Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

<p>Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.</p> <p>Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).</p> <p>Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).</p&gt

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

Analysis of complications and revisions after spine surgery in 270 multiple myeloma patients with spinal involvement

BACKGROUND CONTEXT: Patients with multiple myeloma (MM) are at increased risk of infections and suffer from poor bone quality due to their disseminated malignant bone disease. Therefore, postoperative complications may occur following surgical treatment of MM lesions. PURPOSE: In this study, we aimed to determine the incidence of postoperative complications and retreatments after spinal surgery in MM patients. Additionally, we sought to identify risk factors associated with complications and retreatments. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: In total, 270 patients with MM who received surgical treatment for spinal involvement between 2008 and 2021 were included. OUTCOME MEASURES: The incidence of perioperative complications within 6 weeks and reoperations within 2.5 years and individual odds ratios for factors associated with these complications and reoperations. METHODS: Data were collected through manual chart review. Hosmer and Lemeshow's purposeful regression method was used to identify risk factors for complications and reoperations. RESULTS: The median age of our cohort was 65 years (SD = 10.8), and 58% were male (n = 57). Intraoperative complications were present in 24 patients (8.9%). The overall 6-week complication rate after surgery was 35% (n = 95). The following variables were independently associated with 6-week complications: higher Genant grading of a present vertebral fracture (OR 1.41; 95% CI 1.04-1.95; p = .031), receiving intramuscular or intravenous steroids within a week prior to surgery (OR 3.97; 95% CI 1.79-9.06; p = .001), decompression surgery without fusion (OR 6.53; 95% CI 1.30-36.86; p = .026), higher creatinine levels (OR 2.18; 95% CI 1.19-5.60; p = .014), and lower calcium levels (OR 0.58; 95% CI 0.37-0.88; p = .013). A secondary surgery was indicated for 53 patients (20%), of which 13 (4.8%) took place within two weeks after the initial surgery. We additionally discovered factors associated with retreatments, which are elucidated within the manuscript. CONCLUSION: The goal of surgical treatment for MM bone disease is to enhance patient quality of life and reduce symptom burden. However, postoperative complication rates remain relatively high after spine surgery in patients with MM, likely attributable to both inherent characteristics of the disease and patient comorbidities. The risk for complications and secondary surgeries should be explored and a multidisciplinary approach is crucial

Neurologic Outcomes After Radiation Therapy for Severe Spinal Cord Compression in Multiple Myeloma: A Study of 162 Patients

BACKGROUND: Bone destruction is the most frequent disease-defining clinical feature of multiple myeloma (MM), resulting in skeletal-related events such as back pain, pathological fractures, or neurologic compromise including epidural spinal cord compression (ESCC). Up to 24% of patients with MM will be affected by ESCC. Radiation therapy has been proven to be highly effective in pain relief in patients with MM. However, a critical knowledge gap remains with regard to neurologic outcomes in patients with high-grade ESCC treated with radiation. METHODS: We retrospectively included 162 patients with MM and high-grade ESCC (grade 2 or 3) who underwent radiation therapy of the spine between January 2010 and July 2021. The primary outcome was the American Spinal Injury Association (ASIA) score after 12 to 24 months, or the last known ASIA score if the patient had had a repeat treatment or died. Multivariable logistic regression was used to assess factors associated with poor neurologic outcomes after radiation, defined as neurologic deterioration or lack of improvement. RESULTS: After radiation therapy, 34 patients (21%) had no improvement in their impaired neurologic function and 27 (17%) deteriorated neurologically. Thirty-six patients (22%) underwent either surgery or repeat irradiation after the initial radiation therapy. There were 100 patients who were neurologically intact at baseline (ASIA score of E), of whom 16 (16%) had neurologic deterioration. Four variables were independently associated with poor neurologic outcomes: baseline ASIA (odds ratio [OR] = 6.50; 95% confidence interval [CI] = 2.70 to 17.38; p < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (OR = 6.19; 95% CI = 1.49 to 29.49; p = 0.015), number of levels affected by ESCC (OR = 4.02; 95% CI = 1.19 to 14.18; p = 0.026), and receiving steroids prior to radiation (OR = 4.42; 95% CI = 1.41 to 16.10; p = 0.015). CONCLUSIONS: Our study showed that 38% of patients deteriorated or did not improve neurologically after radiation therapy for high-grade ESCC. The results highlight the need for multidisciplinary input and efforts in the treatment of high-grade ESCC in patients with MM. Future studies will help to improve patient selection for specific and standardized treatments and to clearly delineate which patients are likely to benefit from radiation therapy. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence

Inpatient Opioid Use Varies by Construct Length Among Laminoplasty Versus Laminectomy and Fusion Patients

BACKGROUND: Laminoplasty (LP) and laminectomy and fusion (LF) are utilized to achieve decompression in patients with symptomatic degenerative cervical myelopathy (DCM). Comparative analyses aimed at determining outcomes and clarifying indications between these procedures represent an area of active research. Accordingly, we sought to compare inpatient opioid use between LP and LF patients and to determine if opioid use correlated with length of stay. METHODS: Sociodemographic information, surgical and hospitalization data, and medication administration records were abstracted for patients \u3e18 years of age who underwent LP or LF for DCM in the Mass General Brigham (MGB) health system between 2017 and 2019. Specifically, morphine milligram equivalents (MME) of oral and parenteral pain medication given after arrival in the recovery area until discharge from the hospital were collected. Categorical variables were analyzed using chi-squared analysis or Fisher exact test when appropriate. Continuous variables were compared using Independent samples RESULTS: One hundred eight patients underwent LF, while 138 patients underwent LP. Total inpatient opioid use was significantly higher in the LF group (312 vs. 260 MME, p=.03); this difference was primarily driven by higher postoperative day 0 pain medication requirements. Furthermore, more LF patients required high dose (\u3e80 MME/day) regimens. While length of stay was significantly different between groups, with LF patients staying approximately 1 additional day, postoperative day 0 MME was not a significant predictor of this difference. When operative levels including C2, T1, and T2 were excluded, the differences in total opioid use and average length of stay lost significance. CONCLUSIONS: Inpatient opioid use and length of stay were significantly greater in LF patients compared to LP patients; however, when constructs including C2, T1, T2 were excluded from analysis, these differences lost significance. Such findings highlight the impact of operative extent between these procedures. Future studies incorporating patient reported outcomes and evaluating long-term pain needs will provide a more complete understanding of postoperative outcomes between these 2 procedures

Effect of Levels of Acetate on the Mevalonate Pathway of Borrelia burgdorferi

Borrelia burgdorferi, the agent of Lyme disease, is a spirochetal pathogen with limited metabolic capabilities that survives under highly disparate host-specific conditions. However, the borrelial genome encodes several proteins of the mevalonate pathway (MP) that utilizes acetyl-CoA as a substrate leading to intermediate metabolites critical for biogenesis of peptidoglycan and post-translational modifications of proteins. In this study, we analyzed the MP and contributions of acetate in modulation of adaptive responses in B. burgdorferi. Reverse-transcription PCR revealed that components of the MP are transcribed as individual open reading frames. Immunoblot analysis using monospecific sera confirmed synthesis of members of the MP in B. burgdorferi. The rate-limiting step of the MP is mediated by HMG-CoA reductase (HMGR) via conversion of HMG-CoA to mevalonate. Recombinant borrelial HMGR exhibited a Km value of 132 µM with a Vmax of 1.94 µmol NADPH oxidized minute−1 (mg protein)−1 and was inhibited by statins. Total protein lysates from two different infectious, clonal isolates of B. burgdorferi grown under conditions that mimicked fed-ticks (pH 6.8/37°C) exhibited increased levels of HMGR while other members of the MP were elevated under unfed-tick (pH 7.6/23°C) conditions. Increased extra-cellular acetate gave rise to elevated levels of MP proteins along with RpoS, CsrABb and their respective regulons responsible for mediating vertebrate host-specific adaptation. Both lactone and acid forms of two different statins inhibited growth of B. burgdorferi strain B31, while overexpression of HMGR was able to partially overcome that inhibition. In summary, these studies on MP and contributions of acetate to host-specific adaptation have helped identify potential metabolic targets that can be manipulated to reduce the incidence of Lyme disease

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Australian National Health and Medical Research CouncilMRCBritish Heart Foundation

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator

Climate Impacts, Political Institutions, and Leader Survival: Effects of Drought and Flooding Precipitation.

We explore how the political survival of leaders in different political regimes is affected by drought and flooding precipitation, which are the two major anticipated impacts of anthropogenic climate change. Using georeferenced climate data for the entire world and the Archigos dataset for the period of 1950-2010, we find that irregular political exits, such as coups or revolutions, are not significantly affected by climate impacts. Similarly, drought has a positive but insignificant effect on all types of political exits. On the other hand, we find that floods increase political turnover through the regular means such as elections or term limits. Democracies are better able to withstand the pressures arising from the economic and social disruptions associated with high precipitation than other institutional arrangements. Our results further suggest that, in the context of floods, political institutions play a more important role than economic development for the leaders’ political survival