Citations

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two‐sample Mendelian randomization (MR). Methods We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P ‐difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

AbstractBackgroundThe overarching goal of the Longitudinal Early‐onset Alzheimer Disease study (LEADS) is to optimally characterize early‐onset AD (EOAD) and establish an EOAD clinical trials network. Here we report the baseline demographic and imaging biomarker comparisons of the LEADS cohort to late‐onset AD (LOAD) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3).Method123 amyloid‐positive EOAD, 47 amyloid‐negative EOnonAD, 60 cognitively normal young controls were compared to 130 amyloid‐positive LOAD, 110 amyloid‐negative LOnonAD and 286 amyloid‐negative cognitively normal older controls. To account for the effect of cognitive aging between EO and LO populations, each cognitive measure was Z‐transformed. Cortical and hippocampal atrophy were quantified using W‐scores adjusted for age, sex and total intracranial volume. Z‐scores and W‐scores were compared using t‐test or Wilcoxson rank test as appropriate. All p‐values were corrected for multiple comparisons using the false discovery rate correction.ResultEOAD showed greater pathology burden and greater cortical atrophy (AD signature) relative to LOAD. EOAD also showed greater cognitive impairment across all cognitive tests. EOAD showed greater functional impairment, more depression but less neuropsychiatric behaviors overall compared to LOAD (Table 1 and Figure 1, all ps<0.05). Repeating the analyses stratified by cognitive stage (MCI/dementia) or CDR global rating (0.5/1) did not result in any major differences.EOnonAD differed from LOnonAD by also showing greater impairment on all cognitive and functional measures There were no significant differences in amyloid and tau burden, or atrophy W‐scores between these groups. EOnonAD were more depressed and showed more functional impairment compared to LOnonAD (Table 2 and Figure 2, all ps<0.05). Repeating the analyses split by cognitive stage (MCI/dementia) or CDR global rating (0.5/1) did not result in any major differences.ConclusionConsistent with our preexisting hypotheses, EOAD and EOnonAD perform much worse relative to their LO counterparts. EOAD also show greater pathological burden as expected. The reported analyses were done in chronological rather than disease time (time since disease onset). Benchmarking individuals along the disease spectrum might prove to be a better strategy especially when conducting analyses on rate of disease progression.

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti‐β‐amyloid passive immunotherapies in sporadic and dominantly inherited Alzheimer Disease (DIAD). However, beyond APOE‐ɛ4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA‐E in the DIAN‐TU‐001 trial evaluating gantenerumab and solanezumab in DIAD.MethodThe DIAN‐TU‐001 trial enrolled 194 participants, including 144 DIAD mutation‐carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB‐PET and safety MR, including T2‐FLAIR and T2*‐GRE. Treatment dosage and APOE‐ɛ4 status were also reported.ResultEleven participants developed a total of 14 ARIA‐E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA‐E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA‐E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=[1.1,75.9], p‐value<0.05). ARIA‐E participants were PiB‐PET+ and 60% were CDR>0. APOE‐ɛ4 tends to be associated with risk for developing ARIA‐E (OR=5.0, 95%CI=[1.0,30.4], p‐value=0.055). ARIA‐E were not observed at initial 225mg dose and were first observed after a titration step (within 4‐24 weeks, after 1‐6 injections, Table 1). Time‐to‐resolution of ARIA‐E was 10.4±6.2weeks. Seven of ten ARIA‐E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA‐E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=[0.34,7.33], p‐value=0.57). ARIA‐E occurred primarily in the occipital lobe (71%) with associated incident ARIA‐H (microhemorrhages or superficial siderosis) in 60% of ARIA‐E participants. ARIA‐E size was associated with microhemorrhage count (Spearman’s rho=0.72, p‐value<0.05), rate of change (rho=0.78, p‐value<0.01), and baseline PiB‐PET (rho=0.68, p‐value<0.05). Normalizing by baseline, PiB‐PET decreased similarly in ARIA‐E+ (‐0.21±0.20) and ARIA‐E‐ (‐0.16±0.20) participants.ConclusionIn DIAD, gantenerumab dose over 225mg increased ARIA‐E risk, possibly more for APOE‐ɛ4 carriers. ARIA‐E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights for managing ARIA‐E occurrence in future trials.

Background: Dislocation is the most common reason for early revision following total hip arthroplasty (THA). More than 40 years ago, Lewinnek et al. proposed an acetabular “safe zone” to avoid dislocation. While novel at the time, their study was substantially limited according to modern standards. The purpose of this study was to determine optimal acetabular cup positioning during THA as well as the effect of surgical approach on the topography of the acetabular safe zone and the hazard of dislocation. Methods: Primary THAs that had been performed at a single institution from 2000 to 2017 were reviewed. Acetabular inclination and anteversion were measured using an artificial intelligence neural network; they were validated with performance testing and comparison with blinded grading by 2 orthopaedic surgeons. Patient demographics and dislocation were noted during follow-up. Multivariable Cox proportional-hazards regression, including multidimensional analysis, was performed to define the 3D topography of the acetabular safe zone and its association with surgical approach. Results: We followed 9,907 THAs in 8,081 patients (4,166 women and 3,915 men; 64 ± 13 years of age) for a mean of 5 ± 3 years (range: 2 to 16); 316 hips (3%) sustained a dislocation during follow-up. The mean acetabular inclination was 44° ± 7° and the mean anteversion was 32° ± 9°. Patients who did not sustain a dislocation had a mean anteversion of 32° ± 9° (median, 32°), with the historic ideal anteversion of 15° observed to be only in the third percentile among non-dislocating THAs (p < 0.001). Multivariable modeling demonstrated the lowest dislocation hazards at an inclination of 37° and an anteversion of 27°, with an ideal modern safe zone of 27° to 47° of inclination and 18° to 38° of anteversion. Three-dimensional analysis demonstrated a similar safe-zone location but significantly different safe-zone topography among surgical approaches (p = 0.03) and sexes (p = 0.02). Conclusions: Optimal acetabular positioning differs significantly from historic values, with increased anteversion providing decreased dislocation risk. Additionally, surgical approach and patient sex demonstrated clear effects on 3D safe-zone topography. Further study is needed to characterize the 3D interaction between acetabular positioning and spinopelvic as well as femoral-sided parameters. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Introduction : Fetal posterior cerebral artery (FPCA) occlusion is a rare but potentially disabling cause of stroke. While endovascular treatment is established for acute large vessel occlusion (LVO) stroke, FPCA occlusions were excluded from acute ischemic stroke trials. We aim to report the feasibility, safety and outcome of mechanical thrombectomy (MT) in acute FPCA occlusions. Methods : We performed a multi‐center retrospective review of consecutive patients who underwent MT of acute FPCA occlusion. Primary FPCA occlusion was defined as an occlusion that was identified on the pre‐procedure CT angiogram or baseline angiogram whereas a secondary FPCA occlusion was defined as an occlusion that occurred secondary to embolization to a new territory after recanalization of a different LVO. Demographics, clinical presentation, imaging findings, endovascular treatment and outcome were reviewed. Results : There were twenty‐five patients with acute FPCA occlusion who underwent MT, distributed across 14 centers. Median NIHSS on presentation was 16. There were 76% (19/25) of patients who presented with primary FPCA occlusion and 24% (6/25) of patients who had a secondary FPCA occlusion. The configuration of the FPCA was full in 64% patients and partial or “fetal‐type” in 36% of patients. FPCA occlusion was missed on initial CTA in 21% of patients with primary FPCA occlusion (4/19). The site of occlusion was posterior communicating artery in 52%, P2 segment in 40% and P3 in 8% of patients. TICI 2b/3 reperfusion was achieved in 96% of FPCA patients. There were no intra‐procedural complications. At 90 days, 48% (12/25) were functionally independent as defined by mRS≤2. Conclusions : Endovascular treatment of acute FPCA occlusion is safe and technically feasible. A high index of suspicion is important to detect occlusion of the fetal posterior cerebral artery in patients presenting with anterior circulation stroke syndrome and patent anterior circulation.

This Phase Ib study combined programmed death-ligand 1 inhibitor, atezolizumab, with other immunomodulatory agents in locally advanced and metastatic solid tumors. Arms B-D evaluated atezolizumab plus interferon-α, with/without vascular endothelial growth factor inhibitor, bevacizumab, in renal cell carcinoma (RCC) and other solid tumors. Arm B predominantly recruited patients with previously treated RCC or melanoma to receive atezolizumab plus interferon α-2b. Arm C investigated atezolizumab plus polyethylene glycol (PEG)-interferon α-2a in previously treated RCC. Arm D evaluated atezolizumab plus PEG-interferon α-2a and bevacizumab. Primary objectives were safety and tolerability; secondary objectives included clinical activity. Combination therapy was well tolerated, with safety profiles consistent with known risks of individual agents. The most frequent treatment-related toxicities were fatigue, chills, and pyrexia. The objective response rate (ORR) in arm B was 20.0% overall and 17.8% in patients with previously treated checkpoint inhibitor–naive RCC (n = 45). No responses were reported in arm C. The highest ORR in arm D was 46.7% in patients with treatment-naive RCC (n = 15). Data showed preliminary clinical activity and acceptable tolerability of atezolizumab plus interferon α-2b in patients with previously treated checkpoint inhibitor–naive RCC and of atezolizumab plus PEG-interferon α-2a and bevacizumab in patients with treatment-naive RCC.

Abstract Background The European Society of Gastrointestinal Endoscopy (ESGE) has developed a core curriculum for high quality optical diagnosis training for practice across Europe. The development of easy-to-measure competence standards for optical diagnosis can optimize clinical decision-making in endoscopy. This manuscript represents an official Position Statement of the ESGE aiming to define simple, safe, and easy-to-measure competence standards for endoscopists and artificial intelligence systems performing optical diagnosis of diminutive colorectal polyps (1 – 5 mm). Methods A panel of European experts in optical diagnosis participated in a modified Delphi process to reach consensus on Simple Optical Diagnosis Accuracy (SODA) competence standards for implementation of the optical diagnosis strategy for diminutive colorectal polyps. In order to assess the clinical benefits and harms of implementing optical diagnosis with different competence standards, a systematic literature search was performed. This was complemented with the results from a recently performed simulation study that provides guidance for setting alternative competence standards for optical diagnosis. Proposed competence standards were based on literature search and simulation study results. Competence standards were accepted if at least 80 % agreement was reached after a maximum of three voting rounds. Recommendation 1 In order to implement the leave-in-situ strategy for diminutive colorectal lesions (1–5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 90 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1–5 mm in the rectosigmoid. Histopathology is used as the gold standard. Level of agreement 95 %. Recommendation 2 In order to implement the resect-and-discard strategy for diminutive colorectal lesions (1–5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 80 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1–5 mm. Histopathology is used as the gold standard. Level of agreement 100 %. Conclusion The developed SODA competence standards define diagnostic performance thresholds in relation to clinical consequences, for training and for use when auditing the optical diagnosis of diminutive colorectal polyps.

Background Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. Methods To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. Results The mean acute effect across all studies was −0.21 ml/min per 1.73 m 2 (95% confidence interval, −0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, −2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. Conclusion The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.