Hand preference predicts behavioral responses to threats in Barbary macaques.

The structure and functioning of the brain are lateralized-the right hemisphere processes unexpected stimuli and controls spontaneous behavior, while the left deals with familiar stimuli and routine responses. Hemispheric dominance, the predisposition of an individual using one hemisphere over the other, may lead to behavioral differences; particularly, an individual may be programed to act in a certain way concerning hemispheric dominance. Hand preference is a robust estimator of hemispheric dominance in primates, as each hemisphere controls the opposing side of the body. Studies have found links between hand preference and the exhibition of behaviors in contexts such as exploring and manipulating objects. However, little is known whether hand preference predicts behavioral variations in other ecologically relevant contexts like predation. We investigated the relationship between hand preference and behavioral responses to two types of predator models in captive Barbary macaques (Macaca sylvanus) (n = 22). Besides, a nonpredator novel object was included as control. We found 91% of the macaques to be lateralized with no group-level bias. A higher rate of tension and focus (behavioral response) behavior was found in predator contexts than in the novel object condition. Unlike their right-hand counterparts, individuals with a strong left-hand preference elicited frequent focus and tension behavior toward the predator models. Additionally, the behavioral response varied with predator type. We also found an interaction effect between hand preference and predator type. Our study suggests that hand preference can reliably predict behavioral variations in the context of potential predation. While these results are consistent with lateralized brain function, indicating lateralization a neural mechanism of behavioral variation, the interaction effect between hand preference and predator type elucidates the importance of context-specificity when investigating laterality noninvasively. Future research on other nonhuman primates using the current framework may provide insights into the evolution of laterality and underlying behavioral predispositions.

Parental experiences of rapid exome sequencing in cases with major ultrasound anomalies during pregnancy.

BACKGROUND: Adding rapid exome sequencing (rES) to conventional genetic tests improves the diagnostic yield of pregnancies showing ultrasound abnormalities but also carries a higher chance of unsolicited findings. We evaluated how rES, including pre- and post-test counseling, was experienced by parents investigating its impact on decision-making and experienced levels of anxiety. METHODS: A mixed-methods approach was adopted. Participating couples (n = 46) were asked to fill in two surveys (pre-test and post-test counseling) and 11 couples were approached for an additional interview. RESULTS: All couples accepted the rES test-offer with the most important reason for testing emphasizing their hope of finding an underlying diagnosis that would aid decision-making. The actual impact on decision-making was low, however, since most parents decided to terminate the pregnancy based on the major and multiple fetal ultrasound anomalies and did not wait for their rES results. Anxiety was elevated for most participants and decreased over time. CONCLUSION: Major congenital anomalies detected on ultrasound seem to have more impact on prenatal parental decision-making and anxiety then the offer and results of rES. However, the impact of rES on reproductive decision-making and experienced anxiety requires further investigation, especially in pregnancies where less (severe) fetal anomalies are detected on ultrasound.

AAV-delivered hepato-adrenal cooperativity in steroidogenesis: Implications for gene therapy for congenital adrenal hyperplasia.

Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia; however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct in vivo gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalized, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.

Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.

Realization of the immense therapeutic potential of epigenetic editing requires development of clinically predictive model systems that faithfully recapitulate relevant aspects of the target disease pathophysiology. In female patients with ornithine transcarbamylase (OTC) deficiency, an X-linked condition, skewed inactivation of the X chromosome carrying the wild-type OTC allele is associated with increased disease severity. The majority of affected female patients can be managed medically, but a proportion require liver transplantation. With rapid development of epigenetic editing technology, reactivation of silenced wild-type OTC alleles is becoming an increasingly plausible therapeutic approach. Toward this end, privileged access to explanted diseased livers from two affected female infants provided the opportunity to explore whether engraftment and expansion of dissociated patient-derived hepatocytes in the FRG mouse might produce a relevant model for evaluation of epigenetic interventions. Hepatocytes from both infants were successfully used to generate chimeric mouse-human livers, in which clusters of primary human hepatocytes were either OTC positive or negative by immunohistochemistry (IHC), consistent with clonal expansion from individual hepatocytes in which the mutant or wild-type OTC allele was inactivated, respectively. Enumeration of the proportion of OTC-positive or -negative human hepatocyte clusters was consistent with dramatic skewing in one infant and minimal to modest skewing in the other. Importantly, IHC and fluorescence-activated cell sorting analysis of intact and dissociated liver samples from both infants showed qualitatively similar patterns, confirming that the chimeric mouse-human liver model recapitulated the native state in each infant. Also of importance was the induction of a treatable metabolic phenotype, orotic aciduria, in mice, which correlated with the presence of clonally expanded OTC-negative primary human hepatocytes. We are currently using this unique model to explore CRISPR-dCas9-based epigenetic targeting strategies in combination with efficient adeno-associated virus (AAV) gene delivery to reactivate the silenced functional OTC gene on the inactive X chromosome.

Sick or Sad? A Qualitative Study on How Dutch GPs Deal With Sadness Complaints Among Young Adults.

Feelings of sadness among young adults related to a certain phase of life or to societal factors run the risk of being interpreted as an individual medical problem. Therefore, healthcare professionals should more often widen their perspective and consider de-medicalization as being part of their professional responsibility too. This article presents results from a qualitative interview conducted with 13 GPs in different phases of their career to get more insight into the way they deal with complaints of sadness among young adults. All participants acted proactively but in different ways. Based on the interviews, a typology of three types of general practitioners has been created: the fast referrer, the expert, and the societal GP. There seems to be a paradox in the way GPs think about de-medicalization on a macro level and the way they act on a micro level. Elaborating on Parsons'(1951) classical concept of the sick role, this study introduces the term semi-legitimized sick role to clarify this paradox. The third type, "the societal GP", appears to be the most able to show a more multifactorial view on complaints of sadness. Therefore, this type connects the most to a course of de-medicalization.

Validation of the Spine Oncology Study Group-Outcomes Questionnaire to assess quality of life in patients with metastatic spine disease.

BACKGROUND CONTEXT: General questionnaires are often used to assess quality of life in patients with spine metastases, although a disease-specific survey did not exist until recently. The Spine Oncology Study Group has developed an outcomes questionnaire (SOSG-OQ) to measure quality of life in these patients. However, a scoring system was not developed, and the questionnaire was not validated in a group of patients, nor was it compared with other general quality of life questionnaires such as the EuroQol 5 Dimensions (EQ-5D) questionnaire. PURPOSE: Our primary null hypothesis is that there is no association between the SOSG-OQ and EQ-5D. Our secondary null hypothesis is that there is no difference in coverage and internal consistency between the SOSG-OQ and EQ-5D. We also assess coverage, consistency, and validity of the domains within the SOSG-OQ. STUDY DESIGN/SETTING: A survey study from a tertiary care spine referral center was used for this study. PATIENT SAMPLE: The patient sample consisted of 82 patients with spine metastases, myeloma, or lymphoma. OUTCOME MEASURES: The SOSG-OQ (27 questions, 6 domains) score ranges from 0 to 80, with a higher score indicating worse quality of life. The EQ-5D (5 questions, 5 domains) index score ranges from 0 to 1, with a higher score indicating better quality of life. METHODS: The association between the SOSG-OQ and EQ-5D index score was assessed using the Spearman rank correlation. Instrument coverage and precision were assessed by determining item completion rate, median score with range, and floor and ceiling effect. Internal consistency was assessed using Cronbach alpha. Multitrait analysis and exploratory factor analysis were used to analyze properties of the individual domains in the SOSG-OQ. RESULTS: The Spearman rank correlation between the SOSG-OQ and EQ-5D questionnaire was high (r=-0.83, p<.001). Internal consistency of the SOSG-OQ (0.92, 95% CI: 0.89-0.94) was higher as compared to the internal consistency of the EQ-5D (0.73, 95% CI: 0.63-0.84; p<.001). The SOSG-OQ score had no floor or ceiling effect indicating good coverage (median 30, range 3-64), whereas the EQ-5D had a ceiling effect of 10% (median 0.71, range 0.05-1). CONCLUSIONS: In conclusion, our study proposes a scoring methodology-after reversing four inversely scored items-for the SOSG-OQ and shows that the questionnaire is a valid tool for the assessment of quality of life in patients with metastatic spine disease. The SOSG-OQ is superior to the EQ-5D in terms of coverage and internal consistency but consists of more questions.

Development of a Prognostic Survival Algorithm for Patients with Metastatic Spine Disease.

BACKGROUND: Current prognostication models for survival estimation in patients with metastatic spine disease lack accuracy. Identifying new risk factors could improve existing models. We assessed factors associated with survival in patients surgically treated for spine metastases, created a classic scoring algorithm, nomogram, and boosting algorithm, and tested the predictive accuracy of the three created algorithms at estimating survival. METHODS: We included 649 patients from two tertiary care referral centers in this retrospective study (2002 to 2014). A multivariate Cox model was used to identify factors independently associated with survival. We created a classic scoring system, a nomogram, and a boosting (i.e., machine learning) algorithm and calculated their accuracy by receiver operating characteristic analysis. RESULTS: Older age (hazard ratio [HR], 1.01; p = 0.009), poor performance status (HR, 1.54; p = 0.001), primary cancer type (HR, 1.68; p < 0.001), >1 spine metastasis (HR, 1.32; p = 0.009), lung and/or liver metastasis (HR, 1.35; p = 0.005), brain metastasis (HR, 1.90; p < 0.001), any systemic therapy for cancer prior to a surgical procedure (e.g., chemotherapy, immunotherapy, hormone therapy) (HR, 1.65; p < 0.001), higher white blood-cell count (HR, 1.03; p = 0.002), and lower hemoglobin levels (HR, 0.92; p = 0.009) were independently associated with decreased survival. The boosting algorithm was best at predicting survival on the training data sets (p < 0.001); the nomogram was more reliable at estimating survival on the test data sets, with an accuracy of 0.75 (30 days), 0.73 (90 days), and 0.75 (365 days). CONCLUSIONS: We identified risk factors associated with survival that should be considered in prognostication. Performance of the boosting algorithm and nomogram were comparable on the testing data sets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision-making. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.