Conducting a meta-analysis: basics and good practices

Meta-analysis is a statistical method to compare and combine effect sizes from a pool of relevant empirical studies. It is now a standard approach to synthesize research findings in many disciplines, including medical and healthcare research. This paper is the third paper of a mini-series introducing systematic review and meta-analysis. First, common effect sizes used in meta-analysis are presented. Fixed-, random- and mixed-effects models are then introduced. Next, a real data set from a published meta-analysis will be used to illustrate the procedures and interpretations. Last, software packages that may be used to conduct meta-analyses will be highlighted.     

Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase

The ubiquitin ligase SCF(Cdc4) (Skp1/Cul1/F-box protein) recognizes its substrate, the cyclin-dependent kinase inhibitor Sic1, in a multisite phosphorylation-dependent manner. Although short diphosphorylated peptides derived from Sic1 can bind to Cdc4 with high affinity, through systematic mutagenesis and quantitative biophysical analysis we show that individually weak, dispersed Sic1 phospho sites engage Cdc4 in a dynamic equilibrium. The affinities of individual phosphoepitopes serve to tune the overall phosphorylation site threshold needed for efficient recognition. Notably, phosphoepitope affinity for Cdc4 is dramatically weakened in the context of full-length Sic1, demonstrating the importance of regional environment on binding interactions. The multisite nature of the Sic1-Cdc4 interaction confers cooperative dependence on kinase activity for Sic1 recognition and ubiquitination under equilibrium reaction conditions. Composite dynamic interactions of low affinity sites may be a general mechanism to establish phosphorylation thresholds in biological responses.     

Natural orifice transluminal endoscopic surgery for the antireflux process in children

The successful deployment of therapeutic delivery systems with natural orifice transluminal endoscopic surgery (NOTES)-like techniques relies on a combination of technology that must be appropriate, and in children that includes size-specific, close team harmony with surgeons and endoscopists working hand in hand, absence of introduction of infection and other complications, and efficacy that is as good as the conventional approaches. Increasingly, cost will become a factor, and the higher cost of the NOTES-type techniques could be balanced by the potential for shorter stays as inpatients. Already the antireflux transoral incisionless fundoplication procedure has gained some acceptance in the United States, and it remains to be seen if it becomes commonplace in pediatrics. How long it will take for other techniques such as NOTES cholecystectomy, appendectomy, bowel resection, etc., to be adopted in a similar fashion will depend on the ongoing studies that are bearing fruit every year, and also on technological developments such as the so-called NOTES “toolbox.” These are interesting times for pediatric gastrointestinal endoscopy     

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.     

Significance of IGFBP-4 in the Development of Fetal Growth Restriction

Background: Fetal growth restriction (FGR) is a leading cause of perinatal mortality and morbidity. Animal studies suggest dysregulation of IGF-binding protein (IGFBP)-4 is significant in the development of FGR, although human data are lacking. We postulated that IGFBP-4 is expressed at the maternal fetal interface and plays a role in regulating IGF bioavailability. Thus, maternal serum levels of IGFBP-4 may be associated with complications of abnormal placental growth and development including FGR. Methods: Circulating levels of IGFBP-4 and its protease, pregnancy-associated plasma protein-A (PAPP-A), were examined in healthy pregnancies. Their expression in villi and bed as possible sources of the circulating products were examined by immunohistochemistry. From the large Ottawa and Kingston (OaK) Birth Cohort, a nested case-control study was conducted to examine circulating levels of IGBP-4, PAPP-A, IGF-I, and IGF-II by Western blot in early gestation in 36 women who went on to develop FGR and 36 controls having normal-weight babies. Results: IGFBP-4 was elevated in early pregnancy compared with nonpregnant women and women in later pregnancy, consistent with the presence of abundant extravillous trophoblasts and decidual cells that highly expressed IGFBP-4. High expression of PAPP-A was observed in extravillous trophoblasts and decidual cells in early pregnancy but hardly detectable in the circulation at this time, suggesting maternal circulating PAPP-A originates more likely from syncytiotrophoblasts. Increased IGFBP-4 in the maternal circulation in early pregnancy was associated with the development of FGR [0.48 (0.28-0.74) in control vs. 1.22 (0.66-1.65) in FGR; odds ratio = 22 (95% confidence interval = 2.7-181)]. No difference was observed in circulating PAPP-A, IGF-I and IGF-II in the FGR vs. control group. Conclusion: Our findings support the role of IGFBP-4 in regulating IGF bioavailability and provide new clues for the prevention and treatment of FGR, raising the possibility of clinical use of IGFBP-4 as an early biomarker for this condition.     

Association between plasma homocysteine and myocardial SPECT abnormalities in patients referred for suspected myocardial ischaemia

Background

Elevated plasma homocysteine level has emerged as a relatively newly recognised risk factor for coronary artery disease (CAD). However, reduction of plasma homocysteine levels in large prospective studies did not appear to reduce the risk for subsequent cardiac events. In this study, we investigated the association between plasma homocysteine levels and quantitative indices of myocardial perfusion SPECT imaging in patients referred for myocardial ischaemia.

Methods

Quantitative myocardial perfusion SPECT indices were obtained for 120 patients who were recruited for the study. All patients underwent a two-day rest–stress myocardial perfusion imaging. Plasma venous sampling was done on all patients after an overnight fast. Of the 120 participants (mean age 56 years, 53% males), 33% had elevated plasma homocysteine levels. The plasma homocysteine level was then compared to the results of imaging and other known risk factors.

Results

After adjustment for traditional risk factors of coronary artery disease, patients with elevated homocysteine levels had a significantly higher mean summed stress score (SSS) (11.3 vs 6.9, p = 0.02) than patients with a normal homocysteine level. This was true for both single- and multivessel disease. Also, patients with elevated homocysteine levels had a higher stress end-systolic volume (SESV) (137 vs 105 ml, p = 0.03) and lower post-stress left ventricular ejection fraction (SEF) (54 vs 64%, p = 0.02). The patients with elevated plasma homocysteine levels also had a significantly lower mean body mass index (BMI) (26.6 vs 30.6 kg/m², p = 0.002). There was a significant relationship between the total number of known risk factors in a patient with CAD and the proportion of patients presenting with elevated plasma homocysteine levels (p = 0.03). Also, the extent of infarct, as measured by the summed rest score (SRS), was more closely correlated with an elevated homocysteine level than with the degree of ischaemia.

Conclusion

There was a correlation between plasma homocysteine level and the presence and extent of myocardial perfusion abnormalities in patients with established coronary artery disease, in particular those with multiple risk factors and multi-vessel infarction.     

The effect of aging on skeletal muscle capillarization in a murine model

Capillarization of skeletal muscle has been reported to be both maintained and reduced with advancing age. This conflict may represent methodological differences between biopsy studies. We have examined capillarization throughout two muscles, soleus and extensor digitorum longus (EDL), from a well-established colony of aging mice, and related this to fiber number (C/F ratio) and type. Labeling of muscle capillaries was performed with the biotinylated Griffonia (Bandeiraea) simplicifolia lectin (GSL 1) using immunochemistry. The results showed a significant increase in the C/F ratio in the aged mice when compared with the younger (6-month mice soleus = 1.296, 95% CI 1.226-1.366 vs 28-month mice soleus = 1.530, 95% CI 1.488-1.572, p <.001; 6-month mice EDL = 0.881, 95% CI 0.751-1.011 vs 28-month mice EDL = 1.124, 95% CI 1.028-1.220, p = .017). These differences could not be accounted for by changes in fiber type but may reflect loss of fibers. Alternatively, there may be increased angiogenic drive or a failure of downregulation of angiogenesis.     

Radiofrequency Neurolysis for Facet Arthropathy: A Retrospective Case Series and Review of the Literature

Abstract Context: Facet arthropathy is a common cause of spine‐related pain. Typically resulting from spondylosis, trauma, including surgical trauma or post surgical stress is also a significant cause. Radiofrequency thermocoagulation or neurolysis may be an effective modality providing long‐term improvement. Objectives: To evaluate the success rates for radiofrequency neurolysis for facet arthropathy in a large retrospective case series in a single pain practice setting. Design: A retrospective case series involving chart reviews and patient follow‐up visits or telephone contacts of radiofrequency neurolytic procedures performed for facet arthropathy over a 4‐year period. Setting: Private practice pain clinic with academic affiliation in Tulsa, OK. Participants: One hundred forty eight patients with confirmed facet arthropathy refractory to conservative measures underwent 230 radiofrequency neurolysis procedures and were followed for a minimum of 1 year post procedure. For cervical facet procedures: 63 patients (106 procedures); age range F: 27‐84 years old; M: 33‐65 years old. For lumbar facet procedures: 85 patients (124 facet procedures); age range F: 19‐81 years old; M: 20‐77 years old. Main Outcome Measures: After the radiofrequency procedure, patients were followed with periodic visits or telephone contacts. Outcome measures were McGill short form pain questionnaire, VAS pain scores, muscle spasm scores, tenderness, range of motion and patient subjective global responses. Results: Subjective patient responses were graded as follows: excellent:greater than 70% improvement, good: 50% to 70% improvement, fair: 30% to 49%, and poor: less than 30%. One hundred six radiofrequency procedures were performed in the 63 cervical cases and 124 in the 85 lumbar cases with those patients who had good to excellent responses undergoing repeat procedures. Of the patients with cervical facet radiofrequency procedures, 38 (37%), 51 (48%), 4 (3%) and 13 (12%) had excellent, good, fair or poor responses, respectively. Of the lumbar facet radiofrequency cases, 37 (30%), 52 (41%), 13 (10%) and 22 (19%) had excellent, good, fair or poor responses, respectively. Excellent responders noted an average duration of 10.8 months (range 3‐34 months before dropping below 70% improvement level) for cervical cases and 7.9 months (range 3‐20) for lumbar. Good responders noted an average duration of 6.5 months (range 3‐22 months before dropping below 50% improvement level) for cervical and 6.8 months (range 3‐48) for lumbar radiofrequency procedures. No significant side effects were experienced (short‐term neuritis was seen in 2 patients who had cervical and 1 who had lumbar RFTC, but resolved in each case after a few weeks). Conclusions: In summary, 85% of cervical and 71% of lumbar RFTC cases had at least a 50% improvement in symptoms for extended periods. RFTC of median branches for facet arthropathy is a safe and efficacious modality with the potential for long‐term benefit.     

Palliative sedation therapy: a review of definitions and usage

Palliative care clinicians are faced with the challenge of managing a multitude of complex symptom combinations in patients for whom they care. Although many symptoms respond favourably to established protocols, others may remain refractory to such intervention. It is within the context of trying to manage such symptoms that the issue of palliative sedation therapy arises. The use of sedation in such circumstances is one that has prompted considerable debate in the palliative care literature. Discourse has been hampered, however, by a lack of consensus regarding the meaning and intent of palliative sedation therapy, when it should be used clinically and how it is to be achieved pharmacologically. There is a dearth of research examining the meanings ascribed to its use from the perspective of patients, families, and health-care providers. This article will provide an overview of these identified issues, and provide suggestions for ways in which palliative sedation therapy might further be examined and understood.