Development of a Novel, Peptide-based Vaccine for Lyme Disease

Lyme disease (LD) is the most prevalent arthropod borne illness in the US. Currently, there is no vaccine to prevent infection with LD in humans, rather, prevention of this disease relies on avoiding exposure to the tick vector or treating for LD retroactively. Present research towards a new LD vaccine has focused on the idea of using multimeric, chimeric, and multivalent molecules. The antigens targeted in this approach are highly heterologous between strains and species of Borrelia burgdorferi, and as such, this vaccine may require reformulation of antigens to remain relevant. As such, this dissertation explored the idea of using a novel, highly conserved peptide antigen derived from B. burgdorferi to prevent infection with LD. This approach utilized reverse vaccinology, in silico and in vitro analysis of potential protein candidates, and in vivo vaccination studies using selected proteins and peptides to evaluate the feasibility of a novel peptide vaccine with potential to be broadly protective against LD. Using this methodology, a previously uncharacterized vonWillebrand factor A domain containing protein, BB0173, was characterized and found to localized to the inner membrane with the VWFA domain exposed to the periplasmic space. Further, a novel, highly-conserved peptide antigen of B. burgdorferi (PepB) was identified the extracellularly exposed VWFA domain containing protein BB0172 that demonstrated the ability to generate a protective immune response against B. burgdorferi challenge both using the needle and tick based methods of infection

Molecular Aspects in the Potential of Vitamins and Supplements for Treating Diabetic Neuropathy

PURPOSE OF REVIEW: To discuss and provide evidence-based data on dietary supplements as part of treating diabetic neuropathy RECENT FINDINGS: Few randomized controlled trials are available, but some have shown beneficial efficacy of various dietary supplements on objective primary endpoints including nerve conduction velocities and axon potentials as well as subjective patient-reported outcomes. SUMMARY: No medical cure for diabetic neuropathy exists, and prevention is therefore crucial. Tight glucose control slows the progression of nerve damage in diabetes, but an unmet clinical need for effective interventions is warranted. Consequently, a growing number of patients turn to dietary supplements proposed to possess neuroprotective properties. However, the postulated effects are often not evidence-based as they have not been tested scientifically. Taken together, this review will focus on dietary supplements investigated in clinical trials for their potential capabilities in targeting the molecular mechanisms involved in the underlying pathogenesis of diabetic neuropathy

Implementing the EffTox dose-finding design in the Matchpoint trial

Background: The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial. Methods: EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes. We describe a nomenclature for succinctly describing outcomes in phase I/II dose-finding trials. We use dose-transition pathways, where doses are calculated for each feasible set of outcomes in future cohorts. We introduce the phenomenon of dose ambivalence, where EffTox can recommend different doses after observing the same outcomes. We also describe our experiences with outcome ambiguity, where the categorical evaluation of some primary outcomes is temporarily delayed. Results: We arrived at an EffTox parameterisation that is simulated to perform well over a range of scenarios. In scenarios where dose ambivalence manifested, we were guided by the dose-transition pathways. This technique facilitates planning, and also helped us overcome short-term outcome ambiguity. Conclusions: EffTox is an efficient and powerful design, but not without its challenges. Joint phase I/II clinical trial designs will likely become increasingly important in coming years as we further investigate non-cytotoxic treatments and streamline the drug approval process. We hope this account of the problems we faced and the solutions we used will help others implement this dose-finding clinical trial design. Trial registration: Matchpoint was added to the European Clinical Trials Database (2012-005629-65) on 2013-12-30

Rewarding Persistence: Effects of a Performance-Based Scholarship Program for Low-Income Parents

This report describes the impacts of a performance-based scholarship program with a counseling component on academic success and persistence among low-income parents. Students who participated in the program, which was operated at two New Orleans-area colleges as part of MDRC's multisite Opening Doors demonstration, were more likely to stay in school, get higher grades, and earn more credits

Low-grade inflammation in type 2 diabetes:a cross-sectional study from a Danish diabetes outpatient clinic

OBJECTIVES: To investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications. DESIGN: Cross-sectional analysis. SETTING: The outpatient diabetes clinic at the Department of Endocrinology at Aalborg University Hospital, Denmark. PARTICIPANTS: 100 participants with type 2 diabetes confirmed by a haemoglobin A1c (HbA1c)≥6.5% for a minimum of 1 year and 21 healthy controls. OUTCOME MEASURES: Serum levels of 27 inflammation-related biomarkers measured by immunoassay. Associations with microvascular and macrovascular complications, body weight, glycaemic control, medication and sex were investigated in the diabetes cohort. RESULTS: Serum levels of tumour necrosis factor (TNF)-α and eotaxin were elevated in type 2 diabetes (p<0.05), while interleukin (IL)-7 was decreased (p<0.001). IL-12/IL-23p40, IL-15, macrophage-derived chemokine (MDC) and C reactive protein (CRP) levels were increased with body weight (p<0.05), while eotaxin and TNF-α were increased with elevated HbA1c levels (p<0.04). Dipeptidyl peptidase-4 inhibitor therapy was associated with lower levels of induced protein-10, MDC and thymus and activation regulated chemokine (p<0.02), while females had higher levels of MDC (p=0.027). Individuals with ≥3 diabetic complications had elevated levels of IL-6, IL-10, IL-12/IL-23p40, IL-15 and CRP compared with those with ≤3 (p<0.05). CONCLUSION: The level of low-grade inflammation in type 2 diabetes is associated with obesity, glycaemic regulation, therapeutical management, sex and complications. Our results underline the importance of addressing inflammatory issues in type 2 diabetes, as these may predispose for crippling comorbidities

Development of a Novel, Peptide-based Vaccine for Lyme Disease

Lyme disease (LD) is the most prevalent arthropod borne illness in the US. Currently, there is no vaccine to prevent infection with LD in humans, rather, prevention of this disease relies on avoiding exposure to the tick vector or treating for LD retroactively. Present research towards a new LD vaccine has focused on the idea of using multimeric, chimeric, and multivalent molecules. The antigens targeted in this approach are highly heterologous between strains and species of Borrelia burgdorferi, and as such, this vaccine may require reformulation of antigens to remain relevant. As such, this dissertation explored the idea of using a novel, highly conserved peptide antigen derived from B. burgdorferi to prevent infection with LD. This approach utilized reverse vaccinology, in silico and in vitro analysis of potential protein candidates, and in vivo vaccination studies using selected proteins and peptides to evaluate the feasibility of a novel peptide vaccine with potential to be broadly protective against LD. Using this methodology, a previously uncharacterized vonWillebrand factor A domain containing protein, BB0173, was characterized and found to localized to the inner membrane with the VWFA domain exposed to the periplasmic space. Further, a novel, highly-conserved peptide antigen of B. burgdorferi (PepB) was identified the extracellularly exposed VWFA domain containing protein BB0172 that demonstrated the ability to generate a protective immune response against B. burgdorferi challenge both using the needle and tick based methods of infection

The effect of transcutaneous vagus nerve stimulation in patients with polymyalgia rheumatica

(1) Polymyalgia rheumatica (PMR) is an inflammatory disease characterised by pain, morning stiffness, and reduced quality of life. Recently, vagus nerve stimulation (VNS) was shown to have anti-inflammatory effects. We aimed to examine the effect of transcutaneous VNS (t-VNS) on PMR. (2) Fifteen treatment-naïve PMR patients completed the study. Patients underwent a 5-day protocol, receiving 2 min of t-VNS stimulation bilaterally on the neck, three times daily. Cardiac vagal tone (CVT) measured on a linear vagal scale (LVS), blood pressure, heart rate, patient-reported outcome, and biochemical changes were assessed. (3) t-VNS induced a 22% increase in CVT at 20 min after initial stimulations compared with baseline (3.4 ± 2.2 LVS vs. 4.1 ± 2.9 LVS, p = 0.02) and was accompanied by a 4 BPM reduction in heart rate (73 ± 11 BPM vs. 69 ± 9, p p = 0.04). No changes in CRP or proinflammatory analytes were observed. (4) t-VNS modulates the autonomic nervous system in patients with PMR, but further investigation of t-VNS in PMR patients is warranted

Study protocol for a multicentre, randomised, parallel group, sham-controlled clinical trial investigating the effect of transcutaneous vagal nerve stimulation on gastrointestinal symptoms in people with diabetes complicated with diabetic autonomic neuropathy:The DAN-VNS Study

Introduction A high proportion of people with diabetes experience gastrointestinal (GI) symptoms, which may be manifestations of diabetic autonomic neuropathy (DAN). The current treatment regime is ineffective and associated with major side effects. Transcutaneous vagal nerve stimulation (tVNS) is a new therapeutic option, which has been shown to increase GI motility and reduce inflammatory responses. As vagus is the main neuronal pathway for extrinsic coordination of GI secretion and motility, we hypothesise that tVNS will improve DAN-induced GI symptoms in subjects with diabetes.Methods and analysis The DAN-VNS study is a randomised multicentre clinical trial investigating the effect of short-term, high intensity as well as long-term, medium-intensity tVNS on GI symptom alleviation in 120 subjects with diabetes. The primary outcome consists of changes from baseline in subjective ratings of symptom severity. Secondary outcomes include changes in gastric motility and GI transit time measured by MRI and wireless motility capsule. Moreover, cardiovascular and sudomotor function, glycaemic control, brain sensory processing and presence of low-grade inflammation will be investigated as secondary outcome measures. Lastly, 15 responders of tVNS treatment will be included in an explorative, randomised, cross-over study, in which the acute endocrine and metabolic response to short-term tVNS will be investigated.Ethics and dissemination The study has been approved by the North Denmark Region Committee on Health Research Ethics (N-20190020). Results will be published in relevant international peer-reviewed journals.Trial registration number NCT04143269