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An accumulating body of evidence indicates that peripheral physiological rhythms help regulate and organize large-scale brain activity. Given that schizophrenia (SZ) is characterized by marked abnormalities in oscillatory cortical activity as well as changes in autonomic function, the present study aimed to identify mechanisms by which central and autonomic nervous system deficits may be related. We evaluated phase-amplitude coupling (PAC) as a physiological mechanism through which autonomic nervous system (ANS) and central nervous system (CNS) activity are integrated and that may be disrupted in SZ.
Methods
PAC was measured between high-frequency heart rate variability (HF-HRV) as an index of parasympathetic activity and electroencephalography (EEG) oscillations in 36 individuals with first-episode SZ and 38 healthy comparison participants at rest.
Results
HRV-EEG coupling was lower in SZ in the alpha and theta bands, and HRV-EEG coupling uniquely predicted group membership, whereas HRV and EEG power alone did not. HRV-EEG coupling in the alpha band correlated with measures of sustained attention in SZ. Granger causality analyses indicated a stronger heart-to-brain effect than brain-to-heart effect, consistent across groups.
Conclusions
Lower HRV-EEG coupling provides evidence of deficient autonomic regulation of cortical activity in SZ, suggesting that patterns of dysconnectivity observed in brain networks extend to brain–body interactions. Deficient ANS–CNS integration in SZ may foster a breakdown in the spatiotemporal organization of cortical activity, which may contribute to core cognitive impairments in SZ such as dysregulated attention. These findings encourage pursuit of therapies targeting autonomic function for the treatment of SZ.
How was trust created and reinforced between the inhabitants of medieval and early modern cities? And how did the social foundations of trusting relationships change over time? Current research highlights the role of kinship, neighbourhood, and associations, particularly guilds, in creating ‘relationships of trust’ and social capital in the face of high levels of migration, mortality, and economic volatility, but tells us little about their relative importance or how they developed. We uncover a profound shift in the contribution of family and guilds to trust networks among the middling and elite of one of Europe's major cities, London, over three centuries, from the 1330s to the 1680s. We examine almost 15,000 networks of sureties created to secure orphans’ inheritances to measure the presence of trusting relationships connected by guild membership, family, and place. We uncover a profound increase in the role of kinship – a re-embedding of trust within the family – and a decline of the importance of shared guild membership in connecting Londoners who secured orphans’ inheritances together. These developments indicate a profound transformation in the social fabric of urban society.
FTIR studies of six partially-deuterated montmorillonites (MS) reveal the presence of two O-D stretching bands, one between 2702–2728 cm-1 and another near 2680 cm-1. For homoionic (Li, Na, Mg, Ca, or La) Wyoming-type MS, the position of the higher frequency band, designated as (O-D)h, is between 2714–2728 cm-1, whereas for homoionic Cheto-type MS it is between 2702–2706 cm-1. The lower frequency band, designated as (O-D)1, is in the narrow range of 2674–2684 cm-1. Resolution of two corresponding O-H bands, appearing near 3670 and 3635 cm-1, was observed only after partial dehydroxylation of the smectites. The changes in the relative intensities of the two O-D stretching bands as a function of the smectite type and of the Lewis acidity (charge density) of the exchangeable ion were determined. For Wyoming-type MS, the intensity of the (O-D)h band is much lower than that of the (O-D)l band, whereas for Cheto-type MS, the intensity of the (O-D)h band is about equal or slightly higher than that of the (O-D)l band. The observed resolution can be ascribed tentatively to the presence of (at least) two types of octahedral OH groups in the smectites, the (O-D)h band being assigned to AlMgOH and the (O-D)1 band to AlAlOH groups. Pillaring of Cheto-type MS with hydroxy-Al13 oligocations resulted in products showing much higher thermal stability between 400–600°C compared to that of identically pillared Wyoming-type MS. Compositional and other factors, e.g., CEC values and mode of pillaring, may cause this difference in stability.
We consider the Vlasov equation in any spatial dimension, which has long been known [ZI76, Mor80, Gib81, MW82] to be an infinite-dimensional Hamiltonian system whose bracket structure is of Lie–Poisson type. In parallel, it is classical that the Vlasov equation is a mean-field limit for a pairwise interacting Newtonian system. Motivated by this knowledge, we provide a rigorous derivation of the Hamiltonian structure of the Vlasov equation, both the Hamiltonian functional and Poisson bracket, directly from the many-body problem. One may view this work as a classical counterpart to [MNP+20], which provided a rigorous derivation of the Hamiltonian structure of the cubic nonlinear Schrödinger equation from the many-body problem for interacting bosons in a certain infinite particle number limit, the first result of its kind. In particular, our work settles a question of Marsden, Morrison and Weinstein [MMW84] on providing a ‘statistical basis’ for the bracket structure of the Vlasov equation.
Two independent temporal-spatial clusters of hospital-onset Rhizopus infections were evaluated using whole-genome sequencing (WGS). Phylogenetic analysis confirmed that isolates within each cluster were unrelated despite epidemiological suspicion of outbreaks. The ITS1 region alone was insufficient for accurate analysis. WGS has utility for rapid rule-out of suspected nosocomial Rhizopus outbreaks.
OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
OBJECTIVES/GOALS: This study proposes a pragmatic approach for tracking institutional changes in research teamwork and productivity in real time using common institutional electronic databases such as eCV and grant management systems. Dissemination of this approach could provide a standard metric for comparing teamwork productivity across different programs. METHODS/STUDY POPULATION: This study tracks research teamwork and productivity using commonly available institutional electronic databases such as eCV and grant management systems. We tested several definitions of interdisciplinary collaborations based on number of collaborations and their fields of discipline. Publication characteristics were compared by faculty seniority and appointment type using non-parametric Wilcoxon Rank Sum Test (p RESULTS/ANTICIPATED RESULTS: Interdisciplinary grants constitute 24% of all grants but the trend has significantly increased over the last five years. Tenure track faculty collaborated with more organizations (3.5, SD 2.5 vs 2.3, SD 1.1, p DISCUSSION/SIGNIFICANCE: This study provides empirical evidence of the benefits of interdisciplinary collaboration in research and identifies an important role that senior faculty may be playing in creating the culture of interdisciplinary teamwork. More research is needed to improve efficiency of interdisciplinary collaborations.
To estimate the incidence, duration and risk factors for diagnostic delays associated with pertussis.
Design:
We used longitudinal retrospective insurance claims from the Marketscan Commercial Claims and Encounters, Medicare Supplemental (2001–2020), and Multi-State Medicaid (2014–2018) databases.
Setting:
Inpatient, emergency department, and outpatient visits.
Patients:
The study included patients diagnosed with pertussis (International Classification of Diseases [ICD] codes) and receipt of macrolide antibiotic treatment.
Methods:
We estimated the number of visits with pertussis-related symptoms before diagnosis beyond that expected in the absence of diagnostic delays. Using a bootstrapping approach, we estimated the number of visits representing a delay, the number of missed diagnostic opportunities per patient, and the duration of delays. Results were stratified by age groups. We also used a logistic regression model to evaluate potential factors associated with delay.
Results:
We identified 20,828 patients meeting inclusion criteria. On average, patients had almost 2 missed opportunities prior to diagnosis, and delay duration was 12 days. Across age groups, the percentage of patients experiencing a delay ranged from 29.7% to 37.6%. The duration of delays increased considerably with age from an average of 5.6 days for patients aged <2 years to 13.8 days for patients aged ≥18 years. Factors associated with increased risk of delays included emergency department visits, telehealth visits, and recent prescriptions for antibiotics not effective against pertussis.
Conclusions:
Diagnostic delays for pertussis are frequent. More work is needed to decrease diagnostic delays, especially among adults. Earlier case identification may play an important role in the response to outbreaks by facilitating treatment, isolation, and improved contact tracing.
We study the relative computational power of structures related to the ordered field of reals, specifically using the notion of generic Muchnik reducibility. We show that any expansion of the reals by a continuous function has no more computing power than the reals, answering a question of Igusa, Knight, and Schweber [7]. On the other hand, we show that there is a certain Borel expansion of the reals that is strictly more powerful than the reals and such that any Borel quotient of the reals reduces to it.
The tower number ${\mathfrak t}$ and the ultrafilter number $\mathfrak {u}$ are cardinal characteristics from set theory. They are based on combinatorial properties of classes of subsets of $\omega $ and the almost inclusion relation $\subseteq ^*$ between such subsets. We consider analogs of these cardinal characteristics in computability theory.
We say that a sequence $(G_n)_{n \in {\mathbb N}}$ of computable sets is a tower if $G_0 = {\mathbb N}$, $G_{n+1} \subseteq ^* G_n$, and $G_n\smallsetminus G_{n+1}$ is infinite for each n. A tower is maximal if there is no infinite computable set contained in all $G_n$. A tower ${\left \langle {G_n}\right \rangle }_{n\in \omega }$ is an ultrafilter base if for each computable R, there is n such that $G_n \subseteq ^* R$ or $G_n \subseteq ^* \overline R$; this property implies maximality of the tower. A sequence $(G_n)_{n \in {\mathbb N}}$ of sets can be encoded as the “columns” of a set $G\subseteq \mathbb N$. Our analogs of ${\mathfrak t}$ and ${\mathfrak u}$ are the mass problems of sets encoding maximal towers, and of sets encoding towers that are ultrafilter bases, respectively. The relative position of a cardinal characteristic broadly corresponds to the relative computational complexity of the mass problem. We use Medvedev reducibility to formalize relative computational complexity, and thus to compare such mass problems to known ones.
We show that the mass problem of ultrafilter bases is equivalent to the mass problem of computing a function that dominates all computable functions, and hence, by Martin’s characterization, it captures highness. On the other hand, the mass problem for maximal towers is below the mass problem of computing a non-low set. We also show that some, but not all, noncomputable low sets compute maximal towers: Every noncomputable (low) c.e. set computes a maximal tower but no 1-generic $\Delta ^0_2$-set does so.
We finally consider the mass problems of maximal almost disjoint, and of maximal independent families. We show that they are Medvedev equivalent to maximal towers, and to ultrafilter bases, respectively.
Recall that B is PA relative to A if B computes a member of every nonempty $\Pi ^0_1(A)$ class. This two-place relation is invariant under Turing equivalence and so can be thought of as a binary relation on Turing degrees. Miller and Soskova [23] introduced the notion of a $\Pi ^0_1$ class relative to an enumeration oracle A, which they called a $\Pi ^0_1{\left \langle {A}\right \rangle }$ class. We study the induced extension of the relation B is PA relative to A to enumeration oracles and hence enumeration degrees. We isolate several classes of enumeration degrees based on their behavior with respect to this relation: the PA bounded degrees, the degrees that have a universal class, the low for PA degrees, and the ${\left \langle {\text {self}\kern1pt}\right \rangle }$-PA degrees. We study the relationship between these classes and other known classes of enumeration degrees. We also investigate a group of classes of enumeration degrees that were introduced by Kalimullin and Puzarenko [14] based on properties that are commonly studied in descriptive set theory. As part of this investigation, we give characterizations of three of their classes in terms of a special sub-collection of relativized $\Pi ^0_1$ classes—the separating classes. These three can then be seen to be direct analogues of three of our classes. We completely determine the relative position of all classes in question.
Women in Congress are highly effective legislators. Yet, if women are more likely than men to be interrupted during committee work, they may face a gender-related impediment. We examine speech patterns during more than 24,000 congressional committee hearings from 1994 to 2018 to determine whether women Members are more likely to be interrupted than men. We find that they are. This is especially true in Senate committees—where women are about 10% more likely to be interrupted. Furthermore, in hearings that discuss women’s issues, women are more than twice as likely to be interrupted than while discussing other issues. We see a similar pattern for rapid-fire “interruption clusters,” an aggressive form of interruption. We further consider a range of moderating factors, which yields little evidence that women change their communication strategy as they gain experience in Congress. We also find suggestive evidence that interruptions are driven by mixed-gender interactions.
OBJECTIVES/GOALS: The goal of this study is to evaluate the role of WNT5A and WNT5a-AS1 in sex-differences of GBM progression. In our preliminary studies, we found that a long non-coding RNA WNT5A-AS1 is overexpressed in male GBM patients. We also found that WNT5A-AS1s expression shows a negative correlation with overall survival within male patients. METHODS/STUDY POPULATION: We will define the mechanism by which WNT5A-AS1 regulates WNT5a-mediated glioma stem cell (GSC) maintenance by assessing the effects of inhibiting WNT5A-AS1 expression on transcriptional activity and stemness in GSCs. We will determine if there are distinct Wnt-signaling patterns in male and female isogenic murine astrocytes by examining the expression of downstream proteins in the Wnt signaling pathway and how inhibition of WNT5A-AS1 alters this expression. We will then examine the impact of WNT5A-AS1 on temozolomide (TMZ) resistance in-vitro and in-vivo. We will assess the cell viability and survival of GBM PDX cells upon treatment with TMZ in vitro. Next, we will assess the capacity of knockdown of WNT5A-AS1 to increase sensitivity to TMZ-induced cell death and prolong survival in vivo in intracranial models. RESULTS/ANTICIPATED RESULTS: We hypothesize that WNT5A-AS1 targets Wnt5a and regulates its expression. We anticipate that knockdown of WNT5A-AS1 will upregulate WNT5A expression. We also expect that inhibiting WNT5A-AS1 will alter GSC stem maintenance and functional effects. We expect to see an increase in downstream Wnt5a signaling proteins in males vs females when treated with exogenous Wnt5a. We hypothesize that knockdown of both, WNT5A-AS1 and WNT5A will alter the expression of downstream proteins. We hypothesize that knockdown of WNT5A-AS1 will decrease tumor growth and therapeutic resistance to TMZ while increasing survival in patient derived xenographs in vivo and in vitro. DISCUSSION/SIGNIFICANCE: This study will provide insight into the mechanisms underlying the difference in GBM onset and progression between male and female patients, which is clinically important. We will also characterize the biological role WNT5A-AS1 which is currently unknown to date and elucidate differential role of GSCs in GBM progression between male and female.
Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in neonatal intensive care units (NICU) that confers significant morbidity and mortality.
Objective:
Improving our understanding of MRSA transmission dynamics, especially among high-risk patients, is an infection prevention priority.
Methods:
We investigated a cluster of clinical MRSA cases in the NICU using a combination of epidemiologic review and whole-genome sequencing (WGS) of isolates from clinical and surveillance cultures obtained from patients and healthcare personnel (HCP).
Results:
Phylogenetic analysis identified 2 genetically distinct phylogenetic clades and revealed multiple silent-transmission events between HCP and infants. The predominant outbreak strain harbored multiple virulence factors. Epidemiologic investigation and genomic analysis identified a HCP colonized with the dominant MRSA outbreak strain who cared for most NICU patients who were infected or colonized with the same strain, including 1 NICU patient with severe infection 7 months before the described outbreak. These results guided implementation of infection prevention interventions that prevented further transmission events.
Conclusions:
Silent transmission of MRSA between HCP and NICU patients likely contributed to a NICU outbreak involving a virulent MRSA strain. WGS enabled data-driven decision making to inform implementation of infection control policies that mitigated the outbreak. Prospective WGS coupled with epidemiologic analysis can be used to detect transmission events and prompt early implementation of control strategies.
From 2014 to 2020, we compiled radiocarbon ages from the lower 48 states, creating a database of more than 100,000 archaeological, geological, and paleontological ages that will be freely available to researchers through the Canadian Archaeological Radiocarbon Database. Here, we discuss the process used to compile ages, general characteristics of the database, and lessons learned from this exercise in “big data” compilation.
Virtual reality (VR) has the potential to improve pain and pain-related symptoms. We examined the feasibility, acceptability, safety, and impact of a 30-min virtual underwater/sea environment (VR Blue) for reducing pain and pain-related symptoms in advanced colorectal cancer patients. A qualitative exit interview was conducted to understand preferences, thoughts, and feelings about the VR session.
Method
Participants (N = 20) had stage IV colorectal cancer and moderate-to-severe pain. Participants completed a 30-min VR Blue session that visually and aurally immersed them in virtual ocean scenarios. Feasibility was assessed by accrual (N = 20), protocol adherence (≥80% completing VR Blue), and completed data (≥80% assessment completion). Acceptability was determined by patients reporting ≥80% intervention satisfaction. Safety was determined by ≥80% of patients completing the session without self-reported side effects. Measures of pain, tension, relaxation, stress, anxiety, and mood were collected before, during, and after the VR Blue session. A semi-structured qualitative interview was conducted after VR Blue to assess participants’ VR experiences.
Results
All participants (100%) completed the VR Blue session. There was 100% data collection at the pre- and post-assessments. Satisfaction with VR Blue was high M = 3.3 (SD = 0.4) (83%). No significant side effects were reported. Pain decreased by 59% (Pre-M = 3 [1]; Post-M = 1 [1]). Tension decreased by 74% (Pre-M = 30 [24]; Post-M = 8 [13]). Relaxation improved by 38% (Pre-M = 62 [21]); Post-M = 86 [17]). Stress decreased by 68% (Pre-M = 24 [24]; Post-M = 8 [14]). Anxiety decreased by 65% (Pre-M = 20 [23]; Post-M = 7 [13]). Mood improved by 70% (Pre-M = 13 [16]; Post-M = 4 [11]). Qualitative data suggested a positive response to the VR Blue protocol.
Significance of results
This work supports the feasibility, acceptability, and safety of VR Blue for advanced colorectal cancer patients. Participants showed significant pre-post improvement in pain and pain-related symptoms hinting to the potential feasibility of VR interventions in this population. Larger, randomized trials with a control condition are needed to examine the efficacy of VR-based interventions for patients with advanced colorectal cancer and pain.
Coronavirus disease 2019 (COVID-19) vaccination rates of a large health system reflected their respective service areas but varied by work role. Nurse vaccination rates were higher (56.9%) and rates among nursing support personnel were lower (38.6%) than those of their communities (51.7%; P < .001). Physician vaccination rates were highest (71.6%) and were not associated with community vaccination levels.
Because of inconsistent findings regarding the relationship between sleep quality and cognitive function in people with age-related memory complaints, we examined how self-reports of sleep quality were related to multiple domains of both objective and subjective cognitive function in middle-aged and older adults.
Design:
A cross-sectional study involving analysis of baseline data, collected as part of a clinical trial.
Measurements:
Two hundred and three participants (mean age = 60.4 [6.5] years, 69.0% female) with mild memory complaints were asked to rate their sleep quality using the Pittsburgh Sleep Quality Index (PSQI) and their memory performance using the Memory Functioning Questionnaire (MFQ), which measures self-awareness of memory ability. Neurocognitive performance was evaluated using the Continuous Performance Test (CPT), Trail Making Test, Buschke Selective Reminding Test, and the Brief Visuospatial Test – Revised (BVMT-R).
Results:
Total PSQI scores were significantly associated with objective measures of sustained attention (CPT hit reaction time by block and standard error by block) and subjective memory loss (MFQ frequency and seriousness of forgetting). The PSQI components of (poorer) sleep quality and (greater) sleep disturbance were related to (worse) sustained attention scores while increased sleep latency and daytime sleepiness were associated with greater frequency and seriousness of forgetting.
Conclusions:
Sleep quality is related to both objective measures of sustained attention and self-awareness of memory decline. These findings suggest that interventions for improving sleep quality may contribute not only to improving the ability to focus on a particular task but also in reducing memory complaints in middle-aged and older adults.
We give several new characterizations of the continuous enumeration degrees. The main one proves that an enumeration degree is continuous if and only if it is not half of a nontrivial relativized
$\mathcal {K}$
-pair. This leads to a structural dichotomy in the enumeration degrees.
The present article contributes to understanding of the Zimbabwe political institution of the southern portion of the Zambesi Valley based on the conceptualization of its population, between the sixteenth and nineteenth centuries. We reconstruct the local perceptions of this institution by detecting information provided by local persons as recounted in Portuguese ethnographic documents. The original information underwent different types and degrees of translation and editing to reach the forms recorded in these documents. We present a critical process of recovering local voices, ideologies, and conceptualizations from written literal translations of excerpts of oral statements that can serve as a valuable methodological tool in expanding our understanding of the history of early African politics.