Interleukin 2 Receptor Antagonists for Kidney Transplant Recipients

Background: Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily, with 38% of new kidney transplant recipients in the United States, and 23% in Australasia receiving IL2Ra in 2002. Objectives: This study aims to systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to other antibody therapy. Search strategy: The Cochrane Renal Group's specialised register (June 2003), the Cochrane Controlled Trials Register (in The Cochrane Library issue 3, 2002), MEDLINE (1966-November 2002) and EMBASE (1980-November 2002). Reference lists and abstracts of conference proceedings and scientific meetings were hand-searched from 1998-2003. Trial groups, authors of included reports and drug manufacturers were contacted. Selection criteria: Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy. Data collection and analysis: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) with 95% confidence intervals (CI). Main results: One hundred and seventeen reports from 38 trials involving 4893 participants were included. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not significantly different at one (RR 0.83, 95% CI 0.66 to 1.04) or three years (RR 0.88, 95% CI 0.64 to 1.22). Acute rejection (AR) was significantly reduced at six months (RR 0.66, 95% CI 0.59 to 0.74) and at one year (RR 0.67, 95% CI 0.60 to 0.75). At one year, cytomegalovirus (CMV) infection (RR 0.82, 95% CI 0.65 to 1.03) and malignancy (RR 0.67, 95% CI 0.33 to 1.36) were not significantly different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but adverse effects strongly favoured IL2Ra. Reviewer's conclusions: Given a 40% risk of rejection, seven patients would need treatment with IL2Ra to prevent one patient having rejection, with no definite improvement in graft or patient survival. There is no apparent difference between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effect

Trial Registration and Declaration of Registration by Authors of Randomized Controlled Trials

Background: Trial registration was introduced to reduce research bias by promoting trial transparency and accountability. We aimed to evaluate the frequency of, and factors associated with, trial registration and declaration of trial registration. Methods: We selected all randomized controlled trials in kidney transplantation published between October 2005 and December 2010 and determined whether a trial was registered and whether a trial declared their registration in subsequent trial reports. Results: Of 307 eligible trials identified, 24% (74/307) were registered, and of those, 59% (44/74) contained trial registration details within at least one trial report. Trial registration was more likely for trials published more than once, in later years or reported in journals that followed the International Committee of Medical Journal Editors guidelines. Trial registration was less likely for trials that did not declare their funding sources. Registered trials were more likely to declare registration details in related reports if published in later years or in a journal that followed International Committee of Medical Journal Editors guidelines. Trials that did not declare their funding sources were less likely to declare registration details. Conclusions: Although still suboptimal, the situation is improving over time, with both trial registration and declaration of registration details more likely in later years

Food groups and risk of coronary heart disease, stroke and heart failure : a systematic review and dose-response meta-analysis of prospective studies

Background: Despite growing evidence for food-based dietary patterns' potential to reduce cardiovascular disease risk, knowledge about the amounts of food associated with the greatest change in risk of specific cardiovascular outcomes and about the quality of meta-evidence is limited. Therefore, the aim of this meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups (whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages [SSB]) and the risk of coronary heart disease (CHD), stroke and heart failure (HF). Methods: We conducted a systematic search in PubMed and Embase up to March 2017 for prospective studies. Summary risk ratios (RRs) and 95% confidence intervals (95% CI) were estimated using a random effects model for highest versus lowest intake categories, as well as for linear and non-linear relationships. Results: Overall, 123 reports were included in the meta-analyses. An inverse association was present for whole grains (RRCHD: 0.95 (95% CI: 0.92-0.98), RRHF: 0.96 (0.95-0.97)), vegetables and fruits (RRCHD: 0.97 (0.96-0.99), and 0.94 (0.90-0.97); RRstroke: 0.92 (0.86-0.98), and 0.90 (0.84-0.97)), nuts (RRCHD: 0.67 (0.43-1.05)), and fish consumption (RRCHD: 0.88 (0.79-0.99), RRstroke: 0.86 (0.75-0.99), and RRHF: 0.80 (0.67-0.95)), while a positive association was present for egg (RRHF: 1.16 (1.03-1.31)), red meat (RRCHD: 1.15 (1.08-1.23), RRstroke: 1.12 (1.06-1.17), RRHF: 1.08 (1.02-1.14)), processed meat (RRCHD: 1.27 (1.09-1.49), RRstroke: 1.17 (1.02-1.34), RRHF: 1.12 (1.05-1.19)), and SSB consumption (RRCHD: 1.17 (1.11-1.23), RRstroke: 1.07 (1.02-1.12), RRHF: 1.08 (1.05-1.12)) in the linear dose-response meta-analysis. There were clear indications for non-linear dose-response relationships between whole grains, fruits, nuts, dairy, and red meat and CHD. Conclusion: An optimal intake of whole grains, vegetables, fruits, nuts, legumes, dairy, fish, red and processed meat, eggs and SSB showed an important lower risk of CHD, stroke, and HF

Interleukin 2 Receptor Antagonists for Kidney Transplant Recipients

Background Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily since their introduction, but the proportion of new transplant recipients receiving IL2Ra differs around the globe, with 27% of new kidney transplant recipients in the United States, and 70% in Australasia receiving IL2Ra in 2007. Objectives To systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to another immunosuppressive induction strategy. Search methods We searched the Cochrane Renal Group’s specialised register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to identify new records, and authors of included reports were contacted for clarification where necessary. Selection criteria Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy. Data collection and analysis Data was extracted and assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). Main results We included 71 studies (306 reports, 10,520 participants). Where IL2Ra were compared with placebo (32 studies; 5,854 patients) graft loss including death with a functioning graft was reduced by 25% at six months (16 studies: RR 0.75, 95% CI 0.58 to 0.98) and one year (24 studies: RR 0.75, 95% CI 0.62 to 0.90), but not beyond this. At one year biopsy‐proven acute rejection was reduced by 28% (14 studies: RR 0.72, 95% CI 0.64 to 0.81), and there was a 19% reduction in CMV disease (13 studies: RR 0.81, 95% CI 0.68 to 0.97). There was a 64% reduction in early malignancy within six months (8 studies: RR 0.36, 95% CI 0.15 to 0.86), and creatinine was lower (7 studies: MD ‐8.18 µmol/L 95% CI ‐14.28 to ‐2.09) but these differences were not sustained. When IL2Ra were compared to ATG (18 studies, 1,844 participants), there was no difference in graft loss at any time point, or for acute rejection diagnosed clinically, but the was benefit of ATG therapy over IL2Ra for biopsy‐proven acute rejection at one year (8 studies:, RR 1.30 95% CI 1.01 to 1.67), but at the cost of a 75% increase in malignancy (7 studies: RR 0.25 95% CI 0.07 to 0.87) and a 32% increase in CMV disease (13 studies: RR 0.68 95% CI 0.50 to 0.93). Serum creatinine was significantly lower for IL2Ra treated patients at six months (4 studies: MD ‐11.20 µmol/L 95% CI ‐19.94 to ‐2.09). ATG patients experienced significantly more fever, cytokine release syndrome and other adverse reactions to drug administration and more leucopenia but not thrombocytopenia. There were no significant differences in outcomes according to cyclosporine or tacrolimus use, azathioprine or mycophenolate, or to the study populations baseline risk for acute rejection. There was no evidence that effects were different according to whether equine or rabbit ATG was used. Authors' conclusions Given a 38% risk of rejection, per 100 recipients compared with no treatment, nine recipients would need treatment with IL2Ra to prevent one recipient having rejection, 42 to prevent one graft loss, and 38 to prevent one having CMV disease over the first year post‐transplantation. Compared with ATG treatment, ATG may prevent some experiencing acute rejection, but 16 recipients would need IL2Ra to prevent one having CMV, but 58 would need IL2Ra to prevent one having malignancy. There are no apparent differences between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effects

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Self-reported colorectal cancer screening of Medicare beneficiaries in family medicine vs. internal medicine practices in the United States: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The benefit of screening for decreasing the risk of death from colorectal cancer (CRC) has been shown, yet many patients in primary care are still not undergoing screening according to guidelines. There are known variations in delivery of preventive health care services among primary care physicians. This study compared self-reported CRC screening rates and patient awareness of the need for CRC screening of patients receiving care from family medicine (FPs) vs. internal medicine (internists) physicians.</p> <p>Methods</p> <p>Nationally representative sample of non-institutionalized beneficiaries who received medical care from FPs or internists in 2006 (using Medicare Current Beneficiary Survey). The main outcome was the percentage of patients screened in 2007. We also examined the percentage of patients offered screening.</p> <p>Results</p> <p>Patients of FPs, compared to those of internists, were less likely to have received an FOBT kit or undergone home FOBT, even after accounting for patients' characteristics. Compared to internists, FPs' patients were more likely to have heard of colonoscopy, but were less likely to receive a screening colonoscopy recommendation (18% vs. 27%), or undergo a colonoscopy (43% vs. 46%, adjusted odds ratios [AOR], 95% confidence interval [CI]-- 0.65, 0.51-0.81) or any CRC screening (52% vs. 60%, AOR, CI--0.80, 0.68-0.94). Among subgroups examined, higher income beneficiaries receiving care from internists had the highest screening rate (68%), while disabled beneficiaries receiving care from FPs had the lowest screening rate (34%).</p> <p>Conclusion</p> <p>Patients cared for by FPs had a lower rate of screening compared to those cared for by internists, despite equal or higher levels of awareness; a difference that remained statistically significant after accounting for socioeconomic status and access to healthcare. Both groups of patients remained below the national goal of 70 percent.</p

Follicle Stimulating Hormone is an accurate predictor of azoospermia in childhood cancer survivors

Funding: RTM is supported by a Wellcome Trust Intermediate Clinical Fellowship (grant no: 098522), https://wellcome.ac.uk/what-we-do/directories/intermediate-clinical-fellowships-people-funded. TWK is supported by Engineering and Physical Sciences Research Council grant EP/P015638/1, http://gow.epsrc.ac.uk/NGBOViewGrant.aspx?GrantRef=EP/P015638/1.The accuracy of Follicle Stimulating Hormone as a predictor of azoospermia in adult survivors of childhood cancer is unclear, with conflicting results in the published literature. A systematic review and post hoc analysis of combined data (n = 367) were performed on all published studies containing extractable data on both serum Follicle Stimulating Hormone concentration and semen concentration in survivors of childhood cancer. PubMed and Medline databases were searched up to March 2017 by two blind investigators. Articles were included if they contained both serum FSH concentration and semen concentration, used World Health Organisation certified methods for semen analysis, and the study participants were all childhood cancer survivors. There was no evidence for either publication bias or heterogeneity for the five studies. For the combined data (n = 367) the optimal Follicle Stimulating Hormone threshold was 10.4 IU/L with specificity 81% (95% CI 76%–86%) and sensitivity 83% (95% CI 76%–89%). The AUC was 0.89 (95%CI 0.86–0.93). A range of threshold FSH values for the diagnosis of azoospermia with their associated sensitivities and specificities were calculated. This study provides strong supporting evidence for the use of serum Follicle Stimulating Hormone as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer.Publisher PDFPeer reviewe

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Are Reports of Psychological Stress Higher in Occupational Studies? A Systematic Review across Occupational and Population Based Studies

This study was funded by the UK Ministry of Defence (MoD)