Enhanced Engraftment of a Very Low-Dose Cord Blood Unit in an Adult Haemopoietic Transplant by Addition of Six Mismatched Viable Cord Units

The report describes the feasibility of the addition of multiple viable HLA-mismatched unrelated cord blood units, to a low cell number matched unrelated cord, to assist clinical engraftment. An ablative stem cell transplant was performed in an adult with relapsed acute lymphoblastic leukaemia (ALL), using a single HLA-matched cord blood unit (mononuclear cell dose 0.8 × 107), supported by six mismatched cord blood units (one unit per 10 kg recipient weight). No adverse reaction occurred following the infusion of mismatched units and engraftment of the suboptimal-dose matched unit occurred rapidly, with no molecular evidence of engraftment of mismatched cords. Early molecular remission of ALL was demonstrated using a novel PCR for a mitochondrial DNA mutation in the leukaemic clone. The cell dose of the matched cord was well below that recommended to engraft a 70 kg recipient. We suggest that a factor or factors in the mismatched cords enhanced/supported engraftment of the matched cord

Pharmacological targeting of cognitive impairment in depression: recent developments and challenges in human clinical research

Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death

Pathways to prevention: protocol for the CAP (Climate and Preventure) study to evaluate the long-term effectiveness of school-based universal, selective and combined alcohol misuse prevention into early adulthood

Background: Alcohol use and associated harms are among the leading causes of burden of disease among young people, highlighting the need for effective prevention. The Climate and Preventure (CAP) study was the first trial of a combined universal and selective school-based approach to preventing alcohol misuse among adolescents. Initial results indicate that universal, selective and combined prevention were all effective in delaying the uptake of alcohol use and binge drinking for up to 3 years following the interventions. However, little is known about the sustainability of prevention effects across the transition to early adulthood, a period of increased exposure to alcohol and other drug use. This paper describes the protocol for the CAP long-term follow-up study which will determine the effectiveness of universal, selective and combined alcohol misuse prevention up to 7 years post intervention, and across the transition from adolescence into early adulthood. Methods: A cluster randomized controlled trial was conducted between 2012 and 2015 with 2190 students (mean age: 13.3 yrs) from 26 Australian high schools. Participants were randomized to receive one of four conditions; universal prevention for all students (Climate); selective prevention for high-risk students (Preventure); combined universal and selective prevention (Climate and Preventure; CAP); or health education as usual (Control). The positive effect of the interventions on alcohol use at 12-, 24- and 36-month post baseline have previously been reported. This study will follow up the CAP study cohort approximately 5- and 7-years post baseline. The primary outcome will be alcohol use and related harms. Secondary outcomes will be cannabis use, alcohol and other drug harms including violent behavior, and mental health symptomatology. Analyses will be conducted using multi-level, mixed effects models within an intention-to-treat framework. Discussion: This study will provide the first ever evaluation of the long-term effectiveness of combining universal and selective approaches to alcohol prevention and will examine the durability of intervention effects into the longer-term, over a 7-year period from adolescence to early adulthood

Antiandrogen withdrawal in castrate-refractory prostate cancer

BACKGROUND. Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial. METHODS. Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration. RESULTS. A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of ≥50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response. CONCLUSIONS. These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (≥1 year) in approximately 19% of patients. Cancer 2008. © 2008 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58635/1/23473_ftp.pd

Weight management interventions in adults with intellectual disabilities and obesity: a systematic review of the evidence

o evaluate the clinical effectiveness of weight management interventions in adults with intellectual disabilities (ID) and obesity using recommendations from current clinical guidelines for the first line management of obesity in adults. Full papers on lifestyle modification interventions published between 1982 to 2011 were sought by searching the Medline, Embase, PsycINFO and CINAHL databases. Studies were evaluated based on 1) intervention components, 2) methodology, 3) attrition rate 4) reported weight loss and 5) duration of follow up. Twenty two studies met the inclusion criteria. The interventions were classified according to inclusion of the following components: behaviour change alone, behaviour change plus physical activity, dietary advice or physical activity alone, dietary plus physical activity advice and multi-component (all three components). The majority of the studies had the same methodological limitations: no sample size justification, small heterogeneous samples, no information on randomisation methodologies. Eight studies were classified as multi-component interventions, of which one study used a 600 kilocalorie (2510 kilojoule) daily energy deficit diet. Study durations were mostly below the duration recommended in clinical guidelines and varied widely. No study included an exercise program promoting 225–300 minutes or more of moderate intensity physical activity per week but the majority of the studies used the same behaviour change techniques. Three studies reported clinically significant weight loss (&#8805; 5%) at six months post intervention. Current data indicate weight management interventions in those with ID differ from recommended practice and further studies to examine the effectiveness of multi-component weight management interventions for adults with ID and obesity are justified

Less than 10 percent of star formation in z=0.6 massive galaxies is triggered by major interactions

Both observations and simulations show that major tidal interactions or mergers between gas-rich galaxies can lead to intense bursts of starformation. Yet, the average enhancement in star formation rate (SFR) in major mergers and the contribution of such events to the cosmic SFR are not well estimated. Here we use photometric redshifts, stellar masses and UV SFRs from COMBO-17, 24 micron SFRs from Spitzer and morphologies from two deep HST cosmological survey fields (ECDFS/GEMS and A901/STAGES) to study the enhancement in SFR as a function of projected galaxy separation. We apply two-point projected correlation function techniques, which we augment with morphologically-selected very close pairs (separation <2 arcsec) and merger remnants from the HST imaging. Our analysis confirms that the most intensely star-forming systems are indeed interacting or merging. Yet, for massive (M* > 10^10 Msun) star-forming galaxies at 0.4<z<0.8, we find that the SFRs of galaxies undergoing a major interaction (mass ratios <1:4 and separations < 40 kpc) are only 1.80 +/- 0.30 times higher than the SFRs of non-interacting galaxies when averaged over all interactions and all stages of the interaction, in good agreement with other observational works. We demonstrate that these results imply that <10% of star formation at 0.4 < z < 0.8 is triggered directly by major mergers and interactions; these events are not important factors in the build-up of stellar mass since z=1.Comment: Submitted to ApJ. 41 pages, 11 figure

Extragalactic Results from the Infrared Space Observatory

More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 micron band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy and spectro-photometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far- IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.Comment: 106 pages, including 17 figures. Ann.Rev.Astron.Astrophys. (in press), a gzip'd pdf file (667kB) is also available at http://www.mpe.mpg.de/www_ir/preprint/annrev2000.pdf.g

Effects of Mindfulness-Based Cognitive Therapy on Specificity of Life Goals

This study explored the immediate effects of a course of Mindfulness-Based Cognitive Therapy (MBCT) for chronically depressed participants with a history of suicidality on the specificity of important goals for the future. Participants were randomly allocated to immediate treatment with MBCT or to a waitlist condition and life goals were assessed both before and after the treatment or waiting period. Results showed that participants receiving MBCT reported significantly more specific goals post-treatment whereas those allocated to the waitlist condition showed no significant change. Similarly, participants allocated to MBCT regarded themselves as significantly more likely to achieve their important goals post-treatment, whilst again there was no significant change in the waitlist group. Increases in goal specificity were associated with parallel increases in autobiographical memory specificity whereas increases in goal likelihood were associated with reductions in depressed mood. These results suggest that MBCT may enable participants to clarify their important goals and in doing so increase their confidence in their capacity to move in valued life directions

A Phase II Trial of Pyrazine Diazohydroxide in Patients with Disseminated Malignant Melanoma and no Prior Chemotherapy – Southwest Oncology Group Study

Malignant melanoma is rapidly increasing inthe United States. Metastatic diseaseresponds poorly to currently availablechemotherapy. Pyrazine diazohydroxide(PZDH) is a new agent inhibiting DNAsynthesis that is active in mouse tumormodels and human xenografts and lackscross resistance withmultiple standard agents. In this phase IItrial, patients with no prior chemotherapyor immunotherapyfor metastatic disease and performancestatus (SWOG) of 0–1, were treated withpyrazine diazohydroxide at a dose of 100 mg/m 2 /day by IV bolus injectionover 5–15 minutes for 5 consecutive daysevery 6 weeks. There were 23 eligiblepatients entered on this trial with 74%having PS of 0 and 91% having visceralmetastases. There were no confirmed anti-tumor responses. Theoverall response rate is 0% (95% CI 0%–15%). Median overall survival is sixmonths (95% CI 5-8months). The most common toxicities were hematologic and consisted of lymphopenia,thrombocytopenia, anemia, and leukopenia. Fatigue, and nausea and vomiting were thenext mostcommon toxicities. Pyrazine diazohydroxideby this dose and schedule has insufficientactivity in thetreatment of disseminated malignantmelanoma to warrant further investigation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45216/1/10637_2004_Article_390690.pd