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Behavioural inactivity is a hallmark of depression. The present study investigates the role future expectancy biases may play in depression-linked behavioural inactivity, in participants varying in self-reported depression symptoms (dysphoria). A novel laboratory paradigm was developed to assess the presence of indirect associations between dysphoria and behavioural inactivity via negative expectancy biases. Specifically, two types of expectancy biases were distinguished: a) the expected likelihood of a negative rather than positive outcome, and b) the expected emotional impact of either outcome. N = 176 undergraduate students with varied levels of dysphoria were given the opportunity to choose to engage in a behavioural activity that could result in a positive or negative outcome in terms of charity donations, and then rated both types of expectancies. Results indicated that higher dysphoria was associated with more negative expectations concerning objective outcome likelihood and the emotional impact of outcomes, and such negative expectancy biases mediated indirect associations between dysphoria and behavioural inactivity. Additionally, preliminary findings show that dysphoria-linked elevations in negative emotional impact expectancy was mediated by dysphoria-linked elevations in negative internal attribution style.

Pleuroscopy with pleural biopsy has a high sensitivity for malignant pleural effusion (MPE). Because MPEs tend to recur, concurrent diagnosis and treatment of MPE during pleuroscopy is desired. However, proceeding directly to treatment at the time of pleuroscopy requires confidence in the on-site diagnosis. The study's primary objective was to create a predictive model to estimate the probability of MPE during pleuroscopy.A prospective observational multicentre cohort study of consecutive patients undergoing pleuroscopy was conducted. We used a logistic regression model to evaluate the probability of MPE with relation to visual assessment, rapid on-site evaluation (ROSE) of touch preparation and presence of pleural nodules/masses on computed tomography (CT). To assess the model's prediction accuracy, a bootstrapped training/testing approach was utilized to estimate the cross-validated area under the receiver operating characteristic curve.Of the 201 patients included in the study, 103 had MPE. Logistic regression showed that higher level of malignancy on visual assessment is associated with higher odds of MPE (OR = 34.68, 95% CI = 9.17-131.14, p 0.001). The logistic regression also showed that higher level of malignancy on ROSE of touch preparation is associated with higher odds of MPE (OR = 11.63, 95% CI = 3.85-35.16, p 0.001). Presence of pleural nodules/masses on CT is associated with higher odds of MPE (OR = 6.61, 95% CI = 1.97-22.1, p = 0.002). A multivariable logistic regression model of final pathologic status with relation to visual assessment, ROSE of touch preparation and presence of pleural nodules/masses on CT had a cross-validated AUC of 0.94 (95% CI = 0.91-0.97).A prediction model using visual assessment, ROSE of touch preparation and CT scan findings demonstrated excellent predictive accuracy for MPE. Further validation studies are needed to confirm our findings.

Background and aimsPruritus is associated with multiple liver diseases, particularly those with cholestasis, but the mechanism remains incompletely understood. Our aim was to evaluate serum IL-31 as a putative biomarker of pruritus in clinical trials of an farnesoid X receptor (FXR) agonist, cilofexor, in patients with NASH, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC).Approach and resultsSerum IL-31 was measured in clinical studies of cilofexor in NASH, PSC, and PBC. In patients with PSC or PBC, baseline IL-31 was elevated compared to patients with NASH and healthy volunteers (HVs). IL-31 correlated with serum bile acids among patients with NASH, PBC, and PSC. Baseline IL-31 levels in PSC and PBC were positively correlated with Visual Analog Scale for pruritus and 5-D itch scores. In patients with NASH, cilofexor dose-dependently increased IL-31 from Week (W)1 to W24. In patients with NASH receiving cilofexor 100 mg, IL-31 was higher in those with Grade 2-3 pruritus adverse events (AEs) than those with Grade 0-1 pruritus AEs. IL-31 weakly correlated with C4 at baseline in patients with NASH, and among those receiving cilofexor 100 mg, changes in IL-31 and C4 from baseline to W24 were negatively correlated. IL-31 messenger RNA (mRNA) was elevated in hepatocytes from patients with PSC and NASH compared to HVs. In a humanized liver murine model, obeticholic acid increased IL-31 mRNA expression in human hepatocytes and serum levels of human IL-31.ConclusionsIL-31 levels correlate with pruritus in patients with cholestatic disease and NASH, with FXR agonist therapy resulting in higher serum levels in the latter group. IL-31 appears to derive in part from increased hepatocyte expression. These findings have therapeutic implications for patients with liver disease and pruritus.

Caplacizumab demonstrated efficacy and safety in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long-term outcomes following caplacizumab treatment are limited.The post-HERCULES trial (NCT02878603) evaluated long-term outcomes of patients with iTTP treated with caplacizumab in HERCULES and safety and efficacy of repeated caplacizumab use.Over 3 years of follow-up, patients could receive open-label caplacizumab with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) in case of recurrence. Adverse events (AEs) were assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences (recurrence population). TTP-related events (TTP-related death, recurrence, major thromboembolic events) were assessed in the efficacy ITO population (patients without recurrence during HERCULES or before post-HERCULES).Among 104 enrolled patients, incidences of AEs and serious AEs were similar between patients who had received caplacizumab + TPE + IST during HERCULES (n = 75) and those treated with placebo + TPE + IST (placebo; n = 29). TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab during HERCULES versus 38% (11/29) randomized to placebo. Nineteen patients had ≥1 recurrence; 13 of these were treated with caplacizumab. The first recurrence episode was resolved or resolving for all patients treated with caplacizumab, including nine patients with repeat caplacizumab use. All second recurrences (6/6) were resolved. Safety profile of caplacizumab for treatment of recurrence was consistent with HERCULES; most bleeding events were nonserious. No major cases of organ dysfunction were observed.Long-term follow-up supports the safety and efficacy of caplacizumab for iTTP and its repeated use for recurrences.

BACKGROUND AND AIMS Treatment-resistant primary focal segmental glomerulosclerosis (FSGS) is a rare glomerulopathy associated with nephrotic range proteinuria (>3.5 g/24 h). Treatment goals are reduction in proteinuria, which can delay progression to end-stage renal disease. Lack of quality repeated measures data for proteinuria in nephrotic patients is an important methodological limitation in current clinical trials research. METHOD We examined the 24-h urine collections (traditionally considered to be the gold standard for proteinuria assessment) compared with average of two consecutive first morning spot urine protein/creatinine (Up/c) ratio results for the patients in the placebo arm (n = 10)of this randomized, double-blind placebo-controlled study (3:3:2 allocation for 1 mg/kg, 4 mg/kg, and placebo treatment groups). Patients received randomized treatment for 112 days and were followed double-blind to 252 days. First morning Up/c was obtained from first morning spot urine collections for all visits; 24-h timed collections were performed for Day 1 and Day 112 visits. For first morning Up/c, the average of two collections at each study time point was used for analysis. RESULTS Median age was 42 years, 40% female, 20% black, median eGFR 60 mL/min/1.73 m2 with median Up/c 6.4 g/g (NCT01665391). Correlation coefficient between 24-h timed collection and averaged spot Up/c was r = 0.63 (P = .004). For 24-h timed urines, between subject SD = 2.015 g/24 h and within subject SD = 7.328 g/24 h. For averaged first morning spot Up/c, between subject SD = 2.5 g/g and within subject SD = 2.3 g/g. CONCLUSION In clinical trials subjects with nephrotic syndrome from biopsy-proven FSGS on stable doses of ACEi/ARB medications, 24-h timed collections do not provide additional useful data beyond average of two first morning spot Up/c. These data suggest that labour intensive, cumbersome timed 24-h urine collections should not be performed in clinical trials of nephrotic syndrome patients. Importantly, these data should allow for more precise power and sample size estimates for future interventional clinical trials of nephrotic syndrome.

BACKGROUND AND AIMS Alport Syndrome (AS) is the second most common genetic kidney disease and results from mutations in COL4A3, A4 or A5 genes. It is characterized by glomerulonephritis, CKD, hearing loss, and ocular lens defects. Estimated incidence is ∼ 1 in 50 000 live births with prevalence of 1 in 5000–10 000. About 80% patients reach ESKD by age 35 years. The UK Alport Registry, part of the National Registry of Rare Kidney Diseases (RaDaR), performs on-going collection of longitudinal data of AS patients. The aims of this study were to characterize demographic and lab data of AS patients and determine the proportion of AS patients at risk for rapid kidney function decline. METHOD Eligible patients had a clinical, histological or genetic diagnosis of ‘Alport syndrome’ or ‘thin basement membrane nephropathy’ by their physician and provided informed consent. Some data were entered manually, but most routine test results were collected by automatic link between RaDaR and renal IT systems. eGFR was calculated using CKD-EPI Cr equation without race adjustment (2021) or Schwartz equation for subjects ≤16 years of age at time of Cr measurement. For eGFR slope calculations, a minimum of four measurements over at least 2 years were required to be included in this analysis; subjects were censored if they reached ESKD, defined as maintenance dialysis, transplant, or ≥ 2 consecutive eGFR measurements of RESULTS Between 4 January 2013 and 29 November 2021, 887 patients were recruited. See Table 1 for summary of data stratified by age groups. Overall, 52% male versus 48% female, and in those with genotyping data, 54% had X-linked AS with a mean age of 25.8 years at diagnosis and a mean age of proteinuria onset of 29.6 years. Clinically meaningful Stage 2 CKD was already present at time of diagnosis (mean eGFR 72.7 mL/min/1.73 m2) in many of those ≥ 18 years of age. A total of 43% of this AS cohort have reached ESKD, at a mean age of 32.8 years. While 37% were on ACEi and 20% on ARB medications, only 4% were on dual RAAS blockade therapy. About 50% had documentation of eGFR loss ≥4 mL/min/1.73 m2 per year, 29% had UPCR > 2 g/g, and 50% of those age ≥ 18 years had reached ESKD. The proportion of patients with ≥1 risk factor for rapid progression of kidney failure (defined as eGFR decline ≥ 4 mL/min/1.73 m2 per year, UPCR > 2 g/g, UACR > 1 g/g or male 18–23 yrs with eGFR < 90 mL/min/1.73 m2 based on ATHENA natural history study) was 41%. CONCLUSION Demographic and genetic characteristics of AS patients in the RaDaR registry are generally comparable with previously reported data. Approximately 50% had eGFR decline ≥ 4 mL/min/1.73 m2 per year and 41% of patients had exhibited ≥ 1 risk factor for future rapid progression of kidney disease. Results should be interpreted with caution, however, in light of the considerable amount of missing data in a number of the analyses. On-going data collection in this open cohort should allow for further insights on the natural history over time as well as identify AS patients for potential enrollment into clinical trials.

OBJECTIVES We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN Prospective observational study. SETTING Large academic medical center between 2013 and 2019. SUBJECTS Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

Theory on the evolution of niche width argues that resource heterogeneity selects for niche breadth. For parasites, this theory predicts that parasite populations will evolve, or maintain, broader host ranges when selected in genetically diverse host populations relative to homogeneous host populations. To test this prediction, we selected the bacterial parasite Serratia marcescens to kill Caenorhabditis elegans in populations that were genetically heterogeneous (50% mix of two experimental genotypes) or homogeneous (100% of either genotype). After 20 rounds of selection, we compared the host range of selected parasites by measuring parasite fitness (i.e. virulence, the selected fitness trait) on the two focal host genotypes and on a novel host genotype. As predicted, heterogeneous host populations selected for parasites with a broader host range: these parasite populations gained or maintained virulence on all host genotypes. This result contrasted with selection in homogeneous populations of one host genotype. Here, host range contracted, with parasite populations gaining virulence on the focal host genotype and losing virulence on the novel host genotype. This pattern was not, however, repeated with selection in homogeneous populations of the second host genotype: these parasite populations did not gain virulence on the focal host genotype, nor did they lose virulence on the novel host genotype. Our results indicate that host heterogeneity can maintain broader host ranges in parasite populations. Individual host genotypes, however, vary in the degree to which they select for specialization in parasite populations.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide. Over the last decade, many studies have validated the use of endobronchial valves (EBVs) for bronchoscopic lung volume reduction (BLVR) in patients who are persistently symptomatic despite optimal medical therapy. We aimed to review the literature and describe appropriate patient selection and procedural considerations. BLVR using EBVs leads to an improvement in FEV1, 6-min walk distance, and health-related quality of life. Two valve systems have recently obtained FDA approval for use for this indication. Appropriate selection of the target lobe and assessment of fissure integrity using quantitative imaging software are essential to obtain best possible outcomes. EBVs are a viable treatment option, with manageable complications, for patients with COPD who have hyperinflation and refractory symptoms, when there is complete fissure integrity (no collateral ventilation).

Purpose In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS. Methods We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort. Results The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2–PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results. Conclusion Arterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.

Patient: Female, 65-year-old Final Diagnosis: Pleural effusion • small cell lung cancer Symptoms: Shortness of breath Medication:— Clinical Procedure: — Specialty: Pulmonology Objective: Unknown etiology Background: As use of immune checkpoint inhibitors consistently grows, so does knowledge of immune-related adverse events. Pleural complications from PD-L1 inhibitors such as atezolizumab have never been reported. We describe the first reported case of biopsy-proven pleuritis manifesting as recurrent pleural effusion in a patient treated with atezolizumab. Case Report: A 66-year-old woman with history of extensive-stage small cell lung cancer presented with a new pleural effusion. She was previously treated with carboplatin, etoposide, and atezolizumab followed by atezolizumab maintenance, but this later was stopped due to pneumonitis. She had been on no systemic therapy for 6 months prior; radiation to the chest was completed 1 year earlier. Thoracentesis revealed an exudate with eosinophilia but no malignancy. She underwent medical thoracoscopy, which showed normal pleura with no evidence of radiation changes. Random pleural biopsies revealed only chronic pleuritis. Given normal-appearing pleura, radiation pleuritis was ruled out. It was felt that the chemotherapy had occurred too long ago to be a present cause of her pleuritis. As such, after extensive workup, the eosinophilic pleural effusion was felt to be due to pleuritis from atezolizumab. The effusion has ultimately recurred 5 times over 1 year, and cytology remains negative for malignancy. Conclusions: Patients with prior cancer presenting with a new pleural effusion should undergo an extensive workup to evaluate for recurrence. When other causes have been ruled out, ongoing immune-related effects of immunotherapy should be considered. Pleural complications from PD-L1 inhibitors have not been reported; we present a possible case of chronic pleuritis and recurrent effusion due to atezolizumab.

BackgroundLow-Dye taping is commonly used to manage foot pathologies and pain. Precut one-piece QUICK TAPE was designed to facilitate taping. However, no study to date has demonstrated that QUICK TAPE offers similar support and off-loading as traditional taping.MethodsThis pilot study compared the performance of QUICK TAPE and low-Dye taping in 20 healthy participants (40 feet) with moderate-to-severe pes planus. Study participants completed arch height index (AHI), dynamic plantar assessment with a plantar pressure measurement system, and subjective rating in three conditions: barefoot, low-Dye, and QUICK TAPE. The order of test conditions was randomized for each participant, and the taping was applied to both feet based on a standard method. A generalized estimating equation with an identity link function was used to examine differences across test conditions while accounting for potential dependence in bilateral data.ResultsParticipants stood with a significantly greater AHI (P = .007) when either taping was applied compared with barefoot. Participants also demonstrated significantly different plantar loading when walking with both tapings versus barefoot. Both tapings yielded reduced force-time integral (FTI) in the medial and lateral forefoot and increased FTI under toes. Unlike previous studies, however, no lateralization of plantar pressure was observed with either taping. Participants ranked both tapings more supportive than barefoot. Most participants (77.8%) ranked low-Dye least comfortable, and 55.6% preferred QUICK TAPE over low-Dye.ConclusionsAdditional studies are needed to examine the clinical utility of QUICK TAPE in individuals with foot pathologies such as heel pain syndrome and metatarsalgia.

Acute mediastinitis is a rare infection that carries high morbidity and mortality. They are complications seen most often with deep sternal wound infections from surgeries with median sternotomies, oropharyngeal and odontogenic infections and esophageal perforations. These conditions should be promptly recognized and treated. Mediastinal granulomas are focal, mass-like lesions commonly resulting from prior granulomatous infections. They are regarded as benign, self-resolving lesions however can cause complications by compression of adjacent mediastinal structures. Chronic fibrosing mediastinitis is a rare, diffuse fibroinflammatory process most often seen with granulomatous infections and carries a worse prognosis than mediastinal granulomas especially when adjacent mediastinal structures are compromised. In this review, we discuss the epidemiology, etiology, clinical presentation, treatment and prognosis of acute mediastinitis, mediastinal granulomas, and chronic fibrosing mediastinitis.

Purpose of review Robotic bronchoscopy is the newest advanced diagnostic bronchoscopy technology for biopsying peripheral pulmonary lesions; sensitivity for malignancy is currently suboptimal using modalities, such as radial endobronchial ultrasound or electromagnetic navigational bronchoscopy. We review the pitfalls of prior methods and the technological advancements with robotic bronchoscopy. Recent findings The contributors to reduced diagnostic sensitivity with current approaches include limitations in: navigation to the target, confirmation once the target is reached, and tissue acquisition. CT to body divergence with virtual reality methods, such as with electromagnetic navigation, potential false-positive confirmation with radial endobronchial ultrasound because of intraprocedural induced atelectasis, and lack of bronchoscopic and instrument maneuverability are all limitations to improving sensitivity. Robotic bronchoscopy enhances navigation through target pathway selection, allows for further reach in the distal airways, and improves tissue acquisition with more flexible and maneuverable biopsy instruments but lacks a high-fidelity target confirmation system. Summary Robotic bronchoscopy shows promise in biopsying peripheral lesions. Current published studies focus on diagnostic yield with robotic bronchoscopy. Future studies with long-term follow-up will be needed to assess diagnostic sensitivity for lung cancer and if robotic bronchoscopy is superior to other advanced diagnostic bronchoscopic techniques for peripheral pulmonary lesions.

The present study assessed target engagement, preliminary efficacy, and feasibility as primary outcomes of a free multi-session online cognitive bias modification of interpretation (CBM-I) intervention for anxiety in a large community sample. High trait anxious participants (N = 807) were randomly assigned to a CBM-I condition: 1) Positive training (90% positive-10% negative); 2) 50% positive-50% negative training; or 3) no-training control. Further, half of each CBM-I condition was randomized to either an anxious imagery prime or a neutral imagery prime. Due to attrition, results from six out of eight sessions were analyzed using structural equation modeling of latent growth curves. Results for the intent-to-treat sample indicate that for target engagement, consistent with predictions, decreases in negative interpretations over time were significantly greater among those receiving positive CBM-I training compared to no-training or 50-50 training, and vice-versa for increases in positive interpretations. For intervention efficacy, the decrease in anxiety symptoms over time was significantly greater among those receiving positive CBM-I training compared to no-training. Interaction effects with imagery prime were more variable with a general pattern of stronger results for those completing the anxious imagery prime. Findings indicate that online CBM-I positive training is feasible and shows some promising results, although attrition rates were very high for later training sessions.

Central airway obstruction (CAO), which results from malignant, benign or iatrogenic etiologies, causes significant morbidity and mortality and can be seen in both the pediatric and adult patient population. Patients frequently present to the hospital with dyspnea, stridor, and respiratory distress, indicating impending respiratory failure. Heliox is used to help alleviate symptoms while procedural planning takes place. A multidisciplinary approach to airway management is often needed. Interventional pulmonologists treat CAO with rigid of flexible bronchoscopy in order to deliver therapeutic interventions under general anesthesia. In severe CAO where there is concern for total loss of the airway creating a life-threatening situation for the patient during procedural intervention, short term extracorporeal membrane oxygenation or ECMO has been successfully reported in the literature to provide ventilation and oxygenation support throughout the procedure. Venoarterial ECMO can be used to augment cardiac output in cases of central tumors with cardiac involvement. ECMO can also be used for the removal of tracheal stents when there is a concern that ventilation will be interrupted for a prolonged period of time. ECMO has also been reported as a salvage measure for patients with life threatening hemoptysis until more definitive interventions can be performed. Short term ECMO cannulation can be used with limited associated morbidity and a heparin-free approach can be pursued when there is a concern for bleeding. We will briefly review the anesthetic considerations in CAO as well as review cases of CAO where ECMO was employed to safely alleviate the airway compromise.

Diabetic kidney disease (DKD), defined as reduced glomerular filtration rate (GFR), elevated urine albumin excretion, or both that is clinically attributable to diabetes, is a common and morbid diabetes complication. Animal-experimental data, observational human studies, and short-term clinical trials suggest that vitamin D and omega-3 fatty acid supplements may be safe and inexpensive interventions to reduce the incidence and progression of DKD. The Vitamin D and Omega-3 Trial to Prevent and Treat DKD (VITAL-DKD) was designed as an ancillary study to the VITAL trial of 25,871 US adults. In a 2 × 2 factorial design, VITAL participants were randomly assigned to vitamin D(3) (cholecalciferol, 2000 IU daily) or placebo and to marine omega-3 fatty acids (eicospentaenoic acid and docosahexaenoic acid, 1 g/d) or placebo. VITAL-DKD enrolled a subset of 1,326 VITAL participants with type 2 diabetes at baseline to test the effects of vitamin D and omega-3 fatty acids on changes in estimated GFR and urine albumin excretion. Over five years of follow-up, VITAL-DKD collected blood and urine samples to quantify changes in estimated GFR (the primary study outcome) and urine albumin excretion. At baseline, mean age of VITAL-DKD participants was 67.6 years, 46% were women, 30% were of racial or ethnic minority, and the prevalence of DKD (estimated GFR

Background: The post-HERCULES trial (NCT02878603) evaluated long-term safety and efficacy of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (aTTP; also known as immune-mediated TTP), and efficacy of repeated use of caplacizumab for aTTP recurrence. Methods: Patients who completed the HERCULES trial were invited to participate in the post-HERCULES study and attend twice-yearly visits for 3 years. In case of aTTP recurrence, patients could receive open-label (OL) caplacizumab with therapeutic plasma exchange (TPE) and immunosuppression (IST). Safety was assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences. TTP-related events (recurrence, mortality, or major thromboembolic events) were assessed in the efficacy ITO population. The ITO population (n=104) included all enrolled patients, grouped by whether they received caplacizumab during HERCULES (randomized or switched to OL after exacerbation). The efficacy ITO population (n=78) included those without aTTP recurrence during HERCULES or prior to the beginning of post-HERCULES. The recurrence population (n=19) included patients with ≥1 recurrence during post-HERCULES; the repeat-use population (n=9) was a subset treated at least twice with caplacizumab (received caplacizumab in HERCULES or treated twice in post-HERCULES). Pharmacodynamics and immunogenicity were assessed in the ITO population. The study was conducted in accordance with the Declaration of Helsinki. Results: Of 104 patients enrolled in post-HERCULES, 75 were treated with caplacizumab along with TPE+IST during HERCULES (caplacizumab group) and 29 were treated with TPE+IST only (placebo group). During the overall post-HERCULES study period, incidence of adverse events (AEs) and serious AEs was similar between the groups. In the ITO population, recurrence occurred in 11/75 patients (15%) in the caplacizumab group and 8/29 patients (28%) in the placebo group. In the efficacy ITO population, TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab versus 38% (11/29) randomized to placebo (Table 1). Prior rituximab use during HERCULES was similar in both groups (21/49 patients [43%] randomized to caplacizumab and 12/29 [41%] randomized to placebo). Incidence of recurrence by prior rituximab use (with vs without) was 10% (2/21) versus 7% (2/28) among patients randomized to caplacizumab, and 17% (2/12) versus 35% (6/17) among patients randomized to placebo. Of 19 patients with ≥1 recurrence, 13 were treated with caplacizumab and 6/13 received concomitant rituximab. Recurrences were resolved (12/13) or resolving (1/13) for all patients treated with caplacizumab, including 9 patients with repeat caplacizumab use. One patient who did not receive caplacizumab in either HERCULES or post-HERCULES died as an outcome of recurrence. Safety profile of caplacizumab for treatment of recurrence was consistent with that observed in HERCULES (Table 2) . The most common treatment-emergent AEs (TEAEs) with caplacizumab during the first recurrence (n=13) were headache and constipation (n=3 each). In the repeat-use population (n=9), bleeding events were reported in 5/9 patients (56%) for the first recurrence; 2 patients had a serious treatment-related TEAE of genitourinary or gastrointestinal bleeding; 2 patients had treatment-emergent anti-drug antibodies (ADAs) positive in a functional neutralizing antibody assay. No apparent impact of treatment-emergent ADAs on RICO activity or change from baseline in von Willebrand factor antigen concentration was found. Conclusions: The long-term safety profile of patients exposed to caplacizumab together with TPE+IST was similar to those who received IST+TPE only, with no observed increases in recurrence of aTTP. Repeat caplacizumab use was efficacious, with no evidence of safety concerns or boosting of ADA response. Funding: This research was funded by Ablynx, a Sanofi company. Figure 1 Figure 1. Disclosures Scully: Shire: Research Funding; Novartis: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Speakers Bureau. de la Rubia: Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy. Pavenski: Alexion: Honoraria, Research Funding; Bioverativ: Research Funding; Ablynx: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria. Metjian: Momenta/Johnson & Johnson, Sanofi Aventis, Takeda: Research Funding; Ablynx/Sanofi: Consultancy; Sanofi Aventis, Takeda: Other: Advisory. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Cataland: Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Sanofi Genzyme: Consultancy. Coppo: Alexion Pharmaceuticals, Sanofi Aventis, Octapharma AG: Consultancy, Other: Advisory; Alexion Pharmaceuticals, Sandoz, Sanofi Aventis, Takeda: Other: Speakers Bureau; Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremer Hovinga Strebel: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at symposia; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Other: Speaker at symposia; Roche: Other: Speaker at symposia; Siemens: Other: Speaker at symposia. Minkue Mi Edou: Sanofi: Current Employment, Other: May hold shares and/or stock options. de Passos Sousa: Sanofi: Current Employment, Other: May hold shares and/or stock options. Callewaert: Sanofi: Current Employment, Other: May hold shares and/or stock options. Gunawardena: Sanofi: Current Employment, Other: May hold shares and/or stock options. Lin: Sanofi: Current Employment, Other: May hold shares and/or stock options.