Citations

AbstractIntroduction/AimsMost persons with amyotrophic lateral sclerosis (ALS) live at home with support of family caregivers, with escalating complexity of care over the trajectory of the disease requiring resources and support to mitigate negative physical, social, and emotional outcomes.MethodsThis scoping review identifies the home health/home care needs of persons with ALS and their caregivers as a basis for creating a home health medical standard. We used the PRISMA Extension for Scoping Reviews (PRISMA‐ScR) to examine studies describing home care needs published between 2011 and 2021.ResultsOur search yielded 481 articles, of which 44 were included with a total of 3592 (9–273) participants. Most studies used a cross‐sectional design and 20 (45%) were rated as high quality. We grouped the needs identified as emotional/psychological, assistive devices and technology, information and education, and human resources and professional services. Most studies demonstrated persistent unmet needs and that available interventions were helpful while needs generally were not met proactively, despite the predictable trajectory.DiscussionThis review describes biopsychosocial and equipment interventions over the trajectory of ALS with implications for anticipatory planning by clinicians, as well as policy for coverage of necessary services and supports. Interdisciplinary expert teams could develop consensus around needs across the trajectory and recommended services and supports. To make knowledge more accessible, encourage availability of services, and clarify the need for coverage of services, we aim to develop an expert consensus‐based ALS home health medical standard guidance document in collaboration with the American Association of Neuromuscular and Electrodiagnostic Medicine.

Objective: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. Background and Aims: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. Methods: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA (CEACAM5) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. Results: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41–59%) and lower specificities (56–96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. Conclusions: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Abstract Background No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture–based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection. Methods We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts. Results Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP. Conclusions This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture–based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

AbstractBackgroundTo determine the impact of personalized risk communication and opioid prescribing on nonprescribed opioid use, we conducted a secondary analysis of randomized controlled trial participants followed prospectively for 90 days after an emergency department (ED) visit for acute back or kidney stone pain.MethodsA total of 1301 individuals were randomized during an encounter at four academic EDs into a probabilistic risk tool (PRT) arm, a narrative‐enhanced PRT arm, or a general risk information arm (control). In this secondary analysis, both risk tool arms were combined and compared with the control arm. We used logistic regressions to determine associations between receiving personalized risk information, receiving an opioid prescription in the ED, and nonprescribed opioid use in general and by race.ResultsComplete follow‐up data were available for 851 participants; 23.3% (n = 198) were prescribed opioids (34.2% of White vs. 11.6% of Black participants, p < 0.001). Fifty‐six (6.6%) participants used nonprescribed opioids. Participants in the personalized risk communication arms had lower nonprescribed opioid use odds (adjusted odds ratio [aOR] 0.58, 95% confidence interval [CI] 0.4–0.83). Black versus White participants had greater nonprescribed opioid use odds (aOR 3.47, 95% CI 2.05–5.87, p < 0.001). Black participants who were prescribed opioids had a lower marginal probability of using nonprescribed opioids versus those who were not (0.06, 95% CI 0.04–0.08, p < 0.001 vs. 0.10, 95% CI 0.08–0.11, p < 0.001). The absolute risk difference in nonprescribed opioid use for Black and White participants, respectively, in the risk communication versus the control arm, was 9.7% and 0.1% (relative risk ratio 0.43 vs. 0.95).ConclusionsAmong Black but not White participants, personalized opioid risk communication and opioid prescribing were associated with lower odds of nonprescribed opioid use. Our findings suggest that racial disparities in opioid prescribing—which have been previously described within the context of this trial—may paradoxically increase nonprescribed opioid use. Personalized risk communication may effectively reduce nonprescribed opioid use, and future research should be designed specifically to explore this possibility in a larger cohort.

Abstract Background Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding. Materials and Methods Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation. Results Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P &lt; .01), stomach (OR 0.40, 95% CI 0.23-0.70, P &lt; .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P &lt; .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P &lt; .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P &lt; .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials. Conclusions Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

Abstract We have engineered an attenuated picornavirus vaccine using Theiler’s murine encephalomyelitis virus (TMEV) and are exploring its usefulness in immunotherapy. We find that two different insertion sites within the leader protein of the TMEV genome allow for effective production of virus vaccine strains. One site is at the amino terminal end of the protein after the third amino acid position (p3); the other is at the XhoI restriction site further downstream. We find that vaccine antigen insertion at p3 disrupts the ability of the virus to inhibit type I interferon production by infected cells, whereas XhoI insertion does not. Further, the p3 modified virus can be cleared from animals lacking functional T and B-cells but replicates to high titer in IFNα/β receptor knockout mice, suggesting that innate immune mechanisms are sufficient for viral clearance. In spite of rapid clearance, p3 vaccines readily stimulate proliferation of transgenic T-cells and induce de novo responses to T-cell antigens in wild-type mice, although to a lesser extent than the XhoI modified vaccines strains. The use of either vaccine however effectively delays tumor growth and enhances survival in mice bearing melanoma and breast tumors. This vaccine provides a safe and effective vaccine strategy for the induction of CD8+ T-cell immunity directed towards cancer and provides support for the development of picornaviruses as vaccine vectors for treating human disease.

Abstract IgM antibodies, as multivalent ligands, have the capacity to activate cells differentially by cross-linking targeted cell surface signaling molecules. For example, hIgM12 (B7DC Xab) activates dendritic cells (DCs), leading to potent immunomodulation, while hIgM22 binds glial cells and causes remyelination in mouse models of multiple sclerosis. Both antibodies activate common signaling intermediates in their respective cellular targets suggesting a common mechanism of action. Elucidation of these shared mechanisms became possible by targeting both antibodies to a common cell type. Our previous studies demonstrate that B7-DC expression is required to activate downstream signaling in DCs by hIgM12. We utilized a phage display system to identify 7mer peptides bound by each IgM and expressed each peptide attached to a surrogate cell surface carrier on retrovirally tranduced bone marrow-derived DCs from B7-DC -/- mice. Transduced cells were treated with hIgM12, hIgM22 or anti-carrier IgM, and subsequent activity was compared against B7-DC +/+ DCs or B7-DC-reconstituted B7-DC -/- DCs. DC activation by each IgM was specific to expression of their conjugate peptide construct. Activation by hIgM22 was indistinguishable from activation by hIgM12, while anti-carrier IgM caused no activation. This indicates that while their target specificity differs, once bound these IgMs activate cells via common mechanisms.

Abstract One limitation to the development of targeted tumor immunity is the availability of safe vectors that can drive strong T-cell responses capable of eradicating tumors. We have designed viral vectors using Theiler’s murine encephalomyelitis virus (TMEV) that effectively inhibit melanoma outgrowth. By cloning the TMEV genome into a eukaryotic expression vector that can easily be manipulated we were able to generate several novel tumor specific virus vaccines. We find that incorporation of defined MHC class I epitopes into sites within the leader protein of the virus can drive strong CD8+ T-cell responses against these target peptides. Further, we find that the site of incorporation can change the elicited cytokine profile and the virulence of the virus. Incorporation of the ovalbumen peptide after the third amino acid of the L protein (p3) generates a strong IFNβ response, whereas insertion within the downstream XhoI restriction site elicits a strong IL6 response similar to wild-type TMEV. Further, the p3 virus is not lethal to RAG-deficient mice, where the XhoI and wild-type TMEV virus are. However, p3 virus persists and kills IFNα/β receptor-deficient mice, suggesting that innate immune responses are responsible for viral clearance. In spite of these differences the p3 and XhoI viruses can stimulate antigen specific T-cell responses and inhibit tumor outgrowth equivalently, demonstrating the efficacy of TMEV and its potential as a therapeutic intervention.

Abstract To evaluate the potential functional role of the alpha- and beta-chain N-linked oligosaccharides we used site-directed mutagenesis to construct class II Ak alpha and Ak beta genes that encode polypeptides with altered N-linked oligosaccharide acceptor sites in the N-terminal domain of both polypeptides. The alpha 1 domain acceptor site at positions 82 to 84 was eliminated by substituting Gln for Asn at position 82. The beta 1 domain acceptor site at positions 19 to 21 was deleted by substituting Gln for Asn at position 19 or Ala for Thr at position 21. The mutant genes (Ak alpha* or Ak beta*) were transfected either individually (mutants T.19, T.21, and T.82) or together (mutant T.82-21) into class II cell surface negative B lymphoma cell lines. Quantitative immunofluorescence with a panel of Ak beta- or Ak alpha- reactive mAb demonstrated that although the oligosaccharide-deleted Ak alpha Ak beta molecules were serologically wild type, the Ad alpha serologic epitope defined by mAb K24-199 was eliminated in both the T.19 and T.21 Ak beta* Ad alpha molecules. Cloned cell lines expressing the T.19 or T.21 Ak beta* Ak alpha molecules exhibited limited functional Ag presentation defects. Cells expressing the T.82 Ak alpha* Ak beta molecules exhibited defects in Ag presentation function to nine of the ten T hybridomas tested. Surprisingly, cells expressing the mutant T.82-21 class II molecule stimulated a response that was equal to the wild-type response from three of the nine T hybrids and a response that was significantly greater than that of wild-type cells from five of nine T hybridomas. These functional and serological analyses also indicate that some of the observed Ag presentation defects may be due to altered secondary structure caused by either deletion of the oligosaccharide or the amino acid substitution used to delete the N-linked oligosaccharide acceptor site.