Perceived stigma related to TB preventive therapy.

BACKGROUND: TB preventative therapy (TPT) is crucial for reducing the burden of TB in endemic settings. We assessed stigma associated with TPT and the social groups from whom stigma was anticipated.METHODS: We conducted an anonymous cross-sectional survey of community-dwelling adults in rural South Africa. Descriptive statistics, exploratory factor analysis, χ² tests, Kruskal-Wallis tests, and Poisson regression were used to identify factors associated with TPT stigma.RESULTS: The mean age of the 104 participants was 35 years, 65% were female, and 26% had completed secondary school. The vast majority perceived stigma associated with TPT (71%; mean score 1.7, SD ± 1.4). Factor analysis identified a two-factor solution that explained 61.9% of the variance. Being single (P < 0.001), previously screened for TB (P = 0.04), worried about being infected by TB (P = 0.006), and interested in taking TPT (P = 0.01) were associated with higher perceived stigma scores. TPT stigma was perceived among 8%, 16%, and 66% of their family, friends, and other community members, respectively.CONCLUSION: The prevalence of TPT-related stigma in a rural South African community was high. Community members anticipated less stigma from family members compared to other social groups. Global expansion and implementation of TPT will require novel interventions, such as engaging patients´ families to support uptake and promote adherence.

Gaps in TB preventive therapy for persons initiating antiretroviral therapy in Uganda: an explanatory sequential cascade analysis.

BACKGROUND: The WHO recommends TB symptom screening and TB preventive therapy (TPT) for latent TB infection (LTBI) in persons living with HIV (PLWH). However, TPT uptake remains limited. We aimed to characterize and contextualize gaps in the TPT care cascade among persons enrolling for antiretroviral therapy (ART).SETTING: Four PEPFAR-supported facilities in Uganda.METHODS: We studied a proportionate stratified random sample of persons registering for ART when TPT was available. Patient-level data on eligibility, initiation, and completion were obtained from registers to determine proportion of eligible patients completing each cascade step. We interviewed providers and administrators and used content analysis to identify barriers to guideline-concordant TPT practices.RESULTS: Of 399 study persons, 309 (77%) were women. Median age was 29 (IQR 25-34), CD4 count 405 cells/µL (IQR 222-573), and body mass 23 kg/m² (IQR 21-25). Of 390 (98%) screened, 372 (93%) were TPT-eligible. Only 62 (17%) eligible PLWH initiated and 36 (58%) of 62 completed TPT. Providers reported hesitating to prescribe TPT because they lacked confidence excluding TB by symptom screening alone and feared promoting drug resistance. Although isoniazid was available, past experience of irregular supply discouraged TPT initiation. Providers pointed to insufficient TB-dedicated staff, speculated that patients discounted TB risk, and worried TPT pill burden and side effects depressed ART adherence.CONCLUSIONS: While screening was nearly universal, most eligible PLWH did not initiate TPT. Only about half of those who initiated completed treatment. Providers feared promoting drug resistance, harbored uncertainty about continued availability, and worried TPT could antagonize ART adherence. Our findings suggest urgent need for stakeholder engagement in TPT provision.

Social determinants of tuberculosis evaluation among household contacts: a secondary analysis.

Setting: Seven public sector tuberculosis (TB) units and surrounding communities in Kampala, Uganda. Objective: To evaluate the influence of household-level socio-economic characteristics on completion of TB evaluation during household contact investigation. Design: A cross-sectional study nested within the control arm of a randomized, controlled trial evaluating home-based sputum collection and short messaging service communications. We used generalized estimating equations to estimate the association between completion of TB evaluation and socio-economic determinants. Results: Of 116 household contacts referred to clinics for TB evaluation, 32 (28%) completed evaluation. Completing evaluation was strongly clustered by household. Controlling for individual symptoms, contacts from households earning below-median income (adjusted risk ratio [aRR] 0.28, 95%CI 0.09-0.88, P = 0.029) and contacts from households in which the head of household had no more than primary-level education (aRR 0.40, 95%CI 0.18-0.89, P = 0.025) were significantly less likely to complete evaluation for TB. Conclusion: Socio-economic factors such as low income and education increase the risk that household contacts of TB patients will experience barriers to completing TB evaluation themselves. Further research is needed to identify specific mechanisms by which these underlying social determinants modify the capability and motivation of contacts to complete contact investigation.

Contexte : Sept unités de tuberculose (TB) du secteur public et les communautés qui les entourent à Kampala, Ouganda.Objectif : Evaluer l'influence des caractéristiques socioéconomiques des foyers sur l'achèvement de la recherche de TB lors de l'investigation des contacts domiciliaires.Schéma : Une étude transversale au sein du bras témoin d'un essai randomisé, contrôlé, évaluant le recueil de crachats à domicile et les communications par messagerie SMS. Nous avons utilisé des équations d'estimations généralisées afin d'estimer l'association entre l'achèvement de l'évaluation de la TB et les déterminants socioéconomiques.Résultats : Parmi les 116 contacts domiciliaires qui ont été référés à des centres de santé pour un bilan de TB, 32 (28%) ont achevé cette évaluation. L'achèvement de l'évaluation a été fortement regroupé par foyer. En contrôlant les symptômes individuels, les contacts des foyers ayant un revenu inférieur à la médiane (ratio de risque ajusté [RRa] 0,28 ; IC95% 0,09­0,88 ; P = 0,029) et les contacts des foyers dont le niveau d'instruction du chef ne dépassait pas l'école primaire (RRa 0,40 ; IC95% 0,18­0,89 ; P = 0,025) ont été significativement moins susceptibles de terminer le bilan de TB.Conclusion : Les facteurs socioéconomiques tels qu'un faible revenu et un faible niveau d'études augmentent le risque que les contacts domiciliaires de patients TB soient confrontés à des obstacles à l'achèvement de l'évaluation de la TB. Davantage de recherche est nécessaire pour identifier les mécanismes spécifiques par lesquels des déterminants sociaux sous-jacents modifient la capacité et la motivation des contacts à terminer leur bilan.

Marco de Referencia: Siete unidades de tuberculosis (TB) del sector público y las comunidades aledañas en Kampala, Uganda.Objetivo: Evaluar la influencia de las características socioeconómicas de los hogares en la compleción de la evaluación de la TB durante la investigación de contactos domiciliarios.Método: Fue este un estudio transversal anidado en la rama de referencia de un ensayo clínico aleatorizado, que evaluaba la recogida de esputo en los hogares y las comunicaciones por servicio de SMS. Se aplicaron ecuaciones de estimación generalizadas con el fin de apreciar la asociación entre la compleción de la investigación de la TB y los determinantes socioeconómicos.Resultados: Se remitieron a los consultorios 116 contactos domiciliarios para investigación de la TB y 32 completaron la evaluación (28%). La compleción de la investigación exhibió una importante distribución en conglomerados por hogares. Al ajustar con respecto a los síntomas individuales, se observó que era mucho menos probable que se completase la investigación de la TB en los contactos de hogares con un ingreso familiar por debajo de la mediana (razón de riesgos ajustada [aRR] 0,28; IC95% 0,09­0,88; P = 0,029) y en los contactos de hogares cuya cabeza de familia no tenía un grado de instrucción superior al nivel primario (aRR 0,40; IC95% 0,18­0,89; P = 0,025).Conclusión: Los factores socioeconómicos como un bajo ingreso y un grado inferior de instrucción aumentan el riesgo de que los contactos domiciliarios encuentren obstáculos propios para completar la investigación de TB. Se precisan nuevas investigaciones que definan los mecanismos mediante los cuales estos determinantes sociales subyacentes modifican la capacidad y la motivación de las personas a finalizar la investigación de contactos.

'Something so hard': a mixed-methods study of home sputum collection for tuberculosis contact investigation in Uganda.

BACKGROUND: Home sputum collection could facilitate prompt evaluation and diagnosis of tuberculosis (TB) among contacts of patients with active TB. We analyzed barriers to home-based collection as part of an enhanced intervention for household TB contact investigation in Kampala, Uganda. DESIGN: We conducted a convergent mixed-methods study to describe the outcomes of home sputum collection in 91 contacts and examine their context through 19 nested contact interviews and two focus group discussions with lay health workers (LHWs). RESULTS: LHWs collected sputum from 35 (39%) contacts. Contacts reporting cough were more likely to provide sputum than those with other symptoms or risk factors (53% vs. 15%, RR 3.6, 95%CI 1.5-2.8, P < 0.001). Males were more likely than females to provide sputum (54% vs. 32%, RR 1.7, 95%CI 1.0-2.8, P = 0.05). Contacts said support from the index patient and the convenience of the home visit facilitated collection. Missing containers and difficulty producing sputum spontaneously impeded collection. Women identified stigma as a barrier. LHWs emphasized difficulty in procuring sputum and discomfort pressing contacts to produce sputum. CONCLUSIONS: Home sputum collection by LHWs entails different challenges from sputum collection in clinical settings. More research is needed to develop interventions to mitigate stigma and increase success of home-based collection.

Integrating home HIV counselling and testing into household TB contact investigation: a mixed-methods study.

Setting: Community health workers (CHWs) increasingly deliver community-based human immunodeficiency virus (HIV) counselling and testing (HCT) services. Less is known about how this strategy performs when integrated with household tuberculosis (TB) contact investigations. Objective: We conducted a prospective mixed-methods study to evaluate the feasibility and quality of CHW-facilitated, home-based HCT among household TB contacts. Design: CHWs visited households of consenting TB patients to screen household contacts for TB and HIV. They performed HIV testing using a serial enzyme-linked immunosorbent assay rapid-antibody testing algorithm. Laboratory technicians at health facilities re-tested the samples and coordinated quarterly HIV panel testing for CHWs. We conducted focus group discussions (FGDs) with CHWs on their experiences in carrying out home-based HCT. Results: Of 114 household contacts who consented to and underwent HIV testing by CHWs, 5 (4%) tested positive, 108 (95%) tested negative, and 1 (1%) had indeterminate results; 110 (96%) samples had adequate volume for re-testing. Overall agreement between CHWs and laboratory technicians was 99.1% (κ = 0.90, 95%CI 0.71-1.00, P < 0.0001). In FGDs, CHWs described context-specific social challenges to performing HCT in a household setting, but said that their confidence grew with experience. Conclusion: Home-based HCT by CHWs was feasible among household TB contacts and produced high-quality results. Strategies to address social challenges are required to optimize yield.

Contexte : Les travailleurs de santé communautaire (CHW) offrent de plus en plus de services de conseil et de test communautaires relatifs au virus de l'immunodéficience humaine (HCT). On sait moins quel est le degré de performance de cette stratégie quand elle est intégrée à des visites à domicile à la recherche de contacts de tuberculose (TB).Objectif : Nous avons réalisé une étude prospective à méthodes variées afin d'évaluer la faisabilité et la qualité de CHW à domicile, facilité par des CHW dans les foyers des contacts de TB.Schéma : Les CHW ont visité les foyers des patients TB consentants afin de dépister les contacts domiciliaires de TB et du virus de l'immunodéficience humaine (VIH). Ils ont réalisé des tests VIH grâce à un algorithme de test rapide de recherche d'anticorps en série par titrage avec immunoadsorbant lié à une enzyme. Les techniciens de laboratoire des structures de santé ont re-testé les échantillons et coordonné un test VIH en groupe trimestriel pour les CHW. Nous avons réalisé des discussions en groupe focal (FGD) avec les CHW à propos de leurs expériences de HCT à domicile.Résultats : Ont été consentants 114 contacts domiciliaires qui ont été testés à la recherche du VIH par les CHW : 5 (4%) ont eu un test positif, 108 (95%) ont eu un test négatif et 1 seul (1%) a eu des résultats indéterminés ; 110 (96%) échantillons avaient un volume suffisant pour un deuxième test. Au total, l'accord entre les CHW et les techniciens de laboratoire a été de 99,1% (κ = 0,90 ; IC95% 0,71­1,00 ; P < 0,0001). Lors des FGD, les CHW ont décrit les défis sociaux spécifiques du contexte de la réalisation du HCT dans le cadre d'un foyer, mais ont affirmé que leur confiance en eux avait augmenté avec leur expérience.Conclusion : Le HCT à domicile par les CHW s'est avéré faisable parmi les contacts domiciliaires de TB et a produit des résultats de très bonne qualité. Des stratégies visant à résoudre les défis sociaux sont requises afin d'optimiser le rendement.

Marco de referencia: Los agentes de salud comunitarios (CHW) prestan cada vez con mayor frecuencia servicios de asesoramiento y pruebas de detección del virus de la inmunodeficiencia humana (HCT) en las comunidades. Se conoce poco sobre la eficacia de esta estrategia cuando se integra en la investigación de contactos domiciliarios de los pacientes con tuberculosis (TB).Objetivo: Se llevó a cabo un estudio prospectivo con métodos mixtos, con el objeto de evaluar la factibilidad y la calidad de los servicios de HCT prestados por los CHW a los contactos de los casos de TB en los hogares.Método: Los CHW visitaron los hogares de los pacientes con TB que dieron su consentimiento, con el fin de realizar el HCT en los contactos domiciliarios. Los CHW practicaron la investigación de la infección por el virus de la inmunodeficiencia humana (VIH) mediante un algoritmo de pruebas rápidas seriadas de anticuerpos de tipo inmunoabsorbente ligado a la enzima. Los auxiliares de laboratorio en los establecimientos de salud practicaban de nuevo las pruebas en las muestras y coordinaban la realización trimestral de series de pruebas por parte de los CHW. Se realizaron sesiones de grupos de opinión (FGD) con estos profesionales, a fin de compartir sus experiencias en HCT en los hogares.Resultados: Tras recibir su consentimiento, los CHW practicaron las pruebas del VIH a 114 contactos domiciliarios. Cinco contactos obtuvieron un resultado positivo (4%), en 108 el resultado fue negativo (95%) y en un caso el resultado fue indeterminado (1%). El volumen de 110 muestras (96%) fue suficiente para repetir las pruebas. La concordancia global entre los CHW y los auxiliares de laboratorio fue 99,1% (κ = 0,90; IC95% 0,71­1,00; P < 0,0001). En las FGD, los CHW describieron las dificultades sociales específicas del contexto que tuvieron que afrontar al prestar estos servicios en los hogares, pero afirmaron que con la práctica habían adquirido mayor confianza.Conclusión: La práctica domiciliaria del HCT a los contactos de los casos de TB por parte de los CHW fue factible y se obtuvieron resultados de gran calidad. Se precisan estrategias que respondan a las dificultades sociales encontradas con el propósito de optimizar el rendimiento.

Patterns of usage and preferences of users for tuberculosis-related text messages and voice calls in Uganda.

BACKGROUND: Little information exists about mobile phone usage or preferences for tuberculosis (TB) related health communications in Uganda. METHODS: We surveyed household contacts of TB patients in urban Kampala, Uganda, and clinic patients in rural central Uganda. Questions addressed mobile phone access, usage, and preferences for TB-related communications. We collected qualitative data about messaging preferences. RESULTS: We enrolled 145 contacts and 203 clinic attendees. Most contacts (58%) and clinic attendees (75%) owned a mobile phone, while 42% of contacts and 10% of clinic attendees shared one; 94% of contacts and clinic attendees knew how to receive a short messaging service (SMS) message, but only 59% of contacts aged 45 years (vs. 96% of contacts aged <45 years, P = 0.0001) did so. All contacts and 99% of clinic attendees were willing and capable of receiving personal-health communications by SMS. Among contacts, 55% preferred detailed messages disclosing test results, while 45% preferred simple messages requesting a clinic visit to disclose results. CONCLUSIONS: Most urban household TB contacts and rural clinic attendees reported having access to a mobile phone and willingness to receive TB-related personal-health communications by voice call or SMS. However, frequent phone sharing and variable messaging abilities and preferences suggest a need to tailor the design and monitoring of mHealth interventions to target recipients.

Abnormal frontostriatal connectivity in adolescent-onset schizophrenia and its relationship to cognitive functioning.

BACKGROUND: Adolescent-onset schizophrenia (AOS) is associated with cognitive impairment and poor clinical outcome. Cognitive dysfunction is hypothesised, in part, to reflect functional dysconnectivity between the frontal cortex and the striatum, although structural abnormalities consistent with this hypothesis have not yet been demonstrated in adolescence. OBJECTIVE: To characterise frontostriatal white matter (WM) tracts in relation to cognition in AOS. DESIGN: A MRI volumetric and diffusion tensor imaging study. PARTICIPANTS: Thirty-seven AOS subjects and 24 age and sex-matched healthy subjects. OUTCOME MEASURES: Using probabilistic tractography, cortical regions with the highest connection probability for each striatal voxel were determined, and correlated with IQ and specific cognitive functions after co-varying for age and sex. Fractional anisotropy (FA) from individual tracts was a secondary measure. RESULTS: Bayesian Structural Equation modeling of FA from 12 frontostriatal tracts showed processing speed to be an intermediary variable for cognition. AOS patients demonstrated generalised cognitive impairment with specific deficits in verbal learning and memory and in processing speed after correction for IQ. Dorsolateral prefrontal cortex connectivity with the striatum correlated positively with these measures and with IQ. DTI voxel-wise comparisons showed lower connectivity between striatum and the motor and lateral orbitofrontal cortices bilaterally, the left amygdalohippocampal complex, right anterior cingulate cortex, left medial orbitofrontal cortex and right dorsolateral prefrontal cortex. CONCLUSIONS: Frontostriatal dysconnectivity in large WM tracts that can explain core cognitive deficits are evident during adolescence. Processing speed, which is affected by alterations in WM connectivity, appears an intermediary variable in the cognitive deficits seen in schizophrenia.

Comparative neuropsychiatry: white matter abnormalities in children and adolescents with schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder.

BACKGROUND: There is considerable evidence that white matter abnormalities play a key role in the pathogenesis of a number of major psychiatric disorders, including schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder. Few studies, however, have compared white matter abnormalities early in the course of the illness. METHODS: A total of 102 children and adolescents participated in the study, including 43 with early-onset schizophrenia, 13 with early-onset bipolar affective disorder, 17 with obsessive-compulsive disorder, and 29 healthy controls. Diffusion tensor imaging scans were obtained on all children and the images were assessed for the presence of non-spatially overlapping regions of white matter differences, a novel algorithm known as the pothole approach. RESULTS: Patients with early-onset schizophrenia and early-onset bipolar affective disorder had a significantly greater number of white matter potholes compared to controls, but the total number of potholes did not differ between the two groups. The volumes of the potholes were significantly larger in patients with early-onset bipolar affective disorder compared to the early-onset schizophrenia group. Children and adolescents with obsessive-compulsive disorder showed no differences in the total number of white matter potholes compared to controls. CONCLUSIONS: White matter abnormalities in early-onset schizophrenia and bipolar affective disorder are more global in nature, whereas children and adolescents with obsessive-compulsive disorder do not show widespread differences in FA.

Sexually dimorphic white matter geometry abnormalities in adolescent onset schizophrenia.

The normal human brain is characterized by a pattern of gross anatomical asymmetry. This pattern, known as the "torque", is associated with a sexual dimorphism: The male brain tends to be more asymmetric than that of the female. This fact, along with well-known sex differences in brain development (faster in females) and onset of psychosis (earlier with worse outcome in males), has led to the theory that schizophrenia is a disorder in which sex-dependent abnormalities in the development of brain torque, the correlate of the capacity for language, cause alterations in interhemispheric connectivity, which are causally related to psychosis (Crow TJ, Paez P, Chance SE. 2007. Callosal misconnectivity and the sex difference in psychosis. Int Rev Psychiatry. 19(4):449-457.). To provide evidence toward this theory, we analyze the geometry of interhemispheric white matter connections in adolescent-onset schizophrenia, with a particular focus on sex, using a recently introduced framework for white matter geometry computation in diffusion tensor imaging data (Savadjiev P, Kindlmann GL, Bouix S, Shenton ME, Westin CF. 2010. Local white geometry from diffusion tensor gradients. Neuroimage. 49(4):3175-3186.). Our results reveal a pattern of sex-dependent white matter geometry abnormalities that conform to the predictions of Crow's torque theory and correlate with the severity of patients' symptoms. To the best of our knowledge, this is the first study to associate geometrical differences in white matter connectivity with torque in schizophrenia.

Prediction for human intelligence using morphometric characteristics of cortical surface: partial least square analysis.

A number of imaging studies have reported neuroanatomical correlates of human intelligence with various morphological characteristics of the cerebral cortex. However, it is not yet clear whether these morphological properties of the cerebral cortex account for human intelligence. We assumed that the complex structure of the cerebral cortex could be explained effectively considering cortical thickness, surface area, sulcal depth and absolute mean curvature together. In 78 young healthy adults (age range: 17-27, male/female: 39/39), we used the full-scale intelligence quotient (FSIQ) and the cortical measurements calculated in native space from each subject to determine how much combining various cortical measures explained human intelligence. Since each cortical measure is thought to be not independent but highly inter-related, we applied partial least square (PLS) regression, which is one of the most promising multivariate analysis approaches, to overcome multicollinearity among cortical measures. Our results showed that 30% of FSIQ was explained by the first latent variable extracted from PLS regression analysis. Although it is difficult to relate the first derived latent variable with specific anatomy, we found that cortical thickness measures had a substantial impact on the PLS model supporting the most significant factor accounting for FSIQ. Our results presented here strongly suggest that the new predictor combining different morphometric properties of complex cortical structure is well suited for predicting human intelligence.

Gyrification of Broca's region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2 year follow-up.

Gyrification of the human cerebral cortex starts in the foetus and progresses in early infancy; the pattern of folding in later life provides a lead to early developmental aberration. By studying gyrification at illness onset in adolescence we hoped to clarify the pathophysiology of schizophrenia. Here we find 1) an area of hypergyria includes Broca's area and extends into the Sylvian fissure to encroach on the anterior insula in the left hemisphere, and 2) an area of hypogyria in the superior temporal lobe approximates to Wernicke's area but is located in the right hemisphere and encroaches on the posterior insula. In Broca's/anterior insula area, right lateralization was present in healthy controls but patients were left lateralized: at two year follow-up gyrification had decreased in patients while it increased in controls, and the reduction predicted impaired category fluency. Progressive change was unaccompanied by cortical thinning (investigated only in the brain regions showing baseline changes in gyrification) indicating that the disease process affecting these brain regions (insula, inferior frontal and superior temporal) is not primarily degenerative. A deviation in the lateralized development of peri-Sylvian areas for language production and comprehension appears critical to the pathophysiology of schizophrenia and may point to its species-specific origin.

Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS).

BACKGROUND: Cannabis use is associated with a higher risk of schizophrenia, however, its specific long-term effect on the structure of the brain of adolescent-onset schizophrenic patients remains unclear. AIMS: To study cognitive and structural (grey and white matter) changes in patients with adolescent-onset schizophrenia (AOS) with early cannabis use (CAN+ve) (more than 3 times/week for at least 6 months) and without cannabis use (CAN-ve) versus controls. METHOD: An optimised voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) MRI study of 32 adolescents with DSM IV schizophrenia-16 CAN+ve and 16 CAN-ve, and 28 healthy adolescents. RESULTS: Compared to CAN-ve subjects, CAN+ve subjects showed GM density loss in temporal fusiform gyrus, parahippocampal gyrus, ventral striatum, right middle temporal gyrus, insular cortex, precuneus, right paracingulate gyrus, dorsolateral prefrontal cortex, left postcentral gyrus, lateral occipital cortex and cerebellum. Similar group comparison showed decreased fractional anisotropy (FA) in particular in brain stem, internal capsule, corona radiata, superior and inferior longitudinal fasciculus in CAN+ve patients. No cognitive differences were apparent between CAN+ve and CAN-ve subjects, and both were impaired relative to controls. CONCLUSION: Cannabis use in early adolescence increases WM and GM deficits in AOS, but does not appear to increase the cognitive deficit associated with this illness.

Learning, decisions and transformation in critical care nursing practice.

Critical care nurses are key providers in a high acuity environment. This qualitative research study explored ethical decision making in a critical care practice setting. Fifteen critical care nurses with varying experience and education levels were purposively sampled to assure the representativeness of the data. The theoretical concepts of experiential learning, perspective transformation, reflection-in-action and principle-based ethics were used as a framework for eliciting information from the participants. A new model of focused reflection in ethical decision making was developed. Findings showed that having a role model or mentor to help guide the ethical decision-making process was critical for focused ethical discourse and the decision making.

Skin excision and groin lymphadenectomy: techniques and outcomes.

A 10-year retrospective review of 25 patients undergoing groin lymphadenectomy for cutaneous malignancy in the Tayside region of the UK was conducted. Comparison was made between patients undergoing the procedure with an elliptical incision orientated as a long oblique of at least 4cm width (group 1) and those undergoing a similarly oriented incision with no skin excision (group 2). Outcome measures including survival, postoperative complications, operative time and hospital stay were analyzed. Patients in group I suffered significantly fewer complications (p < 0.004) and shorter hospital stay (p < 0.008). Elliptical excision of at least 4cm width is our preferred technique for groin lymphadenectomy in the treatment of cutaneous malignancy of the lower limb.

Loss of Ubr1 promotes aneuploidy and accelerates B-cell lymphomagenesis in TLX1/HOX11-transgenic mice.

The TLX1/HOX11 homeobox gene was originally identified at the recurrent t(10;14)(q24;q11) translocation breakpoint, a chromosomal abnormality observed in 5-7% of T-cell acute lymphoblastic leukemias (T-ALLs). Proviral insertional mutagenesis studies performed on transgenic mice ectopically expressing TLX1/HOX11 in B lymphocytes (IgHmu-HOX11(Tg) mice) revealed the Ubr1 gene locus as a frequent site of proviral insertion, concomitant with accelerated development of diffuse large B-cell lymphoma. Insertion into this genomic region was confirmed by Southern blotting and by the ability to generate a polymerase chain reaction (PCR) amplicon across the viral-genome junction. Western immunoblot and semiquantitative reverse transcriptase-PCR analysis revealed downregulated expression of the Ubr1 gene product subsequent to viral integration. Loss or reduced levels of Ubr1 expression was associated with 5/14 spontaneous B-cell lymphomas in IgHmu-HOX11(Tg) mice and one of nine primary human T-ALLs. To gain mechanistic insight into the cooperativity between TLX1/HOX11 and Ubr1, IgHmu-HOX11(Tg)/Ubr1(-/-) mice were generated. IgHmu-HOX11(Tg)/Ubr1(-/-) mice exhibited a modest but statistically significant acceleration of disease onset relative to IgHmu-HOX11(Tg)/Ubr1(+/-) mice. Moreover, micronucleus assays to detect for chromosome missegregation were conducted and revealed increased presence of micronuclei in IgHmu-HOX11(Tg)/Ubr1(-/-) primary B lymphocyte cultures, and in both TLX1/HOX11-overexpressing T cell lines and fibroblast cultures following transfection with short interfering RNAs (siRNAs) targeting Ubr1. Karyotyping of primary B lymphocyte cultures revealed increased incidences of hypodiploid karyotypes. Finally, mitotic figures analysed from Ubr1 siRNA-transfected fibroblast cultures revealed no defects in chromosome congression to the metaphase plate, but increased incidences of atypical anaphase figures, including the development of anaphase bridges and lagging chromosomes. Based on these findings, we identify a synergistic role between TLX1/HOX11 overexpression and Ubr1 inactivation in promoting chromosome missegregation, permitting the accrual of additional chromosome losses and cytogenic abnormalities en route to malignancy.

Dysregulated expression of mitotic regulators is associated with B-cell lymphomagenesis in HOX11-transgenic mice.

Dysregulated expression of the homeobox gene, HOX11 is a frequent etiologic event in T-cell acute lymphoblastic leukemias. HOX11-transgenic mice (IgHmu-HOX11Tg)-expressing HOX11 in the B-cell compartment develop B-cell lymphomas with extended latency. The latency suggests that additional genetic events are required prior to the onset of malignant lymphoma. We report the identification of 17 HOX11 collaborating genes, revealed through their propensity to be targeted in a proviral insertional mutagenesis screen. Seven integrations disrupted genes in mitotic spindle checkpoint control, suggesting that cells with elevated HOX11 expression are especially sensitive to dysregulation of chromosome segregation during mitosis. IgHmu-HOX11Tg primary B-lymphocyte cultures exposed to the aneugenic agents, colchicine and colcemid, exhibited increased incidences of chromosome missegregation as assessed by cytokinesis-block micronucleus assays. Additionally, IgHmu-HOX11Tg cultures were shown to exhibit aberrant bypass of spindle checkpoint arrest, as assessed by the increased presence of cycling cells determined by assessment of DNA content and by BrdU immunolabelling. Western immunoblotting revealed elevated expression of the mitotic effector molecules, cyclin A, cyclin B1 and cdc20 in IgHmu-HOX11Tg cultures. Moreover, spontaneously arising lymphoid neoplasms in IgHmu-HOX11Tg mice frequently exhibit aberrant expression of mitotic regulators, concomitant with increased development of micronuclei, abnormal mitotic checkpoint control and increased incidences of abnormal karyotypes when expanded in culture. Collectively, these findings indicate that abnormal regulation of spindle checkpoint control as a result of HOX11 overexpression leads to a heightened predisposition for development of aneuploidy, contributing to oncogenesis.

Student satisfaction with technology-enhanced learning.

The purpose of this descriptive study was to determine student satisfaction with technology-enhanced learning through a survey of nursing and health science students. Satisfaction generally was high, and there were few differences between nursing and health science students, or between undergraduate and graduate students. Faculty expertise in the creation, selection, and use of the technology is a major factor influencing student satisfaction.