Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation.

Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate the mechanisms controlling IL-1α/ß release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1-Ripk3-Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor and IL-1α/ß expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1α/ß release.

Energy Requirement Is Higher During Weight-Loss Maintenance in Adults Consuming a Low- Compared with High-Carbohydrate Diet.

BACKGROUND: Longer-term feeding studies suggest that a low-carbohydrate diet increases energy expenditure, consistent with the carbohydrate-insulin model of obesity. However, the validity of methodology utilized in these studies, involving doubly labeled water (DLW), has been questioned. OBJECTIVE: The aim of this study was to determine whether dietary energy requirement for weight-loss maintenance is higher on a low- compared with high-carbohydrate diet. METHODS: The study reports secondary outcomes from a feeding study in which the primary outcome was total energy expenditure (TEE). After attaining a mean Run-in weight loss of 10.5%, 164 adults (BMI ≥25 kg/m2; 70.1% women) were randomly assigned to Low-Carbohydrate (percentage of total energy from carbohydrate, fat, protein: 20/60/20), Moderate-Carbohydrate (40/40/20), or High-Carbohydrate (60/20/20) Test diets for 20 wk. Calorie content was adjusted to maintain individual body weight within ± 2 kg of the postweight-loss value. In analyses by intention-to-treat (ITT, completers, n = 148) and per protocol (PP, completers also achieving weight-loss maintenance, n = 110), we compared the estimated energy requirement (EER) from 10 to 20 wk of the Test diets using ANCOVA. RESULTS: Mean EER was higher in the Low- versus High-Carbohydrate group in models of varying covariate structure involving ITT [ranging from 181 (95% CI: 8-353) to 246 (64-427) kcal/d; P ≤0.04] and PP [ranging from 245 (43-446) to 323 (122-525) kcal/d; P ≤0.02]. This difference remained significant in sensitivity analyses accounting for change in adiposity and possible nonadherence. CONCLUSIONS: Energy requirement was higher on a low- versus high-carbohydrate diet during weight-loss maintenance in adults, commensurate with TEE. These data are consistent with the carbohydrate-insulin model and lend qualified support for the validity of the DLW method with diets varying in macronutrient composition. This trial was registered at clinicaltrials.gov as NCT02068885.

Omalizumab facilitates rapid oral desensitization for peanut allergy.

BACKGROUND: Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti-IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. OBJECTIVE: We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. METHODS: Thirty-seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1-day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. RESULTS: The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab-treated subjects versus 22.5 mg for placebo-treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty-three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000-mg food challenge. Overall reaction rates were not significantly lower in omalizumab-treated versus placebo-treated subjects (odds ratio, 0.57; P = .15), although omalizumab-treated subjects were exposed to much higher peanut doses. CONCLUSION: Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

Are Expectations Too High for Transitioning Adolescents With Inflammatory Bowel Disease? Examining Adult Medication Knowledge and Self-Management Skills.

OBJECTIVE: Transition readiness assessment has focused attention on adolescent knowledge and skills, but data-driven benchmarks have not been established. METHODS: Patients with inflammatory bowel disease (IBD), ages 25 to 50 years, attending an outpatient gastroenterology clinic, were recruited to complete a voluntary, confidential survey asking patients to recall medications and potential side effects, and to rate their degree of independence performing health maintenance tasks. RESULTS: The 141 respondents (48% response rate) had mean age of 36 years with median disease duration of 11 years. They were 60% female, 54% had Crohn disease, and 23% were diagnosed before age 18. Nearly all patients were fully independent answering doctor's questions during the visit (93%) and scheduling office visits (92%). Excluding pharmacy pick up, full independence seen in only 57%, whereas 16% significantly delegated tasks. No differences by sex, disease type, medication class, age at disease onset, or disease duration were found across levels of self-management. Almost all (97%) respondents could recall medication name, whereas fewer were able to recall dose (63%) or frequency (65%). Side effect knowledge was poor; among 81 patients on a biologic or immunomodulator, only 17 (21%) cited cancer and 22 (27%) cited infection. CONCLUSIONS: Adolescent IBD transition programs now have empirical data from the present study about adult benchmarks for independence in self-management skills. Further research can establish which skills correlate with medication adherence and active collaboration with the medical team. The present study also exposes important gaps in medication risk knowledge and may allow improved patient education for subgroups of adult patients with IBD.

A Real-World Effectiveness Study Using a Mobile Application to Evaluate Early Outcomes with Upadacitinib in Rheumatoid Arthritis.

INTRODUCTION: The impact of upadacitinib on rheumatoid arthritis (RA) symptoms was evaluated during the first 12 weeks of treatment via patient-reported outcomes (PROs) using a mobile health application (app). METHODS: Participating rheumatologists from the CorEvitas RA Registry (prospective, observational cohort) recruited patients with RA initiating upadacitinib treatment. A modified version of the ArthritisPower® app was used to collect PROs, including the Routine Assessment of Patient Index Data 3 (RAPID3), duration of morning joint stiffness, and the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue 7a Short Form at baseline and weeks 1-4, 8, and 12. RAPID3 responses over time were assessed using Kaplan-Meier estimation to determine the proportion of patients achieving disease activity improvement and minimal clinically important difference (MCID). Results were analyzed for all patients initiating upadacitinib and a subsample of TNF inhibitor (TNFi)-experienced patients with moderate to severe disease at baseline. RESULTS: A total of 103 patients with RA initiating upadacitinib (62.1% TNFi-experienced) were included. At week 12, 53 patients (51.4%) completed the study and provided PRO data via the app. Among all patients, improvements in RAPID3, pain, morning stiffness, and fatigue were observed at week 1 and were maintained or further improved through week 12. At week 12, 37.5% of patients achieved RAPID3 low disease activity. Starting at week 1, improvements in RAPID3 disease activity category (19.4% of patients) and achievement of MCID (16.3%) were reported, with nearly 50% of patients achieving these outcomes by week 4 (RAPID3 category: 48.8%; MCID: 49.2%) and 60% by week 12 (RAPID3 category: 59.6%; MCID: 59.8%). TNFi-experienced patients generally reported similar outcomes. Patient-reported medication convenience and compliance were generally high. CONCLUSIONS: In this real-world cohort of patients with RA, treatment with upadacitinib was associated with early and significant improvement in RAPID3, pain, morning stiffness, and fatigue regardless of prior TNFi experience. Clinically meaningful improvement in RAPID3 patient-reported disease activity was observed as early as week 1, with continued improvement reported through week 12.

Transjugular intrahepatic portosystemic shunt creation using intravascular ultrasound guidance.

PURPOSE: To describe the use of intravascular ultrasound (US) guidance for creation of transjugular intrahepatic portosystemic shunts (TIPSs) in humans. MATERIALS AND METHODS: The initial 25 cases of intravascular US-guided TIPS were retrospectively compared versus the last 75 conventional TIPS cases during the same time period at the same institution in terms of the number of needle passes required to establish portal vein (PV) access, fluoroscopy time, and needle pass-related complications. RESULTS: Intravascular US-guided TIPS creation was successful in all cases, and there was no statistically significant difference in number of needle passes, fluoroscopy time, or needle pass-related complications between TIPS techniques. Intravascular US-guided TIPS creation was successful in cases in which conventional TIPS creation had failed as a result of PV thrombosis or distorted anatomy. Intravascular US guidance for TIPS creation was additionally useful in a patient with Budd-Chiari syndrome and in a patient with intrahepatic tumors. CONCLUSIONS: Intravascular US is a safe and reproducible means of real-time image guidance for TIPS creation, equivalent in efficacy to conventional fluoroscopic guidance. Real-time sonographic guidance with intravascular US may prove advantageous for cases in which there is PV thrombus, distorted anatomy, Budd-Chiari syndrome, or hepatic tumors.

Evaluation of Clinical Diagnosis of Axial Psoriatic Arthritis (PsA) or Elevated Patient-reported Spine Pain in CorEvitas' PsA/Spondyloarthritis Registry.

OBJECTIVE: To determine the presence of axial symptoms in patients with psoriatic arthritis (PsA) and examine differences between those with or without a diagnosis of axial PsA (axPsA). METHODS: Patients with PsA at their Corevitas' (formerly Corrona) Psoriatic Arthritis/Spondyloarthritis Registry enrollment visit were stratified into 4 mutually exclusive groups based on axial manifestations: physician-diagnosed axPsA only (Dx+Sx-), patient-reported elevated spine symptoms only (Dx-Sx+; defined as Bath Ankylosing Spondylitis Disease Activity Index ≥ 4 and spine pain visual analog scale ≥ 40), physician-diagnosed and patient-reported manifestations (Dx+Sx+), and no axial manifestations (Dx-Sx-). Patient characteristics, disease activity, and patient-reported outcomes (PROs) at enrollment in each axial manifestation group were compared with the Dx-Sx- group. Associations of patient characteristics with the odds of having axial manifestations were estimated using multinomial logistic regression (reference: Dx-Sx-). RESULTS: Of 3393 patients included, 226 (6.7%) had Dx+Sx-, 698 (20.6%) had Dx-Sx+, 165 (4.9%) had Dx+Sx+, and 2304 (67.9%) had Dx-Sx-. Patients with Dx-Sx+ or Dx+Sx+ were more frequently women and had a history of depression and fibromyalgia (FM) vs patients who had Dx-Sx-. Patients with Dx+Sx- or Dx+Sx+ were more frequently HLA-B27 positive than those with Dx-Sx-. FM was significantly associated with increased odds of Dx+Sx- or Dx+Sx+. Disease activity and PROs were worse in patients with Dx-Sx+ or Dx+Sx+ than in those with Dx-Sx-. CONCLUSION: Patients who had self-reported elevated spine symptoms, with or without physician-diagnosed axPsA, had worse quality of life and higher disease activity overall than patients without axial manifestations, suggesting an unmet need in this patient population.

Utilization of Patient Navigators in an Urban Academic Pediatric Primary Care Practice.

Navigating health care systems can be a challenge for families. A retrospective descriptive cohort analysis was conducted assessing referrals to patient navigators (PNs) in one urban academic pediatric primary care practice. PNs tracked referral processes and a subset of PN referrals was assessed for markers of successful referrals. The most common reasons for referral were assistance overcoming barriers to care (46%), developmental concerns (38%), and adherence/care coordination concerns (14%). Significant predictors of referral were younger age, medical complexity, public insurance, male sex, and higher rates of no-show to visits in primary or subspecialist care. The majority of referrals were resolved. The referrals for process-oriented needs were significantly more successful than those for other concerns. PNs were more effective for discrete process tasks than for those that required behavior change by patients or families. Future directions include analysis of cost effectiveness of the PN program and analysis of parent and primary care provider experience.

Systemic Reactions in Pediatric Patients Receiving Standardized Allergen Subcutaneous Immunotherapy with and without Seasonal Dose Adjustment.

BACKGROUND: The 2003 Joint Task Force on Practice Parameters recommended standardizing allergen subcutaneous immunotherapy (SCIT). Data from longitudinal surveillance survey in North America reported a systemic reaction (SR) rate of 0.1% to 0.2% of injection visits. The rate of SR to standardized SCIT in pediatric patients has not been well evaluated. OBJECTIVE: The objective of this study was to evaluate the rate of SRs to standardized SCIT in pediatric patients aged 5 to 18 years in a single tertiary care center in the United States. METHODS: A retrospective chart review was conducted in 2 groups: group 1 started SCIT within a period extending from January 2009 to June 2012, whereas group 2 started SCIT within a period extending from January 2013 to June 2016. The protocol was modified in group 2 such that updosing and maintenance doses were adjusted in the spring for tree and grass pollen and in the fall for weed pollen. RESULTS: There were a total of 128 patients in group 1 and 118 patients in group 2. The rate of SR was 0.429% in group 1 and 0.364% in group 2, which was not significant. There was no difference in the severity of SR in the 2 groups with no-fatal or near-fatal SR noted. Asthma was a significant risk factor in the younger age subgroup aged 5 to 11 years. CONCLUSIONS: Standardized SCIT appears to be associated with an SR rate of 0.429% to 0.364% of visits in pediatric patients. Protocol modification did not lead to a significant drop in SR. Larger multicenter studies are required to further evaluate the rate of SRs from standardized SCIT.

An Academia-Industry Partnership for Planning and Executing a Community-Based Feeding Study.

A research team from Boston Children's Hospital and Harvard Medical School conducted a community-based feeding study in collaboration with Framingham State University (FSU) and Sodexo, the food service contractor at FSU. The study was a randomized controlled trial, implemented on the FSU campus. For the final year of the study, a satellite feeding site was established at Assabet Valley Regional Technical High School. The purpose of the study was to assess the biological effects of different macronutrient diets. An academia-industry partnership was developed to overcome common challenges associated with hospital-based feeding studies. Benefits included the following: a study site outside of Boston (reducing inconvenience for participants), access to a large commercial kitchen and study-specific kiosk (promoting efficiency), collaboration with Sodexo chefs (ensuring palatability of meals), and opportunity to procure food from contracted vendors. The research (academia) and food service (industry) teams worked together to design, plan, and execute intervention protocols using an integrated approach. During execution, the research team was primarily responsible for overseeing treatment fidelity, whereas the food service team provided culinary expertise, with a strong focus on hospitality and food quality. The study was conducted in 3 cohorts between August 2014 and May 2017. Participants received all of their food for ∼30 wk, totaling >160,000 meals. For all 3 cohorts combined, 234 participants provided informed consent, 229 started a standard run-in weight-loss diet, 164 lost a mean ± SD 12% ± 2% of baseline body weight and were randomly assigned to different macronutrient diets for weight-loss maintenance, and 148 completed the study. During the final and largest cohort, as many as 114 participants received daily meals concurrently. The daily cost per participant for preparation and service of weighed meals and snacks was ∼$65. This academia-industry partnership provides a model for controlled feeding protocols in nutrition research, potentially with enhanced cost-effectiveness, practicality, and generalizability. This trial was registered at http://www.clinicaltrials.gov as NCT02068885.

Safety of inferior vena cava filter retrieval in anticoagulated patients.

PURPOSES: To evaluate the safety of inferior vena cava (IVC) filter retrieval in therapeutically anticoagulated patients in comparison to prophylactically or not therapeutically anticoagulated patients with respect to retrieval-related hemorrhagic complications. MATERIALS AND METHODS: This was a retrospective study of 115 consecutive attempted IVC filter retrievals in 110 patients. Filter retrievals were stratified as performed in patients who were therapeutically anticoagulated (group 1), prophylactically anticoagulated (group 2), or not therapeutically anticoagulated (group 3). The collected data included anticoagulant and antiplatelet medications (type, form and duration of administration, dosage) at the time of retrieval. Phone interviews and chart review was performed for the international normalized ratio (INR), activated partial thromboplastin time, platelet count, infusion of blood products, and retrieval-related hemorrhagic complications. RESULTS: Group 1 included 65 attempted filter retrievals in 61 therapeutically anticoagulated patients by measured INR or dosing when receiving low-molecular-weight heparin (LMWH). Four retrievals were not successful. In patients receiving oral anticoagulation, the median INR was 2.35 (range, 2 to 8). Group 2 comprised 23 successful filter retrievals in 22 patients receiving a prophylactic dose of LMWH. Group 3 included 27 attempted filter retrievals in 27 patients not receiving therapeutic anticoagulation. Six retrievals were not successful. Five patients were receiving oral anticoagulation with a subtherapeutic INR (median, 1.49; range, 1.16 to 1.69). No anticoagulation medication was administered in 22 patients. In none of the groups were hemorrhagic complications related to the retrieval procedures identified. CONCLUSIONS: These results suggest that retrieval of vena cava filters in anticoagulated patients is safe. Interruption or reversal of anticoagulation for the retrieval of vena cava filters is not indicated.

Pathologically determined tumor volume vs pathologic T stage in the prediction of outcome after surgical treatment of oropharyngeal squamous cell carcinoma.

IMPORTANCE: Traditional prognostic models for squamous cell carcinoma of the head and neck are based on the TNM staging system. However, there is growing evidence that tumor volume (TV) may be a more accurate predictor of outcome. OBJECTIVE: To determine whether pathologic TV (pTV) in patients with oropharyngeal squamous cell carcinoma treated surgically is a more significant predictor of outcome compared with pathologic tumor (pT) stage. DESIGN, SETTING, AND PARTICIPANTS: Review of patients whose treatment was managed between January 1, 1985, and December 2005 at a US tertiary referral cancer center. The participants included 159 patients who had undergone primary surgery for oropharyngeal squamous cell carcinoma and had 3 dimensions reported on histopathologic testing. MAIN OUTCOMES AND MEASURES: The pTV was calculated as the product of the 3 dimensions expressed in cubic centimeters. For comparison of pT stage with pTV in outcome prediction, concordance indexes were generated using the bootstrap method (n = 1000) to quantify the predictive accuracy of recurrence and survival outcomes. Concordance indexes were then compared and a significant difference was considered when P < .05. RESULTS: The median age of the patients was 59 years (range, 22-84 years) and 106 were male (67%). Sites of the tumors were base of the tongue (86 patients [54%]), tonsil (48 [30%]), soft palate (24 [15%]), and posterior pharyngeal wall (1 [1%]). The median follow-up time was 64 months (range, 1-272 months). The median tumor volume was 6.8 cm3 (range, 0.1-162.5 cm³). Pathologic TV was a significant predictor of disease-specific mortality. Unlike pT stage, pTV was a significant predictor of local recurrence, regional recurrence, and distant recurrence. Comparison of concordance indexes showed that pTV was a significantly better predictor of disease-specific mortality, local recurrence, and distant recurrence (all P < .05). CONCLUSIONS AND RELEVANCE: Pathologic TV outperforms pT stage in the prediction of outcome following surgical treatment of oropharyngeal cancer. Tumor volume should be considered in the design of prospective surgical trials.

Transjugular liver biopsy via the left internal jugular vein.

PURPOSE: To retrospectively review the indications and outcomes of transjugular liver biopsy (TJLB) with the left internal jugular vein (IJV) approach. MATERIALS AND METHODS: A retrospective review of all TJLBs performed at one institution was performed. From August 1995 to October 2004, 293 liver biopsies were performed. Nineteen of the 293 procedures (6.5%) were performed from the left IJV in 17 patients. There were 11 men and six women aged 36-59 years (mean, 49.3 years). All patients were suspected of having diffuse hepatic parenchymal disease and had contraindications to conventional percutaneous liver biopsy. The stiff metal biopsy cannula was advanced across the mediastinum and through the heart over a stiff guide wire. Biopsy was performed from the right hepatic vein in 15 procedures, the middle hepatic vein in two, and the intrahepatic IVC in two. RESULTS: The indications for using the left IJV approach were nonusable right IJV in 12 procedures, difficult previous catheterization of the hepatic veins from the right IJV due to distorted hepatic anatomy in six procedures, and the operator's predilection for this approach in one procedure (the patient had previously undergone liver transplantation). All biopsies were successful, with diagnostic tissue obtained in 100% of cases. Two patients had chest pain during the procedure associated with placement of the rigid cannula through the mediastinal veins. One patient had a vaso-vagal episode that necessitated the use of intravenous atropine but subsequently underwent successful biopsy. All episodes of chest pain resolved after the cannula was removed. There were no recorded hemorrhagic or cardiac complications. CONCLUSION: TJLB can be safely and repeatedly performed from the left IJV when the right IJV is not available or the hepatic anatomy prevents catheterization of the hepatic veins from the right IJV.

Successful endovascular treatment of aortoenteric fistula secondary to eroding duodenal stent.

Aortoenteric fistulas are characterized as either primary or secondary on the basis of their cause. Most aortoenteric fistulas occur between the aorta and duodenum and are a rare but well-known cause of catastrophic gastrointestinal hemorrhage. Conventional treatment of aortoenteric fistulas uses bypass grafting and aortic ligation, but endovascular treatments have become more common. The authors describe the successful endovascular repair of a primary aortoenteric fistula caused by eroding duodenal stent.

Guenther tulip filter retrieval from a left-sided inferior vena cava.

Optional (retrievable) inferior cava filters (IVC) may have advantages over permanent filters in a certain subset of patients, especially in view of recent concerns about the long-term thrombotic complications of the latter. Retrieval of the Guenther Tulip Filter (GTF), an optional filter, has been reported in a total of 76 patients. We present the first description of GTF retrieval from a left-sided IVC using the right internal jugular approach.

Clinical outcome after intrahepatic venous stent placement for malignant inferior vena cava syndrome.

We evaluated the clinical outcome of malignant inferior vena cava (IVC) syndrome after intrahepatic IVC stent placement by retrospective analysis of 50 consecutive patients (25 men, 25 women, age 32-83 years) with malignant IVC syndrome who were treated with intrahepatic stent placement. Gianturco-Rosch-Z (GRZ) stents (n = 45), and Wallstents (n = 5) were inserted. Clinical outcome was assessed from patients' records using a score based on leg swelling, scrotal/vulvar edema, ascites and anasarca before and after stent placement, as well as at last follow-up visit before death. Clinical follow-up was supplemented by duplex sonography in 36 patients. Inferior venocavography was performed in 5 patients prior to re- intervention. Follow-up time ranged from 1 to 932 days (mean 62 days). Mean pressure gradient in the IVC was reduced from 14 +/- 4.1 mmHg before to 2.9 +/- 3.2 mmHg after stent placement (p < 0.001). Four patients had stent occlusion, 2 of whom were successfully re-stented. Primary and secondary patency was 59% and 100%, respectively at 540 days. Immediate clinical data were available in 44 patients: 38 improved; 6 did not respond. Last follow-up visit data were available in 36 patients: 24 showed persistent symptom relief till death. All symptom scores were significantly improved after stent placement (p < 0.001) and with the exception of ascites, remained significantly improved (p < 0.05) until the last follow-up. Increased serum bilirubin was a common characteristic of clinical failures and recurrences. Intrahepatic IVC stent placement resulted in significant symptomatic relief in patients with malignant IVC syndrome. Palliation was effective even in patients with a very short life expectancy.