Interstitial Lung Disease and Progressive Pulmonary Fibrosis: a World Trade Center Cohort 20-Year Longitudinal Study.

PURPOSE: World Trade Center (WTC) exposure is associated with obstructive airway diseases and sarcoidosis. There is limited research regarding the incidence and progression of non-sarcoidosis interstitial lung diseases (ILD) after WTC-exposure. ILD encompasses parenchymal diseases which may lead to progressive pulmonary fibrosis (PPF). We used the Fire Department of the City of New York's (FDNY's) WTC Health Program cohort to estimate ILD incidence and progression. METHODS: This longitudinal study included 14,525 responders without ILD prior to 9/11/2001. ILD incidence and prevalence were estimated and standardized to the US 2014 population. Poisson regression modeled risk factors, including WTC-exposure and forced vital capacity (FVC), associated with ILD. Follow-up time ended at the earliest of incident diagnosis, end of study period/case ascertainment, transplant or death. RESULTS: ILD developed in 80/14,525 FDNY WTC responders. Age, smoking, and gastroesophageal reflux disease (GERD) prior to diagnosis were associated with incident ILD, though FVC was not. PPF developed in 40/80 ILD cases. Among the 80 cases, the average follow-up time after ILD diagnosis was 8.5 years with the majority of deaths occurring among those with PPF (PPF: n = 13; ILD without PPF: n = 6). CONCLUSIONS: The prevalence of post-9/11 ILD was more than two-fold greater than the general population. An exposure-response gradient could not be demonstrated. Half the ILD cases developed PPF, higher than previously reported. Age, smoking, and GERD were risk factors for ILD and PPF, while lung function was not. This may indicate that lung function measured after respirable exposures would not identify those at risk for ILD or PPF.

Additional Data in Expanded Patient Populations and New Indications Support the Practice of Biosimilar-to-Biosimilar Switching.

As of 31 December, 2023, 31 observational studies have been published, including a total of 6081 patients who underwent a switch from one biosimilar to another biosimilar of the same reference biologic. Most studies evaluated infliximab, while a smaller number evaluated adalimumab, rituximab or etanercept. Indications studied now include sarcoidosis, as well as the indications previously reported of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis/ankylosing spondylitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis). This updated data set includes eight additional studies and 2386 more patients compared with those included in an earlier systematic review of biosimilar-to-biosimilar switching. In addition, since the earlier systematic review was published in 2022, the European Medicines Agency has stated that reference-to-biosimilar and biosimilar-to-biosimilar switching in the European Union is safe and efficacy remains unchanged after switching. Furthermore, following a review of the available evidence, the US Food and Drug Administration has confirmed that initial safety and immunogenicity concerns related to biosimilar switching are unfounded and that no differences are observed in efficacy, safety or immunogenicity following one or more switches. The availability of this new efficacy and safety data together with the supportive statements from the European Medicines Agency and the Food and Drug Administration re-confirm the conclusion that as a scientific matter, biosimilar-to-biosimilar switching is an effective clinical practice, with no new safety concerns. Any suggestions to the contrary are not supported by the evidence.

Normal Lung Function and Mortality in World Trade Center Responders and National Health and Nutrition Examination Survey III Participants.

Rationale: Low FEV1 is a biomarker of increased mortality. The association of normal lung function and mortality is not well described. Objectives: To evaluate the FEV1-mortality association among participants with normal lung function. Methods: A total of 10,999 Fire Department of the City of New York (FDNY) responders and 10,901 Third National Health and Nutrition Examination Survey (NHANES III) participants, aged 18-65 years with FEV1 ⩾80% predicted, were analyzed, with FEV1 percent predicted calculated using Global Lung Function Initiative Global race-neutral reference equations. Mortality data were obtained from linkages to the National Death Index. Cox proportional hazards models estimated the association between FEV1 and all-cause mortality, controlling for age, sex, race/ethnicity, smoking history, and, for FDNY, work assignment. Cohorts were followed for a maximum of 20.3 years. Measurements and Main Results: We observed 504 deaths (4.6%) of 10,999 for FDNY and 1,237 deaths (9.4% [weighted]) of 10,901 for NHANES III. Relative to FEV1 ⩾120% predicted, mortality was significantly higher for FEV1 100-109%, 90-99%, and 80-89% predicted in the FDNY cohort. In the NHANES III cohort, mortality was significantly higher for FEV1 90-99% and 80-89% predicted. Each 10% higher predicted FEV1 was associated with 15% (hazard ratio, 0.85; 95% confidence interval, 0.80-0.91) and 23% (hazard ratio, 0.77; 95% confidence interval, 0.71-0.84) lower mortality for FDNY and NHANES III, respectively. Conclusions: In both cohorts, higher FEV1 is associated with lower mortality, suggesting higher FEV1 is a biomarker of better health. These findings demonstrate that a single cross-sectional measurement of FEV1 is predictive of mortality over two decades, even when FEV1 is in the normal range.

Self-reported Cardiovascular Disease in Career Firefighters With and Without World Trade Center Exposure.

OBJECTIVE: To assess the effect of World Trade Center (WTC) exposure on cardiovascular disease (CVD) in career firefighters. Methods: Firefighters from four US cities completed health questionnaires that provide information about demographics, CVD diagnoses, and CVD risk factors. Firefighters were also compared with respondents of the 2019 National Health Interview Survey. Results: Greater WTC exposure was positively associated with combined coronary artery disease, myocardial infarction, and angina (termed "CAD") when comparing WTC-exposed with non-WTC-exposed firefighters. Compared with the National Health Interview Survey population, firefighters had lower odds of CAD and stroke. Conclusions: An occupationally appropriate comparison is important to mitigate potential bias from the healthy worker effect. While the risk of CVD in WTC-exposed and non-WTC-exposed firefighters was significantly lower than a general US population, we observed an exposure gradient where greater WTC exposure was associated with greater odds of CVD.

Long-Term Real-World Post-approval Safety Data of Multiple Biosimilars from One Marketing-Authorization Holder After More than 18 Years Since Their First Biosimilar Launch.

BACKGROUND: Biosimilars are additional treatment options that are approved based on robust analytical and clinical comparisons with their reference biologic. At the time of initial approval, the full safety profile of a biosimilar is inferred from the reference biologic. Nonetheless, there are still lingering concerns related to the long-term safety of biosimilars. Therefore, we reviewed the post-approval pharmacovigilance data for eight marketed biosimilars from one Marketing Authorization Holder (MAH) to summarize their safety experience in a real-world setting for up to 18 years since their first biosimilar launch. METHODS: Post-approval cumulative patient exposure and safety experience for eight Sandoz biosimilars [adalimumab (Hyrimoz®), epoetin alfa (Binocrit®), etanercept (Erelzi®), filgrastim (Zarzio®), infliximab (Zessly®), pegfilgrastim (Ziextenzo®), rituximab (Rixathon®), and somatropin (Omnitrope®)] was summarized based on the available pharmacovigilance data from Periodic Safety Update Reports (PSURs) and the corresponding health authority-authored PSUR assessment reports, where available, as of 31 January 2023. Exposure to all biosimilars was calculated in patient treatment days (PTD) except for rituximab, which was expressed in number of patient doses (PD). RESULTS: The combined post-approval cumulative exposure to seven out of the eight marketed Sandoz biosimilars was more than 1.3 billion PTD and for rituximab more than 1.8 million PD. Overall, a critical analysis of the cumulative safety data of all eight Sandoz biosimilar PSURs concluded that the overall benefit-risk profile of each remains favorable and is consistent with the respective reference biologics. CONCLUSIONS: This is one of the largest reviews of post-approval biosimilar pharmacovigilance data to date by one MAH. The real-world experience of all eight marketed Sandoz biosimilars for up to 18 years demonstrates that Sandoz biosimilars can be used as safely as their respective reference biologics. Therefore, patients and healthcare providers can be confident in the clinical benefit and safety of Sandoz biosimilars. It is reasonable to believe that similar conclusions about safety may be reached for other biosimilars developed and approved to the high standards as are already in place by major health authorities such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The long-term safety of biosimilars demonstrated here provides strong support for the concept of biosimilarity.

Future Evolution of Biosimilar Development by Application of Current Science and Available Evidence: The Developer's Perspective.

Biosimilars have been available in the USA for over a decade, and in Europe for almost two decades. In that time, biosimilars have become established in the treatment landscape for a wide range of diseases, facilitating patient access and affordability of healthcare. However, patients can still struggle to access biological therapies in some markets. There is a need to streamline the process of developing biosimilars without compromising their quality, safety, or efficacy. This opinion piece considers the efficiencies that could be achieved within the biosimilar approval process. In clinical trials for biosimilars, clinical efficacy endpoints have been shown to be less sensitive measures of biosimilarity than biochemical, biophysical, and biological functional assays. Additional clinical efficacy studies comparing potential biosimilars and reference products do not add information that is useful for regulatory purposes. Large clinical studies of biosimilars with immunogenicity endpoints are of limited value, given the quality control processes in place for all biologics, including biosimilars. The expectation for multiple-switch studies for US interchangeability designation should be reconsidered immediately, and the category should be eliminated in the future. As biosimilars are typically approved globally based on a single set of clinical trials, and all subsequent manufacturing changes are already carefully monitored by regulatory authorities, comparative pharmacokinetic testing of EU and US reference products is unnecessary. Manufacturers and regulators could take greater advantage of existing real-world evidence. Streamlining biosimilar development would enable biosimilar development of more and a wider variety of biological drugs, accelerating biosimilar development without impacting patient safety or effectiveness.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. OBJECTIVE: The aim of this study is to characterize disease progression in N-ERD. METHODS: Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. RESULTS: Patients (N = 240) were mostly female (68%) and self-identified as non-White (77%). Half (N = 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.06-1.7, P = .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR = 3.3, 95% CI: 1.5-7.4, P = .004) and pollution exposure (OR = 4.4, 95% CI: 1.6-11.9, P = .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P = .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). CONCLUSIONS: In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Association of Lung Function Decline with All-Cause and Cancer-Cause Mortality after World Trade Center Dust Exposure.

Rationale: In numerous cohorts, lung function decline is associated with all-cause and cardiovascular-cause mortality, but the association between the decrease in forced expiratory volume in 1 second (FEV1) and cancer-cause mortality, particularly after occupational/environmental exposure(s), is unclear. Exposure to dust/smoke from the World Trade Center (WTC) disaster caused inflammation and lung injury in Fire Department of the City of New York rescue/recovery workers. In addition, prior research found that >10% of the cohort experienced greater than twice the age-related decrease in FEV1 (⩾64 ml/yr). Objectives: To evaluate the association of longitudinal lung function with all-cause and cancer-cause mortality after exposure to the WTC disaster. Methods: We conducted a prospective cohort study using longitudinal prebronchodilator FEV1 data for 12,264 WTC-exposed firefighters and emergency medical service providers. All-cause and cancer-cause mortality were ascertained using National Death Index data from September 12, 2001, through December 31, 2021. Joint longitudinal survival models evaluated the association of baseline FEV1 and change in FEV1 from baseline with all-cause and cancer-cause mortality adjusted for age, race/ethnicity, height, smoking, work assignment (firefighters vs. emergency medical service providers), and WTC exposure. Results: By December 31, 2021, 607 of the 12,264 individuals in the cohort (4.9%) had died (crude rate = 259.5 per 100,000 person-years), and 190 of 12,264 (1.5%) had died from cancer (crude rate = 81.2 per 100,000 person-years). Baseline FEV1 was ⩾80% predicted in 10,970 of the 12,264 (89.4%); final FEV1 was ⩾80% in 9,996 (81.5%). Lower FEV1 at baseline was associated with greater risk for all-cause mortality (hazard ratio [HR] per liter = 2.32; 95% confidence interval [95% CI] = 1.98-2.72) and cancer-cause mortality (HR per liter = 1.99; 95% CI = 1.49-2.66). Longitudinally, each 100-ml/yr decrease in FEV1 was associated with an 11% increase in all-cause mortality (HR = 1.11; 95% CI = 1.06-1.15) and a 7% increase in cancer-cause mortality (HR = 1.07; 95% CI = 1.00-1.15). Compared with FEV1 decrease <64 ml/yr, those with FEV1 decrease ⩾64 ml/yr had higher all-cause (HR = 2.91; 95% CI = 2.37-3.56) and cancer-cause mortality (HR = 2.68; 95% CI = 1.90-3.79). Conclusions: Baseline FEV1 and longitudinal FEV1 decrease are associated with increased risk of all-cause and cancer-cause mortality in a previously healthy occupational cohort, the majority of whom had normal lung function, after intense exposure to dust/smoke. Further investigation is needed to define pathways by which lung function impacts mortality after an irritant exposure.

Switching from One Biosimilar to Another Biosimilar of the Same Reference Biologic: A Systematic Review of Studies.

BACKGROUND: Multiple switches (transitions) between biosimilars of the same reference biologic are now a reality, and they are expected to become more common in the future as more biosimilars enter the market. Switching between two biosimilars of the same reference biologic is generally driven by affordability, formulary requirements, or the relocation/travel of the patient. Evidence of whether switching between biosimilars of the same reference biologic provides similar safety and efficacy profiles is reviewed here. METHODS: A systematic search was undertaken using electronic databases (to December 2021): Biosis, Embase, MEDLINE, and EBM Reviews/Cochrane Database of Systematic Reviews via Ovid. Publications were evaluated for effectiveness and/or safety data linked to switching from one biosimilar to another. RESULTS: The systematic search yielded 982 citations. After eliminating duplicates, 626 citations remained for the initial title/abstract screening phase. Following the initial screening, 240 records were chosen; more thorough examination yielded 35 citations. After comprehensive screening and expert advice, 23 studies were selected, of which 13 were published in peer-reviewed journals; the remainder have been published as abstracts. Overall, 3657 patients were included in these studies. All studies were observational in nature; no randomized clinical trials were identified. The studies were heterogeneous in size, design, and endpoints. Across the studies, data are provided on safety, effectiveness, immunogenicity, pharmacokinetics, patient retention, patient and physician perceptions, and drug-use patterns. The majority of studies examined switches between biosimilar infliximabs, although switches between biosimilar adalimumabs, etanercepts, and rituximabs were also identified. Two use-pattern studies and one case report were also detected and are discussed. CONCLUSION: Within the limitations of this systematic review, available data suggests that biosimilar-to-biosimilar switching is a safe and effective clinical practice, although it is not covered by current health authority regulations or guidance. No reduction in effectiveness or increase in adverse events was detected in biosimilar-to-biosimilar switching studies conducted to date.

Serum Th-2 cytokines and FEV1 decline in WTC-exposed firefighters: A 19-year longitudinal study.

BACKGROUND: Accelerated-FEV1 -decline, defined as rate of decline in FEV1 > 64 ml/year, is a risk factor for asthma and chronic obstructive pulmonary disease in World Trade Center (WTC)-exposed firefighters. Accelerated-FEV1 -decline in this cohort is associated with elevated blood eosinophil concentrations, a mediator of Th-2 response. We hypothesized that an association exists between Th-2 biomarkers and FEV1 decline rate in those with accelerated-FEV1 -decline. METHODS: Serum was drawn from Fire Department of the City of New York (FDNY) firefighters 1-6 months (early) (N = 816) and 12-13 years (late) (N = 983) after 9/11/2001. Th-2 biomarkers IL-4, IL-13, and IL-5 were assayed by multiplex Luminex. Individual FEV1 decline rates were calculated using spirometric measurements taken: (1) between 9/11/2001 and 9/10/2020 for the early biomarker group and (2) between late measurement date and 9/10/2020 for the late biomarker group. Associations of early and late Th-2 biomarkers with subsequent FEV1 decline rates were analyzed using multivariable linear regression controlling for demographics, smoking status, and other potential confounders. RESULTS: In WTC-exposed firefighters with accelerated-FEV1 -decline, IL-4, IL-13, and IL-5 measured 1-6 months post-9/11/2001 were associated with greater FEV1 decline ml/year between 9/11/2001 and 9/10/2020 (-2.9 ± 1.4 ml/year per IL-4 doubling; -8.4 ± 1.2 ml/year per IL-13 doubling; -7.9 ± 1.3 ml/year per IL-5 doubling). Among late measured Th-2 biomarkers, only IL-4 was associated with subsequent FEV1 decline rate (-4.0 ± 1.6 ml/year per IL-4 doubling). CONCLUSIONS: In WTC-exposed firefighters with accelerated-FEV1 -decline, elevated serum IL-4 measured both 1-6 months and 12-13 years after 9/11 is associated with greater FEV1 decline/year. Drugs targeting the IL-4 pathway may improve lung function in this high-risk subgroup.

Improving Team Skills of Health Care Practitioners: Effects of an Interprofessional Education Program.

INTRODUCTION: Health care practitioners in Parkinson's care need to learn effective interprofessional team skills. This study examines posttraining effects on team skills of health practitioners attending an interprofessional education (IPE) program for team-based Parkinson's care. METHODS: Using a quasi-experimental pre-post design, practitioners (n = 236) in nine professions (physician, nurse and nurse practitioner, physician assistant, occupational, physical and music therapy, speech-language pathology, and social work) completed the validated, self-report Team Skills Scale, before and after the training. Associations of Team Skills Scale change with intention to change practice, measured at end of each training day, and with improved attitudes toward team, knowledge, confidence, and amount of new information were examined. RESULTS: All professions, except physician assistant, significantly improved perceived team skills, as did those showing greatest intention to change practice, with no meaningful differences in magnitude of change across profession groups. Team skills change was significantly associated with improved attitudes toward health care teams, increased knowledge about team and the role of other professions, and new knowledge gained. Confidence in Parkinson's care showed modest, statistically significant association with team skills improvement. DISCUSSION: The Allied Team Training for Parkinson-IPE program significantly improved perceived team skills of health care practitioners, effectively teaching about skills for collaborative teamwork. Future IPE research should explore whether similar programs in other settings achieve the enhanced team skills competencies with postlicensure practitioners observed here and validate our findings from self-developed measures using larger samples, additional professions, and follow-up of transfer of learning effects through direct observation of skills of actual teams.

Tracheotomy in a High-Volume Center During the COVID-19 Pandemic: Evaluating the Surgeon's Risk.

OBJECTIVE: Performing tracheotomy in patients with COVID-19 carries a risk of transmission to the surgical team due to potential viral particle aerosolization. Few studies have reported transmission rates to tracheotomy surgeons. We describe our safety practices and the transmission rate to our surgical team after performing tracheotomy on patients with COVID-19 during the peak of the pandemic at a US epicenter. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic hospital. METHODS: Tracheotomy procedures for patients with COVID-19 that were performed April 15 to May 28, 2020, were reviewed, with a focus on the surgical providers involved. Methods of provider protection were recorded. Provider health status was the main outcome measure. RESULTS: Thirty-six open tracheotomies were performed, amounting to 65 surgical provider exposures, and 30 (83.3%) procedures were performed at bedside. The mean time to tracheotomy from hospital admission for SARS-CoV-2 symptoms was 31 days, and the mean time to intubation was 24 days. Standard personal protective equipment, according to Centers for Disease Control and Prevention, was worn for each case. Powered air-purifying respirators were not used. None of the surgical providers involved in tracheotomy for patients with COVID-19 demonstrated positive antibody seroconversion or developed SARS-CoV-2-related symptoms to date. CONCLUSION: Tracheotomy for patients with COVID-19 can be done with minimal risk to the surgical providers when standard personal protective equipment is used (surgical gown, gloves, eye protection, hair cap, and N95 mask). Whether timing of tracheotomy following onset of symptoms affects the risk of transmission needs further study.

Factors Predicting Treatment of World Trade Center-Related Lung Injury: A Longitudinal Cohort Study.

The factors that predict treatment of lung injury in occupational cohorts are poorly defined. We aimed to identify patient characteristics associated with initiation of treatment with inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) >2 years among World Trade Center (WTC)-exposed firefighters. The study population included 8530 WTC-exposed firefighters. Multivariable logistic regression assessed the association of patient characteristics with ICS/LABA treatment for >2 years over two-year intervals from 11 September 2001-10 September 2017. Cox proportional hazards models measured the association of high probability of ICS/LABA initiation with actual ICS/LABA initiation in subsequent intervals. Between 11 September 2001-1 July 2018, 1629/8530 (19.1%) firefighters initiated ICS/LABA treatment for >2 years. Forced Expiratory Volume in 1 s (FEV1), wheeze, and dyspnea were consistently and independently associated with ICS/LABA treatment. High-intensity WTC exposure was associated with ICS/LABA between 11 September 2001-10 September 2003. The 10th percentile of risk for ICS/LABA between 11 September 2005-10 Septmeber 2007 was associated with a 3.32-fold increased hazard of actual ICS/LABA initiation in the subsequent 4 years. In firefighters with WTC exposure, FEV1, wheeze, and dyspnea were independently associated with prolonged ICS/LABA treatment. A high risk for treatment was identifiable from routine monitoring exam results years before treatment initiation.

Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis.

Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.

The Importance of Countering Biosimilar Disparagement and Misinformation.

Biosimilar use is limited in some healthcare systems because biosimilars are not well understood by many healthcare professionals and patients. The knowledge gap is exacerbated by disparagement of biosimilars and dissemination of misinformation, whether intentional or otherwise. There are several different types of disparagement and misinformation directed towards biosimilars as a class, including statements about biosimilar science or policy that are factually incorrect; misleading information, where the information is correct, but is provided out of context; incomplete information, where only partial or a limited set of facts are provided; creation of a false narrative, especially in scientific and medical literature, that provides a set of references to support incorrect conclusions; and negative message framing of factual statements to create a negative perception. Disparagement and misinformation about biosimilars can be countered by educational efforts, appropriate oversight, and regulatory activities with the option of enforcement action by governmental agencies, if warranted. Balanced educational materials about biosimilars should be made easily accessible. Physicians, nurses, pharmacists, and patient advocacy groups should work together to provide patients with consistent, positive messages about the value of biosimilars.

Methodologic considerations for noninterventional studies of switching from reference biologic to biosimilars.

PURPOSE: As more biosimilars become available in the United States, postapproval noninterventional studies describing biosimilar switching and comparing effectiveness and/or safety between switchers and nonswitchers will play a key role in generating real-world evidence to inform clinical practices and policy decisions. Ensuring sound methodology is critical for making valid inferences from these studies. METHODS: The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) convened a workgroup consisting of academic researchers, industry scientists, and practicing clinicians to establish best practice recommendations for the conduct of noninterventional studies of biosimilar and reference biologic switching. The workgroup members participated in eight teleconferences between August 2017 and February 2018 to discuss specific topics and build consensus. RESULTS: This report provides workgroup recommendations covering five main considerations relating to noninterventional studies describing reference biologic to biosimilar switching and comparing reference biologic to biosimilars for safety and effectiveness in the presence of switching at treatment initiation and during follow-up: (a) selecting appropriate data sources from a range of available options including insurance claims, electronic health records, and registries; (b) study designs; (c) outcomes of interest including health care utilization and clinical endpoints; (d) analytic approaches including propensity scores, disease risk scores, and instrumental variables; and (e) special considerations including avoiding designs that ignore history of biologic use, avoiding immortal time bias, exposure misclassification, and accounting for postindex switching. CONCLUSION: Recommendations provided in this report provide a framework that may be helpful in designing and critically evaluating postapproval noninterventional studies involving reference biologic to biosimilar switching.

Long-term Cardiovascular Disease Risk Among Firefighters After the World Trade Center Disaster.

Importance: Published studies examining the association between World Trade Center (WTC) exposure on and after September 11, 2001, and longer-term cardiovascular disease (CVD) outcomes have reported mixed findings. Objective: To assess whether WTC exposure was associated with elevated CVD risk in Fire Department of the City of New York (FDNY) firefighters. Design, Settings, and Participants: In this cohort study, the association between WTC exposure and the risk of CVD was assessed between September 11, 2001, and December 31, 2017, in FDNY male firefighters. Multivariable Cox regression analyses were used to estimate CVD risk in association with 2 measures of WTC exposure: arrival time to the WTC site and duration of work at the WTC site. Data analyses were conducted from May 1, 2018, to March 8, 2019. Main Outcomes and Measures: The primary CVD outcome included myocardial infarction, stroke, unstable angina, coronary artery surgery or angioplasty, or CVD death. The secondary outcome (all CVD) included all primary outcome events or any of the following: transient ischemic attack; stable angina, defined as either use of angina medication or cardiac catheterization without intervention; cardiomyopathy; and other CVD (aortic aneurysm, peripheral arterial vascular intervention, and carotid artery surgery). Results: There were 489 primary outcome events among 9796 male firefighters (mean [SD] age on September 11, 2001, was 40.3 [7.4] years and 7210 individuals [73.6%] were never smokers). Age-adjusted incident rates of CVD were higher for firefighters with greater WTC exposure. The multivariable adjusted hazard ratio (HR) for the primary CVD outcome was 1.44 (95% CI, 1.09-1.90) for the earliest arrival group compared with those who arrived later. Similarly, those who worked at the WTC site for 6 or more months vs those who worked less time at the site were more likely to have a CVD event (HR, 1.30; 95% CI, 1.05-1.60). Well-established CVD risk factors, including hypertension (HR, 1.41; 95% CI, 1.10-1.80), hypercholesterolemia (HR, 1.56; 95% CI, 1.28-1.91), diabetes (HR, 1.99; 95% CI, 1.33-2.98), and smoking (current: HR, 2.13; 95% CI, 1.68-2.70; former: HR, 1.55; 95% CI, 1.23-1.95), were significantly associated with CVD in the multivariable models. Analyses with the all-CVD outcome were similar. Conclusions and Relevance: The findings of the study suggest a significant association between greater WTC exposure and long-term CVD risk. The findings appear to reinforce the importance of long-term monitoring of the health of survivors of disasters.

Splenectomy is not associated with a higher tricuspid regurgitant jet velocity in people with sickle cell anemia.

BACKGROUND: Vascular complications such as pulmonary hypertension (PH) occur at an increased rate following splenectomy in patients with various hemolytic blood disorders including thalassemia. The goal of this retrospective cross-sectional analysis was to assess the independent association of splenectomy with an elevated tricuspid regurgitation velocity (TRV) in people with homozygous sickle cell disease (HbSS). TRV is a noninvasive screening test for PH and a surrogate marker of prognosis in sickle cell disease (SCD). PROCEDURE: Data were obtained from the multicenter Walk-PHaSST (treatment of pulmonary hypertension and sickle cell disease with sildenafil therapy) study of PH (NCT00492531). We compared TRV in the cohort of patients with HbSS who were surgically splenectomized with patients who were not surgically splenectomized. RESULTS: We found no significant differences in TRV between the two groups. CONCLUSIONS: The lack of difference in TRV between the two groups is most likely because members of the comparator nonsurgical group in many cases experienced autoinfarction of the spleen in childhood. Splenectomy does not seem to confer additional risk for the development of a higher TRV in HbSS, unlike in patients with thalassemia or other hemolytic anemias. This could be an important consideration when weighing the risks and benefits of splenectomy in patients with HbSS.

Abnormalities on Chest Computed Tomography and Lung Function Following an Intense Dust Exposure: A 17-Year Longitudinal Study.

Fire Department of the City of New York (FDNY) firefighters experienced intense dust exposure working at the World Trade Center (WTC) site on and after 11/9/2001 (9/11). We hypothesized that high-intensity WTC exposure caused abnormalities found on chest computed tomography (CT). Between 11/9/2001-10/9/2018, 4277 firefighters underwent a clinically-indicated chest CT. Spirometric measurements and symptoms were recorded during routine medical examinations. High-intensity exposure, defined as initial arrival at the WTC on the morning of 9/11, increased the risk of bronchial wall thickening, emphysema, and air trapping. Early post-9/11 symptoms of wheeze and shortness of breath were associated with bronchial wall thickening, emphysema, and air trapping. The risk of accelerated forced expiratory volume at one second (FEV1) decline (>64 mL/year decline) increased with bronchial wall thickening and emphysema, but decreased with air trapping. The risk of airflow obstruction also increased with bronchial wall thickening and emphysema but decreased with air trapping. In a previously healthy occupational cohort, high-intensity WTC exposure increased the risk for CT abnormalities. Bronchial wall thickening and emphysema were associated with respiratory symptoms, accelerated FEV1 decline, and airflow obstruction. Air trapping was associated with respiratory symptoms, although lung function was preserved. Physiologic differences between CT abnormalities suggest that distinct types of airway injury may result from a common exposure.