Prevalence of potentially preventable unplanned hospitalizations caused by therapeutic failures and adverse drug withdrawal events among older veterans.

AIMSDeprescribing is a suggested intervention to reverse the potential iatrogenic harms of inappropriate polypharmacy. The review aimed to determine whether or not deprescribing is a safe, effective and feasible intervention to modify mortality and health outcomes in older adults. METHODSSpecified databases were searched from inception to February 2015. Two researchers independently screened all retrieved articles for inclusion, assessed study quality and extracted data. Data were pooled using RevMan v5.3. Eligible studies included those where older adults had at least one medication deprescribed. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, psychological and physical health outcomes, quality of life, and medication usage (e.g. successful deprescribing, number of medications prescribed, potentially inappropriate medication use). RESULTSA total of 132 papers met the inclusion criteria, which included 34 143 participants aged 73.8 ± 5.4 years. In nonrandomized studies, deprescribing polypharmacy was shown to significantly decrease mortality (OR 0.32, 95% CI: 0.17-0.60). However, this was not statistically significant in the randomized studies (OR 0.82, 95% CI 0.61-1.11). Subgroup analysis revealed patientspecific interventions to deprescribe demonstrated a significant reduction in mortality (OR 0.62, 95% CI 0.43-0.88). However, generalized educational programmes did not change mortality (OR 1.21, 95% CI 0.86-1.69). CONCLUSIONSAlthough nonrandomized data suggested that deprescribing reduces mortality, deprescribing was not shown to alter mortality in randomized studies. Mortality was significantly reduced when applying patient-specific interventions to deprescribe in randomized studies. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Polypharmacy in older adults is correlated to poor health outcomes.• Deprescribing is one proposed intervention to reduce the harm associated with polypharmacy.• Limited evidence is available to support deprescribing as an intervention. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 82 583-623 583

IntroductionThe division of chronic lymphocytic leukemia (CLL) into 2 major subsets, based on the presence or absence of a significant level of somatic mutations in the immunoglobulin variable (V) region genes has had a major effect on our understanding of this B-cell malignancy. [1][2][3] The difference in clinical behavior, with unmutated CLL (U-CLL) showing a worse prognosis, is clearly relevant for clinical management, and has led to an intensive search for more easily measurable markers that parallel V-gene status. Meanwhile the subtle differences in the biology of the tumor cells that dictate the variable course are being sought. Gene expression analysis detected up-regulation of several cell cycle-associated genes in U-CLL. 4 A powerful discriminator was identified as the protein tyrosine kinase -associated protein 70 (ZAP-70), with a 4-to 5-fold increase in U-CLL. 5 Expression at the protein level was also shown to be highly associated with U-CLL, 6 and measurement by flow cytometry appears to provide a clinically relevant surrogate marker for prognosis. 7 ZAP-70 is a member of the Syk family of tyrosine kinases and is known to be a critical component of the T-cell receptor signaling pathway. 8 It was an unexpected component of a B-cell malignancy because it was thought to be confined to T cells and natural killer (NK) cells. 9 However, ZAP-70 can be expressed in normal B cells, 9 and the high level of expression in U-CLL, but not in mutated CLL (M-CLL), added to the interest in possible differences in signaling pathways between the subsets.The B-cell receptor (BCR) is critical for survival of normal peripheral B cells. 10 It is also likely to have a role in maintenance or growth of tumors derived from mature B cells, which are rarely sIg Ϫ . In CLL, levels are low compared to normal B lymphocytes and to other B-cell malignancies. Based on observations of self-reactive B cells in double transgenic mice continuously expressing antigen, 11 it has been suggested that the low levels reflect an anergic state consequent on interaction with antigen in the absence of T-cell help. 12 However, no direct evidence for this had been obtained.The BCR includes sIg and the Ig-␣/Ig-␤ heterodimer (CD79a and CD79b) associated noncovalently in a 1:1 ratio. 13 Following engagement of antigen, receptors aggregate leading to phosphorylation of the Ig-␣/Ig-␤ ITAM motifs by Src-family tyrosine kinases, including Lyn. 14 Recruitment and phosphorylation of other kinases, with Syk being an important component, then activates intracellular signaling cascades. Phosphorylation of Syk therefore provides an indicator of membrane proximal events that depend on the structural integrity and oligomeric form of the BCR. It is this ability to signal via Ig-␣/Ig-␤ that is critical for survival of mature normal B cells. 15 We 16 and others 17 have reported that this early response to ligation of sIgM in CLL varies between the subsets, with an increased tendency for U-CLL to phosphorylate Syk. A parallel phosphorylation of ZAP-70 with recruitmen...