Standard Measures are Inadequate to Monitor Pediatric Adherence in a Resource-Limited Setting

This study aims to compare the use and cost of objective and subjective measures of adherence to pediatric antiretroviral treatment in a primary care facility in South Africa. In a 1-month longitudinal study of 53 caregiver-child dyads, pharmacy refill (PR), measurement of returned syrups (RS), caregiver self-report (3DR) and Visual Analogue Scale (VAS) were compared to Medication Event Monitoring System (MEMS). Adherence was 100% for both VAS and 3DR; by PR and RS 100% and 103%, respectively. MEMS showed that 92% of prescribed doses were administered, but only 66% of these within the correct 12-hourly interval. None of the four measures correlated significantly with MEMS. MEMS data suggest that timing of doses is often more deviant from prescribed than expected and should be better addressed when monitoring adherence. Of all, MEMS was by far the most expensive measure. Alternative, cheaper electronic devices need to be more accessible in resource-limited settings

Error Signals from the Brain: 7th Mismatch Negativity Conference

The 7th Mismatch Negativity Conference presents the state of the art in methods, theory, and application (basic and clinical research) of the MMN (and related error signals of the brain). Moreover, there will be two pre-conference workshops: one on the design of MMN studies and the analysis and interpretation of MMN data, and one on the visual MMN (with 20 presentations). There will be more than 40 presentations on hot topics of MMN grouped into thirteen symposia, and about 130 poster presentations. Keynote lectures by Kimmo Alho, Angela D. Friederici, and Israel Nelken will round off the program by covering topics related to and beyond MMN

Antibody Response to SARS-CoV-2 Vaccination in Patients following Allogeneic Hematopoietic Cell Transplantation

Vaccines against SARS-CoV-2 have been rapidly approved. Although pivotal studies were conducted in healthy volunteers, little information is available on the safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). Here we used a novel assay to analyze patient- and transplantation-related factors and their influence on immune responses to SARS-CoV-2 vaccination over an extended period (up to 6 months) in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivity against SARS-CoV-2 antigens (receptor-binding domain, spike glycoprotein subunits S1 and S2, and nucleocapsid protein) was performed before vaccination, before the second dose, and at 1, 3, and 6 months after the second dose. Patients were stratified to 3 groups: 3 to 6 months post-allo-HCT, 6 to 12 months post-allo-HCT, and >12 months post-allo-HCT. Patients in the 3 to 6 months and 6 to 12 months post-allo-HCT groups developed significantly lower antibody titers after vaccination compared with patients in the >12 months post-allo-HCT group and healthy controls (P 65 years (P = .030), those receiving immunosuppression for prevention or treatment of graft-versus-host disease (GVHD) (P = .033), and patients with relapsed disease (P = .014) displayed low humoral immune responses to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels at 1 month after the second dose of the vaccine but waned substantially in all transplantation groups and healthy controls over time. This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding revaccination and social behavior during the SARS-CoV-2 pandemic. Keywords: Allogeneic hematopoietic cell transplantation; SARS-CoV-2; Vaccinatio

BibGlimpse: The case for a light-weight reprint manager in distributed literature research

Background While text-mining and distributed annotation systems both aim at capturing knowledge and presenting it in a standardized form, there have been few attempts to investigate potential synergies between these two fields. For instance, distributed annotation would be very well suited for providing topic focussed, expert knowledge enriched text corpora. A key limitation for this approach is the availability of literature annotation systems that can be routinely used by groups of collaborating researchers on a day to day basis, not distracting from the main focus of their work. Results For this purpose, we have designed BibGlimpse. Features like drop-to-file, SVM based automated retrieval of PubMed bibliography for PDF reprints, and annotation support make BibGlimpse an efficient, light-weight reprint manager that facilitates distributed literature research for work groups. Building on an established open search engine, full-text search and structured queries are supported, while at the same time making shared collections of annotated reprints accessible to literature classification and text-mining tools. Conclusion BibGlimpse offers scientists a tool that enhances their own literature management. Moreover, it may be used to create content enriched, annotated text corpora for research in text-mining

Single-Batch Production of Recombinant Human Polyclonal Antibodies

We have previously described the development and implementation of a strategy for production of recombinant polyclonal antibodies (rpAb) in single batches employing CHO cells generated by site-specific integration, the SympressTM I technology. The SympressTM I technology is implemented at industrial scale, supporting a phase II clinical development program. Production of recombinant proteins by site-specific integration, which is based on incorporation of a single copy of the gene of interest, makes the SympressTM I technology best suited to support niche indications. To improve titers while maintaining a cost-efficient, highly reproducible single-batch manufacturing mode, we have evaluated a number of different approaches. The most successful results were obtained using random integration in a new producer cell termed ECHO, a CHO DG44 cell derivative engineered for improved productivity at Symphogen. This new expression process is termed the SympressTM II technology. Here we describe proof-of-principle data demonstrating the feasibility of the SympressTM II technology for single-batch rpAb manufacturing using two model systems each composed of six target-specific antibodies. The compositional stability and the batch-to-batch reproducibility of rpAb produced by the ECHO cells were at least as good as observed previously using site-specific integration technology. Furthermore, the new process had a significant titer increase

Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand

Efficacy and safety of mycophenolate mofetil and tacrolimus as second-line therapy for patients with autoimmune hepatitis

Background: Predniso(lo)ne, alone or in combination with azathioprine, is the standard of care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. Patients and methods: We performed a retrospective study of data (from 19 centres in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 months). Patients were categorized according to their response to SOC. Patients in group 1 (n=108) had a complete response to the SOC, but were switched to second line therapy due to side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n=93) had not responded to SOC. Results: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P=.639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P=.682). Significantly more group 2 patients given tacrolimus compared to MMF had a complete response (56.5 % vs. 34%, P=.029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P=.472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. Conclusions: Long-term therapy with MMF or tacrolimus was generally well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous non-responder patients compared to MMF