Afamelanotide for Treatment of the Protoporphyrias: Impact on Quality of Life and Laboratory Parameters in a US Cohort.

BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare disorders of heme biosynthesis characterized by severe cutaneous phototoxicity. Afamelanotide, an α-melanocyte-stimulating hormone analogue, is the only approved treatment for protoporphyria and leads to increased light tolerance and improved quality of life (QoL). However, published experience with afamelanotide in the US is limited. METHODS: Here, we report on all adults who received at least one dose of afamelanotide at the Massachusetts General Hospital Porphyria Center from 2021 to 2022. Changes in the time to phototoxic symptom onset, QoL, and laboratory parameters were assessed before and during treatment with afamelanotide. RESULTS: A total of 29 patients with protoporphyria were included, 26 of whom (72.2%) received ≥2 afamelanotide implants. Among the patients who received ≥2 implants, the median time to symptom onset following sunlight exposure was 12.5 min (IQR, 5-20) prior to the initiation of afamelanotide and 120 min (IQR, 60-240) after treatment (p < 0.001). Improvements in QoL during afamelanotide treatment were measured using two QoL tools, with good correlation observed between these two instruments. Finally, we found no improvements in the median levels of metal-free erythrocyte protoporphyrin, plasma protoporphyrin, or liver biochemistries during versus prior to the initiation of afamelanotide treatment. CONCLUSIONS: This study highlights a dramatic clinical benefit of afamelanotide in relation to light tolerance and QoL in protoporphyria, albeit without improvement in protoporphyrin levels or measures of liver function.

Patient Reported Ease-of-Use with a Disposable Autoinjector in Individuals with Migraine.

PURPOSE: Erenumab-aooe (erenumab, Aimovig®)-a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide (CGRP) receptor-is approved for the prevention of migraine in adults in a number of countries. The approved monthly dosage of erenumab (70 and/or 140 mg, depending on the country) is available as a single, prefilled autoinjector for subcutaneous administration in most countries where it is approved. This study evaluated the patient-reported ease-of-use, ability to learn self-injection, confidence in performing a simulated self-injection, and ergonomics of a prefilled autoinjector device for erenumab (SureClick® autoinjector) in individuals in the US with migraine. PATIENTS AND METHODS: Participants with migraine headaches, all of whom were naïve to the use of an autoinjector for migraine or another condition and CGRP therapy, were recruited from three US-based headache centers. Each participant received a supervised demonstration of the autoinjector during a 30-minute one-on-one session using a standard protocol-driven script. Participants then practiced a simulated injection into an artificial tissue pad using the autoinjector and were asked to rate their agreement with 19 statements about the device on a 5-point Likert scale (1 = completely disagree, 2 = somewhat disagree, 3 = neutral, 4 = somewhat agree, 5 = completely agree). RESULTS: Participants who completed the study and provided responses (n = 204) were between 21 and 85 years of age, inclusive, and 73% were female. More than 90% of the participants completely or somewhat agreed with 16/19 statements relating to the device, including ease-of-use, ability to self-inject, and confidence in using the device, with an average rating of >4.5 on the 5-point Likert scale. Participants rated the size of the device and the compactness of the device as 4.23/5 and 4.26/5, respectively. CONCLUSION: The erenumab-prefilled disposable autoinjector was consistently highly rated across categories by individuals with migraine, with an average rating of >4.5 on the 5-point Likert scale; results were consistent across the three study centers.

Adopting Evidence-Based Caregiver Training Programs in the Real World: Outcomes and Lessons Learned From the STAR-C Oregon Translation Study.

OBJECTIVES: This article describes the translation and evaluation of STAR-Community Consultants program (STAR-C), an evidence-based dementia caregiver training program, within the Oregon Department of Human Services. METHOD: Staff from two regional Area Agencies on Aging (AAAs) were trained to implement all aspects of STAR-C, including screening, recruitment of caregiver/care-receiver dyads, and treatment delivery. Mailed assessments of caregiver depression, burden, and care-receiver mood, behavior, and quality of life were collected at pre-treatment, post-treatment, and 6-month follow-up. RESULTS: One hundred fifty-one dyads entered the program; 96 completed the 8-week intervention. Significant positive post-treatment effects were obtained for caregiver depression, burden, and reactivity to behavior problems, and care-receiver depression and quality of life. At 6-month follow-up, improvements in caregiver reactivity and care-receiver depression were maintained. Caregivers reported high levels of satisfaction with the program. DISCUSSION: STAR-C was successfully and effectively implemented by participating AAAs. Recommendations for replication, including training, recruitment, and assessment procedures are provided.

Hormones and the bone marrow: panhypopituitarism and pancytopenia in a man with a pituitary adenoma.

In rare cases, pancytopenia results from hormonal deficiencies that arise in the setting of panhypopituitarism. Here we describe the unusual case of a 60-year-old man who presented with progressive fatigue and polyuria, and whose laboratory workup revealed a deficiency of the five hormones associated with the action of the anterior pituitary (thyroid hormone, testosterone, cortisol, prolactin, and insulin-like growth factor-1). Imaging of the pituitary demonstrated a cystic mass consistent with a pituitary adenoma replacing much of the normal pituitary tissue. His symptoms and hematologic abnormalities rapidly resolved with prednisone and levothyroxine supplementation. While the majority of reported cases of panhypopituitarism with bone marrow suppression are the result of peripartum sepsis or hemorrhage leading to pituitary gland necrosis (Sheehan's syndrome), it is also important to consider the diagnosis of hypopituitarism in patients with hypothyroidism, low cortisol levels, and pancytopenia. The causal relationship between pancytopenia and panhypopituitarism is not well understood, though it does reinforce the important influence of these endocrine hormones on the health of the bone marrow.

Evidence supporting an altered immune response in ASD.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interactions, communication, and increased stereotypical repetitive behaviors. The immune system plays an important role in neurodevelopment, regulating neuronal proliferation, synapse formation and plasticity, as well as removing apoptotic neurons. Immune dysfunction in ASD has been repeatedly described by many research groups across the globe. Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior. Discussion of immune abnormalities in ASD will be the focus of this review.

RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response.

Recognition of virus infection by innate pattern recognition receptors (PRRs), including membrane-associated toll-like receptors (TLR) and cytoplasmic RIG-I-like receptors (RLR), activates cascades of signal transduction pathways leading to production of type I interferons (IFN) and proinflammatory cytokines that orchestrate the elimination of the viruses. Although it has been demonstrated that PRR-mediated innate immunity plays an essential role in defending virus from infection, it also occasionally results in overwhelming production of proinflammatory cytokines that cause severe inflammation, blood vessel leakage and tissue damage. In our efforts to identify small molecules that selectively enhance PRR-mediated antiviral, but not the detrimental inflammatory response, we discovered a compound, RO 90-7501 ('2'-(4-Aminophenyl)-[2,5'-bi-1H-benzimidazol]-5-amine), that significantly promoted both TLR3 and RLR ligand-induced IFN-ß gene expression and antiviral response, most likely via selective activation of p38 mitogen-activated protein kinase (MAPK) pathway. Our results thus imply that pharmacological modulation of PRR signal transduction pathways in favor of the induction of a beneficial antiviral response can be a novel therapeutic strategy.

Translation of two evidence-based programs for training families to improve care of persons with dementia.

The need for evidence-based non-pharmacological community programs to improve care of older adults with dementia is self-evident, considering the sheer numbers of affected individuals; the emotional, physical, and financial toll on affected individuals and their caregivers; the impact on our health care system; and the growing availability of evidence regarding the potential for psychosocial interventions to enhance care and decrease costs. To address this need, the Administration on Aging has begun funding translation of evidence-based programs into community settings. Two programs, Reducing Disability in Alzheimer's Disease and STAR-Community Consultants (STAR-C), were selected by the Ohio Department of Aging (in collaboration with the Alzheimer's Association Chapters in Ohio) and the Oregon Department of Health Services (in partnership with Area Agencies on Aging and the Oregon Chapter of the Alzheimer's Association) to be implemented by their staff. Both programs are designed to improve care, enhance life quality, and reduce behavioral problems of persons with dementia and have demonstrated efficacy via randomized controlled trials. This article addresses the developmental and ongoing challenges encountered in the translation of these programs to inform other community-based organizations considering the translation of evidence-based programs and to assist researchers in making their work more germane to their community colleagues.

Free computational resources for designing selected reaction monitoring transitions.

Selected reaction monitoring (SRM) is a technique for quantifying specific proteins using triple quadrupole MS. Proteins are digested into peptides and fed into MS following HPLC separation. The stream of ionized peptides is filtered by m/z ratio so only specific peptide targets enter the collision cell, where they are fragmented into product ions. A specific product ion is then filtered from the cell and its intensity measured. By spiking an isotopically labeled version of each target peptide into a sample, both native and surrogate peptides enter MS, pass the filters and transition into product ions in tandem; thus the quantity of the native peptide may be calculated by examining the relative intensities of the native and surrogate signals. The choice of precursor-to-product ion transitions is critical for SRM, but predicting the best candidates is challenging and time-consuming. To alleviate this problem, software tools for designing and optimizing transitions have recently emerged, predominantly driven by data from public proteomics repositories, such as the Global Proteome Machine and PeptideAtlas. In this review, we provide an overview of the state-of-the-art in automated SRM transition design tools in the public domain, explaining how the systems work and how to use them.

Mining proteomic MS/MS data for MRM transitions.

Multiple reaction monitoring (MRM) of peptides is a popular proteomics technique that employs tandem mass spectrometry to quantify selected proteins of interest, such as those previously identified in differential protein identification studies. Using this technique, the specificity of precursor to product transitions is exploited to determine the absolute quantity of multiple proteins in a single sample. Selection of suitable transitions is critical for the success of MRM experiments, but accurate theoretical prediction of fragmentation patterns and peptide signal intensity is currently not possible. A recently proposed solution to this problem is to combine knowledge of the preferred properties of transitions for MRM, taken from expert practitioners, with MS/MS evidence extracted from a proteomics data repository. In addition, by predicting retention time for each peptide candidate, it allows selection of several compatible transition candidates that can be monitored simultaneously, permitting MRM. In this chapter, we explain how to go about designing transitions using the web-based transition design tool, MRMaid, which leverages high quality MS/MS evidence from the Genome Annotating Proteomic Pipeline (GAPP).

Comparison of novel decoy database designs for optimizing protein identification searches using ABRF sPRG2006 standard MS/MS data sets.

Decoy database searches are used to filter out false positive protein identifications derived from search engines, but there is no consensus about which decoy is "the best". We evaluate nine different decoy designs using public data sets from samples of known composition. Statistically significant performance differences were found, but no single decoy stood out among the best performers. Ultimately, we recommend peptide level reverse decoys searched independently from the target.

Recent developments in public proteomic MS repositories and pipelines.

This article provides an overview of publicly available proteomic data repositories in a single document with a particular focus on the latest developments, many of which are not announced through traditional publications. The review is intended to inform the proteomics practitioner of the options for storage and dissemination of their MS/MS data in the public domain, and to help those who want to mine proteomic data generated by others. The latter area has arguably seen the most development in recent times, as repositories have sprouted new tools for data analysis, visualisation and experimental design. We also highlight key biological datasets available at each repository, including standard datasets. Finally, we touch upon areas of significant challenge and future directions.

MRMaid, the web-based tool for designing multiple reaction monitoring (MRM) transitions.

Multiple reaction monitoring (MRM) of peptides uses tandem mass spectrometry to quantify selected proteins of interest, such as those previously identified in differential studies. Using this technique, the specificity of precursor to product transitions is harnessed for quantitative analysis of multiple proteins in a single sample. The design of transitions is critical for the success of MRM experiments, but predicting signal intensity of peptides and fragmentation patterns ab initio is challenging given existing methods. The tool presented here, MRMaid (pronounced "mermaid") offers a novel alternative for rapid design of MRM transitions for the proteomics researcher. The program uses a combination of knowledge of the properties of optimal MRM transitions taken from expert practitioners and literature with MS/MS evidence derived from interrogation of a database of peptide identifications and their associated mass spectra. The tool also predicts retention time using a published model, allowing ordering of transition candidates. By exploiting available knowledge and resources to generate the most reliable transitions, this approach negates the need for theoretical prediction of fragmentation and the need to undertake prior "discovery" MS studies. MRMaid is a modular tool built around the Genome Annotating Proteomic Pipeline framework, providing a web-based solution with both descriptive and graphical visualizations of transitions. Predicted transition candidates are ranked based on a novel transition scoring system, and users may filter the results by selecting optional stringency criteria, such as omitting frequently modified residues, constraining the length of peptides, or omitting missed cleavages. Comparison with published transitions showed that MRMaid successfully predicted the peptide and product ion pairs in the majority of cases with appropriate retention time estimates. As the data content of the Genome Annotating Proteomic Pipeline repository increases, the coverage and reliability of MRMaid are set to increase further. MRMaid is freely available over the internet as an executable web-based service at www.mrmaid.info.

Translation of an effective tai chi intervention into a community-based falls-prevention program.

Tai chi--moving for better balance, a falls-prevention program developed from a randomized controlled trial for community-based use, was evaluated with the re-aim framework in 6 community centers. The program had a 100% adoption rate and 87% reach into the target older adult population. All centers implemented the intervention with good fidelity, and participants showed significant improvements in health-related outcome measures. This evidence-based tai chi program is practical to disseminate and can be effectively implemented and maintained in community settings.

Public proteomic MS repositories and pipelines: available tools and biological applications.

As proteomic MS has increased in throughput, so has the demand to catalogue the increasing number of peptides and proteins observed by the community using this technique. As in other 'omics' fields, this brings obvious scientific benefits such as sharing of results and prevention of unnecessary repetition, but also provides technical insights, such as the ability to compare proteome coverage between different laboratories, or between different proteomic platforms. Journals are also moving towards mandating that proteomics data be submitted to public repositories upon publication. In response to these demands, several web-based repositories have been established to store protein and peptide identifications derived from MS data, and a similar number of peptide identification software pipelines have emerged to deliver identifications to these repositories. This paper reviews the latest developments in public domain peptide and protein identification databases and describes the analysis pipelines that feed them. Recent applications of the tools to pertinent biological problems are examined, and through comparing and contrasting the capabilities of each system, the issues facing research users of web-based repositories are explored. Future developments and mechanisms to enhance system functionality and user-interfacing opportunities are also suggested.

Evaluation of a genomics platform for cross-species transcriptome analysis of recombinant CHO cells.

Microarray technology for mammalian cells has been utilized mainly for humans, mouse, and rat gene expression analysis. In this approach the feasibility of cross-species hybridization experiments using Chinese hamster ovary (CHO) cells was evaluated. Sequence alignments of available data for CHO were performed against mouse and rat transcripts to determine the homology between the investigated species. We implemented a probability model based on this homology in order to estimate the chance for successful hybridization using Agilent's 60-mer oligonucleotide platform. Heat-shock expression data from CHO, mouse 3T3, and rat A10 cells were generated to determine intraspecies variability, reproducibility, and specificity in order to assess the accuracy of this method. Detected signature genes, in particular from studies with the mouse arrays, showed a reliable similarity between these two rodents and were confirmed by quantitative RT-PCR. Our findings provide evidence that cross-species analysis can be a useful tool to study gene expression profiles of related organisms for which species-specific microarrays are not available.