Acute polyradiculopathy secondary to idelalisib in Relapsed Classical Hodgkin's lymphoma.

Patients with relapsed or refractory Hodgkin's lymphoma are likely incurable with standard treatment. Idelalisib, a delta-isoform specific Phosphatidyl-inositol-3-kinase (PI3K) inhibitor has shown its efficacy in other hematopoietic B malignancies. We report the case of a 51-years old patient with relapsed and refractory Hodgkin's Lymphoma receiving idelalisib after several regimens of chemotherapy. He achieved a good partial response for several months, unfortunately, idelalisib had to be stopped because of the onset of a severe polyradiculoneuritis attributed to this treatment. We assume here that the polyradiculoneuritis could be caused by T cell mediated autoimmunity to myelin proteins. To our knowledge, this adverse event has never been described so far with idelalisib.

Mental health and well-being in parents of excessively crying infants: Prospective evaluation of a support package.

BACKGROUND: During the first 4 months of age, approximately 20% of infants cry a lot without an apparent reason. Most research has targeted the crying, but the impact of the crying on parents, and subsequent outcomes, need to receive equal attention. This study reports the findings from a prospective evaluation of a package of materials designed to support the well-being and mental health of parents who judge their infant to be crying excessively. The resulting "Surviving Crying" package comprised a website, printed materials, and programme of Cognitive Behaviour Therapy-based support sessions delivered to parents by a qualified practitioner. It was designed to be suitable for United Kingdom (UK) National Health Service (NHS) use. METHODS: Parents were referred to the study by 12 NHS Health Visitor/Community Public Health Nurse teams in one UK East Midlands NHS Trust. Fifty-two of 57 parents of excessively crying babies received the support package and completed the Edinburgh Postnatal Depression Scale and Generalized Anxiety Disorder-7 anxiety questionnaire, as well as other measures, before receiving the support package and afterwards. RESULTS: Significant reductions in depression and anxiety were found, with numbers of parents meeting clinical criteria for depression or anxiety halving between baseline and outcome. These improvements were not explained by reductions in infant crying. Reductions also occurred in the number of parents reporting the crying to be a large or severe problem (from 28 to 3 parents) or feeling very or extremely frustrated by the crying (from 31 to 1 parent). Other findings included increases in parents' confidence, knowledge of infant crying, and improvements in parents' sleep. CONCLUSIONS: The findings suggest that the Surviving Crying package may be effective in supporting the well-being and mental health of parents of excessively crying babies. Further, large-scale controlled trials of the package in NHS settings are warranted.

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.

Changes in management policies for extremely preterm births and neonatal outcomes from 2003 to 2012: two population-based studies in ten European regions.

OBJECTIVE: To investigate changes in maternity and neonatal unit policies towards extremely preterm infants (EPTIs) between 2003 and 2012, and concurrent trends in their mortality and morbidity in ten European regions. DESIGN: Population-based cohort studies in 2003 (MOSAIC study) and 2011/2012 (EPICE study) and questionnaires from hospitals. SETTING: 70 hospitals in ten European regions. POPULATION: Infants born at <27 weeks of gestational age (GA) in hospitals participating in both the MOSAIC and EPICE studies (1240 in 2003, 1293 in 2011/2012). METHODS: We used McNemar's Chi2 test, paired t-tests and conditional logistic regression for comparisons over time. MAIN OUTCOMES MEASURES: Reported policies, mortality and morbidity of EPTIs. RESULTS: The lowest GA at which maternity units reported performing a caesarean section for acute distress of a singleton non-malformed fetus decreased from an average of 24.7 to 24.1 weeks (P < 0.01) when parents were in favour of active management, and 26.1 to 25.2 weeks (P = 0.01) when parents were against. Units reported that neonatologists were called more often for spontaneous deliveries starting at 22 weeks GA in 2012 and more often made decisions about active resuscitation alone, rather than in multidisciplinary teams. In-hospital mortality after live birth for EPTIs decreased from 50% to 42% (P < 0.01). Units reporting more active management in 2012 than 2003 had higher mortality in 2003 (55% versus 43%; P < 0.01) and experienced larger declines (55 to 44%; P < 0.001) than units where policies stayed the same (43 to 37%; P = 0.1). CONCLUSIONS: European hospitals reporting changes in management policies experienced larger survival gains for EPTIs. TWEETABLE ABSTRACT: Changes in reported policies for management of extremely preterm births were related to mortality declines.

Economic costs associated with moderate and late preterm birth: a prospective population-based study.

OBJECTIVE: We sought to determine the economic costs associated with moderate and late preterm birth. DESIGN: An economic study was nested within a prospective cohort study. SAMPLE: Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. METHODS: Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. MAIN OUTCOME MEASURES: Cumulative resource use and economic costs over the first two years of life. RESULTS: Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. CONCLUSIONS: Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. TWEETABLE ABSTRACT: Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life.

Contrast-enhanced magnetic resonance angiography in diabetic patients with infra-genicular peripheral arterial disease: systematic review.

OBJECTIVE: Diabetes is a leading risk factor for the development of peripheral arterial disease (PAD). The optimal imaging modality for patients with diabetes and PAD is uncertain. We sought to analyse the literature to determine the accuracy of contrast enhanced magnetic resonance angiography (CE-MRA) in differentiating extent of disease in patients with infragenicular PAD and diabetes, using digital subtraction angiography (DSA) as the gold standard. METHODS: Online databases were searched for relevant keywords (January 1998-June 2012). Eligible studies prospectively compared CE-MRA and DSA of infragenicular vessels and provided data to construct contingency tables in at least 10 patients with diabetes and PAD symptoms. Pooled sensitivity and specificity values were calculated using random effects modelling. RESULTS: Only three studies (83 patients) provided data regarding the infragenicular vessels. The pooled sensitivity of MRA was 86% while the pooled specificity of MRA was 93%. CONCLUSIONS: The assumptions regarding CE-MRA's efficacy for infragenicular disease in diabetics are based upon low patient numbers. Inadequate diagnostic imaging in this high-risk group risks adoption of incorrect revascularisation strategies. Further studies are required.

Residents and ICU nurses get reliable static and dynamic haemodynamic assessments with aortic oesophageal Doppler.

BACKGROUND: Aortic oesophageal Doppler (ODM) allows continuous non-invasive haemodynamic monitoring. We tested to confirm if residents and nurses were able to reposition oesophageal probe (OP), obtain aortic blood flow of good quality and so perform reliable static and dynamic haemodynamic assessments. METHODS: Prospective observational study assessing ODM measurements were obtained by six residents and three nurses after they have participated in training. Measured (aortic diameter) and calculated haemodynamic data [indexed stroke volume (SVI), cardiac index] were directly obtained from ODM, after residents and nurses repositioned the OP. In a second group of patients, we tested the ability of residents and nurses to detect rapid haemodynamic changes after a passive leg raising. SVI comparison was the primary end point. Statistical analysis was performed using the method of Bland and Altman. RESULTS: Sixty-six haemodynamic measurements were performed on 42 patients. Mean bias for SVI between the skilled physician and residents, and between the skilled physician and nurses were -0.9 ± 5.2 ml/m(2) (P = 0.15), with a percentage error of 31%, and 0.9 ± 5.1 ml/m(2) (P = 0.14), with a percentage error of 33%, respectively. There was an excellent correlation for SVI between the physician and residents (r = 0.9; P < 0.0001) and between the physician and nurses (r = 0.9; P < 0.0001). Induced changes in SVI measured by residents and nurses strongly followed those of our skilled physician. CONCLUSION: Residents and nurses get reliable static and dynamic haemodynamic assessments with ODM compared to our skilled physician.

Video gaming enhances psychomotor skills but not visuospatial and perceptual abilities in surgical trainees.

INTRODUCTION: There is considerable interest in the identification and assessment of underlying aptitudes or innate abilities that could potentially predict excellence in the technical aspects of operating. However, before the assessment of innate abilities is introduced for high-stakes assessment (such as competitive selection into surgical training programs), it is essential to determine that these abilities are stable and unchanging and are not influenced by other factors, such as the use of video games. The aim of this study was to investigate whether experience playing video games will predict psychomotor performance on a laparoscopic simulator or scores on tests of visuospatial and perceptual abilities, and to examine the correlation, if any, between these innate abilities. METHODS: Institutional ethical approval was obtained. Thirty-eight undergraduate medical students with no previous surgical experience were recruited. All participants completed a self-reported questionnaire that asked them to detail their video game experience. They then underwent assessment of their psychomotor, visuospatial, and perceptual abilities using previously validated tests. The results were analyzed using independent samples t tests to compare means and linear regression curves for subsequent analysis. RESULTS: Students who played video games for at least 7 hours per week demonstrated significantly better psychomotor skills than students who did not play video games regularly. However, there was no difference on measures of visuospatial and perceptual abilities. There was no correlation between psychomotor tests and visuospatial or perceptual tests. CONCLUSIONS: Regular video gaming correlates positively with psychomotor ability, but it does not seem to influence visuospatial or perceptual ability. This study suggests that video game experience might be beneficial to a future career in surgery. It also suggests that relevant surgical skills may be gained usefully outside the operating room in activities that are not related to surgery.

Morphine analgesia and gastrointestinal morbidity in preterm infants: secondary results from the NEOPAIN trial.

OBJECTIVE: To investigate the influence of morphine therapy and other factors on the attainment of full enteral feeds and on acquired gastrointestinal pathology in preterm infants. DESIGN: Secondary data analysis from a randomised, placebo controlled trial. SETTING: 16 neonatal intensive care units in USA, Sweden, France and UK. PATIENTS: 898 infants (treatment group 449, control 449). Gestation (median (range)): 27 (23-32) weeks; birth weight (median (range)): 985 (420-2440) g. INTERVENTIONS: Morphine (M) or placebo (Pl) given pre-emptively by intravenous loading dose (100 microg/kg of morphine) and infusion (10-30 microg/kg/h depending on gestation) while infants were ventilated, for up to 14 days. "Open-label" morphine (A) could be given if clinically indicated. MAIN OUTCOME MEASURES: Age at full enteral feeds and major acquired gastrointestinal pathology. RESULTS: The group randomised to morphine was later in attaining full feeds (median days (quartiles): M 20 (13-29), Pl 17 (12-26); p = 0.003), and in starting feeds (median days (quartiles): M 5 (3-8), Pl 4 (2-7)). In a linear regression model, age at full feeds was independently associated with birth weight, a score of neonatal morbidities, neonatal dexamethasone use and cumulative morphine dose. There was no relationship between morphine use and acquired gastrointestinal pathology (M 9/449, Pl 8/449; chi2 p = 0.81). CONCLUSIONS: Morphine delays the attainment of full enteral feeds, partly by delaying the start of feeding, but does not discernibly increase gastrointestinal complications. The attainment of full feeds is influenced by morphine dose, but other factors seem to be important, including birth weight and neonatal morbidity.

Non-invasive measurement of reduced ventilation:perfusion ratio and shunt in infants with bronchopulmonary dysplasia: a physiological definition of the disease.

BACKGROUND: An objective definition of bronchopulmonary dysplasia (BPD) is required to interpret trial outcomes and provide a baseline for prognostic studies. Current definitions do not quantify disease severity. The cardinal measures of impaired gas exchange are a reduced ventilation:perfusion ratio (V(A):Q) and increased right to left shunt. These can be determined non-invasively by plotting arterial oxygen saturation (Spo(2)) against inspired oxygen pressure (PIo(2)). AIMS: To describe the reduced V(A):Q and shunt in infants with BPD and evaluate these as graded measures of pulmonary dysfunction. METHODS: 21 preterm infants with BPD were studied. PIo(2) was changed stepwise to vary Spo(2) between 86% and 94%. Pairs of PIo(2) and Spo(2) data points for each infant were plotted and analysed to derive reduced V(A):Q ratio and shunt. RESULTS: In every infant, the Spo(2) versus PIo(2) curve was shifted to the right of the normal because of a reduced V(A):Q. The mean (SD) shift was 16.5 (4.7) kPa (normal 6 kPa). Varying degrees of shunt were also present, but these were less important in determining Spo(2) within the studied range. The degree of shift was strongly predictive of the PIo(2) required to achieve any Spo(2) within the range 86-94% (R(2)>0.9), permitting shift and V(A):Q to be determined from a single pair of PIo(2) and SpO(2) values in this range. CONCLUSIONS: The predominant gas exchange impairment in BPD is a reduced V(A):Q, described by the right shift of the Spo(2) versus PIo(2) relationship. This provides a simpler method for defining BPD, which can grade disease severity.

Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomised controlled trial.

BACKGROUND: Screening is necessary for infants at risk of retinopathy of prematurity. Despite local anaesthetic drops, infants find eye examinations distressing, displaying behavioural and physiological changes indicating acute pain. Oral sucrose and non-nutritive sucking reduce pain responses associated with invasive procedures. OBJECTIVE: To evaluate the use of oral sucrose and/or pacifier for reducing pain responses during eye examinations. METHODS: Forty infants <32 weeks gestation or <1500 g birth weight, in two neonatal units, were randomised to one of four interventions administered two minutes before their first screening examination: 1 ml sterile water as placebo (group 1, n = 10), 1 ml 33% sucrose solution (group 2, n = 10), 1 ml sterile water with pacifier (group 3, n = 9), or 1 ml 33% sucrose solution with pacifier (group 4, n = 11). Examinations were videotaped. Two observers, blind to the intervention, assessed recordings. Pain responses were scored using the premature infant pain profile (PIPP). RESULTS: The groups were similar in gestation, birth weight, and age at examination. Mean PIPP scores were 15.3, 14.3, 12.3, and 12.1 for groups 1, 2, 3, and 4 respectively. Analysis of variance showed a significant difference in PIPP score between groups (p = 0.023). Infants randomised to pacifiers scored lower than those without pacifiers (p = 0.003). There was no difference between groups receiving sucrose and those receiving water (p = 0.321). CONCLUSIONS: Non-nutritive sucking reduced distress responses in infants undergoing screening for retinopathy of prematurity. The difference in response was large enough to be detected by a validated assessment tool. No synergistic effect of sucrose and pacifier was apparent in this group.

Best paediatric evidence; is it accessible and used on-call?

BACKGROUND: Paediatricians wanting to use evidence based medicine (EBM) strategies, need to be able to track down and critically appraise evidence. This requires access to quality filtered resources (for example, Cochrane Library), bibliographic databases (for example, Medline), and paediatric journals. AIMS: To determine whether paediatricians have access to these resources when on-call and if they use them to answer clinical questions. METHOD: A telephone survey of paediatric and neonatal units was performed during November 2001. The "paediatrician-on-call" was asked whether they could access Medline, Cochrane, and paediatric journals, and if they used these when on-call. RESULTS: Paediatric trainees were available in 87 of the 97 units contacted. All except one had access to Medline; although only 56 (64%) could do this near their ward. Eighty had access to Cochrane. Thirteen (15%) could not gain access to their library out-of-hours. All except one department had local guidelines, with 71% having >15 guidelines. Access to any of the top seven "best evidence" paediatric journals varied from 64% to 100%. Only 26% of trainees had read the evidence based section of Archives of Disease of Childhood, Archimedes. Many trainees claimed to use guidelines when on-call (61; 70%), but few used Medline (14; 16%). CONCLUSIONS: Paediatric trainees mostly have access to facilities to help them to track down and critically appraise evidence. However, few of them have used it to help make clinical decisions when on-call. Many of the doctors contacted said they used local guidelines as their source of information on-call.

Ophthalmic Pseudomonas infection in infancy.

Four infants developed invasive Pseudomonas aeruginosa ophthalmic infections between 5 and 90 days of age. Three died from septicaemia, and the fourth required enucleation of one eye. Absent red reflexes or other eye signs in a septicaemic infant merit urgent ophthalmological assessment for endophthalmitis, in particular, Pseudomonas.

Inhibition of the initial wave of NF-kappaB activity in rat muscle reduces ischemia/reperfusion injury.

Nuclear factor kappaB (NF-kappaB) is thought to play an important role in the expression of genes expressed in response to ischemia/reperfusion (I/R) injury. In this report, the activation of NF-kappaB in rat skeletal muscle during reperfusion following a 4-h ischemic period was studied. NF-kappaB activation displayed a biphasic pattern, showing peak activities from 30 min to 3 h postperfusion and 6 h to 16 h postperfusion, with a decline to baseline binding activity levels between 3 h and 6 h. Inhibition of NF-kappaB activation was investigated using proline dithiocarbamate (Pro-DTC). NF-kappaB binding activity during reperfusion was significantly reduced by intravenous administration of Pro-DTC. Additionally, Pro-DTC resulted in decreased muscle edema and neutrophil activity, with an increased percentage of muscle survival compared with vehicle controls. These results demonstrate that NF-kappaB is activated during reperfusion in a biphasic manner and that the regulation of the initial phase of NF-kappaB activation affords physiological protection against a severe ischemic stress. Selective inhibition of NF-kappaB during early reperfusion may therefore be a therapeutic intervention for I/R injury.

Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation.

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

Treating myocardial ischemia-reperfusion injury by targeting endothelial cell transcription.

Exacerbation of, rather than improvement in, a hypoxic injury after reperfusion of ischemic tissues is recognized as the specific clinicopathologic entity referred to as ischemia/reperfusion (I/R) injury. Arguably, one of the most common forms of I/R injury occurs during cardiac surgery, which has a mandatory period of myocardial ischemia required to allow surgery in a bloodless, motionless field, followed by coronary artery reperfusion after removal of the aortic cross-clamp. In this review, we examine the endothelial cell activation phenotype that initiates and propagates myocardial I/R injury. Emphasis is given to the biology of one transcription factor, NF-kappaB, that has the principal role in the regulation of many endothelial cell genes expressed in activated endothelium. NF-kappaB-dependent transcription of endothelial cell genes that are transcribed in response to I/R injury may be a favorable approach to preventing tissue injury in the setting of I/R. Elucidating safe and effective therapy to inhibit transcription of endothelial cell genes involved in promoting injury after I/R injury may have wide applicability to the patients with heart disease and other forms of I/R injury.