Tectonic trigger to the first major extinction of the Phanerozoic: The early Cambrian Sinsk event.

The Cambrian explosion, one of the most consequential biological revolutions in Earth history, occurred in two phases separated by the Sinsk event, the first major extinction of the Phanerozoic. Trilobite fossil data show that Series 2 strata in the Ross Orogen, Antarctica, and Delamerian Orogen, Australia, record nearly identical and synchronous tectono-sedimentary shifts marking the Sinsk event. These resulted from an abrupt pulse of contractional supracrustal deformation on both continents during the Pararaia janeae trilobite Zone. The Sinsk event extinction was triggered by initial Ross/Delamerian supracrustal contraction along the edge of Gondwana, which caused a cascading series of geodynamic, paleoenvironmental, and biotic changes, including (i) loss of shallow marine carbonate habitats along the Gondwanan margin; (ii) tectonic transformation to extensional tectonics within the Gondwanan interior; (iii) extrusion of the Kalkarindji large igneous province; (iv) release of large volumes of volcanic gasses; and (v) rapid climatic change, including incursions of marine anoxic waters and collapse of shallow marine ecosystems.

Risk of Venous Thromboembolism by Cancer Type: A Network Meta-Analysis.

Patients with cancer have an increased risk of venous thromboembolism (VTE). Comparing tumor-specific VTE risk is complicated by factors such as surgery, disease stage, and chemotherapy. Network meta-analysis (NMA) using cancer types as network nodes enabled us to estimate VTE rates by leveraging comparisons across cancer types while adjusting for baseline VTE risk in individual studies. This study was conducted to estimate the risk of VTE by cancer type and factors influencing VTE risk. The Embase, MEDLINE, and Cochrane Library repositories were systematically searched to identify clinical trials and observational studies published from 2005 to 2022 that assessed the risk of primary cancer-related VTE among two or more distinct cancer types. Studies with similar cancer populations and study methods reporting VTE occurring within 1 year of diagnosis were included in the NMA. Relative VTE rates across cancer types were estimated with random-effects Bayesian NMAs. Absolute VTE rates were calculated from these estimates using the average VTE incidence in lung cancer (the most frequently reported type) as the "anchor." From 2,603 records reviewed, 30 studies were included in this NMA. The general network described 3,948,752 patients and 18 cancer types: 3.1% experienced VTE within 1 year of diagnosis, with cancer-specific rates ranging from 0.7 to 7.4%. Consistent with existing VTE risk prediction tools, pancreatic cancer was associated with higher-than-average VTE risk. Other cancer types with high VTE risk were brain and ovarian cancers. The relative rankings of VTE risk for certain cancers changed based on disease stage and/or receipt of chemotherapy or surgery.

Tubule system of earliest shells as a defense against increasing microbial attacks.

The evolutionary mechanism behind the early Cambrian animal skeletonization was a complex and multifaceted process involving environmental, ecological, and biological factors. Predation pressure, oxygenation, and seawater chemistry change have frequently been proposed as the main drivers of this biological innovation, yet the selection pressures from microorganisms have been largely overlooked. Here we present evidence that calcareous shells of the earliest mollusks from the basal Cambrian (Fortunian Age, ca. 539-529 million years ago) of Mongolia developed advanced tubule systems that evolved primarily as a defensive strategy against extensive microbial attacks within a microbe-dominated marine ecosystem. These high-density tubules, comprising approximately 35% of shell volume, enable nascent mineralized mollusks to cope with increasing microbial bioerosion caused by boring endolithic cyanobacteria, and hence represent an innovation in shell calcification. Our finding demonstrates that enhanced microboring pressures played a significant role in shaping the calcification of the earliest mineralized mollusks during the Cambrian Explosion.

A Systematic Literature Review of Psychological Interventions for Adults with Type 1 Diabetes.

INTRODUCTION: The psychological burden of type 1 diabetes mellitus (T1DM) is considerable. The condition affects the daily lives of adults living with T1DM (ALWT1DM) in many ways. International guidelines highlight the importance of providing psychological support to ALWT1DM to improve health outcomes and well-being. METHODS: We conducted a systematic literature review of randomised controlled trials (RCTs) to identify the evidence on the impact of psychological interventions on glycaemic control and psychological outcomes in ALWT1DM. Literature searches of Medline, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, and the grey literature were performed to identify relevant RCTs, published in English, from 2001 onward. Fourteen RCTs of ten psychological interventions in ALWT1DM were eligible and included in the qualitative synthesis. The studies varied considerably in terms of duration, target population, endpoints, and efficacy. RESULTS: Overall, psychological interventions did not perform significantly better than control treatments in improving glycaemic control, although selected patient groups did report benefits from some psychological intervention types, such as cognitive behavioural therapy. Although most of the psychological interventions produced small, nonsignificant improvements in self-reported patient functioning, some treatments were effective in reducing diabetes distress and improving mental health, even if no impact on glycaemic control was observed. DISCUSSION: Current guidelines for the treatment of T1DM recommend access to psychological services; however, there is a paucity of high-quality evidence from clinical trials on the effectiveness or preferred structure of psychological support. There is a clear need for more rigorous, large-scale, international research to address the efficacy of psychological interventions in ALWT1DM.

Predictive value of quantitative fetal fibronectin for spontaneous preterm birth in asymptomatic pregnancies: a systematic literature review and meta-analysis.

OBJECTIVE: Tests capable of accurate prediction of spontaneous preterm birth (sPTB) are crucial to inform clinical decisions to prevent neonatal deaths and reduce the risk of morbidity in surviving infants. A systematic literature review and meta-analysis were performed to assess the utility of the quantitative fetal fibronectin (fFN) test to predict sPTB at different test concentration thresholds. METHODS: Literature searches were conducted in MEDLINE, Embase, and the Cochrane Library in May 2022. Observational studies and clinical trials investigating the clinical utility of the quantitative fFN test in asymptomatic pregnancies prior to 37 weeks of gestation were eligible for inclusion. Meta-analysis quantified the risk of sPTB prior to four gestational age milestones (<28, <30, <34 and <37 weeks) based on quantitative fFN levels. No risk of bias assessment was performed however, clinical and methodological heterogeneity was explored to determine the feasibility of performing analyses. RESULTS: 11 studies showed a quantitative assessment of fFN can differentiate between very high and very low risks of sPTB in asymptomatic pregnancies with <10% of women with very low fFN (<10 ng/mL) versus 37-67% of women with very high fFN (>200 ng/mL) delivering before 34 weeks. A meta-analysis of two studies showed, albeit with a low number of events, the odds of sPTB prior to 28 weeks was nine times higher in women testing positive at ≥50 ng/mL, whereas the odds of sPTB was 25 times higher in women with fFN concentrations >200 ng/mL (versus <50 ng/mL reference). Similarly, pooling three studies showed the odds of sPTB prior to 37 weeks was four times higher in women who tested positive at ≥50 ng/ml whereas the odds of delivery before 37 weeks was seven times higher for women with fFN concentrations ≥200 ng/ml (versus <50 ng/mL reference). CONCLUSION: Quantitative fFN testing demonstrates increased predictive capabilities and utility of fFN testing in clinical practice, potentially preventing unnecessary intervention for women at very low risk and allowing an opportunity to optimize the management of asymptomatic patients at high risk of preterm delivery.

Handling related publications reporting real-world evidence in network meta-analysis: a case study in multiple sclerosis.

Aim: The presence of two or more publications that report on overlapping patient cohorts poses a challenge for quantitatively synthesizing real-world evidence (RWE) studies. Thus, we evaluated eight approaches for handling such related publications in network meta-analyses (NMA) of RWE studies. Methods: Bayesian NMAs were conducted to estimate the annualized relapse rate (ARR) of disease-modifying therapies in multiple sclerosis. The NMA explored the impact of hierarchically selecting one pivotal study from related publications versus including all of them while adjusting for correlations. Results: When selecting one pivotal study from related publications, the ARR ratios were mostly similar regardless of the pivotal study selected. When including all related publications, there were shifts in the point estimates and the statistical significance. Conclusion: An a priori hierarchy should guide the selection among related publications in NMAs of RWE. Sensitivity analyses modifying the hierarchy should be considered for networks with few or small studies.

Risk of Adverse Events Associated with Domperidone and Metoclopramide in Gastroparesis: Systematic Review and Meta-analysis.

BACKGROUND: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis. METHODS: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI). RESULTS: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs. CONCLUSIONS: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions. REGISTRATION: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).

Fibrous or Prismatic? A Comparison of the Lamello-Fibrillar Nacre in Early Cambrian and Modern Lophotrochozoans.

The Precambrian-Cambrian interval saw the first appearance of disparate modern metazoan phyla equipped with a wide array of mineralized exo- and endo-skeletons. However, the current knowledge of this remarkable metazoan skeletonization bio-event and its environmental interactions is limited because uncertainties have persisted in determining the mineralogy, microstructure, and hierarchical complexity of these earliest animal skeletons. This study characterizes in detail a previously poorly understood fibrous microstructure-the lamello-fibrillar (LF) nacre-in early Cambrian mollusk and hyolith shells and compares it with shell microstructures in modern counterparts (coleoid cuttlebones and serpulid tubes). This comparative study highlights key differences in the LF nacre amongst different lophotrochozoan groups in terms of mineralogical compositions and architectural organization of crystals. The results demonstrate that the LF nacre is a microstructural motif confined to the Mollusca. This study demonstrates that similar fibrous microstructure in Cambrian mollusks and hyoliths actually represent a primitive type of prismatic microstructure constituted of calcitic prisms. Revision of these fibrous microstructures in Cambrian fossils demonstrates that calcitic shells are prevalent in the so-called aragonite sea of the earliest Cambrian. This has important implications for understanding the relationship between seawater chemistry and skeletal mineralogy at the time when skeletons were first acquired by early lophotrochozoan biomineralizers.

Comparative Efficacy of Biologic Disease-Modifying Anti-Rheumatic Drugs for Non-Radiographic Axial Spondyloarthritis: A Systematic Literature Review and Bucher Indirect Comparisons.

INTRODUCTION: Biologic disease-modifying anti-rheumatic drugs (bDMARDs), including certolizumab pegol (CZP), are effective treatment options for the management of non-radiographic spondyloarthritis (nr-axSpA). In the absence of head-to-head comparisons in nr-axSpA, we conducted a systematic literature review (SLR) and indirect treatment comparison (ITC) to better understand the comparative efficacy of CZP vs. other bDMARDs. METHODS: Literature searches were conducted in October 2020 in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials in patients with nr-axSpA who had failed at least one non-steroidal anti-inflammatory drug and were treated with bDMARDs. Outcomes of interest included the Assessment of Spondyloarthritis international Society (ASAS), Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Functional Index (BASFI) and Disease Activity Index (BASDAI), and spinal pain score. Comparative efficacy was examined using a series of Bucher ITCs in subgroups matched by prior exposure to bDMARDs, disease duration, baseline C-reactive protein (CRP) levels/magnetic resonance imaging (MRI) status, and timepoints, to ensure comparability between studies. RESULTS: At 12-16 weeks, treatment with CZP was significantly more likely to achieve ASAS20/40 response and ASDAS-inactive disease status vs. etanercept (ETN), ixekizumab (IXE), and secukinumab (SEC). CZP showed statistically significant improvement in BASDAI, BASFI, and total spine pain score over adalimumab (ADA), ETN, and IXE, and in BASFI over SEC. Among patients with objective signs of inflammation (OSI; elevated CRP levels and/or inflammation on MRI at baseline), CZP had a statistically significant advantage over ETN and SEC (with or without loading dose) in achieving ASAS40, whereas the comparisons with other bDMARDs did not show any statistically significant differences. CONCLUSION: In the overall matched population, CZP performed significantly better than most comparators in improving the clinical outcomes. Among patients with OSI, CZP was found to be superior to SEC (in the MRI-/CRP + and MRI + /CRP- subgroups) and ETN (in the MRI + /CRP- subgroup) and it was comparable to golimumab and IXE across the different OSI subgroups.

Efficacy of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: A Systematic Literature Review and a Network Meta-Analysis.

INTRODUCTION: Biologic treatments are increasingly being used in the management of moderate to severe plaque psoriasis (PSO). Bimekizumab is a selective inhibitor of both interleukin (IL)-17A and IL-17F approved for the treatment of moderate to severe PSO. Although bimekizumab trials provide comparisons to secukinumab, adalimumab and ustekinumab, there are no further head-to-head comparisons of bimekizumab to other biologics. This network meta-analysis (NMA) aimed to compare the short-term efficacy of bimekizumab versus other biologic systemic therapies for moderate to severe PSO. METHODS: A systematic literature review was conducted to identify randomised controlled trials (RCTs) in patients with moderate to severe PSO. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews and PsycINFO were searched on July 1, 2020. An enhanced multinomial Bayesian NMA model was used to evaluate the comparative efficacy in 50%, 75%, 90% and 100% improvement from baseline Psoriasis Area and Severity Index (PASI 50/75/90/100) at 10-16 weeks. The model was also adjusted for baseline risk, given the variable placebo responses across the trials. RESULTS: Eighty-six RCTs (including 34,476 patients) were included in the NMA. IL-17 and IL-23 inhibitors were the most effective treatments across all PASI levels. At 10-16 weeks, bimekizumab had the highest probability of achieving PASI 75 (92.3%), PASI 90 (84.0%) and PASI 100 (57.8%). Bimekizumab demonstrated statistical superiority over all biologics in achieving PASI 90 and PASI 100 thresholds. For PASI 75, the benefit of bimekizumab was statistically significant compared to all other treatments except risankizumab and ixekizumab. CONCLUSION: This analysis demonstrated that IL-17 and IL-23 inhibitors were highly effective in achieving short-term improvement among patients with moderate to severe PSO. Patients receiving bimekizumab were significantly more likely to achieve PASI 90 or PASI 100 within 10-16 weeks of the first injection than all other biologics.

Real-world evidence comparing oral anticoagulants in non-valvular atrial fibrillation: a systematic review and network meta-analysis.

Aim: To compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. Materials & methods: A systematic review of electronic databases yielded 7661 citations published from January 2013 to January 2020. Fifty-five studies were included in Bayesian network meta-analyses of hazard ratios. Results & conclusion: In comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.

This study aimed to compare real-world effectiveness/safety of non-vitamin K antagonist oral anticoagulants and vitamin K antagonists among patients with non-valvular atrial fibrillation. A systematic review was conducted from January 2013 to January 2020, and a total of 7661 references were assessed for relevance. Fifty-five studies were combined in the analysis; in comparison with vitamin K antagonists, apixaban, dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, ischemic stroke, intracranial hemorrhage and all-cause mortality. Apixaban, dabigatran and edoxaban, but not rivaroxaban, were associated with a reduced risk of major bleeding. This study confirmed the effectiveness and safety of non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation in real-world settings, consistent with clinical trial evidence.

Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer.

BACKGROUND: Eribulin mesylate (ERI; Halaven®) is a microtubule inhibitor approved in the United States for metastatic breast cancer patients with at least two prior chemotherapy regimens for metastatic breast cancer, and in the European Union in locally advanced breast cancer or metastatic breast cancer patients who progressed after at least one chemotherapy for advanced disease. This network meta-analysis compared the efficacy and safety of ERI versus other chemotherapies in this setting. METHODS: Systematic searches conducted in MEDLINE, Embase, and the Cochrane Central Register of Clinical Trials identified randomized controlled trials of locally advanced breast cancer/metastatic breast cancer chemotherapies in second- or later-line settings. Efficacy assessment included pre-specified subgroup analysis of breast cancer subtypes. Included studies were assessed for quality using the Centre for Reviews and Dissemination tool. Bayesian network meta-analysis estimated primary outcomes of overall survival and progression-free survival using fixed-effect models. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician's choice (TPC), and vinorelbine (VIN). RESULTS: The network meta-analysis included seven trials. Results showed that second- or later-line patients treated with ERI had statistically longer overall survival versus TPC (hazard ratio [HR]: 0.81; credible interval [CrI]: 0.66-0.99) or GEM+VIN (0.62; 0.42-0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64-0.90), but statistically shorter progression-free survival versus CAP+IXA (1.40; 1.17-1.67) and CAP+UTI (1.61; 1.23-2.12). In triple negative breast cancer, ERI had statistically longer overall survival versus CAP (0.70; 0.54-0.90); no statistical differences in progression-free survival were observed in triple negative breast cancer. CONCLUSIONS: This network meta-analysis suggests that ERI may provide an overall survival benefit in the overall locally advanced breast cancer/metastatic breast cancer populations and triple negative breast cancer subgroup compared to standard treatments. These findings support the use of ERI in second- or later-line treatment of patients with locally advanced breast cancer/metastatic breast cancer.

New insight into the soft anatomy and shell microstructures of early Cambrian orthothecids (Hyolitha).

Hyoliths (hyolithids and orthothecids) were one of the most successful early biomineralizing lophotrochozoans and were a key component of the Cambrian evolutionary fauna. However, the morphology, skeletogenesis and anatomy of earliest members of this enigmatic clade, as well as its relationship with other lophotrochozoan phyla remain contentious. Here, we present a new orthothecid, Longxiantheca mira gen. et sp. nov. preserved as part of secondarily phosphatized small shelly fossil assemblage from the lower Cambrian Xinji Formation of North China. Longxiantheca mira retains some ancestral traits of the clade with an undifferentiated disc-shaped operculum, a simple conical conch with apical septa and a two-layered microstructure of aragonitic fibrous bundles. The operculum interior exhibits impressions of soft tissues, including muscle attachment scars, mantle epithelial cells and a central kidney-shaped platform interpreted as a support structure in association with its presumptive feeding apparatus. The muscular system in orthothecids appears to be similar to that in hyolithids, suggesting a consistent anatomical configuration among the total group of hyoliths. The new finding of shell secreting cells demonstrates a mantle regulating the mode of growth for the operculum. Investigations of shell microstructures support the placement of hyoliths as total group molluscs with an unsettled position within the phylum Mollusca.

Utility value estimates in cardiovascular disease and the effect of changing elicitation methods: a systematic literature review.

OBJECTIVE: Identify the most recent utility value estimates for cardiovascular disease (CVD) via systematic literature review (SLR) and explore trends in utility elicitation methods in the last 6 years. METHODS: This SLR was updated on January 25, 2018, and identified studies reporting utilities for myocardial infarction (MI), stroke, angina, peripheral artery disease (PAD), and any-cause revascularization by searching Embase, PubMed, Health Technology Assessment Database, and grey literature. RESULTS: A total of 375 studies reported CVD utilities (pre-2013 vs post-2013: MI, 38 vs 32; stroke, 86 vs 113; stable angina, 8 vs 9; undefined/unstable angina, 23 vs 8; PAD, 29 vs 13; revascularization, 54 vs 40). Median average utilities for MI, stroke, and revascularization increased over time (pre-2013 vs post-2013: MI, 0.71 vs 0.79; stroke, 0.63 vs 0.64; revascularization, 0.76 vs 0.81); angina and PAD showed a decrease in median values over time (stable angina, 0.83 vs 0.72; undefined/unstable angina, 0.70 vs 0.69; PAD, 0.76 vs 0.71). The proportion of utility estimates from trials increased across health states (pre-2013 vs post-2013: 22.5% vs 37.2%), as did the proportion of trials using the EuroQol Five Dimensions Questionnaire (EQ-5D; pre-2013 vs post-2013: 73.8% vs 91.4%). Use of methods such as the standard gamble, time trade-off, and Health Utilities Index has declined. CONCLUSIONS: Health state utilities for cardiovascular health states have changed in the last 6 years, likely due to changes in the types of studies conducted, the patient populations evaluated, and possibly changing utility elicitation methods. The EQ-5D has been used more frequently.

Systematic Literature Review of the Burden of Disease and Treatment for Transfusion-dependent ß-Thalassemia.

PURPOSE: ß-Thalassemia is an inherited blood disorder characterized by reduced or no production of adult hemoglobin. Systematic identification of the burden of ß-thalassemia with contemporary treatments is lacking in published literature. Thus, a gap exists in understanding the baseline burden on which to assess future treatments. Therefore, a systematic literature review (SLR) was performed to assess management and outcomes in patients with transfusion-dependent ß-thalassemia (TDT) who received long-term transfusion regimens. METHODS: Searches of MEDLINE, EMBASE, and 5 conference websites were conducted to identify clinical-practice studies in Italy, France, Germany, Greece, the United States, and the United Kingdom, published since January 2007. The review found 135 articles meeting the SLR criteria. FINDINGS: Among patients carrying 2 ß-thalassemia mutations, 64%-89% underwent regular transfusions at intervals of between 2 and 4 weeks. Transfusion-associated complications that were reported included iron overload, transfusion reactions, alloimmunization, and infections. Analyses of 42, 25, and 73 studies reporting liver iron concentration (median, 8.5 mg/g of dry weight [dw]; interquartile range [IQR], 4.5-11.0 mg/g dw), cardiac T2* magnetic resonance imaging (median, 27.4 ms; IQR, 26.0-30.2 ms), and serum ferritin (median, 1465.0 ng/mL; IQR, 1238.2-1797.0 ng/mL), respectively, showed wide ranges in iron levels and a general trend toward improved iron control in recent years. Adverse transfusion reactions and alloimmunization were reported in ~50% and 10%-20% in patients, respectively. Rates of transfusion-transmitted infections were highly variable by study but were lower in more recent cohorts. Complications stemming from iron overload and underlying disease captured in this SLR included cardiac disease, liver disease, and endocrine and musculoskeletal disorders. Approximately 10% of patients were diagnosed with heart failure, with rates ranging from 2.9% to 20.9% across 6 studies. Other significant complications reported with ß-thalassemia included pain (25%-69%), psychiatric disorders (25%-30%), and reduced health-related quality of life. Despite substantial improvements in survival, patients with TDT remained at an increased risk for early mortality. IMPLICATIONS: Consistent with improvements in transfusion practices and iron monitoring and management, outcomes in patients with TDT have improved. However, iron overload and disease-associated complications remain a challenge in this population. This review supports the burden of disease affecting patients with ß-thalassemia and provides a baseline health status against which to assess future improvements in care.

Comparison of Recommendations and Use of Cardiovascular Risk Equations by Health Technology Assessment Agencies and Clinical Guidelines.

OBJECTIVES: To identify risk equations for cardiovascular diseases (CVDs) in primary and secondary prevention settings that are used or recommended by health technology assessment (HTA) organizations and in clinical guidelines (CGs). METHODS: A targeted literature review was conducted using a two-stage search strategy. First, HTA reviews of manufacturers' drug submissions, reports from established HTA organizations (Europe, Canada, and Australia), and CGs from countries with and without HTA organizations, including the United States, were identified. Documents published between September 30, 2006 and September 30, 2016, were examined for cardiovascular risk equations, recommendations, and commentaries. Next, publications associated with risk equations and cited by HTA and CG documents were retrieved. This literature was examined to extract commentaries and risk equation study characteristics. RESULTS: The review identified 47 risk equations, 25 in the primary CVD prevention setting (i.e., patients with no CVD history), including 5 for CVD prevention in diabetes and 22 solely in secondary prevention settings; 11 were identified for heart failure, 3 for stroke or transient ischemic attack, 2 for stable angina, and 11 for acute coronary syndrome or related conditions. A small set of primary prevention equations was found to be commonly used by HTAs, whereas secondary prevention equations were less common in HTA documents. CGs provided more risk equations as options than HTA documents. CONCLUSIONS: Although there is an abundance of risk equations developed for primary and secondary prevention, there remains a need for additional research to provide sufficient clinical and HTA guidance for risk estimation, particularly in high-risk or secondary prevention settings.

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy. RESEARCH DESIGN AND METHODS: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis. RESULTS: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (-5.49) and QoL-DN (-13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses. CONCLUSIONS: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.

Differences in utility elicitation methods in cardiovascular disease: a systematic review.

AIMS: Utility values inform estimates of the cost-effectiveness of treatment for cardiovascular disease (CVD), but values can vary depending on the method used. The aim of this systematic literature review (SLR) was to explore how methods of elicitation impact utility values for CVD. MATERIALS AND METHODS: This review identified English-language articles in Embase, MEDLINE, and the gray literature published between September 1992 and August 2015 using keywords for "utilities" and "stroke", "heart failure", "myocardial infarction", or "angina". Variability in utility values based on the method of elicitation, tariff, or type of respondent was then reported. RESULTS: This review screened 4,341 citations; 290 of these articles qualified for inclusion in the SLR because they reported utility values for one or more of the cardiovascular conditions of interest listed above. Of these 290, the 41 articles that provided head-to-head comparisons of utility methods for CVD were reviewed. In this sub-set, it was found that methodological differences contributed to variation in utility values. Direct methods often yielded higher scores than did indirect methods. Within direct methods, there were no clear trends in head-to-head studies (standard gamble [SG] vs time trade-off); but general population respondents often provided lower scores than did patients with the disease when evaluating the same health states with SG methods. When comparing indirect methods, the EQ-5D typically yielded higher values than the SF-6D, but also showed more sensitivity to differences in health states. CONCLUSIONS: When selecting CVD utility values for an economic model, consideration of the utility elicitation method is important, as this review demonstrates that methodology of choice impacts utility values in CVD.