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AbstractBackgroundDelirium and dementia are common causes of cognitive impairment in older adults and frequently co‐exist. Delirium is associated with poor clinical outcomes when comorbid with dementia. Identifying delirium superimposed on dementia (DSD) is clinically challenging given the overlap in symptoms, including inattention, cognitive impairment, and altered level of consciousness, especially in advanced stages of dementia. Recognition of delirium is also critical in ADRD (Alzheimer’s Disease and Related Dementias) clinical trials for both validity and safety reasons. The ECT‐AD study is one such trial investigating the safety and efficacy of electroconvulsive therapy (ECT) for treatment‐refractory agitation and aggression in individuals with advanced ADRD. Herein we review the Confusion Assessment Method (CAM) for identifying delirium in the ECT‐AD study.MethodInclusion criteria for ECT‐AD are hospitalized individuals diagnosed with ADRD (ages 55–89, MMSE ≤ 15) and refractory agitation/aggression, as measured by the Cohen‐Mansfield Agitation Inventory (CMAI). Procedures for detecting baseline and treatment‐emergent delirium involve a 3‐step approach conducted by raters trained in the CAM, which assesses inattention, disorganized thinking, altered levels of consciousness, and fluctuating mental status. Step 1 involves gathering information from nurse informants regarding the patient’s mental status over the past 24 hours. Step 2 involves collecting observational data through informal patient interaction (e.g., brief conversation). Step 3 is an objective assessment of cognitive status using the Severe Impairment Battery – 8 Item (SIB‐8), while also making qualitative observations about delirium features (e.g., level of consciousness). The rater then codes the CAM and determines delirium status based on these 3 steps.ResultOf our 6 consented subjects, 1 experienced delirium detected by the CAM during the Randomization Phase. The subject received three positive CAMs on consecutive treatment days, citing change in mental status, inability to arouse, restlessness, psychomotor agitation, and swearing. ECT/S‐ECT was held each treatment day and the subject was withdrawn from the Randomization Phase.ConclusionIdentifying DSD is challenging due to overlapping symptoms and the fluctuating nature of delirium. The CAM may be useful in this regard by using a multi‐step approach that incorporates observations from reliable informants, direct patient interactions, and structured cognitive assessments.

AbstractBackgroundGiven the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.MethodWe assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.ResultThe relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).ConclusionThese results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.

Abstract Background Invasive Mold Infections (IMI) cause significant morbidity and mortality, particularly in patients with hematologic malignancies (HM) and hematopoietic stem cell transplant (HSCT) recipients. Although the risk has significantly decreased with the use of triazole agents as primary prophylaxis, breakthrough infections still occur. Risk factors for IMI have been well-described. Limited data exist on factors predicting mortality. Methods We identified cases using the Cancer registry and Microbiology data at Mayo Clinic Minnesota from 11/19/2011–8/6/2021 and Mayo Clinic Arizona and Florida from 09/13/2017–11/19/2021. We conducted a retrospective review to identify cases of proven/probable IMI per EORTC/MSG criteria. Patients who received at least 7 days of anti-mold prophylaxis were considered having breakthrough infection (Br-IMI). Survival function was estimated using the Kaplan-Meier method. We evaluated predictors of mortality using Cox regression analysis. Results 401 cases of IMI were included (80.2% aspergillosis, 10.2% fusariosis, 8.4% mucormycosis, 1.2% scedosporiosis). 189 patients had proven/probable and 212 had possible disease. 12-week mortality for the entire cohort was 33%. There were 87 cases of Br-IMI (21.6%) on mold-active prophylaxis (posaconazole n=54, voriconazole n=26, isavuconazole n=5, itraconazole n=1, liposomal amphotericin B n=1). A comparison between patients not receiving prophylaxis and those with Br-IMI is shown in Table 1. Higher proportion of patients with Br-IMI had prolonged neutropenia/lymphopenia and graft-versus-host disease involving the gastrointestinal tract or lungs. Positive Aspergillus galactomannan (index ≥ 1.0) was seen more in patients who were not on mold-active prophylaxis. Mortality was 31.5% in patients not receiving prophylaxis and 41.3% with Br-IMI (Figure 1). In multivariate analysis, age, prolonged neutropenia, active HM, Br-IMI and HSCT were associated with increased mortality (Table 2). Conclusion In this cohort, the rate of Br-IMI was significant despite the use of primary prophylaxis (mainly posaconazole). Mortality was higher in patients with Br-IMI compared to those not receiving mold-active prophylaxis. Therefore, clinicians should remain alert to the possibility of Br-IMI. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support.

Abstract Background There are not established clinical breakpoints (CBP) for antifungals against Cryptococcus species; However, the analysis of their MICs using epidemiological cut-off values (ECVs) can help to distinguish wild-type (WT) isolates from non-WT strains that may harbor intrinsic or acquired resistance to antifungals. Herein, we analyze the MIC distribution of antifungals against Cryptococcus spp. isolated over the last decade at our reference laboratory. Methods We conducted a retrospective evaluation of antifungals MICs for Cryptococcus neoformans and Cryptococcus gattii complex isolates from various sources that were processed at the Mayo Clinic Laboratory from November 18, 2011 to June 7, 2021. Antifungal susceptibility testing was performed by the Clinical & Laboratory Standards Institute (CLSI) standards (CLSI M59-ED3:2020). We used recommended ECVs to define if the isolates were WT or non-WT, and described the change in the percentage of WT isolates over time. Results During the study period, C. neoformans was isolated from 632 samples collected from 533 patients. Sample sources included cultures from blood (n=301), cerebrospinal fluid (n=230), respiratory (n=71), and other sources (n=30). The overall percentage of WT isolates for amphotericin B (AMB), 5-flucytosine, and fluconazole were 77%, 98% and 91% respectively with no significant difference based on various sources (Table). We noticed an overall increase in MICs for AMB, with 100% WT isolates in 2011 compared to 79% in 2021. No such increase was seen for fluconazole or 5-Flucytosine (Figure). Irrespective of the source or the year of isolation, WT strains for itraconazole, voriconazole, and posaconazole were consistently > 93%. C. gattii was isolated from 16 samples, and 94% were WT strains for AMB and 100% for the other antifungals. CLSI, Clinical and Laboratory Standard Institute; CSF, cerebrospinal fluid; ECVs, epidemiologic cut-off values. AMB, amphotericin B; FLU, fluconazole; 5FC, 5-flucytosine. Conclusion In the last decade, we have observed an overall increase in MICs of AMB for C. neoformans. The number of WT strains for other antifungals was high and not significantly changed during the study frame. Further studies are needed to identify the clinical implications of these findings. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support.

AbstractSince the publication of AAPM Task Group (TG) 148 on quality assurance (QA) for helical tomotherapy, there have been many new developments on the tomotherapy platform involving treatment delivery, on‐board imaging options, motion management, and treatment planning systems (TPSs). In response to a need for guidance on quality control (QC) and QA for these technologies, the AAPM Therapy Physics Committee commissioned TG 306 to review these changes and make recommendations related to these technology updates. The specific objectives of this TG were (1) to update, as needed, recommendations on tolerance limits, frequencies and QC/QA testing methodology in TG 148, (2) address the commissioning and necessary QA checks, as a supplement to Medical Physics Practice Guidelines (MPPG) with respect to tomotherapy TPS and (3) to provide risk‐based recommendations on the new technology implemented clinically and treatment delivery workflow. Detailed recommendations on QA tests and their tolerance levels are provided for dynamic jaws, binary multileaf collimators, and Synchrony motion management. A subset of TPS commissioning and QA checks in MPPG 5.a. applicable to tomotherapy are recommended. In addition, failure mode and effects analysis has been conducted among TG members to obtain multi‐institutional analysis on tomotherapy‐related failure modes and their effect ranking.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Abstract Novel treatment strategies are needed for the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell–engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.