Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.

Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.

Framework for an interprofessional experience addressing health and disability for health professional students.

BACKGROUND AND PURPOSE: A Health and Disabilities Interprofessional Education (IPE) course was implemented to join three healthcare disciplines together to collaboratively plan, implement, and reflect on professional roles and responsibilities. The goal and purpose of this course was to create an advancement of interprofessional education and practice within health science professions early in their students' programs utilizing innovative teaching methods working directly with individuals with disabilities. EDUCATIONAL ACTIVITY AND SETTING: 72 students were assigned to interprofessional teams of 10-11 people. Through asynchronous and synchronous learning activities, student teams worked together to plan and conduct community-based client interviews. FINDINGS: Quantitative and qualitative evaluation methods were used to explore the impact of interprofessional experiential learning experiences. Qualitative data showed a greater awareness and understanding of the different roles and responsibilities in interprofessional teams as well as a greater appreciation for the value of interacting with persons with disabilities (PWD) during their training. Quantitative data showed a significant change in students' understanding of their roles and responsibilities as a member of an interprofessional team, their confidence with working with PWD in a future healthcare capacity, as well as their understanding of how the social determinants of health may influence the healthcare experience of a PWD. SUMMARY: Interprofessional education and experiential learning opportunities are good ways to facilitate "real" patient care experiences and team roles and responsibilities. This enables healthcare students to practice communication, build relationships, and understand the lived experience of their patients.

A systematic review of vestibular stimulation in post-stroke visual neglect.

Unilateral visual neglect is a condition that negatively impacts the lives of many stroke survivors. Studies have investigated different forms of vestibular stimulation as a potential therapy, but evidence is yet to be systematically reviewed. We therefore reviewed the effects of vestibular stimulation on outcomes of neglect and activities of daily living (ADL) for people with visual neglect. We searched relevant databases up until September 2022. Eligible articles included any form of vestibular stimulation, study design, or control condition. Included participants were 18 years or older, presenting with neglect following a haemorrhagic or ischaemic stroke. Relevant outcomes were clinically validated measures of neglect and ADL. Cochrane risk of bias tools were used to assess study quality. Meta-analyses and narrative methods were used to synthesize the data. Our search returned 17 relevant studies comprising 180 participants. Meta-analyses showed no difference between galvanic vestibular stimulation and sham conditions on outcomes, whereas caloric vestibular stimulation led to improvement compared to pre-stimulation scores. Narrative syntheses showed mixed results. Clinical and methodological heterogeneity was found both within and between studies. Overall, results were inconsistent regarding the effects of vestibular stimulation as a treatment for neglect. Further trials are warranted but require more careful methodological planning.

Incorporating a Psychiatric Telehealth Simulation in a Family Nurse Practitioner Curriculum.

The prevalence of mental health disorders in primary care is high and challenges related to the COVID pandemic warrant further training of the family nurse practitioner. A telehealth simulation learning experience that included common primary care diagnoses in mental health-general anxiety, depression, and substance use disorder-was incorporated into a non-clinical behavioral health course. Formative evaluation provided by licensed nurse practitioners confirmed the need for improving interviewing techniques, engaging clients, and promoting safety among this population. Students' confidence during the encounter was measured using the Simulation Effectiveness Tool. Findings suggest a simulation learning experience is an effective resource for training nurse practitioner students to treat mental health disorders.

Returning to Work Following Hematopoietic Cell Transplantation: The Survivor's Perspective.

While curing a patient's underlying disease is the primary goal of physicians performing hematopoietic cell transplantation (HCT), the ultimate objective is to provide patients with optimal post-HCT quality of life. For many survivors, this includes returning to work (RTW). We conducted a survey of 1- to 5-yr post-HCT survivors at our center to evaluate their perspective on facilitators and barriers to RTW as well as to gauge interest in potentially useful RTW support interventions. Survivors aged 18 to 65 yrs (n = 994) were sent an annual survey that included 36 supplementary questions about post-HCT RTW. Survey questions were selected from published national cancer survivor surveys and then modified specifically for HCT survivors. Three hundred forty-four (35%) survivors with a mean age of 53 yrs completed the survey, of whom 272 (79%) had worked prior to their diagnosis. Of those 272 patients, 145 (53%) were working currently and another 22 (8%) had attempted to go back to work following HCT but were not presently working. We found that having had an allogeneic versus autologous HCT (P = .006) was associated with a decreased likelihood of currently working, whereas frequent employer communication (>once a month) (P = .070) and having a more supportive employer (P = .036) were associated with a greater chance of currently working. Of survivors currently working, 45% reported that they had made one or more changes to their work schedule (e.g., flexible schedule or part-time work) or environment (e.g., work from home) upon RTW. Ninety-five percent of responders reported that they could have benefited from RTW support provided by the transplant center, but only 13% indicated that they had received it. Education on RTW challenges, information on disability benefits, and access to physical therapy were among the most requested support interventions. To improve post-HCT quality of life for survivors open to assistance, providers should address work status and goals, recognize barriers to successful return, and offer RTW support including working directly with employers. Allogeneic HCT survivors are particularly vulnerable to failing attempts to RTW and should be the target of retention interventions. A previously published manuscript on RTW guidance for providers of stem cell transplant patients endorsed by the American Society of Transplant and Cellular Therapy is available in Open Access and can be used as a tool to counsel and support these patients.

Validation of a CFD model for cell culture bioreactors at large scale and its application in scale-up.

Among all the operating parameters that control the cell culture environment inside bioreactors, appropriate mixing and aeration are crucial to ensure sufficient oxygen supply, homogeneous mixing, and CO2 stripping. A model-based manufacturing facility fit approach was applied to define agitation and bottom air flow rates during the process scale-up from laboratory to manufacturing, of which computational fluid dynamics (CFD) was the core modeling tool. The realizable k-ε turbulent dispersed Eulerian gas-liquid flow model was established and validated using experimental values for the volumetric oxygen transfer coefficient (kLa). Model validation defined the process operating parameter ranges for application of the model, identified mixing issues (e.g., impeller flooding, dissolved oxygen gradients, etc.) and the impact of antifoam on kLa. Using the CFD simulation results as inputs to the models for oxygen demand, gas entrance velocity, and CO2 stripping aided in the design of the agitation and bottom air flow rates needed to meet cellular oxygen demand, control CO2 levels, mitigate risks for cell damage due to shear, foaming, as well as fire hazards due to high O2 levels in the bioreactor gas outlet. The recommended operating conditions led to the completion of five manufacturing runs with a 100% success rate. This model-based approach achieved a seamless scale-up and reduced the required number of at-scale development batches, resulting in cost and time savings of a cell culture commercialization process.

Bone Marrow Harvest: A White Paper of Best Practices by the NMDP Marrow Alliance.

Data on recent bone marrow harvest collections from the NMDP has shown that bone marrow quality has decreased based on total nucleated cell count in the product. To ensure that quality bone marrow products are available to all recipients, the NMDP Marrow Alliance was formed in April of 2021 to increase the ability for bone marrow collection centers to safely deliver high-quality products consistently and to identify and disseminate guidelines for performing bone marrow harvests. This White Paper describes the best practices of performing a bone marrow harvest as defined by the NMDP Marrow Alliance.

History, politics, and variolation vaccination hesitancy in the American South during the American Civil War.

Examining the history of vaccination in the Civil War reveals lessons about why citizens resisted vaccination and how physicians tried to respond to the problems associated with combating epidemic diseases like smallpox. The Confederate government and physicians failed to effectively advocate to the public and collect information in an organized manner, and they suffered failures in getting enough citizens and soldiers vaccinated. Some Confederate physicians like Joseph Jones studied vaccination, but this came after the war, and the Confederate government failed to embrace and combat vaccine hesitancy. In some cases, more radical political elements tried to control the conversation through newspaper articles. Criticisms of vaccination likely continued to haunt the perceptions of vaccination in the Southern United States.

Nudging During Pediatric Intensive Care Conferences With Family Members: Retrospective Analysis of Transcripts From a Single-Center, 2015-2019.

OBJECTIVES: Nudging, a behavioral economics concept, subtly influences decision-making without coercion or limiting choice. Despite its frequent use, the specific application of nudging techniques by clinicians in shared decision-making (SDM) is understudied. Our aim was to analyze clinicians' use of nudging in a curated dataset of family care conferences in the PICU. DESIGN: Between 2019 and 2020, we retrospectively studied and coded 70 previously recorded care conference transcripts that involved physicians and families from 2015 to 2019. We focused on decision-making discussions examining instances of nudging, namely salience, framing, options, default, endowment, commission, omission, recommend, expert opinion, certainty, and social norms. Nudging instances were categorized by decision type, including tracheostomy, goals of care, or procedures. SETTING: Single-center quaternary pediatric facility with general and cardiac ICUs. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS: We assessed the pattern and frequency of nudges in each transcript. MAIN RESULTS: Sixty-three of the 70 transcripts contained SDM episodes. These episodes represented a total of 11 decision categories based on the subject matter of nudging instances, with 308 decision episodes across all transcripts (median [interquartile range] 5 [4-6] per conference). Tracheostomy was the most frequently discussed decision. A total of 1096 nudging instances were identified across the conferences, with 8 (6-10) nudge types per conference. The most frequent nudging strategy used was gain frame (203/1096 [18.5%]), followed by loss frame (150/1096 [13.7%]). CONCLUSIONS: Nudging is routinely employed by clinicians to guide decision-making, primarily through gain or loss framing. This retrospective analysis aids in understanding nudging in care conferences: it offers insight into potential risks and benefits of these techniques; it highlights ways in which their application has been used by caregivers; and it may be a resource for future trainee curriculum development.

Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.

Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigen Dermatophagoides pteronyssinus (Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2 in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3- than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2 was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers.NEW & NOTEWORTHY The PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers.

Optimization of Patient Progression in a New Era: A Comprehensive Framework.

PURPOSE/OBJECTIVES: The onset of the coronavirus disease 2019 pandemic increased the demand for inpatient services and led to widespread staffing shortages in the acute and post-acute setting, contributing to delayed inpatient throughput and leading to capacity crises. Novel strategies are needed to facilitate the efficient progression of hospitalized patients when medically ready for lower levels of care. The authors have developed a foundational strategic framework for patient progression to ensure capture of patient progression data, enhance efficiency, and optimal utilization of post-acute resources in increasingly complex and resource-constrained acute and post-acute environments. PRIMARY PRACTICE SETTINGS: Interventions were implemented, and metrics of success tracked as part of an overarching framework to test new models of care or optimize existing assets related to barriers to patient progression. Brigham and Women's Hospital (BWH) and Brigham and Women's Faulkner Hospital (BWFH) comprise an academic medical center and a community hospital, respectively, that are affiliated with Massachusetts General Brigham (MGB), a nonprofit health care system in Massachusetts. Key interventions include (1) screening to prioritize patients needing case management services through a modified early screening for discharge planning tool and process; (2) communicating, documenting, identifying patient progression status, barriers to discharge and post-acute needs through interdisciplinary care optimization rounds, a novel tool in the electronic health record, and an associated dashboard; (3) managing active high-risk patients through a novel complex care team and post-acute strategy development; (4) developing novel transportation and hospice pathways; and (5) establishing community hospital repatriation and a physical therapy "Why Not Home" campaign. FINDINGS: Key metrics of success were (1) modified discharge planning tool resulting in screening out low-risk patients (53%) and impacting length of stay (0.55-day reduction, p = .083) during a 3-month intervention versus control study; (2) documentation adherence in more than 98% of patients 10 months postimplementation; (3) complex care team achieving a 2.5% reduction in Case Mix Index-adjusted length of stay 6 months postimplementation; (4) use of care van offsetting ambulance/chair car in 10% of cases, and earlier discharge time/length of stay in 21% of cases 3 months postimplementation; and (5) implementation of community repatriation impacting delay days to discharge (10-month pilot, 40 patients accounting for 1,000 delay days). CONCLUSIONS: Implementation of a novel comprehensive framework focusing on optimizing patient progression resulted in increased operational efficiency and positively impacted length of stay at our academic and community hospitals. Additional study is actively ongoing to understand long-term benefit of the innovations that the authors have developed. Further interventions are needed to wholly mitigate evolving capacity challenges in the acute and post-acute settings. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The authors' implementation of the Brigham framework for progression demonstrates that innovative approaches to case management can help address the evolving challenges in care transitions planning. Notable opportunities include approaches that empower case managers as multidisciplinary team leaders, improve workflow, utilize patient progression data, prioritize patients with complex care needs support key patient populations, and promote post-acute collaboration.

Cognition in vestibular disorders: state of the field, challenges, and priorities for the future.

Vestibular disorders are prevalent and debilitating conditions of the inner ear and brain which affect balance, coordination, and the integration of multisensory inputs. A growing body of research has linked vestibular disorders to cognitive problems, most notably attention, visuospatial perception, spatial memory, and executive function. However, the mechanistic bases of these cognitive sequelae remain poorly defined, and there is a gap between our theoretical understanding of vestibular cognitive dysfunction, and how best to identify and manage this within clinical practice. This article takes stock of these shortcomings and provides recommendations and priorities for healthcare professionals who assess and treat vestibular disorders, and for researchers developing cognitive models and rehabilitation interventions. We highlight the importance of multidisciplinary collaboration for developing and evaluating clinically relevant theoretical models of vestibular cognition, to advance research and treatment.

Real-world evidence of heparin and citrate use in extracorporeal photopheresis: A hypothesis-generating data review of device settings and performance.

Extracorporeal photopheresis (ECP) is widely used for the treatment of cutaneous T-cell lymphoma, graft-vs-host disease, and other immune-related conditions. To avoid clotting during treatment, the ECP system used must be effectively primed with an anticoagulant. Heparin is the recommended anticoagulant for the THERAKOS CELLEX System, but acid citrate dextrose-A (ACDA) is often used. We compared system performance between these two anticoagulants for this ECP system. Deidentified data for ECP device performance were obtained at each treatment session, from automatically logged Smart Cards or labels completed by device operators. We compared the effects of ACDA or heparin on overall treatment duration, buffy coat (leukocyte) collection time, photoactivation time and the number of alarms and warnings. The variability in these parameters was also assessed. Data from 23 334 treat sessions were analyzed; ACDA was used in 34.4% and heparin in 65.6%. Overall, the ECP procedure duration, buffy coat collection time and photoactivation time were numerically similar regardless of whether ACDA or heparin was used, and regardless of needle mode. Photoactivation time variability was lower with ACDA compared with heparin in all needle modes. Among treatments that were completed automatically without any operator intervention, total treatment duration and photoactivation time were significantly reduced with ACDA use in both the double- and single-needle modes. The data presented indicate that, in both double- and single-needle modes, the THERAKOS® CELLEX® integrated ECP system performed similarly with ACDA compared to heparin, although ACDA demonstrated potential benefits in reducing variability in photoactivation time.

Dissection, media portrayals, and reaction: Black bodies and medical education in nineteenth-century newspapers.

Throughout the nineteenth century, medical schools in both the Northern and Southern regions of the United States required a regular supply of bodies for medical study and experimentation. Physicians and medical students targeted the bodies of African Americans, both freedmen and the enslaved, to meet this demand. Simultaneously, the nation's booming newspaper market became a stage on which debates about the cruelty of slavery and the social consequences of pursuing medical knowledge played out in articles about the dissection of Black bodies. Such stories increased fears about dissection and mistrust towards the medical profession among African American communities, which manifested in riots against physicians, vandalism against medical schools, and corrective responses from African American newspaper editors and journalists. Through an extensive examination of nineteenth-century U.S. newspapers, this article identifies themes evident in the coverage of dissection during this period. Southern newspapers crafted stories of dissection that served the dual purpose of entertaining White readers and humiliating African Americans. This public humiliation fostered what became a popular genre of derogatory and vile humor that reinforced negative and inaccurate racialized stereotypes as well as racist science. Ultimately, such newspaper coverage provoked reactions within Black communities and among antislavery advocates that showcase how people often excluded from practicing medicine themselves viewed issues like medical education. Newspaper rhetoric around these themes amplified tensions between religious and scientific perspectives, reflected differences and similarities between the northern and southern areas of the United States, and fortified racist views in both cultural and scientific contexts.

Oral medroxyprogesterone acetate for the use of ovulation suppression in in vitro fertilization: a cohort trial.

OBJECTIVE: To broadly assess the efficacy of medroxyprogesterone acetate (MPA) for ovulatory suppression during in vitro stimulation compared with gonadotropin-releasing hormone (GnRH) antagonist cycles. DESIGN: Cohort trial. SETTING: A single academic-affiliated private fertility practice. PATIENTS: Patients of all diagnoses aged 18-44 years undergoing autologous in vitro fertilization (IVF) for fertility treatment between 2020 and 2023. INTERVENTIONS: Comparison of MPA vs. antagonist IVF stimulation cycles. MAIN OUTCOME MEASURES: Rates of premature ovulation, oocyte and embryo yield, embryo quality, pregnancy rates, and logistical benefits. RESULTS: Prospective data was collected on 418 patients who underwent MPA protocol ovarian stimulation (MPA group), which was compared with 419 historical control gonadotropin hormone-releasing hormone antagonist cycles (control group). Age was similar between groups (35.6 ± 4.6 vs. 35.7 ± 4.8 years; P = .75). There were no cases of premature ovulation in the MPA group compared with a total of five cases in the control group (0% vs. 1.2%; risk ratio [RR] = 0.09; 95% confidence interval [CI], 0.01, 1.66). No differences were seen between number of oocytes retrieved (14.3 ± 10.2 vs. 14.3 ± 9.7; P = .83), blastocysts (4.9 ± 4.6 vs. 5.0 ± 4.6; P = .89), or euploid blastocysts (2.4 ± 2.6 vs. 2.2 ± 2.4; P = .18) in the MPA vs. control group respectively. Clinical pregnancy rate was similar between groups (70.4% vs. 64.2%; RR = 0.92; 95% CI, 0.72, 1.18). There was no difference in length of IVF stimulation or dose of stimulation medications. Patients in the MPA group saved an average of $491 ± $119 on medications, had an average of one less monitoring visit (4.4 ± 0.9 vs. 5.6 ± 1.1; P<.01), and 5.0 ± 1.2 less injections per cycle. When adjusting for age and ovarian reserve, protocol group (MPA vs. control) did not influence having an embryo available for transfer (76.6% vs. 73.4%; adjusted RR = 1.05; 95% CI, 0.94, 1.14). CONCLUSION: For ovulatory suppression during IVF cycles, MPA was effective at preventing ovulation while demonstrating similar cycle and reproductive outcomes, with the additional benefits of patient cost savings, increased convenience with decreased number of visits, and fewer injections.

The American Association for Thoracic Surgery (AATS) 2023 Expert Consensus Document: Recommendation for the care of children with trisomy 13 or trisomy 18 and a congenital heart defect.

OBJECTIVES: Recommendations for surgical repair of a congenital heart defect in children with trisomy 13 or trisomy 18 remain controversial, are subject to biases, and are largely unsupported with limited empirical data. This has created significant distrust and uncertainty among parents and could potentially lead to suboptimal care for patients. A working group, representing several clinical specialties involved with the care of these children, developed recommendations to assist in the decision-making process for congenital heart defect care in this population. The goal of these recommendations is to provide families and their health care teams with a framework for clinical decision making based on the literature and expert opinions. METHODS: This project was performed under the auspices of the AATS Congenital Heart Surgery Evidence-Based Medicine Taskforce. A Patient/Population, Intervention, Comparison/Control, Outcome process was used to generate preliminary statements and recommendations to address various aspects related to cardiac surgery in children with trisomy 13 or trisomy 18. Delphi methodology was then used iteratively to generate consensus among the group using a structured communication process. RESULTS: Nine recommendations were developed from a set of initial statements that arose from the Patient/Population, Intervention, Comparison/Control, Outcome process methodology following the groups' review of more than 500 articles. These recommendations were adjudicated by this group of experts using a modified Delphi process in a reproducible fashion and make up the current publication. The Class (strength) of recommendations was usually Class IIa (moderate benefit), and the overall level (quality) of evidence was level C-limited data. CONCLUSIONS: This is the first set of recommendations collated by an expert multidisciplinary group to address specific issues around indications for surgical intervention in children with trisomy 13 or trisomy 18 with congenital heart defect. Based on our analysis of recent data, we recommend that decisions should not be based solely on the presence of trisomy but, instead, should be made on a case-by-case basis, considering both the severity of the baby's heart disease as well as the presence of other anomalies. These recommendations offer a framework to assist parents and clinicians in surgical decision making for children who have trisomy 13 or trisomy 18 with congenital heart defect.

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Resting-state EEG signatures of Alzheimer's disease are driven by periodic but not aperiodic changes.

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer's disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in higher frequencies (alpha and beta), together with slowing of the peak alpha frequency. However, the pathophysiological processes underlying these changes remain unclear. For instance, recent studies have shown that apparent shifts in EEG power from high to low frequencies can be driven either by frequency specific periodic power changes or rather by non-oscillatory (aperiodic) changes in the underlying 1/f slope of the power spectrum. Hence, to clarify the mechanism(s) underlying the EEG alterations associated with AD, it is necessary to account for both periodic and aperiodic characteristics of the EEG signal. Across two independent datasets, we examined whether resting-state EEG changes linked to AD reflect true oscillatory (periodic) changes, changes in the aperiodic (non-oscillatory) signal, or a combination of both. We found strong evidence that the alterations are purely periodic in nature, with decreases in oscillatory power at alpha and beta frequencies (AD < HC) leading to lower (alpha + beta) / (delta + theta) power ratios in AD. Aperiodic EEG features did not differ between AD and HC. By replicating the findings in two cohorts, we provide robust evidence for purely oscillatory pathophysiology in AD and against aperiodic EEG changes. We therefore clarify the alterations underlying the neural dynamics in AD and emphasize the robustness of oscillatory AD signatures, which may further be used as potential prognostic or interventional targets in future clinical investigations.

Engineered In Vitro Tumor Model Recapitulates Molecular Signatures of Invasion in Glioblastoma.

Glioblastoma stem cells (GSCs) play an important role in the invasive nature of glioblastoma (GBM); yet, the mechanisms driving this behavior are poorly understood. To recapitulate tumor invasion in vitro, we developed a GBM tumor-mimetic hydrogel using extracellular matrix components upregulated in patients. We show that our hydrogel facilitates the infiltration of a subset of patient-derived GSCs, differentiating samples based on phenotypic invasion. Invasive GSCs are enriched for injury-responsive pathways while noninvasive GSCs are enriched for developmental pathways, reflecting established GSC stratifications. Using small molecule inhibitors, we demonstrate that the suppression of matrix metalloprotease and rho-associated protein kinase processes results in a significant reduction of cell invasion into the hydrogel, reflecting mesenchymal- and amoeboid-dependent mechanisms. Similar reduction in cell invasion was observed by siRNA knockdown of ITGB1 and FAK focal adhesion pathways. We elucidate the transcriptomic profile of cells invading in the hydrogel by performing bulk RNA sequencing of cells cultured in the hydrogel and compare these to cells cultured in conventional tissue culture polystyrene (TCP). In our 3D hydrogel cultures, invasion-related molecular signatures along with proliferation and injury response pathways are upregulated while development processes are downregulated compared to culture on 2D TCP. With this validated in vitro model, we establish a valuable tool to find therapeutic intervention strategies against cellular invasion in glioblastoma.