PLEs. To examine the construct validity and psychometric properties of a measure of PLEs, the Prodromal Questionnaire-Brief Child Version (PQ-BC). This validation study used data from the first wave of the Adolescent Brain and Cognitive Development (ABCD) Study, a prospective longitudinal study aimed at assessing risk factors associated with adverse physical and mental health outcomes from ages 9 to 10 years into late adolescence and early adulthood. The population-based sample of 3984 children within the ABCD data set was recruited from 20 research sites across the United States. Data for this study were collected from June 1, 2016, through August 31, 2017. The PQ-BC Total and Distress scores were analyzed for measurement invariance across race/ethnicity and sex, their associations with measures of PLEs, and their associations with known correlates of PLEs, including internalizing and externalizing symptoms, neuropsychological test performance, and developmental milestones. The study analyses included 3984 participants (1885 girls [47.3%] and 2099 boys [52.7%]; mean [SE] age, 10.0 [0.01] years). The results demonstrated measurement invariance across race/ethnicity and sex. A family history of psychotic disorder was associated with higher mean (SE) PQ-BC Total (3.883 [0.352]; β = 0.061; 95% CI, 0.027-0.094) and Distress (10.210 [1.043]; β = 0.051; 95% CI, 0.018-0.084) scores, whereas a family history of depression or mania was not. Higher PQ-BC scores were associated with higher rates of child-rated internalizing symptoms (Total score: β range, 0.218 [95% CI, 0.189-0.246] to 0.273 [95% CI, 0.245-0.301]; Distress score: β range, 0.248 [95% CI, 0.220-0.277] to 0.310 [95% CI, 0.281-0.338]), neuropsychological test performance deficits such as working memory (Total score: β = -0.042 [95% CI, -0.077 to -0.008]; Distress score: β = -0.051 [95% CI, -0.086 to -0.017]), and motor and speech developmental milestone delays (Total score: β = 0.057 [95% CI, 0.026-0.086] for motor; β = 0.042 [95% CI, 0.010-0.073] for speech; Distress score: β = 0.048 [95% CI, 0.017-0.079] for motor; β = 0.049 [95% CI, 0.018-0.081] for speech). These results provide support for the construct validity and demonstrate adequate psychometric properties of a self-report instrument designed to measure childhood PLEs, providing evidence that the PQ-BC may be a useful measure of early risk for psychotic disorders. Furthermore, these data suggest that PLEs at school age are associated with many of the same familial, cognitive, and emotional factors associated with psychotic symptoms in older populations, consistent with the dimensionality of psychosis across the lifespan.

The influence of sagittal profile alteration and final lordosis on the clinical outcome of cervical spondylotic myelopathy. A Delta-Omega-analysis.

PurposeDecompression and maintaining or restoring a cervical lordosis are major goals in the surgical treatment of cervical spondylotic myelopathy (CSM). Numerous studies support the assumption that cervical lordosis is a key factor for neurological recovery and pain reduction. However, even kyphotic patients can be asymptomatic. The balance of the spine is subject of an increasing number of publications. The main purpose of the study was to evaluate the validity of lordotic alignment on the course of CSM and to set this parameter in context with well-validated tools, namely the modified Japanese Orthopaedic Association scoring system (mJOAS) and the visual analogue scale (VAS), to predict and measure the clinical outcome after surgery.MethodsThis is a retrospective study with prospectively collected data of a heterogeneous cohort. The authors analyzed the records of 102 patients suffering from CSM that underwent decompressive surgery and instrumentation. Clinical outcome was assessed by using the mJOAS, VAS and Odom’s criteria. The radiological analysis involved comparison of pre- and postoperative radiographs. The patients were divided into subgroups to be able to compare the influence of various amounts of correction (3 Delta-groups: <0°, 1–7° and ≥8°) and final lordosis (4 Omega-groups: 0–7°, 8–14°, 15–21°, ≥22°).Results219 levels were fused in 102 patients. Surgery improved the clinical outcome of all groups significantly. A lordotic profile was achieved in all analyzed groups. Patients that showed small lordosis after surgery (<8°) did not have an inferior clinical outcome compared to patients with larger cervical lordosis (>14°). The comparison of Odom’s criteria showed that preoperatively kyphotic patients benefitted more from surgery than lordotic patients (p = 0.029), but no differences could be seen comparing neck pain and neurological improvement. The improvement of pain and neurological impairment measured by VAS and mJOAS supports the statistical impact and validity of the data despite comparatively small numbers of patients. The lack of postoperative kyphosis is a major limitation of the study to encompass the impact of sagittal alignment on clinical outcome.ConclusionsDecompression and stabilization appear to be key elements of surgical treatment of CSM. While the achievement of cervical lordosis remains a major goal of surgery, clinical improvement is not hindered in patients who show small lordosis. However, kyphosis should be eliminated in symptomatic patients. The terms “balance” and “physiologic lordosis” remain complex entities without clear definition. To check the results of our study controlled randomized trials to validate and determine the exact role of cervical balance on the course of CSM would be helpful.

Monitoring Academic and Social Skills in Elementary School

Numerous well-validated academic progress monitoring tools are used in schools, but there are fewer behavioral progress monitoring measures available. Some brief behavior rating scales have been shown to be effective in monitoring students’ progress, but most focus only on students’ social skills and do not address critical academic-related behaviors. We conducted a quasi-replication of a study by Brady, Evans, Berlin, Bunford, and Kern examining the Classroom Performance Survey (CPS) by using a multi-step analytic strategy, including confirmatory factor analysis and reliability analysis. Over a period of 3 years, 160 elementary schoolteachers in 19 schools across three states completed a modified CPS on 356 elementary students identified as at-risk for emotional and behavioral disorders. The modified CPS was found to be comprised of two factors (Academic Competence and Interpersonal Competence) and showed evidence of reliability and validity. These results suggest that the CPS shows promise as a brief behavior rating scale for progress monitoring in elementary schools.

The influence of maternal dietary exposure to dioxins and PCBs during pregnancy on ADHD symptoms and cognitive functions in Norwegian preschool children

BackgroundPolychlorinated dibenzo-p-dioxins/dibenzofurans (dioxins) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) with potentially adverse impact on child neurodevelopment. Whether the potential detrimental effects of dioxins and PCBs on neurodevelopment are of specific or unspecific character is not clear. ObjectivesThe purpose of the current study was to examine the influence of maternal dietary exposure to dioxins and PCBs on ADHD symptoms and cognitive functioning in preschoolers. We aimed to investigate a range of functions, in particular IQ, expressive language, and executive functions. Material and methodsThis study includes n=1024 children enrolled in a longitudinal prospective study of ADHD (the ADHD Study), with participants recruited from The Norwegian Mother and Child Cohort Study (MoBa). Boys and girls aged 3.5years participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview (PAPA), Stanford-Binet 5th revision (SB-5), Child Development Inventory (CDI), and Behavior Rating Inventory of Executive Function, Preschool version (BRIEF-P). Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl-compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndl-PCBs). Generalized linear and additive models adjusted for confounders were used to examine exposure-outcome associations. ResultsExposure to PCB-153 or dl-compound was not significantly associated with any of the outcome measures when analyses were performed for boys and girls together. After stratifying by sex, adjusted analyses indicated a small inverse association with language in girls. An increase in the exposure variables of 1 SD was associated with a reduction in language score of −0.2 [CI −0.4, −0.1] for PCB-153 and −0.2 [CI −0.5, −0.1] for dl-compounds in girls. For boys, exposure to PCB-153 or dl-compounds was not associated with language skills. The difference between sex-specific associations was not statistically significant (p-value=0.13). No sex-specific effects were observed for ADHD-symptoms, IQ scores, or executive functions. ConclusionsWe found no indications that variation in current low-level exposure to PCB-153 or dl-compounds in Norway is associated with variation ADHD-symptoms, verbal/non-verbal IQ, or executive functions including working memory in preschoolers. However, our findings indicated that maternal dietary exposure to PCB-153 or dl-compounds during pregnancy was significantly associated with poorer expressive language skills in preschool girls, although the sex-specific associations were not significantly different.

Withdrawn: Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the "-Omics" Era.

The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015).

Demographically Corrected Normative Standards for the Spanish Language Version of the NIH Toolbox Cognition Battery

Hispanics are the fastest growing ethnicity in the United States, yet there are limited well-validated neuropsychological tools in Spanish, and an even greater paucity of normative standards representing this population. The Spanish NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neurocognitive screener; however, the original norms were developed combining Spanish- and English-versions of the battery. We developed normative standards for the Spanish NIHTB-CB, fully adjusting for demographic variables and based entirely on a Spanish-speaking sample. A total of 408 Spanish-speaking neurologically healthy adults (ages 18-85 years) and 496 children (ages 3-7 years) completed the NIH Toolbox norming project. We developed three types of scores: uncorrected based on the entire Spanish-speaking cohort, age-corrected, and fully demographically corrected (age, education, sex) scores for each of the seven NIHTB-CB tests and three composites (Fluid, Crystallized, Total Composites). Corrected scores were developed using polynomial regression models. Demographic factors demonstrated medium-to-large effects on uncorrected NIHTB-CB scores in a pattern that differed from that observed on the English NIHTB-CB. For example, in Spanish-speaking adults, education was more strongly associated with Fluid scores, but showed the strongest association with Crystallized scores among English-speaking adults. Demographic factors were no longer associated with fully corrected scores. The original norms were not successful in eliminating demographic effects, overestimating children's performances, and underestimating adults' performances on the Spanish NIHTB-CB. The disparate pattern of demographic associations on the Spanish versus English NIHTB-CB supports the need for distinct normative standards developed separately for each population. Fully adjusted scores presented here will aid in more accurately characterizing acquired brain dysfunction among U.S. Spanish-speakers.

Review of Cardiovascular Disease in HIV-Infected Women

Rates of coronary heart disease (CHD) are over twice as high in younger HIV-infected patients compared to uninfected patients, but most of these studies were conducted in men or in predominantly male cohorts. In the general population, the death rate from CHD has decreased among men, but continues to increase in women. It is unclear if the same increased rate of deaths due to CHD exist in HIV-infected women, and whether rates or risk of CHD differ between HIV-infected men and women, and between seropositive and seronegative women. We reviewed the literature on the rates of cardiovascular events and surrogate measures of atherosclerosis or CHD risk in HIV-infected women. We also reviewed rates of metabolic disease and other markers of inflammation and immune activation that could contribute to increased cardiovascular risk. We found that HIV-infected women have increased rates of acute myocardial infarctions and ischemic strokes compared to HIV-uninfected women and likely HIV-infected men despite women being projected to have lower CHD risk based on Framingham risk scores. Studies assessing CHD risk by measuring anatomical or physiological measures of subclinical atherosclerosis have reported mixed results, and there are no well-validated risk assessment tools or surrogate measures of subclinical CHD among HIV-infected patients to help identify high-risk women for targeting intensive preventive measures. Potential explanations for the increased rates of CHD and subclinical atherosclerosis may be partly explained by increased levels of inflammation and immune activation in HIV-infected women despite virological suppression on antiretroviral therapy. It appears unlikely that disproportionate representation of traditional CHD risk factors and metabolic indices among HIV-infected women can explain well the observed increased rates of CHD. Future studies that include large numbers of HIV-infected women with extended follow-up periods using surrogate measure of CVD and investigating pathogenic mechanisms underlying these observations are urgently needed.

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

AbstractThe neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the “known” genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603–621, 2015)