Citations

Abstract Background Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and death. The use of low-molecular-weight heparin (LMWH), despite being the standard of care to prevent VTE, comes with some challenges. Shared decision-making (SDM) interventions are recommended to support patients and clinicians in making preference-sensitive decisions. The quality of the SDM process has been widely assessed with the decisional conflict scale (DCS). Our aim is to report participants’ perspectives of each of the components of an SDM intervention (DASH-TOP) in relation to the different subscales of the DCS. Methods Design: A convergent, parallel, mixed-methods design. Participants: The sample consisted of 22 health care professionals, students of an Applied Clinical Research in Health Sciences (ICACS) master program. Intervention: We randomly divided the participants in three groups: Group 1 received one component (evidence -based information), Group 2 received two components (first component and value elicitation exercises), and Group 3 received all three components (the first two and a decision analysis recommendation) of the SDM intervention. Analysis: For the quantitative strand, we used a non-parametric test to analyze the differences in the DCS subscales between the three groups. For the qualitative strand, we conducted a content analysis using the decisional conflict domains to deductively categorize the responses. Results Groups that received more intervention components experienced less conflict and better decision-making quality, although the differences between groups were not statistically significant. The decision analysis recommendation improved the efficacy with the decision-making process, however there are some challenges when implementing it in clinical practice. The uncertainty subscale showed a high decisional conflict for all three groups; contributing factors included low certainty of the evidence-based information provided and a perceived small effect of the drug to reduce the risk of a VTE event. Conclusions The DASH-TOP intervention reduced decisional conflict in the decision -making process, with decision analysis being the most effective component to improve the quality of the decision. There is a need for more implementation research to improve the delivery of SDM interventions in the clinical encounter.

AbstractOral lichen planus (OLP) confers an approximately 1% risk of transformation to oral squamous cell carcinoma (OSCC). Early identification of high‐risk OLP would be very helpful for optimal patient management. We aimed to discover specific tissue‐based protein biomarkers in patients with OLP who developed OSCC compared to those who did not. We used laser capture microdissection– and nanoLC–tandem mass spectrometry to assess protein expression in fixed lesional mucosal specimens in patients with indolent OLP (no OSCC after at least 5‐year follow‐up, n = 6), transforming OLP (non‐dysplastic epithelium with lichenoid inflammation marginal to OSCC, n = 6) or normal oral mucosa (NOM, n = 5). Transforming OLP protein profile was enriched for actin cytoskeleton, mitochondrial dysfunction and oxidative phosphorylation pathways. CA1, TNNT3, SYNM and MB were overexpressed, and FBLN1 was underexpressed in transforming OLP compared with indolent OLP. Integrin signalling and antigen presentation pathways were enriched in both indolent and transforming OLP compared with NOM. This proteomic study provides potential biomarkers, such as CA1 overexpression, for higher‐risk OLP. While further validation studies are needed, we propose that epithelial–mesenchymal transition may be involved in OLP carcinogenesis.

Abstract We have studied the molecular diversity of the allogeneic TCR repertoire specific for the HLA-DR4 variant, DRB1*0404, by analyzing the V beta gene segment usage of CD4+ T cell clones from nine different donors and comparing the V beta repertoire in allospecific and unselected T cell populations. To investigate the forces shaping the repertoire of the alloreactive T cell response we compared the diversity of TCR specificities utilized in very similar and in disparate responder/stimulator combinations. Six of the responders shared the HLA-DRB1*0401 allele, which differs from the HLA-DRB1*0404 allele by only two amino acid substitutions at positions 71 and 86 of the HLA-DR beta 1 chain; three responders expressed HLA-DRB1 alleles with extensive polymorphisms compared with the stimulator HLA-DRB1 allele. In all nine responders, TCR specificities recruited to recognize HLA-DRB1*0404 were strongly biased toward the dominant usage of one to three V beta elements. Despite some degree of heterogeneity between different responders, the overall pattern was very similar with a hierarchy of TCR V beta elements expressed by HLA-DRB1*0404 specific T cells. A core group of V beta elements (V beta 6, 5, 2, 13.2, 18, and 7) was preferentially used, whereas other V beta elements including V beta 3, 4, and 8 were infrequently used or not used at all. Sequencing of the VDJ beta region from selected T cell clones showed no junctional bias associated with the preferential V beta gene segment usage. Surprisingly, the T cell diversity in focused and in complex alloreactive responses were equally biased. The finding that HLA-DR4+ and DR4- donors exhibited a similar bias supports the interpretation that the alpha-helical HLA-DR structure of the stimulator cell has a dominant contribution in shaping the alloreactive repertoire.

ObjectiveRecent evidence supports a link between increased TDP‐43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP‐43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP‐43 pathology and related neurodegeneration in the absence of typical AD pathologies.MethodsWe overexpressed human TDP‐43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe‐knockout (Apoe‐KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP‐43 overexpression‐related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP‐43 pathology in 160 postmortem brains from autopsy‐confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD‐MND) in the Mayo Clinic Brain Bank.ResultsWe found that TDP‐43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe‐KO mice. In the motor cortex of the ALS and FTLD‐MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP‐43‐positive dystrophic neurites.InterpretationOur data suggest a genotype‐specific effect of APOE on TDP‐43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843

Abstract Bone marrow (BM) niche plays critical roles in promoting progression and chemoresistance of multiple myeloma (MM), but the iron metabolism bridging the malignant plasma cells and BM stromal cells (BMSCs) has not been well elucidated. Using in vitro and in vivo models of interaction of MM and BMSCs, we identified that iron level was augmented due to the elevated expression of transferrin in MM cells, and the accumulation of iron desensitized MM cells to proteasome inhibitors (PIs) treatment and promoted productions of cholesterol and lanosterol. Simultaneously, direct contact with BMSCs remarkably upregulated the protein level of GPX4, a ROS eraser, to obviate ferroptosis in MM cells. Mechanistic studies revealed that CD40/CD40 ligand (CD40L) signaling promoted the expressions of transferrin and SUMO-specific protease 3 (SENP3), and SENP3 stabilized GPX4 protein via deSUMOylation modification. GPX4 inhibitor induced ferroptosis was cell-cell contact dependent, since blocking CD40/CD40L interaction, or depletion of Cd40l in BMSCs from Cd40lfl/fl;Prx1Cre/+ mice, eliminated the anti-MM efficacy of RSL3 in the Vk*MYC mouse model of myeloma, but not in the patient-derived xenografts (PDX) model. Our study deciphers mechanism of iron metabolism in regulating MM chemoresistance, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

Objective To examine the utility of telemedicine in a tertiary otologic practice. Study Design Retrospective case series. Setting Tertiary neurotology clinic. Patients Consecutive adult patients presenting via video visit between January 2020 and January 2021. Intervention(s) Televideo modality to conduct visits with patients seeking evaluation for new concerns, second opinions, or routine follow-up for established conditions. Main Outcome Measure(s) Success of the televideo visit defined by the televideo visit being sufficient for determining a definitive plan and not requiring deferment of recommendations for a subsequent in-person visit. Results A total of 102 televideo visits were performed among 100 unique patients. Of those, 92 (90.2%) visits were for second opinions or evaluation of new concerns, most commonly for vestibular schwannoma (n = 32, 31.4%), followed by sensorineural hearing loss (n = 20, 19.6%). Other visits were conducted for early postoperative follow-up and established general follow-up. In 91.2% of cases (n = 93), patients were successfully evaluated and provided recommendations from the initial video visit. All visits with patients having a diagnosis of meningioma (n = 7), and nearly all with vestibular Schwannoma (97%, n = 31) and sensorineural hearing loss (95%, n = 19) were successful. Of the 79 patients offered surgery as one potential treatment option, 31 patients underwent surgery at our institution by time of review. Patients with unsuccessful visits (n = 9, 8.8%) were advised to schedule additional in-person diagnostic imaging, vestibular testing, or cochlear implant candidacy evaluation to establish a more definitive care plan. Conclusion Virtual televideo visits were successful for a high percentage of selected patients seen at a tertiary neurotology practice, particularly those seeking evaluation of vestibular schwannoma or sensorineural hearing loss.