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Abstract During the 20th century, inflammatory bowel disease (IBD) was considered a disease of early-industrialized regions in North America, Europe, and Oceania. At the turn of the 21st century, incidence of IBD increased in newly-industrialized and emerging regions in Africa, Asia, and Latin America, while prevalence in early-industrialized regions started to grow steadily. Changes in incidence and prevalence denote evolution of IBD across four epidemiologic stages: Stage 1 (Emergence), characterized by low incidence and prevalence; stage 2 (Acceleration in Incidence), characterized by rapidly rising incidence and low prevalence; and stage 3 (Compounding Prevalence), characterized by decelerating, plateauing, or declining incidence and steadily rising prevalence. A fourth stage (Prevalence Equilibrium) has been proposed where the slope of prevalence plateaus due to shifting demographics of an aging IBD population, but it has not yet been evidenced. To date, these stages have been theoretical without specific incidence/prevalence indicators defining transition points. Using real-world data from 490 population-based studies comprising 80 global regions and spanning over a century (1920–2023), we show spatiotemporal transitions across stages 1–3 and model transition towards stage 4. Understanding the evolution of IBD across epidemiologic stages allows healthcare systems to better prepare for the future worldwide burden of IBD.

OBJECTIVE It is not clear whether there is an additive effect of social factors in keeping patients with cervical spondylotic myelopathy (CSM) from achieving both a minimum clinically important difference (MCID) in outcomes and satisfaction after surgery. The aim of this study was to explore the effect of multiple social factors on postoperative outcomes and satisfaction. METHODS This was a multiinstitutional, retrospective study of the prospective Quality Outcomes Database (QOD) CSM cohort, which included patients aged 18 years or older who were diagnosed with primary CSM and underwent operative management. Social factors included race (White vs non-White), education (high school or below vs above), employment (employed vs not), and insurance (private vs nonprivate). Patients were considered to have improved from surgery if the following criteria were met: 1) they reported a score of 1 or 2 on the North American Spine Society index, and 2) they met the MCID in patient-reported outcomes (i.e., visual analog scale [VAS] neck and arm pain, Neck Disability Index [NDI], and EuroQol-5D [EQ-5D]). RESULTS Of the 1141 patients included in the study, 205 (18.0%) had 0, 347 (30.4%) had 1, 334 (29.3%) had 2, and 255 (22.3%) had 3 social factors. The 24-month follow-up rate was > 80% for all patient-reported outcomes. After adjusting for all relevant covariates (p < 0.02), patients with 1 or more social factors were less likely to improve from surgery in all measured outcomes including VAS neck pain (OR 0.90, 95% CI 0.83–0.99) and arm pain (OR 0.88, 95% CI 0.80–0.96); NDI (OR 0.90, 95% CI 0.83–0.98); and EQ-5D (OR 0.90, 95% CI 0.83–0.97) (all p < 0.05) compared to those without any social factors. Patients with 2 social factors (outcomes: neck pain OR 0.86, arm pain OR 0.81, NDI OR 0.84, EQ-5D OR 0.81; all p < 0.05) or 3 social factors (outcomes: neck pain OR 0.84, arm pain OR 0.84, NDI OR 0.84, EQ-5D OR 0.84; all p < 0.05) were more likely to fare worse in all outcomes compared to those with only 1 social factor. CONCLUSIONS Compared to those without any social factors, patients who had at least 1 social factor were less likely to achieve MCID and feel satisfied after surgery. The effect of social factors is additive in that patients with a higher number of factors are less likely to improve compared to those with only 1 social factor.

OBJECTIVE The aim of this study was to identify predictors of the best 24-month improvements in patients undergoing surgery for cervical spondylotic myelopathy (CSM). For this purpose, the authors leveraged a large prospective cohort of surgically treated patients with CSM to identify factors predicting the best outcomes for disability, quality of life, and functional status following surgery. METHODS This was a retrospective analysis of prospectively collected data. The Quality Outcomes Database (QOD) CSM dataset (1141 patients) at 14 top enrolling sites was used. Baseline and surgical characteristics were compared for those reporting the top and bottom 20th percentile 24-month Neck Disability Index (NDI), EuroQol-5D (EQ-5D), and modified Japanese Orthopaedic Association (mJOA) change scores. A multivariable logistic model was constructed and included candidate variables reaching p ≤ 0.20 on univariate analyses. Least important variables were removed in a stepwise manner to determine the significant predictors of the best outcomes (top 20th percentile) for 24-month NDI, EQ-5D, and mJOA change. RESULTS A total of 948 (83.1%) patients with 24-month follow-up were included in this study. For NDI, 204 (17.9%) had the best NDI outcome and 200 (17.5%) had the worst NDI outcome. Factors predicting the best NDI outcomes included symptom duration less than 12 months (OR 1.5, 95% CI 1.1–1.9; p = 0.01); procedure other than posterior fusion (OR 1.5, 95% CI 1.03–2.1; p = 0.03); higher preoperative visual analog scale neck pain score (OR 1.2, 95% CI 1.1–1.3; p < 0.001); and higher baseline NDI (OR 1.06, 95% CI 1.05–1.07; p < 0.001). For EQ-5D, 163 (14.3%) had the best EQ-5D outcome and 169 (14.8%) had the worst EQ-5D outcome. Factors predicting the best EQ-5D outcomes included arm pain–only complaints (compared to neck pain) (OR 1.9, 95% CI 1.3–2.9; p = 0.002) and lower baseline EQ-5D (OR 167.7 per unit lower, 95% CI 85.0–339.4; p < 0.001). For mJOA, 222 (19.5%) had the best mJOA outcome and 238 (20.9%) had the worst mJOA outcome. Factors predicting the best mJOA outcomes included lower BMI (OR 1.03 per unit lower, 95% CI 1.004–1.05; p = 0.02; cutoff value of ≤ 29.5 kg/m 2 ); arm pain–only complaints (compared to neck pain) (OR 1.7, 95% CI 1.1–2.5; p = 0.02); and lower baseline mJOA (OR 1.6 per unit lower, 95% CI 1.5–1.7; p < 0.001). CONCLUSIONS Compared to the worst outcomes for EQ-5D, the best outcomes were associated with patients with arm pain–only complaints. For mJOA, lower BMI and arm pain–only complaints portended the best outcomes. For NDI, those with the best outcomes had shorter symptom durations, higher preoperative neck pain scores, and less often underwent posterior spinal fusions. Given the positive impact of shorter symptom duration on outcomes, these data suggest that early surgery may be beneficial for patients with CSM.

AbstractBackgroundWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use at the midway point of data collection of the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS). We compared amyloid‐positive early‐onset Alzheimer’s disease (EOAD) participants and amyloid‐negative early‐onset non‐Alzheimer’s disease [EOnonAD]) participants across NPS domains and psychotropic medication categories.Method282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid‐negative EOnonAD (n = 70). All participants were between ages 40 and 64 at baseline. NPS were measured with the Neuropsychiatric Inventory – Questionnaire (NPI‐Q) and Geriatric Depression Scale – Short Form (GDS‐SF). Medications were categorized into psychotropic category (e.g., antidepressants, antipsychotics, benzodiazepines). Groups were compared on NPI‐Q using binary logistic regression adjusting for sex and disease severity, on GDS‐SF using linear regression adjusting for sex and disease severity, and on psychotropic medication use using Chi square or Fisher’s exact test.ResultDemographic data are presented in Table 1. Average total NPI‐Q score was higher in EOnonAD than EOAD (p = .002, ŋp 2 = .03). Regardless of diagnostic group, informants endorsed Affective behaviors most frequently (76.2%). EOAD informants endorsed fewer Distress‐Tension behaviors (p = .02, OR = .498) and Impulse Control behaviors (p = .01, OR = .438). EOAD informants also endorsed apathy (p < .001, OR = .316), irritability (p = .02, OR = .498), and disinhibition (p = .04, OR = .476) at lower frequency than EOnonAD. GDS‐SF showed that the EOnonAD participants self‐reported more symptoms of depression than the EOAD group (p = .002, ŋp 2 = .03). (Table 2A). A minority of participants, regardless of diagnostic group, reported psychotropic medication use (35%). There was higher use in EOnonAD (38%) than EOAD (24%) (p = .03, Cohen W = .14) (Table 2B).ConclusionNPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants, despite EOnonAD being less severely impaired. LEADS continues to collect data. Future studies will examine etiologies that may be larger drivers of NPS than AD neuropathology, mediators (e.g., race, ethnicity) in the association between NPS and diagnostic group classication, compare NPS in EOAD vs. LOAD, and examine longitudinal changes in neuropsychiatric profiles.

AbstractBackgroundApproximately 10‐25% of amnestic early‐onset dementia are negative for amyloid (Early‐onset non‐Alzheimer’s Disease, EOnonAD). EOnonAD is a heterogenous group with various etiologies. In order to better understand the traits of EOnonAD, we clustered amnestic EOnonAD individuals according to cognitive patterns.MethodCognitive data of 62 EOnonAD individuals from the Longitudinal Early‐onset AD study (LEADS) were Z‐normalized to 91 intact individuals after adjusting for age, sex, and education. This led to domain‐averaged composite Z‐scores for memory, language, speed/attention, visuospatial, and executive function. Cluster analysis using the Ward method on the residuals for the five composites was performed. We used Scree plot using the pseudo T‐squared to determine the optimal number of clusters. We compared demographics, imaging biomarkers (amyloid and tau PET SUVR, hippocampal volume), plasma (pTau231, Aß40, Aß42, glial fibrillary acidic protein, and neurofilament light chain (NfL)), and cerebrospinal fluid (CSF) biomarkers (Aß42/40, NfL, Neurogranin, Visinin‐like protein, YKL‐40, and Synaptosome Associated Protein 25) across the clusters after adjusting for age, sex, and education. We compared gray matter density of each EOnonAD cluster to controls (n = 84) using voxel‐wise multiple linear regressions in SPM12, adjusting for age, sex, education, and intracranial volume.ResultScree plot using the pseudo‐T‐squared suggested three clusters. Cluster 1 (38/62, 61.3%) was characterized by having the mildest cognitive impairment in all domains. Cluster 2 (19/62, 30.6%) was characterized by more severe memory and language impairment. Cluster 3 (5/62, 8.1%) was characterized by more severe impairment in speed/attention, visuospatial, and executive function (Table 1). Cluster 3 showed significantly higher NfL for both plasma (Cluster 1 vs 3, p<0.001; Cluster 2 vs 3, p < 0.004) and CSF (Cluster 1 vs 3, p = 0.001). Other biomarkers did not show significant difference (Table 1). Only Cluster 3 showed significant atrophy in the bilateral fronto‐parietal areas at p<0.01, uncorrected (Figure 1).ConclusionWe identified heterogeneity in cognitive patterns among amnestic EOnonAD individuals. Cluster 1 had mildest cognitive impairment; Cluster 2 had predominant impairment in memory and language; and Cluster 3 had predominant impairment in speed/attention, visuospatial, and executive function, with significant fronto‐parietal atrophy and high NfL indicating active neurodegeneration.

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players.MethodIn this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria.ResultSignificantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C).ConclusionElevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology.

AbstractINTRODUCTIONTau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project.METHODWe compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES).RESULTSSignificantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups.DISCUSSIONAdditional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

AbstractThe DPYD gene encodes dihydropyrimidine dehydrogenase, the rate‐limiting enzyme for the metabolism of fluoropyrimidines 5‐fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129‐5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single‐nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function‐altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129‐5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129‐5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false‐positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129‐5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.