Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

/pdf/bias-in-meta-analysis-detected-by-a-simple-graphical-test-5erh428s5c.pdf

Bias in meta-analysis detected by a simple, graphical test

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

2007 Guidelines for the Management of Arterial Hypertension : The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

Background Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. Methods We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter and maintenance of glucose at a level between 180 and 200 mg per deciliter). Results At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011300

Intensive Insulin Therapy in Critically Ill Patients

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

This report describes the prenatal detection of isochromosome 5p, resulting in tetrasomy (5p) in one affected fetus of a monochorionic/diamniotic, spontaneously conceived, twin pair. The co-twin was found to be structurally and karyotypically normal. To our knowledge, the present case is the first report of iso(5p) seen in 100% of cells from a single tissue (aspirated cystic hygroma fluid). Although it is unknown whether complete iso(5p) was present in other fetal tissues, the clinical picture in the present case likely represents the severe end of the phenotypic spectrum of tetrasomy (5p). The patient was a 23-year old, gravida 1 para 0, with a known monochorionic (MC) twin gestation, who presented for first trimester screening at 13 weeks of gestation. The placentation had previously been determined to be MC and diamniotic based on a 10-week ultrasound demonstrating a single posterior placenta with a very thin inter-twin membrane (Figure 1). Ultrasound performed as part of the first trimester screen revealed an MC twin pregnancy with nuchal translucency (NT) measurements of 10.1 mm (5.12 MoM) in twin A and 1.9 mm (0.97 MoM) in twin B. Twin A was also smaller than twin B with a crown–rump length of 60.4 mm (12 weeks and 4 days) versus 72.6 mm (13 weeks 3 days). First trimester serum screening showed a PAPP-A of 0.8 MoM and hCG1 of 2.4 MoM. The adjusted risk for a chromosome abnormality (in one or both twins) was calculated to be 1 : 8 for trisomy 21 and 1 : 520 for trisomy 18. The patient was counseled about her diagnostic options and offered chorionic villus sampling (CVS) of the MC placenta with a likely need for subsequent amniocentesis given the discordant features identified, or deferring diagnosis until amniocentesis could be performed (>15 weeks of gestation). She elected to proceed with immediate CVS, which was performed transabdominally on the single placenta and revealed a male karyotype with mosaicism for a supernumerary marker

Complete isochromosome 5p in one fetus of a monochorionic twin pair

459: Unstable housing is linked to adverse obstetric outcomes

All structures of the eye are susceptible to the deleterious effects of diabetes mellitus. Early diagnosis and treatment of diabetes mellitus, identification of ocular abnormalities, and patient education can mitigate many of these effects.


Keywords:

diabetes mellitus;
ophthalmoplegia;
refractive error;
cataract;
glaucoma;
neovascularization of the iris

Nonretinal Ocular Complications of Diabetes Mellitus

Monochorionic (MC) twin pregnancies are associated with significantly higher morbidity and mortality rates than dichorionic twins. Approximately 50% of MC twin pregnancies develop complications arising from the shared placenta and associated vascular connections. Severe twin-to-twin syndrome (TTTS) is reported to account for approximately 20% of these complications. Inter-twin vascular connections occur in almost all MC placentas and are related to the prognosis and outcome of these high-risk twin pregnancies. The number, size and type of connections have been implicated in the development of TTTS and other MC twin conditions. Three types of inter-twin vascular connections occur: 1) artery to vein connections (AVs) in which a branch artery carrying deoxygenated blood from one twin courses along the fetal surface of the placenta and dives into a placental cotyledon. Blood flows via a deep intraparenchymal capillary network into a draining vein that emerges at the fetal surface of the placenta and brings oxygenated blood toward the other twin. There is unidirectional flow from the twin supplying the afferent artery toward the twin receiving the efferent vein; 2) artery to artery connections (AAs) in which a branch artery from each twin meets directly on the superficial placental surface resulting in a vessel with pulsatile bidirectional flow, and 3) vein to vein connections (VVs) in which a branch vein from each twin meets directly on the superficial placental surface allowing low pressure bidirectional flow. In utero obstetric sonography with targeted Doppler interrogation has been used to identify the presence of AV and AA connections. Prenatally detected AAs that have been confirmed by postnatal placental injection studies have been shown to be associated with an improved prognosis for both twins. Furthermore, fetoscopic laser ablation of inter-twin vascular connections on the fetal surface of the shared placenta is now the preferred treatment for early, severe TTTS. Postnatal placental injection studies provide a valuable method to confirm the accuracy of prenatal Doppler ultrasound findings and the efficacy of fetal laser therapy. Using colored dyes separately hand-injected into the arterial and venous circulations of each twin, the technique highlights and delineates AVs, AAs, and VVs. This definitive demonstration of MC placental vascular anatomy may then be correlated with Doppler ultrasound findings and neonatal outcome to enhance our understanding of the pathophysiology of MC twinning and its sequelae. Here we demonstrate our placental injection technique.

/pdf/guide-wire-assisted-catheterization-and-colored-dye-2v9u7danf1.pdf

Larry Rand

Papers

Complete isochromosome 5p in one fetus of a monochorionic twin pair

459: Unstable housing is linked to adverse obstetric outcomes

Nonretinal Ocular Complications of Diabetes Mellitus

Guide wire assisted catheterization and colored dye injection for vascular mapping of monochorionic twin placentas.

33: Diastolic cardiac pathology predicts clinical twin-twin transfusion syndrome in discordant monochorionic/diamniotic twins