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Importance: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. Objective: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. Design, Setting, and Participants: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502682 participants, 117279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. Exposures: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. Main Outcomes and Measures: Odds ratios (ORs) of polygenic risk scores in replication samples. Results: A total of 51841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). Conclusions and Relevance: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM..

Although metastatic breast cancer (MBC) survival is improving, symptoms remain a significant burden. Returning to a cancer center for symptom management can be challenging. Technology-enabled supportive care platforms are worth exploration. Seventeen patients with MBC were randomized to immediate or delayed start for a 3-month intervention that included daily tablet-based guideline-concordant self-care for pain, distress, fatigue, and sleep disturbance, as well as weekly calls with a patient navigator. The primary outcome was patient acceptability. We also assessed feasibility, patient satisfaction, and cost and compared between group differences for symptoms. RM-ANOVA examined between group differences over time. Hedges’ d effect sizes quantified magnitude of differences in change between immediate and delayed start. Sixty-eight percent of patients approached accepted the tablet-based intervention. Patients interacted with the tablet 48% of possible days. Patient satisfaction ranged from 83 for walking to 49% for the psychological interventions. The cost of delivering Nurse AMIE for 3 months was $570.23. Small nonsignificant improvements were found for fatigue (d=0.24). Nonsignificant, but potentially clinically meaningful, moderate reductions were found for sleep (d=0.65) and distress (d=0.74). A tablet-based supportive care platform that offers guideline-concordant self-care for pain, fatigue, sleep, and distress was observed to be highly acceptable and feasible for patients with metastatic breast cancer. Patient satisfaction scores and initial evaluation of efficacy are promising, and the platform warrants further investigation. Technology-based self-care is a promising option to address symptoms in patients with metastatic breast cancer.

Background The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. Methods CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). Results In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. Conclusions In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

Background: Cancer cells have altered metabolism, which contributes to their ability to proliferate, survive in unusual microenvironments, and invade other tissues. Measuring the complete set of metabolites in an individual (i.e. the metabolome) provides a functional readout for cellular pathways. Further, changes in the metabolome can be correlated with disease status, prognosis and progression. Using a metabolomics platform and machine learning algorithms, biomarker signatures can be identified to predict response to therapy. Metabolite analysis of pretreatment plasma has shown promise for predicting response in a small retrospective study of the CDK 4/6 inhibitors palbociclib and ribociclib in hormone receptor-positive metastatic breast cancer (Zhang B et al, ASCO 2019 Abstr 3043). HER2-positive metastatic breast cancer patients have significant heterogeneity in response and progression-free survival (PFS) to HER2-targeted therapy. Here we retrospectively evaluated the pretreatment serum metabolome for association with PFS in a cohort of trastuzumab-treated metastatic breast cancer patients from a single institution. Methods: Pretreatment serum from 26 HER2-positive trastuzumab-naive metastatic breast cancer patients who were treated with first-line trastuzumab and chemotherapy were included in this exploratory analysis. Metabolites were extracted from previously frozen serum (1 mL) using ice-cold methanol and chloroform. The resulting metabolites were isolated and quantified using an unbiased, non-destructive, nuclear magnetic resonance (NMR)-based profiling platform (Olaris, Inc., Cambridge, MA). The serum was analyzed via 1D 1H NMR and 2D 13C-1H heteronuclear single quantum coherence spectroscopy (HSQC) using customized non-uniform sampling (NUS) techniques and processed with proprietary Olaris software. Supervised and unsupervised machine learning algorithms were used to identify patients with shorter and longer PFS to trastuzumab-based therapy. Results: The median PFS for this cohort was 301 days. Patients were subdivided into early progressors (PFS < 301 days) and late progressors (PFS ≥ 301 days). 23 metabolite resonance levels were statistically different between the two groups (KW test p Citation Format: Elizabeth O'Day, Kim Leitzel, Suhail M Ali, Bo Zhang, Chen Dong, Haiwei Gu, Xiajian Shi, Joseph J Drabick, Leah Cream, Monali Vasekar, Hyma V Polimera, Vinod Nagabhairu, Prashanth Moku, Ashok Maddukuri, Harry Menon, Neha Pancholy, Walter P Carney, Wolfgang Koestler, Allan Lipton. Pretreatment serum metabolome predicts PFS in first-line trastuzumab-treated metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-25.

Highlights • The role and efficacy of chemotherapy in angiosarcoma treatment remains uncertain. • Doxorubicin, paclitaxel, and cisplatin may be an effective alternative to surgery. • Chemotherapy may limit the need for debilitating, radical excision in extremity. • Neoadjuvant chemotherapy may increase chances of curative surgery in the breast., Introduction Angiosarcoma is a rare soft tissue malignancy of endothelial cells, generally associated with a poor prognosis. Due to its rarity, randomized trials are difficult to conduct and a consensus on the treatment of angiosarcoma has not been reached. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations. Case descriptions Here we describe the successful use of chemotherapy followed by radiation for a case of lower extremity angiosarcoma, and a case of breast angiosarcoma treated with neoadjuvant chemotherapy followed by surgical resection. Systemic therapy consisted of weekly doxorubicin, paclitaxel, and cisplatin. This regimen resulted in a full clinical remission in the first patient and a pathologic complete response in the second. Discussion These cases suggest that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas, and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against angiosarcoma. A randomized trial utilizing neoadjuvant combined doxorubicin, paclitaxel and cisplatin followed by either surgery or radiation, with endpoints assessing pathologic and overall response as well as progression free survival is warranted based on these cases. Conclusion The role of neoadjuvant chemotherapy in the treatment of angiosarcoma should be reconsidered considering its ability to provide important prognostic information and improve the likelihood of curative surgery.

Background: In the CCTG (Canadian Clinical Trials Group) MA.31 randomized phase 3 trial, the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2-positive metastatic breast cancer (MBC). We previously reported the prognostic utility of pretreatment serum PD-L1 in the trastuzumab arm of MA.31 (ASCO 2018, #1031), and here we evaluate serum PD-L1 in the lapatinib arm, and in the whole trial. Higher serum PD-L1 has been reported to be associated with reduced response to treatment with the immune checkpoint inhibitors in melanoma and lung cancer. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positivepatients; 186 in the trastuzumab arm, and 202 in the lapatinib armhad pretreatment serum available. TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Step-wise forward Cox multivariate analysis was used for PFS and OS, and testing for treatment-biomarker interaction was based on the local partial-likelihood method (Liu Y, Jiang W, and Chen BE, Statistics in Medicine 34, 3516-3530, 2015). Results: In the total study population, pretreatment serum PD-L1 concentration had a median of 86.2 pg/ml, and 25% and 75% interquartiles of 64.1 and 134.3 pg/ml, respectively. In univariate analysis in the whole trial, and within both treatment arms, serum PD-L1 was not a significant biomarker for PFS. For OS, higher serum PD-L1 (as a continuous variable) was significant for shorter OS within the trastuzumab arm (HR=3.84, p=0.04), but was not associated with OS in the lapatinib arm (p=0.37). In the whole trial, in multivariate analysis for OS [15 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, treatment arm, and serum PD-L1 (with median cut point)], serum PD-L1 remained a significant independent covariate (HR= 2.27, p= 0.001 (Table).There was significant interaction between treatment arm and continuous serum PD-L1 (Bootstrap method, p=0.0025); above 214.2 pg/ml serum PD-L1 (89% percentile), higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in the advanced breast cancer setting is warranted to identify HER2-positive MBC patients who may benefit from novel immune-targeted therapies in addition to trastuzumab. Multivariate Analysis (whole trial): Significant Independent CovariatesCovariateP-ValueHRLower 95% CIHigher 95% CISerum PD-L1 (pretreatment) (>median vs Citation Format: Moku PR, Shepherd LE, Ali SM, Leitzel K, Parulekar WE, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Drabick JJ, Cream L, Halstead SE, Umstead T, Mckeone D, Maddukuri A, Polimera HV, Ali A, Poulose J, Pancholy N, Spiegel H, Nagabhairu V, Chen BE, Lipton A. Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-10.

Women with metastatic breast cancer desire interventions that would allow them to self‐manage symptoms, but which do not require additional clinic appointments. We used a community based participatory research approach to develop a tablet based supportive care intervention called Nurse AMIE to address this need. The intervention modules are drawn from published evidence based clinical guidelines from ASCO and NCCN, including physical activity, soothing music, mindfulness meditation, guided imagery, cognitive behavioral therapy, and psychoeducation. Preliminary results include 61% and 55% acceptability from clinicians and patients, respectively, as well as 86% feasibility, defined as using the tablet for at least 30 of the 90‐day intervention. These preliminary results warrant additional research, particularly given the potential for this intervention to address needs of rural and medically underserved patients.

Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia.Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7 , CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS.Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians.Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.

Mental health programs to improve problem-solving skills and reduce stress through social gameplay can improve psychiatric outcomes, but little is known about whether adult patients are interested in using them. Primary care patients (n = 467) completed a cross-sectional survey to assess interest in using 2 types of group programs for mental health. A significantly greater percentage (23.7%) of patients expressed interest in a gameplay-based program than in interpersonal therapy (17.6%) (P < .001). Lonely patients and younger patients were more likely to report interest in gameplay. Results suggest that diverse patient populations are interested in using gameplay programs for mental health.

Olaparib was first FDA approved for use in women with advanced ovarian cancer and germline BRCA mutations. Based on the results of subsequent research, the use of this drug has been expanded to patients with metastatic breast cancer with germline BRCA mutation. With the use of a relatively new medication and a larger patient population eligible for therapy, monitoring for novel adverse events associated with therapy is important. This case represents a patient with metastatic breast cancer and germline BRCA2 mutation who developed erythema nodosum after initiation of therapy with olaparib capsules. Her characteristic rash appeared shortly after starting olaparib and recurred after restarting olaparib an additional two times. She was treated with short courses of prednisone therapy with or without holding olaparib with resolution of her rash. The patient was later restarted on olaparib capsules 200 mg twice daily, and she more recently has been maintained on olaparib tablets 300 mg twice daily. On both regimens, the patient experienced only attenuated episodes of erythema nodosum that have not required cessation of therapy or steroid therapy.

Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300 mM SM for 1 h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50 mu M BER for 24 h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate-kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies.

The National Health Service (NHS) outcomes frameworks for public health, health and adult social care in England were launched in 2010–2012 with ambitions that they would transform health outcomes in England. However, unprecedented financial pressures in the NHS are compelling changes in government policy designed to make the NHS financially sustainable while ensuring high-quality care for a population with a growing burden of chronic disease and multimorbidity. Radical changes in the way health and care services are commissioned and delivered locally are under way or planned. The models of care emerging are almost without exception predicated on greater integration of public health, health and care services, making the three discrete outcomes frameworks increasingly anomalous. As a centrally funded service working to policies defined by government, the NHS needs a performance framework that clearly articulates national priorities and the systemic changes needed to deliver them. The authors argue for a review of the NHS outcomes frameworks, rationalisation of the disparate performance requirements the NHS is expected to comply with and make suggestions for an alternative model more fitting for the challenges the NHS faces. New governments like to put clear water between themselves and their predecessors. However, the political currents unleashed by the 2017 UK election mean that major changes in health policy and direction are unlikely. But it is an opportune moment for the government to give a facelift to long-standing policies that most informed consensus would describe as obsolete and in need of a rethink. The 2010 coalition government hailed its NHS Outcomes Framework (NHSOF) for England1 as a radical transition from the previous Labour government’s process targets to measuring outcomes of healthcare. The Public Health Outcomes Framework (PHOF) and Adult Social Care Framework (ASCOF) followed shortly thereafter.2 3 The frameworks were designed to show performance nationally …

Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066–76. ©2017 AACR.

Background Very early aphasia rehabilitation studies have shown mixed results. Differences in therapy intensity and therapy type contribute significantly to the equivocal results. Aims To compare a standardized, prescribed very early aphasia therapy regimen with a historical usual care control group at therapy completion (4–5 weeks post-stroke) and again at follow-up (6 months). Methods & Procedures This study compared two cohorts from successive studies conducted in four Australian acute/sub-acute hospitals. The studies had near identical recruitment, blinded assessment and data-collection protocols. The Very Early Rehabilitation (VER) cohort (N = 20) had mild–severe aphasia and received up to 20 1-h sessions of impairment-based aphasia therapy, up to 5 weeks. The control cohort (n = 27) also had mild–severe aphasia and received usual care (UC) therapy for up to 4 weeks post-stroke. The primary outcome measure was the Aphasia Quotient (AQ) and a measure of communicative efficiency (DA) at therapy completion. Outcomes were measured at baseline, therapy completion and 6 months post-stroke and were compared using Generalised Estimating Equations (GEE) models. Outcomes & Results After controlling for initial aphasia and stroke disability, the GEE models demonstrated that at the primary end-point participants receiving VER achieved 18% greater recovery on the AQ and 1.5% higher DA scores than those in the control cohort. At 6 months, the VER participants maintained a 16% advantage in recovery on the AQ and 0.6% more on DA scores over the control cohort participants. Conclusions & Implications A prescribed, impairment-based aphasia therapy regimen, provided daily in very early post-stroke recovery, resulted in significantly greater communication gains in people with mild–severe aphasia at completion of therapy and at 6 months, when compared with a historical control cohort. Further research is required to demonstrate large-scale and long-term efficacy.

As an introduction to this journal issue devoted to qualitative research methods in stuttering research, the present paper provides an overview of some of the underlying questions and issues arising from the use of qualitative approaches in research. The overview is written mindful of the historical domination of quantitative approaches to stuttering research and the likelihood that many readers of the present issue will have long experience and familiarity with quantitative approaches as opposed to qualitative ones. Consequently, qualitative research approaches are overviewed with particular reference to what have been, in our experiences, recurring queries about those methods from within the quantitative perspective. A broad definition of the inductive methods of qualitative approaches is offered and contrasted with the deductive methods of quantitative research. Subsequently, the issue of “bias” in qualitative approaches is considered, along with insights into ways of determining the quality of such ap...

Myopia is a complex inherited ocular trait resulting from an interplay of genes and environmental factors, most of which are currently unknown. In two independent population-based cohorts consisting of 5,256 and 3,938 individuals from European descent, we tested for biological interaction between genetic predisposition and level of education on the risk of myopia. A genetic risk score was calculated based on 26 myopia-associated single nucleotide polymorphisms recently discovered by the Consortium for Refractive Error and Myopia. Educational level was obtained by questionnaire and categorized into primary, intermediate, and higher education. Refractive error was measured during a standardized ophthalmological examination. Biological interaction was assessed by calculation of the synergy index. Individuals at high genetic risk in combination with university-level education had a remarkably high risk of myopia (OR 51.3; 95 % CI 18.5–142.6), while those at high genetic risk with only primary schooling were at a much lower increased risk of myopia (OR 7.2, 95 % CI 3.1–17.0). The combined effect of genetic predisposition and education on the risk of myopia was far higher than the sum of these two effects (synergy index 4.2, 95 % CI 1.9–9.5). This epidemiological study provides evidence of a gene-environment interaction in which an individual’s genetic risk of myopia is significantly affected by his or her educational level. Electronic supplementary material The online version of this article (doi:10.1007/s10654-013-9856-1) contains supplementary material, which is available to authorized users.

Cells disseminated from primary epithelial tumors into peripheral blood, called circulating tumor cells (CTCs), can be monitored to assess metastases and to provide a surrogate marker of treatment response. Here, we demonstrate how the flexible micro spring array (FMSA) device—a novel microfluidic device that enriches CTCs by two physical parameters: size and deformability—could be used in the rational development of treatment intervention and as a method to study the fundamental biology of CTCs. Cancer cells of different origins were spiked into healthy samples of donor blood to mimic blood samples of metastatic cancer patients. This spiked human blood was filtered using the FMSA device, and the recovered cells were successfully expanded in vitro and in a novel in vivo system. A series of experiments were performed to characterize these cells and to investigate the effect of chemotherapy on the resulting cultures. As few as 20 colon cancer cells in 7.5 mL blood could be isolated with the FMSA device, expanded both in vitro and in vivo and used at 25 cells per well to obtain significant and reliable chemosensitivity data. We also show that isolating a low number of viable patient CTCs and maintaining them in culture for a few weeks is possible. The isolation of viable cancer cells from human blood using the FMSA device provides a novel and realistic means for studying the biology of viable CTCs and for testing drug efficacy on these rare cells—a hypothesis that can be tested in future clinical trials.

Author version made available in accordance with the publisher's policy., Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia., Australian National Health and Medical Research Council.

© 2015 Taylor & Francis. Background: Communication outcomes following stroke are improved when treatments for aphasia are administered early, within the first 3 months after stroke, and provided for more than 2 hours per week. However, uncertainty remains about the optimal type of aphasia therapy. Aims: We compared constraint-induced aphasia therapy (CIAT) with individual, impairment-based intervention, both administered early and daily after acute stroke. Methods&Procedures: This prospective, single-blinded, randomised, controlled trial recruited participants with mild to severe aphasia within 10 days of an acute stroke from acute/subacute Perth metropolitan hospitals (n = 20). Participants were allocated by computer-generated block randomisation method to either the CIAT (n = 12) or individual, impairment-based intervention group (n = 8) delivered at the same intensity (45–60 min, 5 days a week) for 20 sessions over 5 weeks (15–20 hours total). The primary outcome, measured after completing the intervention, was the Aphasia Quotient (AQ) from the Western Aphasia Battery. Secondary outcomes were the AQ at 12 and 26 weeks post stroke, a Discourse Analysis (DA) score and the Stroke and Aphasia Quality of Life Scale (SAQoL), measured at therapy completion, 12 and 26 weeks post stroke. There was a 10% (n = 2) dropout at the primary end point, both participants were in the CIAT group. The estimates for each treatment group were compared using repeated measures ANOVAs. Data from the 26-week follow-up assessment are presented, however, were not included in the between-group comparisons due to the low number of data points in each group. Outcomes & Results: Within groups analyses comparing performance at baseline, therapy completion, and 12 weeks post stroke revealed a statistically significant treatment effect for the AQ (p

Summary Objective The study aim was to evaluate the psychological impact on parents of the provision of a paediatric intensive care follow-up clinic. Design Exploratory randomised controlled trial. Families were allocated to intervention (follow-up clinic appointment two months after discharge) or control (no appointment) condition. Setting An eight-bed Paediatric Intensive Care Unit (PICU) in an inner city teaching hospital. Measurements Parents’ baseline stress was assessed using the Parental Stressor Scale: PICU. Post-traumatic stress, anxiety and depression were assessed at five months using the Impact of Event Scale and the Hospital Anxiety and Depression Scale. Results Only 18/72 families (25%) in the intervention group chose to attend the clinic. Outcome data were provided by 55/82 parents in the intervention group and 50/72 in the control group. Although no significant differences were found between the groups as a whole, parents with higher baseline stress reported lower rates of post-traumatic stress ( n = 8/32(25%) vs. n = 13/23(57%), p = 0.018) and depression ( n = 6/32(19%) vs. n = 12/23(52%), p = 0.009) at five months if they had been offered an appointment than if they had not. Conclusions Whilst these results do not justify routine follow-up for all, they suggest that, for the most traumatised parents, rates of long-term distress could be reduced by this intervention.

e12534Background: Genetic polymorphisms in drug metabolizing enzymes can have significant impact on drug toxicity and/or efficacy. Exemestane (Exe), a steroidal aromatase inhibitor, is extensively ...

1031Background: In MA.31 the lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We previously reported the positive prognostic utility of pre...

The ability to reduce stuttering in everyday speaking situations is the core component of the management plan of many who stutter. However, the ability to maintain the benefits of speech-restructuring treatment is known to be compromised, with only around a third of clients achieving this [Craig, A. R., & Hancock, K. (1995). Self-reported factors related to relapse following treatment for stuttering. Australian Journal of Human Communication Disorders, 23 , 48–60; Martin, R. (1981). Introduction and perspective: Review of published research. In E. Boberg (Ed.), Maintenance of fluency . New York: Elsevier]. The aim of this study was to determine whether the presence of mental health disorders contributes to this failure to maintain fluency after treatment. Assessments for mental health disorders were conducted with 64 adults seeking speech-restructuring treatment for their stuttering. Stuttering frequency, self-rated stuttering severity and self-reported avoidance were measured before treatment, immediately after treatment and 6 months after treatment. Stuttering frequency and situation avoidance were significantly worse for those participants who had been identified as having mental health disorders. The only subgroup that maintained the benefits of the treatment for 6 months was the third of the participants without a mental health disorder. These results suggest that prognosis for the ability to maintain fluency after speech restructuring should be guarded for clients with mental health disorders. Further research is needed to determine the benefits of treating such disorders prior to, or in combination with, speech-restructuring. Educational objectives: The reader will (1) evaluate the impact of one or more mental health disorders on medium-term outcomes from speech-restructuring treatment for stuttering, (2) describe how this finding affects prognosis for certain groups of stuttering clients, (3) evaluate how these finding are consistent with estimates of post-treatment relapse after speech-restructuring treatment, (4) describe two test instruments for detecting mental health disorders, and (5) outline the findings about the relation between pre-treatment stuttering severity and mental health disorders.

Speech restructuring is an efficacious method for the alleviation of stuttered speech. However, post-treatment relapse is common.To investigate whether the use of video self-modelling using restructured stutter-free speech reduces stuttering in adults who had learnt a speech-restructuring technique and subsequently relapsed.Participants were twelve adults who had previously had speech-restructuring treatment for stuttering and relapsed. They were video recorded for 1 hour within the clinic, practising their speech-restructuring technique. The videos were then edited to remove all observable stuttering. Participants then viewed the resulting video of themselves using restructured stutter-free speech each day for 1 month and were instructed to speak as they did on the video. Beyond-clinic speech samples and self-report severity data were collected before and after the intervention.Very large effect sizes were found. The mean per cent syllables stuttered was 7.7 pre-intervention and 2.3 post-intervention. For all but one participant there was a reduction in stuttering from pre-intervention to post-intervention. These results were verified with self-report data. Speech naturalness was not compromised by the video self-modelling procedure.Video self-modelling as a relapse management tool does not involve excessive time expenditure by the clinician or the client. The study indicates video self-modelling is potentially useful for managing relapse after speech-restructuring treatment for stuttering, and in some cases may be a stand-alone procedure to manage relapse. Phase II and III trials are warranted to determine the size and duration of the effect. It is suggested video self-modelling could also be included in a relapse management plan.

SUMMARY In 2007, the World Health Organization, together with United Nations and international organization as well as experts, met to draw upon existing evidence and practical experience from regions, countries and individual schools in promoting health through schools. The goal of the meeting was to identify current and emerging global factors affecting schools, and to help them respond more effectively to health, education and development opportunities. At the meeting, a Statement was developed describing effective approaches and strategies that can be adopted by schools to promote health, education and development. Five key challenges were identified. These described the need to continue building evidence and capturing practical experience in school health; the importance of improving implementation processes to ensure optimal transfer of evidence into practice; the need to alleviating social and economic disadvantage in access to and successful completion of school education; the opportunity to harness media influences for positive benefit, and the continuing challenge to improve partnerships among different sectors and organizations. The participants also identified a range of actions needed to respond to these challenges, highlighting the need for action by local school communities, governments and international organizations to invest in quality education, and to increase participation of children and young people in school education. This paper describes the rationale for and process of the meeting and the development of the Statement and outlines some of the most immediate efforts made to implement the actions identified in the Statement. It also suggests further joint actions required for the implementation of the Statement.

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10−4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10−3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10−3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10−4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10−4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10−4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10−4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10−4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development., Author Summary Gene variants identified by GWAS studies to date explain only a small fraction of myopia cases because myopia represents a complex disorder thought to be controlled by dozens or even hundreds of genes. The majority of genetic variants underlying myopia seems to be of small effect and/or low frequency, which makes them difficult to identify using classical genetic approaches, such as GWAS, alone. Here, we combined gene expression profiling in a monkey model of myopia, human GWAS, and a gene-targeted mouse model of myopia to identify one of the “missing” myopia genes, APLP2. We found that a low-frequency risk allele of APLP2 confers susceptibility to myopia only in children exposed to large amounts of daily reading, thus, providing an experimental example of the long-hypothesized gene-environment interaction between nearwork and genes underlying myopia. Functional analysis of APLP2 using an APLP2 knockout mouse model confirmed functional significance of APLP2 in refractive development and implicated a potential role of synaptic transmission at the level of glycinergic amacrine cells of the retina for the development of myopia. Furthermore, mouse studies revealed that lack of Aplp2 has a dose-dependent suppressive effect on susceptibility to form-deprivation myopia, providing a potential gene-specific target for therapeutic intervention to treat myopia.

Background Xeroderma pigmentosum (XP) is an autosomal recessive disorder of, in most cases, defective nucleotide excision repair (NER) of ultraviolet radiation (UV)- and chemical-induced DNA damage. The condition is characterized by an increased sensitivity of the skin to UV radiation, with early development of pigmentary changes and premalignant lesions in sun-exposed areas of the skin, signs of photoageing and a greatly increased incidence from a young age of skin tumours including melanoma. Approximately 20% of patients with XP show neurological abnormalities of varying severity due to primary neuronal degeneration. Genetic analysis by somatic cell hybridization has led to the identification in the NER-defective form of XP of seven complementation groups, designated XP-A to XP-G. These complementation groups correspond to different proteins involved in the NER process. XP-A classically includes some of the most severely affected patients. Objectives We describe a 61-year-old Punjabi woman with XP. Remarkably she had only mild cutaneous abnormalities, minimal neurological features and unusual longevity, and developed a malignant spindle cell melanoma. There are few previous reports of spindle cell melanoma associated with XP. To gain insight into the aetiology of these unusual features, we sought to analyse the DNA repair properties of the patient and identify the complementation group and the causative mutation in the defective gene. Methods Unscheduled DNA synthesis and the inhibition of RNA synthesis were measured. The complementation group was assigned by fusing the cells of our patient with XP cells of known complementation groups and determining the ability to carry out unscheduled DNA repair. Molecular analysis of the cDNA was carried out by polymerase chain reaction and DNA sequencing. Results Levels of DNA repair were extremely low and complementation analysis assigned the defect to the XP-A group. Sequencing of the XPA gene revealed a novel homozygous mutation of A?G at the eighth nucleotide of intron 4 causing aberrant splicing and a nonfunctional truncated XP-A protein. However, a small amount of normally spliced mRNA was detected at

In a qualitative study, 10 adults who stutter were interviewed to investigate their experience of treatment. They had all previously participated in behavioural treatments for stuttering that involved one of the variants of prolonged speech. In this type of treatment, people learn to use prolonged speech to control their stuttering. One of the themes to emerge was how difficult it is to use prolonged speech in many everyday communication contexts. The participants reported having an ongoing fear that they would lose control over their stuttering. A metaphor involving the playground rocker was developed to illustrate this experience. The metaphor also suggests strategies that might help people reduce these feelings of loss of control. These include improving conversational skills and reducing speech-related anxiety. Although developed for people who stutter, the metaphor also has implications for other communication disorders.

In 2001, the International Rett Syndrome Association funded the establishment of a World Wide Web—based database to collect and display the genetic data of children and adults with Rett syndrome from around the world. RettBASE () encompasses both published and unpublished data; includes pathogenic mutations, benign polymorphisms, and sequence variations of uncertain significance; and has a range of query capabilities, allowing for simple or complex interrogation of the database. To undertake genotype—phenotype correlations and to identify the likely subtle differences in phenotype, detailed phenotype data on large samples will be provided by the International Rett Syndrome Association International Phenotype database InterRett. InterRett is under development by the Australian Rett syndrome study group at the Telethon Institute for Child Health Research in Perth, Western Australia. It will collect data from clinicians and families and provide deidentified, collated data on the Internet (). Data records will be linked with RettBASE through a common unique identifier. An international reference panel is advising on the development of the database. Data collection procedures from families and clinicians are currently being piloted. Full data collection from both groups began in the second half of 2003. Concurrently, the output database will be developed to provide deidentified individual records and collated data for clinicians and researchers and collated data for families and the general public. This Web-based database will be an invaluable resource for understanding the nature of the disorder and managing children and adults with Rett syndrome. ( J Child Neurol 2003;18:709—713).

Considerable research has been directed at the outcomes of prolonged-speech (PS) treatment for the control of chronic stuttering, but little research to date has focused on the PS treatment process. This report examines a Stage 2 clinical trial of a reconceptualized PS treatment model known as the Camperdown Program. This program requires fewer clinician hours than traditional programs and has no formal transfer phase. Additionally, it incorporates the following treatment process innovations, which replace treatment process components that are intuitively and empirically problematic: (a) PS is taught without incorporating target behaviors in clinician instruction, (b) participants learn to control stuttering without programmed instruction, and (c) the treatment process does not involve clinician identification of stuttering moments. Thirty participants were initially enrolled in the trial. Final outcome data are presented for the 16 participants who completed all trial requirements, including 12 months posttreatment data collection. These 16 participants showed minimal or no stuttering in everyday speaking situations for up to 12 months after entering the maintenance program, with speech rates in the normal range. Speech naturalness and social validation data were also favorable. Although self-report data generally confirmed the speech data, the results were not as positive. The present outcomes were achieved in a mean of 20 hours of clinic attendance per participant, which is much fewer than the hours required by treatment programs reported recently that run intensively over 2–3 weeks. The promise of this Stage 2 clinical trial has led the authors to initiate a Stage 3 randomized controlled trial of the Camperdown Program.

It is well documented that adults can control stuttering if they use certain novel speech patterns referred to generically as prolonged-speech (PS). These speech patterns were refined in the 1960s and developed into behavioural treatment programmes. The bulk of available PS treatment research has focused on speech parameters thought to reflect favourable treatment outcome. Considering this, and that post-treatment relapse is known to be common, clinicians and researchers could be usefully informed by knowledge about the experiences of those who receive these treatments. Subsequently, they could use such information in attempts to control stuttering in their clients. Yet, at present, systematic research on this topic is scant.The continued development of PS treatments could be usefully informed by research into the experiences of those who use PS to control stuttering. Hence, that is the topic of the present report.The method used was phenomenology. Participants were a purposive sample of 10 people who had received PS treatment. During a 2-year period, a collaborative approach to the study of the topic was developed between the participants and interviewer. Interviews were from 1.5 to 2 hours, and a total of 34 interviews and discussions were undertaken with participants. Transcripts of these were used to generate text from which themes were identified using line-by-line, holistic and selective approaches.The main findings were that even after therapy with PS there is a continued risk of stuttering occurring, and although adults have the novel experience of controlling stuttering, they also continue to experience feeling different from those who do not stutter, which may be exacerbated after therapy. Given the negative consequences associated with stuttering and feeling different, the essence of the experience after therapy with PS is that adults use their own resources to integrate behavioural skills with existing experiences in order to protect themselves from the harm of stuttering as best they can. PS changes speech, but not the dynamic and often unpredictable communication situations of everyday life. Hence, the maximum benefits of PS are attained when clients use a strategic approach to control stuttered speech and daily communication.These findings are consistent with the results of existing outcome research as well as with other current research from the present group. Their implications are discussed in relation to the structure of PS treatments as well as in relation to future PS outcome research. The clinical implications of these findings are discussed in terms of informing prospective clients of the experiential consequences of PS, selecting clients who might benefit from PS and in terms of assisting clients to achieve optimal benefits from PS.

The retrotrapezoid nucleus (RTN) provides a source of tonic drive to respiratory neurons and is one of many sites for central chemoreception. Here we evaluate in the rat the local neuronal cytoarchitecture in the RTN histologically 2-4 h after neurobiotin injection and the afferent connections to the RTN 24 h after injection. Our neurobiotin injections often overlapped the RTN and the adjacent neurons of the parapyramidal region, so we group these two regions together in this study. The RTN is made up of small and medium sized neurons and has a low neuronal density compared to other nuclei. The organization of the RTN is reticular in nature and there are prominent small neurons at the ventral medullary border. Adjacent to the pyramids there are medium sized neurons with connections to the raphé pallidus. Major afferent connections include the regions of the dorsal and ventral respiratory groups, the medullary raphé, the contralateral parapyramidal and RTN regions, portions of the nucleus paragigantocellularis lateralis, and portions of the reticular fields. Other sources of input include the Kölliker-fuse nucleus, subceruleus, A5 region, and the paralemniscal zone.

INTRODUCTION: Single-agent chemotherapy was abandoned decades ago in favor of multi-agent regimens for nearly all malignancies, but single-agent intraventricular chemotherapy remains the standard of care for patients with neoplastic meningitis (NM). In the five decades since Ommaya reservoirs became available, overall survival has remained dismal, and NM remains the most devastating and feared complication of cancer. METHODS: For the last five years, we have treated patients with NM with multi-agent intraventricular chemotherapy regimens tailored to the histology of the underlying cancer. From a list of 12 cytotoxic and targeted drugs which can safely be administered into the cerebrospinal fluid (CSF) we select the 4 most appropriate agents, and treat patients with two drugs at a time in alternating weekly cycles. We queried our multinational NM registry to identify patients with NM treated with this multi-agent regimen. We collected detailed demographic, treatment, and outcome data, and compared these characteristics with corresponding patient level data acquired from 6 of the 7 randomized controlled trials (RCTs) conducted in patients with NM, all of which used single-agent intraventricular therapies. RESULTS: Two-hundred and three patients with NM (139 with solid tumors, 44 with lymphoma, 20 with leukemia) were identified from our registry, and were compared to 300 patients from the RCTs (238 with solid tumors, 62 with lymphoma). RCT data for adults with leukemic meningitis are not available. Age, gender, KPS at the start of treatment, tumor histology, status of the primary cancer, and frequency of concurrent systemic chemotherapy or radiation did not differ between registry and RCT patients, or were less favorable in the registry patients. All patients from the registry patient group were included for analysis regardless of how many cycles of intraventricular therapy they received (intent-to-treat model). Median survival for the solid tumor, lymphoma, and leukemia groups (multi-agent vs. single-agent treatment) were 211 vs. 93.1 days (p

Recent research has challenged some assumptions upon which many prolonged speech programmes are based. This paper presents preliminary data from a new programme designed to redress this situation. The new programme operates without any of the following procedures: (1) a multiday, intensive treatment format; (2) formal transfer procedures; (3) programmed instruction; (4) standardized, prescriptive prolonged speech target behaviours, and (5) instrumentation for the on-line counting of stuttering rate and speech rate. The latter procedures have been replaced by the use of a severity rating scale. Data are presented for the first three clients to reach the maintenance phase of the programme. All clients reduced stuttering to very low levels both within and beyond the clinic.

Many different types of activities can be modified or eliminated in order to maintain older adults independently in their homes, but one activity essential to independence, the use of the telephone by older adults, has not been researched.The purpose of this study is to investigate whether older adults have made changes to their homes in order to make the telephone more accessible and if so, what changes have they made. Reasons for not making modifications are also examined.The sample included 34 older adults, age 65 and older living alone in the community as homeowners and renters. A questionnaire was administered in the homes of participants for whom information was recorded about telephone location.The subjects reported making few modifications to their telephone. Most subjects have three to four telephones. The most common technology related to the telephone used by subjects was an answering machine. The study has implications for physical and occupational therapists working with older homeowners who ...

Julia Cream describes the prevalence and common symptoms of dementia, and discusses the challenges facing society in caring for an increasingly ageing population. In an era of tight budgets and shrinking resources, she suggests ways to focus care on those most in need of it.

We describe a 69-year-old woman who presented with purpura on the legs. Examination of a blood film revealed a homogenous population of abnormal lymphoid cells with villous projections. The immunophenotype was consistent with a diagnosis of splenic lymphoma with villous lymphocytes (SLVL). A type II (IgM-IgG) cryoglobulin was detected in the serum. Renal biopsy demonstrated a membranoproliferative type I glomerulonephritis with intraluminal IgG and IgM deposits, and a skin biopsy showed a leucocytoclastic vasculitis with outlining of the vessels by IgG and IgM. Vasculitis has been reported in association with a number of haematological malignancies, most frequently with hairy cell leukaemia. To our knowledge this is the first report of SLVL presenting with cryoglobulinaemic vasculitis.

We describe an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) in a dermatology day-care unit and the methods used to determine the mechanism of spread and control it. The epidemic strain had a characteristic sensitivity pattern and was typeable with phages 29, 80, 95, 47, 54 and 77, which was of considerable value in interpreting the epidemiological data. The method of spread was studied by examination of the medical and nursing records of patients who had acquired MRSA (to determine which members of staff they had encountered and which other MRSA-positive patients had been present in the department at the same time) and by the microbiological screening of all patients and staff. However, screening of all staff by nasal swabbing failed to identify carriage of the epidemic strain, while extensive swabbing of surfaces on the day-care unit also failed to show any evidence of MRSA in the environment. This suggests that the MRSA was most probably spread from patient to patient via the hands of staff, although there was also the possibility of direct transmission from patient to patient. Nine patients acquired the unique strain of MRSA and once acquired it proved difficult to eradicate, although in the majority, the infection did not appear to be clinically significant. However, in two patients MRSA contributed to a fatal outcome: these were the two most elderly patients and were the only two who were receiving systemic corticosteroids. The outbreak was brought under control with rigorous hygienic measures and the decision to discharge all patients with MRSA from the day-care unit. Repeat screening (swabs of nose, axilla and groin) of all day-care unit and in-patients 11 months after the last MRSA case showed no evidence of any residual MRSA infection in the day-care unit.

Cream, Carlos L., Aihua Li, and Eugene E. Nattie. RTN TRH causes prolonged respiratory stimulation. J. Appl. Physiol. 83(3): 792–799, 1997.—We injected thyrotropin-releasing hormone (TRH; 10 nl; 0.25, 0.5, 1.0, or 10 mM), its inactive free acid form (TRHOH; 1 mM), or a metabolite with low TRH-receptor binding affinity, histidine-proline diketopiperazine (cHP; 1 mM), into the retrotrapezoid nucleus of anesthetized rats. Injection location was verified by anatomic analysis. Lower doses (0.25–0.5 mM) significantly increased both the product of integrated phrenic amplitude and frequency ([Formula: see text]Phr ⋅ f) and f for 20–30 min compared with artificial cerebrospinal fluid control injections. Higher doses (1.0–10 mM) produced greater and long-lasting stimulation of [Formula: see text]Phr ⋅ f,[Formula: see text]Phr, and f and of blood pressure. This stimulation reached values 150% of baseline and durations of 270 min after a single injection. TRHOH (1 mM ) or cHP (1 mM) had no effect on[Formula: see text]Phr but increased f, as did 1 mM TRH. We conclude that TRH has a very powerful stimulatory effect in the retrotrapezoid nucleus region on [Formula: see text]Phr ⋅ f, with the [Formula: see text]Phr response seemingly specific for TRH receptors. Similar responses of f to TRHOH and cHP suggest it may be nonspecific.

We report a 63-year-old woman who presented with an 8-week history of widespread indurated, purpuric lesions associated with weight loss of 7 kg and several episodes of epistaxis. A skin biopsy demonstrated a lymphocytic vasculitis with haemorrhage and parakeratosis. A blood film and bone marrow examination showed features of a myelodysplastic syndrome in transformation to acute myeloid leukaemia. Leucocytoclastic vasculitis and polyarteritis nodosa occur in association with acute myeloid leukaemia, but the association with lymphocytic vasculitis is new.

OBJECTIVE Acne vulgaris is androgen dependent but the hormonal mechanisms are unclear. Although there have been many studies of serum hormones in women with acne there are few studies in men and the results are conflicting. We have therefore carried out a further study in men. DESIGN AND PATIENTS Fifty men with acne vulgaris were age-matched against 50 normal men. MEASUREMENTS Serum levels of dehydroepiandrosterone sulphate (DHEAS), 17 alpha-hydroxyprogesterone, 11-deoxycortisol, androstenedione and testosterone were measured by radioimmunoassay, sex hormone binding globulin (SHBG) by immunoradiometric assay and LH, FSH and oestradiol by automated ELISA. RESULTS The acne patients had higher levels of androstenedione, median 7.35 nmol/l, (interquartile range 2-7) vs 6.05 (2.3), P = 0.004; testosterone, 21.7 nmol/l (7.5) vs 17.55 (7.7), P = 0.04; and free androgen index (FAI) 78.26 (40) vs 65.06 (20), P = 0.007, but also had higher levels of 11-deoxycortisol, 13.65 nmol/l (4.3) vs 12.0 (4.3), P = 0.022. The LH, FSH, 17 alpha-hydroxyprogesterone, DHEAS, oestradiol and SHBG levels were not significantly different. Examination of the Spearman rank correlation coefficient matrices for the serum levels of 17 alpha-hydroxyprogesterone, androstenedione and 11-deoxycortisol showed that the strongest correlation was between androstenedione and 11-deoxycortisol. CONCLUSION Although there was overlap between the results of the acne patients and controls the acne patients tended to have higher levels of androstenedione, testosterone, free androgen index and 11-deoxycortisol. The higher levels of 11-deoxycortisol are suggestive of 11 beta-hydroyxlase dysfunction which could be due to a primary adrenal defect or a consequence of raised androgens. Also, a pathway between androstenedione and 11-deoxycortisol has been described in sheep and, although unsubstantiated in man, requires consideration.

558Background: Despite considerabletreatment advances,resistance to hormone therapy remains a major clinical problem. We correlated the protein levels of multiple tyrosine kinase receptors, signal ...

2549Background: PARP inhibitor therapy of BRCA-associated cancer exploits the concept of synthetic lethality, yet there have been limited PD markers of efficacy. We report here on baseline PAR and ...

Breast cancer is the most commonly diagnosed cancer in women in United States. From data of American Cancer Society from 2007 reported total of 178,480 women diagnosed with breast cancer. The death rate from breast cancer has decreased in North America over time, but still accounts for second highest cancer death, following lung cancer. Breast cancer is staged based on tumor size, nodal involvement, and distant metastasis like any other solid tumors. However clinical staging is not the only important factor in management of breast cancer. Various molecular features divides breast cancer into many subgroups – that act differently, and respond differently from therapy. Thus the focus of breast cancer treatment has evolved focusing on specific targets. The most important biologic markers in subtyping of breast cancer so far are hormone receptor positivity and HER2/neu protein expression. Five molecular subtypes using intrinsic gene set include Basal mRNA, HER2 + mRNA, Luminal AmRNA, Luminal B mRNA, and Normal-like mRNA. In addition, better understanding of genetic target of breast cancer has given us arsenal of personalized, and more effective treatment approach.