Patient outcomes of genetic counseling: Assessing the impact of different approaches to family history collection.

No studies have yet evaluated whether different modalities for the collection of family history data influence patient outcomes of genetic counseling. We retrospectively compared outcomes of genetic counseling between patients whose family history (Fhx) was collected (1) via telephone prior to their appointment (FhxPrior) or (2) during the appointment (FhxDuring). We used a psychiatric genetic counseling clinic database, where information about demographics and Fhx timing is recorded, and patients complete the Genetic Counseling Outcomes Scale (GCOS, measuring empowerment) and Illness Management Self-Efficacy Scale (IMSES) immediately prior to (T1) and 1 month after their appointment (T2). We used ANCOVA to evaluate the effect of the Fhx method on patient outcomes at T2. Complete data were available for 240 patients and were used for analysis (FhxPrior, n = 206; FhxDuring, n = 34). GCOS and IMSES scores increased from T1 to T2 (P < .0005 and P = .004, respectively). Although there was no difference between groups for GCOS (P = .412), T2 IMSES scores were significantly higher for FhxPrior than FhxDuring after controlling for T1 scores (P = .011). Our data suggest that obtaining Fhx via telephone prior to genetic counseling may lead to greater increases in patients' self-efficacy as compared to obtaining Fhx during the genetic counseling appointment.

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.

The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

DECIDE: a Decision Support Tool to Facilitate Parents' Choices Regarding Genome-Wide Sequencing.

We describe the rationale, development, and usability testing for an integrated e-learning tool and decision aid for parents facing decisions about genome-wide sequencing (GWS) for their children with a suspected genetic condition. The online tool, DECIDE, is designed to provide decision-support and to promote high quality decisions about undergoing GWS with or without return of optional incidental finding results. DECIDE works by integrating educational material with decision aids. Users may tailor their learning by controlling both the amount of information and its format - text and diagrams and/or short videos. The decision aid guides users to weigh the importance of various relevant factors in their own lives and circumstances. After considering the pros and cons of GWS and return of incidental findings, DECIDE summarizes the user's responses and apparent preferred choices. In a usability study of 16 parents who had already chosen GWS after conventional genetic counselling, all participants found DECIDE to be helpful. Many would have been satisfied to use it alone to guide their GWS decisions, but most would prefer to have the option of consulting a health care professional as well to aid their decision. Further testing is necessary to establish the effectiveness of using DECIDE as an adjunct to or instead of conventional pre-test genetic counselling for clinical genome-wide sequencing.

Prenatal ultrasound and MRI findings of temporal and occipital lobe dysplasia in a twin with achondroplasia.

Thanatophoric dysplasia, hypochondroplasia and achondroplasia are all caused by FGFR3 (fibroblast growth factor receptor 3) mutations. Neuropathological findings of temporal lobe dysplasia are found in thanatophoric dysplasia, and temporal and occipital lobe abnormalities have been described recently in brain imaging studies of children with hypochondroplasia. We describe twins discordant for achondroplasia, in one of whom the prenatal diagnosis was based on ultrasound and fetal MRI documentation of temporal and occipital lobe abnormalities characteristic of hypochondroplasia, in addition to the finding of short long bones. Despite the intracranial findings suggestive of hypochondroplasia, achondroplasia was confirmed following postnatal clinical and genetic testing. These intracranial abnormalities have not been previously described in a fetus with achondroplasia.

Evidence of ancillary trigeminal innervation of levator palpebrae in the general population.

The cranial synkineses are a group of disorders encompassing a variety of involuntary co-contractions of the facial, masticatory, or extraocular muscles that occur during a particular volitional movement. The neuroanatomical pathways for synkineses largely remain undefined. Our studies explored a normal synkinesis long observed in the general population - that of jaw opening during efforts to open the eyelids widely. To document this phenomenon, we observed 186 consecutive participants inserting or removing contact lenses to identify jaw opening. Seeking electrophysiological evidence, in a second study we enrolled individuals undergoing vascular decompression for trigeminal neuralgia or hemifacial spasm, without a history of jaw-winking, ptosis, or strabismus, to record any motor responses in levator palpebrae superioris (LPS) upon stimulation of the trigeminal motor root. Stimulus was applied to the trigeminal motor root while an electrode in levator recorded the response. We found that 37 participants (20%) opened their mouth partially or fully during contact lens manipulation. In the second study, contraction of LPS with trigeminal motor stimulation was documented in two of six patients, both undergoing surgery for trigeminal neuralgia. We speculate these results might provide evidence of an endogenous synkinesis, indicating that trigeminal-derived innervation of levator could exist in a significant minority of the general population. Our observations demonstrate plasticity in the human cranial nerve innervation pattern and may have implications for treating Marcus Gunn jaw-winking.

Extracting insights from the shape of complex data using topology.

This paper applies topological methods to study complex high dimensional data sets by extracting shapes (patterns) and obtaining insights about them. Our method combines the best features of existing standard methodologies such as principal component and cluster analyses to provide a geometric representation of complex data sets. Through this hybrid method, we often find subgroups in data sets that traditional methodologies fail to find. Our method also permits the analysis of individual data sets as well as the analysis of relationships between related data sets. We illustrate the use of our method by applying it to three very different kinds of data, namely gene expression from breast tumors, voting data from the United States House of Representatives and player performance data from the NBA, in each case finding stratifications of the data which are more refined than those produced by standard methods.

Sustained outcomes of a peer-taught family education program on mental illness.

OBJECTIVE: This study examines 6-month follow-up data from participants in a randomized trial of a peer-driven 12-session family support and education program, called family-to-family (FTF) and offered by the US National Alliance on Mental Illness, to determine whether improvements in distress, family functioning, coping and empowerment were sustained. METHOD: Individuals randomized to the FTF condition were assessed after program completion and then 3 months later on measures of distress, family functioning, coping, and empowerment. We used a multilevel regression model (sas proc mixed) to test for significant changes over time (baseline, 3 and 9 months). RESULTS: All significant benefits that FTF participants gained between baseline and immediately post-FTF were sustained at 9 months including reduced anxiety, improved family problem-solving, increased positive coping, and increased knowledge. Greater class attendance was associated with larger increases in empowerment and reductions in depression and displeasure with ill relative. CONCLUSION: Evidence suggests that benefits of the FTF program were sustained for at least 6 months without any additional boosters or supports. Peer-based programs may produce sustained benefits for individuals seeking help in addressing challenges and stresses related to having a family member with a mental illness.

Treatable inborn errors of metabolism causing neurological symptoms in adults.

BACKGROUND: The identification of inborn errors of metabolism (IEM) in adults presenting with a wide range of neurological symptoms is a relatively new field in medicine. We sought to identify which treatable IEM have been diagnosed for the first time in adults and generate a protocol for metabolic screening targeting those treatable disorders. METHODS: Medline/Pubmed searches of English language literature limited to the adult age group were performed. Diseases identified through this search were then compared to previously published lists of treatable IEM in both adults and children. RESULTS: 85% of the treatable conditions known to cause global developmental delay or intellectual disability in children had reports where the diagnosis of that IEM was made in one or more adult patients with neurological symptoms. Screening tests in blood, urine, CSF and MRI can detect most of these treatable conditions but the diagnostic accuracy of these screening tests in adults is not clear. CONCLUSION: Treatable IEM need to be considered in the differential diagnosis of neurological symptoms in patients of any age.

Oral cancer screening and dental care use among women from Ohio Appalachia.

INTRODUCTION: Residents of Appalachia may benefit from oral cancer screening given the region's higher oral and pharyngeal cancer mortality rates. The current study examined the oral cancer screening behaviors and recent dental care (since dentists perform most screening examinations) of women from Ohio Appalachia. METHODS: Women from Ohio Appalachia were surveyed for the Community Awareness Resources Education (CARE) study, which was completed in 2006. A secondary aim of the CARE baseline survey was to examine oral cancer screening and dental care use among women from this region. Outcomes included whether women (n=477; cooperation rate = 71%) had ever had an oral cancer screening examination and when their most recent dental visit had occurred. Various demographic characteristics, health behaviors and psychosocial factors were examined as potential correlates. Analyses used multivariate logistic regression. RESULTS: Most women identified tobacco-related products as risk factors for oral cancer, but 43% of women did not know an early sign of oral cancer. Only 15% of women reported ever having had an oral cancer screening examination, with approximately 80% of these women indicating that a dentist had performed their most recent examination. Women were less likely to have reported a previous examination if they were from urban areas (OR=0.33, 95% CI: 0.13-0.85) or perceived a lower locus of health control (OR=0.94, 95% CI: 0.89-0.98). Women were more likely to have reported a previous examination if they had had a dental visit within the last year (OR=2.24, 95% CI: 1.03-4.88). Only 65% of women, however, indicated a dental visit within the last year. Women were more likely to have reported a recent dental visit if they were of a high socioeconomic status (OR=2.83, 95% CI: 1.58-5.06), had private health insurance (OR=2.20, 95% CI: 1.21-3.97) or had consumed alcohol in the last month (OR=2.03, 95% CI: 1.20-3.42). CONCLUSION: Oral cancer screening was not common among women from Ohio Appalachia, with many missed opportunities having occurred at dental visits. Education programs targeting dentists and other healthcare providers (given dental providers are lacking in some areas of Ohio Appalachia) about opportunistic oral cancer screening may help to improve screening in Appalachia. These programs should include information about populations at high risk for oral cancer (eg smokers) and how screening may be especially beneficial for them. Future research is needed to examine the acceptability of such education programs to healthcare providers in the Appalachian region and to explore why screening was less common among women living in urban areas of Ohio Appalachia.

19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.

miR-21 and miR-155 are associated with mitotic activity and lesion depth of borderline melanocytic lesions.

BACKGROUND: Expression of microRNAs (miRs) has been shown to be altered in many solid tumours and is being explored in melanoma. The malignant potential of some melanocytic lesions is difficult to predict. We hypothesised that characterisation of miR expression in borderline melanocytic proliferations would lead to the identification of a molecular profile that could be used with known prognostic factors to differentiate lesions with high malignant potential. METHODS: The miR expression profile of melanocytic lesions (benign naevi, malignant melanoma and borderline melanocytic tumours) was evaluated by real-time PCR. RESULTS: PCR analysis revealed primary cutaneous melanomas had an 8.6-fold overexpression of miR-21 and a 7.5-fold overexpression of miR-155 compared with benign naevi (P<0.0001). In situ hybridisation confirmed these results. miR-21 and miR-155 were significantly overexpressed within borderline lesions (P=0.0011 and P=0.0048, respectively). When borderline lesions were categorised by mitotic activity and Breslow thickness, miR-21 was associated with mitotic activity and miR-155 was associated with thickness (P<0.025). Among 14 patients with borderline lesions who underwent sentinel lymph node biopsy (SLNB), positive SLNB was associated with increased miR-21 and miR-155 in the primary lesion compared with lesions with a negative SLNB. CONCLUSION: MicroRNA expression profiles can be used to characterise atypical melanocytic lesions.

Stereoscopic visualization and haptic technology used to create a virtual environment for remote surgery - biomed 2011.

The objective of this research is to study the effectiveness of using a stereoscopic visualization system for performing remote surgery. The use of stereoscopic vision has become common with the advent of the da Vinci® system (Intuitive, Sunnyvale CA). This system creates a virtual environment that consists of a 3-D display for visual feedback and haptic tactile feedback, together providing an intuitive environment for remote surgical applications. This study will use simple in vivo robotic surgical devices and compare the performance of surgeons using the stereoscopic interfacing system to the performance of surgeons using one dimensional monitors. The stereoscopic viewing system consists of two cameras, two monitors, and four mirrors. The cameras are mounted to a multi-functional miniature in vivo robot; and mimic the depth perception of the actual human eyes. This is done by placing the cameras at a calculated angle and distance apart. Live video streams from the left and right cameras are displayed on the left and right monitors, respectively. A system of angled mirrors allows the left and right eyes to see the video stream from the left and right monitor, respectively, creating the illusion of depth. The haptic interface consists of two PHANTOM Omni® (SensAble, Woburn Ma) controllers. These controllers measure the position and orientation of a pen-like end effector with three degrees of freedom. As the surgeon uses this interface, they see a 3-D image and feel force feedback for collision and workspace limits. The stereoscopic viewing system has been used in several surgical training tests and shows a potential improvement in depth perception and 3-D vision. The haptic system accurately gives force feedback that aids in surgery. Both have been used in non-survival animal surgeries, and have successfully been used in suturing and gallbladder removal. Bench top experiments using the interfacing system have also been conducted. A group of participants completed two different surgical training tasks using both a two dimensional visual system and the stereoscopic visual system. Results suggest that the stereoscopic visual system decreased the amount of time taken to complete the tasks. All participants also reported that the stereoscopic system was easier to utilize than the two dimensional system. Haptic controllers combined with stereoscopic vision provides for a more intuitive virtual environment. This system provides the surgeon with 3-D vision, depth perception, and the ability to receive feedback through forces applied in the haptic controller while performing surgery. These capabilities potentially enable the performance of more complex surgeries with a higher level of precision.

Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy.

Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.

Intracranial calcification after cord blood neonatal transplantation for krabbe disease.

Infantile-onset Krabbe disease results from a deficiency of the lysosomal enzyme galactocerebrosidase and leads to death from profound central and peripheral demyelination. Neonatal hematopoietic cell transplantation may result in near-normal cognitive development and partial rescue of gross motor development. The long-term course of the disorder for treated patients seems to involve slowly progressive neurological impairment. We describe the detailed 3-year outcomes of this experimental procedure using umbilical cord blood in a prenatally-diagnosed newborn with Krabbe disease. Substantial perivascular calcifications and atrophy of the white matter developed in the first year post-transplantation. Despite persistent neuroradiological and electrophysiological evidence of leukodystrophy, at age 3 years she has had only mildly impaired non-motor development and moderately impaired motor skills. The cause of these severe white matter changes may have been due to ongoing Krabbe disease or to effects of the chemotherapy regimen or to an interaction of these factors. Extended long-term follow-up of children neonatally transplanted for Krabbe disease is needed before the full utility and limitations of neonatal transplantation can be determined.

Quantification of plasma DNA as a prognostic indicator in canine lymphoid neoplasia.

Dogs have a similar incidence of spontaneous cancers as people, and a noninvasive test to monitor disease status in dogs would be of great value. Humans with cancer often have increased levels of cell-free circulating DNA in their plasma, which has shown promise for diagnosis, prognosis and detection of residual disease. We hypothesized that dogs with cancer have increased circulating DNA compared with healthy dogs or dogs with non-neoplastic diseases. Plasma DNA was measured in 40 healthy dogs, 20 dogs with non-neoplastic diseases and 80 dogs with cancer. The reference interval for plasma DNA in healthy dogs was 1-15 ng mL(-1). Dogs with lymphoma and lymphoid leukaemia had significantly higher concentrations (range: 0-91 ng mL(-1), P < 0.0001). Antigen receptor rearrangement assays suggest that plasma DNA had the same clonality as the primary lymphoid tumours. Dogs with lymphoid neoplasia and plasma DNA >25 ng mL(-1) had shorter remission times than those with < 25 ng mL(-1) (P = 0.0116). In contrast to humans, where increased plasma DNA is seen in many diseases, dogs with nonlymphoid malignancies and non-neoplastic diseases had plasma DNA concentrations similar to healthy dogs. This study shows that a portion of dogs with lymphoid neoplasia have increased tumour-derived plasma DNA, which serves as a negative prognostic indicator.

Agreement among Ayurvedic practitioners in the identification and treatment of three cases of inflammatory arthritis.

OBJECTIVE: To conduct a preliminary investigation into the consistency of approach between three Ayurvedic medicine experts on treatments for inflammatory polyarthritis. METHODS: A convenience sample of three experienced Ayurvedic practitioners was recruited. These practitioners independently assessed three subjects with inflammatory polyarthritis for health status, treatment history, and lifestyle, conducted a physical examination, and then independently determined the treatment plan. The treatment plan was recorded on standardized collection forms. The subject examination order was randomized for each practitioner. Following completion of the assessments, a facilitated discussion among the practitioners permitted each to discuss all aspects of the recommended therapies. Proceedings were audio-taped and the content analyzed. RESULTS: All three practitioners agreed upon a unified concept of Ayurvedic disease origin, disease diagnosis, and treatment approach for each patient. Seven specific treatment groupings (i.e. modalities) emerged: diet, exercise, relaxation, analgesic, anti-inflammatory, immune-enhancing, and detoxification/cleansing. Based on the single visit, the practitioners agreed upon 17 of 21 treatment groups for the three patients. CONCLUSION: Despite Ayurvedic medicine's individualized approach, considerable agreement existed among the practitioners studied. The identified Ayurvedic treatment approaches require investigation in a controlled clinical setting.

MRI correlates of suicide attempt history in unipolar depression.

BACKGROUND: Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS: In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS: Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS: Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Use and costs of ambulatory care services among Medicare enrollees with schizophrenia.

OBJECTIVE: The objective of this study was to identify predictors of the use and cost of ambulatory care services among Medicare recipients with schizophrenia. METHODS: The design was a cross-sectional analysis of Medicare claims in 1991. The study subjects were a 5 percent random sample of all persons in the United States who had at least one Medicare service claim in 1991 and who were diagnosed as having schizophrenia in any care setting. Outcome measures included use and cost of any ambulatory care service, individual therapy, psychiatric somatotherapy, group therapy, or family therapy. RESULTS: For nearly 25 percent of the total sample of 12,440, no claims were filed for ambulatory care services in 1991. The mean+/-SD number of ambulatory care visits during the year was 7.9+/-21. The most frequently used type of therapy was individual therapy (5+/-14 visits). The mean+/-SD yearly cost of care for persons who received ambulatory care services was $470+/-$1,028. Among persons under 65 years of age, Caucasians were about 1.5 times as likely as African Americans to have received an ambulatory care service and 1.3 times as likely to have received individual therapy. Persons who were 65 or older were less likely to have received any service. Among service recipients, costs of care were lower for African Americans and for older people. CONCLUSIONS: The use of Medicare-funded ambulatory care services by persons with schizophrenia varied by race and age. Further investigation is required to determine whether subgroups of individuals who do not have additional insurance coverage or access to services are receiving substandard care.

Correlates of insight in serious mental illness.

This study extends research into insight by examining its relationship to a variety of demographic, clinical, neurocognitive, and psychosocial variables among a broad diagnostic sample of 211 adults with serious mental illness. Participants completed a full battery of instruments measuring these variables. Results support a relationship between ratings of poor insight and a psychotic (vs. mood) diagnosis, increased psychiatric symptoms, poorer social skills, and negative medication attitudes. Minorities and those with a substance abuse diagnosis were also more likely to be rated as having poor insight. No relationship was found between level of insight and age, gender, education level, neurocognitive deficits, hospitalization history, size of one's social network, or quality of life measures. Results are discussed in the context of improving the measurement and assessment of insight, conceptualizing interventions aimed at addressing level of insight, and improving outcomes for patients with severe and persistent mental illness. Findings also support a need for continued investigation of how mental illness is understood, experienced, and expressed across diverse groups of people living with mental illness.