Long-term changes in nutritional status and body composition in patients with malignant pancreatic disease - A systematic review.

BACKGROUND AND AIMS: Patients with pancreatic cancer often experience significant deterioration in nutritional status over time. Malnutrition is complex and multifactorial, with malabsorption, pain, toxic dependencies, co-morbidities and malignant processes all playing a role. The aims of this systematic review were to assess nutritional changes over time and identify tolerance of nutritional intervention, thus identifying potential areas for further research to improve patient outcomes. MATERIALS AND METHODS: A systematic review of MEDLINE, EMBASE and PubMed was carried out in February 2020, identifying 2620 articles. After screening to exclude those reporting short-term measures, with only one data point, or in the wrong population, thirteen papers were selected for analysis (four trials in neo-adjuvant treatment, five in populations undergoing palliative treatment for pancreatic cancer, and four in mixed populations undergoing pancreatic resection). RESULTS: Overall, studies were limited by predominantly retrospective designs, and poor control of potentially confounding variables. Meta-analysis could not be performed due to heterogenicity in study design and reporting methods. Surgery in mixed cohorts did not appear to result in weight loss. Only one small intervention study was identified. Patients with pancreatic cancer experienced a decline in nutritional status, with 44-63% of patients undergoing neoadjuvant chemotherapy having low muscle mass prior to starting treatment. CONCLUSION: There is a paucity of data regarding nutritional intervention in pancreatic cancer. Future work should include the use of validated functional and clinical assessment tools to further explore the impact of nutritional intervention, and the relationship between nutritional status and outcome.

A systematic review of droplet and aerosol generation in dentistry.

OBJECTIVES: This review aimed to identify which dental procedures generate droplets and aerosols with subsequent contamination, and for these, characterise their pattern, spread and settle. DATA RESOURCES: Medline(OVID), Embase(OVID), Cochrane Central Register of Controlled Trials, Scopus, Web of Science and LILACS databases were searched for eligible studies from each database's inception to May 2020 (search updated 11/08/20). Studies investigating clinical dental activities that generate aerosol using duplicate independent screening. Data extraction by one reviewer and verified by another. Risk of bias assessed through contamination measurement tool sensitivity assessment. STUDY SELECTION: A total eighty-three studies met the inclusion criteria and covered: ultrasonic scaling (USS, n = 44), highspeed air-rotor (HSAR, n = 31); oral surgery (n = 11), slow-speed handpiece (n = 4); air-water (triple) syringe (n = 4), air-polishing (n = 4), prophylaxis (n = 2) and hand-scaling (n = 2). Although no studies investigated respiratory viruses, those on bacteria, blood-splatter and aerosol showed activities using powered devices produced greatest contamination. Contamination was found for all activities, and at the furthest points studied. The operator's torso, operator's arm and patient's body were especially affected. Heterogeneity precluded inter-study comparisons but intra-study comparisons allowed construction of a proposed hierarchy of procedure contamination risk: higher (USS, HSAR, air-water syringe, air polishing, extractions using motorised handpieces); moderate (slow-speed handpieces, prophylaxis, extractions) and lower (air-water syringe [water only] and hand scaling). CONCLUSION: Gaps in evidence, low sensitivity of measures and variable quality limit conclusions around contamination for procedures. A hierarchy of contamination from procedures is proposed for challenge/verification by future research which should consider standardised methodologies to facilitate research synthesis. CLINICAL SIGNIFICANCE: This manuscript addresses uncertainty around aerosol generating procedures (AGPs) in dentistry. Findings indicate a continuum of procedure-related aerosol generation rather than the common binary AGP or non-AGP perspective. The findings inform discussion around AGPs and direct future research to support knowledge and decision making around COVID-19 and dental procedures.

A randomised controlled trial of the pectoral nerves-2 (PECS-2) block for radical mastectomy.

We randomly allocated 50 women scheduled for radical mastectomy to pectoral nerves-2 (PECS-2) block (n = 25) or no block (n = 25), 20 and 22 of whom we analysed for the primary outcome of a cumulative 24-h postoperative morphine dose. We gave intra-operative sufentanil, magnesium, dexamethasone and droperidol. Participants received regular postoperative paracetamol, ibuprofen and patient-controlled intravenous morphine. Pectoral nerves-2 block reduced mean (SD) cumulative 24 h postoperative morphine dose from 9.7 (8.9) mg to 5.0 (5.4) mg and 48 h morphine dose from 12.8 (12.5) mg to 6.0 (6.5) mg, p = 0.04 for both. The mean (SD) pain scores 24 h and 48 h after surgery were similar with or without block: 0.8 (1.4) vs. 1.2 (1.9), p = 0.39; and 0.2 (0.4) vs. 0.9 (1.8), p = 0.09, respectively. Rates of postoperative nausea, vomiting and pruritus were unaffected. Rates of chronic pain at six postoperative months were 2/19 and 2/18 after block and no block, respectively, p = 0.95.

Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men.

BACKGROUND & AIMS: Serum lipids and lipoproteins are established biomarkers of cardiovascular disease risk that could be influenced by impaired gut barrier function via effects on the absorption of dietary and biliary cholesterol. The aim of this study was to examine the potential relationship between gut barrier function (gut permeability) and concentration of serum lipids and lipoproteins, in an ancillary analysis of serum samples taken from a previous study. METHODS AND RESULTS: Serum lipids, lipoproteins and functional gut permeability, as assessed by the percentage of the urinary recovery of 51Cr-labelled EDTA absorbed within 24 h, were measured in a group of 30 healthy men. Serum lipopolysaccharide, high sensitivity C-reactive protein and interleukin-6 were also measured as markers of low-grade inflammation. The group expressed a 5-fold variation in total gut permeability (1.11-5.03%). Gut permeability was unrelated to the concentration of both serum total and low density lipoprotein (LDL)-cholesterol, but was positively associated with serum high density lipoprotein (HDL)-cholesterol (r = 0.434, P = 0.015). Serum HDL-cholesterol was also positively associated with serum endotoxaemia (r = 0.415, P = 0.023). CONCLUSION: The significant association between increased gut permeability and elevated serum HDL-cholesterol is consistent with the role of HDL as an acute phase reactant, and in this situation, potentially dysfunctional lipoprotein. This finding may have negative implications for the putative role of HDL as a cardio-protective lipoprotein.

Motivation for physical activity and the moderating effect of cancer diagnosis: A nationally representative cross-sectional study.

The aim of this study was to investigate associations between types of motivation for physical activity and self-reported weekly aerobic moderate-to-vigorous physical activity (MVPA) in the 2012 and 2014 waves of the nationally representative Health Information National Trends Survey 4 (n = 7307). We further explored differential associations between MVPA and types of motivation for physical activity by cancer survivor status. We found that those who were more motivated by "getting enjoyment from exercise" reported 26.4% more MVPA (+49.8 min/week) than those who were less motivated by this factor, adjusting for covariates (p = 0.025). Conversely, those who were more motivated by "concern over the way you look" reported 22.1% less MVPA (-55.5 min/week) than those who were less motivated by this factor, adjusting for covariates (p = 0.002). We found no evidence for a relationship between motivation from either "pressure from others" or "feeling guilty when you skip exercising" and MVPA. We identified a significant interaction for "feeling guilty when you skip exercising" and cancer survivor status, adjusting for covariates (p = 0.034). Cancer survivors who reported being more motivated by "feeling guilty when you skip exercising" reported 36.2% less MVPA (-71.75 min/week) than those who were less motivated by this factor; there was no statistically reliable difference in those without a history of cancer. Findings are concordant with previous literature highlighting the primacy of enjoyment for physical activity adherence. There is a need for further inquiry into guilt-related motivation for physical activity among cancer survivors, as it may have a unique, negative impact in this population.

Relationship of ECMO duration with outcomes after pediatric cardiac surgery: a multi-institutional analysis.

BACKGROUND: There are very sparse data on the outcomes of children receiving prolonged extracorporeal membrane oxygenation (ECMO) after cardiac surgery. This study was aimed to evaluate the association of ECMO duration with outcomes in children undergoing surgery for congenital heart disease using the Pediatric Health Information System (PHIS) database. METHODS: Patients aged ≤18 years receiving ECMO after pediatric cardiac surgery (with or without cardiopulmonary bypass) at a PHIS-participating hospital (2004-2013) were included. De-identified data obtained from retrospective, observational dataset included demographic information, baseline characteristics, pre-ECMO risk factors, operation details, patient diagnoses, and center data. Outcomes evaluated included in-hospital mortality, length of mechanical ventilation, length of ICU stay, length of hospital stay, and hospital charges. Cox proportional hazards models were fitted to study the probability of study outcomes as a function of ECMO duration. RESULTS: Nine hundred ninety-eight patients from 37 hospitals qualified for inclusion. The median duration of ECMO run was 4 days (IQR: 1.7). After adjusting for patient and center characteristics, there was 12% increase in the odds of mortality for every 24 hours increase in ECMO duration (OR: 1.12, 95% CI: 1.07-1.18, P<0.001). Patients receiving longer duration of ECMO were associated with longer length of mechanical ventilation, longer length of ICU stay, longer length of hospital stay, and higher hospital charges. CONCLUSION: Data from this large multicenter database suggest that longer duration of ECMO support after pediatric cardiac surgery is associated with worsening outcomes.

Increased intestinal permeability to oral chromium (51 Cr) -EDTA in human Type 2 diabetes.

OBJECTIVE: In animal models of obesity and Type 2 diabetes, permeability of the intestine is increased because of impairment of tight junction proteins, allowing translocation of bacterial endotoxin and resulting in low-grade systemic inflammation. This has yet to be demonstrated in humans. The objective of this study was the demonstration of increased intestinal permeability in human Type 2 diabetes. METHODS: We examined intestinal permeability using chromium ((51) Cr)-EDTA urinary recovery in twenty well-controlled men with Type 2 diabetes compared with control subjects matched for age, gender and BMI. RESULTS: Intestinal permeability was significantly increased (P = 0.002) in the diabetic group and was correlated to increased levels of systemic inflammatory markers high-sensitivity C-reactive protein (r = 0.694, P = 0.001), interleukin 6 (r = 0.548, P = 0.012) and tumour necrosis factor alpha (r = 0.564, P = 0.010). CONCLUSION: This is the first demonstration that increased intestinal permeability may be a feature of human Type 2 diabetes.

Interventions for preventing falls in older people in care facilities and hospitals.

BACKGROUND: Falls in care facilities and hospitals are common events that cause considerable morbidity and mortality for older people. This is an update of a review first published in 2010. OBJECTIVES: To assess the effectiveness of interventions designed to reduce falls by older people in care facilities and hospitals. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (March 2012); The Cochrane Library 2012, Issue 3; MEDLINE, EMBASE, and CINAHL (all to March 2012); ongoing trial registers (to August 2012), and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials of interventions to reduce falls in older people in residential or nursing care facilities or hospitals. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We used a rate ratio (RaR) and 95% confidence interval (CI) to compare the rate of falls (e.g. falls per person year) between intervention and control groups. For risk of falling we used a risk ratio (RR) and 95% CI based on the number of people falling (fallers) in each group. We pooled results where appropriate. MAIN RESULTS: We included 60 trials (60,345 participants), 43 trials (30,373 participants) in care facilities, and 17 (29,972 participants) in hospitals.Results from 13 trials testing exercise interventions in care facilities were inconsistent. Overall, there was no difference between intervention and control groups in rate of falls (RaR 1.03, 95% CI 0.81 to 1.31; 8 trials, 1844 participants) or risk of falling (RR 1.07, 95% CI 0.94 to 1.23; 8 trials, 1887 participants). Post hoc subgroup analysis by level of care suggested that exercise might reduce falls in people in intermediate level facilities, and increase falls in facilities providing high levels of nursing care.In care facilities, vitamin D supplementation reduced the rate of falls (RaR 0.63, 95% CI 0.46 to 0.86; 5 trials, 4603 participants), but not risk of falling (RR 0.99, 95% CI 0.90 to 1.08; 6 trials, 5186 participants).For multifactorial interventions in care facilities, the rate of falls (RaR 0.78, 95% CI 0.59 to 1.04; 7 trials, 2876 participants) and risk of falling (RR 0.89, 95% CI 0.77 to 1.02; 7 trials, 2632 participants) suggested possible benefits, but this evidence was not conclusive.In subacute wards in hospital, additional physiotherapy (supervised exercises) did not significantly reduce rate of falls (RaR 0.54, 95% CI 0.16 to 1.81; 1 trial, 54 participants) but achieved a significant reduction in risk of falling (RR 0.36, 95% CI 0.14 to 0.93; 2 trials, 83 participants).In one trial in a subacute ward (54 participants), carpet flooring significantly increased the rate of falls compared with vinyl flooring (RaR 14.73, 95% CI 1.88 to 115.35) and potentially increased the risk of falling (RR 8.33, 95% CI 0.95 to 73.37).One trial (1822 participants) testing an educational session by a trained research nurse targeting individual fall risk factors in patients at high risk of falling in acute medical wards achieved a significant reduction in risk of falling (RR 0.29, 95% CI 0.11 to 0.74).Overall, multifactorial interventions in hospitals reduced the rate of falls (RaR 0.69, 95% CI 0.49 to 0.96; 4 trials, 6478 participants) and risk of falling (RR 0.71, 95% CI 0.46 to 1.09; 3 trials, 4824 participants), although the evidence for risk of falling was inconclusive. Of these, one trial in a subacute setting reported the effect was not apparent until after 45 days in hospital. Multidisciplinary care in a geriatric ward after hip fracture surgery compared with usual care in an orthopaedic ward significantly reduced rate of falls (RaR 0.38, 95% CI 0.19 to 0.74; 1 trial, 199 participants) and risk of falling (RR 0.41, 95% CI 0.20 to 0.83). More trials are needed to confirm the effectiveness of multifactorial interventions in acute and subacute hospital settings. AUTHORS' CONCLUSIONS: In care facilities, vitamin D supplementation is effective in reducing the rate of falls. Exercise in subacute hospital settings appears effective but its effectiveness in care facilities remains uncertain due to conflicting results, possibly associated with differences in interventions and levels of dependency. There is evidence that multifactorial interventions reduce falls in hospitals but the evidence for risk of falling was inconclusive. Evidence for multifactorial interventions in care facilities suggests possible benefits, but this was inconclusive.

Interventions for preventing falls in older people living in the community.

BACKGROUND: Approximately 30% of people over 65 years of age living in the community fall each year. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To assess the effects of interventions designed to reduce the incidence of falls in older people living in the community. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (February 2012), CENTRAL (The Cochrane Library 2012, Issue 3), MEDLINE (1946 to March 2012), EMBASE (1947 to March 2012), CINAHL (1982 to February 2012), and online trial registers. SELECTION CRITERIA: Randomised trials of interventions to reduce falls in community-dwelling older people. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We used a rate ratio (RaR) and 95% confidence interval (CI) to compare the rate of falls (e.g. falls per person year) between intervention and control groups. For risk of falling, we used a risk ratio (RR) and 95% CI based on the number of people falling (fallers) in each group. We pooled data where appropriate. MAIN RESULTS: We included 159 trials with 79,193 participants. Most trials compared a fall prevention intervention with no intervention or an intervention not expected to reduce falls. The most common interventions tested were exercise as a single intervention (59 trials) and multifactorial programmes (40 trials). Sixty-two per cent (99/159) of trials were at low risk of bias for sequence generation, 60% for attrition bias for falls (66/110), 73% for attrition bias for fallers (96/131), and only 38% (60/159) for allocation concealment.Multiple-component group exercise significantly reduced rate of falls (RaR 0.71, 95% CI 0.63 to 0.82; 16 trials; 3622 participants) and risk of falling (RR 0.85, 95% CI 0.76 to 0.96; 22 trials; 5333 participants), as did multiple-component home-based exercise (RaR 0.68, 95% CI 0.58 to 0.80; seven trials; 951 participants and RR 0.78, 95% CI 0.64 to 0.94; six trials; 714 participants). For Tai Chi, the reduction in rate of falls bordered on statistical significance (RaR 0.72, 95% CI 0.52 to 1.00; five trials; 1563 participants) but Tai Chi did significantly reduce risk of falling (RR 0.71, 95% CI 0.57 to 0.87; six trials; 1625 participants).Multifactorial interventions, which include individual risk assessment, reduced rate of falls (RaR 0.76, 95% CI 0.67 to 0.86; 19 trials; 9503 participants), but not risk of falling (RR 0.93, 95% CI 0.86 to 1.02; 34 trials; 13,617 participants).Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment.Home safety assessment and modification interventions were effective in reducing rate of falls (RR 0.81, 95% CI 0.68 to 0.97; six trials; 4208 participants) and risk of falling (RR 0.88, 95% CI 0.80 to 0.96; seven trials; 4051 participants). These interventions were more effective in people at higher risk of falling, including those with severe visual impairment. Home safety interventions appear to be more effective when delivered by an occupational therapist.An intervention to treat vision problems (616 participants) resulted in a significant increase in the rate of falls (RaR 1.57, 95% CI 1.19 to 2.06) and risk of falling (RR 1.54, 95% CI 1.24 to 1.91). When regular wearers of multifocal glasses (597 participants) were given single lens glasses, all falls and outside falls were significantly reduced in the subgroup that regularly took part in outside activities. Conversely, there was a significant increase in outside falls in intervention group participants who took part in little outside activity.Pacemakers reduced rate of falls in people with carotid sinus hypersensitivity (RaR 0.73, 95% CI 0.57 to 0.93; three trials; 349 participants) but not risk of falling. First eye cataract surgery in women reduced rate of falls (RaR 0.66, 95% CI 0.45 to 0.95; one trial; 306 participants), but second eye cataract surgery did not.Gradual withdrawal of psychotropic medication reduced rate of falls (RaR 0.34, 95% CI 0.16 to 0.73; one trial; 93 participants), but not risk of falling. A prescribing modification programme for primary care physicians significantly reduced risk of falling (RR 0.61, 95% CI 0.41 to 0.91; one trial; 659 participants).An anti-slip shoe device reduced rate of falls in icy conditions (RaR 0.42, 95% CI 0.22 to 0.78; one trial; 109 participants). One trial (305 participants) comparing multifaceted podiatry including foot and ankle exercises with standard podiatry in people with disabling foot pain significantly reduced the rate of falls (RaR 0.64, 95% CI 0.45 to 0.91) but not the risk of falling.There is no evidence of effect for cognitive behavioural interventions on rate of falls (RaR 1.00, 95% CI 0.37 to 2.72; one trial; 120 participants) or risk of falling (RR 1.11, 95% CI 0.80 to 1.54; two trials; 350 participants).Trials testing interventions to increase knowledge/educate about fall prevention alone did not significantly reduce the rate of falls (RaR 0.33, 95% CI 0.09 to 1.20; one trial; 45 participants) or risk of falling (RR 0.88, 95% CI 0.75 to 1.03; four trials; 2555 participants).No conclusions can be drawn from the 47 trials reporting fall-related fractures.Thirteen trials provided a comprehensive economic evaluation. Three of these indicated cost savings for their interventions during the trial period: home-based exercise in over 80-year-olds, home safety assessment and modification in those with a previous fall, and one multifactorial programme targeting eight specific risk factors. AUTHORS' CONCLUSIONS: Group and home-based exercise programmes, and home safety interventions reduce rate of falls and risk of falling.Multifactorial assessment and intervention programmes reduce rate of falls but not risk of falling; Tai Chi reduces risk of falling.Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment.

Insulin-sensitizing effects on muscle and adipose tissue after dietary fiber intake in men and women with metabolic syndrome.

CONTEXT: Dietary fibers have been associated with a reduced incidence of type 2 diabetes mellitus in epidemiological studies; however, the precise mechanisms are unknown. OBJECTIVE: The objective of the study was to evaluate the efficacy and site of action of an insoluble dietary fiber derived from maize (HAM-RS2) in improving insulin resistance in subjects at increased risk of type 2 diabetes mellitus. DESIGN: This study was a randomized, controlled crossover, dietary intervention study. SETTING: The study was conducted at the Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. PARTICIPANTS: Fifteen men and women with insulin resistance participated in the study. INTERVENTION: The intervention included 40 g/d HAM-RS2 compared with a matched placebo for 8 wk. MAIN OUTCOME MEASURES: After each supplement, participants underwent a two-step hyperinsulinemic-euglycemic clamp study with the addition of glucose tracers; a meal tolerance test; arteriovenous sampling across forearm muscle tissue; and a sc adipose tissue biopsy for assessment of gene expression. RESULTS: There was enhanced uptake of glucose into the forearm muscle measured by arteriovenous sampling (65 ± 15% increase after resistant starch; P < 0.001). Adipose tissue function was also affected, with enhanced fatty acid suppression after HAM-RS2 treatment and an increase in gene expression for hormone sensitive lipase (P = 0.005), perilipin (P = 0.011), lipoprotein lipase (P = 0.014), and adipose triglyceride lipase (P = 0.03) in biopsy samples. There was no effect on the insulin sensitivity of hepatic glucose production or plasma lipids after HAM-RS2. CONCLUSION: HAM-RS2 improved peripheral but not hepatic insulin resistance and requires further study as an intervention in patients with or at risk for type 2 diabetes.

The AMPK stress response pathway mediates anoikis resistance through inhibition of mTOR and suppression of protein synthesis.

Suppression of anoikis after detachment of cancer cells from the extracellular matrix is a key step during metastasis. Here we show that, after detachment, mouse embryonic fibroblasts (MEFs) transformed by K-Ras(V12) or ETV6-NTRK3 (EN) activate a transcriptional response overrepresented by genes related to bioenergetic stress and the AMP-activated protein kinase (AMPK) energy-sensing pathway. Accordingly, AMPK is activated in both transformed and non-transformed cells after detachment, and AMPK deficiency restores anoikis to transformed MEFs. However, AMPK activation represses the mTOR complex-1 (mTORC1) pathway only in transformed cells, suggesting a key role for AMPK-mediated mTORC1 inhibition in the suppression of anoikis. Consistent with this, AMPK-/- MEFs transformed by EN or K-Ras show sustained mTORC1 activation after detachment and fail to suppress anoikis. Transformed TSC1-/- MEFs, which are incapable of suppressing mTORC1, also undergo anoikis after detachment, which is reversed by mTORC1 inhibitors. Furthermore, transformed AMPK-/- and TSC1-/- MEFs both have higher total protein synthesis rates than wild-type controls, and translation inhibition using cycloheximide partially restores their anoikis resistance, indicating a mechanism whereby mTORC1 inhibition suppresses anoikis. Finally, breast carcinoma cell lines show similar detachment-induced AMPK/mTORC1 activation and restoration of anoikis by AMPK inhibition. Our data implicate AMPK-mediated mTORC1 inhibition and suppression of protein synthesis as a means for bioenergetic conservation during detachment, thus promoting anoikis resistance.

An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: results from a randomized placebo-controlled trial (the Step study).

BACKGROUND: The Step study was a randomized trial to determine whether an adenovirus type 5 (Ad5) vector vaccine, which elicits T cell immunity, can lead to control of human immunodeficiency virus (HIV) replication in participants who became HIV-infected after vaccination. METHODS: We evaluated the effect of the vaccine on trends in HIV viral load, CD4+ T cell counts, time to initiation of antiretroviral therapy (ART), and AIDS-free survival in 87 male participants who became infected with HIV during the Step study and who had a median of 24 months of post-infection follow-up. RESULTS: There was no overall effect of vaccine on mean log(10) viral load (estimated difference between groups, -0.11; P = .47). In a subset of subjects with protective HLA types (B27, B57, B58), mean HIV-1 RNA level over time was lower among vaccine recipients. There was no significant difference in CD4+ T cell counts, time to ART initiation, or in AIDS-free survival between HIV-1-infected subjects who received vaccine versus those who received placebo. CONCLUSIONS: HIV RNA levels, CD4+ T cell counts, time to initiation of ART, and AIDS-free survival were similar in vaccine and placebo recipients. There may have been a favorable effect of vaccine on HIV-1 RNA levels in participants with HLA types associated with better control of HIV-1.

Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia.

We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days -6 to -3 and clofarabine 30-60 mg/m(2) per day on days -6 to -2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days -2 to +180). A total of 15 patients, median age 48 (30-58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m(2) per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3-4 non-hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33-86%), and the 1-year overall survival was 60% (95% confidence interval: 40-91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m(2) per day × 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia.

Interleukin-18: biology and role in the immunotherapy of cancer.

Interleukin-18 (IL-18) is an immunostimulatory cytokine belonging to the IL-1 family. IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells, T cells, and possibly other cell types. Systemic administration of IL-18 has been shown to have significant antitumor activity in several preclinical animal models. Phase I clinical trials of recombinant human IL-18 have demonstrated that it can be safely administered to patients with advanced cancer. Biologic effects of IL-18 therapy include activation of monocytes, NK cells, and T cells and production of IFN-γ as well as other cytokines in vivo. A phase II study of IL-18 in patients with metastatic melanoma confirmed its safety but suggested limited efficacy of IL-18 monotherapy in this setting. IL-18 appears to act predominantly as a costimulatory cytokine and its optimal use for cancer immunotherapy may be in combination with other immunostimulatory cytokines, vaccines, or monoclonal antibodies.

Outreach and screening following the 2005 London bombings: usage and outcomes.

BACKGROUND: Little is known about how to remedy the unmet mental health needs associated with major terrorist attacks, or what outcomes are achievable with evidence-based treatment. This article reports the usage, diagnoses and outcomes associated with the 2-year Trauma Response Programme (TRP) for those affected by the 2005 London bombings.MethodFollowing a systematic and coordinated programme of outreach, the contact details of 910 people were obtained by the TRP. Of these, 596 completed a screening instrument that included the Trauma Screening Questionnaire (TSQ) and items assessing other negative responses. Those scoring ≥6 on the TSQ, or endorsing other negative responses, received a detailed clinical assessment. Individuals judged to need treatment (n=217) received trauma-focused cognitive-behaviour therapy (TF-CBT) or eye movement desensitization and reprocessing (EMDR). Symptom levels were assessed pre- and post-treatment with validated self-report measures of post-traumatic stress disorder (PTSD) and depression, and 66 were followed up at 1 year. RESULTS: Case finding relied primarily on outreach rather than standard referral pathways such as primary care. The effect sizes achieved for treatment of DSM-IV PTSD exceeded those usually found in randomized controlled trials (RCTs) and gains were well maintained an average of 1 year later. CONCLUSIONS: Outreach with screening, linked to the provision of evidence-based treatment, seems to be a viable method of identifying and meeting mental health needs following a terrorist attack. Given the failure of normal care pathways, it is a potentially important approach that merits further evaluation.

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia.

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)+/-mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Improved outcomes in paediatric intestinal failure with aggressive prevention of liver disease.

BACKGROUND/PURPOSE: A protocol-driven care algorithm for the care of intestinal failure (IF) centred on therapies to prevent Parenteral Nutrition Associated Cholestasis (PNAC) was instituted in 2006. We report our results from 2006-2009, and compare them to the outcomes of our previous cohort of patients (1998-2006). METHODS: With regional ethics board approval, we have been prospectively gathering data on patient with IF cared for by our regional surgical unit. IF was defined as a residual bowel length of <40 cm or a requirement for PN for greater than 60 days. With the development of a multidisciplinary care team, a protocol-driven strategy to prevent PNAC was instituted in 2006, with aggressive introduction of enteral feeds, use of prophylactic antibiotics to prevent bacterial overgrowth, lipid reduction and use of a fish oil-derived lipid preparation for cholestasis and Serial Transverse Enteroplasty (STEP) if bowel dilation occurred. RESULTS: In the era from 1998-2006, 33 patients were identified, with a 72% survival; the direct bilirubin averaged 112+/-34 microM/L after 3 months of PN. 8/33 (27%) of patients received prophylactic antibiotics, and none received fish oil-based lipids. The most common causes of IF were gastroschisis (30%) and atresia (21%); 31 of 33 patients were infants. Average time to intestinal rehabilitation/death was 4.5+/-3 months. All deaths were related to sepsis or PN/liver failure. In the era from 2006-2009, 22 patients have been followed, with 100% survival*. Average bilirubin after 3 months of PN was 8+/-2.2 microM/L*, 20/22 (90%)* received prophylactic antibiotics, and 6/22(27%)* received fish oil-based lipid PN. The common causes of IF were gastroschisis 15/22 (68%) and atresia (27%). 18/22 are weaned from PN, and the average time to intestinal rehabilitation was 2.7+/-1.3 months, 4 patients underwent STEP procedures. (*p<0.05 by Fischer's exact or Student's t-test, data mean+/-SD). CONCLUSIONS: The institution of an aggressive protocol of advancing enteric feeds, oral antibiotic prophylaxis for bacterial overgrowth, fish oil-based lipid use, and the STEP procedure for dilated bowel has resulted in an apparent increase in survival and a remarkable improvement in liver function in a paediatric IF population. Further studies to define the relative importance of these therapies are recommended.

Thalamic deep brain stimulation for treatment-refractory Tourette syndrome: two-year outcome.

BACKGROUND: Eighteen patients with severe and refractory Tourette syndrome (TS) underwent bilateral thalamic deep brain stimulation (DBS). OBJECTIVE: To assess the long-term outcome on tics, behavioral symptoms, and cognitive functions in the largest case series of thalamic DBS for TS to date. METHODS: In this prospective cohort study, 15 of the original 18 patients were evaluated before and after surgery according to a standardized protocol that included both neuropsychiatric and neuropsychological assessments. RESULTS: In addition to marked reduction in tic severity (p = 0.001), 24-month follow-up ratings showed improvement in obsessive-compulsive symptoms (p = 0.009), anxiety symptoms (p = 0.001), depressive symptoms (p = 0.001), and subjective perception of social functioning/quality of life (p = 0.002) in 15 of 18 patients. There were no substantial differences on measures of cognitive functions before and after DBS. CONCLUSIONS: At 24-month follow-up, tic severity was improved in patients with intractable Tourette syndrome (TS) who underwent bilateral thalamic deep brain stimulation. Available data from 15 of 18 patients also showed that neuropsychiatric symptoms were improved and cognitive performances were not disadvantaged. Controlled studies on larger cohorts with blinded protocols are needed to verify that this procedure is effective and safe for selected patients with TS. LEVEL OF EVIDENCE: This study provides class IV evidence that bilateral thalamic deep brain stimulation reduces global tic severity measured 24 months after implantation in patients with severe intractable Tourette syndrome.

Interventions for preventing falls in older people living in the community.

BACKGROUND: Approximately 30% of people over 65 years of age living in the community fall each year. OBJECTIVES: To assess the effects of interventions to reduce the incidence of falls in older people living in the community. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE, EMBASE, CINAHL, and Current Controlled Trials (all to May 2008). SELECTION CRITERIA: Randomised trials of interventions to reduce falls in community-dwelling older people. Primary outcomes were rate of falls and risk of falling. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Data were pooled where appropriate. MAIN RESULTS: We included 111 trials (55,303 participants).Multiple-component group exercise reduced rate of falls and risk of falling (rate ratio (RaR) 0.78, 95%CI 0.71 to 0.86; risk ratio (RR) 0.83, 95%CI 0.72 to 0.97), as did Tai Chi (RaR 0.63, 95%CI 0.52 to 0.78; RR 0.65, 95%CI 0.51 to 0.82), and individually prescribed multiple-component home-based exercise (RaR 0.66, 95%CI 0.53 to 0.82; RR 0.77, 95%CI 0.61 to 0.97).Assessment and multifactorial intervention reduced rate of falls (RaR 0.75, 95%CI 0.65 to 0.86), but not risk of falling.Overall, vitamin D did not reduce falls (RaR 0.95, 95%CI 0.80 to 1.14; RR 0.96, 95%CI 0.92 to 1.01), but may do so in people with lower vitamin D levels. Overall, home safety interventions did not reduce falls (RaR 0.90, 95%CI 0.79 to 1.03); RR 0.89, 95%CI 0.80 to 1.00), but were effective in people with severe visual impairment, and in others at higher risk of falling. An anti-slip shoe device reduced rate of falls in icy conditions (RaR 0.42, 95%CI 0.22 to 0.78).Gradual withdrawal of psychotropic medication reduced rate of falls (RaR 0.34, 95%CI 0.16 to 0.73), but not risk of falling. A prescribing modification programme for primary care physicians significantly reduced risk of falling (RR 0.61, 95%CI 0.41 to 0.91).Pacemakers reduced rate of falls in people with carotid sinus hypersensitivity (RaR 0.42, 95%CI 0.23 to 0.75). First eye cataract surgery reduced rate of falls (RaR 0.66, 95%CI 0.45 to 0.95).There is some evidence that falls prevention strategies can be cost saving. AUTHORS' CONCLUSIONS: Exercise interventions reduce risk and rate of falls. Research is needed to confirm the contexts in which multifactorial assessment and intervention, home safety interventions, vitamin D supplementation, and other interventions are effective.

Actions and comparative efficacy of phosphatidylcholine formulation and isolated sodium deoxycholate for different cell types.

BACKGROUND: Phosphatidylcholine formulation has been used to dissolve local fat deposits. This study aimed to evaluate and compare the effects of phosphatidylcholine formulation and its vehicle sodium deoxycholate alone on different cell lines to understand better its mechanism of action. METHODS: Cells and media including 3T3-L1 preadipocytes, normal foreskin fibroblasts, neonatal human dermal microvascular endothelial cells (CADMEC), and fetal human skeletal muscle cells (HSkMC) were used. After 24 h, cells were exposed in 3-4, 5-dimethylthiazol-2-yl-2, 3-diphenyl tetrazolium bromide reagent (MTT assays) to increasing dosages of phosphatidylcholine formulation (0.0156-0.5 mg/ml) or an equivalent vehicle, sodium deoxycholate solution, pH 9.0 (0.0066-0.210 mg/ml). Viability was assessed after 1, 2, and 3 days of treatment. Fat tissue (4 x 4 cm) obtained ex vivo from the dorsal fat pads of five rabbits was injected with 2 ml of phosphatidylcholine formulation (50 mg/ml), sodium deoxycholate (21 mg/ml), or normal saline and incubated for 24 h. These were examined histologically to identify cell lysis and morphologic changes. RESULTS: At 0.125- and 0.25-mg/ml doses of phosphatidylcholine solution, CADMEC and HSkMC were more sensitive (P < 0.001, one-way ANOVA) than adipocytes at all time points examined. Phosphatidylcholine formulation at a dose of 0.5 mg/ml and the equivalent vehicle, sodium deoxycholate, at a dose of 0.21-mg/ml both induced nearly 100% fat cell lysis after 24 h, and evidence of cell lysis as early as 6 h after exposure. After incubation of fat tissue for 24 h with phosphatidylcholine formulation, loss of intracellular lipid staining with an increase in extracellular lipids was seen. CONCLUSIONS: Isolated sodium deoxycholate was almost as effective as the phosphatidylcholine formulation, at clinical concentrations, in reducing the viability of mature adipocytes over time. Similar cytotoxic effects of phosphatidylcholine formulation on normal foreskin fibroblasts, endothelial cells, and human skeletal muscle cells also were observed. The data prove that the formulation acts in a nonspecific manner and that its unintentional administration to other tissues causes cell death.