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Learning of adaptive behaviors requires the refinement of coordinated activity across multiple brain regions. However, how neural communications develop during learning remains poorly understood. Here, using two-photon calcium imaging, we simultaneously recorded the activity of layer 2/3 excitatory neurons in eight regions of the mouse dorsal cortex during learning of a delayed-response task. Across learning, while global functional connectivity became sparser, there emerged a subnetwork comprising of neurons in the anterior lateral motor cortex (ALM) and posterior parietal cortex (PPC). Neurons in this subnetwork shared a similar choice code during action preparation and formed recurrent functional connectivity across learning. Suppression of PPC activity disrupted choice selectivity in ALM and impaired task performance. Recurrent neural networks reconstructed from ALM activity revealed that PPC-ALM interactions rendered choice-related attractor dynamics more stable. Thus, learning constructs cortical network motifs by recruiting specific inter-areal communication channels to promote efficient and robust sensorimotor transformation. How learning refines the coordinated activitity of neurons across multiple regions of the mouse cortex remains unclear. Here, the authors identified the emergence of cortical subnetworks during learning of a sensorimotor task.

Interference from distracting stimuli renders short-term memory vulnerable. While behavioral evidence suggests short-term memory deficits in Alzheimer’s disease (AD), the underlying neural mechanisms remain poorly understood. Using a mouse model of AD (APP-KI), we identified increased susceptibility of short-term memory to sensory perturbations. Simultaneous two-photon calcium imaging across eight cortical regions during a delayed-response task showed that distractors disrupted neural selectivity at both single-neuron and population levels in APP-KI mice. Recurrent neural network models replicating the neural activity of APP-KI mice exhibited decreased stability, consistent with reduced functional connectivity across the dorsal cortex. Furthermore, analyses of multi-regional corticocortical communication revealed reduced spatiotemporal degeneracy in activity transmission within the dorsal cortex of APP-KI mice, which could account for their attenuated robustness during sensorimotor transformations. Collectively, these findings identify reduced functional connectivity and impaired spatiotemporal degeneracy as central mechanisms of short-term memory deficits in the APP-KI mouse model of AD.

Background The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC. Methods Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse. Results The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios [AHRs]: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p  < 0.0001 (AHR: 3.10 [2.69 − 3.57]) and OS: 49% versus 22%, p  < 0.0001 (AHR: 3.32 [2.89 − 3.81]). Conclusion After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification.

Understanding the particle size distribution in the air and patterns of environmental contamination of SARS-CoV-2 is essential for infection prevention policies. Here we screen surface and air samples from hospital rooms of COVID-19 patients for SARS-CoV-2 RNA. Environmental sampling is conducted in three airborne infection isolation rooms (AIIRs) in the ICU and 27 AIIRs in the general ward. 245 surface samples are collected. 56.7% of rooms have at least one environmental surface contaminated. High touch surface contamination is shown in ten (66.7%) out of 15 patients in the first week of illness, and three (20%) beyond the first week of illness ( p  = 0.01, χ 2 test). Air sampling is performed in three of the 27 AIIRs in the general ward, and detects SARS-CoV-2 PCR-positive particles of sizes >4 µm and 1–4 µm in two rooms, despite these rooms having 12 air changes per hour. This warrants further study of the airborne transmission potential of SARS-CoV-2. Here, the authors sample air and surfaces in hospital rooms of COVID-19 patients, detect SARS-CoV-2 RNA in air samples of two of three tested airborne infection isolation rooms, and find surface contamination in 66.7% of tested rooms during the first week of illness and 20% beyond the first week of illness.

Obstructive sleep apnea syndrome (OSAS) is prevalent among children and is associated with elevated blood pressure (BP), posing a risk for future hypertension and cardiovascular diseases. While the roles of gut microbiota and systemic inflammation in OSAS pathogenesis are recognized in adults and animal models, their impact on pediatric BP remains less understood. This cross-sectional study explored the relationships between polysomnographic parameters, gut microbiota, systemic inflammation, and BP in 60 children with OSAS. Significant associations between specific microbial profiles—including beta diversity and 31 marker microbes—and BP variations were observed. These microbial profiles correlated with significant alterations in systemic inflammation markers like interleukin-17 and tumor necrosis factor-α. Notably, the relative abundance of Acinetobacter was related to fluctuations in these inflammatory markers and BP levels. The research further highlighted the unique microbial and cytokine profiles exhibited by children with different BP levels, indicating a substantial role of gut microbiota and systemic inflammation in influencing pediatric cardiovascular health. The findings suggest integrating gut microbiota management into comprehensive cardiovascular risk strategies for children with OSAS. This initiative underscores the need for further investigations to decode the mechanisms behind these associations, which could lead to innovative treatments for pediatric OSAS.

Background Operational training is a key component of resident education. Recently, innovative virtual reality (VR) training methods have been introduced to enhance training efficiency. Image-based VR (IBVR), which incorporates cognitive load, is theorized to improve task performance. However, the impact of IBVR on learning outcomes requires further investigation. This study aims to assess the efficacy of IBVR compared to textbook-based VR (TBVR) in teaching operational skills to junior residents. Methods In a prospective cross-over pilot study, ten volunteers were randomly assigned to either the IBVR-TBVR or TBVR-IBVR group. Participants engaged in four learning sessions using either IBVR or TBVR modules during the first phase. Performance was assessed using quizzes, and Milestone/Direct Observation of Procedural Skills (DOPS) ratings on real patients. After one month, participants switched to the alternate VR module for further training. Cognitive load and stress were assessed during each session through questionnaires and heart rate variability (HRV). At the end of the study, learning satisfaction, experience, and overall effectiveness were evaluated using a global satisfaction scale, the AttrakDiff2 questionnaire, and group interviews. Qualitative data were analyzed using a thematic analysis framework. Results The IBVR module yielded significantly better Milestone ( p  = 0.04), and DOPS ( p  < 0.01) scores compared to TBVR. There were no significant differences in knowledge gain, cognitive load, or HRV between the two modules. TBVR was favored in terms of global satisfaction ( p  = 0.03), hedonic stimulation ( p  = 0.01), and hedonic identification ( p  = 0.03), whereas IBVR was perceived as a more immersive and enriching experience. The majority (70%) of participants reported a positive experience with IBVR, while 50% expressed positive feedback regarding TBVR. Thematic analysis identified two key themes: usability of instructional content and ease of engagement. Conclusion Although TBVR yielded higher learner satisfaction and hedonic appeal, IBVR resulted in greater improvements in operational performance and was positively received by most participants. This proof-of-concept study highlights the complementary strengths of both VR approaches and calls for further research to validate these preliminary findings and inform the design of effective VR-based surgical education strategies. Trial registration Clinicaltrials.gov NCT03501641; https://clinicaltrials.gov/ct2/show/NCT03501641 ; date of registration: April 18, 2018.

iPS cell model of LEOPARD syndrome Patient-specific iPS (induced pluripotent stem) cells are seen as key to modelling genetic disorders and developing new treatments for them. Now iPS cell lines have been generated by nuclear reprogramming from patients with LEOPARD syndrome, a rare developmental disorder characterized by skin lesions, heart abnormalities and deafness. Cardiomyocytes derived from the resulting LEOPARD iPS cells have hypertrophic properties resembling those typical of the disease — cardiac hypertrophy occurs in 90% of children with the syndrome. The reprogrammed cells feature extensive alterations in various signal transduction pathway components, including RAS–MAPK, some previously described in association with cardiac hypertrophy. Using these cell lines, together with robust differentiation protocols, it may be possible to identify compounds that reverse diseased cellular phenotypes. The generation of induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders promises to help the basic understanding of complex diseases and the development of therapeutics. Here iPSCs have been generated from patients with LEOPARD syndrome, a developmental disorder with pleiomorphic effects on several tissues and organs. The iPSCs are characterized and the phenotype of cardiomyocytes derived from these cells is investigated. The generation of reprogrammed induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders holds the promise of increased understanding of the aetiologies of complex diseases and may also facilitate the development of novel therapeutic interventions. We have generated iPSCs from patients with LEOPARD syndrome (an acronym formed from its main features; that is, lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness), an autosomal-dominant developmental disorder belonging to a relatively prevalent class of inherited RAS–mitogen-activated protein kinase signalling diseases, which also includes Noonan syndrome, with pleomorphic effects on several tissues and organ systems 1 , 2 . The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSCs have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro -derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization and preferential localization of NFATC4 in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wild-type iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signalling pathways that may promote the disease phenotype.

Methods We sought to compare the prognostic impact of tumor differentiation with respect to adverse risk factors (RFs) identified by the National Comprehensive Cancer Network (NCCN) guidelines––including extranodal extension (ENE), positive/close margins, perineural invasion, lymphatic invasion, and vascular invasion––in patients with locally advanced oral cavity squamous cell carcinoma (OCSCC). Results Between 1996 and 2018, 1179 consecutive patients with first primary pT3–4 OCSCC were included. A three‐level grading system was adopted––in which the final classification was assigned according to the most prevalent tumor grade. We identified 382/669/128 patients with well/moderately/poorly differentiated tumors, respectively. Compared with well/moderately differentiated tumors, poorly differentiated OCSCC had a higher prevalence of the following variables: female sex (4%/6%/11%), ENE, (14%/36%/61%), positive margins (0.5%/2%/4%), close margins (10%/14%/22%), perineural invasion (22%/50%/63%), lymphatic invasion (2%/9%/17%), vascular invasion (1%/4%/10%), and adjuvant therapy (64%/80%/87%). The 5‐year rates of patients with well/moderately/poorly differentiated OCSCC were as follows: local control (LC, 85%/82%/84%, p = 0.439), neck control (NC, 91%/83%/70%, p < 0.001), distant metastases (DM, 6%/18%/40%, p < 0.001), disease‐free survival (DFS, 78%/63%/46%, p < 0.001), disease‐specific survival (DSS, 85%/71%/49%, p < 0.001), and overall survival (OS, 68%/55%/39%, p < 0.001). Multivariable analysis identified the following variables as independent prognosticators for 5‐year outcomes: ENE (LC/NC/DM/DFS/DSS/OS), poorly differentiated tumors (NC/DM/DFS/DSS/OS), positive margins (LC/DFS), lymphatic invasion (DFS/DSS/OS), perineural invasion (DM), and age ≥65 years (OS). Conclusions In addition to ENE, poor tumor differentiation was identified as the second most relevant adverse RF for patients with pT3–4 OCSCC. We suggest that the NCCN guidelines should include poor tumor differentiation as an adverse RF to refine and tailor clinical management. Final tumor grading of oral cavity squamous cell carcinoma (OCSCC) is assigned according to the most prevalent grade. Relapses of poorly differentiated OCSCC tended to occur regionally and distantly. Poor tumor differentiation was the second most relevant adverse risk factor after extranodal extension. The NCCN guidelines should include poor differentiation as an adverse risk factor.

Background The evidence for adjuvant chemoradiotherapy (CRT) of oral cavity squamous cell carcinoma (OCSCC) with extra-nodal extension (ENE) in National Comprehensive Cancer Network (NCCN) guidelines is derived from patients with head and neck cancer. The guidelines further suggest a radiation dose ranging from 6000 to 6600 cGy. In this nationwide study, we sought to evaluate the prognostic significance of adjuvant therapy and the specific radiation dosage in Taiwanese patients with pure OCSCC and ENE. Methods A retrospective analysis of 1577 OCSCC patients with ENE who underwent resection and received adjuvant CRT or radiotherapy (RT) between January 2011 and December 2020 was conducted. Results Multivariable analysis revealed that adjuvant RT, more than four pathologically positive nodes, and radiation dosage below 6000 cGy were independent risk factors for unfavorable 5-year disease-specific survival (DSS) and overall survival (OS). Comparing patients who received CRT ( n  = 1453) to those treated with RT ( n  = 124) before and after propensity score (PS) matching, the 5-year outcomes were as follows: before PS matching, DSS (54% versus 30%, p  < 0.0001), OS (42% versus 18%, p  < 0.0001); after PS matching ( n  = 111 in each group), DSS (52% versus 30%, p  = 0.0016), OS (38% versus 21%, p  = 0.0019). For patients who underwent CRT, the 5-year outcomes for different radiation dose groups (6600 − 7000 cGy, n  = 1155 versus 6000 − 6500 cGy, n  = 199) were as follows: before PS matching, DSS (52% versus 54%, p  = 0.1904), OS (43% versus 46%, p  = 0.1610); after PS matching ( n  = 199 in each group), DSS (55% versus 54%, p  = 0.8374), OS (46.5% versus 46.3%, p  = 0.7578). Conclusions For OCSCC patients with ENE, our study shows CRT improved survivals than RT alone, underscoring the clinical significance of chemotherapy. Patients undergoing CRT with irradiation doses ranging from 6000 to 6500 cGy exhibited comparable survival outcomes to those receiving doses of 6600–7000 cGy. This observation suggests that irradiation doses exceeding the 6600 cGy may not confer the survival advantage in these patients. Further research is needed to confirm our results and explore the optimal irradiation dose for managing these patients.

Electronic learning (e-learning) through mobile technology represents a novel way to teach emergent otorhinolaryngology-head and neck surgery (ORL-HNS) disorders to undergraduate medical students. Whether a cognitive style of education combined with learning modules can impact learning outcomes and satisfaction in millennial medical students is unknown. The aim of this study was to assess the impact of cognitive styles and learning modules using mobile e-learning on knowledge gain, competence gain, and satisfaction for emergent ORL-HNS disorders. This randomized controlled trial included 60 undergraduate medical students who were novices in ORL-HNS at an academic teaching hospital. The cognitive style of the participants was assessed using the group embedded figures test. The students were randomly assigned (1:1) to a novel interactive multimedia (IM) group and conventional Microsoft PowerPoint show (PPS) group matched by age, sex, and cognitive style. The content for the gamified IM module was derived from and corresponded to the textbook-based learning material of the PPS module (video lectures). The participants were unblinded and used fully automated courseware containing the IM or PPS module on a 7-inch tablet for 100 min. Knowledge and competence were assessed using multiple-choice questions and multimedia situation tests, respectively. Each participant also rated their global satisfaction. All of the participants (median age 23 years, range 22-26 years; 36 males and 24 females) received the intended intervention after randomization. Overall, the participants had significant gains in knowledge (median 50%, interquartile range [IQR]=17%-80%, P<.001) and competence (median 13%, IQR=0%-33%, P=.006). There were no significant differences in knowledge gain (40%, IQR=13%-76% vs 60%, IQR=20%-100%, P=.42) and competence gain (0%, IQR= -21% to 38% vs 25%, IQR=0%-33%, P=.16) between the IM and PPS groups. However, the IM group had a higher satisfaction score (8, IQR=6-9 vs 6, IQR=4-7, P=.01) compared with the PPS group. Using Friedman's two-way nonparametric analysis of variance, cognitive styles (field-independent, field-intermediate, or field-dependent classification) and learning modules (IM or PPS) had significant effects on both knowledge gain (both adjusted P<.001) and satisfaction (both adjusted P<.001). Mobile e-learning is an effective modality to improve knowledge of emergent ORL-HNS in millennial undergraduate medical students. Our findings suggest the necessity of developing various modules for undergraduate medical students with different cognitive styles. Clinicaltrials.gov NCT02971735; https://clinicaltrials.gov/ct2/show/NCT02971735 (Archived by WebCite at http://www.webcitation.org/6waoOpCEV).