Eosinophil Depletion with Benralizumab for Eosinophilic Esophagitis.

BACKGROUND: Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear. METHODS: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24. RESULTS: A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events. CONCLUSIONS: In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.).

Non-cigarette tobacco products, aryl-hydrocarbon receptor repressor gene methylation and smoking-related health outcomes.

INTRODUCTION: Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. METHODS: Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. RESULTS: Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95% CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95% CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). CONCLUSION: Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials.

INTRODUCTION: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials. METHODS: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels. RESULTS: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52, and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular traps-(NET)osis-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment. DISCUSSION: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis.

Benralizumab in children with severe eosinophilic asthma: Pharmacokinetics and long-term safety (TATE study).

BACKGROUND: Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children. METHODS: TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (Cmax ), clearance, half-life (t1/2 ), and blood eosinophil count. Clearance and t1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed. RESULTS: Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean Cmax was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death. CONCLUSION: PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT04305405.

Unusual encephalopathy with Wernicke-Korsakoff syndrome-like features due to adjuvant nivolumab for malignant melanoma.

INTRODUCTION: Autoimmune encephalitis is a rare immune-related adverse event of PD-1 inhibitors, nivolumab and pembrolizumab. Autoimmune hypophysitis can also be seen with the use of these agents. The relationship between these two phenomena is currently unknown. CASE REPORT: We describe a 79-year-old man with anterior scalp melanoma who received adjuvant nivolumab therapy. Sixteen weeks after the completion of nivolumab therapy, the patient presented to the hospital with altered mental status, anterograde amnesia, and symptoms of nausea and vomiting. The patient's encephalopathy was associated with confabulations. Workup identified increased CSF protein without increased cellularity, along with decreased serum cortisol and ACTH levels. This was consistent with encephalitis and central adrenal insufficiency. MANAGEMENT AND OUTCOME: The patient had a robust clinical response to steroids, with resolution of mental status changes and normalization of blood pressure. He continues to receive maintenance steroid therapy without any further symptoms six months later. CONCLUSIONS: We report herein a unique case of encephalopathy in the setting of nivolumab use for the treatment of melanoma. The condition resembled Korsakoff psychosis seen in the setting of alcoholism and was associated with central adrenal insufficiency. A prompt response to steroids was both diagnostic and therapeutic in our case, suggesting the resolution of autoimmune phenomena related to nivolumab.

The role community-based healthcare providers play in managing hard-to-heal wounds.

It is common for community-based healthcare providers (CHPs)-many of whom have not received specialised training in wound care-to deliver initial and ongoing management for various wound types and diverse populations. Wounds in any setting can rapidly transition to a stalled, hard-to-heal wound (HTHW) that is not following a normal healing trajectory. Failure to recognise or address issues that cause delayed healing can lead to increased costs, healthcare utilisation and suffering. To encourage early intervention by CHPs, a panel of wound care experts developed actionable evidence-based recommendations for CHPs delineating characteristics and appropriate care in identifying and treating HTHWs. A HTHW is a wound that fails to progress towards healing with standard therapy in an orderly and timely manner and should be referred to a qualified wound care provider (QWCP) for advanced assessment and diagnosis if not healed or reduced in size by 40%-50% within 4 weeks. HTHWs occur in patients with multiple comorbidities, and display increases in exudate, infection, devitalised tissue, maceration or pain, or no change in wound size. CHPs can play an important initial role by seeing the individual's HTHW risk, addressing local infection and providing an optimal wound environment. An easy-to-follow one-page table was developed for the CHP to systematically identify, evaluate and treat HTHWs, incorporating a basic toolkit with items easily obtainable in common office/clinic practice settings. A flow chart using visual HTHW clinical cues is also presented to address CHPs with different learning styles. These tools encourage delivery of appropriate early interventions that can improve overall healthcare efficiency and cost.

Promoting Cardiovascular Health in the Community: Training the Next Generation of Scientists in the Jackson Heart Study.

PURPOSE: The aim of this article is to show the impact of the use of National Institutes of Health (NIH) research supplements in the training of African American students affiliated with the Jackson Heart Study (JHS). RECENT FINDINGS: The JHS Undergraduate Training and Education Center (UTEC) at Tougaloo College has had 19 students to be awarded research supplements. The awardees gained invaluable skills while working on the research supplements. Additionally, research supplement awards inspired these students to not only consider working in health-related fields, but to continue to engage in research activities and to mentor.

Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic mucosal melanoma.

INTRODUCTION: Nivolumab is an immune checkpoint inhibitor used in the treatment of several malignancies. A number of immune-related endocrinopathies have been linked to its use. CASE REPORT: We report a unique case of a 74-year-old man with well-controlled diabetes mellitus type 2 and metastatic mucosal anorectal melanoma who presented with diabetic ketoacidosis after receiving his third cycle of nivolumab 240 mg intravenous (IV) every 2 weeks. He was found to have autoantibodies against glutamic acid decarboxylase 65. Genotyping for human leukocyte antigens showed the presence of DQB1*02:01 and DRB1*03:01. MANAGEMENT AND OUTCOME: His presentation was complicated by acute renal failure. He required aggressive fluid resuscitation and insulin supplementation to reverse severe acid-base disturbance and multiple electrolyte abnormalities. After an 8-week interruption, the patient restarted nivolumab without any further evidence of adverse events over the next 12 weeks. He continues to require insulin replacement therapy. DISCUSSION AND CONCLUSION: Development of type 1 diabetes with the use of immune checkpoint inhibitors has been increasingly reported in the literature. The exact mechanism for autoimmune diabetes precipitated by nivolumab is yet to be elucidated. Patient education about the symptoms of diabetes and regular glucose monitoring cannot be overemphasized. Testing for antibodies against glutamic acid decarboxylase 65, insulin receptors, and islet cells may also prove useful. Human leukocyte antigen DQ and DR haplotyping prior to immune checkpoint inhibitor treatment might help determine susceptibility toward developing type 1 diabetes, and provide opportunities for earlier recognition, intervention, and possibly prevention.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

Implementing best practice occupational therapist-led environmental assessment and modification to prevent falls: A qualitative study of two regional and rural public health services in Australia.

BACKGROUND: Occupational therapist-led environmental assessment and modification (EAM) is effective in reducing falls for populations at high risk. Two regional and rural public health services in Queensland devised an implementation strategy to embed best practice occupational therapist-led EAM. METHODS: A qualitative study was conducted to compare the determinants of implementation success across the different health services, using the COM-B model of behaviour change. Six semi-structured interviews were completed with occupational therapists involved at each site, following 12 months of implementation. Interview data were triangulated with minutes from three combined site steering committee meetings, eight local steering committee meetings, and field notes. Thematic analysis was completed to compare barriers and facilitators to best practice uptake of EAM and differences in outcomes between the two sites. RESULTS: Both sites commenced implementation with similar states of capability and motivation. After 12 months, one site considered that practice change had been embedded as noted in steering committee minutes and comments; however, the other site observed limited progress. According to the COM-B analysis, opportunity (the factors that lie outside the individual's control) had a significant influence on how both sites were able to respond to the practice change and navigate some of the unexpected challenges that emerged, including the COVID-19 pandemic. Existing team structure, multiple responsibilities of key stakeholders, differences in access to resources, and lack of connection between complementary services meant that COVID-19 disruptions were only a catalyst for unveiling other systemic issues. CONCLUSION: This study highlights the power of external factors on influencing behaviour change for best practice implementation. Learnings from the study will provide deeper understanding of completing implementation projects in regional and rural contexts and support the future implementation of EAM in occupational therapy clinical settings.

Thinking Ahead to the Next Generation of Cardiometabolic Investigators: What It Takes to Successfully Engage Underrepresented Minorities in Biomedical and Public Health Careers.

PURPOSE OF REVIEW: The purpose of this review is to examine the existing information regarding cardiometabolic syndrome (CMS) manifestations among underrepresented minority populations, underrepresented minorities' representation in the cardiometabolic workforce, and the models that successfully recruit and retain underrepresented minorities in the field. RECENT FINDINGS: The scientific literature is replete with information on methods to recruit and train URM in research careers. However, there are few programs that are specifically designed to train URM to become diabetes researchers, or more specifically cardiometabolic researchers. The CMS scientific community leaders do not have to design a new learning program to engage URM in research. They only have to follow the prototypes by other organizations and make applicable to cardiometabolic research.

Mechanisms of vascular dysfunction in the interleukin-10-deficient murine model of preeclampsia indicate nitric oxide dysregulation.

Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

Pelvic floor changes in the first term pregnancy and postpartum period.

OBJECTIVE: To follow a prospective cohort of women during their first term pregnancy to elucidate the nature and timing of changes to the pelvic floor during pregnancy and after vaginal delivery. METHODS: Enrolled subjects were evaluated at four time points with dynamic MRI, POP-Q examinations, and validated symptom questionnaires. The four assessments occurred during the first trimester (ePG), late third trimester (lPG), within a week after vaginal delivery (ePP), and three months postpartum (lPP). Two-dimensional T1-weighted MRI measurements included bladder descent and area of the levator hiatus at rest and during Valsalva maneuvers. Sample size of ten subjects was calculated for a power of 0.8 to detect a 20% change in bladder position with p < 0.05. Comparative statistical tests were used for parametric and non-parametric data, respectively. RESULTS: Twelve subjects completed the study. At lPP, the bladder descent was increased (p = 0.03) at rest and with Valsalva compared to ePG. Levator hiatus area did not differ (p = 0.63) between time points at rest or with Valsalva. Median POP stage increased (p = 0.001) to 1.5 at lPP. Mean genital hiatus increased (p = 0.0003) at each time point. Higher scores were recorded on the UDI-6 (p < 0.001) and the PFDI-20 (p = 0.003) questionnaires at lPG and ePP, but returned to ePG levels by lPP. CONCLUSION: Anatomic changes measured by dynamic MRI and POP-Q examinations demonstrate significant descent at 3 months postpartum. However, these anatomic changes did not significantly correlate with changes in symptoms.

Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]). Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline.

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study.

RATIONALE: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD. OBJECTIVES: To test whether albuminuria was associated with lung function decline and incident CLRDs. METHODS: Six U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications. MEASUREMENTS AND MAIN RESULTS: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV1 decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV1 decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV1/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease. CONCLUSIONS: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

A rare disease patient/caregiver perspective on fair pricing and access to gene-based therapies.

Gene-based therapies are changing the landscape of medicine for patients with rare diseases. These one-time, potentially curative treatments pose a challenge in the US healthcare model, where high prices and insurance coverage variation may prevent patients from receiving life-altering therapies. Questioning of high prices occurs when patients, payers, and policy makers hold divergent views on the value and uncertainty of therapies. The key for patients is that high prices need to be justified, and companies need to partner authentically with patients. Companies should not automatically assume that the combination of the "gene therapy" label and a small patient population justifies high prices. To speed up the development process and potentially reduce costs, patients want the industry to improve clinical trial efficiency by sharing data, including natural history studies and failed trial results. From the patient perspective, current value assessment frameworks disadvantage people with disabilities, may not accurately reflect patients' and societal views, and omit necessary factors such as impact on caregivers, lost productivity, and the future value of innovation. Value determination methods need to provide fair incentives and outcomes to industry, payers, regulators, and especially patients-the courageous pioneers who need equitable and sustainable access to life-changing gene-based therapies.

Cigarette Smoking and Incident Heart Failure: Insights From the Jackson Heart Study.

BACKGROUND: Cigarette smoking has been linked with several factors associated with cardiac dysfunction. We hypothesized that cigarette smoking is associated with left ventricular (LV) structure and function, and incident heart failure (HF) hospitalization. METHODS: We investigated 4129 (never smoker n=2884, current smoker n=503, and former smoker n=742) black participants (mean age, 54 years; 63% women) without a history of HF or coronary heart disease at baseline in the Jackson Heart Study. We examined the relationships between cigarette smoking and LV structure and function by using cardiac magnetic resonance imaging among 1092 participants, cigarette smoking and brain natriuretic peptide levels among 3325 participants, and incident HF hospitalization among 3633 participants with complete data. RESULTS: After adjustment for confounding factors, current smoking was associated with higher mean LV mass index and lower mean LV circumferential strain (P<0.05, for both) in comparison with never smoking. Smoking status, intensity, and burden were associated with higher mean brain natriuretic peptide levels (all P<0.05). Over 8.0 years (7.7-8.0) median follow-up, there were 147 incident HF hospitalizations. After adjustment for traditional risk factors and incident coronary heart disease, current smoking (hazard ratio, 2.82; 95% confidence interval, 1.71-4.64), smoking intensity among current smokers (≥20 cigarettes/d: hazard ratio, 3.48; 95% confidence interval, 1.65-7.32), and smoking burden among ever smokers (≥15 pack-years: hazard ratio, 2.06; 95% confidence interval, 1.29-3.3) were significantly associated with incident HF hospitalization in comparison with never smoking. CONCLUSIONS: In blacks, cigarette smoking is an important risk factor for LV hypertrophy, systolic dysfunction, and incident HF hospitalization even after adjusting for effects on coronary heart disease.

The VICM biomarker is released from activated macrophages and inhibited by anti-GM-CSFRα-mAb treatment in rheumatoid arthritis patients.

OBJECTIVES: Macrophages possess widespread pro-inflammatory, destructive, and remodelling capabilities that can critically contribute to acute and chronic diseases, such as rheumatoid arthritis (RA). Continuous monitoring and measurement of selective counteraction of macrophage activity in patients require a sensitivity and non-invasive marker. We characterised the VICM (citrullinated and MMP degraded vimentin fragment) biomarker by investigating the release from in vitro activated macrophages and by monitoring the change in serum levels after treatment with the anti-GM-CSFRα-mAb (mavrilimumab). METHODS: Peripheral blood mononuclear cells were isolated, and lipopolysaccharide (LPS) was used to activate the macrophages and calcium chloride (CaCl2) was used to facilitate the citrullination process of vimentin. Supernatants, cell lysates, was collected and analysed by ELISA, and western blotting. RA patients were treated with mavrilimumab+methotrexate or methotrexate alone in a phase 2b study (NCT01706926) once every two weeks for 24 weeks. Serum levels of VICM were measured at baseline and multiple time points post-treatment. In addition, whole blood expression of peptidylarginine deiminase-2 (PAD-2) and matrix metalloproteinase-9 (MMP-9) transcripts were tested by quantitative reverse transcriptase PCR assays at day 0 and day 169 post-treatment. RESULTS: VICM levels were significantly higher at day 5 and 8 in supernatants of activated macrophages compared to controls (p<0.01), which was confirmed by Western blot. In RA patients, VICM correlated with disease activity (DAS28), modified total sharp score (mTSS), joint space narrowing (JSN), joint erosions and CRP at baseline. VICM was dose-dependently and significantly (p<0.01) inhibited by mavrilimumab. This suppression of VICM serum levels was supported by a decreased expression of PAD2 and MMP9 transcripts in patients treated with mavrilimumab. CONCLUSIONS: These data verified that VICM is released by activated macrophages. Treatment of RA patients with mavrilimumab significantly reduced release of VICM and peptidylarginine deiminases-2 (PAD-2) gene expression indicating that mavrilimumab indeed is targeting activated macrophages and that VICM may be a novel blood-based marker of anti-GM-CSF response.