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Summary: The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high‐dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression‐free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR‐matched controls. We now integrate the second‐generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end‐points were safety and tolerability. Secondary end‐points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R‐ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2. Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2‐year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned. [ABSTRACT FROM AUTHOR]

Melanoma detection, prognosis, and treatment represent challenging and complex areas of cutaneous oncology with considerable impact on patient outcomes and healthcare economics. Artificial intelligence (AI) applications in these tasks are rapidly developing. Neural networks with increasing levels of sophistication are being implemented in clinical image, dermoscopic image, and histopathologic specimen classification of pigmented lesions. These efforts hold promise of earlier and highly accurate melanoma detection, as well as reliable prognostication and prediction of therapeutic response. Herein, we provide a brief introduction to AI, discuss contemporary investigational applications of AI in melanoma, and summarize challenges encountered with AI. [ABSTRACT FROM AUTHOR]

Background: As with many nations, the prevalence of dementia in Canada is expected to rise dramatically in the upcoming decades as the population ages. The Landmark Study is aimed at updating these estimates and the broader population changes associated for the Canadian population made in the 2010 Rising Tide Report. Method: Using the Canadian Centre for Economic Analysis's socio‐economic statistical analysis platform, a simulation model was developed using demographic characteristics (age, sex, ethnicity) and risk factors for dementia to forecast the burden of dementia in Canada over the next 30 years. This approach allows for comparisons across sex, ethnicity, provinces, while accounting for population dynamics including immigration. The model was also used to examine how a delay in incidence (1‐year, 5‐years, 10‐years) would impact prevalence and incident cases. Result: As expected, the model forecasts the number of Canadians with dementia to more than double in the next 30 years: 493,718 (2020; 59.6% female) to 1,296,707(2050; 61.2% female; Figure 1). With changing immigration patterns, the ethnic background of people with dementia will be quite different than today. People with Asian origin could increase from 8% of people with dementia today to 24% by 2050 (Figure 2). The changes are driven both by future immigration, and people who have already immigrated to Canada in the past. Delays in onset of 1 year would avoid over 300K cases, whereas a deferred incidence of 10 years would bring Canadian dementia rates to lower than where it is today (Figure 3). With the increase in prevalence of dementia, comes an increase in the number of informal caregivers and the number of hours providing care to persons living with dementia. The number of informal caregivers in 2020 (349,551; 472.6 million hours/year) is projected to increase in 2050 to 1,005,815 (1,386 million hours/year; Figure 4). Conclusion: This study forecasts rising dementia prevalence in Canada, illustrates the changing landscape of ethnicity in Canadians living with dementia, and estimates the population‐level impacts of interventions that delay onset of dementia would have on prevalence, incidence, and informal care. [ABSTRACT FROM AUTHOR]

Summary: In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front‐line setting. Recently, time‐to‐event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post‐autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six‐month [hazard ratio (HR) = 7·68], 12‐month (HR = 6·68), and 18‐month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non‐relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high‐risk group with inferior post‐relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up‐front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse. [ABSTRACT FROM AUTHOR]

Summary: ZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population. [ABSTRACT FROM AUTHOR]

Hemoptysis in pregnancy is rare and can be life‐threatening. This case describes management of hemoptysis in pregnancy requiring veno‐venous extracorporeal membrane oxygenation (VV‐ECMO). The patient presented with massive hemoptysis in respiratory failure at 26 weeks gestation. VV‐ECMO was utilized for maternal stability due to severe hypoxia from lung parenchymal damage. An extensive work‐up for hemoptysis returned negative except for an elevated Bordetella pertussis IgG antibody. The patient was delivered via cesarean section with a complicated post‐partum course. She and the infant were discharged in stable condition after long hospital stays. Prior publications describing VV‐ECMO use in pregnancy are limited to treatment of respiratory infections such as influenza or pneumonia. This case is the first in the literature to describe VV‐ECMO utilization for hemoptysis in pregnancy, specifically, and demonstrates its significant benefit in cases of respiratory failure due to hemoptysis. [ABSTRACT FROM AUTHOR]

The role of phonics instruction in early reading development has been the subject of significant conjecture. Recently, England implemented a phonics screening check to assess the phonetic decoding of 6‐year‐old students, to ensure that all students master this foundational literacy skill and attain adequate phonemic awareness in the early years of primary schooling. Students who fail this check are obliged to retake the assessment the following year. In this article, we compare the performance of students who initially pass this check (pass) and students who fail the original assessment but pass the retaken assessment (fail–pass), with students who fail both the original and retaken assessments (fail–fail). Using data from the Key Stage 1 assessment of reading and the Progress in International Reading Literacy Study (PIRLS), we examined the reading comprehension performance of these students approximately 1 and 4 years after their first phonics screening. The results suggested that fail–pass students performed substantially better than fail–fail students, even after performance on the initial phonics check was controlled for. While fail–pass students do not appear to entirely catch up with pass students in reading comprehension, their relatively better performance underscores the importance of intervening for those students who are identified as having problems with phonetic decoding to increase their likelihood of success at reading comprehension in later schooling. [ABSTRACT FROM AUTHOR]

Background: With the rapidly increasing size of the dementia population, it is important to get a better understanding of the similarities and differences that are found across the people living with dementia. This work expands on the first report from the Landmark Study and takes a closer look at the many faces of dementia in Canada by highlighting some of the diversity that is found within the national projections for dementia. Method: Using the Canadian Centre for Economic Analysis's socio‐economic statistical analysis platform, a simulation model was developed using demographic characteristics and risk factors for dementia to forecast the numbers of people living with dementia in Canada from 2020‐2050. Here, we will examine findings related to sex, Indigenous Peoples, ethnic origins, and young‐onset dementia. Result: In 2020, 61.3% of dementia diagnoses were in females and this sex ratio is projected to stay relatively constant over the three decades. By 2050, 1.08 million females and 637,000 males are projected to be living with dementia. For Indigenous Peoples of Canada, dementia numbers are estimated to increase by 273% (2020: 10,800; 2050: 40,300). By 2050, the ethnic background of people living with dementia will be quite different than today. People of Asian origin will increase from 8% of people living with dementia in 2020 to 24% by 2050. The changes are driven both by future immigration, and by people who have already immigrated to Canada in the past few decades. While most cases of dementia are found in older age groups, by 2050, the Landmark Study projects that there could be over 40,000 people under the age of 65 living with dementia in Canada, compared to the 28,000 in 2020. Conclusion: This study illustrates the changing landscape of dementia in Canada. The characteristics examined in this study, as well as other distinctions between people, can profoundly affect the way in which dementia is experienced and their care needs. When it comes to these differences, we propose that the best way forward is to examine them, generate evidence, listen closely to the recommendations that come from these communities, and collectively advocate for systemic change. [ABSTRACT FROM AUTHOR]

B Introduction: b CD19 CAR T-cell therapy (CD19 CTCT) is now the standard of care for many patients (pts) with relapsed/refractory large cell lymphoma (LCL), but nearly two-thirds of patients will still progress. Relapsed disease post CD19 CTCT is poorly responsive to subsequent therapies, and patient survival is dismal. SWOG 2114: A RANDOMIZED PHASE II TRIAL OF CONSOLIDATION THERAPY FOLLOWING CD19 CAR T-CELL TREATMENT FOR RELAPSED/REFRACTORY LARGE B-CELL OR GRADE IIIB FOLLICULAR LYMPHOMA. [Extracted from the article]

For pts with 1 prior therapy ( I n i = 10), the CR/CRi rate was 90% (95% CI, 55-100) and for pts with >=2 prior therapies ( I n i = 45), the CR/CRi rate was 67% (95% CI, 51-80); medians (95% CI) for OS were not reached (NR; 2.1-NE) and 25.6 mo (14.2-38.9), respectively. 3-Year outcomes of adults with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexu-cel in ZUMA-3 by age, prior therapies, and subsequent transplant B Background: b Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the US for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and in the EU for adults >=26 years with R/R B-ALL based on positive results of ZUMA-3. [Extracted from the article]

Background: Obesity presents a unique challenge in caring for surgical patients and has been shown to adversely affect outcomes for several operative procedures. However, quantitative data on surgical resource utilization attributable to obesity are scarce. The aim of this study was to quantify day-of-surgery resource utilization by degree of obesity.Methods: Patients undergoing one of 14 common surgical procedures at our multicenter institution between 2008 and 2017 were identified from our operating room management databank. Multiple-variable regression analysis (MVRA) was performed to quantify the independent effect of body mass index (BMI) category on day-of-surgery resource utilization variables including procedure time, non-operative OR time, PACU time, number of unique staff and number of supplies used. Trends in mean BMI were examined for each procedure studied.Results: MVRA of the 189,264 cases in the database revealed consistently significant (p < 0.05) stepwise increase in procedure time by BMI category for all procedures studied. Non-operative OR time was also significantly prolonged, though to a lesser degree. There was no significant impact on number of unique staff, supplies utilized or PACU time by BMI category. Procedures most impacted by BMI category in terms of resource utilization were ventral hernia repair, laminectomy and hysterectomy.Conclusion: Our study quantified day-of-surgery resource utilization for 14 major surgical procedures by BMI category. The need for additional resources to accommodate patients in higher BMI groups was consistent across all procedures studied and was primarily reflected by lengthened operative times. [ABSTRACT FROM AUTHOR]

Background: Telomerase activity in leukemic blasts frequently is increased among patients with high-risk acute myeloid leukemia (AML). In the current study, the authors evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in adult patients with AML.Methods: hTERT-DCs were produced from patient-specific leukapheresis, electroporated with an mRNA-encoding hTERT and a lysosomal-targeting sequence, and cryopreserved. A total of 22 patients with a median age of 58 years (range, 30-75 years) with intermediate-risk or high-risk AML in first or second complete remission (CR) were enrolled. hTERT-DCs were generated for 24 patients (73%). A median of 17 intradermal vaccinations (range, 6-32 intradermal vaccinations) containing 1×107 cells were administered as 6 weekly injections followed by 6 biweekly injections. A total of 21 patients (16 in first CR, 3 in second CR, and 2 with early disease recurrence) received hTERT-DCs.Results: hTERT-DCs were well tolerated with no severe toxicities reported, with the exception of 1 patient who developed idiopathic thrombocytopenic purpura. Of the 19 patients receiving hTERT-DCs in CR, 11 patients (58%) developed hTERT-specific T-cell responses that primarily were targeted toward hTERT peptides with predicted low human leukocyte antigen (HLA)-binding affinities. With a median follow-up of 52 months, 58% of patients in CR (11 of 19 patients) were free of disease recurrence at the time of their last follow-up visit; 57% of the patients who were aged ≥60 years (4 of 7 patients) also were found to be free of disease recurrence at a median follow-up of 54 months.Conclusions: The generation of hTERT-DCs is feasible and vaccination with hTERT-DCs appears to be safe and may be associated with favorable recurrence-free survival. Cancer 2017;123:3061-72. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Brentuximab vedotin ( BV) significantly improved progression-free survival in a phase 3 study in patients with relapsed or refractory Hodgkin lymphoma ( RR- HL) post-autologous-haematopoietic stem cell transplant (auto-HSCT); we report the impact of BV on quality of life ( QOL) from this trial. The European Quality of Life five dimensions questionnaire was administered at the beginning of each cycle, end of treatment, and every 3 months during follow-up; index value scores were calculated using the time trade-off ( TTO) method for UK-weighted value sets. Questionnaire adherence during the trial was 87·5% ( N = 329). In an intent-to-treat analysis, compared with placebo, TTO scores in the BV arm did not exceed the minimally important difference ( MID) of 0·08 except at month 15 (−0·084; 95% confidence interval, −0·143 to −0·025). On-treatment index scores were similar between arms and did not reach the MID at any time point; mixed-effect modelling showed that BV treatment effect was not significant ( P = 0·2127). BV-associated peripheral neuropathy did not meaningfully impact QOL. Utility scores for patients who progressed declined compared with those who did not; TTO scores between these patients exceeded the MID beginning at month 15. In conclusion, QOL decreased modestly with BV consolidation treatment in patients with RR- HL at high risk of relapse after auto- HSCT. [ABSTRACT FROM AUTHOR]

Double hit lymphoma ( DHL) and double protein-expressing ( MYC, BCL2) lymphomas ( DPL) fare poorly with R- CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone); consolidative autologous stem cell transplant ( ASCT) may improve outcomes. S9704, a phase III randomized study of CHOP +/−R with or without ASCT enabled evaluation of intensive consolidation. Immunohistochemistry ( IHC) identified 27 of 198 patients (13·6%) with MYC overexpression; 20 (74%) harboured concurrent BCL2 overexpression. Four had DHL and 16 had DPL only. With median 127 months follow-up, there is a trend favouring outcomes after ASCT in DPL and MYC protein overexpressing patients, whereas all DHL patients have died irrespective of ASCT. [ABSTRACT FROM AUTHOR]

It was recently discovered that the NRAS isoform 5 (20 amino acids) is expressed in melanoma and results in a more aggressive cell phenotype. This novel isoform is responsible for increased phosphorylation of downstream targets such as AKT, MEK, and ERK as well as increased cellular proliferation. This structure report describes the NMR solution structure of NRAS isoform 5 to be used as a starting point to understand its biophysical interactions. The isoform is highly flexible in aqueous solution, but forms a helix-turn-coil structure in the presence of trifluoroethanol as determined by NMR and CD spectroscopy. [ABSTRACT FROM AUTHOR]

Though solar eclipses are traditionally thought of as astronomic events with no real bearing on society, in fact they do manage to influence processes of practical importance by affecting the energy conversion of photovoltaic systems. The main goal of this study is to explore what could have happened to the German power supply and its reliability during the partial solar eclipse on the 20th March 2015. Comparing results of a simulation with an ex post analysis shows that: 1.) the possible effects could be predicted very accurately, 2.) the electrical supply was not threatened during the solar eclipse and would not have been subject to problems, even in a worst-case scenario, 3.) the actual solar power gradients during the eclipse exceeded the maximum solar power gradients during normal operation observed in the past by at least a factor of two, and 4.) grid frequency analysis for the day of the solar eclipse shows that the maximum and minimum frequency values are well within manageable limits. [ABSTRACT FROM AUTHOR]

The International Prognostic Score ( IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma ( HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression ( FFP) and overall survival ( OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [ FFP ( P = 0·0001) and OS ( P < 0·0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned. [ABSTRACT FROM AUTHOR]

BACKGROUND Survival after surgical resection for pancreatic cancer remains poor. A subgroup of patients die early (<6 months), and understanding factors associated with early mortality may help to identify high-risk patients. The Khorana score has been shown to be associated with early mortality for patients with solid tumors. In the current study, the authors evaluated the role of this score and other prognostic variables in this setting. METHODS The current study was a cohort study of patients who underwent surgical resection for pancreatic cancer from January 2006 through June 2013. Baseline (diagnosis ±30 days) parameters were used to define patients as high risk (Khorana score ≥3). Statistically significant univariable associations and a priori prognostic variables were tested in multivariable models; adjusted hazard ratios (HR) were calculated. RESULTS The study population comprised 334 patients. The median age was 67 years, 50% of the study population was female, and 86% of the patients were white. The pancreatic head was the primary tumor site for 73% of patients; 67% of tumors were T3 and 63% were N1. The median Khorana score was 2; 152 patients (47%) were determined to be high risk. Adjunctive treatment included chemotherapy (70%) and radiotherapy (40%). The postoperative (30-day) mortality rate was 0.9%. The 6-month mortality rate for the entire cohort was 9.4%, with significantly higher rates observed for high-risk patients (13.4% vs 5.6%; P = .02). On multivariable analyses (examining a total of 326 patients), the Khorana score (HR for high risk, 2.31; P = .039) and elevated blood urea nitrogen (HR, 4.34; P<.001) were associated with early mortality. CONCLUSIONS Patients at high risk of early mortality after surgical resection of pancreatic adenocarcinoma can be identified using simple baseline clinical and laboratory parameters. Future studies should address preoperative interventions in these patients at high risk of early mortality. Cancer 2015;121:1779-1784. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Cosmetic, functional, and structural sequelae of scarring are innumerable, and measures exist to optimize and ultimately minimize these sequelae. To evaluate the innumerable methods available to decrease the cosmetic, functional, and structural repercussions of scarring, pub Med search of the English literature with key words scar, scar revision, scar prevention, scar treatment, scar remodeling, cicatrix, cicatrix treatment, and cicatrix remodeling was done. Original articles and reviews were examined and included. Seventy-nine manuscripts were reviewed. Techniques, comparisons, and results were reviewed and tabulated. Overall, though topical modalities are easier to use and are usually more attractive to the patient, the surgical approaches still prove to be superior and more reliable. However, advances in topical medications for scar modification are on the rise and a change towards medical treatment of scars may emerge as the next best approach. Comparison studies of the innumerable specific modalities for scar revision and prevention are impossible. Standardization of techniques is lacking. Scarring, the body's natural response to a wound, can create many adverse effects. At this point, the practice of sound, surgical fundamentals still trump the most advanced preventative methods and revision techniques. Advances in medical approaches are available, however, to assist the scarring process, which even the most advanced surgical fundamentals will ultimately lead to. Whether through newer topical therapies, light treatment, or classical surgical intervention, our treatment armamentarium of scars has expanded and will allow us to maximize scar prevention and to minimize scar morbidity. [ABSTRACT FROM AUTHOR]

Children's responses to bullying are context related; they will vary depending on the specific bullying episode. The aim of the present study was to explore whether children's responses to bullying vary depending on the gender of the bully and victim and the type of bullying portrayed. In total, 437 children aged 9-11 years from four primary schools in the UK took part in the study. Each child read a story about one child bullying another. There were 12 different versions of the story, varying the type of bullying (verbal, physical, or relational/indirect) and the gender of the bully and victim (i.e., male bully-female victim, female bully-male victim, male bully-male victim, female bully-female victim). Each child was randomly allocated to one of the 12 stories. After reading the story the children then responded to a series of questions to assess their perceptions of the victim and bully and situation. Overall females liked the bully more than males; females also reported liking the female victim more than the male victim and females were more likely than males to intervene with a female victim. The bullying was viewed as more serious, more sympathy was shown to the victim, and there was a greater likelihood of intervention when the incident involved a female bully. There was less liking for the bully if the situation involved a female victim of physical bullying. The findings are explained in terms of social identity theory and social norms about typical male and female behavior. Aggr. Behav. 40:359-368, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Anti-reflection (AR) coatings designed for glass and other rigid, inorganic substrates are commercially available; however, these inorganic AR coatings tend to crack or delaminate on flexible substrates. A polymeric film with a gradient refractive index (GRIN) profile would make an ideal AR coating for flexible substrates, but such coatings are challenging to fabricate using traditional, solution-based techniques. Emulsion-based resonant infrared, matrix-assisted pulsed laser evaporation (RIR-MAPLE) offers a straightforward approach to enabling the desired GRIN profile in polymeric materials. Two homopolymers (polystyrene (PS) and poly(methyl methacrylate) (PMMA)) are deposited as a blend and one component (PMMA) is dissolved, leaving behind a porous PS film. The porosity and refractive index (RI) are controlled by the volume ratio of the two homopolymers in the film. Structural and optical characterizations, as well as comparison to modeled optical properties, confirm that porous films fabricated from polymer blends deposited by RIR-MAPLE behave as effective media over most of the visible spectrum. While evidence for the partial collapse of the porous polymer networks is observed, the RI of the porous films is reduced from that of the bulk material. Importantly, these studies demonstrate that RIR-MAPLE should enable broadband, omnidirectional, polymeric AR coatings appropriate for flexible substrates. [ABSTRACT FROM AUTHOR]

Aim The ongoing evolution of treatment strategies for colorectal liver metastases necessarily requires all patients to be reviewed at some point by the specialist hepatobiliary unit. This process can be streamlined through close collaboration with the local colorectal multidisciplinary team ( MDT). The study was performed to see if a local colorectal MDT was able to make a correct decision regarding potential operability of liver metastases, by comparing its decision with that of two hepatobiliary surgeons in our referral centre. Method CT scans of 38 patients found to have liver metastases from colorectal cancer were anonymized and sent to two hepatobiliary surgeons in our cancer network. They classified them into three categories: R, resectable; C, chemotherapy to downsize then consider resection; U, unresectable. The results were then compared with the opinion of our colorectal MDT, made before the referral to the hepatobiliary surgeons. Results The two independent hepatobiliary surgeons agreed with each other on 35/38 (92%) of CT scans. Our colorectal MDT agreed with the hepatobiliary surgeons in 36/38 (95%) of cases. Only 9 (32%) of the 28 patients deemed suitable on the CT scan by the hepatobiliary surgeons actually had a liver resection. Conclusion The results show that a local colorectal MDT is able to make an accurate assessment of the operability of liver metastases. Patients deemed to be inoperable by the colorectal MDT could be 'fast-tracked' to the hepatobiliary MDT with review of imaging only, saving time and resources by avoiding referral of patients who are not suitable for liver resection. [ABSTRACT FROM AUTHOR]

Background Quantifying diagnostic transitions across development is needed to estimate the long-term burden of mental illness. This study estimated patterns of diagnostic transitions from childhood to adolescence and from adolescence to early adulthood. Methods Patterns of diagnostic transitions were estimated using data from three prospective, longitudinal studies involving close to 20,000 observations of 3,722 participants followed across multiple developmental periods covering ages 9-30. Common DSM psychiatric disorders were assessed in childhood (ages 9-12; two samples), adolescence (ages 13-18; three samples), and early adulthood (ages 19 to age 32; three samples) with structured psychiatric interviews and questionnaires. Results Having a disorder at an early period was associated with at least a threefold increase in odds for having a disorder at a later period. Homotypic and heterotypic transitions were observed for every disorder category. The strongest evidence of continuity was seen for behavioral disorders (particularly ADHD) with less evidence for emotional disorders such as depression and anxiety. Limited evidence was found in adjusted models for behavioral disorders predicting later emotional disorders. Adult substance disorders were preceded by behavioral disorders, but not anxiety or depression. Conclusions Having a disorder in childhood or adolescence is a potent risk factor for a range of psychiatric problems later in development. These findings provide further support for prevention and early life intervention efforts and suggest that treatment at younger ages, while justified in its own right, may also have potential to reduce the risk for disorders later in development. [ABSTRACT FROM AUTHOR]

There is a lack of contemporary prospective data examining the adriamycin, bleomycin, vinblastine, dacarbazine ( ABVD) and Stanford V ( SV; doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone) regimens in older Hodgkin lymphoma ( HL) patients. Forty-four advanced-stage, older HL patients (aged ≥60 years) were treated on the randomized study, E2496. Toxicities were mostly similar between chemotherapy regimens, although 24% of older patients developed bleomycin lung toxicity ( BLT), which occurred mainly with ABVD (91%). Further, the BLT-related mortality rate was 18%. The overall treatment-related mortality for older HL patients was 9% vs. 0·3% for patients aged <60 years ( P < 0·001). Among older patients, there were no survival differences between ABVD and SV. According to age, outcomes were significantly inferior for older versus younger patients (5-year failure-free survival: 48% vs. 74%, respectively, P = 0·002; 5-year overall survival: 58% and 90%, respectively, P < 0·0001), although time-to-progression ( TTP) was not significantly different (5-year TTP: 68% vs. 78%, respectively, P = 0·37). Furthermore, considering progression and death without progression as competing risks, the risk of progression was not different between older and younger HL patients (5 years: 30% and 23%, respectively, P = 0·30); however, the incidence of death without progression was significantly increased for older HL patients (22% vs. 9%, respectively, P < 0·0001). Altogether, the marked HL age-dependent survival differences appeared attributable primarily to non- HL events. [ABSTRACT FROM AUTHOR]

Translation errors and conceptual misunderstandings made by students translating among graphical, tabular, and symbolic representations of linear functions were examined. The study situated student errors in the context of the 'Translation-Verification Model' developed specifically for the purpose of explaining student behavior during the process of translating relationships from one mathematical representation to another. Three distinct error types were identified to explain student performance. An examination of the error types revealed that specific translation errors tend to occur at different stages of the translation process. Translation errors are also related to 'attribute density,' the amount of information inherently encoded in a given representation. The findings of the study have implications for teaching linear relationships-student weaknesses and strengths are identified. [ABSTRACT FROM AUTHOR]

Background Nonalcoholic steatohepatitis ( NASH), the most severe form of nonalcoholic fatty liver disease ( NAFLD), is associated with inflammation and increased oxidative stress. The neutrophil/lymphocyte ratio ( N/L) integrates information on the inflammatory milieu and physiological stress. Aims The aim of this study was to determine the utility of N/L ratio to predict the presence of NASH in patients with NAFLD. Methods Our cohort consisted of 101 consecutive patients undergoing liver biopsy for clinical suspicion of NAFLD. Patients were divided into two groups: NASH group ( n = 50) and not NASH group ( n = 51). The stage of fibrosis was measured using a 4-point scale. The total white cell count, neutrophil and lymphocyte counts were recorded, and the N/L ratio was calculated. Results The mean age was 49.5 (±10.8) years and the mean BMI was 31.4 (±4.9) kg/m2. Patients with NASH had a higher N/L ratio compared with patients with not NASH [2.5 (1.9-3.3) and 1.6 (1.2-2.0), respectively, P < 0.001]. The N/L ratio correlated with the NAFLD activity score and its individual components (steatosis, inflammation and ballooning P < 0.001). Patients with advanced fibrosis (F3-4) had an elevated N/L ratio [2.9 (2.0-3.9)] compared with patients with fibrosis stage 1-2 [1.8 (1.2-2.2)], P < 0.001. For each one-unit increase in N/L ratio, the likelihood of having NASH increased by 70% and the likelihood of having fibrosis increased by 50%. Conclusion The N/L ratio is higher in patients with NASH and advanced fibrosis. This ratio can be used as a novel noninvasive marker to predict advanced disease. [ABSTRACT FROM AUTHOR]

Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty-seven patients were treated. The median age was 41 years, 44% of patients were either in ≥2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing. [ABSTRACT FROM AUTHOR]

CCR9 has been identified on T cells as a chemokine receptor that directs these cells to migrate to the intestine. CCR9 has also been reported on different cell types in the intestine, thymus, liver and peripheral blood. Little is reported concerning the presence of or functional implications of this chemokine receptor on myeloid dendritic cells (DC). In the host, DC encounter a multiplicity of antigenic stimuli to which they mount immune responses. In addition to intracellular and functional changes on sensing antigen, maturation of DC is typically reflected in the up-regulation of costimulatory molecules on DC. However, alterations in other surface markers may also be an indicator of DC activation. Using bone marrow-propagated DC these studies investigated cellular maturation in the presence of microbial stimuli and analyzed the relationship of CCR9 expression with DC maturation. Fractionation of DC into CCR9high and CCR9lowsubsets revealed a distinct ability of each subset to induce division in naïve CD4+ T cells. Our results suggest that DC expressing high levels of CCR9 are less activated/mature than DC expressing low levels of CCR9. [ABSTRACT FROM AUTHOR]

Transient transaminitis has been identified following laparoscopic abdominal surgery. However, the importance of posture, duration of surgery, and mechanical retraction in its etiology remain unclear. Liver function was assessed preoperatively then at 8, 24, 48 and 72 h following laparoscopic surgery including the following procedures: Nissen fundoplication (LN: n = 10); cholecystectomy (LC: n = 10); inguinal herniorrhaphy (LH: n = 10); and gastrectomy (LG: n = 5). Aspartate aminotransferase (AST) levels in LN patients exhibited a rapid rise within 8 h, peaking at 48 h before returning toward baseline. In the LN group, AST levels were significantly higher at 8 h and 24 hours compared to all other groups and compared to LG at 48 h and 72 h. At 6-week follow-up all AST levels were normal. No significant differences were seen in other hepatic parameters, and no correlation between AST and duration of operation, gender, or age was identified. Antireflux surgery is associated with transaminitis related to hepatic retraction, which is independent of patient posture or duration of observation, and it resolves spontaneously with no clinical consequences. [ABSTRACT FROM AUTHOR]

Abstract: Rb/E2F regulates many genes that encode proteins required for the cell cycle. Using affymetrix microarrays we previously identified genes regulated by the Rb proteins p130 and p107, many of which are involved in the cell cycle. Several genes with unknown functions were also repressed by p130 and p107, of which some have recently been found to have various roles in mitosis, the spindle checkpoint and cytokinesis. This study focuses on the regulation of borealin/dasra/cdca8, which encodes a recently discovered member of the chromosomal passenger complex. It is recorded that borealin is a cell cycle regulator, down-regulated in response to p53/Rb-signaling, and up-regulated in many types of cancerous tissues. [Copyright &y& Elsevier]

We describe the clinical courses of 3 patients with hematologic malignancies (2 with acute myelogenous leukemia and 1 with multiple myeloma) who developed invasive fungal infections due to uncommon molds ( Alternaria spp., Paecilomyces lilacinus, and Zygomycetes). Breakthrough invasive fungal infections of the sinus ( n=1), lung ( n=3), and pericardium ( n=1) developed despite fluconazole prophylaxis and failed to respond to treatment with other licensed antifungal therapies, including amphotericin B ( n=3), caspofungin ( n=2), and voriconazole ( n=3), and surgical intervention ( n=2). Salvage therapy with posaconazole oral suspension resulted in successful outcomes in all 3 patients, who subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) while on continued posaconazole therapy. The median duration of posaconazole treatment before HSCT was 5 months (range: 1.5–6 months). Posaconazole salvage therapy allowed successful allogeneic HSCT in 3 patients with refractory invasive mold infections. [ABSTRACT FROM AUTHOR]

The phosphatidyl inositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) regulate parallel damage response signalling pathways. ATM is reported to be activated by DNA double-strand breaks (DSBs), whereas ATR is recruited to single-stranded regions of DNA. Although the two pathways were considered to function independently, recent studies have demonstrated that ATM functions upstream of ATR following exposure to ionising radiation (IR) in S/G2. Here, we show that ATM phosphorylation at Ser1981, a characterised autophosphorylation site, is ATR-dependent and ATM-independent following replication fork stalling or UV treatment. In contrast to IR-induced ATM-S1981 phosphorylation, UV-induced ATM-S1981 phosphorylation does not require the Nbs1 C-terminus or Mre11. ATR-dependent phosphorylation of ATM activates ATM phosphorylation of Chk2, which has an overlapping function with Chk1 in regulating G2/M checkpoint arrest. Our findings provide insight into the interplay between the PIKK damage response pathways. [ABSTRACT FROM AUTHOR]

Nijmegen breakage syndrome (NBS) is characterised by microcephaly, developmental delay, characteristic facial features, immunodeficiency and radiosensitivity. Nbs1, the protein defective in NBS, functions in ataxia telangiectasia mutated protein (ATM)-dependent signalling likely facilitating ATM phosphorylation events. While NBS shares overlapping characteristics with ataxia telangiectasia, it also has features overlapping with ATR-Seckel (ATR: ataxia-telangiectasia and Rad3-related protein) syndrome, a subclass of Seckel syndrome mutated in ATR. We show that Nbs1 also facilitates ATR-dependent phosphorylation. NBS cell lines show a similar defect in ATR phosphorylation of Chk1, c-jun and p-53 in response to UV irradiation- and hydroxyurea (HU)-induced replication stalling. They are also impaired in ubiquitination of FANCD2 after HU treatment, which is ATR dependent. Following HU-induced replication arrest, NBS and ATR-Seckel cells show similarly impaired G2/M checkpoint arrest and an impaired ability to restart DNA synthesis at stalled replication forks. Moreover, NBS cells fail to retain ATR in the nucleus following HU treatment and extraction. Our findings suggest that Nbs1 functions in both ATR- and ATM-dependent signalling. We propose that the NBS clinical features represent the result of these combined defects. [ABSTRACT FROM AUTHOR]

Both single and tandem cycles of high dose therapy and autologous peripheral blood stem cell transplantation (ASCT) have been shown to improve survival in multiple myeloma (MM) patients. We report outcomes in 104 MM patients undergoing a single transplant after conditioning with a conventional myeloablative regimen, busulphan and cyclophosphamide. The patients were either in a first (71%), or subsequent remission (29%). Peripheral blood stem cells were mobilized using cyclophosphamide and granulocyte colony stimulating factor. The conditioning regimen consisted of busulphan 0·85 mg/kg given orally every 6 h (16 doses) and cyclophosphamide 60 mg/kg/d given intravenously for 2 d. The entire conditioning, transplant and post-transplant course were in the outpatient setting for 45% patients. At a median follow-up of 26 months (range 2–98 months), the median overall and progression-free survival were 57 months [95% confidence interval (CI) 47–68] and 26 months (95% CI 20–32) respectively. Younger age and higher CD34+ cell dose infused were independently predictive of improved overall and progression-free survival. Busulphan and cyclophosphamide is an effective and well-tolerated preparative regimen for ASCT that can be given to MM patients in the outpatient setting. [ABSTRACT FROM AUTHOR]

Background: Upper gastrointestinal complications have historically resulted in considerable morbidity and mortality to renal transplant recipients. Over the last decade, antiulcer prophylaxis with proton-pump inhibitors and immunosuppression with tacrolimus-based regimes have been introduced. Little has been written about foregut complications after renal transplantation since the use of these agents. The aim of this study was to compare the frequency of upper gastrointestinal complications after renal transplantation in patients treated with (i) omeprazole vs. ranitidine, and (ii) tacrolimus vs. cyclosporin based immunosuppression. Methods: Information on 236 patients undergoing renal transplantation between January 1996 and December 1998 was collected prospectively onto a computerized database. Results: Overall, 20 patients (8%) developed upper gastrointestinal complications, opportunistic infections accounted for 9/20 (45%). No patient developed gastroduodenal ulceration, required laparotomy, suffered graft loss or died. There was no significant difference in the frequency of complications between patients that received antisecretory therapy with omeprazole (9/118, 8%) and those that received ranitidine (11/118, 9%), nor between those that were on tacrolimus (7/101, 7%) and those on cyclosporin (13/135, 10%) based immunosuppression regimes. Patients that developed foregut complications were significantly older than those not developing complications (mean age 50 vs. 43 yrs, p=0.05). Further, patients that developed opportunistic infections were more frequently diabetic than those in whom opportunistic infections were not seen (4/31, 13% vs. 5/205, 2%), p=0.02. Conclusions: We observed a low frequency (8%) of upper gastrointestinal tract complications after renal transplantation. There was no difference in the frequency of complications between patients on tacrolimus and those on cyclosporin based immunosuppression. Furthermore, the complication rates were... [ABSTRACT FROM AUTHOR]

The term evaluation has taken on multiple definitions, depending on the perspective of the organization. The concept of evaluation reached a new level of importance in the legislative/regulatory process following the perceived excesses of executive power in the Vietnam conflict and Watergate affair. As a consequence, a program evaluation component was included in many programs, particularly social programs. This movement toward more systematic evaluation of programs came to the U.S. Federal Trade Commission (FTC) in 1975 with the FTC improvements Act, PL 93-637. The Act required that proposed Commission Trade Rules contain a statement as to the economic effect of the rule, taking into account the effect on small business and consumers.

Innovative methods to attract legal services clients and produce legal services introduced during the 1970s have raised questions about the possible harmful effects of these innovations on consumers who may receive lower quality legal services. This paper discusses the issues involved in the definition of quality and argues that the focus should be on the quality of outcomes as judged from the perspective of the consumer the service The limited research on the evaluation of legal quality is reviewed, and research design issues for the measurement of outcome quality are discussed. The focus of this discussion is on routine legal services. [ABSTRACT FROM AUTHOR]