Attention challenges in Kabuki syndrome.

BACKGROUND: Understanding the specific neurobehavioural profile of rare genetic diseases enables clinicians to provide the best possible care for patients and families, including prognostic and treatment advisement. Previous studies suggested that a subset of individuals with Kabuki syndrome (KS), a genetic disorder causing intellectual disability and other neurodevelopmental phenotypes, have attentional deficits. However, these studies looked at relatively small numbers of molecularly confirmed cases and often used retrospective clinical data instead of standardised assessments. METHODS: Fifty-five individuals or caregivers of individuals with molecularly confirmed KS completed assessments to investigate behaviour and adaptive function. Additionally, information was collected on 23 unaffected biological siblings as controls. RESULTS: Attention Problems in children was the only behavioural category that, when averaged, was clinically significant, with the individual scores of nearly 50% of the children with KS falling in the problematic range. Children with KS scored significantly higher than their unaffected sibling on nearly all behavioural categories. A significant correlation was found between Attention Problems scores and adaptive function scores (P = 0.032), which was not explained by lower general cognitive ability. CONCLUSIONS: We found that the rates of children with attentional deficits are much more elevated than would be expected in the general population, and that attention challenges are negatively correlated with adaptive function. When averaged across KS participants, none of the behavioural categories were in the clinically significant range except Attention Problems for children, which underscores the importance of clinicians screening for attention deficit hyperactivity disorder (ADHD) in children with KS.

2013 multistate outbreaks of Cyclospora cayetanensis infections associated with fresh produce: focus on the Texas investigations.

The 2013 multistate outbreaks contributed to the largest annual number of reported US cases of cyclosporiasis since 1997. In this paper we focus on investigations in Texas. We defined an outbreak-associated case as laboratory-confirmed cyclosporiasis in a person with illness onset between 1 June and 31 August 2013, with no history of international travel in the previous 14 days. Epidemiological, environmental, and traceback investigations were conducted. Of the 631 cases reported in the multistate outbreaks, Texas reported the greatest number of cases, 270 (43%). More than 70 clusters were identified in Texas, four of which were further investigated. One restaurant-associated cluster of 25 case-patients was selected for a case-control study. Consumption of cilantro was most strongly associated with illness on meal date-matched analysis (matched odds ratio 19·8, 95% confidence interval 4·0-∞). All case-patients in the other three clusters investigated also ate cilantro. Traceback investigations converged on three suppliers in Puebla, Mexico. Cilantro was the vehicle of infection in the four clusters investigated; the temporal association of these clusters with the large overall increase in cyclosporiasis cases in Texas suggests cilantro was the vehicle of infection for many other cases. However, the paucity of epidemiological and traceback information does not allow for a conclusive determination; moreover, molecular epidemiological tools for cyclosporiasis that could provide more definitive linkage between case clusters are needed.

Health care delivery for head-and-neck cancer patients in Alberta: a practice guideline.

BACKGROUND: The treatment of head-and-neck cancer is complex and requires the involvement of various health care professionals with a wide range of expertise. We describe the process of developing a practice guideline with recommendations about the organization and delivery of health care services for head-and-neck cancer patients in Alberta. METHODS: Outcomes of interest included composition of the health care team, qualification requirements for team members, cancer centre and team member volumes, infrastructure needs, and wait times. A search for existing practice guidelines and a systematic review of the literature addressing the organization and delivery of health care services for head-and-neck cancer patients were conducted. The search included the Standards and Guidelines Evidence (sage) directory of cancer guidelines and PubMed. RESULTS: One practice guideline was identified for adaptation. Three additional practice guidelines provided supplementary evidence to inform guideline recommendations. Members of the Alberta Provincial Head and Neck Tumour Team (consisting of various health professionals from across the province) provided expert feedback on the adapted recommendations through an online and in-person review process. Selected experts in head-and-neck cancer from outside the province participated in an external online review. SUMMARY: The recommendations outlined in this practice guideline are based on existing guidelines that have been modified to fit the Alberta context. Although specific to Alberta, the recommendations lend credence to similar published guidelines and could be considered for use by groups lacking the resources of appointed guideline panels. The recommendations are meant to be a guide rather than a fixed protocol. The implementation of this practice guideline will depend on many factors, including but not limited to availability of trained personnel, adequate funding of infrastructure, and collaboration with other associations of health care professionals in the province.

Genetic and environmental contributions to the relationship between education and anxiety disorders - a twin study.

OBJECTIVE: To examine the negative statistical relationship between educational level and risk of anxiety disorders, and to estimate to what extent this relationship may be explained by genes or environmental factors influencing both phenotypes. METHOD: Registry data on educational level for 3339 young adult Norwegian twin pairs and diagnostic data on anxiety disorders for 1385 of these pairs were analysed, specifying structural equations models using MX software. RESULTS: In the best-fitting model, genes accounted for 59% of the variance in education. 18% of the variance was due to environmental factors shared by co-twins, and the remaining 23% due to non-shared environment; 46% of the variance in liability to anxiety disorders was genetic, the remaining variance was due to non-shared environment. A phenotypic polychoric correlation of -0.30 between educational level and 'any anxiety disorder' was estimated to be primarily (83% in the best-fitting model) caused by genes common to the two traits. CONCLUSION: The relationship between low education and risk of anxiety disorders appears to be primarily determined by genetic effect common to educational level and anxiety disorders.

Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen.

BACKGROUND: Cryptococcus gattii (Cg) has caused increasing infections in the US Pacific Northwest (PNW) since 2004. We describe this outbreak and compare clinical aspects of infection in the United States among patients infected with different Cg genotypes. METHODS: Beginning in 2005, PNW state health departments conducted retrospective and prospective passive surveillance for Cg infections, including patient interviews and chart reviews; clinical isolates were genotyped at the US Centers for Disease Control and Prevention (CDC). We examined symptom frequency and underlying conditions in US patients with Cg infection and modeled factors associated with death. RESULTS: From 1 December 2004 to July 2011, 96 Cg infections were reported to the CDC. Eighty-three were in patients in or travelers to the PNW, 78 of which were genotypes VGIIa, VGIIb, or VGIIc (outbreak strains). Eighteen patients in and outside the PNW had other molecular type Cg infections (nonoutbreak strains). Patients with outbreak strain infections were more likely than those with nonoutbreak-strain infections to have preexisting conditions (86% vs 31%, respectively; P < .0001) and respiratory symptoms (75% vs 36%, respectively; P = .03) and less likely to have central nervous system (CNS) symptoms (37% vs 90%, respectively; P = .008). Preexisting conditions were associated with increased pneumonia risk and decreased risk of meningitis and CNS symptoms. Nineteen (33%) of 57 patients died. Past-year oral steroid use increased odds of death in multivariate analysis (P = .05). CONCLUSIONS: Clinical differences may exist between outbreak-strain (VGIIa, VGIIb, and VGIIc) and nonoutbreak-strain Cg infections in the United States. Clinicians should have a low threshold for testing for Cg, particularly among patients with recent travel to the PNW.

Relationship of depth of invasion to survival outcomes and patterns of recurrence for T3 oral tongue squamous cell carcinoma.

INTRODUCTION: Current research is elucidating how the addition of depth of invasion (DOI) to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging for oral cavity squamous cell carcinoma influences its prognostic accuracy. However, there is limited research on survival in pT3N0M0 oral tongue SCC (OTSCC) patients when stratifying by DOI. OBJECTIVES: Determine 5-year overall survival (OS), and cancer-specific survival (CSS) for patients with pT3N0M0 oral OTSCC based on shallow DOI (<10 mm) and deep DOI (10-20 mm). METHODS: Retrospective review involving three tertiary care cancer centers in North America. cT3N0M0 OTSCC patients receiving primary surgical treatment from 2004 to 2018 were identified. Inclusion: age > 18 years old and confirmation of pT3N0M0 OTSCC on surgical pathology. Exclusion: patients undergoing palliative treatment or previous head and neck surgery/radiotherapy. Analysis comprised two groups: shallow pT3 (tumor diameter > 4 cm, DOI < 10 mm) and deep pT3 (DOI 10 mm-20 mm). RESULTS: One hundred and four patients with pT3N0M0 OTSCC were included. Mean age was 59.1 years (range: 18-80.74). Age, gender, and Charlson Comorbidity Index were similar between the two groups (p > 0.05). Recurrence, LVI, PNI, and positive margins were more common in deep T3 tumors (P < 0.05). 5-year OS (50% vs 26%, p = 0.006) and CSS (72% vs 24%, p = 0.005) were worse in deep pT3 tumors. Deep pT3 disease was an independent predictor of OS (p = 0.004) and CSS (p = 0.01) on Cox-Regression analysis. CONCLUSION: DOI is an independent predictor of poor survival in pT3N0M0 OTSCC patients. Consideration should be given to escalating adjuvant therapy for deep pT3N0M0 OTSCC patients.

Evaluation of sex differences in relative dilatation of thoracic aortic aneurysms.

OBJECTIVES: Treatment recommendations based on thoracic aortic aneurysm (TAA) diameter (D) ignore differences in proportional dilatation between patients of different body habitus and sex. This study's goal is to compare TAA diameters between sexes as a function of relative aortic size as determined by aortic size index (ASI). METHODS: This is a retrospective review of all TAA's treated between 2003 and 2008. ASI was calculated for each patient, which considers aneurysm diameter, patient's height and weight. Values for males and females were plotted separately (TAA diameter vs ASI) and the resulting linear regression equations permitted comparison of proportional dilatation between sexes. RESULTS: In 40 patients (25 males, 15 females) mean TAA diameter did not differ between sexes (6.56 +/- 0.99 vs 7.03 +/- 1.14, P = 0.18), while ASI was larger in females than males (4.21 +/- 0.85 vs 3.24 +/- 0.63, P = 0.0003). Values for ruptured and intact aneurysms did not differ. Linear regression analysis permitted comparison of TAA diameter with ASI between sexes resulting in the following equation: D(Female) = 0.91D(Male) - 0.49. This correlates a 6 cm TAA in a male with a 4.97 cm TAA in a female. CONCLUSIONS: TAA of equal diameter represent a larger proportional dilatation in females compared to males. This could influence repair thresholds that are historically diameter based.

Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci.

OBJECTIVE: To identify common loci and potential genetic variants affecting body mass index (BMI, kg m(-2)) in study populations originating from Europe. DESIGN: We combined genome-wide linkage scans of six cohorts from Australia, Denmark, Finland, the Netherlands, Sweden and the United Kingdom with an approximately 10-cM microsatellite marker map. Variance components linkage analysis was carried out with age, sex and country of origin as covariates. SUBJECTS: The GenomEUtwin consortium consists of twin cohorts from eight countries (Australia, Denmark, the Netherlands, Finland, Italy, Norway, Sweden and the United Kingdom) with a total data collection of more than 500,000 monozygotic and dizygotic (DZ) twin pairs. Variance due to early-life events and the environment is reduced within twin pairs, which makes DZ pairs highly valuable for linkage studies of complex traits. This study totaled 4401 European-originated twin families (10,535 individuals) from six countries (Australia, Denmark, the Netherlands, Finland, Sweden and the United Kingdom). RESULTS: We found suggestive evidence for a quantitative trait locus on 3q29 and 7q36 in the combined sample of DZ twins (multipoint logarithm of odds score (MLOD) 2.6 and 2.4, respectively). Two individual cohorts showed strong evidence independently for three additional loci: 16q23 (MLOD=3.7) and 2p24 (MLOD=3.4) in the Dutch cohort and 20q13 (MLOD=3.2) in the Finnish cohort. CONCLUSION: Linkage analysis of the combined data in this large twin cohort study provided evidence for suggestive linkage to BMI. In addition, two cohorts independently provided significant evidence of linkage to three new loci. The results of our study suggest a smaller environmental variance between DZ twins than full siblings, with a corresponding increase in heritability for BMI as well as an increase in linkage signal in well-replicated regions. The results are consistent with the possibility of locus heterogeneity for some genomic regions, and indicate a lack of major common quantitative trait locus variants affecting BMI in European populations.

Longitudinal density modulation and energy conversion in intense beams.

Density modulation of charged particle beams may occur as a consequence of deliberate action, or may occur inadvertently because of imperfections in the particle source or acceleration method. In the case of intense beams, where space charge and external focusing govern the beam dynamics, density modulation may, under some circumstances, be converted to velocity modulation, with a corresponding conversion of potential energy to kinetic energy. Whether this will occur depends on the properties of the beam and the initial modulation. This paper describes the evolution of discrete and continuous density modulations on intense beams and discusses three recent experiments related to the dynamics of density-modulated electron beams.

Public health surveillance for the Toronto 2015 Pan/Parapan American Games.

BACKGROUND: Public health surveillance for previous Olympic and Paralympic Games have been described in the literature, but surveillance for regional, multisport events on a smaller scale have rarely been explored. OBJECTIVE: To describe the public health surveillance planning, implementation, results, and lessons learned from the 2015 Pan/Parapan American Games in Toronto, Ontario, Canada. INTERVENTION: Public health surveillance planning for the Games began two years in advance and involved local, provincial and federal partners, primarily focusing on infectious disease. From June to August, 2015, enhanced public health surveillance was conducted to support situational awareness and to facilitate the detection of infectious diseases and outbreaks, environmental health hazards and impacts and other major health events. OUTCOMES: No major public health incidents occurred that were associated with or a result of hosting the Games. There were two cases of reportable infectious diseases associated with the Games, and 18 public health investigations involving Games-accredited individuals (six related to vaccine-preventable diseases and 12 related to gastrointestinal illnesses or food/water safety violations). Enhanced communication mechanisms, rather than routine and syndromic surveillance systems, were the primary sources of initial notification to surveillance partners on investigations. CONCLUSION: Working with its partners, Ontario created a robust public health surveillance system for the 2015 Pan/Parapan American Games. Lessons learned, as well as the relationships and capacity developed through this experience, will be applied towards public health surveillance planning for future events.

Recommendations for the management of premature ejaculation: BASHH Special Interest Group for Sexual Dysfunction.

We present the British Association for Sexual Health and HIV (BASHH), Special Interest Group for Sexual Dysfunction updated recommendations for the management of premature ejaculation. The recommendations outline the physiology, prevalence, definitions, aetiological factors and patient assessment for this common sexual problem. Behavioural, local and systemic pharmacological treatments are discussed along with general recommendations and auditable outcomes.

Factors associated with sexual dysfunction in men with HIV infection.

Where men have had access to successful treatment for HIV (highly active antiretroviral therapy), expectations of both patients and physicians alike have changed significantly over the past decade. Such men, living with HIV, expect to lead fully functional lives including a normal sex life. Sexual dysfunction is well described among men with HIV. We retrospectively analysed details of 190 consecutive men attending a dedicated sexual dysfunction service in our HIV unit over an 18-month period. We took note of the specifics of their HIV disease, illnesses other than HIV, as well as other risk factors associated with sexual dysfunction. Men with sexual dysfunction all commonly reported recreational drug use, hepatitis B and C co-infection, anxiety and depressive illnesses, peripheral neuropathy and lipodystrophy. There was a significant relationship between men complaining of retarded ejaculation and peripheral neuropathy. Sexual dysfunction in non-HIV settings is known to lead to poor adherence to prescribed medications, e.g. antihypertensive agents. Iatrogenic sexual dysfunction in patients may similarly have a potential to lead to poor antiretroviral compliance if not addressed.

Local control following breast-conserving surgery for invasive cancer: results of clinical trials.

Prospective, randomized clinical trials have demonstrated that the alternatives of mastectomy or conservative surgery plus radiation therapy provide equivalent survival for patients with invasive breast cancer. The identification of a subset of women who could undergo conservative surgery without radiotherapy would avoid the costs, inconvenience, and complications of radiotherapy and is an important research goal. Four randomized trials comparing conservative surgery alone with conservative surgery plus radiotherapy have demonstrated an average reduction in the risk of disease recurrence in the breast of 84% with the use of radiotherapy. No significant differences in survival have been observed, although the available studies lack sufficient numbers of patients to demonstrate a potential small, but clinically important, survival advantage for patients treated with radiotherapy. Subset analysis in the randomized trials and prospective studies of highly selected patients have failed to consistently identify a group of patients who do not benefit from radiation therapy. Any recurrence of breast cancer is psychologically devastating, and fewer than one half of the patients who have had disease recurrence after conservative surgery alone have undergone further breast-conserving treatment. At present, a group of patients who do not require radiotherapy has not been reproducibly identified, and radiotherapy should remain a part of breast-conserving therapy for invasive carcinoma.

Microvessel density and distribution in ductal carcinoma in situ of the breast.

BACKGROUND: Prior studies have suggested that microvessel density is an important prognostic factor in invasive breast cancer. However, the extent and distribution of microvessels in association with ductal carcinoma in situ (DCIS) have not been well defined. PURPOSE: Our goal was to determine the density and distribution of stromal microvessels in DCIS and to investigate the relationships among microvessel density, histopathologic features, HER2/neu oncogene expression, and tumor proliferation rate. METHODS: Of 61 consecutive cases of DCIS identified from hospital pathology reports, 55 cases were evaluated. Breast biopsy specimens had been preserved in paraffin blocks for each DCIS case. Histologic sections of formalin-fixed, paraffin-embedded tissue were stained with hematoxylin-eosin and immunostained for factor VIII-related antigen, the HER2/neu oncoprotein, and the proliferative-associated antigen detected by the Ki-S1 antibody. Factor VIII-stained sections from each case were independently examined by two pathologists and overall tumor-associated stromal microvessel density was scored semiquantitatively on a 1+ to 3+ scale by each observer. Quantitative microvessel counts of DCIS-associated stromal microvessel density were performed. The presence or absence of a cuff of microvessels in immediate apposition to the basement membrane of involved spaces was also evaluated. RESULTS: A variable number of microvessels were found to be present in a diffuse pattern surrounding spaces involved with DCIS. Semiquantitative microvessel scores were 2+ in the majority of cases (53%); 22% of cases were 1+, and 25% were 3+. Quantitative microvessel counts ranged from 17 to 80 vessels per 100x field (0.45 mm2), with a mean +/- SD of 42.9 +/- 16.6. Comedo-type lesions were significantly (P = .004) more often associated with 3+ microvessel density than non-comedo-type lesions by semiquantitative assessment. As determined by both semiquantitative and quantitative analysis, respectively, the presence of prominent microvessel density was significantly associated with marked stromal desmoplasia (P = .05 and P = .04), HER2/neu expression (P = .03 and P = .0002), and high Ki-S1 proliferation index (P = .05 and P = .01). Vascular cuffing around involved spaces was identified in 21 of the 55 cases (38%) and was not significantly associated with histologic features, HER2/neu expression, or Ki-S1 proliferation index. CONCLUSIONS: DCIS of the breast is characterized by two patterns of stromal microvessels. The first pattern is a diffuse increase in stromal microvessels surrounding involved spaces. This pattern is particularly prominent in comedo-type lesions with marked stromal desmoplasia. The second pattern is microvessel cuffing of involved spaces that is present in only a minority of cases and appears unrelated to histologic features evaluated, including DCIS subtype.

Patient preferences for axillary dissection in the management of early-stage breast cancer.

BACKGROUND: Recent data on the value of adjuvant therapy in lymph node-negative breast cancer and promising early data on less invasive strategies for managing the axilla have raised questions about the appropriate role of axillary lymph node dissection (ALND) in the management of early-stage breast cancer. We sought to evaluate how women weigh potential benefits of ALND-prognostic information, enhanced local control, and tailored therapy-against the risks of long-term morbidity that are associated with the procedure. METHODS: We used hypothetical scenarios to survey 82 randomly selected women with invasive breast cancer who had been treated with ALND and 62 women at risk for invasive breast cancer by virtue of a history of ductal carcinoma in situ (DCIS) who had not undergone ALND. RESULTS: Women in both the invasive cancer and the DCIS groups required substantial improvements in local control of the cancer (5% and 15%, respectively) and overall survival (3% and 10%, respectively) before they would opt for this procedure. Women with invasive cancer would choose ALND if it had only a 1% chance of altering treatment recommendations, whereas DCIS subjects required a 25% chance. Sixty-eight percent and 29% of women in the invasive cancer and DCIS groups, respectively, would accepted a 40% risk of arm dysfunction to gain prognostic information that would not change treatment. CONCLUSIONS: For most subjects treated previously for invasive breast cancer and almost half those at risk of the disease, the potential benefits of ALND, particularly the value of prognostic information, were sufficient to outweigh the risks of morbidity. However, women varied considerably in their preferences, highlighting the need to tailor decisions regarding management of the axilla to individual patients' values.

Repair following combined X-ray and heat at 41 degrees in plateau-phase mammalian cells.

Plateau-phase V79 Chinese hamster cells maintained at 37 degrees following X-irradiation demonstrated both sublethal damage repair and potentially lethal damage repair. When cells were kept at 41 degrees for 1 hr following irradiation, no sublethal damage repair was seen. In contrast, irradiated cells maintained at 41 degrees for 1 hr and then returned to 37 degrees were capable of repairing both sublethal and potentially lethal radiation damage; hyperthermic (41 degrees) inhibition of radiation damage repair was reversible. Repair was similar for cells heated before or after irradiation. The extent of sublethal damage repair (as measured by recovery ratios and quasi-threshold doses) and potentially lethal damage repair (as measured by recovery ratios and dose-modifying factors) was similar following combined heat and X-ray treatment and following X-ray treatment alone.

Further studies on the characterization of cylindrin and torin, two extrinsic proteins of the erythrocyte membrane.

The subunit composition of the high molecular weight proteins cylindrin and torin from human erythrocyte ghosts has been studied by sodium dodecyl sulphate polyacrylamide gel electrophoresis on 3 to 30% "Gradipore' polyacrylamide gradient slab gels. Torin has been shown to be a multimer of a single polypeptide of approx. Mr 20 000. Cylindrin appears to contain five polypeptides, three of which predominate, in the Mr range 22 000 to 25 000. The isoelectric points (pI) of cylindrin and torin have been determined as 4.6 and 4.8, respectively. The molecular properties of cylindrin and torin are discussed in relation to the previous studies by the authors and others on these proteins.

The subunit composition of two high molecular weight extrinsic proteins from human erythrocyte membranes.

Purified hollow cylinder (22.5 S) and torus protein (9.0 S) from human erythrocyte membranes, together with the intact membranes, have been dissociated using 2% sodium dodecyl sulphate and electrophoresed in the presence of 0.1% sodium dodecyl sulphate. The torus protein gives rise to a single subunit migrating slightly ahead of band 8 of the polypeptide profile of the intact membranes (Mr approximately 20 000) and the hollow cylinder gives rise to two main subunits, which migrate slightly behind that of the torus protein. It is clearly shown that neither protein is related to erythrocyte membrane spectrin (bands 1 + 2) or actin (band 5).