Root Canal Shaping Using Nickel Titanium,M-Wire,and Gold Wire: A Micro–computed Tomographic Comparative Study of One Shape,ProTaper Next,and WaveOne Gold Instruments in Maxillary First Molars

Introduction

The aim of this study was to evaluate the root canal shaping effect of instruments manufactured from nickel titanium, M-Wire, and Gold wire with different glide path preparation techniques.

Impact of comorbidities on fatigue in rheumatoid arthritis patients: Results from a nurse-led program for comorbidities management (COMEDRA)

Objectives

To analyze the factors associated with fatigue focusing on comorbidities in a large cohort of rheumatoid arthritis (RA).

Prolonged mechanical ventilation after cardiac surgery: substudy of the Transfusion Requirements in Cardiac Surgery III trial

Purpose

Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications.

Methods

Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included. Prolonged MV was defined based on the Society of Thoracic Surgeons definition as MV lasting 24 hr or longer. Adjusted associations of patient and surgical factors with prolonged MV were examined using multivariable logistic regression. Associations of prolonged MV with complications were assessed using odds ratios, and adjusted associations between prolonged MV and mortality were evaluated using multinomial regression. Associations of shorter durations of MV with survival and complications were explored.

Results

Prolonged MV occurred in 15% (725/4,809) of participants. Prolonged MV was associated with surgical factors indicative of complexity, such as previous cardiac surgery, cardiopulmonary bypass duration, and separation attempts; and patient factors such as critical preoperative state, left ventricular impairment, renal failure, and pulmonary hypertension. Prolonged MV was associated with perioperative but not long-term complications. After risk adjustment, prolonged MV was associated with perioperative mortality; its association with long-term mortality among survivors was weaker. Shorter durations of MV were not associated with increased risk of mortality or complications.

Conclusion

In this substudy of the TRICS III trial, prolonged MV was common after cardiac surgery and was associated with patient and surgical risk factors. Although prolonged MV showed strong associations with perioperative complications and mortality, it was not associated with long-term complications and had weaker association with long-term mortality among survivors.

Study registration

www.ClinicalTrials.gov (NCT02042898); registered 23 January 2014. This is a substudy of the Transfusion Requirements in Cardiac Surgery (TRICS) III trial.

     

Routine diagnostics for neural antibodies,clinical correlates,treatment and functional outcome

Objective

To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.

Methods

Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.

Results

Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6–46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-d-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.

Conclusions

This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

     

Pharmacokinetics,Pharmacodynamics, and Exposure‐Response of Lanadelumab for Hereditary Angioedema

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (C_min,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Hereditary angioedema (HAE) is a long‐term, debilitating, and potentially life‐threatening disease caused by C1‐inhibitor deficiency. Lanadelumab is a fully human monoclonal antibody inhibitor of plasma kallikrein that is effective in preventing attacks in patients with HAE.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What are the pharmacokinetic and pharmacodynamic characteristics of lanadelumab, and how are they related to the observed efficacy of lanadelumab in preventing HAE attacks?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Lanadelumab clearance and volume of distribution are dependent on body weight; however, significant attack rate reduction is still observed in patients with high body weight, and dose adjustment is not necessary. The findings of this study provide a greater understanding of the factors driving the efficacy and safety of lanadelumab to ensure optimal use.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Selective binding of lanadelumab to plasma kallikrein provides a novel approach for long‐term prophylaxis against HAE attacks.

Hereditary angioedema (HAE) is a rare, debilitating, and potentially life‐threatening disease with an estimated prevalence of 1 in 50,000. ¹ It manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia. Swelling may last several days, and most patients have multiple attacks per year. ² Symptoms usually begin during childhood, sometimes as young as age 2 years, and persist throughout life. ² HAE is caused by mutations in SERPING1, the gene encoding C1 inhibitor (C1‐INH), resulting in deficiency of C1‐INH protein or function. ³ C1‐INH is involved in regulating the contact, complement, and coagulation systems. ³ In the contact system, C1‐INH is the natural inhibitor of plasma kallikrein. Dysregulated contact system activation and subsequent uncontrolled plasma kallikrein activity lead to production of cleaved high molecular weight kininogen (cHMWK) and the edema‐inducing peptide bradykinin, which initiates signaling pathways leading to HAE attacks. Management of patients with HAE involves on‐demand medications to treat attacks when they occur, and long‐term or short‐term prophylaxis to prevent attacks. ¹ , ² Lanadelumab is a fully human immunoglobulin G1 monoclonal antibody that binds specifically to active plasma kallikrein. ⁴ It is approved in several countries for the prevention of HAE attacks in patients ≥ 12 years of age. In clinical trials, treatment with lanadelumab significantly reduced attack rates in patients with HAE, and this was associated with a reduction in cHMWK levels. ⁵ , ⁶ The pharmacokinetics (PK), pharmacodynamics (PD), exposure‐response relationships, and potential interactions of lanadelumab with rescue medications (for treatment of attacks that occur during long‐term prophylaxis), and with medications commonly used concomitantly in patients with HAE, were characterized using data from clinical studies to support the dosing rationale for long‐term prophylaxis with lanadelumab in patients with HAE.     

Association Between Patient and Physician Sex and Physician-Estimated Stroke and Bleeding Risks in Atrial Fibrillation

Background

Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain.