ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.

ObjectiveWe aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations.MethodsPatients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features.ResultsA total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy.ConclusionsARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy

A Multi-cell, Multi-scale Model of Vertebrate Segmentation and Somite Formation

Somitogenesis, the formation of the body's primary segmental structure common to all vertebrate development, requires coordination between biological mechanisms at several scales. Explaining how these mechanisms interact across scales and how events are coordinated in space and time is necessary for a complete understanding of somitogenesis and its evolutionary flexibility. So far, mechanisms of somitogenesis have been studied independently. To test the consistency, integrability and combined explanatory power of current prevailing hypotheses, we built an integrated clock-and-wavefront model including submodels of the intracellular segmentation clock, intercellular segmentation-clock coupling via Delta/Notch signaling, an FGF8 determination front, delayed differentiation, clock-wavefront readout, and differential-cell-cell-adhesion-driven cell sorting. We identify inconsistencies between existing submodels and gaps in the current understanding of somitogenesis mechanisms, and propose novel submodels and extensions of existing submodels where necessary. For reasonable initial conditions, 2D simulations of our model robustly generate spatially and temporally regular somites, realistic dynamic morphologies and spontaneous emergence of anterior-traveling stripes of Lfng. We show that these traveling stripes are pseudo-waves rather than true propagating waves. Our model is flexible enough to generate interspecies-like variation in somite size in response to changes in the PSM growth rate and segmentation-clock period, and in the number and width of Lfng stripes in response to changes in the PSM growth rate, segmentation-clock period and PSM length

AIDS-related mycoses: the way forward.

The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

A model selection approach to analysis of variance and covariance

An alternative to analysis of variance is a model selection approach where every partition of the treatment means into clusters with equal value is treated as a separate model. The null hypothesis that all treatments are equal corresponds to the partition with all means in a single cluster. The alternative hypothesis correspond to the set of all other partitions of treatment means. A model selection approach can also be used for a treatment by covariate interaction, where the null hypothesis and each alternative correspond to a partition of treatments into clusters with equal covariate effects. We extend the partition-as-model approach to simultaneous inference for both treatment main effect and treatment interaction with a continuous covariate with separate partitions for the intercepts and treatment-specific slopes. The model space is the Cartesian product of the intercept partition and the slope partition, and we develop five joint priors for this model space. In four of these priors the intercept and slope partition are dependent. We advise on setting priors over models, and we use the model to analyze an orthodontic data set that compares the frictional resistance created by orthodontic fixtures

Prospective Cross-Sectional Study of Repeatability of Peripapillary Capillary Density Measurement Using Optical Coherence Tomography Angiography in Eyes With Optic Nerve and Retinal Vascular Pathology

BackgroundOptical coherence tomography angiography (OCTA) is a new noninvasive imaging modality that provides high resolution images of the optic nerve head and peripapillary retinal capillary vasculature which can be affected by optic nerve or retinal pathologies. High repeatability of peripapillary capillary density measurement using OCTA has been demonstrated in normal eyes and eyes with glaucoma. The purpose of our study was to quantify the repeatability of peripapillary capillary density measurement using OCTA in both normal eyes and eyes with optic atrophy, optic disc edema, and retinal vasculopathy.MethodsThis prospective cross-sectional study enrolled 31 patients (59 eyes) including 16 eyes with optic nerve pathology (7 with disc edema from papilledema and 9 with optic atrophy), 35 eyes with retinal vascular disease, and 8 normal eyes. All eyes were imaged twice (30 minutes apart) with the Optovue AngioVue OCTA instrument to obtain 4.5 × 4.5 mm peripapillary scans. Scans were considered good quality if signal strength was 6 or greater. The OCTA parameters obtained include the radial peripapillary capillary (RPC) density of the whole disc, inside the disc, peripapillary region, and the 4 quadrants of the disc (superior, nasal, inferior, and temporal). A Student's t test was used to compare means. Intraclass correlation coefficient (ICC) was calculated to measure repeatability.ResultsRepeatability of RPC density measurements for all regions analyzed demonstrated good to excellent repeatability for the whole cohort {ICC for the whole image was 0.915 (95% confidence interval [CI] = 0.855-0.951)}; ICC for the peripapillary region was 0.945 (95% CI = 0.905-0.969). In the subset of eyes with good image quality (i.e., signal strength ≥ 6), ICC was slightly higher for all regions, with excellent repeatability of the peripapillary region (ICC was 0.971 [95% CI = 0.943-0.986]). Conversely, for eyes with poor image quality scans (i.e., signal strength < 6), ICC was lower, corresponding to moderate to good repeatability for most parameters. For the subset of eyes with optic atrophy, disc edema from papilledema or retinal vasculopathy, all had good to excellent repeatability of the vessel density of the entire disc (ICC values were 0.954 [95% CI = 0.804-0.990], 0.921 [95% CI = 0.711-0.982], and 0.895 [95% CI = 0.788-0.951, respectively]) and of the peripapillary region (ICC values were 0.980 [95% CI = 0.904-0.996], 0.966 [95% CI = 0.854-0.993], and 0.916 [95% CI = 0.827-0.961], respectively).ConclusionsThe peripapillary capillary density measurement obtained using a commercial OCTA instrument is highly repeatable in eyes with optic nerve atrophy, disc edema from papilledema, or retinal vasculopathy

Randomized trial to increase colorectal cancer screening in an ethnically diverse sample of first-degree relatives.

BackgroundEthnic minorities, especially African Americans and Latinos, bear a disproportionate burden of colorectal cancer (CRC), as reflected in incidence, cancer stage, and mortality statistics. In all ethnic groups, first-degree relatives (FDRs) of CRC cases are at an elevated disease risk. However, underuse of CRC screening persists and is particularly evident among minority groups. The current study tested a stepped intervention to increase CRC screening among an ethnically diverse sample of FDRs of CRC cases.MethodsA statewide cancer registry was used to recruit CRC cases and through them their FDRs. Relatives who were not current on CRC screening were randomized to intervention or usual-care control arms. The stepped intervention consisted of ethnically targeted and individually tailored print materials followed by telephone counseling for those unscreened at 6 months.ResultsThe study sample of 1280 individuals consisted of 403 Latino, 284 African American, 242 Asian, and 351 white FDRs. Statistically significant effects were observed for the cumulative print plus telephone intervention at 12 months (26% in the intervention vs 18% in the control group) and the print intervention alone at 6 months (15% in the intervention vs 10% in the control group). The effect of the print intervention alone versus the cumulative interventions was not statistically significantly different. Stratified analyses indicated that the intervention was effective among white, Latino, and Asian individuals, but not among African-Americans.ConclusionsOverall, the intervention was effective in increasing screening rates. Oversampling racial/ethnic minorities allowed for the examination of effects within subgroups, revealing no effect among African American individuals. This finding illustrates the importance of including sufficient numbers of participants from diverse ethnic subgroups in intervention research to enable such stratified analyses

They are not always a burden: older people and child fostering in Uganda during the HIV epidemic.

This qualitative study examines the role of older people (60 years and above) in fostering decisions for orphans and non-orphans within extended families in a rural Ugandan community heavily affected by HIV. Fieldwork conducted in 2006 provided information on the influence of HIV on fostering decisions through 48 individual in-depth interviews and two group interviews with foster-children and family members to develop detailed case studies related to 13 fostered adolescents. The adolescents included five non-orphans and eight orphans (five were double orphans because they had lost both parents). Older people play a very important role in fostering decisions as potential foster-parents, advisers, mediators and gatekeepers. They have a high level of authority over the foster-children, who are regarded as important resources within the extended family. With fewer potential caregivers available because of HIV-related deaths, the responsibility for fostering orphans has often fallen to surviving older people. Fostering is used by older people and the child's extended family as a strategy to ensure the welfare of the foster-child. When the foster-parent is an older person, it is also used to ensure physical and emotional support for the older person themselves. Support from the extended family towards foster households is widely reported to have been reduced by HIV by diminishing resources that would otherwise have been made available to support foster care. New initiatives and investment are required to complement community and family resources within well-managed social protection and welfare programmes. To be effective, such programmes will require adequate investment in administrative capacity and monitoring. They must aim to strengthen families and, recognizing that resources are limited, should prioritize the community's poorest households, rather than specifically targeting households with orphans or other foster-children

ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.

ObjectiveWe aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations.MethodsPatients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features.ResultsA total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy.ConclusionsARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy