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ImportanceBlood culture (BC) use benchmarks in US hospitals have not been defined.ObjectiveTo characterize BC use in adult intensive care units (ICUs) and wards in US hospitals.Design, Setting, and ParticipantsA retrospective cross-sectional study of BC use in adult medical ICUs, medical-surgical ICUs, medical wards, and medical-surgical wards from acute care hospitals from the 4 US geographic regions was conducted. Critical access hospitals, less than 6 months of BC data, and non-US hospitals were excluded. The study included BC use data from September 1, 2019, to August 31, 2021. Data were analyzed from February 23 to July 14, 2024.Main Outcomes and MeasuresThe primary outcome was BC use per 1000 patient-days. Adjusted means with 95% CIs were calculated using mixed-effects negative binomial regression models adjusted for unit type, hospital bed size, geographic region, seasonality, and state COVID-19 case load, with random intercepts accounting for clustering at unit and hospital levels. Secondary outcomes included blood culture positivity, single BCs, BC contamination, and minimum threshold for BC use where blood culture positivity would be optimized.ResultsA total of 362 327 blood cultures were analyzed from 27 medical ICUs, 35 medical-surgical ICUs, 121 medical wards, and 109 medical-surgical wards from 48 hospitals in 19 states and the District of Columbia. The adjusted mean BC use per 1000 patient-days was 273.1 (95% CI, 270.2-275.9) for medical ICUs, 146.0 (95% CI, 144.5-147.5) for medical-surgical ICUs, 80.3 (95% CI, 79.8-80.7) for medical wards, and 65.1 for medical-surgical wards. Blood culture use was significantly higher across all 4 unit types in hospitals with more than 500 beds compared with 500 or less beds and in the West-Midwest compared with other regions. Single blood culture and positive blood culture rates were below 10% across all 4 unit types. Of the 292 units, 97% had a mean BC contamination rate within 3% of the recommended threshold, and 51% were within 1%. The minimum BC use thresholds (ie, BC use below this number may represent undertesting) were 120 BCs per 1000 patient-days for medical ICUs, 80 BCs per 1000 patient-days for medical-surgical ICUs, and 30 BCs per 1000 patient-days for medical-surgical wards.Conclusions and RelevanceThe findings of this study suggest that blood culture positivity may help determine appropriate BC use for individual unit types.

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

Objective The aim of this study was to determine whether pollutants such as fire smoke–related particulate matter <2.5 μm (PM 2.5 ) are associated with incident rheumatoid arthritis (RA) and RA‐associated interstitial lung disease (RA‐ILD). Methods This patient–control study used Veterans Affairs (VA) data from October 1, 2009, to December 31, 2018. We identified patients with incident RA and RA‐ILD using validated algorithms, matching each patient to ≤10 controls on age, sex, and VA enrollment year. We obtained pollutants including fire smoke PM 2.5 , carbon monoxide, nitrogen oxides (NOx), ozone, overall PM 2.5 , PM 10 , and sulfur dioxide (SO 2 ) at least one year before the index date. We fit conditional logistic regression models to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for incident RA and RA‐ILD, adjusted for confounders. Results We identified 9,701 patients with incident RA (mean age 65 years, 86% male), including 531 patients with RA‐ILD (mean age 69 years, 91% male), and 68,852 matched controls. Fire smoke PM 2.5 was not associated with RA (aOR 1.07, 95% CI 0.92–1.23) but was associated with RA‐ILD (aOR 1.98, 95% CI 1.08–3.62, per 1 μg/m 3 ). Increased levels of NOx were associated with RA (aOR 1.16, 95% CI 1.06–1.27, highest vs lowest quartile). The highest quartiles of ozone (aOR 1.19, 95% CI 1.06–1.34) and PM 10 (aOR 1.25, 95% CI 1.10–1.43) were associated with seronegative RA. Carbon monoxide, overall PM 2.5 , and SO 2 were not, or negatively, associated with RA and RA‐ILD. Conclusion Increased fire smoke PM 2.5 was associated with RA‐ILD, whereas NOx, ozone, and PM 10 were associated with RA risk. Thus, air pollution may increase the risk of RA and RA‐ILD. image

AbstractBackgroundTau PET provides continuous measurements of tau tangle pathology in the human brain. However, establishing cutoffs is crucial for selecting individuals for treatment in clinical trials or practice. In the absence of postmortem data, PET cutoffs must be established using statistical methods based on what is considered normal tracer uptake. In this study, we tested the impact of various methods to determine tau positivity using two different tau PET tracers in individuals scanned head‐to‐head.MethodsWe studied 147 individuals from Head‐to‐Head Harmonization of Tau Tracers in Alzheimer's Disease (HEAD) study with tau tangle PET scans with [18F]Flortaucipir and [18F]MK‐6240, and amyloid‐β (Aβ) PET. Tau deposition was measured with the standardized uptake value ratio (SUVR) of each agent in the Medial Temporal Lobe (MTL) and the Entorhinal Cortex (EC). To determine Tau positivity three different methods were used: >2.5 standard deviations (SD) than the mean of the young, >1.5 SD mean of the cognitively unimpaired (CU) and >1.5 SD mean of CUAβ‐.ResultsDemographic characteristics of the study population are reported in Table 1. Using the cutoff >2.5 SD mean of young, [18F]Flortaucipir was positive in 35 (23.8%) and 69 (46.9%) individuals in the EC and MTL, respectively. [18F]MK‐6240 was positive in 49 (33.3%) and 58 (39.5%) individuals in EC and in MTL. Using >1.5 SD mean of CUAβ‐, [18F]Flortaucipir was positive in 38 (25.9%) and 45 (30.6%) individuals in EC and MTL, while [18F]MK‐6240 was positive in 51 (34.7%) and 50 (34.0%) in EC and in MTL (Figure 1).ConclusionsOur findings indicate variations in tau positivity when employing different methods based on either the young or CUAβ‐. [18F]Flortaucipir exhibited a higher rate of positive results when the method based on young individuals was applied in the MTL. Conversely, [18F]MK‐6240 showed more consistent and generally higher positivity when other methods were used for cutoff determination and/or in the EC region. Further research with a larger sample size is required to gain a better understanding of the optimal cutoff determination methods for these tracers.

AbstractBackgroundUtilizing PET amyloid‐beta (Aβ) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aβ PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.MethodWe evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aβ‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aβ positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).ResultsWe found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).ConclusionOur findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.

AbstractBackgroundIdentification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances. We hypothesize that sub‐categorizing the CU group based on the presence of amyloid (A) and tau (T) pathologies, as measured by PET, can reveal subtle cognitive deficits, even in a clinical test with low sensitivity such as MoCA.MethodWe included 88 CU [defined as CDR global score of 0] older adults with available head‐to‐head MK6240 tau‐PET and Flortaucipir tracers from the ongoing HEAD multi‐site observational study. They also underwent Amyloid PET imaging using PiB or NAV4694. MoCA testing was done around the imaging time. To increase similarity with clinical practice, Amyloid and Tau PET positivity was defined using visual reads. Based on tracer uptake status, we categorized the individuals into A‐T‐, A‐T+, A+T‐ and A‐T‐ groups. Unpaired t‐test and one‐way ANOVA were used to test for significant differences between groups.Result2‐tailed p‐values were significant between the A‐T‐ group and the A+T+ group for MoCA total score [p: 0.0025 and p: 0.0025]. When we stratified MoCA in the different cognitive domains, we found that the results were driven by MoCA (memory) Delayed Recall score [p: 0.0007 and p: 0.0162]. A‐T+ vs A+T+ was also significant [p: 0.0099] for MoCA Delayed Recall. Both tau tracers (MK6240 and Flortaucipir) showed similar performance for determining T+ and identifying cognitive decline.ConclusionMoCA, a simple and commonly administered in‐office neuropsychological test, can detect subtle cognitive dysfunction in CU older adults who are Aβ and tau positive (A+/T+). These CU A+/T+ individuals are likely on the path to developing AD dementia.

AbstractBackgroundAutopsy studies in Lewy Body Disease (LBD) indicate that cardiac sympathetic denervation precedes Lewy body pathology and neuronal loss in the brain. Myocardial 123I‐metaiodobenzylguanidine (MIBG) scintigraphy noninvasively assesses postganglionic cardiac sympathetic denervation in LBD and is considered an important biomarker in the international diagnostic criteria of Dementia with Lewy Bodies and Parkinson’s Disease (PD). Despite the internationally recognized importance of MIBG scintigraphy in LBD, its use in neurodegenerative disorders is not FDA approved for this indication and is rarely used in the US for neurological research. We sought to add MIBG scintigraphy to our multimodal imaging research in prodromal LBD. We launched pilot MIBG scintigraphy study in isolated REM Sleep Behavior Disorder (iRBD) individuals, who are typically regarded as representing evolving LBD.MethodWe conducted MIBG scintigraphy and 123I‐FP‐CIT SPECT in seven individuals with iRBD including two RBD with mild cognitive impairment (MCI), one with PD, and one healthy control (mean age of 71.5±8.3). Heart‐to‐mediastinum (H/M) ratio of the MIBG uptake on delayed image (3‐4 hours after Adreview® injection) was calculated with MIM. Cutoff value of 1.68 was used for determining abnormal H/M ratio (Yoshita et al, 2006). Nigrostriatal dopamine transporter uptake was evaluated with DaTQUANT 2.0 software.ResultFour iRBD participants including two RBD with MCI had abnormal MIBG scintigraphy (mean age 73.5±8.6, delayed H/M ratio 1.25±0.29)) and three iRBD participants had a normal scan (mean age 67.8±4.5, delayed H/M ratio 2.57±0.25). Delayed H/M ratio was 1.00 for the PD participant and 2.60 for healthy control participant. Among the four iRBD participants with abnormal MIBG scintigraphy, one participant had 123I‐FP‐CIT SPECT with DaTQUANT putamen z‐score <‐2.0 and three participants had z‐score in the range of ‐1.5 and ‐1.0. All iRBD participants with normal MIBG scintigraphy had normal 123I‐FP‐CIT SPECT with DaTQUANT putamen z‐score >‐1.0.ConclusionMIBG scintigraphy was abnormal in half of this small cohort. Our preliminary data suggests its utility in detecting early signs of evolving LBD. Increasing the number of the MIBG scintigraphy in iRBD participants and controls are planned to determine if MIBG scintigraphy can facilitate early detection of progression for use in clinical trials targeting LBD.

AbstractBackgroundTau PET provides continuous measurements of tau tangle pathology in the human brain. However, establishing cutoffs is crucial for selecting individuals for treatment in clinical trials or practice. In the absence of postmortem data, PET cutoffs must be established using statistical methods based on what is considered normal tracer uptake. In this study, we tested the impact of various methods to determine tau positivity using two different tau PET tracers in individuals scanned head‐to‐head.MethodsWe studied 147 individuals from Head‐to‐Head Harmonization of Tau Tracers in Alzheimer's Disease (HEAD) study with tau tangle PET scans with [18F]Flortaucipir and [18F]MK‐6240, and amyloid‐ß (Aß) PET. Tau deposition was measured with the standardized uptake value ratio (SUVR) of each agent in the Medial Temporal Lobe (MTL) and the Entorhinal Cortex (EC). To determine Tau positivity three different methods were used: >2.5 standard deviations (SD) than the mean of the young, >1.5 SD mean of the cognitively unimpaired (CU) and >1.5 SD mean of CUAß‐.ResultsDemographic characteristics of the study population are reported in Table 1. Using the cutoff >2.5 SD mean of young, [18F]Flortaucipir was positive in 35 (23.8%) and 69 (46.9%) individuals in the EC and MTL, respectively. [18F]MK‐6240 was positive in 49 (33.3%) and 58 (39.5%) individuals in EC and in MTL. Using >1.5 SD mean of CUAß‐, [18F]Flortaucipir was positive in 38 (25.9%) and 45 (30.6%) individuals in EC and MTL, while [18F]MK‐6240 was positive in 51 (34.7%) and 50 (34.0%) in EC and in MTL (Figure 1).ConclusionsOur findings indicate variations in tau positivity when employing different methods based on either the young or CUAß‐. [18F]Flortaucipir exhibited a higher rate of positive results when the method based on young individuals was applied in the MTL. Conversely, [18F]MK‐6240 showed more consistent and generally higher positivity when other methods were used for cutoff determination and/or in the EC region. Further research with a larger sample size is required to gain a better understanding of the optimal cutoff determination methods for these tracers.

AbstractBackgroundIdentification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances. We hypothesize that sub‐categorizing the CU group based on the presence of amyloid (A) and tau (T) pathologies, as measured by PET, can reveal subtle cognitive deficits, even in a clinical test with low sensitivity such as MoCA.MethodWe included 88 CU [defined as CDR global score of 0] older adults with available head‐to‐head MK6240 tau‐PET and Flortaucipir tracers from the ongoing HEAD multi‐site observational study. They also underwent Amyloid PET imaging using PiB or NAV4694. MoCA testing was done around the imaging time. To increase similarity with clinical practice, Amyloid and Tau PET positivity was defined using visual reads. Based on tracer uptake status, we categorized the individuals into A‐T‐, A‐T+, A+T‐ and A‐T‐ groups. Unpaired t‐test and one‐way ANOVA were used to test for significant differences between groups.Result2‐tailed p‐values were significant between the A‐T‐ group and the A+T+ group for MoCA total score [p: 0.0025 and p: 0.0025]. When we stratified MoCA in the different cognitive domains, we found that the results were driven by MoCA (memory) Delayed Recall score [p: 0.0007 and p: 0.0162]. A‐T+ vs A+T+ was also significant [p: 0.0099] for MoCA Delayed Recall. Both tau tracers (MK6240 and Flortaucipir) showed similar performance for determining T+ and identifying cognitive decline.ConclusionMoCA, a simple and commonly administered in‐office neuropsychological test, can detect subtle cognitive dysfunction in CU older adults who are Aß and tau positive (A+/T+). These CU A+/T+ individuals are likely on the path to developing AD dementia.

AbstractBackgroundUtilizing PET amyloid‐beta (Aß) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aß PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.MethodWe evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aß‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aß positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).ResultsWe found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).ConclusionOur findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.