Partial volume correction in longitudinal tau PET studies: is it really needed?

BACKGROUND: [18F]flortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging. METHODS: A cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aß) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aß-negative (A-) and Aß-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline. RESULTS: Among off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28-0.82), with CSF coming in second (R2=0.28-0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00-0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26-0.66; RBV: Cohen's d = 0.43-0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline. CONCLUSION: Quantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.

Diagnostic delay is associated with uveitis and inflammatory bowel disease in AS: a study of extra-musculoskeletal manifestations in SpA.

OBJECTIVES: To examine the prevalence of extra-musculoskeletal manifestations (EMM) and the association between diagnostic delay and their incidence in AS and PsA. METHODS: This was a retrospective, cohort study comprising two single centre cohorts in Europe and one multicentre cohort in Latin America (RESPONDIA). Crude prevalence of EMMs (uveitis, IBD and psoriasis) was calculated across geographic area and adjusted by direct standardization. Cox proportional hazard analysis was performed to assess the association between diagnostic delay and EMM incidence. RESULTS: Of 3553 patients, 2097 had AS and 1456 had PsA. The overall prevalence of uveitis was 22.9% (95% CI: 21.1, 24.8) in AS and 3.8% (95% CI: 2.9, 5.0) in PsA; 8.1% (95% CI: 7.0, 9.4) and 2.1% (1.3, 2.9), respectively, for IBD; and 11.0% (95% CI: 9.7, 12.4) and 94.6% (93.0, 95.9), respectively, for psoriasis. The EMM often presented before the arthritis (uveitis 45.1% and 33.3%, and IBD 37.4% and 70%, in AS and PsA, respectively). In the multivariable model, longer diagnostic delay (≥5 years) associated with more uveitis (hazard ratio [HR] 4.01; 95% CI: 3.23, 4.07) and IBD events (HR 1.85; 95% CI: 1.28, 2.67) in AS. Diagnostic delay was not significantly associated with uveitis (HR 1.57; 95% CI: 0.69, 3.59) or IBD events (HR 1.59; 95% CI: 0.39, 6.37) in PsA. CONCLUSION: EMMs are more prevalent in AS than PsA and often present before the onset of the articular disease. A longer diagnostic delay is associated with the 'de novo' appearance of uveitis and IBD in AS, highlighting the need to enhance diagnostic strategies to shorten the time from first symptom to diagnosis in SpA.

Clinical characteristics and outcomes of aortic prosthetic valve endocarditis: comparison between transcatheter and surgical bioprostheses.

PURPOSE: Most data regarding infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) comes from TAVI registries, rather than IE dedicated cohorts. The objective of our study was to compare the clinical and microbiological profile, imaging features and outcomes of patients with IE after SAVR with a biological prosthetic valve (IE-SAVR) and IE after TAVI (IE-TAVI) from 6 centres with an Endocarditis Team (ET) and broad experience in IE. METHODS: Retrospective analysis of prospectively collected data. From the time of first TAVI implantation in each centre to March 2021, all consecutive patients admitted for IE-SAVR or IE-TAVI were prospectively enrolled. Follow-up was monitored during admission and at 12 months after discharge. RESULTS: 169 patients with IE-SAVR and 41 with IE-TAVI were analysed. Early episodes were more frequent among IE-TAVI. Clinical course during hospitalization was similar in both groups, except for a higher incidence of atrioventricular block in IE-SAVR. The most frequently causative microorganisms were S. epidermidis, Enterococcus spp. and S. aureus in both groups. Periannular complications were more frequent in IE-SAVR. Cardiac surgery was performed in 53.6% of IE-SAVR and 7.3% of IE-TAVI (p=0.001), despite up to 54.8% of IE-TAVI patients had an indication. No differences were observed about death during hospitalization (32.7% vs 35.0%), and at 1-year follow-up (41.8% vs 37.5%), regardless of whether the patient underwent surgery or not. CONCLUSION: Patients with IE-TAVI had a higher incidence of early prosthetic valve IE. Compared to IE-SAVR, IE-TAVI patients underwent cardiac surgery much less frequently, despite having surgical indications. However, in-hospital and 1-year mortality rate was similar between both groups.

Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology.

A clinical diagnosis of Alzheimer's disease dementia (ADD) encompasses considerable pathological and clinical heterogeneity. While Alzheimer's disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on 18F-fluorodeoxyglucose (FDG)-PET imaging, previous studies have identified a subset of patients showing a distinct posterior-occipital hypometabolism pattern associated with Lewy body pathology. Here, we aimed to improve the understanding of the clinical relevance of these posterior-occipital FDG-PET patterns in patients with Alzheimer's disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of ADD (n = 305) or amnestic mild cognitive impairment (aMCI, n = 909) from the Alzheimer's Disease Neuroimaging Initiative, who had FDG-PET scans available. Individual FDG-PET scans were classified as being suggestive of Alzheimer's (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier trained on a separate set of patients with autopsy-confirmed Alzheimer's disease or Lewy body pathology. AD- and LB-like subgroups were compared on amyloid-ß and tau-PET, domain-specific cognitive profiles (memory versus executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6 years for aMCI, ≈3 years for ADD). Around 12% of the aMCI and ADD patients were classified as LB-like. For both aMCI and ADD patients, the LB-like group showed significantly lower regional tau-PET burden than the AD-like subgroup, but amyloid-ß load was only significantly lower in the aMCI LB-like subgroup. LB- and AD-like subgroups did not significantly differ in global cognition (aMCI: d = 0.15, P = 0.16; ADD: d = 0.02, P = 0.90), but LB-like patients exhibited a more dysexecutive cognitive profile relative to the memory deficit (aMCI: d = 0.35, P = 0.01; ADD: d = 0.85 P < 0.001), and had a significantly higher risk of developing hallucinations over follow-up [aMCI: hazard ratio = 1.8, 95% confidence interval = (1.29, 3.04), P = 0.02; ADD: hazard ratio = 2.2, 95% confidence interval = (1.53, 4.06) P = 0.01]. In summary, a sizeable group of clinically diagnosed ADD and aMCI patients exhibit posterior-occipital FDG-PET patterns typically associated with Lewy body pathology, and these also show less abnormal Alzheimer's disease biomarkers as well as specific clinical features typically associated with dementia with Lewy bodies.

Seroprevalence of IgM/IgG and Neutralizing Antibodies against SARS-CoV-2 in Unvaccinated Young Adults from Mexico Who Reported Not Having Had a Previous COVID-19 Infection.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). It is estimated that more than half of new infections are transmitted by asymptomatic people; therefore, the isolation of symptomatic people is not enough to control the spread of the disease. Methods: A total of 171 unvaccinated young adults (18-35 years) from Sonora, Mexico, who underwent a structured survey to identify prior COVID-19 infections, were included in this study. A qualitative determination of anti-SARS-CoV-2 antibodies in serum was performed by lateral flow immunoassay (Certum IgG/IgM Rapid Test™ cassette kit) and neutralizing antibodies were also determined (GenScript cPass assay). Results: A total of 36 people reported a history of COVID-19 infection, and 135 reported no history of COVID-19. In contrast, 49.6% (67/135) of individuals who had not reported a previous SARS-CoV-2 infection were seropositive to the rapid anti-SARS-CoV-2 antibody test, and 48.1% (65/135) of them had neutralizing antibodies. Conclusions: These results suggest that in young adults, SARS-CoV-2 infections could be asymptomatic in a high percentage of individuals, which could contribute in part to the slow control of the current pandemic due to the large number of asymptomatic cases that are contagious and that could be a silent spread of the virus.

Safety of early oral ambulatory treatment of adult patients with bloodstream infections discharged from the emergency department.

This study evaluates the safety of early oral ambulatory treatment of adult patients diagnosed with bacteremia after their discharge from the emergency department. A cohort of 206 febrile ambulatory patients was assessed. Bacteremic low-risk patients were recommended an oral treatment and were compared with matched febrile non-bacteremic outpatients. Rates of 14-day mortality and unplanned re-consultations were similar and below 5% in both cohorts, highlighting the safety of oral therapy of low-risk bacteremia, even from its onset.

Early outcomes from the Minimally Invasive Right Colectomy Anastomosis study (MIRCAST).

BACKGROUND: The impact of method of anastomosis and minimally invasive surgical technique on surgical and clinical outcomes after right hemicolectomy is uncertain. The aim of the MIRCAST study was to compare intracorporeal and extracorporeal anastomosis (ICA and ECA respectively), each using either a laparoscopic approach or robot-assisted surgery during right hemicolectomies for benign or malignant tumours. METHODS: This was an international, multicentre, prospective, observational, monitored, non-randomized, parallel, four-cohort study (laparoscopic ECA; laparoscopic ICA; robot-assisted ECA; robot-assisted ICA). High-volume surgeons (at least 30 minimally invasive right colectomy procedures/year) from 59 hospitals across 12 European countries treated patients over a 3-year interval The primary composite endpoint was 30-day success, defined by two measures of efficacy-absence of surgical wound infection and of any major complication within the first 30 days after surgery. Secondary outcomes were: overall complications, conversion rate, duration of operation, and number of lymph nodes harvested. Propensity score analysis was used for comparison of ICA with ECA, and robot-assisted surgery with laparoscopy. RESULTS: Some 1320 patients were included in an intention-to-treat analysis (laparoscopic ECA, 555; laparoscopic ICA, 356; robot-assisted ECA, 88; robot-assisted ICA, 321). No differences in the co-primary endpoint at 30 days after surgery were observed between cohorts (7.2 and 7.6 per cent in ECA and ICA groups respectively; 7.8 and 6.6 per cent in laparoscopic and robot-assisted groups). Lower overall complication rates were observed after ICA, specifically less ileus, and nausea and vomiting after robot-assisted procedures. CONCLUSION: No difference in the composite outcome of surgical wound infections and severe postoperative complications was found between intracorporeal versus extracorporeal anastomosis or laparoscopy versus robot-assisted surgery.

Basal Forebrain Atrophy, Cortical Thinning, and Amyloid-ß Status in Parkinson's disease-Related Cognitive Decline.

BACKGROUND: Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is a well-established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. OBJECTIVES: To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. METHODS: We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow-up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear-mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid-ß biomarker positivity on these associations. RESULTS: After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning (PFDR < 0.05), and thinning in cBF-associated cortical areas mediated the association between cBF degeneration and cognitive decline (rcBF-MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid-ß status. CONCLUSIONS: cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid-ß status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Peripheral Inflammation Is Associated with Dopaminergic Degeneration in Parkinson's Disease.

BACKGROUND: Peripheral inflammatory immune responses are suggested to play a major role in dopaminergic degeneration in Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR) is a well-established biomarker of systemic inflammation in PD. Degeneration of the nigrostriatal dopaminergic system can be assessed in vivo using [123 I]FP-CIT single photon emission computed tomography imaging of striatal dopamine transporter (DAT) density. OBJECTIVES: To assess the relationship between the peripheral immune profile (NLR, lymphocytes, and neutrophils) and striatal DAT density in patients with PD. METHODS: We assessed clinical features, the peripheral immune profile, and striatal [123 I]FP-CIT DAT binding levels of 211 patients with PD (primary-cohort). Covariate-controlled associations between the immune response and striatal DAT levels were assessed using linear regression analyses. For replication purposes, we also studied a separate cohort of 344 de novo patients with PD enrolled in the Parkinson's Progression Markers Initiative (PPMI-cohort). RESULTS: A higher NLR was significantly associated with lower DAT levels in the caudate (primary-cohort: ß = -0.01, p < 0.001; PPMI-cohort: ß = -0.05, p = 0.05) and the putamen (primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = -0.06, p = 0.02). Intriguingly, a lower lymphocyte count was significantly associated with lower DAT levels in both the caudate (primary-cohort: ß = +0.09, p < 0.05; PPMI-cohort: ß = +0.11, p = 0.02) and the putamen (primary-cohort: ß = +0.09, p < 0.05, PPMI-cohort: ß = +0.14, p = 0.01), but an association with the neutrophil count was not consistently observed (caudate; primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = 0, p = 0.94; putamen; primary-cohort: ß = -0.04, p = 0.08; PPMI-cohort: ß = -0.01, p = 0.73). CONCLUSIONS: Our findings across two independent cohorts suggest a relationship between systemic inflammation and dopaminergic degeneration in patients with PD. This relationship was mainly driven by the lymphocyte count. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Infection-related mortality after HLA-identical and haploidentical hematopoietic cell transplantation using reduced-intensity conditioning in an outpatient setting.

BACKGROUND: Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. METHODS: We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. RESULTS: More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p = 0.003). Viral (14.9% vs. 4.5%, p = 0.016) and fungal (12.1% vs. 1.1%, p = 0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). CONCLUSIONS: No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.

Protective ileostomy creation after anterior resection of the rectum: Shared decision-making or still subjective?

AIM: The choice of whether to perform protective ileostomy (PI) after anterior resection (AR) is mainly guided by risk factors (RFs) responsible for the development of anastomotic leakage (AL). However, clear guidelines about PI creation are still lacking in the literature and this is often decided according to the surgeon's preferences, experiences or feelings. This qualitative study aims to investigate, by an open-ended question survey, the individual surgeon's decision-making process regarding PI creation after elective AR. METHOD: Fifty four colorectal surgeons took part in an electronic survey to answer the questions and describe what usually led their decision to perform PI. A content analysis was used to code the answers. To classify answers, five dichotomous categories (In favour/Against PI, Listed/Unlisted RFs, Typical/Atypical, Emotions/Non-emotions, Personal experience/No personal experience) have been developed. RESULTS: Overall, 76% of surgeons were in favour of PI creation and 88% considered listed RFs in the question of whether to perform PI. Atypical answers were reported in 10% of cases. Emotions and personal experience influenced surgeons' decision-making process in 22% and 49% of cases, respectively. The most frequently considered RFs were the distance of the anastomosis from the anal verge (96%), neoadjuvant chemoradiotherapy (88%), a positive intraoperative leak test (65%), blood loss (37%) and immunosuppression therapy (35%). CONCLUSION: The indications to perform PI following rectal cancer surgery lack standardization and evidence-based guidelines are required to inform practice. Until then, expert opinion can be helpful to assist the decision-making process in patients who have undergone AR for adenocarcinoma.

Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC.

INTRODUCTION: Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. METHODS: Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. RESULTS: Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course. DISCUSSION: An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.

Cataphryxus zapoteca sp. nov. (Isopoda, Bopyridae) and new hosts and records of bopyrid isopods from the Mexican Eastern Pacific.

Based on the examination of diverse crustacean taxa collected along the Mexican Pacific and deposited in the Colección Nacional de Crustáceos of the Instituto de Biología, UNAM, six species of bopyrid isopods were detected. New hosts and localities are reported for Munidion pleuroncodis Markham, 1975, Probopyrus pacificensis Román-Contreras, 1993, Probopyrus markhami Román-Contreras, 1996, Progebiophilus bruscai Salazar-Vallejo & Leija-Tristán, 1990 and Schizobopyrina striata (Nierstrasz & Brender à Brandis, 1929). Cataphryxus zapoteca sp. nov., is described as abdominal parasite of the shrimp Lysmata galapagensis Schmitt; this bopyrid is the second species described in the genus Cataphryxus Shiino, 1936 and the first registered on the American continent. Taxonomic characters, distribution and some reproductive data for five of the six species examined are provided in order to update the knowledge of this parasite group in this Eastern Pacific region.

Experience of Subcutaneous Levetiracetam in Palliative Care.

BACKGROUND: Seizures are common in palliative care patients and its control is essential in the management of these patients as it helps to reduce suffering at the end of life. Subcutaneous levetiracetam has been used off-license for seizure control in palliative care. OBJECTIVE: The objective of the study was to describe our experience with subcutaneous levetiracetam in two hospitals in Bogota, Colombia. METHODS: We conducted a retrospective review of patients treated with subcutaneous levetiracetam in two hospitals in Colombia during 2019-2021. Data were extracted from medical records, and participants were followed up as outpatients. RESULTS: Twenty-one patients were included into the study. No severe adverse effects or rise in ictal frequency were documented. Twelve patients died during hospitalization and nine continued treatments as outpatients. The principal diagnosis was structural focal epilepsy. The daily dose of levetiracetam ranged from 1,000 mg to 3,000 mg, and the duration of treatment varied among subjects between 1 and 360 days. CONCLUSION: Subcutaneous levetiracetam was well tolerated and effective in controlling seizures in palliative care when oral administration or intravenous access was not an option. Randomized controlled trials are needed to elucidate the efficacy and tolerability of subcutaneous levetiracetam in clinical practice.

Identification of the Remains of an Adult Using DNA from Their Deciduous Teeth as a Reference Sample.

In many forensic cases, the identification of human remains is performed by comparing their genetic profile with profiles from reference samples of relatives, usually the parents. Here, we report, for the first time, the identification of the remains of an adult using DNA from the person's deciduous teeth as a reference sample. Fragments of a skeletonized and burned body were found, and a short tandem repeat (STR) profile was obtained. A woman looking for her missing son went to the authorities. When the DNA profile of the woman was compared to a database, a positive match suggested a first-degree kinship with the person to whom the remains belonged. The woman had kept three deciduous molars from her son for more than thirty years. DNA typing of dental pulp was performed. The genetic profiles obtained from the molars and those from the remains coincided in all alleles. The random match probability was 1 in 2.70 × 1021. Thus, the remains were fully identified. In the routine identification of human remains, ambiguous STR results may occur due to the presence of null alleles or other mutational events. In addition, erroneous results can be produced by false matches with close family members or even with people who are completely unrelated to the victim, such that, in some cases, a probability of paternity greater than 99.99% does not necessarily indicate biological paternity. Whenever possible, it is preferable to use reference samples from the putative victim as a source of DNA for identification.

Impact of spill-in counts from off-target regions on [18F]Flortaucipir PET quantification.

BACKGROUND: [18F]Flortaucipir (FTP) PET quantification is usually hindered by spill-in counts from off-target binding (OFF) regions. The present work aims to provide an in-depth analysis of the impact of OFF in FTP PET quantification, as well as to identify optimal partial volume correction (PVC) strategies to minimize this problem. METHODS: 309 amyloid-beta (Aß) negative cognitively normal subjects were included in the study. Additionally, 510 realistic FTP images with different levels of OFF were generated using Monte Carlo simulation (MC). Images were corrected for PVC using both a simple two-compartment and a multi-region method including OFF regions. FTP standardized uptake value ratio (SUVR) was quantified in Braak Areas (BA), the hippocampus (which was not included in Braak I/II) and different OFF regions (caudate, putamen, pallidum, thalamus, choroid plexus (ChPlex), cerebellar white matter (cerebWM), hemispheric white matter (hemisWM) and cerebrospinal fluid (CSF)) using the lower portion of the cerebellum as a reference region. The correlations between OFF and cortical SUVRs were studied both in real and in simulated PET images, with and without PVC. RESULTS: In-vivo, we found correlations between all OFF and target regions, especially strong for the hemisWM (slope>0.63, R2>0.4). All the correlations were attenuated but remained significant after applying PVC, except for the ChPlex. In MC simulations, the hemisWM and CSF were the main contributors to PVE in all BA (slopes 0.15-0.26 and 0.13-0.21 respectively). The hemisWM (slope=0.2), as well as the ChPlex (slope=0.02), influenced SUVRs in the hippocampus. The CerebWM was negatively correlated with all target regions (slope<-0.02, R2>0.8). While no other correlations between OFF and target regions were found, hemisWM was correlated with all OFF regions but the cerebWM (slopes 0.06-0.33). HemisWM correlations attenuated (slopes<0.06) when applying two-compartment PVC, but the hippocampus-ChPlex and the cerebWM correlations required more complex PVC with dedicated compartments for these regions. In-vivo, PVC removed a notably higher fraction of the correlation between OFF regions found to be affected by PVE in the simulation studies and BA (≈50%) than for OFF regions not affected by PVE (16%). CONCLUSION: HemisWM is the main driver of spill-in effects in FTP PET, affecting both target regions and the rest of OFF regions. PVC successfully reduces PVE, even when using a simple two-compartment method. Despite PVC, non-zero correlations were still observed between target and OFF regions in vivo, which suggests the existence of biological or tracer-related contributions to these correlations.

PADI4 Haplotypes Contribute to mRNA Expression, the Enzymatic Activity of Peptidyl Arginine Deaminase and Rheumatoid Arthritis Risk in Patients from Western Mexico.

Citrullination is catalyzed by the peptidyl arginine deiminase 4 (PAD4) enzyme, encoded by the PADI4 gene. Increased PAD4 activity promotes the onset and progression of rheumatoid arthritis (RA). This study aimed to evaluate the association of PADI4 haplotypes with RA risk, mRNA expression, and the PAD4 activity in patients with RA from Mexico. Methodology: 100 RA patients and 100 control subjects (CS) were included. Genotyping was performed by PCR-RFLP method, PADI4 mRNA expression was quantified by real-time PCR, the contribution of PADI4 alleles (PADI4_89 G>A, PADI4_90 T>C, and PADI4_92 G>C) to mRNA expression by the ASTQ method, and PAD4 activity by HPLC. Also, the anti-CCP and anti-PADI4 antibodies were quantified by ELISA. Results: The three PADI4 polymorphisms were associated with RA susceptibility (OR = 1.72, p = 0.005; OR = 1.62; p = 0.014; OR = 1.69; p = 0.009; respectively). The 89G, 90T, and 92G alleles have a higher relative contribution to PADI4 mRNA expression from RA patients than 89A, 90C, and 92C alleles in RA patients. Moreover, the GTG/GTG haplotype was associated with RA susceptibility (OR = 2.86; p = 0.024). The GTG haplotype was associated with higher PADI4 mRNA expression (p = 0.04) and higher PAD4 enzymatic activity (p = 0.007) in RA patients. Conclusions: The evaluated polymorphisms contribute to PADI4 mRNA expression and the enzymatic activity of PAD4 in leukocytes. Therefore, the GTG haplotype is a genetic risk factor for RA in western Mexico, and is associated with increased PADI4 mRNA expression and higher PAD4 activity in these patients.

Relevant SARS-CoV-2 viremia is associated with COVID-19 severity: Prospective cohort study and validation cohort.

Early kinetics of SARS-CoV-2 viral load (VL) in plasma determined by quantitative reverse-transcription polymerase chain reaction (RT-PCR) was evaluated as a predictor of poor clinical outcome in a prospective study and assessed in a retrospective validation cohort. Prospective observational single-center study including consecutive adult patients hospitalized with COVID-19 between November 2020 and January 2021. Serial plasma samples were obtained until discharge. Quantitative RT-PCR was performed to assess SARS-CoV-2 VL. The main outcomes were in-hospital mortality, admission to the Intensive Care Unit (ICU), and their combination (Poor Outcome). Relevant viremia (RV), established in the prospective study, was assessed in a retrospective cohort including hospitalized COVID-19 patients from April 2021 to May 2022, in which plasma samples were collected according to clinical criteria. Prospective cohort: 57 patients were included. RV was defined as at least a twofold increase in VL within ≤2 days or a VL > 300 copies/ml, in the first week. Patients with RV (N = 14; 24.6%) were more likely to die than those without RV (35.7% vs. 0%), needed ICU admission (57% vs. 0%) or had Poor Outcome (71.4% vs. 0%), (p < 0.001 for the three variables). Retrospective cohort: 326 patients were included, 18.7% presented RV. Patients with RV compared with patients without RV had higher rates of ICU-admission (odds ratio [OR]: 5.6 [95% confidence interval [CI]: 2.1-15.1); p = 0.001), mortality (OR: 13.5 [95% CI: 6.3-28.7]; p < 0.0001) and Poor Outcome (OR: 11.2 [95% CI: 5.8-22]; p < 0.0001). Relevant SARS-CoV-2 viremia in the first week of hospitalization was associated with higher in-hospital mortality, ICU admission, and Poor Outcome. Findings observed in the prospective cohort were confirmed in a larger validation cohort.

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer's disease spectrum.

PURPOSE: Recent evidence suggests that PET imaging with amyloid-ß (Aß) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer's disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aß PET, contributes to AD progression remains unexplored. METHODS: Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aß-positive cognitively impaired, and 207 Aß-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. RESULTS: In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aß, and WMH burden. Most of these associations were also observed in Aß-negative cognitively impaired individuals. CONCLUSION: These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

Evaluating the human capacity of carrying loads without costs: A scoping review of the Free-Ride phenomenon.

OBJECTIVES: Several researchers have obtained discordant results testing the human capability to transport loads without added locomotion costs. Carrying loads has an extended relevance to human ecology, thus a review of the Free-Ride phenomenon detection according to the existing literature is needed. METHOD: A search was made in November 2021 in SCOPUS, Google Scholar, and Web of Science to identify studies comparing the energy expenditure of loaded and unloaded locomotion. Descriptive percentages were calculated with the data obtained from each study, and a Chi-squared (χ2 ) independency test and a contingency table were applied to observe the relationship between sample characteristics, experimental procedures, and the detection of the Free-Ride. RESULTS: A total of 45 studies met the inclusion criteria. Eighty two percent do not detect the Free-Ride phenomenon. The general detection is independent of sex, experience, load position, load size, and speed (p value >.05) although the papers detecting the Free-Ride have some common characteristics. CONCLUSION: The literature does not support a Free-Ride capacity, but future research testing this phenomenon should consider the load size, the load position, the level of expertise, or the speed. As the Free-Ride is not generalizable, it can be hypothesized that other mechanisms may have emerged during human evolution to buffer the energetic demands of load carrying.