The CDC introduced ventilator-associated event (VAE) definitions in January 2013. Little is known about VAE prevention. We hypothesized that daily, coordinated spontaneous awakening trials (SATs) and ...spontaneous breathing trials (SBTs) might prevent VAEs.
To assess the preventability of VAEs.
We nested a multicenter quality improvement collaborative within a prospective study of VAE surveillance among 20 intensive care units between November 2011 and May 2013. Twelve units joined the collaborative and implemented an opt-out protocol for nurses and respiratory therapists to perform paired daily SATs and SBTs. The remaining eight units conducted surveillance alone. We measured temporal trends in VAEs using generalized mixed effects regression models adjusted for patient-level unit, age, sex, reason for intubation, Sequential Organ Failure Assessment score, and comorbidity index.
We tracked 5,164 consecutive episodes of mechanical ventilation: 3,425 in collaborative units and 1,739 in surveillance-only units. Within collaborative units, significant increases in SATs, SBTs, and percentage of SBTs performed without sedation were mirrored by significant decreases in duration of mechanical ventilation and hospital length-of-stay. There was no change in VAE risk per ventilator day but significant decreases in VAE risk per episode of mechanical ventilation (odds ratio OR, 0.63; 95% confidence interval CI, 0.42-0.97) and infection-related ventilator-associated complications (OR, 0.35; 95% CI, 0.17-0.71) but not pneumonias (OR, 0.51; 95% CI, 0.19-1.3). Within surveillance-only units, there were no significant changes in SAT, SBT, or VAE rates.
Enhanced performance of paired, daily SATs and SBTs is associated with lower VAE rates. Clinical trial registered with www.clinicaltrials.gov (NCT 01583413).
IMPORTANCE: Drug survival of biologic therapies for psoriasis is a proxy for longer-term treatment effectiveness and safety. Patient factors that are associated with the survival of each biologic ...differently (effect modifiers) may inform the decision to choose between biologics. OBJECTIVE: To assess the drug survival associated with the effectiveness and safety of commonly used biologics for psoriasis in the UK and Ireland and identify effect modifiers for these biologics and their survival. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study of patients with psoriasis using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2021. EXPOSURES: Adalimumab, ustekinumab, secukinumab, guselkumab, ixekizumab. MAIN OUTCOMES AND MEASURES: We conducted a survival analysis and fitted separate flexible parametric models for drug survival as a proxy for effectiveness and safety. RESULTS: A total of 16 122 treatment courses were included: 6607 (41.0%) in which treatment with adalimumab was initiated, 5405 (33.5%) with ustekinumab, 2677 (16.6%) with secukinumab, 730 (4.5%) with guselkumab, and 703 (4.4%) with ixekizumab. The crude survival functions at year 1 for measures of effectiveness for treatment with adalimumab was 0.81 (95% CI, 0.80-0.82), 0.89 for ustekinumab (95% CI, 0.88-0.89), 0.86 for secukinumab (95% CI, 0.85-0.87), 0.94 for guselkumab (95% CI, 0.92-0.96), and 0.86 for ixekizumab (95% CI, 0.83-0.89). The adjusted survival curves from the multivariable model for effectiveness showed that treatment with guselkumab had the higher survival (adjusted hazard ratio, 0.13; 95% CI, 0.03-0.56) and adalimumab had the lower survival (adjusted hazard ratio, 2.37; 95% CI, 2.03-2.76) compared with ustekinumab. Secukinumab and ixekizumab had similar survival curves over time. Psoriatic arthritis, previous biologic exposure, nail involvement, and ethnicity were effect modifiers for survival in association with treatment effectiveness. The crude survival functions at year 1 for safety were 0.91 for treatment with adalimumab (95% CI, 0.90-0.91), 0.94 for ustekinumab (95% CI, 0.94-0.95), 0.94 for secukinumab (95% CI, 0.92-0.94), 0.96 for guselkumab (95% CI, 0.94-0.98), and 0.92 for ixekizumab (95% CI, 0.89-0.94). Guselkumab, ustekinumab, and secukinumab had similar adjusted survival curves for safety, while adalimumab (adjusted hazard ratio, 1.66; 95% CI, 1.46-1.89) and ixekizumab (adjusted hazard ratio, 1.52; 95% CI, 1.13-2.03) had lower survival compared with ustekinumab. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that guselkumab had the highest drug survival in BADBIR of the included biologics for treatment persistence that was associated with effectiveness, and guselkumab had highest drug survival for safety compared with other biologics except ustekinumab. Psoriatic arthritis, nail involvement, previous biologic exposure, and ethnicity were effect modifiers for biologics and their survival in association with treatment effectiveness. This information on longer-term treatment persistence, safety, and tolerability may help patients and their clinicians make an informed decision to initiate treatment with a biologic therapy.
BACKGROUND:The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin ...type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab.
METHODS:The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared.
RESULTS:A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval CI,1.22–1.53), 1.78 (95% CI, 1.59–1.99), and 1.39 (95% CI, 1.24–1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71–0.91), 18% (HR, 0.82; 95% CI, 0.72–0.93), and 21% (HR, 0.79; 95% CI, 0.69–0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85–1.05), 8% (HR, 0.92; 95% CI, 0.84–1.02), and 7% (HR, 0.93; 95% CI, 0.85–1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%).
CONCLUSIONS:Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01764633.
Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection ...could improve patient outcomes and treatment cost-effectiveness.
We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti–TNF-α) and ustekinumab (anti–IL-12/23).
This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables.
HLA-C*06:02–negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio OR, 2.95; P = 5.85 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10−5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10−4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1.
This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.
IMPORTANCE: Patients with psoriasis enrolled in clinical trials of biologics may not be representative of the real-world population. There is evidence that patients ineligible for such trials have a ...greater risk of serious adverse events (SAEs), but the effect on drug discontinuation and effectiveness are unknown. OBJECTIVE: To determine whether (1) drug discontinuation, (2) effectiveness, and (3) rates of SAEs differ in patients with psoriasis categorized as eligible or ineligible for clinical trials. DESIGN, SETTING, AND PARTICIPANTS: An observational study using 157 dermatology centers in the United Kingdom and Republic of Ireland was carried out wherein we applied the eligibility criteria of clinical trials of biologic therapies for psoriasis to patients who were being followed up in the British Association of Dermatologists Biologic Interventions Register (BADBIR) and being prescribed biologics as part of standard clinical care. Patients with psoriasis registered to BADBIR who were taking etanercept (enbrel only; n = 1509), adalimumab (n = 4000), and ustekinumab (n = 1627) with at least 1 follow-up visit. Eligibility criteria were extracted from phase 3 licensing trials for etanercept, adalimumab, and ustekinumab for the treatment of moderate to severe psoriasis. Patients in BADBIR with a missing baseline Psoriasis Area and Severity Index (PASI) or baseline PASI value less than 10 (etanercept) or less than 12 (adalimumab; ustekinumab) but who would otherwise be eligible were investigated separately. Eligibility categories applied to BADBIR included: eligible, ineligible, insufficient baseline PASI only, and missing baseline PASI only. MAIN OUTCOMES AND MEASURES: (1) Drug discontinuation: cumulative incidence at 12 months by stop reason per eligibility category and drug; (2) effectiveness: linear regression of absolute change in PASI from baseline to 6 and 12 months; and (3) SAEs: incidence rate ratio (IRR) at 12 months between eligibility categories per drug. RESULTS: The mean (SD) age of the 7136 patients included in the analysis was 45 (13) years and 2924 (41%) were women and 4212 (59%) were men. Of 7136 patients, 839 (56%) etanercept, 2219 (56%) adalimumab, and 754 (46%) ustekinumab registrations were categorized as eligible. The most common reasons for ineligibility were diabetes (etanercept, 143 9%; ustekinumab, 201 12%) and nonchronic plaque psoriasis (adalimumab, 157 4%). Patients categorized as ineligible (etanercept, 367 24%; adalimumab, 282 7%; ustekinumab, 394 24%) achieved a smaller absolute change in PASI after 6 and 12 months (adalimumab, ustekinumab), and had significantly higher rates of SAEs compared with the eligible category (etanercept: IRR, 1.9; 95% CI, 1.4-2.6; adalimumab: IRR, 2.0; 95% CI, 1.5-2.6; ustekinumab: IRR, 2.8; 95% CI, 2.1-3.8). No significant differences in drug discontinuation were observed between categories. CONCLUSIONS AND RELEVANCE: Clinical trial effectiveness and safety outcomes are not representative of real-world patients in BADBIR patients categorized as ineligible for such trials.
Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the ...oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.
Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large ...numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.
Medication non-adherence and the clinical implications in difficult-to-control asthma were audited. Prescription issue data from 115 patients identified sub-optimal adherence (<80%) in 65% of ...patients on inhaled corticosteroids (ICS) or combined ICS/long-acting β2 agonist (LABA). In those using separate ICS and LABA, adherence to LABA (50%) was significantly better than to ICS (14.3%). Patients with sub-optimal ICS adherence had reduced FEV(1) and higher sputum eosinophil counts. Adherence ratio was an independent predictor of previous ventilation for acute severe asthma (p=0.008). The majority of patients with difficult-to-control asthma are non-adherent with their asthma medication. Non-adherence is correlated with poor clinical outcomes.
Background
Both the adrenergic and renin‐angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome (POTS). Activating ...autoantibodies to the α1‐adrenergic and β1/2‐adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor (AT1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT1R autoantibodies in POTS.
Methods and Results
Serum immunoglobulin G from 17 patients with POTS, 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT1R and alter AT1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT1R antibody activity in immunoglobulin G purified from their serum. No significant AT1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT1R activation by POTS immunoglobulin G was specifically blocked by the AT1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT1R and α1‐adrenergic receptor.
Conclusions
Most patients with POTS harbor AT1R antibody activity. This supports the concept that AT1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS.
IMPORTANCE: High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of ...circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab. OBJECTIVE: To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria. EXPOSURE: Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline primary outcome), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less. RESULTS: A total of 491 patients (171 women and 320 men; mean SD age, 45.7 12.8 years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5). CONCLUSIONS AND RELEVANCE: This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.
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