CiteULike: jyuh Tomlinson

Understanding the Concept of Effect Size to Guide Clinical Decisions about Treatment

James Tomlinson — 2008-06-10T04:26:45-00:00

Journal of Hand Therapy, Vol. 20, No. 3. ( 2007), pp. 277-279.

Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration.

AV Bakin — 2008-05-30T03:26:07-00:00

The Journal of biological chemistry, Vol. 275, No. 47. (24 November 2000), pp. 36803-36810.

We have studied the role of phosphatidylinositol 3-OH kinase (PI3K)-Akt signaling in transforming growth factor beta (TGFbeta)-mediated epithelial to mesenchymal transition (EMT). In NMuMG mammary epithelial cells, exogenous TGFbeta1 induced phosphorylation of Akt at Ser-473 and Akt in vitro kinase activity against GSK-3beta within 30 min. These responses were temporally correlated with delocalization of E-cadherin, ZO-1, and integrin beta(1) from cell junctions and the acquisition of spindle cell morphology. LY294002, an inhibitor of the p110 catalytic subunit of PI3K, and a dominant-negative mutant of Akt blocked the delocalization of ZO-1 induced by TGFbeta1, whereas transfection of constitutively active p110 induced loss of ZO-1 from tight junctions. In addition, LY294002 blocked TGFbeta-mediated C-terminal phosphorylation of Smad2. Consistent with these data, TGFbeta-induced p3TP-Lux and p(CAGA)(12)-Lux reporter activities were inhibited by LY294002 and transiently expressed dominant-negative p85 and Akt mutants in NMuMG and 4T1 cells. Dominant-negative RhoA inhibited TGFbeta-induced phosphorylation of Akt at Ser-473, whereas constitutively active RhoA increased the basal phosphorylation of Akt, suggesting that RhoA in involved in TGFbeta-induced EMT. Finally, LY294002 and neutralizing TGFbeta1 antibodies inhibited ligand-independent constitutively active Akt as well as basal and TGFbeta-stimulated migration in 4T1 and EMT6 breast tumor cells. Taken together, these data suggest that PI3K-Akt signaling is required for TGFbeta-induced transcriptional responses, EMT, and cell migration.

Methods for the purification of ubiquitinated proteins.

E Tomlinson — 2008-02-27T05:47:03-00:00

Proteomics, Vol. 7, No. 7. (April 2007), pp. 1016-1022.

Post-translational protein modification by the covalent conjugation of ubiquitin, originally implicated as a signal for proteolytic degradation by 26S proteasome, has now been realised to play important roles in the regulation of almost all biological processes in eukaryotes. In order to understand these processes in greater detail there is a requirement for techniques that can purify mixtures of ubiquitin-conjugated proteins, as a prerequisite to their identification and characterisation. Here we review the methods that have been applied to the bulk purification of ubiquitinated proteins and discuss their applications in proteomic analyses of the 'ubiquitome'.

How do we re-design the treatment? A background paper prepared for the UK Consensus Conference on early chronic kidney disease.

J Tomlinson — 2008-02-13T08:37:16-00:00

Nephrol Dial Transplant, Vol. 22 Suppl 9 (September 2007)

Methodological quality and homogeneity influenced agreement between randomized trials and nonrandomized studies of the same intervention for back pain

Andrea Furlan — 2008-02-04T03:45:02-00:00

Journal of Clinical Epidemiology, Vol. 61, No. 3. (March 2008), pp. 209-231.

Objective To determine the influence of methodological quality and homogeneity on the agreement between pairs of randomized trials (RCTs) and nonrandomized studies (NRSs) of the same interventions for low-back problems. Homogeneity was assessed regarding settings, population, interventions, and outcomes.Study Design and Setting We searched Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE up to May 2005 for matching pairs of NRS and RCT. Analyses were done using correlation, linear and logistic regression.Results Forty-eight matched pairs were included with no significant overall correlation between effect sizes (r = 0.09). There was a trend showing more agreement among the 22 pairs with higher methodological quality (r = 0.33). The correlation among the 20 very homogeneous pairs was 0.59, and among the 28 heterogeneous pairs was -0.09. The agreement of authors' recommendations was influenced by the pair's homogeneity (odds ratio [OR] = 2.78, 95% CI = 1.44-5.37) rather than by methodological quality of the NRS (OR = 0.93, 95% CI = 0.67-1.29) or the RCT (OR = 1.03, 95% CI = 0.73-1.45).Conclusions Pairs of low-quality studies disagreed more than pairs where at least one study was of high quality. However, pairs with similar settings, population, interventions, and outcomes showed higher agreement than pairs that were not as homogeneous.

Assessment of the potential impact of a reminder system on the reduction of diagnostic errors: a quasi-experimental study

Padmanabhan Ramnarayan — 2006-06-06T16:27:19-00:00

BMC Medical Informatics and Decision Making, Vol. 6 (28 April 2006), 22.

Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest.

CM Booth — 2006-12-07T14:47:13-00:00

JAMA, Vol. 291, No. 7. (18 February 2004), pp. 870-879.

CONTEXT: Most survivors of cardiac arrest are comatose after resuscitation, and meaningful neurological recovery occurs in a small proportion of cases. Treatment can be lengthy, expensive, and often difficult for families and caregivers. Physical examination is potentially useful in this clinical scenario, and the information obtained may help physicians and families make accurate decisions about treatment and/or withdrawal of care. OBJECTIVE: To determine the precision and accuracy of the clinical examination in predicting poor outcome in post-cardiac arrest coma. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE for English-language articles (1966-2003) using the terms coma, cardiac arrest, prognosis, physical examination, sensitivity and specificity, and observer variation. Other sources came from bibliographies of retrieved articles and physical examination textbooks. Studies were included if they assessed the precision and accuracy of the clinical examination in prognosis of post-cardiac arrest coma in adults. Eleven studies, involving 1914 patients, met our inclusion criteria. DATA EXTRACTION: Two authors independently reviewed each study to determine eligibility, abstract data, and classify methodological quality using predetermined criteria. Disagreement was resolved by consensus. DATA SYNTHESIS: Summary likelihood ratios (LRs) were calculated from random effects models. Five clinical signs were found to strongly predict death or poor neurological outcome: absent corneal reflexes at 24 hours (LR, 12.9; 95% confidence interval [CI], 2.0-68.7), absent pupillary response at 24 hours (LR, 10.2; 95% CI, 1.8-48.6), absent withdrawal response to pain at 24 hours (LR, 4.7; 95% CI, 2.2-9.8), no motor response at 24 hours (LR, 4.9; 95% CI, 1.6-13.0), and no motor response at 72 hours (LR, 9.2; 95% CI, 2.1-49.4). The proportion of individuals' dying or having a poor neurological outcome was calculated by pooling the outcome data from the 11 studies (n = 1914) and used as an estimate of the pretest probability of poor outcome. The random effects estimate of poor outcome was 77% (95% CI, 72%-80%). The highest LR increases the pretest probability of 77% to a posttest probability of 97% (95% CI, 87%-100%). No clinical findings were found to have LRs that strongly predicted good neurological outcome. CONCLUSIONS: Simple physical examination maneuvers strongly predict death or poor outcome in comatose survivors of cardiac arrest. The most useful signs occur at 24 hours after cardiac arrest, and earlier prognosis should not be made by clinical examination alone. These data provide prognostic information, rather than treatment recommendations, which must be made on an individual basis incorporating many other variables.

Does this patient with headache have a migraine or need neuroimaging?

ME Detsky — 2007-07-18T06:33:56-00:00

JAMA, Vol. 296, No. 10. (13 September 2006), pp. 1274-1283.

CONTEXT: In assessing the patient with headache, clinicians are often faced with 2 important questions: Is this headache a migraine? Does this patient require neuroimaging? The diagnosis of migraine can direct therapy, and information obtained from the history and physical examination is used by physicians to determine which patients require neuroimaging. OBJECTIVE: To determine the usefulness of the history and physical examination that distinguish patients with migraine from those with other headache types and that identify those patients who should undergo neuroimaging. DATA SOURCES AND STUDY SELECTION: A systematic review was performed using articles from MEDLINE (1966-November 2005) that assessed the performance characteristics of screening questions in diagnosing migraine (with the International Headache Society diagnostic criteria as a gold standard) and addressed the accuracy of the clinical examination in predicting the presence of underlying intracranial pathology (with computed tomography/magnetic resonance imaging as the reference standard). DATA EXTRACTION: Two authors independently reviewed each study to determine eligibility, abstract data, and classify methodological quality using predetermined criteria. Disagreement was resolved by consensus with a third author. DATA SYNTHESIS: Four studies of screening questions for migraine (n = 1745 patients) and 11 neuroimaging studies (n = 3725 patients) met inclusion criteria. All 4 of the migraine studies illustrated high sensitivity and specificity if 3 or 4 criteria were met. The best predictors can be summarized by the mnemonic POUNDing (Pulsating, duration of 4-72 hOurs, Unilateral, Nausea, Disabling). If 4 of the 5 criteria are met, the likelihood ratio (LR) for definite or possible migraine is 24 (95% confidence interval [CI], 1.5-388); if 3 are met, the LR is 3.5 (95% CI, 1.3-9.2), and if 2 or fewer are met, the LR is 0.41 (95% CI, 0.32-0.52). For the neuroimaging question, several clinical features were found on pooled analysis to predict the presence of a serious intracranial abnormality: cluster-type headache (LR, 10.7; 95% CI, 2.2-52); abnormal findings on neurologic examination (LR, 5.3; 95% CI, 2.4-12); undefined headache (ie, not cluster-, migraine-, or tension-type) (LR, 3.8; 95% CI, 2.0-7.1); headache with aura (LR, 3.2; 95% CI, 1.6-6.6); headache aggravated by exertion or a valsalva-like maneuver (LR, 2.3; 95% CI, 1.4-3.8); and headache with vomiting (LR, 1.8; 95% CI, 1.2-2.6). No clinical features were useful in ruling out significant pathologic conditions. CONCLUSIONS: The presence of 4 simple historical features can accurately diagnose migraine. Several individual clinical features were found to be associated with a significant intracranial abnormality, and patients with these features should undergo neuroimaging.