Citations

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

BACKGROUND Previous epidemiologic studies of autoimmune diseases in the US have included a limited number of diseases or used metaanalyses that rely on different data collection methods and analyses for each disease. METHODS To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from 6 large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time. RESULTS Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least 1 autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than 1 autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age. CONCLUSION Here, we provide, for what we believe to be the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age. FUNDING Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.

Abstract Objectives Patients with hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) experience a wide array of symptoms and system disorders. This study aimed to identify whether differences occurred in 115 self-reported symptoms and comorbidities in patients diagnosed with hEDS or HSD. Methods In this study we analysed self-reported data from an EDS Clinic intake questionnaire in patients diagnosed with hEDS, HSD or no hypermobile conditions. Results From 1 November 2019 to 7 March 2024, the EDS Clinic saw 2088 patients. Using the 2017 diagnostic criteria, 66.5% were diagnosed with HSD (n = 1389), 20.3% with hEDS (n = 423), 10.6% with historic HSD (H-HSD) or localized HSD (L-HSD) (n = 256) (hypermobile controls) and 2.6% were not diagnosed with hEDS, HSD, H-HSD or L-HSD (n = 55) (controls). Symptoms/comorbidities that occurred with high prevalence in both hEDS and HSD included joint pain (hEDS 82.0%, HSD 88.9%), allergy (hEDS 77.0%, HSD 77.0%), subluxations (hEDS 71.2%, HSD 72.6%), brain fog (hEDS 70.0%, HSD 74.7%), headache (hEDS 68.1%, HSD 69.1%), anxiety (hEDS 60.3%, HSD 69.3%), depression (hEDS 52.2%, HSD 58.0%), migraine (hEDS 53.7%, HSD 52.5%), nausea (hEDS 54.6%, HSD 59.5%) and constipation (hEDS 53.0%, HSD 57.2%). In contrast, 9/115 (8%) symptoms/comorbidities were self-reported significantly more often in hEDS but 42/115 (37%) in HSD. hEDS patients reported more symptoms that suggest a defect in collagen, such as dislocation, hernias and rectal prolapse, while HSD patients reported more joint, muscle, allergy, neurological, gastrointestinal, sleep and psychological symptoms/comorbidities. Conclusion Although we found an overlap in some symptoms and comorbidities self-reported by hEDS/HSD patients, such as allergy/atopy, headache/migraine and gastrointestinal symptoms, our findings suggest key differences exist between the two diagnoses, suggesting that hEDS and HSD may be distinct conditions.

Abstract Context Diagnosing adrenal insufficiency (AI) often requires complex testing, which can be time-consuming and expensive. Dehydroepiandrosterone sulfate (DHEAS) is a promising marker of hypothalamic-pituitary-adrenal axis function; however, its diagnostic performance has not yet been evaluated in a large-scale study. Objective Evaluate the performance of DHEAS and baseline cortisol in assessing AI. Design Single-center retrospective cohort study. Setting Referral center. Patients Adults who underwent cosyntropin stimulation testing (CST) between 2005 and 2023 and had DHEAS measured within 3 months prior to CST. Main Outcome Measures Area under receiver operating characteristic curve (AUROC) for DHEAS and baseline cortisol. Prevalence of AI based on various DHEAS and baseline cortisol concentrations. Results Among 1135 patients, 195 (17.2%) had AI. Both baseline cortisol and DHEAS independently had good diagnostic performance with AUROC 0.81 [95% confidence interval (CI) 0.77-0.84 and 0.81 (95% CI 0.78-0.85)], respectively. Time of CST performance had no significant effect on diagnostic accuracy of baseline cortisol while recent glucocorticoid use decreased diagnostic performance of DHEAS (AUROC 0.72 vs 0.83). Only 1.2% of patients with baseline cortisol ≥10 mcg/dL had AI based on CST. Among patients with baseline cortisol between 5 and 9.9 mcg/dL, only 1.3% had AI if DHEAS was ≥60 mcg/dL. Conversely, the majority (72.2%) of patients with both baseline cortisol <5 mcg/dL and DHEAS <25 mcg/dL were found to have AI. Conclusion DHEAS has good diagnostic performance in assessing AI. Measuring both baseline cortisol and DHEAS concentrations may eliminate the need for further dynamic testing in many patients.

In this case series, we present several examples from participants (2 patients and 1 healthy control) of a 12-week pilot feasibility study to create a digital phenotype of depression (unipolar or bipolar) through active and passive data collection from a smartphone and a wearable device combined with routine clinical care for mood disorders. The selected cases represent real clinical examples that highlight the intrinsic challenges that should be expected when conducting similar studies, including appropriate health data privacy protection, clinical standardization, and interindividual differences in levels of engagement and acceptability of active and passive data collection (ie, self-reported, behavioral, cognitive, and physiological data), particularly with patient-generated data in mobile apps, digital proficiency habituation, and consistent use of wearable devices. In the context of the rapidly growing use of digital technologies in psychiatry, anticipating challenges for the integration of personal mobile devices and smartphone mental health apps as aides to track specific aspects of depressive disorders is critical for a clinically meaningful digital transformation of mood disorders care.

OBJECTIVE To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring. RESEARCH DESIGN AND METHODS At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks. RESULTS Prestudy, AID was used by 48% and MDI by 45%. Mean ± SD HbA1c was 7.57% ± 0.97% at baseline and 7.62% ± 1.06% at 17 weeks in the TI group and 7.59% ± 0.80% and 7.54% ± 0.77%, respectively, in the UC group (adjusted difference 0.11%, 95% CI −0.10 to 0.33, P value for noninferiority = 0.01). HbA1c improved from baseline to 17 weeks by >0.5% (5.5 mmol/mol) in 12 (21%) in the TI group and in 3 (5%) in the UC group and worsened by >0.5% (5.5 mmol/mol) in 15 (26%) in the TI group and in 2 (3%) in the UC group. The most common TI side effect was a brief cough; eight participants discontinued TI due to side effects. CONCLUSIONS In adults with type 1 diabetes, HbA1c after 17 weeks with a regimen of TI and degludec was noninferior to UC, which consisted predominately of either AID or MDI. TI should be considered an option for people with type 1 diabetes, particularly those who are motivated to further reduce postprandial hyperglycemia.

Background: The BeatAML Master Trial (BAMT) began in 2016 with a goal of determining the feasibility of a precision-medicine approach in treating acute myeloid leukemia (AML) in older adults ≥ 60 years of age where outcomes are poor. At the time, standard of care (SOC) for older patients with AML was intensive 7+3 chemotherapy (cytarabine + daunorubicin) if fit and hypomethylating agents (HMA: azacitidine or decitabine) if unfit. Besides confirming the feasibility, the early results (2019) from the Master Trial suggested that patients who received therapy on one of the sub-studies had a lower early death rate and superior overall survival compared to patients receiving off-protocol SOC, which was primarily single-agent HMA at the time. Since then, the 2019 approval of venetoclax (ven) + azacitidine for older unfit AML patients has been transformative and emerged as the SOC. Using data from the BAMT from 2016-2024, we suggest that knowing the comprehensive genomic profile of AML at the time of diagnosis is still beneficial in determining therapy that would lead to the optimal outcome and that development of targeted therapies and combination regimens with ven/HMA is still needed. Methods: This is a retrospective analysis of 1096 patients who consented and enrolled on the BAMT (NCT03013998) from Nov 2016 through Jun 2024. Patients ≥ 60 years with newly diagnosed AML were included. Patients underwent therapy on a BeatAML sub-study based on their genetics (N=433) or treatment off-protocol (N=663). We divided the patients according to what therapy they received: (1) Non-Intensive (Off-Protocol, N=121), (2) Ven/HMA (Off-Protocol, N=234), (3) Non-Intensive (Sub-Study, N=407), (4) Intensive (Sub-Study, N=26), and (5) Intensive (Off-Protocol, N=155). 94 patients received no treatment and 59 were unknown. Non-intensive therapies included primarily targeted agents or non-ven combinations. We analyzed baseline characteristics and demographics, overall survival (OS), and the impact of allogenic stem cell transplant (SCT). OS, using Kaplan-Meier method, was measured from the start of therapy to all-cause death, censoring patients at last follow-up. Results: Characteristics and demographics were similar between Groups 1, 2 and 3. Group 4 and 5 were treated with intensive chemotherapy and their characteristics are reflective of younger/fit patients appropriate for the intensive regimen. Groups 4 and 5 also had the longest median OS (mOS) of 40.2 months (95% CI: 13.9-not reached (NR)) and 42.3 months (95% CI: 25.1-NR) respectively. Group 3, which included patients treated with a non-intensive, targeted therapy on a sub-study, had an mOS of 14.0 months (95% CI: 12.3-16.7), which was similar to Group 2, treated with Ven/HMA, that had an mOS of 13.2 months (95% CI: 10.9-16.3). Lastly, patients in Group 1, who were treated primarily with HMA monotherapy, did poorly in comparison, with an mOS of 6.0 months (95% CI: 3.3-10.1). Additionally, we looked at the cumulative incidence rate (CIR) of SCT. The CIR in 12 months of Group 1 was 9.8% (95% CI: 6.9-13.4), Group 2: 5.4% (95% CI: 2.2-10.7), Group 3 and 4 combined: 35.0% (95% CI: 628.1-42.1), and Group 5: 13.1% (95% CI: 6.9-13.4). In a multi-variable analysis, after adjusting for typical favorable risk factors like NPM1 mutations and core binding factor, SCT was highly significant (p<0.0001) in improving OS with a hazard ratio of 0.23 (95% CI: 0.16-0.32), and Group 3 performed similarly to Group 2 (p=0.20). Conclusions: First, our results suggest that it is clinically relevant to correctly identify whether an intensive chemotherapy, targeted-therapy, or ven/HMA regimen is best suited for older AML patients, for which a precision-medicine trial is ideal for. Secondly, in this group of patients, our results show that patients treated with a non-intensive targeted therapy (Group 3) has a similar mOS to those treated with ven/HMA (Group 2). Especially after controlling for patient characteristics, patients in Group 2 performed similar to those in Group 3 (p=0.20). Patients in Group 3 were treated on Beat AML sub-studies which included targeted therapy alone or with non-venetoclax combinations, which is a strong rationale for continued development of targeted agents to optimize toxicity and quality of life with similar survival. Lastly, this data also supports the need to improve the ven/HMA SOC by developing combination regimens with targeted agents to further improve outcomes.

Background: Mutations of isocitrate dehydrogenase (IDH) are recurrent in acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH1 and IDH2 mutations remains controversial. IDH inhibitors are small molecules that bind within the IDH enzymatic active site, blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation. While they can lead to differentiation syndrome, they generally have a more favorable side-effect profile, making them an attractive option for older patients. We aimed to describe the prevalence and prognostic impact of IDH mutations in newly diagnosed (ND) AML patients ≥ 60 years in a large cohort of patients treated on a Leukemia and Lymphoma Society-sponsored trial. Methods: We performed a retrospective observational analysis including patients ≥ 60 years with ND AML who were enrolled on the Beat AML clinical trial (NCT03013998) before May 10, 2023. Patients were treated with a variety of treatment regimens. Cytogenetic analysis and next-generation sequencing (FoundationOne®Heme) were obtained. Mutations were considered present at any detectable VAF. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion. Results: A total of 1023 patients with ND AML were identified. Patients had a median age of 72 (range 60-92) years and the majority were non-Hispanic White (83.2%), and male (57.6%). Ninety-nine (9.7%) patients were IDH1MUT, 193 (18.9%) patients were IDH2MUT including 10 (1.0%) patients with a co-occurring IDH1 and IDH2 gene mutations. Both IDH1MUT and IDH2MUT were associated with 2022 ELN favorable-risk (26.3% and 22.3% for IDH1 and IDH2 respectively, vs 15.5% overall (P<0.001)). IDH1MUT significantly co-occurred with DNMT3AMUT (42.4%), NPM1MUT (44.4%) and less frequently with TP53MUT (10.1%) (P<0.001 for all). IDH2MUT was associated with DNMT3AMUT (35.8%), NPM1MUT (31.1%), SRSF2MUT (38.3%), and less frequently with TET2MUT (6.7%) and TP53MUT (9.3%) (P<0.001 for all). Normal karyotype was higher in IDH1MUT (P<0.001) and IDH2MUT (P<0.001), whereas complex karyotype (P<0.001 for both) and core-binding factor AML (P=0.047, P=0.015) were lower in IDH1MUT and IDH2MUT. To evaluate the impact of IDH mutations in patients ≥ 60 years, we focused on patients evaluable for outcome treated with lower-intensity therapy (LIT) (N=674), and intensive chemotherapy (IC) (N=178), separately. Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax. For patients treated with LIT, the hazard ratios (HRs) of death over time were 0.58 [95% CI 0.47-0.72; P<0.002], 0.81 [95% CI 0.59-1.13; P=0.214] and 0.56 [95% CI 0.44-0.72; P<0.001] for IDHMUT, IDH1MUT, IDH2MUT respectively. Among patients receiving IC, the HRs were 1.05 [95% CI 0.68-1.69; P=0.777], 0.70 [95% CI 0.31-1.61; P=0.406] and 1.27 [95% CI 0.77-2.1; P=0.352] for IDHMUT, IDH1MUT, and IDH2MUT respectively. The HR of death for IDH1MUT patients treated with LIT with the addition of an IDH1 inhibitor (N=24) was significantly lower (HR 0.47 [95% CI 0.24-0.92; P=0.027] vs IDH1MUT patients treated without an IDH1 inhibitor, while an IDH2 inhibitor did not change survivial outcomes in patients with IDH2MUT (N=71). Discussion: To our knowledge this is the largest retrospective study characterizing the prevalence of IDH mutations in patients ≥ 60 years with AML. We demonstrated that IDH mutations were detected in ~27% of older patients with AML. Although there could have been selection bias as the Beat AML study had separate IDHMUT study arms, these findings are concordant with other studies showing an increase in frequency of IDH mutations with age. IDH2MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

Introduction: The presence of integrative oncology programs in cancer care institutions is rapidly increasing globally, however specialized training in integrative oncology is still limited. In 2022, we launched the first Integrative Medicine in Hematology Oncology (IMHO) fellowship within a traditional Accreditation Council for Graduate Medical Education (ACGME) Hematology Oncology Fellowship in the US. In 2024, the fellowship received accreditation from the Academic Consortium for Integrative Medicine and Health. Here we describe the educational model and report on the fellowship experience via qualitative analysis. Methods: Fellows are recruited from Hematology Oncology Fellows at University of Arizona and Mayo Clinic Arizona. A total of 1000+ hours of Integrative medicine curriculum is completed over 3-years to fulfill American Board of Integrative Medicine requirements for board eligibility. Curriculum is a hybrid delivered via The Andrew Weil Center for Integrative Medicine Foundational Fellowship Curriculum (550 hours), dedicated Integrative Oncology curriculum of didactic and clinical training (250 hours), and research training and investigator-initiated project (200 hours).. Didactic and clinical compentecy-based assessments are required for programmatic completion. Interview-based assessments of acceptability are conducted annually throughout the fellowship duration. Results: IMHO Model Acceptability: Successful recruitment occurred annually since the program's inception (2022, 2023, 2024) of at least 2 fellows of 8 traditional ACGME matched fellows. Additionally, ACGME fellows expressed interest in IMHO fellowship exceeding IMHO recruitment goals. The optimal year of start for IMHO fellowship was determined to be post-graduate year 4 (PGY-4). Five of seven fellows met research goal milestones, and it was determined robust mentorship and research should also start in PGY-4 year. Incentives and cohort visible “dashboard” of progress was deemed necessary when online curriculum milestones were not routinely met by fellows. We received accreditation from the Academic Consortium for Integrative Medicine and Health in spring of 2024. Our first fellow graduate completed requirements in 2024 and is board-eligible in Hematology, Oncology, and Integrative Medicine. Qualitative Analysis: Fellows actively participating in the IMHO fellowship program participated in focus groups. Common themes included: 1) application of resiliency building applied to fellows lives personally and 2) providing tools that allowed them to incorporate integrative medicine to enhance the overall care of their patients. One Fellow stated, “I don't regret picking this choice (the IMHO Fellowship) because I have seen that from my own experience with the patients that I've been able to help them throughout their journey with cancer ...using aspects of Integrative Medicine.” In applying the tools clinically another stated, “I feel like we're really trying to treat the person as a whole, not just treating their condition, and we're really emphasizing their overall goals in life beyond just whatever diagnosis that they have.” One fellow pointed out in regard to their own resiliency “the fellowship program has actually helped improve my resilience and my own wellness ”and “I think it's a really good foundation to have for the future” and another stated “I think it helps me not fall off track because it's a constant reminder of things that you're already interested in, and things that you believe in, that are good coping mechanisms and good ways to kind of, find a balance in your life with your own wellbeing and the wellbeing of others around you.” Finally, “I would say that from my experience I think it's made me a well-rounded physician.” Conclusion: The IMHO Fellowship is the first accreditated Integrative Hematology Oncology training program in the nation. We found the IMHO model an acceptable and desirable model of Integrative Oncology education. Our program revealed optimal timing of initiation is the PGY-4 year, incentive and productivity dashboards are needed for online learning productivity, and research productivity is contingent on robust mentorship and productivity milestones. Ongoing assessment is necessary to continue to optimize the IMHO fellowship model.

Background: Financial toxicity (FT), or the negative impact of medical expenses experienced by patients, is a known adverse effect of cancer treatment that result in worse health outcomes for patients. However, there is limited literature investigating FT in lymphoma with even less data on predictors such as age, gender, and socioeconomic factors. As lymphoma treatment options expand, it is vital to understand the impact of these treatments on patients' financial well-being. We investigate FT through patient reported outcomes from the Lymphoma Epidemiology of Outcomes (LEO), a large multi-institution prospective cohort study of non-Hodgkin lymphoma (NHL). Methods: Patients with newly diagnosed NHL were enrolled into the LEO cohort from 2015-2020. Clinical, pathology and treatment data were abstracted from medical records, and participants were offered self-administered surveys at enrollment and selected follow-up time points. Participants were included if they completed at least four of six survey questions on FT adapted from the Medical Expenditure Panel Survey (MEPS) within the first year after diagnosis. Questions focused on either material hardship (unable to cover costs; file for bankruptcy; borrow money; work extra job or hours) or psychological stress (worried about paying large medical bills). We evaluated FT as answering positively to any question (any vs none). Associations with FT were evaluated using chi-squared tests. All analyses were performed using R (v4.2.2). Results: 3202 patients completed at least four survey questions relating to FT. Mean age at diagnosis was 62 years (18-94), 56% were male, and majority identified as white (90%). Characteristics associated with FT are reported (p<0.001). FT was more likely in younger patients: 18-25 years (64%, 30/47), 26-44 years (73%, 299/313), and 45-64 years (58%, 799/1375) as compared to those 65-79 years (36%, 459/1272) and ≥80 years (35%, 69/195). FT was highest in patients without a high school diploma (54%, 45/84), followed by patients with a high school diploma (52%, 209/402), and an associate's degree (57%, 358/627). It was lowest in patients with a bachelor's (45%, 224/296) or post-graduate degree (39.6%, 216/545). Higher FT was seen in those receiving disability income (65%, 47/72); whereas less FT was seen in retired patients (36%, 299/828). FT rates inversely correlated with income: 65% for income < $21,000 (184/283), 61% for $21,000- $39,999 (224/370) and 60% for $40,000-$65,999 (293/491). Lower FT noted for income range of $66,000-$106,000 (47%, 323/681) or > $106,000 (37%, 324/872). Patients separated from a partner (82.9%, 19/23) had the highest FT, followed by patients living with a partner (64%, 48/75), divorced (56%, 103/184), and never married (53.4%, 79/148). Patients who were married (47%, 793/1672) or widowed (41%, 60/146) reported the lowest FT. Higher FT was reported in DLBCL (55%, 631/1146), MCL (55%, 172/315), and TCL (53%, 119/226) when compared to FL (44%, 327/746), MZL (44%, 137/316), and other NHL (44%, 200/453). This is likely related to treatment as more FT was seen in patients who received an anthracycline and/or alkylator containing therapy (54%, 1066/1963) versus non-systemic (43%, 120/278) and observation (35%, 168/483). In multivariable analyses, FT strongly correlated with age at diagnosis, household income, and treatment type. The odds ratio and 95% confidence intervals for the most significant category within each variable are as follows: age per 1 year (0.96, [0.95-0.97]), income > $106,000 vs < $21,000 (0.28, [0.21-0.38]), and observation vs anthracycline and/or alkylator (0.56, [0.44-0.71]). Conclusion: Nearly 50% of patients with lymphoma experience FT, seen as material hardship and psychological stress, within the first year of diagnosis. Patients with a younger age (18-44), less education, and lower household income reported higher levels of FT; whereas those who were retired or married/widowed reported lower FT. Lymphoma subtypes that require more anthracycline and/or alkylator containing therapy imposed higher FT. Understanding these risk factors can help clinicians identify patients who may benefit from additional resources during lymphoma management.