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IntroductionTo investigate cortical network changes using Magnetoencephalography (MEG) signals in Parkinson’s disease (PD) patients undergoing Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy.MethodsWe evaluated the MEG signals in 16 PD patients with drug-refractory tremor before and after 12-month from MRgFUS unilateral lesion of the ventralis intermediate nucleus (Vim) of the thalamus contralateral to the most affected body side. We recorded patients 24 h before (T0) and 24 h after MRgFUS (T1). We analyzed signal epochs recorded at rest and during the isometric extension of the hand contralateral to thalamotomy. We evaluated cortico-muscular coherence (CMC), the out-strength index from non-primary motor areas to the pre-central area and connectivity indexes, using generalized partial directed coherence. Statistical analysis was performed using RMANOVA and post hoct-tests.ResultsMost changes found at T1 compared to T0 occurred in the beta band and included: (1) a re-adjustment of CMC distribution; (2) a reduced out-strength from non-primary motor areas toward the precentral area; (3) strongly reduced clustering coefficient values. These differences mainly occurred during motor activation and with few statistically significant changes at rest. Correlation analysis showed significant relationships between changes of out-strength and clustering coefficient in non-primary motor areas and the changes in clinical scores.DiscussionOne day after MRgFUS thalamotomy, PD patients showed a topographically reordered CMC and decreased cortico-cortical flow, together with a reduced local connection between different nodes. These findings suggest that the reordered cortico-muscular and cortical-networks in the beta band may represent an early physiological readjustment related to MRgFUS Vim lesion.

ObjectiveTo assess whether Alzheimer disease (AD) clinical presentation and APOE4 relate to the burden and topography of β-amyloid (Aβ) and tau pathologies using in vivo PET imaging.MethodsWe studied 119 Aβ-positive symptomatic patients aged 48-95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with posterior cortical atrophy (PCA). Pittsburgh compound B (PiB)-Aβ and flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), APOE4, and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the Clinical Dementia Rating Sum of Boxes.ResultsPiB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or APOE4. Flortaucipir-PET was commonly elevated in temporoparietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other AD. Cortical flortaucipir-PET binding was higher in younger patients across phenotypes (r = -0.63, 95% confidence interval [CI] -0.72, -0.50), especially in parietal and dorsal prefrontal cortices. The presence of APOE4 was associated with a focal medial temporal flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR, 95% CI 0.091, 0.530).ConclusionsClinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and APOE4 are not only risk factors for AD but also seem to affect disease expression by promoting a more medial temporal lobe-predominant pattern of tau pathology.

Group-equivariant neural networks have emerged as an efficient approach to model complex data, using generalized convolutions that respect the relevant symmetries of a system. These techniques have made advances in both the supervised learning tasks for classification and regression, and the unsupervised tasks to generate new data. However, little work has been done in leveraging the symmetry-aware expressive representations that could be extracted from these approaches. Here, we present holographic-(variational) autoencoder [H-(V)AE], a fully end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space, suitable for unsupervised learning and generation of data distributed around a specified origin in 3D. H-(V)AE is trained to reconstruct the spherical Fourier encoding of data, learning in the process a low-dimensional representation of the data (i.e., a latent space) with a maximally informative rotationally invariant embedding alongside an equivariant frame describing the orientation of the data. We extensively test the performance of H-(V)AE on diverse datasets. We show that the learned latent space efficiently encodes the categorical features of spherical images. Moreover, the low-dimensional representations learned by H-VAE can be used for downstream data-scarce tasks. Specifically, we show that H-(V)AE's latent space can be used to extract compact embeddings for protein structure microenvironments, and when paired with a random forest regressor, it enables state-of-the-art predictions of protein-ligand binding affinity.

INTRODUCTION: Immunotherapy led to increased survival in advanced non-small cell lung cancer; however, it has also increased treatment costs. In this study, real-world data was used to evaluate the average cost of treatment of patients with lung cancer. MATERIAL AND METHODS: This is a retrospective study that extracted patient-level data from a Brazilian Oncology Group database. The inclusion criteria were patients with non-small cell lung cancer from stage I-IV, and that received at least one line of treatment from 2018 to 2019. The primary endpoint was the average cost of treatment according to the disease stage, and secondary endpoints were the average cost of each line of treatment among patients with advanced disease, and the percentage of this amount that was related to immunotherapy acquisition. The study also assessed overall survival and the cost-effectiveness of immunotherapy at first-line versus immunotherapy at second-line or beyond, that was presented as the incremental cost effectiveness ratio per quality-adjusted life years. RESULTS: Fifty patients were included, being four (8%) at early-stage (I and II), 10 (20%) at locally advanced disease (III) and 36 (72%) at advanced-stage (IV). The average costs of treatment for each disease stage were respectively US$30,040, US$52,162, and US$95,607 =0.071). Among patients with advanced disease that received IO, the average cost of the entire treatment was highest with immunotherapy at first line (US$116,623) compared with immunotherapy at second-line (US$112,967) or third-line (US$37,279). Immunotherapy at first-line resulted in an estimated additional 0.26 quality-adjusted life years compared to immunotherapy at second-line (US$19,240). CONCLUSION: The cost of treating non-small cell lung cancer is higher as more advanced is the neoplasm stage at diagnosis. Regarding immunotherapy, the cost of treatment is higher as earlier the treatment is performed, even tough, the cost-effectiveness ratio for first-line treatment seems to be favorable compared to second-line treatment.

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II–IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III–IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.

The prognosis of adult acute lymphoblastic leukemia (ALL) is variable but more often dismal. Indeed, its clinical management is challenging, current therapies inducing complete remission in 65–90% of cases, but only 30–40% of patients being cured. The major determinant of treatment failure is relapse; consequently, measurement of residual leukemic blast (minimal residual disease, MRD) has become a powerful independent prognostic indicator in adults. Numerous evidences have also supported the clinical relevance of MRD assessment for risk class assignment and treatment selection. MRD can be virtually evaluated in all ALL patients using different technologies, such as polymerase chain reaction amplification of fusion transcripts and clonal rearrangements of antigen receptor genes, flow cytometric study of leukemic immunophenotypes and, the most recent, high throughput sequencing (HTS). In this review, the authors focused on the latest developments on MRD monitoring with emphasis on the use of HTS, as well as on the clinical impact of MRD monitoring.

Abstract Background context Fast-track is an evidence-based multidisciplinary strategy for pre-, intra-, and postoperative management of patients during major surgery. To date, fast-track has not been recognized or accepted in all surgical areas, particularly in orthopedic spine surgery where it still represents a relatively new paradigm. Purpose The aim of this review was provided an evidenced-based assessment of specific interventions, measurement, and associated outcomes linked to enhanced recovery pathways in spine surgery field. Methods We conducted a systematic review in three databases from February 2012 to August 2022 to assess the pre-, intra-, and postoperative key elements and the clinical evidence of fast-track protocols as well as specific interventions and associated outcomes, in patients undergoing to spine surgery. Results We included 57 full-text articles of which most were retrospective. Most common fast-track elements included patient’s education, multimodal analgesia, thrombo- and antibiotic prophylaxis, tranexamic acid use, urinary catheter and drainage removal within 24 hours after surgery, and early mobilization and nutrition. All studies demonstrated that these interventions were able to reduce patients’ length of stay (LOS) and opioid use. Comparative studies between fast-track and non-fast-track protocols also showed improved pain scores without increasing complication or readmission rates, thus improving patient’s satisfaction and functional recovery. Conclusions According to the review results, fast-track seems to be a successful tool to reduce LOS, accelerate return of function, minimize postoperative pain, and save costs in spine surgery. However, current studies are mainly on degenerative spine diseases and largely restricted to retrospective studies with non-randomized data, thus multicenter randomized trials comparing fast-track outcomes and implementation are mandatory to confirm its benefit in spine surgery.

In recent weeks, the rate of SARS-CoV-2 infections has been progressively increasing all over the globe, even in countries where vaccination programs have been strongly implemented. In these regions in 2021, a reduction in the number of hospitalizations and deaths compared to 2020 was observed. This decrease is certainly associated with the introduction of vaccination measures. The process of the development of effective vaccines represents an important challenge. Overall, the breakthrough infections occurring in vaccinated subjects are in most cases less severe than those observed in unvaccinated individuals. This review examines the factors affecting the immunogenicity of vaccines against SARS-CoV-2 and the possible role of nutrients in modulating the response of distinct immune cells to the vaccination.

Background and purpose: Preoperative partial breast irradiation (PBI) has got the advantage of treating a well-defined target. We report the results of the phase II ROCK trial (NCT03520894), enrolling early breast cancer (BC) patients treated with preoperative robotic radiosurgery (prRS), in terms of acute and early late toxicity, disease control, and cosmesis. Material and methods: The study recruited between 2018 and 2021 at our Radiation Oncology Unit. Eligible patients were 50 + years old BC, hormonal receptors positive/human epidermal growth factor receptor 2 negative (HR+/HER2-), sized up to 25 mm. The study aimed to prospectively assess the toxicity and feasibility of a robotic single 21 Gy-fraction prRS in preoperative setting. Results: A total of 70 patients were recruited and 22 patients were successfully treated with pRS. Overall, three G1 adverse events (13.6 %) were recorded within 7 days from prRS. Three events (13.6 %) were recorded between 7 and 30 days, one G2 breast oedema and two G1 breast pain. No acute toxicity greater than G2 was recorded. Five patients experienced early late G1 toxicity. One patient reported G2 breast induration. No early late toxicity greater than G2 was observed. At a median follow up of 18 months (range 6–29.8), cosmetic results were scored excellent/good and fair in 14 and 5 patients, respectively, while 3 patients experienced a poor cosmetic outcome. Conclusions: ROCK trial showed that a single 21 Gy dose prRS represents a feasible technique for selected patients affected by early BC, showing an acceptable preliminary toxicity profile.

Aim of the study: Maternal mortality and ICU admissions have increased during the COVID-19 pandemic. We reported a case-series of pregnant patients with COVID-19 admitted to an ICU and we compared them with a historical cohort of pregnant patients admitted to an ICU without COVID-19. Methods: We included all pregnant patients with laboratory-confirmed COVID-19 infection admitted to our ICU in 2021. As a historical control group, we included all pregnant women who were admitted to our ICU between 1 January 2008 and 31 December 2013. Results: In 2021, 11 pregnant patients (pts) with COVID-19 were admitted to an ICU, representing 2.87% of ICU admissions. We found that pregnant patients with COVID-19 (1) had a higher BMI (34.6 vs. 28.8, p = 0.04) and a lower gestational age (30.6 vs. 34 weeks, p = 0.03), (2) were mainly admitted for respiratory failure (100% vs. 2.7%; p = 0.001) and (3) required more days of invasive and non-invasive ventilations (54.5% vs. 5.2%, p = 0.002), a longer duration of stay at the ICU (21.9 vs. 4.8 days, p < 0.0001) and had a higher mortality rate (27.3% vs. 0%, p = 0.0192). Conclusions: Pregnant patients with COVID-19 represent a challenge for ICU physicians due to their different characteristics and outcomes when compared to pregnant patients without COVID-19.

BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages.