Direct quantitative measurement of the kinetics of HLA-specific antibody interactions with isolated HLA proteins

HLA specific antibodies vary in their pathogenicity and this is likely to be the net effect of constant chain usage, quantity, specificity, and affinity. Here we have measured the affinity of human monoclonal antibodies for a range of HLA proteins. Purified antibodies and ligands allowed dynamic interactions to be measured directly by surface plasmon resonance. Physiochemical differences between pairs of ligands were quantified using electrostatic mismatch and hydrophobic mismatch scores.All antibodies were characterized by fast on-rates and slow off rates but with a wide range of association rates (k_on, 3.63–24.25?×?10⁵ per mol per second) and dissociation rates (k_off, 0.99–10.93?×?10^?3 per second). Dissociation constants (K_D) ranged from 5.9?×?10^?10?M to 3.0?×?10^?8?M. SN320G6 has approximately a twenty-fold greater affinity for HLA A2 compared with SN607D8, but has a similar affinity for HLA-A2 and B57. In contrast, SN607D8 has greater than a twofold greater affinity for HLA-A2 compared with A68. Similarly, WK1D12 has about a threefold greater affinity for HLA-B27 compared with B7. The higher affinity interactions correlate with the specificity of stimulating antigen. This is the first study to directly measure the binding kinetics and affinity constants for human alloantibodies against HLA.     

The Nottingham Prognostic Index: five- and ten-year data for all-cause Survival within a Screened Population

Introduction

The Nottingham Prognostic Index (NPI) is an established prognostication tool in the management of breast cancers (BCs). Latest ten-year survival data have demonstrated an improved outlook for each NPI category and the latest UK five- and ten-year survival from BC has been reported to be 85% and 77%, respectively. We compared survival of each NPI category for BCs diagnosed within the national breast screening service in Wales (Breast Test Wales (BTW)) to the latest data, and reviewed its validity in unselected cases within a screened population.

Methods

All women screened between 1998 and 2001 within BTW were included. The NPI score for each cancer was calculated using the size, nodal status, and grade of the primary tumour. Survival data (all-cause) were calculated after ten years of follow-up.

Results

In the three-year screening period, 199,082 women were screened. A total of 1,712 cancers were diagnosed, and 1,546 had data available for calculating the NPI. Overall five-year and ten-year survival was 94% and 82%, respectively.

Conclusions

Overall five-year and ten-year survival (all-cause) has improved even when compared with UK data for BC-specific survival. We found that the NPI remains valid for BC treatment, and that our data provide a reference for updating the all-cause survival of women diagnosed with BCs within a screened population.     

Outcomes of transcutaneous nerve stimulation for migraine headaches: a systematic review and meta-analysis

Journal of Neurology - Implanted and transcutaneous nerve stimulators have shown promise as novel non-pharmacologic treatment for episodic and chronic migraines. The purpose of this study was to...     

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized,Double-Blind Primary Endpoint

ObjectivePublished reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.Materials and MethodsParticipants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.ResultsThe study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period.ConclusionDirectional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.     

Sex-Specific Muscular Mediation of the Relationship Between Physical Activity and Cortical Bone in Young Adults

Muscle mass is a commonly cited mediator of the relationship between physical activity (PA) and bone, representing the mechanical forces generated during PA. However, neuromuscular properties (eg, peak force) also account for unique portions of variance in skeletal outcomes. We used serial multiple mediation to explore the intermediary role of muscle mass and force in the relationships between cortical bone and moderate-to-vigorous intensity PA (MVPA). In a cross-sectional sample of young adults (n = 147, 19.7 ± 0.7 years old, 52.4% female) cortical diaphyseal bone was assessed via peripheral quantitative computed tomography at the mid-tibia. Peak isokinetic torque in knee extension was assessed via Biodex dynamometer. Thigh fat-free soft tissue (FFST) mass, assessed via dual-energy X-ray absorptiometry, represented the muscular aspect of tibial mechanical forces. Habitual MVPA was assessed objectively over 7 days using Actigraph GT3X+ accelerometers. Participants exceeded MVPA guidelines (89.14 ± 27.29 min/day), with males performing 44.5% more vigorous-intensity activity relative to females (p < 0.05). Males had greater knee extension torque and thigh FFST mass compared to females (55.3%, and 34.2%, respectively, all p < 0.05). In combined-sex models, controlling for tibia length and age, MVPA was associated with strength strain index (pSSI) through two indirect pathways: (i) thigh FFST mass (b = 1.11 ± 0.37; 95% CI, 0.47 to 1.93), and (i) thigh FFST mass and knee extensor torque in sequence (b = 0.30 ± 0.16; 95% CI, 0.09 to 0.73). However, in sex-specific models MVPA was associated with pSSI indirectly through its relationship with knee extensor torque in males (b = 0.78 ± 0.48; 95% CI, 0.04 to 2.02) and thigh FFST mass in females (b = 1.12 ± 0.50; 95% CI, 0.37 to 2.46). Bootstrapped CIs confirmed these mediation pathways. The relationship between MVPA and cortical structure appears to be mediated by muscle in young adults, with potential sex-differences in the muscular pathway. If confirmed, these findings may highlight novel avenues for the promotion of bone strength in young adults. © 2019 American Society for Bone and Mineral Research.     

NF1 optic pathway glioma: analyzing risk factors for visual outcome and indications to treat

BackgroundThe aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1 associated optic pathway glioma (NF1-OPG).MethodsA multidisciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists, and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from 6 European countries with complete clinical, imaging, and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes.ResultsEighty-three patients (37 males, 46 females, mean age 5.1 ± 2.6 y; 1–13.1 y) registered in the European treatment trial SIOP LGG-2004 (recruited 2004–2012) were included. They were either observed or treated (at diagnosis/after follow-up).In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjusted odds ratio [adjOR]: 8.33; 95% CI: 1.9–36.45), abnormal visual behavior (adjOR: 4.15; 95% CI: 1.20–14.34), new onset of visual symptoms (adjOR: 4.04; 95% CI: 1.26–12.95), and optic atrophy (adjOR: 3.73; 95% CI: 1.13–12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis.ConclusionsThe analysis identified the importance of symptomatology, optic atrophy, and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG.