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Introduction Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress. Methods We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations. Results To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in >1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers. As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5). We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5). 11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years. Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5). Conclusion Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Objective: This single-arm, pre–post interventional trial (clinicaltrials.gov, NCT04515095) investigates the safety, feasibility, and potential effectiveness of prolonged water-only fasting followed by a whole-plant-food diet in the long-term management of hypertension and other cardiometabolic disorders. Methods: Safety was assessed based on adverse events (AEs) that were recorded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Feasibility was assessed based on retention rate, ability to complete minimal fast length, and intervention acceptability. Twenty-nine participants with stage 1 and 2 hypertension and without type 2 diabetes were enrolled from a residential fasting center. Results: Study retention was 100% at the end of the refeed and 93% at the six-week follow-up visit. Median (range) fasting and refeeding duration were 11 (7–40) and 5 (3–17) days, respectively, and 90% of participants were able to complete at least 7 days of fasting. The majority of AEs were mild (grade 1) and transient and there were no higher-grade or serious AEs. At the end of the intervention, median systolic/diastolic blood pressure had normalized to below 130/80 mmHg, body weight reduced by >5%, and anti-hypertensive medication was completely discontinued. These results were sustained for at least six weeks and potentially up to one year. Conclusions: Our data suggest that the intervention may be a feasible, well-tolerated, low-risk option for lowering and managing high blood pressure, excess body weight, and other cardiometabolic disorders in people with stage 1 and 2 hypertension.

A BSTRACT Purpose/Background: To identify the proportion of patients with prediabetes who have prescribed metformin and factors related to doing so as a preventive measure for diabetes in primary care at a Family Medicine Unit in northeastern Mexico. Methods: This retrospective observational study included 372 adults who met the criteria for prediabetes diagnosis according to the American Diabetes Association. Data was collected from medical records from January 2020 to December 2021. Possible associations between the variables of interest and the prescription of metformin were tested via hypothesis tests, furthermore, binary logistic regression was performed. Results: Nearly 85% of the patients met at least one criterion for receiving metformin according to ADA recommendations, but only 60% of them were prescribed this medication. Patients with metformin prescriptions differed from those without in aspects such as having a documented diagnosis of prediabetes in their medical records, a higher BMI, and higher glucose levels. Conclusions: Almost one out of two patients with a high risk of type 2 diabetes are not treated with metformin as a preventive measure. Factors associated with metformin prescription included a high BMI, elevated baseline glucose levels, and a prediabetes diagnosis in the medical record. These findings suggest the need for studies to evaluate physicians’ reasons for different treatments and implementation of recommendations for type 2 diabetes prevention in patients with prediabetes in primary health care.

Abstract T cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary Thymic Epithelial Cells (mTEC) of the thymus. AIRE induces expression of SELF peripheral tissue-specific antigens for presentation to naïve T cells to promote activation/deletion of potentially autoreactive T cells. We show, for the first time to our knowledge, that tumors mimic the role of AIRE in mTEC to evade immune rejection. Thus, by expressing a broad range of SELF epitopes against which minimal functional T cell reactivities exist because of thymic deletion, AIRE acts as a master controller of SELFNESS, effectively cloaking the tumor from T cell attack. Moreover, we describe a completely novel immunotherapy in which engineered changes in AIRE expression in tumor cells alters their profile of SELFNESS, exposing both AIRE-modified, and parental unmodified, tumor cells to T cell attack. Consistent with our studies, patient RNAseq shows expression of AIRE predicts response to immune therapies with a strong correlation between AIRE expression and markers of TCR signaling. Therefore, by re-setting the immunological SELFNESS of cancer cells, this novel AIRE-mediated immunotherapy 1). converts a highly tolerized T cell compartment into a heteroclitic tumor-reactive T cell population; 2) confers de novo sensitivity to immune checkpoint blockade upon non-immunogenic tumors; 3). completely removes the need to identify potentially immunogenic tumor-associated antigens as targets for generation of de novo CD8+ and helper CD4+ T cell responses; and 4) leads to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors.

Abstract Background The NIH Pragmatic Trials Collaboratory supports the design and conduct of 31 embedded pragmatic clinical trials, and many of these trials use patient-reported outcome measures (PROMs) to provide valuable information about the patients' health and wellness. Often these trials enroll medically underserved patients, including people with incomes below the federal poverty threshold, racial or ethnic minority groups, or rural or frontier communities. Objectives In this series of trial case reports, we provide lessons learned about collecting PROMs in these populations. Unbiased collection of PROM data is critical to increase the generalizability of trial outcomes and to address health inequities. Use of electronic health records (EHRs) and other digital modes of PROM administration has gained traction. However, engagement with these modes is often low among populations prone to disparity due to lower digital proficiency, device access, and uptake of EHR portals and web interfaces. Methods To maximize the completeness and representativeness of their trial outcome data, study teams tested a range of strategies to improve PROM response rates with emphasis on disparities prone and underserved patient groups. This manuscript describes the approaches, their implementation, and the targeted populations. Conclusion Optimized PROM collection required hybrid approaches with multiple outreach modes, high-touch methods, creativity in promoting digital uptake, multimodal participant engagement, and text messaging.

Abstract Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic value of increased LV elastance at rest in patients with HCM. Methods We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure. Results At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force > median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (<3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (>7.8 mmHg/mL), see figure. Conclusion HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients. Table Legends E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles

Background: Long-lived, re-activatable immunity to SARS-CoV-2 and its emerging variants will rely on T cells recognizing conserved regions of viral proteins across strains. Heterologous prime–boost regimens can elicit elevated levels of circulating CD8+ T cells that provide a reservoir of first responders upon viral infection. Although most vaccines are currently delivered intramuscularly (IM), the initial site of infection is the nasal cavity. Methods: Here, we tested the hypothesis that a heterologous prime and boost vaccine regimen delivered intranasally (IN) will generate improved immune responses locally at the site of virus infection compared to intramuscular vaccine/booster regimens. Results: In a transgenic human ACE2 murine model, both a Spike-expressing single-cycle adenovirus (SC-Ad) and an IFNß safety-enhanced replication-competent Vesicular Stomatitis Virus (VSV) platform generated anti-Spike antibody and T-cell responses that diminished with age. Although SC-Ad-Spike boosted a prime with VSV-Spike-mIFNß, SC-Ad-Spike alone induced maximal levels of IgG, IgA, and CD8+ T-cell responses. Conclusions: There were significant differences in T-cell responses in spleens compared to lungs, and the intranasal boost was significantly superior to the intramuscular boost in generating sentinel immune effectors at the site of the virus encounter in the lungs. These data show that serious consideration should be given to intranasal boosting with anti-SARS-CoV-2 vaccines.

Abstract As cancer patients with intracranial metastatic disease experience increasingly prolonged survival, the diagnosis and management of recurrent brain metastasis pose significant challenges in clinical practice. Prior to deciding upon a management strategy, it is necessary to ascertain whether patients have recurrent/progressive disease vs adverse radiation effect, classify the recurrence as local or distant in the brain, evaluate the extent of intracranial disease (size, number and location of lesions, and brain metastasis velocity), the status of extracranial disease, and enumerate the interval from the last intracranially directed intervention to disease recurrence. A spectrum of salvage local treatment options includes surgery (resection and laser interstitial thermal therapy [LITT]) with or without adjuvant radiotherapy in the forms of external beam radiotherapy, intraoperative radiotherapy, or brachytherapy. Nonoperative salvage local treatments also range from single fraction and fractionated stereotactic radiosurgery (SRS/FSRS) to whole brain radiation therapy (WBRT). Optimal integration of systemic therapies, preferably with central nervous system (CNS) activity, may also require reinterrogation of brain metastasis tissue to identify actionable molecular alterations specific to intracranial progressive disease. Ultimately, the selection of the appropriate management approach necessitates a sophisticated understanding of patient, tumor, and prior treatment-related factors and is often multimodal; hence, interdisciplinary evaluation for such patients is indispensable.