A matching method for improving covariate balance in cost-effectiveness analyses

In cost-effectiveness analyses (CEA) that use randomized controlled trials (RCTs), covariates of prognostic importance may be imbalanced and warrant adjustment. In CEA that use non-randomized studies (NRS), the selection on observables assumption must hold for regression and matching methods to be unbiased. Even in restricted circumstances when this assumption is plausible, a key concern is how to adjust for imbalances in observed confounders. If the propensity score is misspecified, the covariates in the matched sample will be imbalanced, which can lead to conditional bias. To address covariate imbalance in CEA based on RCTs and NRS, this paper considers Genetic Matching. This matching method uses a search algorithm to directly maximize covariate balance. We compare Genetic and propensity score matching in Monte Carlo simulations and two case studies, CEA of pulmonary artery catheterization, based on an RCT and an NRS. The simulations show that Genetic Matching reduces the conditional bias and root mean squared error compared with propensity score matching. Genetic Matching achieves better covariate balance than the unadjusted analyses of the RCT data. In the NRS, Genetic Matching improves on the balance obtained from propensity score matching and gives substantively different estimates of incremental cost-effectiveness. We conclude that Genetic Matching can improve balance on measured covariates in CEA that use RCTs and NRS, but with NRS, this will be insufficient to reduce bias; the selection on observables assumption must also hold.     

Kinetics and mechanism of the acid-catalyzed hydrolysis of O-benzylguanine

A variety of analytical techniques were used to elucidate the kinetics, reaction pathway and mechanism of hydrolysis of O⁶-benzylguanine, an O⁶-alkylguanine-DNA alkyltransferase depleting agent, as a function of pH, buffer concentration, temperature, substituents and halide nucleophiles. The reaction was also carried out in H₂¹⁸O in order to determine the site of cleavage. The pH-rate profile indicated that the hydrolysis of O⁶-benzylguanine was acid-catalyzed, with the neutral O⁶-benzylguanine having greater intrinsic susceptibility to undergo acid catalyzed hydrolysis compared to its protonated form. Alternatively, the kinetics could be described by the kinetically indistinguishable process of spontaneous degradation of fully di- and mono-protonated O⁶-benzylguanine. In this case, the di-protonated species is more susceptible than the mono-protonated species. Based on the ¹⁸O incorporation data, the site of the bond cleavage for hydrolysis of O⁶-benzylguanine was unambiguously assigned to the benzylic carbon-oxygen bond leading to the formation of benzyl alcohol and guanine as the predominant products. Benzyl chloride was also detected as a degradation product when the ionic strength of the solution was adjusted with sodium chloride. The rate of hydrolysis of p-substituted O⁶-benzylguanines increased with increasing electron donating capability of p-substituents, consistent with a mechanism involving positive charge formation on the benzylic carbon in the transition state. An Eyring plot resulted in a value for the observed entropy of activation, ΔS^≠, of −2.4 e.u. which was consistent with a unimolecular, S ^₁, reaction. Although the rate of hydrolysis of O⁶-benzylguanine was well correlated with the nucleophilicity of various halide nucleophiles, the magnitude of the catalysis was less than anticipated for S ^₂ type reactions. The results suggested that in the presence of bromide and iodide, the transition state had some S ^₂ character. Based on the above observations, a late transition state for this reaction was suggested, where positive charge development at the benzylic carbon atom was quite advanced.     

Microincision cataract surgery combined with vitrectomy: a case series

Aim

The objective of this study was to present the results of combined phacovitrectomy using 1.8 mm microincision cataract surgery (MICS) with special emphasis on the anterior segment complications in this group.

Methods

Retrospective, single-centre case series involving consecutive patients undergoing phacovitrectomy in a single centre in the United Kingdom during a 6-month period.

Results

A total of 52 eyes underwent combined MICS and pars plana vitrectomy. Intraoperative complications included posterior capsule rupture (n=2), minor iris trauma during phacoemulsification (n=1), iatrogenic retinal tears (n=2), and entry site break (n=1). Postoperatively two cases had significant inflammation, one of which resulted in 360° posterior synaechiea, iris bombe, and raised intraocular pressure. Other complications included mild posterior synaechiae (n=2), posterior capsular opacification (n=3), cystoid macular oedema (n=1), and hyphaema (n=1), which spontaneously resolved. There were no cases of intraocular lens decentration. Two patients who underwent surgery for retinal detachment repair subsequently redetached. Among those having surgery for macular hole, non-closure was seen in one patient and one patient developed a retinal detachment.

Conclusion

In conclusion, sub-2 mm MICS is a safe and effective technique in dealing with vitreoretinal disorders necessitating cataract surgery at the same time.     

State of the art: the evolving role of RT in combined modality therapy for GBM

Atypical teratoid/rhabdoid tumors (ATRT) are highly malignant brain tumors arising in young children. The majority of ATRT is characterized by inactivation of the chromatin remodeling complex member SMARCB1 (INI1/hSNF5). Little is known, however, on downstream pathways involved in the detrimental effects of SMARCB1 deficiency which might also represent targets for treatment. Using Drosophila melanogaster and the Gal4-UAS system, modifier screens were performed in order to identify the role of SMAD dependent signaling in the lethal phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. Expression and functional role of human homologs was next investigated in ATRT tumor samples and SMARCB1-deficient rhabdoid tumor cells. The lethal phenotype associated with snr1 knockdown in Drosophila melanogaster could be shifted to later stages of development upon additional knockdown of several decapentaplegic pathway members including Smox, and Med. Similarly, the transforming growth factor beta (TGFbeta) receptor type I kinase inhibitor SB431542 ameliorated the detrimental effect of snr1 knockdown in the fruit fly. Examination of homologs of candidate decapentaplegic pathway members in human SMARCB1-deficent ATRT samples revealed SMAD3 and SMAD6 to be over-expressed. In SMARCB1-deficent rhabdoid tumor cells, siRNA-mediated silencing of SMAD3 or SMAD6 expression reduced TGFbeta signaling activity and resulted in decreased proliferation. Similar results were obtained upon pharmacological inhibition of TGFbeta signaling using SB431542. Our data suggest that SMAD dependent signaling is involved in the detrimental effects of SMARCB1-deficiency and provide a rationale for the investigation of TGFbeta targeted treatments in ATRT.     

Seroprevalence of Cytomegalovirus among Voluntary Blood Donors

Background

Primary cytomegalovirus (CMV) infection in immunocompetent host is self limiting infection, leading to latency of virus. However congenital CMV and CMV infections in immunocompromised patients are associated with high morbidity and mortality. Transfusion transmitted-cytomegalovirus (TT-CMV) infection in low birth weight neonate and immunocompromised transfusion recipients is being increasingly reported. Studies recommended transfusion of CMV free or CMV safe blood in prevention of TT-CMV. In this background, the study was undertaken to assess the CMV seroprevalence in blood donor.

Methods

A prospective study was conducted in which 431 voluntary blood donors were screened for CMV IgG and IgM by EIA (Enzyme Immuno Assay).

Result

A total of 379 (87.9 %) voluntary blood donors were seropositive for CMV IgG. There was no statistical difference of CMV seropositivity and age. Further, seven (1.6%) subjects were both CMV IgM and IgG seropositive.

Conclusion

High seroprevalence of CMV in our donor population is a threat to the blood safety. Strategies in reducing the risk of TT- CMV are discussed. Use of prestorage leucodepleted ‘CMV safe’ blood components along with judicious use of blood is recommended in prevention of TT-CMV in high risk recipients.Key Words: Cytomegalovirus, Transfusion transmitted infections, Blood donors, Leucodepletion     

New non-oral drug delivery systems for Parkinson's disease treatment

INTRODUCTION: Parkinson's disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, but still unmet needs regarding its long-term management. Levodopa (LD) remains the most effective treatment; however, chronic use is associated with potentially disabling motor complications. AREAS COVERED: This review highlights a variety of new non-oral drug delivery strategies for non-invasive and invasive routes of drug administration for the treatment of PD. It also includes current and future trends of liposomes, solid lipid nanoparticles and biocompatible microparticles as new non-oral drug delivery systems. EXPERT OPINION: The long-term complications and limitations of LD treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with a new non-oral drug delivery system, with the aim of achieving long-lasting and less fluctuating drug levels, minimization of peak levels and thereby reduction of side effects.