Citations

Background/Objectives: Multi-cancer detection (MCD) tests have emerged as a promising tool to redefine the landscape of early cancer detection. Implementation of this novel technology will likely fall to primary care clinicians (PCC). The purpose of this study is to characterize and explore differences in PCCs perceptions and preferences towards MCD testing. Methods: Between March and May of 2023, this cross-sectional survey was administered to 281 PCCs, including physicians and advanced care providers practicing within an integrated healthcare system spanning five states. The survey collected data on self-reported characteristics, perceptions of MCD testing, and preferences for learning about MCD testing. Analysis was limited to those with no prior experience with MCD testing (N = 181, response rate 22.8%). Descriptive statistics summarized key variables and chi-square tests assessed differences in perceptions and preferences by key characteristics. Results: Most PCCs were interested in MCD testing (66.3%), but limited knowledge/awareness of MCD testing and confidence to manage patients with a positive test were observed, along with concerns around cost (76.7%) and misuse/poor implementation. The primary preferences for learning about MCD testing were online courses or classroom instruction (64.5%). Significant differences in perceptions and preferences for learning were observed by location, degree, and years in practice. Conclusions: PCCs in our study held positive views towards MCD testing, but gaps and variation in knowledge and confidence towards MCD testing and concerns around the cost and misuse/poor implementation were observed. While efforts to train and educate all PCCs on MCD testing is a critical first step, more research is needed to understand how best to support implementation tailored to individual and system-level needs and characteristics.

Abstract Objectives Emotional impairments in people with dementia can be taxing for family caregivers. However, caregivers differ in their resilience to these challenges. We previously found that, compared to healthy controls and people with Alzheimer’s disease, people with frontotemporal lobar degeneration (FTLD) have smaller physiological responses when anticipating upcoming emotional stimuli. This impairment may leave these people with FTLD unprepared for upcoming emotional stimuli because they cannot mount responses needed for appropriate behaviors, which may create stress and difficulties for caregivers. We examined (a) whether smaller preparatory physiological responses in people with dementia are associated with lower emotional well-being and physical functioning in caregivers; and (b) whether these associations are moderated by the dyads’ relationship quality. Methods A total of 158 individuals with FTLD or Alzheimer’s disease and their family caregivers participated. Preparatory physiological responses in people with dementia were quantified as decreases in cardiac interbeat intervals from baseline to an instruction period, during which they were told they would be watching an upcoming emotional film. Caregivers self-reported their emotional well-being, physical functioning, and relationship quality with the people with dementia. Results Smaller preparatory physiological responses in people with dementia were associated with lower emotional well-being (but not physical functioning) in caregivers. This association was moderated by relationship quality (i.e., weakened for caregivers in higher-quality relationships). Discussion Findings advance understanding of risk and resilience factors for negative caregiver outcomes. Positive interpersonal processes in high-quality relationships (e.g., positive appraisal of aberrant behaviors) may buffer caregivers from the impact of emotional impairments in people with dementia.

ABSTRACT Herpes simplex virus type 1 replicates in the nucleus of the host cell and utilizes many cellular proteins to facilitate DNA replication. HSV-1 DNA replication is closely linked with homologous recombination, and HSV-1 encodes a two-subunit recombinase consisting of an exonuclease (UL12) and a single-strand DNA-binding protein (ICP8). We identified the cellular deubiquitinating enzyme USP15 as a new UL12-binding partner. USP15 is one of the most enriched proteins on viral DNA and has recently been implicated in regulating cellular homologous recombination. Utilizing isolation of proteins on nascent DNA (iPOND) to compare the proteins on wild-type and UL12-deficient viruses, we observed that USP15 is not recruited to newly replicated DNA in the absence of UL12. We also observed that UL12 and USP15 interact directly in vitro using purified proteins. Together, these data suggest that UL12 directly recruits USP15 to viral DNA. UL12 stimulates a type of homology-directed repair called single-strand annealing (SSA). We generated a USP15 knockout cell line with an integrated GFP-based SSA reporter and observed that UL12 and USP15 both contribute to the maximal induction of SSA. In addition to the reporter cell line, there is a 10-fold reduction in the frequency of marker rescue, and individual replication forks move slower in the absence of USP15. These data support a role for USP15 in facilitating recombination during the virus life cycle and the maintenance of replication fork stability. IMPORTANCE HSV-1 is a ubiquitous pathogen in the global population that causes lifelong latent infection with sporadic reactivation in the host. It has long been appreciated that HSV-1 DNA replication exhibits high rates of recombination and is linked to the host DNA damage response. In this study, we show a novel interaction between UL12, a member of the HSV recombinase, and the deubiquitinating host enzyme USP15. We show that USP15 physically interacts with UL12 and is required for UL12 to maximally stimulate recombination. In the absence of USP15, we also observe an overall reduction in virus growth. This work demonstrated that host proteins facilitate viral-induced recombination. The interaction of USP15 with UL12 represents a potential target for intervention against HSV-1 infection and associated disease.

Introduction Given the rising incidence and importance of treatment adherence for gestational diabetes (GDM), this study aimed to examine patient perspectives on social support's role in gestational diabetes (GDM) management during pregnancy and early postpartum. Methods This is an analysis of qualitative data collected during a feasibility randomized controlled trial of postpartum patient navigation for individuals with GDM. Participants completed semistructured interviews at 4 to 12 weeks postpartum on their experiences with GDM as well as facilitators and barriers to its management, including social support. Data were analyzed using the constant comparative method. Results Of 38 participants, 55% reported a family member or friend with a history of GDM, type 1, or type 2 diabetes mellitus. The analysis identified 4 themes: (1) communal support, (2) indirect GDM support (ie, removing logistical barriers to care), (3) direct GDM support, and (4) barriers of social support (eg, stigma), which impeded disease understanding. Participants identified communal support as a catalyst for lifestyle change and a source for advice and emotional support. Indirect support included transportation, childcare, and work accommodations. Direct support included providing healthy food, giving insulin shots, or providing accountability. Discussion Harnessing social support may be a key strategy to activate and sustain lifestyle and self‐management skills in GDM and should be considered in intervention development.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

ABSTRACT Background A novel individualized antitachycardia pacing (IATP) algorithm using the post‐pacing interval for real‐time control has been introduced. Performance information is limited to a small safety and feasibility study with additional single‐center and case studies. A larger‐scale analysis is needed to better understand algorithm performance. Methods Deidentified remote monitoring transmissions from devices with the IATP therapy applied were randomly selected. Rhythms were classified and effects of the novel algorithm were assessed. For monomorphic ventricular tachycardias (MVTs) proportions of successful therapy, shock‐free episodes, and acceleration were calculated using generalized estimating equations to correct for multiple episodes and compute statistics of the algorithm's performance. Results There were 2259 MVT episodes in 336 patients. IATP succeeded in 87.1% of MVT episodes with 89.9% of MVT episodes ultimately free of shock therapy. Based on multivariate analysis, significant factors in therapy success were programming of at least the recommended number of sequences (90% at least recommended vs 73%, p = 0.00088) and female sex (95% for females vs 86%, p = 0.002). A trend to higher success was found for MVT with a cycle length of 320 ms or greater (90% vs. 83%, p = 0.10). The IATP accelerated 3.6% of MVT episodes. None of the available factors was significantly associated with acceleration in the multivariate analysis. Conclusions The IATP algorithm succeeded in a large proportion of MVT episodes and with low acceleration in patients randomly selected from remote monitoring transmissions. Using at least the recommended number of sequences had the strongest association with successful therapy.