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The term “Anthropocene” is obfuscatory, and as an analytic framework it has a serious blind spot: the conflicts stemming from the uneven distribution of the costs and benefits of the “Age of Man,” which are the very eco-conflicts on which artists in our field should focus. We should be talking about the “Capitalocene,” a term that locates climate change within the history of capitalism and colonialism, and suggests stories that deserve time on our stages.

The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

The ability of news media to criticize government is a core pillar of media freedom and is often taken as evidence of meaningful democratization. Existing indices typically use scoring criteria or expert surveys to develop over-time measures of media freedom. In this article, we use the largest existing dataset of Arabic-language news to evaluate how political reporting about the government changes over the course of successful and failed democratic transitions in Egypt and Tunisia. Using entirely unsupervised ALC word-embedding techniques, we demonstrate how to generate temporally granular measurements of media criticism that closely correlate with measurements derived from expert surveys for both countries. Crucially, the technique we propose is computationally inexpensive, open-source, and cost-free––making it eminently scalable. Our work therefore points to new possibilities in the monitoring and measurement of media capture within authoritarian and transitional settings.

MSLN sequence showing positioning of the Exon 3 gRNA site.

Successful reconstitution of WT or Y318A MSLN expression in KLM1 KO#2 and over-expression in MIA PaCa-2.

Figure Legends and Supplementary Methods

In vivo BLI of mice inoculated IP with Luc/GFP+ KLM1 Mock or KO#2 on day 3 (D3), 7 (D7) and 14 (D14) post-injection.

Examination of involvement of NF-κB pathway in MSLN IP pro-tumorigenicity.

Examination of protein signaling pathways.

Identifying a novel mediator for MSLN activity using qPCR.

Background Short-term rehabilitation units present unique infection control challenges because of high turnover and medically complex residents. In June 2021, the Maricopa County Department of Public Health was notified of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta outbreak in a skilled nursing facility short-term rehabilitation unit. We describe the outbreak and assess vaccine effectiveness (VE). Methods Facility electronic medical records were reviewed for residents who spent > 1 night on the affected unit between June 10 and July 23, 2021, to collect demographics, SARS-CoV-2 test results, underlying medical conditions, vaccination status, and clinical outcomes. Coronavirus disease 2019 VE estimates using Cox proportional hazards models were calculated. Results Forty (37%) of 109 short-stay rehabilitation unit residents who met inclusion criteria tested positive for SARS-CoV-2. SARS-CoV-2-positive case-patients were mostly male (58%) and White (78%) with a median age of 65 (range, 27-92) years; 11 (27%) were immunocompromised. Of residents, 39% (10 cases, 32 noncases) received 2 doses and 9% (4 cases, 6 noncases) received 1 dose of messenger RNA (mRNA) vaccine. Among nonimmunocompromised residents, adjusted 2-dose primary-series mRNA VE against symptomatic infection was 80% (95% confidence interval, 15-95). More cases were hospitalized (33%) or died (38%) than noncases (10% hospitalized; 16% died). Conclusions In this large SARS-CoV-2 Delta outbreak in a high-turnover short-term rehabilitation unit, a low vaccination rate and medically complex resident population were noted alongside severe outcomes. VE of 2-dose primary-series mRNA vaccine against symptomatic infection was the highest in nonimmunocompromised residents. Health departments can use vaccine coverage data to prioritize facilities for assistance in preventing outbreaks.

What is already known about this topic? A novel HIV infection surveillance initiative was implemented in Malawi to collect data on recent HIV infections among new diagnoses to characterize the epidemic and guide the public health response. What is added by this report? Higher proportions of recent infections were identified among females, persons aged

Introduction: Hyperlipidemia is a modifiable risk factor for stroke, with the magnitude of LDL-C reduction correlating to risk of recurrent ischemic stroke. A high-intensity statin is considered standard of care in addition to dietary modification. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are used if the LDL-C target is not achieved despite maximally tolerated statins with ezetimibe. We investigated the role for PCSK9 inhibitors in our ischemic stroke population. Methods: An IRB approved retrospective review of patients admitted for acute ischemic stroke between 2019 – 2020 was performed. We estimated the probability of benefit from PCSK9 treatment with the following criteria: LDL > 190 regardless of treatment, LDL 161-190 on any dose statin therapy, and LDL 131-160 on high intensity statin therapy. Results: 774 patients with ischemic stroke were admitted during this time frame. Mean age 62.8 +/- 13.2 with 57% male (52% Black, 42% White). 584 (75%) of these patients had LDL above goal. One patient was on PCSK9 therapy on admission. Although the majority of our patients had uncontrolled cholesterol, only one additional patient would meet the strict prescription criteria for PCSK9 therapy of being adherent to maximal tolerated statin dose and ezetimibe with LDL above goal. Other potential patients with estimated benefit include LDL >190 (20 patients), LDL 161-190 (16 patients), LDL 131-160 (13 patients). In total this amounts to 6.7% of stroke patients who we would expect to need PCSK9 inhibitors in the future. Conclusion: Using conservative projections, we estimate that about 1 in 14 patients with ischemic stroke could benefit from PCSK9 therapy. Achieving LDL targets more consistently is a promising approach to decreasing the recurrent stroke rate. Further prospective data evaluating outcomes after initiating PCSK9 inhibitor treatment are needed to validate these findings.

Background To describe post-COVID-19 vaccination [fully vaccinated (FV) and first booster] immune response and occurrence of reinfection ( >90 days from prior infection) in nursing home residents (NHr) with/without evidence of prior SARS-CoV-2 infection. Methods In a longitudinal prospective cohort of 36 NHr from 3 NHs, interviews, chart abstractions, and specimens [blood and anterior nasal swabs (ANs)] were collected at baseline and monthly visits. ANs underwent molecular and BinaxNOW™ antigen testing. Quantitative Meso Scale Discovery platform tested blood specimens for anti-spike (S) protein and anti-nucleocapsid (N) antibodies. In addition, in a subset (n=13), S-specific memory B cells (MBCs) were tested with ELISpot assays. Results The cohort's median age was 72 years; 46% male, 64% White Non-Hispanic, 80% had ≥3 comorbidities, and 29 (81%) had prior SARS-CoV-2 infection. Of 36, 76% received Pfizer-BioNTech and 24% Moderna homologous vaccine. The median distribution of anti-S IgG concentrations among those with prior infection increased 15‒30 days post-FV, remained stable for 90 days, and declined by 120 days. The anti-S IgG remained above the estimated vaccine effectiveness (VE) thresholds published [Pfizer-BioNTech (95% VE: 530 BAU/ml), Moderna (90% VE: 298 BAU/ml)]. Among those without previous infection, anti-S IgG declined after 60 days and stayed near the VE thresholds until a recent infection/booster. Age, sex, and comorbidities had no appreciable impact on anti-S IgG. From enrollment to November 2021, 1of 29 had reinfection. From December 2021 to January 2022, 2 of 7 had a new infection, and 4 of 29 had reinfection, as shown by anti-N IgG rise. Persistently low numbers of total and anti-S MBC were seen across the evaluation, even with post-booster anti-S MBC rise. There was an immediate rise in anti-S IgG concentrations in all participants post-booster, irrespective of recent infection. Conclusion These findings from a NH convenience cohort suggest that prior SARS-CoV-2 infection has a pronounced immunomodulatory enhancing effect on the magnitude and duration of FV immune response. The decline of anti-S antibodies post-FV and rise after booster supported the booster recommendation in this cohort. The low MBC counts indicate immunosenescence in this high-risk population. Disclosures Hollis Houston, BA, Fidelity: Stocks/Bonds.

Drawing from a wide range of ecocritical theories, Woynarski’s Ecodramaturgies: Theatre, Performance and Climate Change maps out the concept of ecodramaturgies by interrogating how intersectional ecological meanings are generated in performance.

Background: The aim of this study was to evaluate the ipsilateral lower extremity (ILE) outcomes of patients who underwent bedside angiography via the distal perfusion catheter while on femoral veno-arterial extracorporeal membrane oxygenation (VA ECMO). Methods: This is a retrospective analysis of all patients placed on VA ECMO at a single center from January 2017 to December 2019 who underwent bedside angiography via the distal perfusion catheter. Results: Twenty-four patients underwent bedside angiography via the distal perfusion catheter after being placed on VA ECMO. A vasodilator was directly administered in three patients for suspected spasm. One patient had distal thrombus and underwent thrombectomy and fasciotomy. One patient had a dislodged catheter and underwent thrombectomy, fasciotomy, and replacement of the catheter. One patient had severe ILE ischemia, however was not intervened upon due to critical acuity. Finally, one patient had inadvertent placement in the saphenous vein and had a new catheter placed in the SFA. No patients underwent amputation. Ultimately, 21 patients (87.5%) had no ILE compromise at the end their ECMO course. Survival to decannulation was 66.7% ( n = 16). Conclusions: Bedside angiography of the distal perfusion catheter is feasible and can be a useful adjunct in informing the need for further intervention to the ILE. Classifications: extracorporeal membrane oxygenation, ischemia

Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiologic features in HCM when relying on resting invasive hemodynamic data alone.Do structural changes to the lung vasculature clarify PH pathophysiologic features in patients with HCM with progressive heart failure?Clinical data and ultrarare lung autopsy specimens were acquired retrospectively from the National Institutes of Health (1975-1992). Patients were included based on the availability of lung tissue and recorded mPAP. Discarded tissue from rejected lung donors served as control specimens. Histomorphology was performed on pulmonary arterioles and veins. Comparisons were calculated using the Student t test and Mann-Whitney U test; Pearson correlation was used to assess association between morphometric measurements and HCM cardiac and hemodynamic measurements.The HCM cohort (n = 7; mean ± SD age, 43 ± 18 years; 71% men) showed maximum mean ± SD LV wall thickness of 25 ± 2.8 mm, mean ± SD outflow tract gradient of 90 ± 30 mm Hg, median mPAP of 25 mm Hg (interquartile range [IQR], 6 mm Hg), median pulmonary artery wedge pressure (PAWP) of 16 mm Hg (IQR, 4 mm Hg), and median pulmonary vascular resistance of 1.8 Wood units (WU; IQR, 2.4 WU). Compared with control samples (n = 5), patients with HCM showed greater indexed pulmonary arterial hypertrophy (20.7 ± 7.2% vs 49.7 ± 12%; P .001) and arterial wall fibrosis (11.5 ± 3.4 mm vs 21.0 ± 4.7 mm; P .0001), which correlated with mPAP (r = 0.84; P = .018), PAWP (r = 0.74; P = .05), and LV outflow tract gradient (r = 0.78; P = .035). Compared with control samples, pulmonary vein thickness was increased by 2.9-fold (P = .008) in the HCM group, which correlated with mPAP (r = 0.81; P = .03) and LV outflow tract gradient (r = 0.83; P = .02).These data demonstrate for the first time that in patients with obstructive HCM, heart failure is associated with pathogenic pulmonary vascular remodeling even when mPAP is elevated only mildly. These observations clarify PH pathophysiologic features in HCM, with future implications for clinical strategies that mitigate outflow tract obstruction.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents. Methods We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic. Results Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide. Conclusions Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.

The idea of the “Anthropocene” is rapidly gaining currency as an ecocritical lens through which to view theater and performance. But as a lens for critical analysis, the concept of the “Anthropocene” is problematic, primarily because it fails to differentiate among humans, many of whom are in conflict precisely because the benefits and costs of the “Age of Man” have been distributed unevenly. Neo-Marxist critics take such conflicts into fuller account in their argument that a better nomenclature and concept for our epoch is the “Capitalocene,” a term that captures the fact that our ecological crises have been precipitated not by humans in some undifferentiated and generalized way, but more specifically by the global spread of capitalism and its socio-economic-ecological injustices. These are also conflicts at the heart of many plays, both historical and recent. This essay offers an overview of a number of works that might productively be categorized as “Tragedies of the Capitalocene,” insofar as they dramatize stories that trace the dynamics of “Capitalocene” exploitation of both human and nonhuman resources. Plays considered include Cherríe Moraga’s Heroes and Saints (1992), Rahul Varma’s Bhopal (2001), Kia Corthron’s A Cool Dip in the Barren Saharan Crick (2010), Annabel Soutar’s Seeds (2012), Robert Schenkkan’s The Kentucky Cycle (1991), and Colleen Murphy’s The Breathing Hole (2017).

Older adults are susceptible to severe coronavirus disease 2019 (COVID-19) outcomes as a consequence of their age and, in some cases, underlying health conditions (1). A COVID-19 outbreak in a long-term care skilled nursing facility (SNF) in King County, Washington that was first identified on February 28, 2020, highlighted the potential for rapid spread among residents of these types of facilities (2). On March 1, a health care provider at a second long-term care skilled nursing facility (facility A) in King County, Washington, had a positive test result for SARS-CoV-2, the novel coronavirus that causes COVID-19, after working while symptomatic on February 26 and 28. By March 6, seven residents of this second facility were symptomatic and had positive test results for SARS-CoV-2. On March 13, CDC performed symptom assessments and SARS-CoV-2 testing for 76 (93%) of the 82 facility A residents to evaluate the utility of symptom screening for identification of COVID-19 in SNF residents. Residents were categorized as asymptomatic or symptomatic at the time of testing, based on the absence or presence of fever, cough, shortness of breath, or other symptoms on the day of testing or during the preceding 14 days. Among 23 (30%) residents with positive test results, 10 (43%) had symptoms on the date of testing, and 13 (57%) were asymptomatic. Seven days after testing, 10 of these 13 previously asymptomatic residents had developed symptoms and were recategorized as presymptomatic at the time of testing. The reverse transcription-polymerase chain reaction (RT-PCR) testing cycle threshold (Ct) values indicated large quantities of viral RNA in asymptomatic, presymptomatic, and symptomatic residents, suggesting the potential for transmission regardless of symptoms. Symptom-based screening in SNFs could fail to identify approximately half of residents with COVID-19. Long-term care facilities should take proactive steps to prevent introduction of SARS-CoV-2 (3). Once a confirmed case is identified in an SNF, all residents should be placed on isolation precautions if possible (3), with considerations for extended use or reuse of personal protective equipment (PPE) as needed (4).

Over 90% of pancreatic ductal adenocarcinomas (PDAC) express mesothelin (MSLN). Overexpression or knockdown of MSLN has been implicated in PDAC aggressiveness. This activity has been ascribed to MSLN-induced activation of MAPK or NF-κB signaling pathways and to interaction of MSLN with its only known binding partner, MUC16. Here, we used CRISPR/Cas9 gene editing to delete MSLN from PDAC, then restored expression of wild-type (WT) or Y318A mutant MSLN by viral transduction. We found that MSLN KO cells grew in culture and as subcutaneous tumors in mouse xenografts at the same rate as WT cells but formed intraperitoneal metastases poorly. Complementation with WT MSLN restored intraperitoneal growth, whereas complementation with Y318A mutant MSLN, which does not bind MUC16, was ineffective at enhancing growth in both MUC16(+) and MUC16(−) models. Restoration of WT MSLN did enhance growth but did not affect cell-to-cell binding, cell viability in suspension or signaling pathways previously identified as contributing to the protumorigenic effect of MSLN. RNA deep sequencing of tumor cells identified no changes in transcriptional profile that could explain the observed phenotype. Furthermore, no histologic changes in tumor cell proliferation or morphology were observed in mature tumors. Examination of nascent MSLN KO tumors revealed decreased microvascular density as intraperitoneal tumors were forming, followed by decreased proliferation, which resolved by 2 weeks postimplantation. These data support a model whereby MSLN expression by tumor cells contributes to metastatic colonization. Implications: MSLN confers a growth advantage to tumor cells during colonization of peritoneal metastasis. Therapeutic blockade of MSLN might limit peritoneal spread.

Clinical trials of treatments for high-grade gliomas have traditionally relied on measures of response or time-dependent metrics; however, these endpoints have limitations because they do not characterise the functional or symptomatic effect of the condition on the person. Including clinical outcome assessments, such as patient- reported outcomes (PROs), to determine net clinical benefit of a treatment strategy is needed because of the substantial burden of symptoms and impaired functioning in this patient population. The US National Cancer Institute convened a meeting to review previous recommendations and existing PRO measures of symptoms and function that can be applied to current trials and clinical practice for high-grade gliomas. Measures were assessed for relevance, relationship to disease and therapy, sensitivity to change, psychometric properties, response format, patient acceptability, and use of self-report. The group also relied on patient input including the results of an online survey, a literature review on available clinical outcomes, expert opinion, and alignment with work done by other organisations. A core set of priority constructs was proposed that allows more comprehensive evaluation of therapies and comparison of outcomes among studies, and enhances efforts to improve the measurement of these core clinical outcomes. The proposed set of constructs was then presented to the Society for Neuro-Oncology Response Assessment in Neuro-Oncology Working Group and feedback was solicited.

Background The Malawi Ministry of Health implemented a new surveillance activity in April 2019 to detect recent HIV infections using a rapid test for recent infection (RTRI) to identify areas of ongoing transmission and guide response activities. Setting At 23 health facilities in Blantyre District, healthcare workers (HCWs) were trained to conduct recent infection testing. In September 2019, we conducted a cross-sectional survey at these sites to explore the acceptability and feasibility of integrating this activity into routine HIV testing services (HTS). Methods Research assistants interviewed HCWs using a semi-structured survey. Descriptive statistics were used to summarize quantitative responses and thematic analysis was used to group open-ended text. Results We interviewed 119 HCWs. Eighty-two percent of participants reported the RTRI was easy-to-use. HCWs perceived high client acceptability; 100% reported clients as ‘somewhat’ or ‘very accepting’. Challenges included 68% of HCWs estimating they spend ≥20 min beyond routine HTS per client for this activity and 51% performing at least two additional finger pricks to complete the testing algorithm. HCWs differed in their perceptions of whether results should be returned to clients. Conclusion This study assessed HCW experiences using point-of-care RTRIs for HIV recent infection surveillance. Overall, HCWs perceived RTRIs to be acceptable, easy-to-use, and valuable. Though only clients with new HIV diagnoses are tested for recent infection, additional time may be substantial at high-volume health service delivery points. Providing response plans or aggregated recent infection results to HCWs and/or clients may support motivation and sustainability of this novel surveillance activity.

Background: Pulsed radiofrequency (PRF) has been used for the treatment of chronic lumbar radicular pain and other chronic pain states. The dorsal root ganglion (DRG) consists of primary afferent somatic and visceral nerve cell bodies that transduce sensory signals from the periphery to the central part of the nervous system. It is a very important part of acute nociception, as well as the development and maintenance of chronic pain. Methods: A total of seven domestic pigs were investigated. All pigs underwent a PRF procedure while under general anesthesia and with X-ray imaging. Four lumbar DRGs were randomly treated. We used the opposite side of the DRGs as controls. The lumbar region of the spine was placed in 10% formaldehyde for one month. After this fixation, DRG samples were prepared for slide analysis. Results: Nestin (Nes, code-Nr. AB 5968, dilution 1:250, rabbit, Abcam, United Kingdom) and matrix metallopeptidase 2 (MMP-2, code-Nr. DUB 03, dilution 1:100, goat) expressions were detected by immunohistochemical staining. The cell numbers with Nes (28.4 ± 3.3 vs. 16.1 ± 3.4; P < 0.05) and MMP-2 (26.2 ± 3.2 vs. 14.1 ± 2.3; P < 0.05) expressions were larger on the PRF side compared to the control side. The glial cells in the spinal ganglia on both sides showed immunoreactivity. Conclusions: The increase of MMP-2-containing gangliocytes one month after PRF procedures highlights active neural cell proliferation. Increased Nes factor expression in spinal gangliocytes of the lumbar region indicates neural remodeling and regeneration.

Additional file 2.

BackgroundSurvivorship for those living with primary CNS cancers begins at diagnosis, continues throughout a person's life, and includes caregivers. Opportunities and challenges exist to advance survivorship care for those living with primary CNS cancers that necessitate stakeholder involvement.MethodsIn June 2021, NCI-CONNECT convened a two-day virtual workshop about survivorship care in neuro-oncology. Two expert panels provided key recommendations and five working groups considered critical questions to identify strengths, weaknesses, opportunities, and threats to the advancement of survivorship care and developed recommendations and action items.ResultsThe following action items emanated from the workshop: seek endorsement of meeting report from stakeholder organizations; address barriers in access to survivorship care and provider reimbursement; advance survivorship research through NIH and private grant support; develop a survivorship tool kit for providers, people living with primary CNS cancers and their caregivers; provide accessible educational content for neuro-oncology, neurology, and oncology community providers about survivorship care in neuro-oncology; and establish core competencies for survivorship care for neuro-oncology providers to be included in training and standardized exams.ConclusionsAction items aim to address access and reimbursement barriers, expand patient and provider education, develop core competencies, and support survivorship research through funding and other supports.

Additional file 1.

Background Survivorship for those living with primary CNS cancers begins at diagnosis, continues throughout a person’s life, and includes caregivers. Opportunities and challenges exist to advance survivorship care for those living with primary CNS cancers that necessitate stakeholder involvement. Methods In June 2021, NCI-CONNECT convened a two-day virtual workshop about survivorship care in neuro-oncology. Two expert panels provided key recommendations and five working groups considered critical questions to identify strengths, weaknesses, opportunities, and threats to the advancement of survivorship care and developed recommendations and action items. Results The following action items emanated from the workshop: seek endorsement of meeting report from stakeholder organizations; address barriers in access to survivorship care and provider reimbursement; advance survivorship research through NIH and private grant support; develop a survivorship tool kit for providers, people living with primary CNS cancers and their caregivers; provide accessible educational content for neuro-oncology, neurology, and oncology community providers about survivorship care in neuro-oncology; and establish core competencies for survivorship care for neuro-oncology providers to be included in training and standardized exams. Conclusions Action items aim to address access and reimbursement barriers, expand patient and provider education, develop core competencies, and support survivorship research through funding and other supports.

This chapter explores the use of class action procedures to resolve crowdfunding-related disputes. In collective proceedings, associations or foundations will typically act as claimants, representing a constituency of investors that allegedly suffered the same type of harm, and taking decisions with (legal) consequences for the individual members of this groups. In principle, this type of dispute seems to be suitable for class action schemes, e.g. aggregating the claims of a multitude of investors against a project owner, or a service provider. Yet, the availability of this sort of procedures varies largely among European legal systems. The chapter discusses class actions as a method for the resolution of crowdfunding-related disputes, also in light of the new EU Directive on collective redress.

Introduction: Advanced-stage pulmonary arterial hypertension (asPAH) is characterized by endothelial dysfunction and fibrotic remodeling of pulmonary arterioles that promotes irreversible right heart failure. Thus, identifying mechanisms that regulate vascular fibrosis in early PAH (esPAH) may have translational importance. Hypothesis: We hypothesized that profibrotic molecular pathways differentiate esPAH from asPAH. Methods: To test this hypothesis, male Sprague-Dawley rats were administered one dose of monocrotaline (60 mg/kg; day 0) to induce inflammatory PAH. Cardiac catheterization and pulmonary artery endothelial cell (PAEC) transcriptomic analyses were performed on days 15 and 21 for esPAH and asPAH, respectively. Results: The esPAH profile included: right ventricular-pulmonary arterial (RV-PA) uncoupling (1.13 ± 0.05 vs. 0.90 ± 0.06, RV end-systolic elastance/PA elastance, P=0.02, N=6) and increased indexed pulmonary vascular resistance (50 ± 8 vs. 213 ± 29 mmHg*min*g -1 *mL -1 , Pin silico . Pulmonary endothelial expression of Csk protein by immunofluorescence correlated with vascular collagen by picrosirius red stain (r=+0.87, P=0.006, N=4). To validate these findings in vitro , human PAECs (HPAEC) were treated with an inflammatory stimulus of lipopolysaccaride (0.03 mg/mL) + interferon-γ (50 ng/mL) + interleukin-1β (50 ng/mL), or vehicle control (V). Compared to V-control, inflammation increased Csk protein and mRNA expression by 2.3- and 2.0-fold, respectively (P-4 , N=4) vs. V-treated cells. Overexpression of Csk by adenovirus transfection attenuated inflammation-mediated hydroxyproline accumulation by 84% (P=1.3x10 -5 , N=3). Conclusions: These data suggest that impaired Csk may underlie HPAEC fibrosis in esPAH, which, in turn, may have potential therapeutic implications for the prevention of fibrotic vascular remodeling and PAH progression.

The paper proposes a Subsynchronous Control Interaction (SSCI) study framework and applies to Southern California Edison System. Frequency impedance scan screening is performed for a large set of contingencies on the entire power network and the severity of the contingencies is ranked based on the damping coefficients. The outcome of these screening and ranking can identify those short-listed scenarios which need to undergo detailed Electromagnetic Transient (EMT) analysis. Based on the screening and ranking results, an EMT model for both a small power network around the Point of Interconnection (POI) and the detailed Distributed Energy Resources (DER) model using EMT/PSCAD are developed. It concludes that the screening techniques and the EMT type time domain analysis are complementary with respect to the investigation of SSCI issues.

Despite major strides in cancer research, care, and therapy, these advances have not been equitable across race and ethnicity. Groups underrepresented in medicine (URM) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black and Latino Americans represent 29% of the population but only reflect 8% of oncology clinical trial participants. Recent studies have shown that this disparity is also present in neuro-oncology as women, Black, and Latino Americans remain under-accrued in clinical trials. Brain tumor patients already face unique barriers to clinical trial enrollment and completion due to disease-specific conditions–such as impaired motor function, cognition, language deficits, and caregiver dependency–which pose additional difficulties in clinical trial consent, enrollment, and adherence. As part of this collaborative initiative, we evaluated the impact of how a lack of diversity in cancer research is detrimental to scientific discovery and propose interventions focused on improving URM engagement with clinical research. Recommendations include the creation of inclusive trial design at the onset, decreasing barriers to care, expanding trial eligibility, and equitable access to tumor profiling for personalized medical trials. Additionally, setting reasonable metrics and goals for accrual and engagement with patient and community stakeholders will ultimately help to diversify trial participants. Lastly, diversification and inclusion practices within the neuro-oncology workforce, including all personnel involved in clinical research, will help to minimize bias, promote concordant care, and assist with developing sustainable solutions. The diversification of participation in neuro-oncology clinical trials is imperative. The lack of diversity in clinical trials can contribute to improper generalizability of treatment efficacy, resulting in potentially harmful practices. Equitable access and inclusion of URM brain tumor patients will not only enhance research discoveries but will also result in improved patient care for all cancer patients.

The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22’s functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest the motor domain α2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of α2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76OAS1variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay ofOAS1. We suggest that genetically-regulated loss ofOAS1expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of theOAS1risk haplotypes.

Hairy cell leukemia (HCL) is an indolent B-cell malignancy, usually driven by the BRAF V600E mutation. For 30 years, untreated and relapsed HCL was successfully treated with purine analogs, but minimal residual disease (MRD) remained in most patients, eventually causing relapse. Repeated purine analogs achieve decreasing efficacy and increasing toxicity, particularly to normal T-cells. MRD-free complete remissions (CRs) are more common using rituximab with purine analogs in both 1st-line and relapsed settings. BRAF inhibitors and Ibrutinib can achieve remission, but due to persistence of MRD, must be used chronically to prevent relapse. BRAF inhibition combined with Rituximab can achieve high MRD-free CR rates. Anti-CD22 recombinant immunotoxin moxetumomab pasudotox is FDA-approved in the relapsed setting and is unique in achieving high MRD-free CR rates as a single-agent. Avoiding chemotherapy and rituximab may be important in ensuring both recovery from COVID-19 and successful COVID-19 vaccination, an area of continued investigation.

In the Seattle, Washington metropolitan area, where the first case of novel coronavirus 2019 disease (COVID-19) in the United States was reported (1), a community-level outbreak is ongoing with evidence of rapid spread and high morbidity and mortality among older adults in long-term care skilled nursing facilities (SNFs) (2,3). However, COVID-19 morbidity among residents of senior independent and assisted living communities, in which residents do not live as closely together as do residents in SNFs and do not require skilled nursing services, has not been described. During March 5-9, 2020, two residents of a senior independent and assisted living community in Seattle (facility 1) were hospitalized with confirmed COVID-19 infection; on March 6, social distancing and other preventive measures were implemented in the community. UW Medicine (the health system linked to the University of Washington), Public Health - Seattle & King County, and CDC conducted an investigation at the facility. On March 10, all residents and staff members at facility 1 were tested for SARS-CoV-2, the virus that causes COVID-19, and asked to complete a questionnaire about their symptoms; all residents were tested again 7 days later. Among 142 residents and staff members tested during the initial phase, three of 80 residents (3.8%) and two of 62 staff members (3.2%) had positive test results. The three residents had no symptoms at the time of testing, although one reported an earlier cough that had resolved. A fourth resident, who had negative test results in the initial phase, had positive test results 7 days later. This resident was asymptomatic on both days. Possible explanations for so few cases of COVID-19 in this residential community compared with those in several Seattle SNFs with high morbidity and mortality include more social distancing among residents and less contact with health care providers. In addition, early implementation of stringent isolation and protective measures after identification of two COVID-19 cases might have been effective in minimizing spread of the virus in this type of setting. When investigating a potential outbreak of COVID-19 in senior independent and assisted living communities, symptom screening is unlikely to be sufficient to identify all persons infected with SARS-CoV-2. Adherence to CDC guidance to prevent COVID-19 transmission in senior independent and assisted living communities (4) could be instrumental in preventing a facility outbreak.

OBJECTIVE: There is wide variation in the number and types of obesity policies enacted across states, and prior studies suggest that partisan factors may not fully explain this variation. In this exploratory analysis, we examined the association of a broad array of state-level factors with the number and types of obesity policies across states. DESIGN: We analyzed 32 predictor variables across seven categories of state-level characteristics. We abstracted data from 1652 state obesity policies introduced during 2009–2014. We used multilevel regression models and principal components analysis to examine the association between state-level characteristics and policy outcomes. MAIN OUTCOME MEASURES: Our outcome measures included whether bills involved topics that were public-health-oriented or business-interest-oriented, whether bills were enacted into law, and the number of introduced bills and enacted laws per state. RESULTS: Numerous state-level characteristics were associated with obesity-related bill introduction and law enactment, and different state characteristics were associated with public-health-oriented versus business-interest-oriented policies. For example, state-level demographics, economic factors, policy environment, public programs, and the prevalence of obesity’s downstream consequences were associated with the number of public-health laws, while obesity prevalence and policy environment were associated with the number of business-interest laws. CONCLUSIONS: Our results support the hypothesis that a variety of factors contribute to a complex state obesity policymaking environment, highlighting the need for future research to disentangle these key predictors.

Outside Switzerland, the Schauspielhaus Zürich (Zürich Playhouse) is best known among theatre historians for the role it played in supporting and advancing the career of German playwright Bertolt Brecht during and just after World War II. We learn, from our studies of Brecht, that while he was living in exile in Finland and the United States his plays Mother Courage and Her Children, The Good Person of Szechwan, and Galileo all received their first productions in Zürich, and that when he returned to Europe from exile the city was also his initial destination. Brecht was not the only exiled playwright to find a producing home at the Schauspielhaus; the theatre has additionally long been recognized, particularly among German and Swiss theatre historians, for the important role it played in producing the work of many other exiled German and Austrian playwrights during World War II. Some American theatre historians have also made note of the quality of the work produced at the Schauspielhaus: for example, Oscar Brockett mentions the Zürich theatre in passing as “one of the best in Europe during the Nazi regime because so many refugees settled in Switzerland.” But what remains underrecognized among historians outside Switzerland is the pivotal role that both the Schauspielhaus and its dramaturg (and later artistic director) Kurt Hirschfeld played in keeping an international repertoire on life support in Europe when most of the Continent was under Nazi occupation (Fig. 1). A look at the list of wartime and postwar productions at the Schauspielhaus reveals a veritable who's who of the modern Western dramatic canon: productions of works by playwrights like Karel Čapek, Thornton Wilder, Jean Giraudoux, Jean-Paul Sartre, Paul Claudel, Federico García Lorca, T. S. Eliot, Arthur Miller, Tennessee Williams, Luigi Pirandello, and many, many—in fact, many dozens—of others.