Elevated lipoprotein(a) Lp(a) is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to ...proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Background Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. Objective We sought to assess the effectiveness ...and safety of BT in asthmatic patients 5 years after therapy. Methods BT-treated subjects from the Asthma Intervention Research 2 trial ( ClinicalTrials.gov NCT01350414 ) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. Results One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV1 values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. Conclusions These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β2 -agonists.
To review the safety of hepatic radioembolization (RE) in patients with high (≥ 10%) hepatopulmonary shunt fraction (HPSF) using various prophylactic techniques.
A review was conducted of 409 ...patients who underwent technetium 99m-labeled macroaggregated albumin scintigraphy before planned RE. Estimated pulmonary absorbed radiation doses based on scintigraphy and hepatic administered activity were calculated. Outcomes from dose reductions and adjunctive catheter-based prophylactic techniques used to reduce lung exposure were assessed.
There were 80 patients with HPSF ≥ 10% who received RE treatment (41 resin microspheres for metastases, 39 glass microspheres for hepatocellular carcinoma). Resin microspheres were used in 17 patients according to consensus guideline-recommended dose reduction; 38 patients received no dose reduction because the expected lung dose was < 30 Gy. Prophylactic techniques were used in 25 patients (with expected lung dose ≤ 74 Gy), including hepatic vein balloon occlusion, variceal embolization, or bland arterial embolization before, during, or after RE delivery. Repeated scintigraphy after prophylactic techniques to reduce HPSF in seven patients demonstrated a median change of -40% (range, +32 to -69%). Delayed pneumonitis developed in two patients, possibly related to radiation recall after chemoembolization. Response was lower in patients treated with resin spheres with dose reduction, with an objective response rate of 13% and disease control rate of 47% compared with 56% and 94%, respectively, without dose reduction (P = .023, P = .006).
Dose reduction recommendations for HPSF may compromise efficacy. Excessive shunting can be reduced by prophylactic catheter-based techniques, which may improve the safety of performing RE in patients with high HPSF.
Although the frequency of noninferiority trials is increasing, the consistency of the reporting of these trials can vary. The aim of this systematic review was to assess the reporting quality of ...radiation therapy noninferiority trials.
The PubMed, Embase, and Cochrane databases were queried for randomized controlled radiation therapy trials with noninferiority hypotheses published in English between January 2000 and July 2022, and this was performed by an information scientist. Descriptive statistics were used to summarize data.
Of 423 records screened, 59 (14%) were included after full-text review. All were published after 2003 and open label. The most common primary cancer type was breast (n = 15, 25%). Altered radiation fractionation (n = 26, 45%) and radiation de-escalation (n = 11, 19%) were the most common types of interventions. The most common primary endpoints were locoregional control (n = 17, 29%) and progression-free survival (n = 14, 24%). Fifty-three (90%) reported the noninferiority margin, and only 9 (17%) provided statistical justification for the margin. The median absolute noninferiority margin was 9% (interquartile range, 5%-10%), and the median relative margin was 1.51 (interquartile range, 1.33-2.04). Sample size calculations and confidence intervals were reported in 54 studies (92%). Both intention-to-treat and per-protocol analyses were reported in 27 studies (46%). In 31 trials (53%), noninferiority of the primary endpoint was reached.
There was variability in the reporting of key components of noninferiority trials. We encourage consideration of additional statistical reasoning such as guidelines or previous trials in the selection of the noninferiority margin, reporting both absolute and relative margins, and the avoidance of statistically vague or misleading language in the reporting of future noninferiority trials.
Background A variety of data sources are available for measuring the quality of health care. Linking records from different sources can create unique and powerful databases that can be used to ...evaluate clinically relevant questions and direct health care policy. The objective of this study was to develop and validate a deterministic linkage algorithm that uses indirect patient identifiers to reliably match records from a surgical clinical registry with Medicare inpatient claims data. Methods Patient records from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), years 2005–2008, were linked to claims data in the Medicare Provider Analysis and Review file (MedPAR) by the use of a deterministic linkage algorithm and the following indirect patient identifiers: hospital, age, sex, diagnosis, procedure and dates of admission, discharge, and procedure. We validated the linkage procedure by systematically reviewing subsets of matched and unmatched records and by determining agreement on patient-level coding of inpatient mortality. Results Of the 150,454 records in ACS-NSQIP eligible for matching, 80.5% were linked to a MedPAR record. This percentage is within the expected match range given the estimated percentage of ACS-NSQIP patients likely to be Medicare beneficiaries. Systematic checks revealed no evidence of bias in the linkage procedure and there was excellent agreement on patient-level coding of mortality (kappa 0.969). The final linked database contained 121,070 patient records from 217 hospitals. Conclusion This study demonstrates the feasibility and validity of a method for linking 2 data sources without direct personal identifiers. As clinical registries and other data sources continue to proliferate, linkage algorithms such as described here will be critical for quality measurement purposes.
•SBRT for ultra-central lung tumors results in high rates of local control.•SBRT-related severe and fatal toxicity risks were generally uncommon, ≤6 %.•Appropriate patient, target, and dosimetric ...constraint selection may keep risk of severe toxicity with SBRT at an acceptable level.•Patients with high-risk factors for toxicity, such as endobronchial tumors and anticoagulant use, should be treated carefully; consider non-SBRT schedules.
Stereotactic body radiotherapy (SBRT) is an effective and safe modality for early-stage lung cancer and lung metastases. However, tumors in an ultra-central location pose unique safety considerations. We performed a systematic review and meta-analysis to summarize the current safety and efficacy data and provide practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).
We performed a systematic review using PubMed and EMBASE databases of patients with ultra-central lung tumors treated with SBRT. Studies reporting local control (LC) and/or toxicity were included. Studies with <5 treated lesions, non-English language, re-irradiation, nodal tumors, or mixed outcomes in which ultra-central tumors could not be discerned were excluded. Random-effects meta-analysis was performed for studies reporting relevant endpoints. Meta-regression was conducted to determine the effect of various covariates on the primary outcomes.
602 unique studies were identified of which 27 (one prospective observational, the remainder retrospective) were included, representing 1183 treated targets. All studies defined ultra-central as the planning target volume (PTV) overlapping the proximal bronchial tree (PBT). The most common dose fractionations were 50 Gy/5, 60 Gy/8, and 60 Gy/12 fractions. The pooled 1- and 2-year LC estimates were 92 % and 89 %, respectively. Meta-regression identified biological effective dose (BED10) as a significant predictor of 1-year LC. A total of 109 grade 3–4 toxicity events, with a pooled incidence of 6 %, were reported, most commonly pneumonitis. There were 73 treatment related deaths, with a pooled incidence of 4 %, with the most common being hemoptysis. Anticoagulation, interstitial lung disease, endobronchial tumor, and concomitant targeted therapies were observed risk factors for fatal toxicity events.
SBRT for ultra-central lung tumors results in acceptable rates of local control, albeit with risks of severe toxicity. Caution should be taken for appropriate patient selection, consideration of concomitant therapies, and radiotherapy plan design.
Background. A study was conducted in the Calgary Health Region between May 2002 and April 2004 to define the population‐based epidemiological characteristics of infections caused by ...imipenem‐resistant Pseudomonas aeruginosa and to explore the clinical outcomes due to metallo‐β‐lactamase (MBL)–producing and non–MBL‐producing strains. Methods. Detailed clinical information was obtained by chart review, and phenotypic and molecular characterizations were performed using the MBL E‐test, polymerase chain reaction with sequencing, and pulsed‐field gel electrophoresis. Results. A total of 228 patients with infections caused by imipenem‐resistant P. aeruginosa were identified (annual incidence, 10.5 cases/100,000 population), with the highest incidence rate in those ⩾75 years old. MBL‐producing strains (98/228) were associated with higher rates of multidrug resistance and bacteremia. Ninety MBL‐producing strains also produced VIM‐2, 4 produced IMP‐7, and 4 were unclassified. A cluster of VIM‐2–producing strains was responsible for a nosocomial outbreak during 2003. The case‐fatality rate was significantly higher for infections caused by MBL‐producing strains than for those caused by non–MBL‐producing strains (25% vs. 13%; relative risk, 1.98 95% confidence interval, 1.00–3.90; P=.05). Conclusion. MBL‐producing P. aeruginosa strains were associated with a higher case‐fatality rate and invasive disease. Our study highlights the potential importance of molecular laboratory techniques in infection control and patient care.
The lack of significant association of apoB with CVD in this study, and the correspondingly modest effect of apoB adjustment on the association of LDL-P with CVD, may reflect the fact that apoB is a ...measure of all very low-density lipoprotein, intermediate-density lipoprotein, and LDL particles, and of these, LDL was predominantly associated with CVD in this study. ...among subjects who were not classified into 1 of the 4 statin benefit groups, lipoprotein subfractions were independently associated with CVD.
Abstract Cervical cancer remains one of the leading causes of cancers in women from Indonesia, Malaysia, the Philippines, Thailand and Vietnam. High-risk human papillomavirus (HPV) types, ...particularly HPV-16 and 18, are consistently identified in cervical cancer cases regardless of geographical region. Factors that have been identified to increase the likelihood of HPV exposure or subsequent development of cervical cancer include young age at first intercourse, high parity and multiple sexual partners. Cervical cancer screening programs in these countries include Pap smears, single visit approach utilizing visual inspection with acetic acid followed by cryotherapy, as well as screening with colposcopy. Uptake of screening remains low in all regions and is further compounded by the lack of basic knowledge women have regarding screening as an opporunity for the prevention of cervical cancer. Prophylactic HPV vaccination with the quadrivalent vaccine has already been approved for use in Malaysia, the Philippines and Thailand, while the bivalent vaccine has also been approved in the Philippines. However, there has been no national or government vaccination policy implemented in any of these countries.
To describe, innovate, recommend, and foster the implementation of point-of-care (POC) testing in disaster caches to enhance crisis standards of care and to improve triage, diagnosis, monitoring, ...treatment, and management of victims and volunteers in complex emergencies and disasters.
The authors compared POC testing in United States disaster caches to commercially available POC testing to enhance the caches and to reflect current state-of-the-art diagnostic capabilities. The authors also provided recommendations based on literature review and knowledge from newly developed POC technologies from the UC Davis Point-of-Care Technologies Center.
Presently, US POC testing caches comprise chemistry/electrolytes, pregnancy, hemoglobin, cardiac biomarkers, hematology, fecal occult blood, drugs of abuse, liver function, blood gases, and limited infectious diseases. Deficiencies with existing POC tests for cardiac biomarkers, hematology, and infectious diseases should be eliminated. POC resources can be customized for pandemics, complex emergencies, or disasters based on geographic location and potential infectious diseases. Additionally, a new thermally stabilized container can help alleviate environmental stresses that reduce test quality.
Innovations in POC technologies can improve response preparedness with enhanced diagnostic capabilities. Several innovations, such as the i-STAT® Wireless, OraQuick ADVANCE® HIV-1/2, VereTrop™ Lab-on-a-Chip, and new compact hematology analyzers will improve test clusters that facilitate evidence-based decision making and crisis standards of care during US national disaster responses. Additionally, strategic resources and operator training should be globally harmonized to improve the efficiency of international responses.
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