Cortical and white matter substrates supporting visuospatial working memory.

OBJECTIVE: In tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance. METHODS: Patients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts. RESULTS: Elevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76. CONCLUSIONS: Optimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways. SIGNIFICANCE: This study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts.

Peripheral Nerve Blocks in the Preoperative Management of Hip Fractures: A Systematic Review and Network Meta-Analysis.

STUDY OBJECTIVE: We conducted a systematic review and network meta-analysis to evaluate the comparative efficacy of peripheral nerve block types for preoperative pain management of hip fractures. METHODS: We searched Cochrane, Central Register of Controlled Trials, MEDLINE, EMBASE, ICTRP, ClinicalTrials.gov, and Google Scholar for randomized clinical trials. We included participants aged more than 16 years with hip fractures who received peripheral nerve blocks or analgesics for preoperative pain management. The primary outcomes were defined as absolute pain score 2 hours after block placement, preoperative consumption of morphine equivalents, and length of hospital stay. We used a random-effects network meta-analysis conceptualized in the Bayesian framework. Confidence of evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 63 randomized controlled studies (4,778 participants), of which only a few had a low risk of bias. The femoral nerve block, 3-in-1 block, fascia iliaca compartment block, and pericapsular nerve group block yielded significantly lowered pain scores at 2 hours after block placement compared with those with no block (standardized mean differences [SMD]: -1.1; 95% credible interval [CrI]: -1.7 to -0.48, [confidence of evidence: low]; SMD: -1.8; 95% CrI: -3.0 to -0.55, [low]; SMD: -1.4; 95% CrI: -2.0 to -0.72, [low]; SMD: -2.3; 95% CrI: -3.2 to -1.4, [moderate], respectively). The pericapsular nerve group block, 3-in-1 block, fascia iliaca compartment block, and femoral nerve block resulted in lower pain scores than the no-block group. Additionally, the pericapsular nerve group block yielded a lower pain score than femoral nerve block or fascia iliaca compartment block (SMD: -1.21; 95% CrI: -2.18 to -0.23, [very low]: SMD: -0.92; 95% CrI: -1.70 to -0.16, [low]). However, both the fascia iliaca compartment block and femoral nerve block did not show a reduction in morphine consumption compared with no block. To our knowledge, no studies have compared the pericapsular nerve group block with other methods regarding morphine consumption. Furthermore, no significant difference was observed between peripheral nerve blocks and no block in terms of the length of hospital stay. CONCLUSIONS: Compared with no block, preoperative peripheral nerve blocks for hip fractures appear to reduce pain 2 hours after block placement. Comparing different blocks, pericapsular nerve group block might be superior to fascia iliaca compartment block and femoral nerve block for pain relief, though the confidence evidence was low in most comparisons because of the moderate to high risk of bias in many of the included studies and the high heterogeneity of treatment strategies across studies. Therefore, further high-quality research is needed.

Developmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves.

We investigated the developmental changes in high-frequency oscillation (HFO) and Modulation Index (MI) - the coupling measure between HFO and slow-wave phase. We generated normative brain atlases, using subdural EEG signals from 8251 nonepileptic electrode sites in 114 patients (ages 1.0-41.5 years) who achieved seizure control following resective epilepsy surgery. We observed a higher MI in the occipital lobe across all ages, and occipital MI increased notably during early childhood. The cortical areas exhibiting MI co-growth were connected via the vertical occipital fasciculi and posterior callosal fibers. While occipital HFO rate showed no significant age-association, the temporal, frontal, and parietal lobes exhibited an age-inversed HFO rate. Assessment of 1006 seizure onset sites revealed that z-score normalized MI and HFO rate were higher at seizure onset versus nonepileptic electrode sites. We have publicly shared our intracranial EEG data to enable investigators to validate MI and HFO-centric presurgical evaluations to identify the epileptogenic zone.

Current Knowledge and Prospects for Renal Hemangioblastoma and Renal Cell Carcinoma with Hemangioblastoma-like Features.

Tumors exhibiting histopathological findings similar to those of hemangioblastoma of the central nervous system (CNS-HB) rarely develop in the kidneys. Currently, renal hemangioblastoma (RHB) is considered analogous to CNS-HB; however, they differ in gross appearance, as well as immunohistochemical and molecular findings. In contrast, some renal cell carcinomas reportedly comprise distinct, clear cell renal cell carcinoma (CCRCC)- and hemangioblastoma (HB)-like areas. Initially, renal cell carcinomas with HB-like features (RCC-HBs) were considered a morphological variant of CCRCC owing to their diverse histological findings. However, the immunohistochemical and molecular findings of RCC-HBs suggest that RCC-HB is distinct from CCRCC. Additionally, one of the RCC-HBs had a focal leiomyomatous stroma and TSC2 variant, suggesting that RCC-HB and RCC with fibromyomatous stroma (RCC-FMS) might belong to the same disease entity. Therefore, we comprehensively reviewed the clinical, pathological, and molecular features of RHB, RCC-HB, and the related tumors and discussed the similarities, differences, and relationships between them. We believe that our review would serve as a foundation for further investigation on elucidating the relationship between CNS-HB, RHB, RCC-HB, and RCC-FMS.

Sevoflurane-induced high-frequency oscillations, effective connectivity and intraoperative classification of epileptic brain areas.

OBJECTIVE: To determine how sevoflurane anesthesia modulates intraoperative epilepsy biomarkers on electrocorticography, including high-frequency oscillation (HFO) effective connectivity (EC), and to investigate their relation to epileptogenicity and anatomical white matter. METHODS: We studied eight pediatric drug-resistant focal epilepsy patients who achieved seizure control after invasive monitoring and resective surgery. We visualized spatial distributions of the electrocorticography biomarkers at an oxygen baseline, three time-points while sevoflurane was increasing, and at a plateau of 2 minimum alveolar concentration (MAC) sevoflurane. HFO EC was combined with diffusion-weighted imaging, in dynamic tractography. RESULTS: Intraoperative HFO EC diffusely increased as a function of sevoflurane concentration, although most in epileptogenic sites (defined as those included in the resection); their ability to classify epileptogenicity was optimized at sevoflurane 2 MAC. HFO EC could be visualized on major white matter tracts, as a function of sevoflurane level. CONCLUSIONS: The results strengthened the hypothesis that sevoflurane-activated HFO biomarkers may help intraoperatively localize the epileptogenic zone. SIGNIFICANCE: Our results help characterize how HFOs at non-epileptogenic and epileptogenic networks respond to sevoflurane. It may be warranted to establish a normative HFO atlas incorporating the modifying effects of sevoflurane and major white matter pathways, as critical reference in epilepsy presurgical evaluation.

Lack of clinical evidence of antiviral therapy for human monkeypox: A scoping review.

Since May 2022, many human monkeypox cases have been reported from non-endemic countries. This systematic review aimed to evaluate and summarize the existing research on the efficacy and safety of tecovirimat, brincidofovir, and cidofovir for patients with monkeypox. We searched studies that reported the efficacy and adverse events of tecovirimat, brincidofovir, or cidofovir for patients with human monkeypox in several databases including preprint servers. Only five studies were included. The efficacy and adverse events were assessed in only five and four patients, respectively. Regarding tecovirimat, all two patients recovered from monkeypox. One had no adverse event and the other has no description of an adverse event. Regarding brincidofovir, all three patients recovered from monkeypox but all of them had increased alanine transaminase, and one had nausea and abdominal discomfort. There was no study on treatment with cidofovir. Based on past studies and our results, tecovirimat might be the best choice due to ease of administration (oral drug), fewer side effects, and past treatment results for human monkeypox administration. However, very few studies were included in this scoping review. Therefore, further studies are needed to assess their efficacy and safety as possible treatments for human monkeypox.

Neuropsychiatric aspects of long COVID: A comprehensive review.

Although some patients have persistent symptoms or develop new symptoms following coronavirus disease 2019 (COVID-19) infection, neuropsychiatric aspects of long COVID are not well known. This review summarizes and provides an update on the neuropsychiatric dimensions of long COVID. Its neuropsychiatric manifestations commonly include fatigue, cognitive impairment, sleep disorders, depression, anxiety, and post-traumatic stress disorder. There are no specific tests for long COVID, but some characteristic findings such as hypometabolism on positron emission tomography have been reported. The possible mechanisms of long COVID include inflammation, ischemic effects, direct viral invasion, and social and environmental changes. Some patient characteristics and the severity and complications of acute COVID-19 infection may be associated with an increased risk of neuropsychiatric symptoms. Long COVID may resolve spontaneously or persist, depending on the type of neuropsychiatric symptoms. Although established treatments are lacking, various psychological and pharmacological treatments have been attempted. Vaccination against COVID-19 infection plays a key role in the prevention of long coronavirus disease. With differences among the SARS-CoV-2 variants, including the omicron variant, the aspects of long COVID are likely to change in the future. Further studies clarifying the aspects of long COVID to develop effective treatments are warranted.

Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis.

Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study's goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. Driver events, copy-number alteration (CNA) analysis and mutational signature profiling were performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels and structural variants as well as CNAs, while transcriptome data were analyzed for differentially expressed genes and through gene set enrichment analysis. ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All acquired cystic disease (ACD)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation and targets of Myc. This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis.

Multi-Scale Deep Learning of Clinically Acquired Multi-Modal MRI Improves the Localization of Seizure Onset Zone in Children With Drug-Resistant Epilepsy.

The present study investigates the effectiveness of a deep learning neural network for non-invasively localizing the seizure onset zone (SOZ) using multi-modal MRI data that are clinically acquired from children with drug-resistant epilepsy. A cortical parcellation was applied to localize the SOZ in cortical nodes of the epileptogenic hemisphere. At each node, the laminar surface analysis was followed to sample 1) the relative intensity of gray matter and white matter in multi-modal MRI and 2) the neighboring white matter connectivity using diffusion tractography edge strengths. A cross-validation was employed to train and test all layers of a multi-scale residual neural network (msResNet) that can classify SOZ node in an end-to-end fashion. A prediction probability of a given node belonging to the SOZ class was proposed as a non-invasive MRI marker of seizure onset likelihood. In an independent validation cohort, the proposed MRI marker provided a very large effect size of Cohen's d = 1.21 between SOZ and non-SOZ, and classified SOZ with a balanced accuracy of 0.75 in lesional and 0.67 in non-lesional MRI groups. The subsequent multi-variate logistic regression found the incorporation of the proposed MRI marker into interictal intracranial EEG (iEEG) markers further improves the differentiation between the epileptogenic focus (defined as SOZ resected during surgery) and non-epileptogenic sites (i.e., non-SOZ sites preserved during surgery) up to 15 % in non-lesional MRI group, suggesting that the proposed MRI marker could improve the localization of epileptogenic foci for successful pediatric epilepsy surgery.

Comparative efficacy of sedation or analgesia methods for reduction of anterior shoulder dislocation: A systematic review and network meta-analysis.

BACKGROUND: We performed a network meta-analysis (NMA) to compare the efficacy and safety of intravenous sedation (IVS), intraarticular anesthetic injection (IAA), and peripheral nerve block (PNB) as sedation or analgesia methods for the reduction of anterior shoulder dislocation. METHODS: We included randomized controlled trials (RCTs) comparing different sedation or analgesia methods for anterior shoulder dislocation reduction. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ICTRP, ClinicalTrials.gov, and Google Scholar databases were searched in October 2021. We conducted a random-effects NMA within a frequentist framework. We evaluated the confidence in each outcome using the CINeMA tool. RESULTS: Sixteen RCTs (957 patients) were included. Regarding the primary outcomes, the three methods might result in little to no difference in the immediate success rate of reduction and patient satisfaction. The IAA method had a shorter emergency department length of stay than that of the IVS method (mean difference [MD] -107.88 min, 95% confidence interval [CI] -202.58 to -13.18). In the secondary outcomes, the IAA method had a lower pain score than that of the PNB method (standardized MD -1.83, 95% CI -3.64 to -0.02). The IAA and PNB methods might require a longer time for reduction than that of the IVS method (MD 5.3 min, 95% CI 2.4 to 10.36; MD 15.25, 95% CI 5.49 to 25.01). The three methods might result in little to no difference in the number of reduction attempts and total success rate of reduction. However, the confidence ratings for all treatment comparisons were very low. IAA and PNB had no adverse respiratory events. CONCLUSIONS: The results of our NMA indicated that three sedation or analgesia methods (IVS, IAA, and PNB) might result in little to no difference in the success rate of reduction and patient satisfaction. IAA and PNB had no adverse respiratory events.

Seizure Control in Patients with Epilepsy during the COVID-19 Pandemic: A Systematic Review and Meta-analysis.

Objective To investigate seizure control in patients with epilepsy during the coronavirus disease 2019 (COVID-19) pandemic. Method A systematic review and meta-analysis was conducted, and the MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov databases were comprehensively searched for relevant studies. Studies that reported seizure control in patients with epilepsy during the COVID-19 pandemic were included. Pooled proportions with 95% confidence intervals (CIs) of patients with epilepsy who experienced seizure worsening during the COVID-19 pandemic were assessed using a random-effects model. The quality of the assessment for each study, heterogeneity between the studies, and publication bias were also evaluated. Subgroup analyses were performed, excluding studies with reports of seizures worsening from caregivers. Results A total of 24 studies with 6,492 patients/caregivers were included in the meta-analysis. The pooled proportion of seizure worsening was 18.5% (95% CI: 13.9-23.6; I2=96%; p<0.01). The pooled proportion of seizure worsening in the subgroup analysis was 18.9% (95% CI: 13.5-25.0; I2=96%; p<0.01). Conclusion Although the heterogeneity was high, our results showed a relatively high incidence of seizure worsening during the COVID-19 pandemic. During the COVID-19 pandemic, physicians should be aware of the likelihood of worsening seizures in patients with epilepsy.

Developmental organization of neural dynamics supporting auditory perception.

PURPOSE: A prominent view of language acquisition involves learning to ignore irrelevant auditory signals through functional reorganization, enabling more efficient processing of relevant information. Yet, few studies have characterized the neural spatiotemporal dynamics supporting rapid detection and subsequent disregard of irrelevant auditory information, in the developing brain. To address this unknown, the present study modeled the developmental acquisition of cost-efficient neural dynamics for auditory processing, using intracranial electrocorticographic responses measured in individuals receiving standard-of-care treatment for drug-resistant, focal epilepsy. We also provided evidence demonstrating the maturation of an anterior-to-posterior functional division within the superior-temporal gyrus (STG), which is known to exist in the adult STG. METHODS: We studied 32 patients undergoing extraoperative electrocorticography (age range: eight months to 28 years) and analyzed 2,039 intracranial electrode sites outside the seizure onset zone, interictal spike-generating areas, and MRI lesions. Patients were given forward (normal) speech sounds, backward-played speech sounds, and signal-correlated noises during a task-free condition. We then quantified sound processing-related neural costs at given time windows using high-gamma amplitude at 70-110 Hz and animated the group-level high-gamma dynamics on a spatially normalized three-dimensional brain surface. Finally, we determined if age independently contributed to high-gamma dynamics across brain regions and time windows. RESULTS: Group-level analysis of noise-related neural costs in the STG revealed developmental enhancement of early high-gamma augmentation and diminution of delayed augmentation. Analysis of speech-related high-gamma activity demonstrated an anterior-to-posterior functional parcellation in the STG. The left anterior STG showed sustained augmentation throughout stimulus presentation, whereas the left posterior STG showed transient augmentation after stimulus onset. We found a double dissociation between the locations and developmental changes in speech sound-related high-gamma dynamics. Early left anterior STG high-gamma augmentation (i.e., within 200 ms post-stimulus onset) showed developmental enhancement, whereas delayed left posterior STG high-gamma augmentation declined with development. CONCLUSIONS: Our observations support the model that, with age, the human STG refines neural dynamics to rapidly detect and subsequently disregard uninformative acoustic noises. Our study also supports the notion that the anterior-to-posterior functional division within the left STG is gradually strengthened for efficient speech-sound perception after birth.

Educational Approaches That Enhance Online Clinical Clerkship during the COVID-19 Pandemic.

Objective This cross-sectional national study determined which educational approaches are associated with the effectiveness of online clerkship for medical students. Method A survey was conducted for medical students at 78 medical schools in Japan from May 29 to June 14, 2020. It comprised the following aspects: (a) participants' profiles, (b) number of opportunities to learn from each educational approach (lecture, medical quiz, assignment, oral presentation, observation of a physician's practice, clinical skill practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clerkship, (c) frequency of technical problems, and (d) educational outcome measurement (satisfaction, motivation, knowledge acquisition, skill acquisition, change in self-study time, and understanding of the importance of medical care team). Results Of the 2,640 respondents, 2,594 (98.3%) agreed to cooperate. Ultimately, 1,711 matched our inclusion criteria. All educational approaches but assignments were positively associated with satisfaction and motivation. All educational approaches excluding assignment submission and interprofessional meeting were positively associated with knowledge acquisition. Observation, practice, and interprofessional meeting were positively associated with skill acquisition. Only assignment submission was positively associated with the change in self-study time. Educational approaches excluding medical quizzes were positively associated with understanding the importance of the medical care team. Technical problems were negatively associated with motivation, knowledge acquisition, and skill acquisition. Conclusions Educators should implement various educational approaches, especially observation and practice, even in online clinical clerkship. They also need to minimize the technical problems associated with the Internet, as they reduce the effectiveness of online clerkship.

Impact of COVID-19 pandemic on epilepsy care in Japan: A national-level multicenter retrospective cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. METHODS: This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy-center-specific monthly data divided by the 12-month average in 2019 for each facility. We determined whether the COVID-19 pandemic-related factors (such as year [2019 or 2020], COVID-19 cases in each prefecture in the previous month, and the state of emergency) were independently associated with these outcomes. RESULTS: In 2020, the frequency of outpatient EEG studies (-10.7%, p<0.001) and cases with telemedicine (+2,608%, p=0.031) were affected. The number of COVID-19 cases was an independent associated factor for epilepsy admission (-3.75*10-3 % per case, p<0.001) and EEG monitoring (-3.81*10-3 % per case, p = 0.004). Further, the state of emergency was an independent factor associated with outpatient with epilepsy (-11.9%, p<0.001), outpatient EEG (-32.3%, p<0.001), telemedicine for epilepsy (+12,915%, p<0.001), epilepsy admissions (-35.3%; p<0.001), EEG monitoring (-24.7%: p<0.001), and epilepsy surgery (-50.3%, p<0.001). SIGNIFICANCE: We demonstrated the significant impact that the COVID-19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic-related factor on epilepsy care.

Molecular Characterization of Metanephric Adenoma, Epithelial Wilms Tumor, and Overlap Lesions: An Integrated Whole-exome and Transcriptome Sequencing Analysis.

Metanephric adenoma (MA) and Wilms tumor (WT) represent 2 prototypes of primary renal neoplasms closely resembling embryonal renal tubules. Tumors with overlapping features may occur, requiring differential diagnoses between the 2. Evidence of divergent oncogenic pathways has been reported, suggesting that MA is driven by BRAF mutation while most WT is of the BRAF wild-type. We collected 4 MA cases, 3 cases of monophasic epithelial WT, and 1 overlap metanephric tumor that contains both conventional MA and high-grade components similar to epithelial WT. Whole-exome sequencing and whole transcriptome sequencing were performed to discover mutations, somatic copy number variation, and differential expression. The findings were compared with those of WT of the TARGET database (WT-TARGET). BRAF V600E mutation was detected in all MAs as well as the overlap tumor but was undetectable in all epithelial WTs and WT-TARGET. The overlap tumor showed an additional pathogenic mutation of SETD2. Three frequent gene mutations observed in WT-TARGET were not common in epithelial WT, in which the mutations appeared sporadic. The profiles of recurrent copy number variations were all different among MA, epithelial WT, and WT-TARGET. Differential expression and unsupervised hierarchical cluster analyses revealed distinct clusters of the 3 categories. Remarkably, the overlap tumor coclustered with MA, separated from epithelial WT and WT-TARGET. The distinctiveness of MA and WT were demonstrated corresponding to BRAF-mutated and non-BRAF-mutated pathways from the molecular perspective. BRAF assay has diagnostic implication for overlap tumors.

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.