We developed a web-based application to help patients with cancer write high-quality secure messages to clinicians. Our objective was to test the effectiveness of the application, SEND, to determine if it positively impacted the clarity, directness, ability to express concerns and questions, specificity, and overall quality of messages. Patients with cancer 18 years and older were recruited through an online data collection and testing resource. They reflected on a time during their cancer treatment and wrote a simulated message to a clinician. After viewing SEND, they wrote another simulated message. Three oncology fellows blindly rated messages (pre- or post-intervention) based on five criteria: clarity, directness, expressiveness, specificity, and overall quality. Each criterion was rated on a five-point Likert scale ranging from 1 =poor to 5 =excellent. Data were analyzed using mixed-effects linear models to examine changes in outcomes over time while accounting for the non-independence of repeated measures within participants. Twenty-eight participants viewed SEND and wrote simulated messages. Most (53.6%) were female, and the mean age was 53 years. Raters evaluated a total of 56 messages (28 pre- and 28 post-). The word count of messages decreased from 47 to 43 words post-intervention. We found a significant improvement in the needs domain (β = 0.40, SE = 0.15, t = 2.64, p = .011), while all other domains increased post-intervention, but were not statistically significant. Our intervention was associated with improving the communication of patient needs (i.e. stating the main goal of the message). Improving the quality of secure messages written by patients has the potential to benefit both patients and clinicians. Patients can learn to craft succinct messages focusing on their main concerns, which may reduce clinicians' workload.
Non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) are malignancies with numerous actionable mutations. Accurate mutation identification is essential for targeted therapies, highlighting the need for next-generation sequencing (NGS). This study evaluated the Oncomine Precision Assay (OPA) as an alternative to single-gene panel (SGP) and send-out NGS (SO-NGS) testing in NSCLC and CRC. Turnaround time (TAT), quantity not sufficient (QNS) rates, and detection of National Comprehensive Cancer Network recommended alterations were compared. NSCLC alterations included EGFR, MET exon 14 skipping, ROS1, ALK fusions, RET fusions, ERBB2 mutations, NTRK1/2/3 fusions, BRAF, and KRAS p.G12C. CRC alterations included RET fusions, ERBB2 amplification, NTRK1/2/3 fusions, BRAF, KRAS, NRAS, and microsatellite instability. A total of 74 NSCLC and 72 CRC cases were analyzed concurrently with OPA and SGP and compared with historical SO-NGS data from 163 NSCLC and 49 CRC cases. OPA demonstrated broader mutation coverage than SGP, detecting all evaluated NSCLC alterations and most CRC alterations, while SO-NGS provided the most comprehensive coverage overall. In both NSCLC and CRC, OPA mean TAT was shorter when compared with SGP and SO-NGS. OPA also demonstrated lower QNS rates and comparable or improved detection rates, supporting its use for community-based molecular testing in NSCLC and CRC.
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This paper examines how Italian teenagers construct meanings, norms and boundaries around sexting within their everyday digital cultures. Drawing on six vignette-based focus groups with 49 participants aged 16-18 years, the study used a media practice approach to analyse how teenagers collectively interpret a hypothetical sexting vignette. Findings show that participants overwhelmingly rely on heteronormative scripts, reproducing the dominant "girl-sends-nude-to-boy" narrative and positioning boys as initiators, while girls bear the potential risks. Sexting was consistently framed through risk discourses-particularly the threat of non-consensual dissemination-leading girls to internalise fear, self-policing, and responsibility for managing potential harm. Peer gossip further reinforced these risk narratives, circulating cautionary tales that blurred the boundaries between consensual and non-consensual practices and sustained moral regulation among peers. In response, teenagers constructed informal boundaries distinguishing "appropriate" from "unsafe" sexting, often limiting acceptable practices to long-term relationships and less explicit content. These findings highlight how risk discourses, peer surveillance and entrenched gender norms constrain teenagers' digital intimacies, particularly in an Italian context marked by limited sexuality education and persistent gender inequalities. The paper argues for research and pedagogical approaches that move beyond risk prevention to support teenagers' rights to agentic digital intimacies.
Patient portals have become a primary mechanism for patient-provider communication, offering convenience for patients while also creating an uncompensated workload burden for providers. This issue is underexplored in shoulder and elbow surgery, where pain, quality of life burden, and complex rehabilitation plans may drive frequent messaging. This study evaluated trends in portal messaging within a shoulder and elbow orthopedic cohort. This study was a retrospective review of all patients evaluated in a tertiary center's shoulder and elbow division between January 1, 2022 and December 31, 2025. Five fellowship-trained shoulder and elbow surgeons and 4 advanced practice providers were included. Demographic data (age, sex, race, ethnicity, preferred language, and surgical status) were collected from the medical record. Associations between patient characteristics and sending ≥1 medical advice message were assessed using logistic regressions, with results reported as adjusted odds ratios (aORs). Patient characteristics associated with the number of messages were characterized using a Poisson regression, with results reported as adjusted incidence rate ratios (aIRRs). The cohort included 23,643 patients; 21% (n = 4,953) sent ≥1 medical advice message. Medical advice requests represented 41,542 (30%) of 137,960 total messages. The number of medical advice messages steadily grew by nearly 400% between 2022 and 2026. Surgical patients were more likely to send messages (aOR: 5.93, P < .001) and had a higher message count (aIRR: 23.3, P < .001) than nonsurgical patients. Black/African American patients had a lower odd of sending a medical advice message (aOR: 0.55, P < .001) and lower message counts (aIRR: 0.58, P < .001) compared to White patients. Spanish-speaking patients had a lower odd of sending a medical advice message (aOR: 0.21, P < .001) and lower message counts (aIRR: 0.17, P < .001) compared to English-speaking patients. This study identified a growing volume of medical advice requests in shoulder and elbow surgery by nearly 400%, representing an expanding administrative concern. The independent negative predictive value of Black race and Spanish language for low messaging use suggests that current portal structures may create or exacerbate disparities in digital health access. Future implementation must address uncompensated provider workload while ensuring patients from all groups have equitable access to portal tools.
Preclinical toxicology study reports contain the expert interpretations required to distinguish test article-related effects from incidental findings, yet these conclusions often remain embedded in unstructured text form that limit systematic reuse and integration with computational safety approaches. To address this gap, we developed a Large Language Model (LLM) - supported pipeline that converts toxicology reports into structured, machine-readable datasets harmonized with SEND terminology. The pipeline combines automated document preprocessing, section identification, schema-constrained information extraction, and semantic harmonization, complemented by targeted human curation. We evaluated the system performance using 200 Roche toxicology study reports, encompassing clinical pathology, histopathology, organ weights, exposure data, and study-level conclusions. Across domains, extraction performance was strong, characterized by consistently high sensitivity and precision for most parameters. Histopathology, organ weight, and NOAEL-related endpoints demonstrated the greatest robustness, with sensitivity typically above 95% and precision frequently exceeding 97%. Lower performance for parameters such as route of administration and substance identifiers reflected heterogeneous reporting practices rather than LLM-based method limitations. The structured datasets generated by this pipeline enable cross-study querying, identification of compounds with defined toxicological liabilities, integration with raw SEND data, and development of high-quality labels for predictive toxicology models. Practical utility has been demonstrated through representative use cases. These results demonstrate that LLM-assisted extraction can reliably capture expert toxicological interpretations at scale and provide a foundation for data-centric safety assessment, strategic decisions, reverse and forward translational toxicology research.
Recent studies following Milgram's seminal experiment have provided insights into what neural, psychological, and contextual factors influence disobedience to immoral orders. According to the engaged followership model, greater identification with the experimenter leads to greater obedience. However, such results were not always replicated. It remains unclear how identifying with the person giving orders modulates (dis)obedience and related mechanisms. Therefore, the current study focussed on neurocognitive mechanisms and cultural factors related to identification with the experimenter to explain one's decision to (dis)obey. We investigated an ecologically valid paradigm wherein participants received orders from the experimenter to send real, mildly painful shocks to a victim. Participants were divided into Low or High identification groups via a median-split on their experimenter identification scores. The results showed that identification with the experimenter did not influence prosocial disobedience (i.e., refusing to obey the orders to send a shock) rate or the neural conflict markers (midfrontal-theta activity), but it modulated the implicit sense of agency (SoA). Participants in the Low identification group showed greater temporal binding effect (more SoA) when disobeying harmful orders than when obeying to shock, whereas this effect was not observed amongst those who identified more with the experimenter. Exploratory analyses revealed that prosocial disobedience was associated with multiple factors: responsibility rating, Right-wing Authoritarianism, and moral-foundation subscale (Authority/Respect). These findings highlight that prosocial disobedience may emerge from an interplay of cognitive processes and sociocultural values rather than from identification with the experimenter alone, indicating the need to study (dis)obedience with a pluralistic approach.
Discharged Emergency Department (ED) patients should receive instructions about their condition, including self-care and return-to-care guidance, while satisfying medicolegal requirements. Verbal instructions are forgotten or poorly understood. Written instructions are best practice, but usage barriers include multifactorial inefficiencies getting them to the patient and patient challenges finding them later when needed. In this feasibility and uptake study, we sought to address these barriers by developing a website that enables physicians to send condition-specific discharge instructions by text message. We recruited from the approximately 60 physicians working in the Saskatoon, Canada adult EDs, which serve > 140,000 patients/year. The physician visits our website, enters the patient's phone number, selects a condition, and taps "send." The patient receives a text message with a link to condition-specific discharge instructions. We analyzed link access data and surveyed physician feedback. Over a 2-month study period, 115 discharge instructions were texted (< 1% of an estimated maximum 17,000 discharges). 83% were accessed, 43% repeatedly. Links were visited quickly: 57% within one minute, 81% within one hour, and 97% within 24 h. 36 conditions were selected, most commonly concussion (19%), abdominal pain (9%), laceration (7%), and renal colic (7%). Seventeen physicians (28%) responded to our survey. 47% indicated they do not typically provide written (paper-based) discharge instructions. 87% ranked our system ≥ 8/10 in ease of use (0 = very difficult, 10 = very easy), 73% ranked it ≥ 7/10 in efficiency compared to usual practice (0 = maximally inefficient, 10 = maximally efficient). 93% said they would use our system going forward. Our study is limited by low physician uptake. However, positive physician feedback and quick and repeated patient access to instructions together suggest our approach might be a feasible way to improve ED discharge practice. RéSUMé: OBJECTIFS: Les patients des services d’urgence (SU) doivent recevoir des instructions sur leur état, y compris des conseils sur l’autosoins et le retour aux soins, tout en respectant les exigences médico-légales. Les instructions verbales sont oubliées ou mal comprises. Les instructions écrites sont la meilleure pratique, mais les obstacles à l’utilisation incluent des inefficacités multifactorielles pour les acheminer au patient et des difficultés pour le patient à les trouver plus tard lorsque cela est nécessaire. Dans cette étude de faisabilité et d’adoption, nous avons cherché à surmonter ces obstacles en développant un site web qui permet aux médecins d’envoyer des instructions de sortie spécifiques à une condition par message texte. MéTHODES: Nous avons recruté parmi les quelque 60 médecins travaillant dans les services d’urgence pour adultes de Saskatoon, au Canada, qui traitent plus de 140 000 patients par année. Le médecin visite notre site web, saisit le numéro de téléphone du patient, sélectionne une condition et tape « envoyer ». Le patient reçoit un message texte avec un lien vers les instructions de sortie spécifiques à la condition. Nous avons analysé les données d’accès aux liens et sondé les commentaires des médecins. RéSULTATS: Sur une période d’étude de 2 mois, 115 instructions de sortie ont été envoyées par texto (<1 % d’un maximum estimé de 17 000 sorties). 83 % ont été consultés, 43 % à plusieurs reprises. Les liens ont été visités rapidement : 57 % en une minute, 81 % en une heure et 97 % en 24 heures. 36 affections ont été sélectionnées, le plus souvent commotion cérébrale (19 %), douleur abdominale (9 %), lacération (7 %) et colique néphrétique (7 %). Dix-sept médecins (28 %) ont répondu à notre sondage. 47 % ont indiqué qu’ils ne fournissent généralement pas d’instructions de congé écrites (sur papier). 87 % ont classé notre système ≥8/10 en termes de facilité d’utilisation (0 = très difficile, 10 = très facile), 73 % l’ont classé ≥7/10 en efficacité par rapport à la pratique habituelle (0 = au maximum inefficace, 10 = au maximum efficace). 93 % ont dit qu’ils utiliseraient notre système à l’avenir. CONCLUSIONS: Notre étude est limitée par la faible adhésion des médecins. Cependant, les commentaires positifs des médecins et l’accès rapide et répété des patients aux instructions suggèrent que notre approche pourrait être un moyen réalisable d’améliorer la pratique de sortie du service d’urgence.
As the opioid epidemic claims over 200 lives per day, there is an urgent need to increase access to evidence-based, non-pharmacologic modalities for pain management. To design, implement, and evaluate an integrative medicine group visit (IMGV) facilitator training program to support group visits incorporating mind-body therapies (eg, acupuncture, meditation, tai chi, yoga) for chronic musculoskeletal pain within the Los Angeles County Department of Health Services (LAC DHS). Prospective cohort pre-post study with mixed methods formative evaluation. Fifty-nine clinical staff from 3 LAC DHS medical centers and associated clinics enrolled in a 40-hour curriculum including online modules, case discussions, and onsite skills workshops in 2020. We used the Self-Efficacy in Using Non-Drug Therapies for Common Symptoms (SEND) scale to measure change in trainees' self-efficacy to teach selected mind-body therapies for chronic pain management. We evaluated feasibility and acceptability with the course completion rate and obtained participant feedback through program evaluations and semi-structured interviews. 49% of staff members completed the course, primarily physicians (37%) and rehabilitation therapists (22%). Most participants (80%) were female and 28% more non-physicians completed the final exam than physicians (P = 0.040). SEND scores increased by 20.9 (P < 0.001). Trainees strongly valued the curriculum content, particularly the in-person tai chi and acupressure instruction, but recommended that the online modules be customizable to reduce time commitment. Disruptions from the COVID-19 pandemic affected course progress and completion rates. Overall, the IMGV facilitator training program was acceptable, feasible with program modifications under pandemic conditions, and increased staff confidence to teach others nonpharmacologic chronic pain management.
The Internet of Medical Things is revolutionizing the concept of patient care. It is empowering the implementation of remote patient care protocols through the use of body sensors to monitor vital signs. However, it produces vast amounts of information, which raises security and privacy concerns. High-dimensional medical data are essential for diagnosis and treatment, but they are not currently connected to blockchain-based electronic health record systems. To overcome these limitations, the authors present a Hyperledger Fabric-based secure remote patient monitoring model for storing and retrieving medical imaging. The system records patient vital signs using sensors and stores medical images off-chain in the InterPlanetary File System. This model uses two organizations and a single channel, with Raft consensus, to ensure data consistency and high performance. Additionally, this study evaluates the performance of the proposed system in terms of throughput and latency. A test was conducted at 1,200 transactions with varying transfer rates. The results reveal that the throughput was near the send rate, up to 90 TPS. At a send rate of 150 TPS, the system reaches its peak throughput of 117.04 TPS. Moreover, no transactions were lost, which means that the system was able to make all its transactions, representing system reliability. The latency was noted to be 0.21 to 2.24 s, whereas the read operation was always characterized by the same latency of 0.01 s.
Recent advances in inherited retinal disease (IRD) management, including genetic testing and emerging therapies, have increased complexity in clinical decision- making. This study examined IRD-related practice patterns among U.S. retina specialists. An 18-item questionnaire developed by a combination of retina and IRD specialists (KCF, CCW, HK) was distributed electronically via email to retinal specialists at 35 non-university-based practices and 37 combined university-based/VA practices across the US. All retinal specialists at each institution were included and were assessed regarding their practice patterns for genetic testing, genetic counseling and education, referral to subspecialists or certified genetic counselors, and overall comfort level in assessing IRD patients. A total of 116 surveys were completed out of 481 distributed. 101 out of 116 (87.1%) indicated they actively manage IRD patients and were eligible to complete the survey in its entirety. Overall, most respondents were between the ages of 40-60 years old (58.6%). 54% were non-university employed, while 46% were university-employed. 60% reported comfort >3 (scale 1-5) in evaluating IRD patients. 92% of providers regularly send genetic tests, while 55% provide pretest counseling. Of the respondents, 92% performed post-test counseling. In-house genetic counselors were available to 40%. For post-test counseling, while almost all respondents actively see IRD patients, 51% stated they felt confident (>3, scale 1-5) interpreting genetic testing results. Over 90% of surveyed retinal specialists were involved in managing IRDs, but wide variation in practice and limited confidence highlight the need for clearer IRD care guidelines.
Inflammatory bowel disease (IBD) requires ongoing monitoring and effective communication between patients and health care providers. Web-based patient portals may enhance engagement, but their association with disease activity remains unclear. We aimed to evaluate the association between patient portal messaging frequency and disease activity among patients with IBD. We conducted a retrospective cohort study using electronic health record data from an urban academic center. Patients with Crohn disease, ulcerative colitis, or indeterminate colitis were included. Portal messaging frequency over 2 years (July 2023-July 2025) was analyzed. Associations with demographic variables and disease activity were assessed using χ2 tests (P<.05 was considered significant). Among 442 patients, 347 (78.5%) sent at least one portal message. Patients sent a mean of 5.27 (SD 7.15) messages over 2 years. High messaging frequency was associated with active disease (P=.047) and age group (P<.001). Patients with active disease were more likely to send ≥16 messages (n=14, 12.5% vs n=18, 6%). No significant associations were found with sex or race. Higher portal messaging frequency was associated with active disease in IBD. Patient portals may serve as a tool for disease monitoring and early intervention.
Carbapenem-resistant Enterobacterales pose a substantial threat to patients and health-care systems. We conducted a survey of carbapenem-resistant and/or colistin-resistant Enterobacterales (CCRE survey) in 37 European countries to describe their occurrence, geographical distribution, and population dynamics and inform control policies. We report the results of Klebsiella pneumoniae species complex isolates in this study. In this cross-sectional, epidemiological, microbiological, and genomic study conducted in all EU, European Economic Area and EU candidate countries as of 2019, hospital microbiology laboratories were selected on the basis of population coverage. Participating laboratories collected, from patient samples, the first ten successive isolates of carbapenem-resistant or carbapenem-susceptible increased exposure (carbapenem-R/I) K pneumoniae species complex or Escherichia coli, and carbapenem-susceptible (carbapenem-S) comparator isolates of the same species, accompanied by patient epidemiological and clinical information. Isolate collection started in 2019, with three possible starting dates-ie, March 1, April 1, or May 1, 2019, and ended after collection of ten carbapenem-R/I and carbapenem-S isolates or a maximum period of 6 months. Isolates were tested for phenotypic susceptibility to 16 antimicrobial agents of relevance to K pneumoniae species complex. Whole-genome sequencing was performed centrally using Illumina technology. Isolates from the CCRE survey were compared with those from the European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) study. 1566 carbapenem-R/I and 1407 carbapenem-S K pneumoniae species complex isolates collected from patients in 302 hospitals in 36 countries (one country did not send isolates) were analysed in this study. The high-risk lineages identified during a previous similar survey in 2013-14 (EuSCAPE) were found to continue to circulate across European hospitals in 2019 (ST11, ST15, ST101, and ST258/512). Moreover, concerning shifts in the pathogen population were observed. First, a higher proportion of carbapenem-R/I isolates was found to carry a carbapenemase gene in the CCRE survey (1398 [89·3%] of 1566) than in EuSCAPE (657 [69·6%] of 944), mainly related to increased acquisition of carbapenemase genes by high-risk lineages. Of note, among ST307 isolates from all hospitals, the proportion of carbapenem-R/I isolates carrying a carbapenemase gene increased from 14 (60·9%) of 23 in EuSCAPE to 164 (91·1%) of 180 in the CCRE survey. Second, an expansion of emerging multidrug-resistant lineages (ST147, ST307, and ST39) was also noted: Among 113 hospitals that contributed K pneumoniae species complex isolates to both EuSCAPE and the CCRE survey, the proportion of ST147 increased from 16 (3·4%) of 476 in EuSCAPE to 49 (7·4%) of 662 carbapenem-R/I isolates in the CCRE survey, that of ST307 increased from 15 (3·2%) of 476 to 88 (13·3%) of 662, and that of ST39 increased from 3 (0·6%) of 476 to 10 (1·5%) of 662. Third, there was an increased spread of isolates harbouring acquired virulence loci: isolates with the highest Kleborate virulence score of five increased from 7 (0·4%) of 1717 in EuSCAPE to 40 (1·3%) of 2973 in the CCRE survey. Notably, the increase was mainly observed in the carbapenem-S-group. The survey findings portray an escalating epidemiological situation and suggest that control measures have not been able to interrupt transmission of high-risk lineages of carbapenemase-producing K pneumoniae in European hospitals. The heterogeneous and evolving situation with regards to circulating lineages and dominant carbapenemase genes requires strengthening and continuous adaptation of diagnostic, treatment, and control measures guided by genomic surveillance. European Centre for Disease Prevention and Control and Centre for Genomic Pathogen Surveillance.
Nervous system and immune system have tight interactions that modulate both nerves and immune cells' activities. The interplay between the nervous and immune systems within the tumor microenvironment is a critical yet underexplored determinant of cancer immunotherapy efficacy. This review presents a new model called the Neuro-Immune Feedback Loop, which suggests that two-way communication (like the immunosuppressive effects of norepinephrine and the influence of cytokines on nerve activity) creates self-perpetuating cycles that tumors use to avoid immune responses. We compile evidence regarding neurotransmitters (such as dopamine), neuropeptides (like CGRP) to suggest innovative strategies to disrupt the immune-nerve loops. The current review proposes that context-sensitive neuro-immune switches (for instance, the dual functions of GABA) and multi-target therapies (such as CRISPR-modified neurons combined with immune checkpoint inhibitors (ICIs) could enhance immunotherapy effectiveness. By connecting neuroscience with immunology and oncology, this review aims to provide a roadmap for overcoming resistance to immunotherapies, presenting testable ideas and a new approach for precision cancer treatment. Literature search: PubMed, Scopus, and Web of Science were searched for relevant studies published between January 2000 and March 2026, with emphasis on recent publications (2024-2026) related to neuro-immune interactions in cancer. Cancer is not only a problem of abnormal cells growing out of control. It is also influenced by how different systems in the body communicate with each other. This review focuses on two of these systems: the nervous system (which controls stress and body signals) and the immune system (which helps fight diseases). We explain that these two systems are closely connected and constantly “talk” to each other. For example, when a person is under stress, the body releases certain signals. These signals can sometimes help cancer grow, spread, and hide from the immune system. At the same time, immune cells can send signals back to the nervous system, creating a cycle of communication. In some cases, this cycle may make it harder for the body to fight cancer. Understanding this connection is important because it opens new ways to treat cancer. Some existing medicines, such as drugs used for heart conditions (called beta-blockers), may help by blocking harmful stress signals. Researchers are also studying new treatments that target both the nervous system and the immune system at the same time to improve cancer therapy. Overall, this review shows that cancer is not just about tumor cells, but also about how the body’s systems interact. By better understanding these interactions, scientists hope to develop more effective treatments and improve outcomes for patients.
Crystals, such as quartz, table salt various gems and snowflakes, were noticed and documented by humankind for as long as we have records, but it took the development of microscope lenses to observe crystallization in detail. Robert Hooke used his 30X power compound microscope to describe crystals in his 1665 master work Micrographia. Leeuwenhoek was a Delft haberdasher, town hall chamberlain and metrologist, and creator of the world's most powerful microscopes until the last quarter of the 19th-century. He was the first person to observe and document dynamic crystallization and sublimation processes. Antoni Leeuwenhoek observed and documented the processes of crystallization and sublimation in dynamic detail, documenting the changes in letters to The Royal Society and to others. Unlike Hooke, who attended Oxford University, Leeuwenhoek was from the Dutch mercantile class and had little formal education. He is thought to have acquired a copy of Micrographia and, possibly inspired by Hooke's observations, would send improved descriptions to The Royal Society of materials Hooke had described (for instance, various fungi and insect parts). Hooke could not have been his only influence, as Leeuwenhoek's observations seem to concentrate on crystals forming from herbaceous materials used by physicians and found in an apothecary. The highly detailed nature of his observations also hints at influences, probably provided second-hand by some of his physician friends, at other influences. He documented these processes with his usual poetic flair, and his usual tendency to observe anything he thought might be interesting, including crystals found in plants and those found in gout sufferers. He sketched out what he saw, although he knew his drawing skills were poor, a fact he related in his correspondence. Examples of his observations, including illustrations and relevant comments from the various editors of his collected letters, are presented.
There are substantial functional changes in the primary motor cortex (M1) in Parkinson's disease (PD). However, the temporal relationship between midbrain dopaminergic (DA) neurodegeneration, M1 circuit dysfunction, and Parkinsonian motor symptoms remains poorly understood. Using a genetic mouse model of progressive nigrostriatal DA degeneration ("MitoPark" mice), we determine the time course of M1 cellular dysfunction and skilled movement impairment as the midbrain DA neurons gradually degenerate. M1 pyramidal neuronal subtypes were identified using AAV-mediated retrograde labeling. During progressive DA loss, MitoPark mice developed gradually impaired performance in a reach-to-grasp single-food-pellet task. These impairments were detectable at a moderate motor stage of Parkinsonism. In vivo GCaMP6f imaging revealed that impaired skilled movement was associated with reduced cellular activity and movement responsiveness of M1 pyramidal neurons at a moderate motor stage of Parkinsonism. While both the corticospinal (CSp) and intratelencephalic (IT) neurons send glutamatergic inputs to the striatum, only the CSp neurons showed a selective and significant reduction in cellular activity and movement responsiveness during reaches. At the population level, we found that M1 pyramidal neurons include heterogeneous functional clusters with distinct temporal profiles in response to skilled movement. While movement encoding by different functional clusters is longitudinally stable in control mice, it degrades and diverges significantly in MitoPark mice. The impaired stability is further supported by a longitudinal analysis of individual neuronal activity related to movements. Together, these results provide novel insights into the emergence of M1 circuit pathophysiology at cellular and neural population levels during progressive Parkinsonism.
Ischemic stroke mobilizes adult neural stem cells (NSCs), which could be leveraged for recovery. However, the intercellular signals that activate NSCs are poorly understood. Cells located in the cerebral lesion may send signals to the NSC niche to initiate the regenerative responses. Here, we computationally inferred cell-cell communication between the ischemic infarct region and ventricular-subventricular zone (V-SVZ) NSC niche from spatial gene expression profiles and identified ligand-receptor pairs in the signal transduction events at three time points. Further, we detailed the regulatory function of galectin-9 on the proliferation of NSCs as a checkpoint molecule that guards the responses of NSCs under physiological conditions. In addition, we show that TIM-3 may mediate the inhibitory effect of galectin-9 on NSC proliferation. Collectively, these data reveal galectin-9 as an important regulator of NSC proliferation under both physiological and injury conditions.
The mesodiencephalic junction (MDJ) is located in a caudorostrally elongated, column-shaped region encompassing the medial accessory oculomotor nucleus and perirubral area. It relays cerebral projections to the rostral subnuclei of the inferior olive (IO), which, in turn, send climbing fibers to the cerebellar hemisphere and receive nucleo-olivary projections from the cerebellar nuclei (CN), forming a parallel, loop-shaped, modular circuitry. However, the topographical organization of the MDJ-IO projection, which may contribute to functional localization within the cerebellar hemisphere, has not been fully elucidated. Here, we analyzed the distribution of labeled neurons in the MDJ in relation to those in the CN by injecting a Lumafluor retrograde tracer into various sites within the rostral IO subnuclei of mice. Injections mainly targeting the lateral or medial parts of the rostral IO subnuclei labeled neurons predominantly in the ventral or dorsal CN, respectively (referred to as v- and d-CN-predominant injection cases). Correspondingly, v-CN-predominant injection cases labeled neurons in the rostromedial, centroventral, and caudolateral regions of the MDJ, collectively termed the "sheathing subarea," whereas d-CN-predominant injection cases labeled neurons primarily in the central "shaft subarea" of the MDJ. Considering the previously reported lobule-related topography among the IO, cerebellar cortex, and CN, the sheathing and shaft subareas of the MDJ are likely to project preferentially to crus I and to other neighboring cerebellar hemispheric lobules, respectively. We speculate that the sheathing subarea of the MDJ is more strongly involved in non-somatosensorimotor cognitive functions than the shaft subarea.
To navigate its environment, an animal extracts salient information from sounds using temporal and intensity cues. In birds, the nucleus laminaris (NL) detects the submillisecond differences in the arrival time of sound to the two ears, the interaural time differences (ITDs), to localize sounds. This ability is facilitated by inhibitory long-range projection neurons from the ipsilateral superior olivary nucleus (SON) that enable NL neurons to remain sensitive to ITDs across a large range of sound intensities. It is well known that the excitatory inputs to NL, from nucleus magnocellularis (NM), innervate a narrow isofrequency band along the ITD axis. However, the organization of the inhibitory input from the SON remains largely unknown. We analyzed the innervation pattern of individual axons from SON neurons within the chicken NL. SON axonal arborizations vary greatly in size and topographic organization. On average, an inhibitory SON neuron innervates one-third of both the tonotopic and ITD axes, markedly larger target regions than do the excitatory inputs from NM. Unlike the excitatory axons that are confined to one dendritic lamina (separating inputs from the two ears), most SON cells innervate both laminae to similar extents, as well as the somata of the NL neurons. In addition, we found that some NL-projecting SON neurons also send collateral axons to NM or the nucleus angularis. The pattern of synapses along SON axons suggests that the inhibitory activity of individual NL neurons is shaped by many SON neurons. A single SON neuron contributes only a small proportion of the inhibition on each NL neuron. This broad innervation pattern of SON neurons is well-suited to control the overall activity of NL, supporting accurate ITD detection in a broad range of sound environments.
Although advancements in electronic health records (EHRs) have improved clinical productivity, digital administrative responsibilities have led to increased physician burnout. With the emergence of large language models (LLMs), their incorporation into medicine is a potential solution to the increase in tasks such as charting and responding to patient messages. Previous studies have evaluated the efficacy of LLMs such as Chat Generative Pre-Trained Transformer-4 (ChatGPT-4) in clinical knowledge-based questions. Few studies, however, have evaluated the responses to clinical decision making in sports medicine. This study aims to evaluate the efficiency and clinical accuracy of ChatGPT-4 responses to common sports medicine questions that patients ask in the EHR system. ChatGPT-4 was prompted with few-shot exemplars involving different sports medicine injuries to generate 80 EHR scenarios. Next, ChatGPT-4 was programmed to respond to the 80 EHR scenarios using the created programmed approaches to generate LLM drafts. In stage 1, four board-certified orthopedic surgeons were asked to respond to the EHR responses, followed by a survey evaluating the difficulty and urgency of the situation. In stage 2, they were asked to edit the LLM drafts so that they were clinically acceptable to send to a patient. In stage 1, the assessing physicians found responding to the LLM clinical question to be trivial in 60 out of 80 cases (75%). Most physicians disagreed that the patients in the LLM drafts were experiencing a severe medical event in 58 out of 80 cases (72.50%). In stage 2, the physicians rated the LLM-assisted responses as acceptable without modifications in 58 out of 80 cases (72.50%). Furthermore, the physicians agreed that the unedited LLM-assisted responses had a low chance of causing harm in 75 out of 80 cases (93.75%). Finally, the physicians rated the responses as generated by artificial intelligence in 65 out of 80 cases (81.25%). Surgeons rated the majority of the LLM responses as both clinically accurate and time-saving, with a low risk of causing harm. This finding suggests that LLMs have the potential to provide adequate responses to EHR messages within the field of sports medicine, potentially lessening physician burden and workload.