Inhaled steroids with and without regular salmeterol for asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between use of beta₂-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta₂-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA).  OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018. SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration. DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations. MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment.However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice

Oral anticoagulant timing and hospitalization in newly diagnosed nonvalvular atrial fibrillation patients

BackgroundNon-valvular atrial fibrillation (NVAF) significantly increases ischemic stroke and systemic embolism (SE) risks. Despite the proven efficacy of oral anticoagulants (OAC) in reducing these risks, their underutilization highlights a gap in clinical practice. This study examined OAC utilization patterns within the first year after NVAF diagnosis in patients without prior OAC use and the association between the timing of OAC initiation and the risk of all-cause and stroke/SE-specific hospitalizations.MethodsA retrospective cohort study was conducted using data from the Premier Healthcare Database and linked claims from 1/1/2017–3/31/2021. Patients newly diagnosed with NVAF, without prior OAC use, were included.ResultsOf 23,148 adults with newly diagnosed NVAF, 11,059 (47.8%) initiated OAC within one year. OAC users predominantly had cardiovascular disease and risk factors, whereas non-OAC users had higher rates of malignancy and dementia. Early OAC initiation (74.9% during the index visit) was linked to lower hospitalization risks compared to those initiating later (29.2% vs. 45.9% for all-cause, p-value < 0.001 and 1.3% vs. 2.6% for stroke/SE-specific, p-value < 0.001). Adjusted odds ratios for all-cause and stroke/SE hospitalization favored early initiation were 0.35 (95% CI: 0.32–0.39) and 0.34 (95% CI: 0.24–0.47), respectively.ConclusionsThis study highlights OAC underutilization in NVAF patients and suggests early initiation may lower hospitalization rates. The findings emphasize the need for further research into real-world compliance with OAC guidelines and call for further research to confirm the benefits of early initiation. Personalized management strategies that consider individual patient profiles are recommended

Effectiveness, safety, and costs of thromboprophylaxis with enoxaparin or unfractionated heparin in inpatients with obesity

BackgroundObesity is a frequent and significant risk factor for venous thromboembolism (VTE) among hospitalized adults. Pharmacologic thromboprophylaxis can help prevent VTE, but real-world effectiveness, safety, and costs among inpatients with obesity are unknown.ObjectiveThis study aims to compare clinical and economic outcomes among adult medical inpatients with obesity who received thromboprophylaxis with enoxaparin or unfractionated heparin (UFH).MethodsA retrospective cohort study was performed using the PINC AI™ Healthcare Database, which covers more than 850 hospitals in the United States. Patients included were ≥18 years old, had a primary or secondary discharge diagnosis of obesity [International Classification of Diseases (ICD)-9 diagnosis codes 278.01, 278.02, and 278.03; ICD-10 diagnosis codes E66.0x, E66.1, E66.2, E66.8, and E66.9], received ≥1 thromboprophylactic dose of enoxaparin (≤40 mg/day) or UFH (≤15,000 IU/day) during the index hospitalization, stayed ≥6 days in the hospital, and were discharged between 01 January 2010, and 30 September 2016. We excluded surgical patients, patients with pre-existing VTE, and those who received higher (treatment-level) doses or multiple types of anticoagulants. Multivariable regression models were constructed to compare enoxaparin with UFH based on the incidence of VTE, pulmonary embolism (PE)­­­­­­­­–related mortality, overall in-hospital mortality, major bleeding, treatment costs, and total hospitalization costs during the index hospitalization and the 90 days after index discharge (readmission period).ResultsAmong 67,193 inpatients who met the selection criteria, 44,367 (66%) and 22,826 (34%) received enoxaparin and UFH, respectively, during their index hospitalization. Demographic, visit-related, clinical, and hospital characteristics differed significantly between groups. Enoxaparin during index hospitalization was associated with 29%, 73%, 30%, and 39% decreases in the adjusted odds of VTE, PE-related mortality, in-hospital mortality, and major bleeding, respectively, compared with UFH (all p < 0.002). Compared with UFH, enoxaparin was associated with significantly lower total hospitalization costs during the index hospitalization and readmission periods.ConclusionsAmong adult inpatients with obesity, primary thromboprophylaxis with enoxaparin compared with UFH was associated with significantly lower risks of in-hospital VTE, major bleeding, PE-related mortality, overall in-hospital mortality, and hospitalization costs

Genome of <i>Leptomonas pyrrhocoris</i>:a high-quality reference for monoxenous trypanosomatids and new insights into evolution of <i>Leishmania</i>

Many high-quality genomes are available for dixenous (two hosts) trypanosomatid species of the genera Trypanosoma, Leishmania, and Phytomonas, but only fragmentary information is available for monoxenous (single-host) trypanosomatids. In trypanosomatids, monoxeny is ancestral to dixeny, thus it is anticipated that the genome sequences of the key monoxenous parasites will be instrumental for both understanding the origin of parasitism and the evolution of dixeny. Here, we present a high-quality genome for Leptomonas pyrrhocoris, which is closely related to the dixenous genus Leishmania. The L. pyrrhocoris genome (30.4 Mbp in 60 scaffolds) encodes 10,148 genes. Using the L. pyrrhocoris genome, we pinpointed genes gained in Leishmania. Among those genes, 20 genes with unknown function had expression patterns in the Leishmania mexicana life cycle suggesting their involvement in virulence. By combining differential expression data for L. mexicana, L. major and Leptomonas seymouri, we have identified several additional proteins potentially involved in virulence, including SpoU methylase and U3 small nucleolar ribonucleoprotein IMP3. The population genetics of L. pyrrhocoris was also addressed by sequencing thirteen strains of different geographic origin, allowing the identification of 1,318 genes under positive selection. This set of genes was significantly enriched in components of the cytoskeleton and the flagellum

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Epidemiology and injectable antiseizure medication treatment patterns of seizure patients treated in United States hospitals

Objective This study aimed to examine the epidemiology of seizures, clinical outcomes, and antiseizure medication treatment patterns among seizure patients treated in United States hospitals.DesignA retrospective cross-sectional study was conducted using data from a large geographically diverse hospital discharge database.Setting860 acute care hospitals in the United States.ParticipantsPatients aged ≥18 years with an outpatient emergency department or inpatient visit between 1 July 2016–31 December 2019 were included. Intervention None. Main outcomes and measures Key outcomes included prevalence of seizure, seizure type, admission point of origin, intensive care unit admission, discharge status, and injectable antiseizure medication utilization. Seizures were identified by the International Classification of Disease, Tenth Revision, Clinical Modification diagnosis codes. Results Among 36,598,627 unique emergency department outpatients (72,372,464 outpatient visits) and 16,543,592 unique inpatients (24,923,489 inpatient admissions) analyzed, seizure was present in 2.1% of outpatients (1.87% of outpatient visits) and 4.9% of inpatients (4.8% of inpatient admissions). In overall seizure patients, 49.1% were unclassified, 4.4% had generalized onset, 2.9% had focal onset, and 42.8% were categorized as other (including 38.5% with convulsion). Among seizure-associated inpatient admissions, <1% were transferred directly from skilled nursing facility or other long-term care facilities but 22.7% were discharged to such facilities. Nearly a third (31%) of all inpatients were admitted to ICU. About 88.3% of patients with injectable ASM use had monotherapy, 4.6% had polytherapy with 1 day or multiple non-consecutive days of overlap, and 7.0% had polytherapy with ≥2 consecutive days of overlap. The percentage of patients with no step down to any oral ASM ranged between 34.0–57.0%. Conclusions Seizures affect a substantial number of hospital-based emergency department outpatient and inpatient encounters and are associated with poor clinical outcomes and significant healthcare burden. Concomitant use of injectable ASMs is uncommon and a high percentage of IV ASM users with a diagnosis of seizure had no step down to oral therapy.RelevanceThe study findings may inform clinicians and hospital decision makers about current clinical practice and burden of seizures and identify areas to improve overall outcomes for patients with seizures

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Disease burden and high-risk populations for complications in patients with acute respiratory infections: a scoping review

BackgroundAcute respiratory infections (ARIs) represent a significant public health concern in the U.S. This study aimed to describe the disease burden of ARIs and identify U.S. populations at high risk of developing complications.MethodsThis scoping review searched PubMed and EBSCO databases to analyze U.S. studies from 2013 to 2022, focusing on disease burden, complications, and high-risk populations associated with ARIs.ResultsThe study included 60 studies and showed that ARI is associated with a significant disease burden and healthcare resource utilization (HRU). In 2019, respiratory infection and tuberculosis caused 339,703 cases per 100,000 people, with most cases being upper respiratory infections and most deaths being lower respiratory infections. ARI is responsible for millions of outpatient visits, especially for influenza and pneumococcal pneumonia, and indirect costs of billions of dollars. ARI is caused by multiple pathogens and poses a significant burden on hospitalizations and outpatient visits. Risk factors for HRU associated with ARI include age, chronic conditions, and socioeconomic factors.ConclusionThe review underscores the substantial disease burden of ARIs and the influence of age, chronic conditions, and socioeconomic status on developing complications. It highlights the necessity for targeted strategies for high-risk populations and effective pathogen detection to prevent severe complications and reduce HRU

Prevalence and healthcare burden of inappropriate antimicrobial treatment in patients at high risk of complications from acute respiratory infections: a scoping review

BackgroundEvidence of inappropriate antimicrobial treatment for acute respiratory infections (ARIs) is well-established in literature. However, comprehensive evaluations of inappropriate antimicrobial use and associated clinical and economic outcomes for patients at high risk of complications from ARIs are lacking. This scoping review described the prevalence of inappropriate antimicrobial use and its healthcare burden in this patient population.Materials and methodsWe queried Medline and CINAHL databases using keywords related to antimicrobials for ARIs in high-risk patients, and included United States studies reporting prescribing patterns, outcomes, adverse events, and costs.ResultsOur search yielded 3,383 studies after de-duplication, from which 482 were selected for full-text evaluation based on exclusion criteria, resulting in 32 papers analyzed that included relevant information on high-risk populations. The analysis suggested that patients at high risk for complications experience improper prescribing of antimicrobials for ARIs, which is associated with higher direct and indirect costs, increased health care resource utilization, higher incidence of adverse events, and more severe disease complications.ConclusionAreas for improving care for this patient population include identifying patients at risk of severe disease and complications from ARIs and following evidence-based protocols for testing, treatment and follow-up to minimize the risk of developing adverse events, antibiotic-resistance, and severe complications

Clonal driver neoantigen loss under EGFR TKI and immune selection pressures

Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1, 2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies