A Multicenter, Randomised Open Study of Early Corticosteroid Treatment (OSECT) in Preterm Infants With Respiratory Illness: Comparison of Early and Late Treatment and of Dexamethasone and Inhaled Budesonide

AIM: To compare early (15 days) steroid therapy and dexamethasone with inhaled budesonide in very preterm infants at risk of developing chronic lung disease. METHODS: Five hundred seventy infants from 47 neonatal intensive care units were enrolled. Criteria for enrollment included gestational age 30%. Infants were randomly allocated to 1 of 4 treatment groups in a factorial design: early (15 days) dexamethasone, and delayed selective budesonide. Dexamethasone was given in a tapering course beginning with 0.50 mg/kg/day in 2 divided doses for 3 days reducing by half until 12 days of therapy had elapsed. Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 microg/kg twice daily for 12 days. Delayed selective treatment was started if infants needed mechanical ventilation and >30% oxygen for >15 days. The factorial design allowed 2 major comparisons: early versus late treatment and systemic dexamethasone versus inhaled budesonide. The primary outcome was death or oxygen dependency at 36 weeks and analysis was on an intention-to-treat basis. Secondary outcome measures included death or major cerebral abnormality, duration of oxygen treatment, and complications of prematurity. Adverse effects were also monitored daily. RESULTS: There were no significant differences among the groups for the primary outcome. Early steroid treatment was associated with a lower primary outcome rate (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.61,1.18) but even after adjustment for confounding variables the difference remained nonsignificant. Dexamethasone-treated infants also had a lower primary outcome rate (OR: 0.86; 95% CI: 0.62,1.20) but again this difference remained not significant after adjustment. For death before discharge, dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; OR: 1.51; 95% CI: 0.99,2.30 after adjustment, respectively) with the results not quite reaching significance. Duration of supplementary oxygen was shorter in the early dexamethasone group (median: 31 days vs 40-44 days). Early dexamethasone was also associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g) compared with early budesonide, but over 30 days there was no difference. In the early dexamethasone group, there was a reduced incidence of persistent ductus arteriosus (34% vs 52%-59%) and an increased risk of hyperglycemia (55% vs 29%-34%) compared with the other 3 groups. Dexamethasone was associated with an increased risk of hypertension and gastrointestinal problems compared with budesonide but only the former attained significance. CONCLUSIONS: Infants given early treatment and dexamethasone therapy had improved survival without chronic lung disease at 36 weeks compared with those given delayed selective treatment and inhaled budesonide, respectively, but results for survival to discharge were in the opposite direction; however, none of these findings attained statistical significance. Early dexamethasone treatment reduced the risk of persistent ductus arteriosus. Inhaled budesonide may be safer than dexamethasone, but there is no clear evidence that it is more or less effective

Eye movements and neurocognitive function in treatment resistant schizophrenia: a pilot study.

Objectives: It is increasingly important to develop predictors of treatment response and outcome in schizophrenia. Neuropsychological impairments, particularly those reflecting frontal lobe function, appear to predict poor outcome. Eye movement abnormalities probably also reflect frontal lobe deficits. We wished to see if these two aspects of schizophrenia were correlated and whether they could distinguish a treatment resistant from a treatment responsive group. Methods: Ten treatment resistant schizophrenic patients were compared with ten treatment responsive patients on three eye movement paradigms (reflexive saccades, antisaccades and smooth pursuit), clinical psychopathology (BPRS, SANS and CGI) and a neuropsychological test battery designed to detect frontal lobe dysfunction. Ten aged-matched controls also carried out the eye movement tasks. Results: Both treatment responsive (p = 0.038) and treatment resistant (p = 0.007) patients differed significantly from controls on the antisaccade task. The treatment resistant group had a higher error rate than the treatment responsive group, but the difference was not statistically significant. Similar poor neuropsychological test performance was found in both groups. Conclusions: To demonstrate the biological differences characteristic of treatment resistance, larger sample sizes and wider differences in outcome between the two groups are necessary.

The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis

Decreased survival in patients with cystic fibrosis has been related to FEV1, BMI, and infection with Burkholderia cepacia complex (BCC). We have assessed the relationship of blood, sputum, and urine inflammatory markers to lung function, BMI, colonization with B cenocepacia (Bc), and patient survival. Thirty-nine stable cystic fibrosis (CF) patients (10 with Bc) were enrolled in a study to determine the effect of alpha-1-antitrypsin on airways inflammation. Pre-treatment measurements were used in this study. Demographics, sputum microbiology, heart rate, oxygen saturation, lung function were recorded. Blood samples were obtained for white blood count (WBC), C-Reactive Protein (CRP), and plasma neutrophil elastase/AAT complexes (pNEC). Neutrophil elastase (NE), neutrophil elastase/AAT complexes (sNEC), interleukin-8 (IL-8), TNF-receptor 1 (sTNFr), and myeloperoxidase (MPO) were measured in sputum and urinary desmosine concentration determined. Patients with Bc had significantly higher levels of pNEC, 332?±?91.4 ng/ml (mean?±?SEM) versus 106?±?18.2 ng/ml (P?=?0.0005) and sNEC, 369?±?76.6 ng/ml versus 197?±?36.0 ng/ml compared to those who were not. Five deaths were reported at the end of 1 year, (four with Bc) (P?=?0.011). Patients who subsequently died had significantly lower lung function FEV1, 1.2?±?0.2 L versus 2.0?±?0.1 L (P?=?0.03) and FVC, 2?±?0.3 L versus 3.1?±?0.2 L (P?=?0.01), compared to those that survived. There was significantly higher NE activity, 3.6?±?1.6 U/ml versus 1.5?±?0.6 U/ml (P?=?0.03), pNEC, 274?±?99 ng/ml versus 142?±?30 ng/ml (P?=?0.05), MPO, 163?±?62 mcg/ml versus 54?±?6.9 mcg/ml (P?=?0.03), and urinary desmosines 108?±?19.9 pM/mg creatinine versus 51.1?±?3.3 pM/mg creatinine (P?=?0.001), in those patients who subsequently died compared to those that survived. These data suggest there is increased neutrophil degranulation in patients infected with Bc and these patients have a poor outcome.

Tooth loss and implant outcomes in patients refractory to treatment in a periodontal practice

Aim: The aim of this study was to investigate the factors associated with continued significant tooth loss due to periodontal reasons during maintenance following periodontal therapy in a specialist periodontal practice in Norway.
Material and Methods: A case-control design was used. Refractory cases were patients who lost multiple teeth during a maintenance period of 13.4 (range 8-19) years following definitive periodontal treatment in a specialist practice. Controls were age- and gender-matched maintenance patients from the same practice. Characteristics and treatment outcomes were assessed, and all teeth classified as being lost due to periodontal disease during follow-up were identified. The use of implants in refractory cases and any complications relating to such a treatment were recorded.
Results: Only 27 (2.2%) patients who received periodontal treatment between 1986 and 1998 in a specialist practice met the criteria for inclusion in the refractory to treatment group. Each refractory subject lost 10.4 (range 4-16) teeth, which represented 50% of the teeth present at baseline. The rate of tooth loss in the refractory group was 0.78 teeth per year, which was 35 times greater than that in the control group. Multivariate analysis indicated that being in the refractory group was predicted by heavy smoking (p=0.026), being stressed (p=0.016) or having a family history of periodontitis (p=0.002). Implants were placed in 14 of the refractory patients and nine (64%) of these lost at least one implant. In total, 17 (25%) of the implants placed in the refractory group were lost during the study period.
Conclusions: A small number of periodontal maintenance patients are refractive to treatment and go on to experience significant tooth loss. These subjects also have a high level of implant complications and failure. Heavy smoking, stress and a family history of periodontal disease were identified as factors associated with a refractory outcome.

MMP expression and abnormal lung permeability are important determinants of outcome in IPF

Matrix metalloproteinases (MMPs) degrade all of the extracellular matrix components of the intersititium and may play a role in abnormal alveolar permeability, which is a feature of idiopathic pulmonary fibrosis (IPF). The aims of the present study were to evaluate MMP protein levels in patients with IPF and determine any relationship to treatment and markers of permeability.

Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol

Background-Asthma, post-nasal drip syndrome (PNDS), and gastrooesophageal reflux (GOR) account for many cases of chronic non-productive cough (CNPC). Each may simultaneously contribute to cough even when clinically silent, and failure to recognise their contribution may lead to unsuccessful treatment.

Methods—Patients (all lifetime non-smokers with normal chest radiographs and spirometric measurements) referred with CNPC persisting for more than three weeks as their sole respiratory symptom underwent histamine challenge, home peak flow measurements, ear, nose and throat (ENT) examination, sinus CT scanning, and 24 hour oesophageal pH monitoring. Treatment was prescribed on the basis of diagnoses informed by investigation results.

RESULTS—Forty three patients (29 women) of mean age 47.5 years (range 18-77) and mean cough duration 67 months (range 2-240) were evaluated. On the basis of a successful response to treatment, a cause for the cough was identified in 35 patients (82%) as follows: cough variant asthma (CVA) (10 cases), PNDS (9 cases), GOR (8cases), and dual aetiologies (8 cases). Histamine challenge correctly predicted CVA in 15 of 17 (88%) positive tests. ENT examination and sinus CT scans each had low positive predictive values for PNDS (10 of 16 (63%) and 12 of 18 (67%) positive cases, respectively), suggesting that upper airways disease frequently co-exists but does not always contribute to cough. When negative, histamine challenge and 24 hour oesophageal pH monitoring effectively ruled out CVA and GOR, respectively, as a cause for cough.

CONCLUSION—This comprehensive approach aids the accurate direction of treatment and, while CVA, PNDS and GOR remain the most important causes of CNPC to consider, a group with no identifiable aetiology remains.

Clinical significance of sperm DNA damage in assisted reproduction outcome

Background: Sperm DNA damage shows great promise as a biomarker of infertility. The study aim is to determine the usefulness of DNA fragmentation (DF), including modified bases (MB), to predict assisted reproduction treatment (ART) outcomes. Methods: DF in 360 couples (230 IVF and 130 ICSI) was measured by the alkaline Comet assay in semen and in sperm following density gradient centrifugation (DGC) and compared with fertilization rate (FR), embryo cumulative scores (ECS1) for the total number of embryos/treatment, embryos transferred (ECS2), clinical pregnancy (CP) and spontaneous pregnancy loss. MB were also measured using formamidopyrimidine DNA glycosylase to convert them into strand breaks. Results: In IVF, FR and ECS decreased as DF increased in both semen and DGC sperm, and couples who failed to achieve a CP had higher DF than successful couples (+12.2 semen, P = 0.004; +9.9 DGC sperm, P = 0.010). When MB were added to existing strand breaks, total DF was markedly higher (+17.1 semen, P = 0.009 and +13.8 DGC sperm, P = 0.045). DF was not associated with FR, ECS or CP in either semen or DGC sperm following ISCI. In contrast, by including MB, there was significantly more DNA damage (+16.8 semen, P = 0.008 and +15.5 DGC sperm, P = 0.024) in the group who did not achieve CP. Conclusion: SDF can predict ART outcome for IVF. Converting MB into further DNA strand breaks increased the test sensitivity, giving negative correlations between DF and CP for ICSI as well as IVF. © 2010 The Author.

Molecular biology: the key to personalised treatment in radiation oncology?

We know considerably more about what makes cells and tissues resistant or sensitive to radiation than we did 20 years ago. Novel techniques in molecular biology have made a major contribution to our understanding at the level of signalling pathways. Before the “New Biology” era, radioresponsiveness was defined in terms of physiological parameters designated as the five Rs. These are: repair, repopulation, reassortment, reoxygenation and radiosensitivity. Of these, only the role of hypoxia proved to be a robust predictive and prognostic marker, but radiotherapy regimens were nonetheless modified in terms of dose per fraction, fraction size and overall time, in ways that persist in clinical practice today. The first molecular techniques were applied to radiobiology about two decades ago and soon revealed the existence of genes/proteins that respond to and influence the cellular outcome of irradiation. The subsequent development of screening techniques using microarray technology has since revealed that a very large number of genes fall into this category. We can now obtain an adequately robust molecular signature, predicting for a radioresponsive phenotype using gene expression and proteomic approaches. In parallel with these developments, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can now detect specific biological molecules such as haemoglobin and glucose, so revealing a 3D map of tumour blood flow and metabolism. The key to personalised radiotherapy will be to extend this capability to the proteins of the molecular signature that determine radiosensitivity.

Treatment Foster Care for Improving Outcomes in Children and Young People: A Systematic Review

Objective: To assess the impact of treatment foster care (TFC) on psychosocial and behavioral outcomes, delinquency, placement stability, and discharge status for children and adolescents who, for reasons of severe medical, social, psychological and behavioural problems, were placed in out-of-home care in restrictive settings or at risk of placement in such settings. Method: Electronic bibliographic databases, web searches, and article reference lists were used to identify randomized controlled trials (RCTs) investigating the effectiveness of TFC with children and young people. The Cochrane Collaboration’s criteria were used to assess the methodological quality of studies that met the inclusion criteria. Wherever possible, extracted outcome data from similar studies were synthesized with random effects meta-analyses. Results: A total of 5 studies including 390 participants were included in this review. Data suggest that TFC may be a useful intervention for children and young people with complex emotional, psychological, and behavioural need, who are at risk of placements in nonfamily settings that restrict their liberty and opportunities for social inclusion. Conclusion: Although the inclusion criteria for this systematic review set a study design threshold higher than that of previous reviews, the findings mirror those of earlier reviews. While the results of individual studies generally indicate that TFC is a promising intervention for children and youth experiencing mental health problems, behavioral problems, or problems of delinquency, the evidence base is not robust and more research is needed due to the limited number of studies in this area.

Breast cancer mortality in neighbouring European countries with different level of breast screening but similar access to treatment: An analysis of WHO mortality database

Objective: To compare trends in breast cancer mortality within three pairs of neighbouring European countries in relation to implementation of screening. Design: Retrospective trend analysis.
Setting: Three country pairs (Northern Ireland (United Kingdom) v Republic of Ireland, the Netherlands v Belgium and Flanders (Belgian region south of the Netherlands), and Sweden v Norway).
Data sources: WHO mortality database on cause of death and data sources on mammography screening, cancer treatment, and risk factors for breast cancer mortality.
Main outcome measures: Changes in breast cancer mortality calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in mortality for all ages began to change.
Results: From 1989 to 2006, deaths from breast cancer decreased by 29% in Northern Ireland and by 26% in the Republic of Ireland; by 25% in the Netherlands and by 20% in Belgium and 25% in Flanders; and by 16% in Sweden and by 24% in Norway. The time trend and year of downward inflexion were similar between Northern Ireland and the Republic of Ireland and between the Netherlands and Flanders. In Sweden, mortality rates have steadily decreased since 1972, with no downward inflexion until 2006. Countries of each pair had similar healthcare services and prevalence of risk factors for breast cancer mortality but differing implementation of mammography screening, with a gap of about 10-15 years.
Conclusions: The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality.

Targeted therapies in the treatment of advanced/metastatic NSCLC

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets has improved the outcome in selected patients with advanced NSCLC. Furthermore, the use of erlotinib and gefitinib is an alternative for second line treatment. Advances in our understanding of molecular biology of cancer and mechanisms of tumourigenesis have further enabled the discovery of several potential molecular targets and development of novel 'targeted therapies'. The purpose of this study is to review current data on the role of targeted therapies in the treatment of advanced NSCLC. (C) 2009 Elsevier Ltd. All rights reserved.

Integrated care: utilisation of complementary and alternative medicine within a conventional cancer treatment centre

Objectives: To estimate the proportion of cancer outpatients who visit a Complementary and Alternative Medicine (CAM) unit that is located within a conventional cancer treatment centre; to compare the characteristics of CAM unit visitors with those of all outpatients; to monitor the demand for 20 CAM therapies delivered by professionals, and the use of the CAM unit for waiting, gathering information and informal support from volunteer staff.

Design: Prospective, observational, over a six month period.

Setting: CAM unit within a NHS cancer treatment centre.

Main outcome measures: Utilisation of the CAM unit for 20 complementary therapies, and for waiting, gathering information, informal support; characteristics of CAM users compared with those of all cancer outpatients attending the cancer centre; predictors of CAM therapy use and frequent use.

Results: 761 (95% of those approached) people were recruited, 498 (65.4%) cancer patients, 202 (26.5%) relatives, 37 (4.8%) friends/carers, 24 (3.2%) staff. Women predominated (n = 560, 73.6%). Of all outpatients attending the cancer centre, 498 (15.8%) visited the CAM unit, 290 (9.2%) accessed therapies. Compared to all outpatients, those visiting the CAM unit were: younger (mean 63.7 vs. 58.4 years), more likely to be female (57.9% vs. 78.7%), have breast (14.8% vs. 51.9%), gynaecological (5.0% vs. 9.1%) cancer, live in local postal district (57.3% vs. 61.6%). Significant predictors of therapy use and frequent visits were being a patient, female, higher education, living closer to the cancer centre.

Conclusions: Despite easy access to CAM therapies, a relatively small number of people regularly used them, whilst a larger number selectively tried a few. The integrated CAM unit meets a demand for information and informal support. The findings inform emerging policy on integrating CAM and conventional cancer treatment to address psychosocial needs of people with cancer. More research is needed on why people do not use integrated CAM services and how charges affect demand. © 2008.

Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial

BACKGROUND:
In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
METHODS:
We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged =16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 µg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
FINDINGS:
We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).
INTERPRETATION:
Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of ß-2 agonist treatment in ventilated patients with this disorder cannot be recommended.

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials

Background Moderate di?erences in e?cacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could a? ect treatment choices. We sought any such di?erences.

Methods We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plusanthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44 000); one anthracyclinebased regimen versus another (n=7000) or versus cyclo phosphamide, methotrexate, and ?uorouracil (CMF; n=18 000); and polychemotherapy versus no chemotherapy (n=32 000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to de? ne standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported.

Findings In trials adding four separate cycles of a taxane to a ?xed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided signi?cance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no signi?cant di?erence (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or
standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little a? ected by age, nodal status, tumour diameter or di?erentiation (moderate or poor; few were well di?erentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality di?erences paralleled breast cancer mortality di?erences, despite taxane, anthracycline, and other toxicities.

Interpretation 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute bene?t, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.

Incidence, determinants and outcome of chronic kidney disease after adult heart transplantation in the United Kingdom

Background: We investigated the incidence of chronic kidney disease (CKD) in the United Kingdom heart transplant population, identified risk factors for the development of CKD, and assessed the impact of CKD on subsequent survival.

Methods: Data from the UK Cardiothoracic Transplant Audit and UK Renal Registry were linked for 1732 adult heart transplantations, 1996 to 2007. Factors influencing time to CKD, defined as National Kidney Foundation CKD stage 4 or 5 or preemptive kidney transplantation, were identified using a Cox proportional hazards model. The effects of distinct CKD stages on survival were evaluated using time-dependent covariates.

Results: A total of 3% of patients had CKD at transplantation, 11% at 1-year and more than 15% at 6 years posttransplantation and beyond. Earlier transplantations, shorter ischemia times, female, older, hepatitis C virus positive, and diabetic recipients were at increased risk of developing CKD, along with those with impaired renal function pretransplantation or early posttransplantation. Significant differences between transplantation centers were also observed. The risk of death was significantly higher for patients at CKD stage 4, stage 5 (excluding dialysis), or on dialysis, compared with equivalent patients surviving to the same time point with CKD stage 3 or lower (hazard ratios of 1.66, 8.54, and 4.07, respectively).

Conclusions: CKD is a common complication of heart transplantation in the UK, and several risk factors identified in other studies are also relevant in this population. By linking national heart transplantation and renal data, we have determined the impact of CKD stage and dialysis treatment on subsequent survival in heart transplant recipients.