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OBJECTIVES/GOALS: Studies have shown that SARS-CoV-2 specific memory B cells can be maintained at least a year after exposure. However, reports show an altered B cell response during infection in severe COVID-19 cases. This study aims to describe the B cell response during COVID-19 convalescence with a focus on signatures that contribute to durable and robust immunity. METHODS/STUDY POPULATION: Our study cohort consisted of individuals who had recovered from non-severe (hospitalized) or severe (hospitalized and requiring invasive mechanical ventilation) COVID-19. In our comparative analysis, samples from both groups were carefully matched to fall within 4-5 weeks post-symptom onset. We also performed a longitudinal analysis of non-severe patients with sampling ending 5 months post-symptom onset. Using high parameter flow cytometry, we characterized the phenotype of memory B cells using 19 distinct cell markers and fluorescently labeled probes to identify B cells reactive with SARS-CoV-2 spike and receptor-binding domain protein. Additionally, serum collected from individuals was used to quantify antibody titers. RESULTS/ANTICIPATED RESULTS: The frequency of spike-specific B cells and serum antibody titers were similar between severe and non-severe groups. However, we observed that individuals recovered from severe COVID-19 have a significantly reduced frequency of spike specific IgG+ memory B cells expressing Tbet and FcRL5 (markers associated with long lived immunity). In the non-severe patients, we observed IgG+Tbet+ B cells targeting the spike protein peak at 2-3 weeks post-symptom onset, decrease by almost fifty percent 4-5 weeks post-symptom onset, and return to baseline 5 months post-symptom onset. Our study also validated previous findings of a short-lived primary response of IgM+ B cells targeting the spike protein. DISCUSSION/SIGNIFICANCE: Our findings highlight potential implications for long-term immunity against re-infection or severity of the resulting disease in patients with severe COVID-19. Further investigation will be necessary to determine whether the maintenance of immunological protection is hindered in patients who overcame severe COVID-19.
The CLEAR Trial recently found that decolonization reduced infections and hospitalizations in MRSA carriers in the year following hospital discharge. In this secondary analysis, we explored whether decolonization had a similar benefit in the subgroup of trial participants who harbored USA300, using two different definitions for the USA300 strain-type.
ABSTRACT IMPACT: This project will use human neuron models and bioinformatics techniques to elucidate mechanisms of cocaine neurotoxicity, which will allow treatments to be developed for minimizing or preventing neurological damage caused by cocaine abuse and overdose. OBJECTIVES/GOALS: The goals of this project are to identify genes and gene networks altered by cocaine exposure in neurons (short term), and to use these pathways to understand mechanisms of cocaine neurotoxicity for the establishment of therapeutic targets (long term). METHODS/STUDY POPULATION: To study the molecular effects of cocaine, we generated preliminary proteomics and next-generation RNA sequencing (RNAseq) data from human postmortem prefrontal cortex (Broadmann area 9 or BA9) of 12 cocaine overdose subjects and 17 controls. Future directions for this project include RNAseq analysis of neuronal nuclei sorted from human postmortem BA9 and a human induced pluripotent stem cell-derived neuron (hiPSN) model of cocaine exposure from the same postmortem subjects from whom we have brain samples. RESULTS/ANTICIPATED RESULTS: We found alterations in neuronal synaptic protein levels and gene expression, including the serotonin transporter SLC6A4, and synaptic proteins SNAP25, SYN2, SYNGR3. Pathway analysis of our results revealed alterations in specific pathways involved with neuronal function including voltage-gated calcium channels, and GABA receptor signaling. In the future, we expect to see an enhancement in neuron-specific gene expression signatures in our sorted neuronal nuclei and our hiPSN model of cocaine exposure. The hiPSN model will help elucidate which effects are due to acute versus chronic exposure of cocaine. DISCUSSION/SIGNIFICANCE OF FINDINGS: Transcriptomic signatures found with this analysis can help us understand mechanisms of cocaine neurotoxicity in human neurons. With this work and future proposed studies, we can discover targetable molecular pathways to develop drugs that can reduce or reverse cocaine-related impairment.
We associate a flow
with a solution of the vortex equations on a closed oriented Riemannian 2-manifold
of negative Euler characteristic and investigate its properties. We show that
always admits a dominated splitting and identify special cases in which
is Anosov. In particular, starting from holomorphic differentials of fractional degree, we produce novel examples of Anosov flows on suitable roots of the unit tangent bundle of
Psychiatry is facing major challenges during the current coronavirus disease 2019 (COVID)-19 pandemic. These challenges involve its actual and perceived role within the medical system, in particular how psychiatric hospitals can maintain their core mission of attending to people with mental illness while at the same time providing relief to overstretched general medicine services. Although psychiatric disorders comprise the leading cause of the global burden of disease, mental healthcare has been deemphasised in the wake of the onslaught of the pandemic: to make room for emergency care, psychiatric wards have been downsized, clinics closed, psychiatric support systems discontinued and so on. To deal with this pressing issue, we developed a pandemic contingency plan with the aim to contain, decelerate and, preferably, avoid transmission of COVID-19 and to enable and maintain medical healthcare for patients with mental disorders.
To describe our plan as an example of how a psychiatric hospital can share in providing acute care in a healthcare system facing an acute and highly infectious pandemic like COVID-19 and at the same time provide support for people with mental illness, with or without a COVID-19 infection.
This was a descriptive study.
The plan was based on the German national pandemic strategy and several legal recommendations and was implemented step by step on the basis of the local COVID-19 situation. In addition, mid- and long-term plans were developed for coping with the aftermath of the pandemic.
The plan enabled the University Hospital to maintain medical healthcare for patients with mental disorders. It has offered the necessary flexibility to adapt its implementation to the first and second waves of the COVID-19 pandemic in Germany. The plan is designed to serve as an easily adaptable blueprint for psychiatric hospitals around the world.
This paper presents a framework aimed at significantly reducing the cost of proving functional correctness for low-level operating systems components. The framework is designed around a new functional programming language, Cogent. A central aspect of the language is its uniqueness type system, which eliminates the need for a trusted runtime or garbage collector while still guaranteeing memory safety, a crucial property for safety and security. Moreover, it allows us to assign two semantics to the language: The first semantics is imperative, suitable for efficient C code generation, and the second is purely functional, providing a user-friendly interface for equational reasoning and verification of higher-level correctness properties. The refinement theorem connecting the two semantics allows the compiler to produce a proof via translation validation certifying the correctness of the generated C code with respect to the semantics of the Cogent source program. We have demonstrated the effectiveness of our framework for implementation and for verification through two file system implementations.
We present continuous estimates of snow and firn density, layer depth and accumulation from a multi-channel, multi-offset, ground-penetrating radar traverse. Our method uses the electromagnetic velocity, estimated from waveform travel-times measured at common-midpoints between sources and receivers. Previously, common-midpoint radar experiments on ice sheets have been limited to point observations. We completed radar velocity analysis in the upper ~2 m to estimate the surface and average snow density of the Greenland Ice Sheet. We parameterized the Herron and Langway (1980) firn density and age model using the radar-derived snow density, radar-derived surface mass balance (2015–2017) and reanalysis-derived temperature data. We applied structure-oriented filtering to the radar image along constant age horizons and increased the depth at which horizons could be reliably interpreted. We reconstructed the historical instantaneous surface mass balance, which we averaged into annual and multidecadal products along a 78 km traverse for the period 1984–2017. We found good agreement between our physically constrained parameterization and a firn core collected from the dry snow accumulation zone, and gained insights into the spatial correlation of surface snow density.
Two hundred days after the first confirmed case of COVID-19 in Brazil, the epidemic has rapidly spread in metropolitan areas and advanced throughout the countryside. We followed the temporal epidemic pattern at São Paulo State, the most populous of the country, the first to have a confirmed case of COVID-19, and the one with the most significant number of cases until now. We analysed the number of new cases per day in each regional health department and calculated the effective reproduction number (Rt) over time. Social distance measures, along with improvement in testing and isolating positive cases, general population mask-wearing and standard health security protocols for essential and non-essential activities, were adopted and impacted on slowing down epidemic velocity but were insufficient to stop transmission.
Background: Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County, California (SHIELD OC) was a CDC-funded regional decolonization intervention from April 2017 through July 2019 involving 38 hospitals, nursing homes (NHs), and long-term acute-care hospitals (LTACHs) to reduce MDROs. Decolonization in NH and LTACHs consisted of universal antiseptic bathing with chlorhexidine (CHG) for routine bathing and showering plus nasal iodophor decolonization (Monday through Friday, twice daily every other week). Hospitals used universal CHG in ICUs and provided daily CHG and nasal iodophor to patients in contact precautions. We sought to evaluate whether decolonization reduced hospitalization and associated healthcare costs due to infections among residents of NHs participating in SHIELD compared to nonparticipating NHs. Methods: Medicaid insurer data covering NH residents in Orange County were used to calculate hospitalization rates due to a primary diagnosis of infection (counts per member quarter), hospital bed days/member-quarter, and expenditures/member quarter from the fourth quarter of 2015 to the second quarter of 2019. We used a time-series design and a segmented regression analysis to evaluate changes attributable to the SHIELD OC intervention among participating and nonparticipating NHs. Results: Across the SHIELD OC intervention period, intervention NHs experienced a 44% decrease in hospitalization rates, a 43% decrease in hospital bed days, and a 53% decrease in Medicaid expenditures when comparing the last quarter of the intervention to the baseline period (Fig. 1). These data translated to a significant downward slope, with a reduction of 4% per quarter in hospital admissions due to infection (P < .001), a reduction of 7% per quarter in hospitalization days due to infection (P < .001), and a reduction of 9% per quarter in Medicaid expenditures (P = .019) per NH resident. Conclusions: The universal CHG bathing and nasal decolonization intervention adopted by NHs in the SHIELD OC collaborative resulted in large, meaningful reductions in hospitalization events, hospitalization days, and healthcare expenditures among Medicaid-insured NH residents. The findings led CalOptima, the Medicaid provider in Orange County, California, to launch an NH incentive program that provides dedicated training and covers the cost of CHG and nasal iodophor for OC NHs that enroll.
Disclosures: Gabrielle M. Gussin, University of California, Irvine, Stryker (Sage Products): Conducting studies in which contributed antiseptic product is provided to participating hospitals and nursing homes. Clorox: Conducting studies in which contributed antiseptic product is provided to participating hospitals and nursing homes. Medline: Conducting studies in which contributed antiseptic product is provided to participating hospitals and nursing homes. Xttrium: Conducting studies in which contributed antiseptic product is provided to participating hospitals and nursing homes.
Background: The Changing Lives by Eradicating Antibiotic Resistance (CLEAR) Trial was a trial of 2,121 recently discharged methicillin-resistant Staphylococcus aureus (MRSA) carriers randomized to MRSA education plus a 5-day decolonization regimen repeated twice monthly for the 6 months following discharge versus MRSA education alone. Decolonization resulted in a 30% reduction in MRSA infection and a 17% reduction in all-cause infection (Huang SS et al, NEJM, 2019) in the year following discharge. We pursued an evaluation of USA300 carriers to determine whether the decolonization benefit differed for this strain type. Methods: A secondary analysis of the CLEAR randomized controlled trial (RCT) was performed, limiting the cohort to participants known to harbor USA300 at or within 30 days of enrollment and who attended all follow-up visits in the year following discharge. Within this subset, we conducted a time-to-event analysis using unadjusted and adjusted Cox proportional-hazard models. Variables in adjusted analyses included demographic data, insurance type, presence of coexisting conditions or medical devices at enrollment, hospitalization or residence in a nursing home in the year before enrollment, receipt of anti-MRSA antibiotics, protocol adherence, and randomization strata. Results: USA300 was identified in 420 of the 783 participants who attended all visits and had strains genetically tested. MRSA infections occurred in 27 of 207 education group participants (0.149 per person year) and in 19 of 213 decolonization group participants (0.099 per-person year). Point estimates from the unadjusted hazard ratios of infection reduction were similar (0.59; 95% CI, 0.32–1.09) to the full trial population (0.61; 95% CI, 0.44–0.85), suggesting nondifferential benefit for the USA300 strain type. Adjusted models were highly similar. Conclusions: The reduction in MRSA infection associated with postdischarge decolonization in the subgroup of participants who harbored the USA300 strain-type was consistent with overall trial findings. Although the original trial was not powered for the evaluation of a USA300 subset, this RCT provides a valuable design for assessing the magnitude of strain-specific responsiveness to decolonization during a time when national rates of MRSA invasive disease have plateaued and USA300 is responsible for an increasing proportion of infections. These data suggest that postdischarge decolonization should be similarly effective in carriers of either USA300 or healthcare-associated MRSA strains.
Disclosure: Gabrielle M. Gussin, Stryker (Sage Products): Conducting studies in which antiseptic product is provided to participating hospitals and nursing homes. Clorox: Conducting studies in which antiseptic product is provided to participating hospitals and nursing homes. Medline: Conducting studies in which antiseptic product is provided to participating hospitals and nursing homes. Xttrium: Conducting studies in which antiseptic product is provided to participating hospitals and nursing homes. Mohamad Sater, Salary-Day Zero Diagnostics.
For many us who have studied, researched, written, and taught about the influenza pandemic of 1918–19, the current period of the global viral pandemic is eerily and unpleasantly familiar. Today, the rapid global spread of a virus has prompted policies calling for widespread closures, social distancing, constant handwashing, and public mask wearing in additional to other non-pharmaceutical interventions (NPIs). We have also seen pushback and resistance to these directives as well as substantial mismanagement of resources and a flood of misinformation. Much health policy has been inconsistently set at the local rather than federal level. These responses to our current pandemic closely mirror those to the pandemic 102 years ago.
OBJECTIVES/GOALS: The goal of this project is to identify new therapeutic targets and biomarkers to treat or prevent cocaine toxicity by investigating proteomic, transcriptomic and epigenetic signatures of cocaine exposure in human subjects. METHODS/STUDY POPULATION: Cocaine is a highly addictive neurotoxic substance, and it is estimated that 1.9 million Americans are current users of cocaine. To study the molecular effects of cocaine, we generated preliminary proteomics and next-generation RNA sequencing (RNAseq) data from human postmortem dorsolateral prefrontal cortex (Broadmann area 9 or BA9) of 12 cocaine-exposed subjects and 17 controls. Future directions for this project include RNAseq and DNA methylation analysis of neuronal nuclei sorted from human postmortem BA9 and a human induced pluripotent stem cell-derived neuron (hiPSN) model of cocaine exposure from the same postmortem subjects from whom we have brain samples. RESULTS/ANTICIPATED RESULTS: We found alterations in neuronal synaptic protein levels and gene expression, including the serotonin transporter SLC6A4, and synaptic proteins SNAP25, SYN2, SYNGR3. Pathway analysis of our results revealed alterations in specific pathways involved with neuronal function including voltage-gated calcium channels, and GABA receptor signaling. In the future, we expect to see an enhancement in neuron-specific gene expression signatures in our sorted neuronal nuclei and our hiPSN model of cocaine exposure. The hiPSN model will help elucidate which effects are due to acute versus chronic exposure of cocaine. DISCUSSION/SIGNIFICANCE OF IMPACT: Neuronal signatures found with this analysis can help us understand mechanisms of cognitive decline in long-term cocaine users as well as the acute effects on the brain of cocaine taken in overdose. With this work and future proposed studies, we can discover novel clinical biomarkers for cocaine neurotoxicity in patients with cocaine use disorder and determine readouts for future therapeutic development on cocaine addiction and overdose.
This chapter tells the story of a research-engagement project called Making, Mapping and Mobilising in Merthyr (otherwise known as the 4Ms project). The project explored young people's sense of place and well-being while growing up in Merthyr Tydfil (hereafter referred to as Merthyr), a small post-industrial ex-mining and steel-making town of roughly 58,000 people in the South Wales Valleys. Once a hub of industrial activity and innovation, along with other geographically close regions, Merthyr has experienced a deep social rupture in recent years owing to deindustrialisation and the closure of ironworks, coal mines and manufacturing industries that had served as cultural links underpinning the rhythms and rituals of Valleys life (Walkerdine and Jimenez, 2011; Ivinson, 2014). Our project took place predominantly in a housing estate based on a design reputed to have been inspired in the 1950s by romantic Italian hilltop villages. The estate expanded in the 1970s, and by the 2000s, had become dilapidated and a place with high levels of unemployment. In a context of tightening austerity, this housing estate and the people living there have been subject to stigmatising media accounts fuelled by television's ‘poverty porn’ industry (Tyler, 2015) and, at times, by local residents themselves (Byrne et al, 2016; Thomas, 2016). The ‘realities’ of poverty tend to be portrayed in popular media through no-hope narratives of despair (Thomas, 2016; Thomas et al, 2018).
In contrast to other projects in the Productive Margins programme, the 4Ms project did not set out to investigate a specific element of regulation. Rather, we approached regulation as it occurred through the everyday experiences of living in a place that is in many ways at the margins, in terms of the explicit as well as the hidden effects and affects of poverty. The initial aim of the project was thus to attune to young people's knowledge as experts of living in this post-industrial place and to co-create research methods and encounters in order to find out how a range of regulatory regimes mediate and impact on their everyday lives.
The 4Ms project took shape across a series of three overlapping phases. We began by exploring the affective contours of the young people's neighbourhoods (Thomas, 2016).
There is an emerging consensus in developmental psychopathology that irritable youth are at risk for developing internalizing problems later in life. The current study explored if irritability in youth is multifactorial and the impact of irritability dimensions on psychopathology outcomes in adulthood.
We conducted exploratory factor analysis on irritability symptom items from a semi-structured diagnostic interview administered to a community sample of adolescents (ages 14–19; 42.7% male; 89.1% white). The analysis identified two factors corresponding to items from the mood disorders v. the oppositional defiant disorder (ODD) (Leibenluft and Stoddard) sections of the interview. These factors were then entered together into regression models predicting psychopathology assessed at age 24 (N = 941) and again at age 30 (N = 816). All models controlled for concurrent psychopathology in youth.
The two irritability dimensions demonstrated different patterns of prospective relationships, with items from the ODD section primarily predicting externalizing psychopathology, items from the mood disorder sections predicting depression at age 24 but not 30, and both dimensions predicting borderline personality disorder symptoms.
These results suggest that the current standard of extracting and compositing irritability symptom items from diagnostic interviews masks distinct dimensions of irritability with different psychopathological outcomes. Additionally, these findings add nuance to the prevailing notion that irritability in youth is specifically linked to later internalizing problems. Further investigation using more sensitive and multifaceted measures of irritability are needed to parse the meaning and clinical implications of these dimensions.
Consultation-liaison psychiatry started in the 1930s when the deinstitutionalisation process allowed the development of new types of psychiatric interventions in primary care and general hospitals. Consultation-liaison is an operational model defined by the environmental and institutional context of practice. It developed progressively as a sub-specialty of psychiatry and gained its own specificity in terms of clinical practice, organisation of care, training and research. More recently and following a similar process, old age psychiatry has developed as another subspecialty in psychiatry, with a scope based on the targeted population of older individuals. Consultation-liaison in old age psychiatry consequently emerged from this double development of consultation-liaison psychiatry and old age psychiatry.
Gregory’s narrative of the human person as an image of God is summarised best as ‘divine, yet vulnerable’. This reflects Gregory’s multifaceted approach, which relates to both human nature and experience. My use of ‘vulnerable’ is not intended to suggest that God might wound the image of God in any way; rather it is applied to indicate a kind of openness which may be positive or negative. The image of God is positively vulnerable (or porous) to God, having been created with the purpose of becoming ‘divine’, but at the same time negatively vulnerable to ‘the world, the flesh and the devil’.
The Council of Chalcedon bestowed the title ‘Blessed Gregory, the Theologian’ upon Saint Gregory of Nazianzus in AD 451.1 Along with Saint John the Evangelist and Saint Symeon the ‘New Theologian’, Gregory is one of only three theologians on whom the title has been conferred in the Eastern Christian tradition. Born circa AD 329 to Gregory the Elder, Bishop of Nazianzus, Gregory’s extensive education equipped him with the philosophical and rhetorical skills to theologise in a vast array of Greek literary forms. This led Gregory to become the most quoted author in Byzantine ecclesiastical literature, after the Bible.2 His neologism ‘theosis’ continues to be applied in contemporary theology as the chief term used to describe deification.