Systematic Literature Review of Risk Factors for Poor Outcomes Among Adults With Respiratory Syncytial Virus Infection in High-Income Countries.

Identification of risk factors for severe respiratory syncytial virus (RSV) disease in adults could facilitate their appropriate vaccine recommendations. We conducted a systematic literature review (last 10 years in PubMed/Embase) to identify quantitative estimates of risk factors for severe RSV infection outcomes in high-income countries. Severe outcomes from RSV infection included hospitalization, excess mortality, lower respiratory tract infection, or a composite measure: severe RSV, which included these outcomes and others, such as mechanical ventilation and extended hospital stay. Among 1494 articles screened, 26 met eligibility criteria. We found strong evidence that the following increased the risk of severe outcomes: age, preexisting comorbid conditions (eg, cardiac, pulmonary, and immunocompromising diseases, as well as diabetes and kidney disease), and living conditions (socioeconomic status and nursing home residence). The frequency of severe outcomes among younger adults with comorbidities was generally similar to that experienced by older adults, suggesting that immunosenescence and chronic conditions are both contributing factors for elevated risk. Trial registration: PROSPERO (CRD42022315239).

The Burden of Metastatic Cancer-Induced Bone Pain: A Narrative Review.

Bone pain is one of the most common forms of pain reported by cancer patients with metastatic disease. We conducted a review of oncology literature to further understand the epidemiology of and treatment approaches for metastatic cancer-induced bone pain and the effect of treatment of painful bone metastases on the patient's quality of life. Two-thirds of patients with advanced, metastatic, or terminal cancer worldwide experience pain. Cancer pain due to bone metastases is the most common form of pain in patients with advanced disease and has been shown to significantly reduce patients' quality of life. Treatment options for cancer pain due to bone metastases include nonsteroidal anti-inflammatory drugs, palliative radiation, bisphosphonates, denosumab, and opioids. Therapies including palliative radiation and opioids have strong evidence supporting their efficacy treating cancer pain due to bone metastases; other therapies, like bisphosphonates and denosumab, do not. There is sufficient evidence that patients who experience pain relief after radiation therapy have improved quality of life; however, a substantial proportion are nonresponders. For those still requiring pain management, even with available analgesics, many patients are undertreated for cancer pain due to bone metastases, indicating an unmet need. The studies in this review were not designed to determine why cancer pain due to bone metastases was undertreated. Studies specifically addressing cancer pain due to bone metastases, rather than general cancer pain, are limited. Additional research is needed to determine patient preferences and physician attitudes regarding choice of analgesic for moderate to severe cancer pain due to bone metastases.

The Role of Congenital Cytomegalovirus Infection in Adverse Birth Outcomes: A Review of the Potential Mechanisms.

Human cytomegalovirus (CMV) is a major cause of nonhereditary adverse birth outcomes, including hearing and visual loss, neurologic deficits, and intrauterine growth retardation (IUGR), and may contribute to outcomes such as stillbirth and preterm delivery. However, the mechanisms by which CMV could cause adverse birth outcomes are not fully understood. This study reviewed proposed mechanisms underlying the role of CMV in stillbirth, preterm birth, and IUGR. Targeted literature searches were performed in PubMed and Embase to identify relevant articles. Several potential mechanisms were identified from in vitro studies in which laboratory-adapted and low-passage strains of CMV and various human placental models were used. Potential mechanisms identified included impairment of trophoblast progenitor stem cell differentiation and function, impairment of extravillous trophoblast invasiveness, dysregulation of Wnt signaling pathways in cytotrophoblasts, tumor necrosis factor-α mediated apoptosis of trophoblasts, CMV-induced cytokine changes in the placenta, inhibition of indoleamine 2,3-dioxygenase activity, and downregulation of trophoblast class I major histocompatibility complex molecules. Inherent challenges for the field remain in the identification of suitable in vivo animal models. Nonetheless, we believe that our review provides useful insights into the mechanisms by which CMV impairs placental development and function and how these changes could result in adverse birth outcomes.

Value of clinical trial narrative data to estimate the costs of adverse event management: a feasibility study.

Aims: The objective of this feasibility study was to determine the extent to which data from randomized controlled trials (RCTs) may serve as a useful source for collecting health care resource use (HCRU) for the purposes of estimating costs of managing adverse events (AEs), specifically, grade 3-4 nausea and thrombocytopenia, which may be experienced during chemotherapy treatment.Materials and Methods: The feasibility study was conducted in four steps: (1) HCRU data were extracted from patient narratives in four phase 3 RCTs in non-small cell lung cancer; (2) missing HCRU data were imputed; (3) unit costs were applied to the resulting HCRU data set and costs of managing AEs were estimated; and (4) the overall utility of using RCT data as a source for estimating costs of AEs was evaluated.Results: 33 nausea and 68 thrombocytopenia AEs met eligibility criteria and were evaluated in this study. Medication usage was recorded as a treatment in 76% of nausea AEs, although only 14% of the instances of medication usage included the minimum data elements required for costing. Platelet transfusions were provided in 24% of thrombocytopenia AEs; however, in only one instance were the minimum data elements recorded. Of nausea and thrombocytopenia AEs, 18% and 72%, respectively, required no missing data assumptions or imputation.Limitations: Only two AEs were considered, and they may not be representative of all AEs in terms of suitability for use in estimating HCRU and costs of managing AEs. Not all grade 3-4 AEs met the criteria for requiring a patient narrative. HCRU data in the narratives were incomplete.Conclusions: The usefulness of RCTs for estimating the costs of AEs may be improved by using a standardized form to collect HCRU data for key AEs, including an appropriate level of detail required to estimate costs of managing the AEs.

Efficacy, safety, and quality-of-life of treatments for acute relapses of multiple sclerosis: results from a literature review of randomized controlled trials.

BACKGROUND: Intravenous methylprednisolone (IVMP), repository corticotropin injection (RCI), plasmapheresis (PMP), and intravenous immunoglobulin (IVIG) are used in the treatment of acute multiple sclerosis (MS) relapse. A systematic literature review (SLR) of randomized controlled trials (RCTs) was conducted to examine the highest quality evidence available for these therapies. METHODS: English-language articles were searched in MEDLINE, Embase, and Cochrane Library through May 2016 per Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. MS conferences, SLRs, and bibliographies of included studies were also searched. Eligible studies included adults treated with ≥1 aforementioned therapy. RESULTS: Twenty-three RCTs were identified: 22 on efficacy, 11 on safety, and 3 on QOL (ie 18 IVMP, 2 RCI, 2 PMP, and 2 IVIG). IVMP and RCI improved relapse-related disability; however, IVIG and PMP showed inconsistent efficacy. QOL data were only ascertained for IVMP. CONCLUSIONS: RCTs indicate IVMP and RCI are efficacious and well tolerated treatments for MS relapse. Overall, many RCTs were dated, with sample sizes of fewer than 30 patients and no definitions for relapse nor clinically significant change. Contemporary evidence generation for all relapse treatments of interest, across efficacy, safety, and QOL outcomes, is still needed.

Randomized controlled trials in relapsed/refractory follicular lymphoma: a systematic review and meta-analysis.

This systematic literature review evaluated the clinical efficacy and safety of interventions used in relapsed/refractory follicular lymphoma. Primary efficacy outcomes were objective response rate, progression-free survival and overall survival. Safety endpoints were grade 3/4 toxicities, serious adverse events and withdrawals or deaths due to toxicity. Studies were selected if they were randomized controlled trials reporting on the efficacy or safety of treatments for relapsed or refractory follicular lymphoma, and if outcomes were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta-analysis. We identified 10 randomized controlled trials of treatments for relapsed/refractory follicular lymphoma. The most prominent drug investigated (alone or in combination) was rituximab. Most trials did not report median overall survival. Two trials reported median event-free survival (range, 1.2-23.2 months). Six of ten trials reported objective response rate (range, 9-93%). Meta-analysis showed only one statistically significant result: rituximab + bortezomib yielded a significantly higher objective response rate than rituximab monotherapy (relative risk, 1.28; 95% confidence interval, 1.11-1.47). Otherwise, there were no discernable differences in overall survival or progression-free survival, partly due to insufficient reporting of results in the clinical trials. The relatively small number of randomized controlled trials, few overlapping treatment arms, and variability in the randomized controlled trial features and in the endpoints studied complicate the formal comparison of therapies for relapsed/refractory follicular lymphoma. Additional well-designed randomized controlled trials are needed to fully understand the relative outcomes of older and more recently developed therapies.

Randomized controlled trials in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis.

This systematic literature review with meta-analysis was conducted on the clinical efficacy and safety of interventions used in the treatment of chronic lymphocytic leukemia (CLL). We systematically searched databases (PubMed, Cochrane Library, and Embase; 1997 to August 2, 2012), conference abstracts, bibliographic reference lists, recent reviews, and Clinicaltrials.gov. Primary efficacy outcomes were objective response rate, progression-free survival, and overall survival. Safety end points were Grade 3/4 toxicities, serious adverse events, withdrawals because of toxicity, and deaths due to toxicity. Studies were selected if they were randomized controlled trials (RCTs) reporting on the efficacy or safety of relapsed or refractory CLL and if outcomes for CLL were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta-analysis. We identified 6 RCTs of pharmacologic treatment for relapsed/refractory CLL. The most common drugs investigated (alone or in combination) were fludarabine and cyclophosphamide. When reported, median overall survival ranged from 27.3 to 52.9 months, and overall response rate from 58% to 82%. Although meta-analysis of efficacy results was considered, details are not presented because only 3 studies qualified and the common comparator treatment was not clinically relevant. The relatively small number of RCTs, few overlapping treatment arms, and variability in end points studied make it difficult to formally compare therapies for relapsed/refractory CLL. Significant variability in RCT features presents a further challenge to meaningful comparisons. Additional well-designed RCTs are needed to fully understand the relative efficacy and safety of older and more recently developed therapies.

Clinical efficacy and safety in relapsed/refractory mantle cell lymphoma: a systematic literature review.

A systematic literature review was performed to collect and review information on the clinical efficacy and safety of treatments for relapsed/refractory (R/R) mantle cell lymphoma (MCL), with a meta-analysis, if possible. PubMed, Embase, and the Cochrane Library were searched for studies published in English from January 1, 1997, to August 2, 2012. Conference proceedings, bibliographic reference lists of included articles, recent reviews, and ClinicalTrials.gov were searched for phase II to IV studies displaying results. Studies were included if they reported on patients with R/R MCL who were ineligible to receive high-dose chemotherapy with stem cell transplant. Studies of patients with several non-Hodgkin lymphoma subtypes were only included if they reported MCL outcomes separately. We identified 59 studies in R/R MCL. Forty distinct treatment regimens were evaluated. Thirty studies included more than 15 patients with R/R MCL. Six studies were comparative (including 5 randomized controlled trials [RCTs]); 53 were single-arm. There were no common treatments among the RCTs; therefore, a meta-analysis was not feasible. Thirty-one of 59 studies reported baseline data for patients with R/R MCL. Of the 30 studies with > 15 patients with R/R MCL, 30 reported overall response rate data, 14 reported progression-free survival (PFS), and 12 reported overall survival (OS). The small number of RCTs in R/R MCL precludes identifying an optimal treatment. Small sample sizes, infrequent reporting of OS and PFS, and limited information on patient characteristics made a comparison of results difficult. High-quality comparative studies of novel therapies that have the potential to demonstrate OS advantages in R/R MCL are needed.

Clinical efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma: a systematic literature review.

This systematic literature review was designed to assess information on the clinical efficacy and safety of interventions used in the treatment of refractory or relapsed diffuse large B-cell lymphoma (R/R DLBCL) and to perform a meta-analysis if possible. We searched databases (PubMed, EMBASE, and Cochrane Library for articles from 1997 to August 2, 2012 reported in English), conference abstracts, bibliographic reference lists, and the ClinicalTrials.gov database for phase II to IV studies with results. Studies had to report on patients with R/R DLBCL who were not eligible to receive high-dose therapy (HDT) with stem cell transplantation (SCT) (autologous or allogeneic). Mixed-type non-Hodgkin lymphoma (NHL) studies were required to report R/R DLBCL outcomes separately. We identified 55 studies that presented outcomes data separately for patients with R/R DLBCL. Of 7 comparative studies, only 4 were randomized controlled trials (RCTs). In the 2 RCTs with a common regimen, the patient populations differed too greatly to perform a valid meta-analysis. The 48 single-arm studies identified were typically small (n < 50 in most), with 31% reporting median progression-free survival (PFS) or overall survival (OS) specifically for the R/R DLBCL population. In these studies, median OS ranged from 4 to 13 months. The small number of RCTs in R/R DLBCL precludes identifying optimal treatments. Small sample size, infrequent reporting of OS and PFS separated by histologic type, and limited information on patient characteristics also hinder comparison of results. Randomized studies are needed to demonstrate which current therapies have advantages for improving survival and other important clinical outcomes in patients with R/R DLBCL.

Mutations in the extracellular domains of glutamate-gated chloride channel alpha3 and beta subunits from ivermectin-resistant Cooperia oncophora affect agonist sensitivity.

Two full-length glutamate-gated chloride channel (GluCl) cDNAs, encoding GluClalpha3 and GluClbeta subunits, were cloned from ivermectin-susceptible (IVS) and -resistant (IVR) Cooperia oncophora adult worms. The IVS and IVR GluClalpha3 subunits differ at three amino acid positions, while the IVS and IVR GluClbeta subunits differ at two amino acid positions. The aim of this study was to determine whether mutations in the IVR subunits affect agonist sensitivity. The subunits were expressed singly and in combination in Xenopus laevis oocytes. Electrophysiological whole-cell voltage-clamp recordings showed that mutations in the IVR GluClalpha3 caused a modest but significant threefold loss of sensitivity to glutamate, the natural ligand for GluCl receptors. As well, a significant decrease in sensitivity to the anthelmintics ivermectin and moxidectin was observed in the IVR GluClalpha3 receptor. Mutations in the IVR GluClbeta subunit abolished glutamate sensitivity. Co-expressing the IVS GluClalpha3 and GluClbeta subunits resulted in heteromeric channels that were more sensitive to glutamate than the respective homomeric channels, demonstrating co-assembly of the subunits. In contrast, the heteromeric IVR channels were less sensitive to glutamate than the homomeric IVR GluClalpha3 channels. The heteromeric IVS channels were significantly more sensitive to glutamate than the heteromeric IVR channels. Of the three amino acids distinguishing the IVS and IVR GluClalpha3 subunits, only one of them, L256F, accounted for the differences in response between the IVS and IVR GluClalpha3 homomeric channels.