Genes and evolutionary fates of the amanitin biosynthesis pathway in poisonous mushrooms.

The deadly toxin α-amanitin is a bicyclic octapeptide biosynthesized on ribosomes. A phylogenetically disjunct group of mushrooms in Agaricales (Amanita, Lepiota, and Galerina) synthesizes α-amanitin. This distribution of the toxin biosynthetic pathway is possibly related to the horizontal transfer of metabolic gene clusters among taxonomically unrelated mushrooms with overlapping habitats. Here, our work confirms that two biosynthetic genes, P450-29 and FMO1, are oxygenases important for amanitin biosynthesis. Phylogenetic and genetic analyses of these genes strongly support their origin through horizontal transfer, as is the case for the previously characterized biosynthetic genes MSDIN and POPB. Our analysis of multiple genomes showed that the evolution of the α-amanitin biosynthetic pathways in the poisonous agarics in the Amanita, Lepiota, and Galerina clades entailed distinct evolutionary pathways including gene family expansion, biosynthetic genes, and genomic rearrangements. Unrelated poisonous fungi produce the same deadly amanitin toxins using variations of the same pathway. Furthermore, the evolution of the amanitin biosynthetic pathway(s) in Amanita species generates a much wider range of toxic cyclic peptides. The results reported here expand our understanding of the genetics, diversity, and evolution of the toxin biosynthetic pathway in fungi.

Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Qualitative Examination of the Experience of Perceived Injustice Following Disabling Occupational Injury.

PURPOSE: The primary objective of this study was to explore individuals' perspectives on the factors, situations or events that contributed to their perceptions of injustice following occupational injury. MATERIALS AND METHODS: The study sample consisted of 30 participants (18 women, 12 men) who had submitted a time-loss claim for a work-related musculoskeletal injury. Participants with elevated scores on a measure of perceived injustice were interviewed about the factors that contributed to their sense of injustice. A thematic analysis was conducted to identify the broad classes of situations or events that participants experienced as unjust in the weeks following occupational injury. RESULTS: Three dominant themes emerged from the interviews: (1) Invalidation, (2) Undeserved suffering and (3) Blame. Inductively derived subthemes reflected specific dimensions of post-injury experiences that contributed to participants' sense of injustice. CONCLUSIONS: Given that suffering and invalidating communication are potentially modifiable factors, there are grounds for optimism that intervention approaches can be developed to prevent or reduce perceptions of injustice in the aftermath of debilitating injury. The development of intervention approaches that are effective in preventing or reducing perceptions of injustice holds promise of contributing to more positive recovery outcomes in individuals who have sustained debilitating work injuries.

Validation of the National Institute of Health Toolbox Cognition Battery (NIHTB-CB) in Children and Adolescents with and without HIV Infection in Lusaka, Zambia.

The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambian children with and without HIV-infection. Children living with HIV and HIV-exposed, uninfected (HEU) children completed traditional neuropsychological and NIHTB-CB tasks. Using pairwise correlation and a linear regression model we measured associations between traditional measure composite scores and parental ratings of children's abilities, and NIHTB-CB scores. A Receiver Operating Characteristic (ROC) curve was developed to identify participants with impairment. 389 children, 8-17 years old participated. NIHTB-CB and traditional measures converged well as a whole and when comparing analogous individual tests across the two batteries. The NIHTB-CB composite score discriminated between the groups and was positively associated with external criteria for cognitive function: parental ratings of intelligence and school performance. Some English vocabulary and/or an unfamiliar cultural context presented challenges. NIHTB-CB was associated with children's everyday cognitive abilities, though future use may require linguistic and cultural adaptation.

The temporal relation between pain and fatigue in individuals receiving treatment for chronic musculoskeletal pain.

BACKGROUND: Numerous investigations have revealed significant relations between pain and fatigue in individuals with persistent pain conditions. However, the direction of influence between pain and fatigue remains unclear. Shortcomings of design and analytic approaches used in previous research limit the nature of conclusions that can be drawn about possible causal or directional relations between pain and fatigue. The present study investigated the temporal relation between changes in pain and changes in fatigue in individuals with musculoskeletal pain enrolled in a 10-week behavioral activation intervention. On the basis of previous findings, it was hypothesized that analyses would support a bi-directional relation between pain and fatigue. METHODS: The study sample consisted of 104 individuals with chronic musculoskeletal pain participating in a 10-week standardized rehabilitation intervention. Measures of pain intensity and fatigue were completed pre-, mid-, and post-treatment. The three-wave data panel permitted examination of the direction of influence between pain and fatigue through the course of the intervention. A random-intercept cross-lagged panel model (RI-CLPM) was used to examine the temporal relation between pain and fatigue. RESULTS: Consistent with previous research, cross-sectional analyses of pre-treatment data revealed significant correlations between measures of pain and fatigue. Significant reductions in pain and fatigue were observed through the course of treatment (d = 0.33 and d = 0.66, p < .001, respectively). RI-CLPM revealed that pain severity predicted later fatigue (pre to mid-treatment standardized path coefficient (ß) = 0.55, p = 0.02; mid to post-treatment ß = 0.36, p = 0.001); however, fatigue did not predict later pain severity. CONCLUSIONS: Discussion addresses the processes that might underlie the temporal relation between pain and fatigue. Clinical implications of the findings are also discussed.

A diagnostic confidence scheme for CLN3 disease.

Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Evaluating the Relationship Between Depression and Cognitive Function Among Children and Adolescents with HIV in Zambia.

Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8-17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2-7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18-15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies.

Anxiety Symptoms Differ in Youth With and Without Tic Disorders.

We compared anxiety symptoms in youth with and without tic disorders by comparing scores on the Multidimensional Anxiety Scale for Children (MASC) in youth with tic disorders to those in a concurrent community control group and in a group of treatment-seeking anxious youth from the Child/Adolescent Anxiety Multimodal Study (CAMS). Data from 176 youth with tic disorders, 93 control subjects, and 488 CAMS participants were included. Compared to youth with tic disorders, controls had lower total MASC scores (p < 0.0001) and CAMS participants had similar total MASC scores (p = 0.13). Separation Anxiety (p = 0.0003) and Physical Symptom (p < 0.0001) subscale scores were higher in youth with tic disorders than in CAMS participants. We conclude that the anxiety symptom profile differs in youth with and without tic disorders, which may have important implications for targeting treatment of anxiety in youth with tic disorders.

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints.

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.

The Sequential Relation Between Changes in Catastrophizing and Changes in Posttraumatic Stress Disorder Symptom Severity.

Catastrophizing has been discussed as a cognitive precursor to the emergence of posttraumatic stress disorder (PTSD) symptoms following the experience of stressful events. Implicit in cognitive models of PTSD is that treatment-related reductions in catastrophizing should yield reductions in PTSD symptoms. The tenability of this prediction has yet to be tested. The present study investigated the sequential relation between changes in a specific form of catastrophizing-symptom catastrophizing-and changes in PTSD symptom severity in a sample of 73 work-disabled individuals enrolled in a 10-week behavioral activation intervention. Measures of symptom catastrophizing and PTSD symptom severity were completed at pre-, mid-, and posttreatment assessment points. Cross-sectional analyses of pretreatment data revealed that symptom catastrophizing accounted for significant variance in PTSD symptom severity, ß = .40, p < .001, sr = .28 (medium effect size), even when controlling for known correlates of symptom catastrophizing, such as pain and depression. Significant reductions in symptom catastrophizing and PTSD symptoms were observed during treatment, with large effect sizes, ds = 1.42 and 0.94, respectively, ps < .001. Cross-lagged analyses revealed that early change in symptom catastrophizing predicted later change in PTSD symptoms; early changes in PTSD symptom severity did not predict later change in symptom catastrophizing. These findings are consistent with the conceptual models that posit a causal relation between catastrophizing and PTSD symptom severity. The clinical implications of the findings are discussed.

Reductions in Fatigue Predict Occupational Re-engagement in Individuals with Work-Related Musculoskeletal Disorders.

Background Symptoms of fatigue have been shown to be associated with heightened levels of disability in patients suffering from a wide range of debilitating health and mental health conditions. The role of fatigue as a determinant of work disability in individuals with work-related musculoskeletal disorders (WRMD) has received little attention. The present study examined the role of fatigue as a determinant of work-disability in individuals with WRMDs. Methods Participants included 117 individuals with WRMDs who completed measures of pain severity, fatigue, depression and disability before and after participating in a behavioral activation rehabilitation intervention. Results Cross-sectional analyses on pre-treatment measures revealed that fatigue contributed significant variance to the prediction of self-reported disability, beyond the variance accounted for by pain severity and depression. Prospective analyses revealed that reductions in fatigue through the course of treatment predicted occupational re-engagement following termination of the intervention. Conclusions The results of the present study suggest fatigue contributes to occupational disability, independent of the effects of pain and depression. The findings also suggest that meaningful reductions in fatigue might be achieved through psychosocial interventions that promote gradual re-integration into discontinued activities, increase participants' exposure to success and achievement experiences, and reduce the severity of depressive symptoms. Behavioural activation interventions such as the one used in the present study might contribute to more positive occupational outcomes in work-disabled individuals who report high levels of fatigue.

Patient-reported study of the impact of pediatric-onset myotonic dystrophy.

INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.

Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study

Background: Approximately one-third of people with schizophrenia have elevated levels of anti-gliadin antibodies of the immunoglobulin G type (AGA IgG) ­ a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG. Methods: In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and endpoint. Results: Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = ­0.75) and in negative symptoms (Cohen d = ­0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the glutencontaining group. Adverse effects were similar between groups. Limitations: This study was limited by its small sample size; larger studies are needed. Conclusion: This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder.

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder.

BACKGROUND: Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. METHODS: We created a "hub and spoke" model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the "hub," conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating "spoke" site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. RESULTS: A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6-9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. CONCLUSIONS: This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

Neurocognitive Function in Children with Primary Hypertension after Initiation of Antihypertensive Therapy.

OBJECTIVE: To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy. STUDY DESIGN: Subjects with hypertension and normotensive control subjects had neurocognitive testing at baseline and again after 1 year, during which time the subjects with hypertension received antihypertensive therapy. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed, and parents completed rating scales of executive function. RESULTS: Fifty-five subjects with hypertension and 66 normotensive control subjects underwent both baseline and 1-year assessments. Overall, the blood pressure (BP) of subjects with hypertension improved (24-hour systolic BP load: mean baseline vs 1 year, 58% vs 38%, P < .001). Primary multivariable analyses showed that the hypertension group improved in scores of subtests of the Rey Auditory Verbal Learning Test, Grooved Pegboard, and Delis-Kaplan Executive Function System Tower Test (P < .05). However, the control group also improved in the same measures with similar effects sizes. Secondary analyses by effectiveness of antihypertensive therapy showed that subjects with persistent ambulatory hypertension at 1 year (n = 17) did not improve in subtests of Rey Auditory Verbal Learning Test and had limited improvement in Grooved Pegboard. CONCLUSIONS: Overall, children with hypertension did not improve in neurocognitive test performance after 1 year of antihypertensive therapy, beyond that also seen in normotensive controls, suggesting improvements with age or practice effects because of repeated neurocognitive testing. However, the degree to which antihypertensive therapy improves BP may affect its impact upon neurocognitive function.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

PURPOSE/BACKGROUND: Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. METHODS/PROCEDURES: Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. FINDINGS/RESULTS: Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. IMPLICATIONS/CONCLUSIONS: Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Ambulatory blood pressure monitoring and neurocognitive function in children with primary hypertension.

BACKGROUND: Children with primary hypertension have been reported to have diminished scores in measures of cognition. However, little is known about the relative correlation between office and ambulatory blood pressure (BP) and neurocognitive test performance, and whether short-term BP variability is associated with decreased neurocognitive function. We sought to determine whether ambulatory BP monitoring (ABPM) was more strongly associated with neurocognitive test performance compared with office BP, and whether increased short-term BP variability was associated with lower neurocognitive scores. METHODS: Seventy-five subjects ages 10-18 years, with untreated primary hypertension, and 75 matched normotensive controls completed neurocognitive testing. All subjects had office BP and ABPM prior to neurocognitive testing. RESULTS: On multivariate analyses, there was no significant association between office BP and neurocognitive tests. However, several ABPM parameters were significantly associated with neurocognitive test scores in the lower quartile, in particular 24 h SBP load and wake systolic blood pressure (SBP) index [Rey Auditory Verbal learning Test (RAVLT) List A Trial 1, 24 h SBP load, odds ratio (OR) = 1.02, wake SBP index, OR = 1.06; List A Total, 24 h SBP load, OR = 1.02, wake SBP index, OR = 1.06; Short Delay Recall, wake SBP index, OR = 1.06; CogState Maze delayed recall, 24 h SBP load, OR = 1.03, wake SBP index, OR = 1.08; Grooved Pegboard, 24 h SBP load, OR = 1.02; all p < 0.05]. In contrast, short-term BP variability measures were not associated with neurocognitive test performance. CONCLUSIONS: ABPM is superior to office BP in distinguishing hypertensive youth with lower neurocognitive test performance.

Cystic placentomegaly on a second-trimester ultrasound.

Placental mesenchymal dysplasia (PMD) is a rare disorder of the placenta characterized by placentomegaly, cystic vesicles, and dilated chorionic blood vessels. Clinically and pathologically, it closely resembles partial molar pregnancy and complete hydatidiform mole with a coexistent healthy fetus, both of which are associated with malignant trophoblastic disease. PMD, however, has no risk of malignant trophoblastic disease and can result in the birth of a normal fetus, highlighting the need for clinician awareness of PMD in order to avoid unnecessary termination of a viable and potentially healthy fetus.