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Taraneh Bahremand,1 Mahyar Etminan,2 Nardin Roshan-Moniri,1 Mary A De Vera,1 Hamid Tavakoli,1 Mohsen Sadatsafavi1 1Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada; 2Department of Ophthalmology, Faculty of Medicine, The University of British Columbia, Vancouver, BC, CanadaCorrespondence: Mohsen SadatsafaviFaculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, CanadaEmail msafavi@mail.ubc.caBackground: In contemporary guidelines for the management of Chronic Obstructive Pulmonary Disease (COPD), the history of acute exacerbations plays an important role in the choice of long-term inhaled therapies. This study aimed at evaluating population-level trends of filled inhaled prescriptions over the time course of COPD and their relation to the history of exacerbations.Methods: We used administrative health databases in British Columbia, Canada (1997– 2015), to create a retrospective incident cohort of individuals with diagnosed COPD. We quantified long-acting inhaled medication prescriptions within each year of follow-up and documented their trend over the time course of COPD. Using generalized linear models, we investigated the association between the frequent exacerbator status (≥ 2 moderate or ≥ 1 severe exacerbation(s) in the previous 12 months) and filling a prescription after a physician visit.Results: 132,004 COPD patients were included (mean age 68.6, 49.2% female). The most common medication class during the first year of diagnosis was inhaled corticosteroids (ICS, used by 49.9%), followed by long-acting beta-2 adrenoreceptor agonists (LABA, 31.8%). Long-acting muscarinic receptor antagonists (LAMA) were the least commonly prescribed (10.4%). ICS remained the most common prescription throughout follow-up, being used by approximately 50% of patients during each year. 39.0% of patients received combination inhaled therapies in their first year of diagnosis, with ICS+LABA being the most common (30.7%). The association with exacerbation history was the most pronounced for triple therapy with an odds ratio (OR) of 2.68 for general practitioners and 2.02 for specialists (p< 0.001 for both). Such associations were generally stronger among GPs compared with specialists, with the exception of monotherapy with LABA or ICS.Conclusion: We documented low utilization of monotherapies (specifically LAMA) and high utilization of combination therapies (particularly ICS containing). Specialists were less likely to consider exacerbation history in the choice of inhaled therapies compared with GPs.Keywords: COPD, prescription, medication, exacerbation, time trend

Background and purpose: There is a lack of comparative safety data on the risk of pseudotumor cerebri syndrome (PTCS) associated with different hormonal contraceptives. We sought to quantify the risk of PTCS associated with eight different types of hormonal contraceptives compared with oral levonorgestrel. Methods: We conducted a retrospective cohort study, with a case–control analysis of 4 871 504 women aged 15–45 years in the period 2008–2015, using IQVIA Ambulatory Electronic Medical Records data in the USA. Patients who used nine different contraceptive agents including intrauterine levonorgestrel, medroxyprogesterone injection, etonogestrel/ethinyl estradiol vaginal ring and combination oral contraceptives (COCs) that contained ethinyl estradiol and the progestins levonorgestrel, norgestimate, desogestrel, norethindrone and drospirenone, were included. Diagnosis of PTCS was defined using the first International Classification of Diseases, 9th or 10th revision, code for intracranial hypertension in patients who had also received an imaging code in the 30 days prior to the index date. Results: A total of 3323 PTCS cases and 13 292 matched controls were identified. No increase in risk was found when analysing intrauterine levonorgestrel or COCs containing desogestrel, norethindrone, drospirenone, norgestimate or norgestrel versus COC levonorgestrel. The adjusted incidence rate ratio for etonogestrel/etonogestrel/ethinyl estradiol vaginal ring and medroxyprogesterone suspension compared with levonorgestrel COC was 4.45 [95% confidence interval (CI) 1.98–9.96] and 2.20 (95% CI 1.33–3.64), respectively. Conclusions: This study found an elevated risk for PTCS among users of etonogestrel vaginal ring and medroxyprogesterone suspension when compared with oral levonorgestrel. Future studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

In this study single and double layer of Cu and Zn nanostructure thin films are prepared by pulse laser deposition technique. The samples are characterized by field emission scanning electron microscopy and optical absorption spectroscopy. The nonlinear refractive index and absorption coefficient of Cu, Zn, Zn/Cu, and Cu/Zn nanostructure thin films are studied by Z-scan method. Zn, Cu/Zn and Zn/Cu nanostructure thin films exhibit positive and Cu nanostructure thin films exhibit negative thermal nonlinear refractive indices, all of the order of 10 − 4 cm 2 /W. Nonlinear absorption coefficient signs of Cu/Zn and Zn nanostructure thin films were positive and those of Zn/Cu and Cu were negative. It is shown that the nonlinear phase shift and the nonlinear refractive index have increased in double layer thin films in comparison with single layer thin films, and also the nonlinear absorption behaviour of double layer thin films is similar to that of the upper layer thin films. Contrary to normal trend, nonlinear absorption coefficient of Cu/Zn double layer thin film has increased in comparison with Zn single layer thin film in spite of increasing thickness. Thus tuneable nonlinear absorption coefficient maybe attainable. [ABSTRACT FROM AUTHOR]

Context: Fluoroquinolones are commonly prescribed classes of antibiotics. Despite numerous case reports of ocular toxicity, a pharmacoepidemiological study of their ocular safety, particularly retinal detachment, has not been performed.Objective: To examine the association between use of oral fluoroquinolones and the risk of developing a retinal detachment.Design, Setting, and Patients: Nested case-control study of a cohort of patients in British Columbia, Canada, who had visited an ophthalmologist between January 2000 and December 2007. Retinal detachment cases were defined as a procedure code for retinal repair surgery within 14 days of a physician service code. Ten controls were selected for each case using risk-set sampling, matching on age and the month and year of cohort entry.Main Outcome Measure: The association between retinal detachment and current, recent, or past use of an oral fluoroquinolone.Results: From a cohort of 989,591 patients, 4384 cases of retinal detachment and 43,840 controls were identified. Current use of fluoroquinolones was associated with a higher risk of developing a retinal detachment (3.3% of cases vs 0.6% of controls; adjusted rate ratio [ARR], 4.50 [95% CI, 3.56-5.70]). Neither recent use (0.3% of cases vs 0.2% of controls; ARR, 0.92 [95% CI, 0.45-1.87]) nor past use (6.6% of cases vs 6.1% of controls; ARR, 1.03 [95% CI, 0.89-1.19]) was associated with a retinal detachment. The absolute increase in the risk of a retinal detachment was 4 per 10,000 person-years (number needed to harm = 2500 computed for any use of fluoroquinolones). There was no evidence of an association between development of a retinal detachment and β-lactam antibiotics (ARR, 0.74 [95% CI, 0.35-1.57]) or short-acting β-agonists (ARR, 0.95 [95% CI, 0.68-1.33]).Conclusion: Patients taking oral fluoroquinolones were at a higher risk of developing a retinal detachment compared with nonusers, although the absolute risk for this condition was small. [ABSTRACT FROM AUTHOR]

Surface seismic data include necessary information for predicting the formation of pore pressure in hydrocarbon reservoirs. In this article, formation pore pressure was predicted based on the velocity inversion method for a gas reservoir located in the southwest of Iran. Firstly, for this purpose, seismic data were inverted to obtain velocity values. Secondly, these values were converted to effective stress by using Bowers' equation (1994). In addition, the overburden stress was estimated from the Amoco equation (Huffman et al., 2011). To obtain formation pore pressure, the effective stress was subtracted from the estimated overburden stress. The results showed a normal distribution of formation pore pressure versus depth. [ABSTRACT FROM AUTHOR]

BACKGROUND: Several studies have suggested that NSAID use may modify the risk of developing Parkinson's disease (PD). OBJECTIVE: Our aim was to conduct a meta-analysis of observational studies evaluating NSAID use and the risk of PD. METHODS: We systematically searched MEDLINE (1966-November 2008), EMBASE (1980-November 2008) and other databases. Data from 11 studies were included in the meta-analysis. We used the random effects model to calculate risk ratios (relative risks) and their corresponding 95% confidence intervals (CIs). RESULTS: The pooled risk ratio of PD with NSAID use was 0.95 (95% CI 0.80, 1.12). The pooled risk ratio of PD with high-dose or long-duration NSAID use was 0.91 (95% CI 0.78, 1.05). The pooled risk ratio of PD for aspirin (acetylsalicylic acid) users was 1.08 (95% CI 0.93, 1.26). The pooled risk ratio of PD among ibuprofen users was 0.76 (95% CI 0.65, 0.89). The pooled risk ratio of PD in men using NSAIDs was 0.79 (95% CI 0.69, 0.92), and in women using NSAIDs, it was 0.72 (95% CI 0.45, 1.15). CONCLUSIONS: NSAIDs as a class do not seem to modify the risk of PD. However, ibuprofen may have a slight protective effect in lowering the risk of PD. Although the risk ratios of PD in male and female NSAID users were similar, the 95% CI for men was suggestive of a slight risk reduction. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids (ICS) are commonly prescribed medications for the management of asthma and chronic obstructive pulmonary disease. It is well established that long-term use of these drugs may lower bone mineral density. However, whether ICS increase the risk of fractures remains unknown. Recent studies that have attempted to explore this risk have had conflicting results. We sought to explore the risk of ICS and fractures among older adults by conducting a systematic review and meta-analysis of the literature.Methods: We systematically searched several databases, including MEDLINE, EMBASE and the Cochrane Library, to identify pertinent studies. Those studies that potentially met our inclusion criteria were identified by two reviewers. Relative risks (RRs) were pooled using the random effects model. We also explored dose-response by stratifying the analysis on high and low doses of ICS. Heterogeneity was assessed using the Q statistic and publication bias was assessed using the funnel plot.Results: Thirteen studies, including four randomized controlled trials, were included in the review. The pooled RRs for hip fractures and any fractures were 0.91 (95% CI 0.87, 0.96) and 1.02 (95% CI 0.96, 1.08), respectively. When we restricted the analysis to users of high-dose ICS, the pooled RRs for any fractures and hip fractures were 1.30 (95% CI 1.07, 1.58) and 1.32 (95% CI 0.90, 1.92), respectively. The funnel plot did not show evidence of publication bias.Conclusion: We found no association between the use of ICS and fractures in older adults. A slight increase in risk was seen in those using high-dose ICS. The significance of this association should be investigated further. [ABSTRACT FROM AUTHOR]

Background: Recently, studies have attempted to explore the interaction between ACE inhibitors and aspirin (acetylsalicylic acid) when both drugs are used concomitantly to reduce mortality in patients with coronary artery disease. Results have been conflicting due, in part, to sub-optimal methods used to explore this interaction.Methods: We reviewed systematically all studies on mortality in patients treated with ACE inhibitors and aspirin and conducted a meta-analysis in order to explore the interaction between both drugs and resolve discrepancies. To be included, each study had to provide data on mortality of patients who received both drugs, either drug and no drug. These data were necessary to calculate the synergy index (S) and its 95% confidence interval (CI) that we used to quantify the effect due to interaction between ACE inhibitors and aspirin. After testing for heterogeneity of effects, we pooled the S values from the individual studies into one summary measure. Subsequently, we compared our results with those obtained through the most common but incorrect method of evaluating interaction. This method uses significance testing of the relative risk of mortality when a 'product term' between ACE inhibitors and aspirin is entered in a logistic regression model.Results: Eight studies met the inclusion criteria. The pooled synergy index S indicates slight but precise antagonism between ACE inhibitors and aspirin (S = 0.91; 95% CI 0.80 to 1.03). In contrast, the pooled 'product term' is not significant and would have lead to the conclusion of absence of interaction (p = 0.15).Conclusion: There seems to be an antagonistic interaction between ACE inhibitors and aspirin. Former discrepancies were due to inadequate assessment of interaction. Results from the Studies on Left Ventricular Dysfunction (SOLVD) and Heart Outcome Prevention Evaluation (HOPE) trials that assessed the effect of combined administration of ACE inhibitors and aspirin were not included in this meta-analysis because those trials did not provide enough data to compute the S statistic. It is possible that results from on-going trials such as Women's Atovarstatin Trial on Cholesterol (WATCH) will shed more light on ACE inhibitor and aspirin interaction in the future. [ABSTRACT FROM AUTHOR]

Background: Recent case reports and letters have alerted practitioners to the risk of sleep attacks, usually preceded by somnolence, in patients with Parkinson's disease treated with pramipexole and ropinirole.Objective: To quantify the risk of somnolence with the new dopamine agonists pramipexole and ropinirole in patients with Parkinson's disease.Methods: We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts and Cochrane Library, contacted experts and pharmaceutical manufacturers, and manually reviewed all references retrieved to identify possible articles to include. Information on randomisation, blinding, type of treatment and reporting of somnolence were abstracted by 2 independent reviewers. Disagreements were resolved by a third author.Analysis: We made 2 separate analyses. The first analysis compared the risk of somnolence in patients taking either pramipexole or ropinirole to that in patients taking placebo. The second analysis compared the risk of somnolence with these drugs (plus levodopa) versus that with levodopa alone. We calculated pooled relative risk estimates using the random effects model and when no heterogeneity was detected we used the fixed effects model.Results: Four trials were included in the analysis of patients taking pramipexole or ropinirole compared with those taking placebo. The pooled relative risk of somnolence in this analysis was 4.98 [95% confidence interval (CI) 1.79 to 13.89]. Seven trials were included in the analysis of patients taking levodopa and pramipexole or ropinirole compared with those taking levodopa alone. The pooled relative risk was 2.06 (95% CI 1.47 to 2.88).Conclusion: Patients with Parkinson's disease using pramipexole or ropinirole are at higher risk of experiencing somnolence relative to patients taking placebo. Patients taking levodopa plus either one of these dopamine agonists are at higher risk than those taking levodopa alone. Clinicians should carefully weigh this risk against the benefit of these agents when prescribing these drugs. [ABSTRACT FROM AUTHOR]

Abstract Background Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD. Methods We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot. Results Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%). Conclusion The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials.

Discusses an abstract of "Macrolide therapy for Chlamydia pneumoniae in the secondary prevention of coronary artery disease: A meta-analysis of randomized controlled trials," by M. Etminan et al published in a 2004 issue of "Pharmacotherapy" journal.

Objective: Aromatase inhibitors (AIs) are a class of medications used for adjuvant treatment of breast cancer. Recent case reports suggest that AIs may be associated with various ocular adverse events (AEs). This study evaluates the risk of ocular AEs in patients who take AIs., Method: Disproportionality analysis was performed using data from the U.S. Food and Drug Administration's Adverse Events Reporting System database from 2004 to 2022. All cases of vitreomacular traction, macular edema, retinal deposits, retinal artery occlusion, macular hole, retinal hemorrhage, uveitis, retinal tear, retinal detachment, dry eye disease, blepharitis, and optic neuropathy were searched for the 3 AIs anastrozole, letrozole, and exemestane. A search also was performed on trastuzumab as a control. Reported odds ratios (RORs) and corresponding 95% CIs were computed., Results: We identified 322 ocular AEs of interest for the 3 AIs and 55 for trastuzumab. Anastrozole had the most AEs (n = 163) and was found to have strong associations with vitreomacular traction (ROR = 665; 95% CI, 352-1255), macular edema (ROR = 37; 95% CI, 25-54), retinal deposits (ROR = 11; 95% CI, 2-77), and uveitis (ROR = 6; 95% CI, 4-9). Letrozole had strong associations with retinal deposits (ROR = 8, 95% CI, 1-57) and retinal artery occlusion (ROR = 6; 95% CI, 3-11). Exemestane had a strong association with macular holes (ROR = 10; 95% CI, 3-30)., Conclusion: Disproportionality analysis revealed an increased risk of ocular AEs with each of the AIs. This study calls for clinicians, especially oncologists and ophthalmologists, to be vigilant in patients who are on AI therapy, allowing them to provide prompt interventions to mitigate further ocular morbidities., (Copyright © 2023. Published by Elsevier Inc.)

In medical research, some variables are conditionally defined on some levels of another variable, leading to conditional missing data. Imputation of this type of structural missing data is needed given inefficiency of listwise deletion inherent in regression modeling. Using some examples, we illustrate handling of conditional missing values using simple imputation procedures in etiologic and prediction research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Attention deficit hyperactivity disorder (ADHD) therapies including atomoxetine, methylphenidate, and amphetamines are some of the most prescribed medications in North America. Due to their sympathomimetic action, these drugs are contraindicated in patients with a history of angle closure glaucoma (ACG). This study aims to determine the risk of ACG and open angle glaucoma (OAG) among users of these treatments., Methods: This is a retrospective cohort study with a case control analysis using the PharMetrics Plus Database (IQVIA, USA). We created a cohort of new users of atomoxetine, methylphenidate, and amphetamines and they were followed to the first diagnosis of (1) ACG or OAG; or (2) end of follow up. For each case, four age-matched controls were selected. A conditional logistic regression model was used to adjust for confounders and to calculate adjusted incidence-rate-ratios (aIRRs)., Results: A total of 240,257 new users of the ADHD medications were identified. The mean age was 45.0 ± 19.4 years and 55% of the cohort was female. Regular users of atomoxetine and amphetamines had a higher aIRR for developing ACG compared with non-users (aIRR = 2.55 95% CI [1.20-5.43] and 2.27 95% CI [1.42-3.63], respectively); while users of methylphenidate had a higher aIRR for developing OAG (aIRR = 1.23 95% CI [1.05-1.59])., Conclusions: Use of amphetamines and atomoxetine had a higher risk for ACG, while use of methylphenidate was associated with a higher risk for OAG. Given the prevalence of ADHD medication use (medically and recreationally), our current data on their associated risk of glaucoma have profound public health implications., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: Fluoroquinolones are popular antibiotics used for a myriad of conditions including ocular procedures. Despite numerous case reports of acute pigmentary degeneration of the iris with fluoroquinolone use, a pharmacoepidemiological study has not been performed to examine and quantify this risk., Design: Retrospective cohort study with a case-control analysis., Participants: A cohort of 1,231,881 new users of oral or topical moxifloxacin, levofloxacin, and azithromycin were followed to first diagnosis of pigmentary degeneration of the iris or pigmentary glaucoma. Four controls were selected for each case using density sampling, matching on age and calendar time., Methods: Users of oral or topical moxifloxacin were compared to levofloxacin and azithromycin, a negative control drug from a separate class., Main Outcomes and Measures: First incidence of pigmentary degeneration of the iris or pigmentary glaucoma., Results: The cohort was comprised of 1,231,881 new users of topical or oral levofloxacin, moxifloxacin, or azithromycin. 542 cases of pigmentary degeneration of the iris and 460 cases of pigmentary glaucoma were identified. The incidence of iris pigmentary degeneration or pigmentary glaucoma for topical moxifloxacin was 10.2/1000 person years compared to 2.6/1000 person years for topical azithromycin. Current topical moxifloxacin users had the highest adjusted IRR for pigmentary degeneration of the iris (IRR = 6.81, [95%CI:2.00-23.18]) and pigmentary glaucoma (IRR = 4.07 [95%CI:1.42-11.62]) respectively., Conclusions: The study findings suggest that patients using topical moxifloxacin may have increased risk of developing pigmentary degeneration of the iris and pigmentary glaucoma although the absolute increase was low. Future studies are needed to confirm this association., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Disease latency is defined as the time from disease initiation to disease diagnosis. Disease latency bias (DLB) can arise in epidemiological studies that examine latent outcomes, since the exact timing of the disease inception is unknown and might occur before exposure initiation, potentially leading to bias. Although DLB can affect epidemiological studies that examine different types of chronic disease (e.g. Alzheimer's disease, cancer etc), the manner by which DLB can introduce bias into these studies has not been previously elucidated. Information on the specific types of bias, and their structure, that can arise secondary to DLB is critical for researchers, to enable better understanding and control for DLB., Development: Here we describe four scenarios by which DLB can introduce bias (through different structures) into epidemiological studies that address latent outcomes, using directed acyclic graphs (DAGs). We also discuss potential strategies to better understand, examine and control for DLB in these studies., Application: Using causal diagrams, we show that disease latency bias can affect results of epidemiological studies through: (i) unmeasured confounding; (ii) reverse causality; (iii) selection bias; (iv) bias through a mediator., Conclusion: Disease latency bias is an important bias that can affect a number of epidemiological studies that address latent outcomes. Causal diagrams can assist researchers better identify and control for this bias., (© The Author(s) 2024; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: To examine the possible link between acute angle closure (AAC) with use of diuretics., Methods: A nested case-control study (NCC) was conducted among a cohort of diuretic users using the PharMetrics Plus database from 2006 to 2020. Cases were identified as the first international classification of diseases 9 th and 10 th editions (ICD-9/10) code for ACC. For each case, 4 controls were selected and matched to the cases by age and sex using density-based sampling. A conditional logistic regression model was used to compute rate ratios (RRs) adjusted for the drugs topiramate, bupropion, sulphonamide antibiotics, acetazolamide, and sulfasalazine. The RRs for a negative control drug, amlodipine, was also assessed., Results: From the initial cohort of 713 574 diuretics users, 1 553 cases and 6 212 controls were identified. No increase in the risk of AAC with current users of diuretics was found (RR = 1.06, (95% CI: 0.81-1.37) for all diuretics; RR = 0.97, (95% CI: 0.71-1.32) for thiazides; RR = 1.24, (95% CI: 0.90-1.73) for loop diuretics; RR = 0.99, (95% CI: 0.73-1.36) for potassium sparing)., Conclusion: We found no increase in the risk of acute angle closure with use of diuretics. Future studies are needed to confirm these findings.

This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)-specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors-using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

The advancement of immuno-oncology has brought about a significant shift in cancer treatment methods, with antibody-based immune checkpoint inhibitors like atezolizumab leading the way in this regard. However, the use of this checkpoint blockade can result in immune-related adverse events due to increased T-cell activity. The full spectrum of these events is not yet completely understood. In this study, the United States FDA Adverse Event Reporting System (FAERS) was utilized to investigate immune-related adverse events linked with the use of atezolizumab. The study identified forty-nine immune-related adverse events that affected multiple organ systems, including cardiovascular, respiratory, hematologic, hepatic, renal, gastrointestinal, neurologic, musculoskeletal, dermatologic, endocrine, and systemic disorders. The strongest signals for relative risk occurred for immune-mediated encephalitis (RR = 93.443), autoimmune myocarditis (RR = 56.641), immune-mediated hepatitis (RR = 49.062), immune-mediated nephritis (RR = 40.947), and autoimmune arthritis (RR = 39.382). Despite the morbidity associated with these adverse events, emerging evidence suggests potential associations with improved survival outcomes. Overall, this report sheds light on the widespread immune-related adverse events that cause significant morbidity and mortality in patients with cancer being treated with atezolizumab and brings attention to them for the clinicians treating these patients.

The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in hematologic malignancies. However, data on their adverse events, particularly of the eye, is under-reported. To assess the ocular adverse events associated with the six FDA-approved CAR-T cell therapies, a disproportionality analysis utilizing the FAERS database was conducted from the first quarter of 2017 to the third quarter of 2023, as well as a systematic review of case reports of ocular events following CAR-T cell therapy up to December 20, 2023. A total of 53 ocular adverse events were identified from the FDAs FAERS database. The adverse events most frequently observed were mydriasis and xerophthalmia with tisagenlecleucel (Kymriah). The systematic review resulted in 8 case reports encompassing 19 patients which included a total of 27 events. This study demonstrates the importance of anticipation of potential ocular adverse events by ophthalmologists and oncologists as they can greatly contribute to morbidity in patients with cancer., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Epidemiologic studies on the risk of multiple sclerosis (MS) or demyelinating events associated with anti-tumor necrosis factor alpha (TNFα) use among patients with rheumatic diseases or inflammatory bowel diseases have shown conflicting results. Causal directed acyclic graphs (cDAGs) are useful tools for understanding the differing results and identifying the structure of potential contributing biases. Most of the available literature on cDAGs uses language that might be unfamiliar to clinicians. This article demonstrates how cDAGs can be used to determine whether there is a confounder, a mediator or collider-stratification bias and when to adjust for them appropriately. We also use a case study to show how to control for potential biases by drawing a cDAG depicting anti-TNFα use and its potential to contribute to MS onset. Finally, we describe potential biases that might have led to contradictory results in previous studies that examined the effect of anti-TNFα and MS, including confounding, confounding by contraindication, and bias due to measurement error. Clinicians and researchers should be cognizant of confounding, confounding by contraindication, and bias due to measurement error when reviewing future studies on the risk of MS or demyelinating events associated with anti-TNFα use. cDAGs are a useful tool for selecting variables and identifying the structure of different biases that can affect the validity of observational studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The prevalence of metabolic syndrome is increasing worldwide. Clinical guidelines consider metabolic syndrome as an all or none medical condition. One proposed method for classifying metabolic syndrome is latent class analysis (LCA). One approach to causal inference in LCA is using propensity score (PS) methods. The aim of this study was to investigate the causal effect of smoking on latent hazard classes of metabolic syndrome using the method of latent class causal analysis., Methods: In this study, we used data from the Tehran Lipid and Glucose Cohort Study (TLGS). 4857 participants aged over 20 years with complete information on exposure (smoking) and confounders in the third phase (2005-2008) were included. Metabolic syndrome was evaluated as outcome and latent variable in LCA in the data of the fifth phase (2014-2015). The step-by-step procedure for conducting causal inference in LCA included: (1) PS estimation and evaluation of overlap, (2) calculation of inverse probability-of-treatment weighting (IPTW), (3) PS matching, (4) evaluating balance of confounding variables between exposure groups, and (5) conducting LCA using the weighted or matched data set., Results: Based on the results of IPTW which compared the low, medium and high risk classes of metabolic syndrome (compared to a class without metabolic syndrome), no association was found between smoking and the metabolic syndrome latent classes. PS matching which compared low and moderate risk classes compared to class without metabolic syndrome, showed that smoking increases the probability of being in the low-risk class of metabolic syndrome (OR: 2.19; 95% CI: 1.32, 3.63). In the unadjusted analysis, smoking increased the chances of being in the low-risk (OR: 1.45; 95% CI: 1.01, 2.08) and moderate-risk (OR: 1.68; 95% CI: 1.18, 2.40) classes of metabolic syndrome compared to the class without metabolic syndrome., Conclusions: Based on the results, the causal effect of smoking on latent hazard classes of metabolic syndrome can be different based on the type of PS method. In adjusted analysis, no relationship was observed between smoking and moderate-risk and high-risk classes of metabolic syndrome., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: This study was conducted to evaluate the effect of alcohol consumption on breast cancer, adjusting for alcohol consumption misclassification bias and confounders., Methods: This was a case-control study of 932 women with breast cancer and 1000 healthy control. Using probabilistic bias analysis method, the association between alcohol consumption and breast cancer was adjusted for the misclassification bias of alcohol consumption as well as a minimally sufficient set of adjustment of confounders derived from a causal directed acyclic graph. Population attributable fraction was estimated using the Miettinen's Formula., Results: Based on the conventional logistic regression model, the odds ratio estimate between alcohol consumption and breast cancer was 1.05 (95% CI: 0.57, 1.91). However, the adjusted estimates of odds ratio based on the probabilistic bias analysis ranged from 1.82 to 2.29 for non-differential and from 1.93 to 5.67 for differential misclassification. Population attributable fraction ranged from 1.51 to 2.57% using non-differential bias analysis and 1.54-3.56% based on differential bias analysis., Conclusion: A marked measurement error was in self-reported alcohol consumption so after correcting misclassification bias, no evidence against independence between alcohol consumption and breast cancer changed to a substantial positive association., (© 2023. The Author(s).)

Purpose: Numerous case reports have associated anti-glaucoma medications with recurrence of herpes simplex virus (HSV) and herpes zoster virus (HZV) keratitis. The aim of our study was to determine whether different anti-glaucoma agents are associated with recurrence of herpetic keratitis., Methods: This was a retrospective cohort study using health databases from a Canadian province from January 2001 to December 2012. A new cohort of users on topical prostaglandins (PGs), beta blockers (BBs), alpha-2 agonists (AAs) and carbonic anhydrase inhibitors (CAIs) was created. The date of the third anti-glaucoma drug dispensation within 90 days was deemed the index date of the case. Herpetic keratitis events, as defined by an ICD-9/10 code for HSV or HZV keratitis, or the dispensation of an anti-viral medication by either an ophthalmologist or an optometrist, were examined prior to and following the index date. Risk ratios (RRs) were computed to compare the risk of HSV/HZV keratitis among the PG, BB, AA, and CAI groups individually and collectively while adjusting for age and sex., Results: Among 19,986 users of glaucoma medications identified, there were 684 cases of HSV/HZV keratitis. There was no increased risk of HSV/HZV keratitis recurrence for any of the four glaucoma medications classes individually or collectively when adjusted for age and sex. There was also no increased risk for redeveloping either HSV keratitis only or HZV keratitis only amongst all anti-glaucoma users., Conclusion: There is no association between the use of topical ocular hypotensive therapies and HSV/HZV keratitis recurrence. Further studies are needed to confirm these findings., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Intraocular pressure increase (IOPi) after intravitreal injections of vascular endothelial growth factor inhibitors (VEGFis) might be different among different VEGFis (bevacizumab, aflibercept, ranibizumab). The purpose of this study was to evaluate the risk of IOPi among new users of bevacizumab, ranibizumab, and aflibercept in nondiabetic patients in Tuscany, Italy., Design: Retrospective cohort study., Methods: Tuscan regional administrative database was used to identify subjects with a first VEGFi intravitreal injection between 2011 and 2020, followed to first incidence of IOPi. Diabetic subjects, those with pre-existing IOPi, or previous use of dexamethasone implants were excluded. Multivariable Cox regression analyses (intention-to-treat and as treated) were conducted to evaluate risk of IOPi among aflibercept, bevacizumab, and ranibizumab, adjusting for potential confounding variables. IOPi was defined as the first record of International Classification of Diseases, Ninth Revision (ICD-9-CM) code 365 or use of 2 glaucoma drugs dispensations within 180 days of each other., Results: We identified 6585 new users of VEGFis: 1749 aflibercept, 1112 bevacizumab, and 3724 ranibizumab. Women made up 60% of the cohort, with a mean age of 73.6 years. In the intention-to-treat analysis, the adjusted hazard ratio (HR) for incident IOPi, compared with aflibercept, was higher for bevacizumab (HR = 2.20, 95% CI = 1.64-2.95) and ranibizumab users (HR = 1.88, 95% CI = 1.46-2.42), respectively. The HRs remained robust after exclusion of patients with proxy of retinal vascular occlusion. As treated analysis confirmed such results (bevacizumab: HR = 3.76, 95% CI = 2.30-6.17; ranibizumab: HR = 2.49, 95% CI = 1.62-3.82)., Conclusions: This study found an increased risk of IOPi among nondiabetic patients with ranibizumab and bevacizumab compared with aflibercept. Future studies are needed to validate these findings., (Copyright © 2022. Published by Elsevier Inc.)