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This paper responds to a recent EPA Exchanges paper by Eric Knight, Andrew Jones and Meric Gertler ( Knight et al., 2021 ). It concurs with their argument for the significance of economic geography for explaining the “local-global” dilemmas facing the university in contemporary society. In response, it will propose three additional optics for understanding the role of the university in the contemporary city. First, as a space of risk, where the neo-liberal university is now undertaking various modes of financing their real estate models, drawing on bond markets to finance future growth, soliciting politically risky philanthropic donations, and betting on future student recruitment trends – including the high-risk international student sector – as being sufficient to fund capital investments in buildings and facilities. Second, as a space of decolonisation, where the university must seek to locate campus development within discussions about the university's responsibilities within systems of settler colonialism, and racially inflected gentrification. Third, as a civic disruptor, where the university campus is seen as more than just a backdrop or context to the university's governance, culture, and business models, but also as a front door to understanding the city and economy within which it is embedded.

Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD).Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed.Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment.In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development.Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments-selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751.

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy., RNA viruses, such as Zika and Dengue, activate the aryl hydrocarbon receptor (AHR) signaling to restrict the antiviral response. Here, the authors report that coronaviruses also activate AHR signaling, potentially allowing them to escape the immune response, and show that AHR antagonism limits SARS-CoV-2 replication in vitro, suggesting that AHR could be targeted for antiviral therapy.

OBJECTIVE End-of-life care for patients with cancer is often overly burdensome, and palliative and hospice care are underutilized. The objective of this study was to evaluate whether the mental health diagnoses of anxiety and depression were associated with variation in end-of-life care in metastatic cancer. METHODS This study used electronic health data from 1,333 adults with metastatic cancer who received care at two academic health centers in Louisiana, USA, and died between 1/1/2011-12/31/2017. The study used descriptive statistics to characterize the sample and logistic regression to examine whether anxiety and depression diagnoses in the six months before death were associated with utilization outcomes (chemotherapy, intensive care unit [ICU] visits, emergency department visits, mechanical ventilation, inpatient hospitalization, palliative care encounters, and hospice utilization), while controlling for key demographic and health covariates. RESULTS Patients (56.1% male; 65.6% White, 31.1% Black) commonly experienced depression (23.9%) and anxiety (27.2%) disorders within six months of death. Anxiety was associated with an increased likelihood of chemotherapy (odds ratio [OR] = 1.42, p = 0.016), ICU visits (OR = 1.40, p = 0.013), and inpatient hospitalizations (OR = 1.85, p

INTRODUCTION Bilateral vestibular failure (BVF) is an uncommon condition with numerous etiologies. It causes chronic oscillopsia and imbalance and is usually irreversible. We report 2 cases of BVF due to unusual causes, both of which improved with treatment of the underlying condition. CASE REPORTS The first patient was a 39-year-old female who developed profound BVF due to neurosarcoidosis. She was started on steroids and azathioprine and her vestibular function gradually improved, with essentially normal function 4.5 years after starting treatment. The second patient was a 54-year-old female who developed BVF in the context of glucagonoma. After treatment with octreotide, her vestibular function improved to almost normal, and she thus met the criteria for a probable paraneoplastic syndrome. CONCLUSIONS While BVF is usually permanent, this report demonstrates that some cases are likely to be reversible with treatment of the underlying cause. It is therefore imperative for clinicians to ensure that patients with BVF are thoroughly investigated.

Objectives: To determine the incidence of gentamicin vestibulotoxicity with current dosing regimens, and to evaluate the feasibility of routine video-oculography on all patients given genta...

Background The phenomenology and neurobiology of depressive symptoms in anxious youth is poorly understood. Methods Association networks of anxiety and depressive symptoms were developed in adolescents with generalized anxiety disorder (GAD; N=52, mean age: 15.4±1.6 years) who had not yet developed major depressive disorder. Community analyses were used to create consensus clusters of depressive and anxiety symptoms and to identify “bridge” symptoms between the clusters. In a subset of this sample (n=39), correlations between cortical thickness and depressive symptom severity was examined. Results Ten symptoms clustered into an anxious community, 5 clustered into a depressive community and 5 bridged the two communities: impaired schoolwork, excessive weeping, low self-esteem, disturbed appetite, and physical symptoms of depression. Patients with more depressive cluster burden had altered cortical thickness in prefrontal, inferior and medial parietal (e.g., precuneus, supramarginal) regions and had decreases in cortical thickness-age relationships in prefrontal, temporal and parietal cortices. Limitations Data are cross-sectional and observational. Limited sample size precluded secondary analysis of comorbidities and demographics. Conclusions In youth with GAD, a sub-set of symptoms not directly related to anxiety bridge anxiety and depression. Youth with greater depressive cluster burden had altered cortical thickness in cortical structures within the default mode and central executive networks. These alternations in cortical thickness may represent a distinct neurostructural fingerprint in anxious youth with early depressive symptoms. Finally, youth with GAD and high depressive symptoms had reduced age-cortical thickness correlations. The emergence of depressive symptoms in early GAD and cortical development may have bidirectional, neurobiological relationships.

Background: The fee-for-service reimbursement system that dominates health care throughout the United States links payment to a billable office visit with a physician or advanced practice provider. Under Oregon’s Alternative Payment and Advanced Care Model (APCM), initiated in 2013, participating community health centers (CHCs) received per-member-per-month payments for empaneled Medicaid patients in lieu of standard fee-for-service Medicaid payments. With Medicaid revenue under APCM no longer tied solely to the volume of visits, the Oregon Health Authority needed a way to document the full range of care and services that CHCs were providing to their patients, including nontraditional patient encounters taking place outside of traditional face-to-face visits with a billable provider. Toward this end, program leadership defined 18 visit and nonvisit-based care activities—“Care Services That Engage Patients” (Care STEPs)—that APCM CHCs were asked to document in the electronic health record to demonstrate continued empanelment. Objective: To describe trends in rates of traditional face-to-face office visits and Care STEPs documentation among CHCs involved in the first 3 phases of APCM implementation. Research Design: The study population included the 9 CHCs involved in the first 3 phases of APCM implementation. Using data from the electronic health record, quarterly summary rates for office visits and Care STEPs were calculated for the first 18 quarters of implementation (March 1, 2013 to June 30, 2017). Results: Among participating CHCs, the mean rate of face-to-face visits with billable providers declined from 635 ± 128 to 461 ± 109 visits/1000 patients/quarter (mean difference, −174; 95% CI, −255, −94). Care STEPs documentation increased from 831 ± 174 to 1017 ± 369 Care Steps/1000 patients/quarter, but the difference was not statistically significant. Care STEPs within the category of New Visit Types were documented most frequently. There were significant increases in documentation of Patient Care Coordination and Integration and a small, albeit significant, increase in Reducing Barriers to Health. There was a significant decline in the documentation of Care STEPs by physicians and advanced practice providers an increase in documentation by ancillary staff. Conclusions: These findings suggest that APCM is increasing CHCs’ capacity to experiment with new ways of providing care beyond the traditional face-to-face office visit with a physician or advanced practice provider. However, CHCs may choose different ways to change the delivery of care and some CHCs have implemented these changes more quickly than others. Future mixed-methods research is needed to understand barriers and facilitators to changing the delivery of care after APCM implementation.

Objective: To explore barriers to utilization of health-facility-based delivery in Kenya, use of which is associated with reduced maternal mortality. Methods: In April 2017, a qualitative study utilizing key informant interviews (KIIs) and focus group discussions (FGDs) was carried out in Bomachoge-Borabu and Kaloleni, Kenya. Twenty-four KIIs were performed including health service providers, community health workers, religious leaders, local government representatives, Ministry of Health representatives, and representatives of women's organizations. Sixteen FGDs were held separately with adolescent females, adult females, adult males, and Community Health Committee members. Data were transcribed, coded, and categorized thematically to illustrate supply-side and demand-side barriers to use of health-facility-based delivery services. Results: Supply-side barriers included staff shortages, inadequate supplies and space, poor interpersonal relations, few trained staff, long distance to services, poor transport infrastructure, and limited service hours. Demand-side barriers included financial constraints, limited spousal support, observance of birthing traditions, limited knowledge on importance of health-facility-based delivery, and fear of health-facility procedures. Conclusions: Diverse barriers continue to influence use of health-facility-based delivery services in Kenya. Practical, integrated interventions are urgently needed to reduce barriers noted, to further reduce the maternal mortality rate.

Objectives: Placebo response is one of the most significant barriers to detecting treatment effects in pediatric (and adult) clinical trials focusing on affective and anxiety disorders. We sought to identify neurofunctional predictors of placebo response in adolescents with generalized anxiety disorder (GAD) by examining dynamic and static functional brain connectivity. Methods: Before randomization to blinded placebo, adolescents, aged 12–17 years, with GAD (N = 25) underwent resting state functional magnetic resonance imaging. Whole brain voxelwise correlation analyses were used to determine the relationship between change in anxiety symptoms from baseline to week 8 and seed-based dynamic and static functional connectivity maps of regions in the salience and ventral attention networks (amygdala, dorsal anterior cingulate cortex [dACC], and ventrolateral prefrontal cortex [VLPFC]). Results: Greater dynamic functional connectivity variability in amygdala, dACC, VLPFC, and regions within salience, default mode, and frontoparietal networks was associated with greater placebo response. Lower static functional connectivity between amygdala and dorsolateral prefrontal cortex, amygdala and medial prefrontal cortex, dACC and posterior cingulate cortex and greater static functional connectivity between VLPFC and inferior parietal lobule were associated with greater placebo response. Conclusion: Placebo response is associated with a distinct dynamic and static connectivity fingerprint characterized by “variable” dynamic but “weak” static connectivity in the salience, default mode, frontoparietal, and ventral attention networks. These data provide granular evidence of how circuit-based biotypes mechanistically relate to placebo response. Finding biosignatures that predict placebo response is critically important in clinical psychopharmacology and to improve our ability to detect medication-placebo differences in clinical trials.

Simple Summary We have previously reported that a combination of clinical chemotherapies and oncolytic HSV-1 works to sensitize tumors to respond to immune checkpoint blockade. We further showed that this therapeutic platform worked via the upregulation of B cells and the concomitant control of immunosuppressive myeloid cells. In this manuscript, we sought to further dissect the mechanism of myeloid cell regulation and differentiation and to identify a therapeutically driven gene signature that is associated with the switch in the myeloid phenotype. This work not only impacts triple-negative breast cancer but all solid tumor phenotypes as we aim to better understand the underlying immunology associated with responses to immune checkpoint therapies in these typically refractory disease types. Abstract The era of immunotherapy has seen an insurgence of novel therapies driving oncologic research and the clinical management of the disease. We have previously reported that a combination of chemotherapy (FEC) and oncolytic virotherapy (oHSV-1) can be used to sensitize otherwise non-responsive tumors to immune checkpoint blockade and that tumor-infiltrating B cells are required for the efficacy of our therapeutic regimen in a murine model of triple-negative breast cancer. In the studies herein, we have performed gene expression profiling using microarray analyses and have investigated the differential gene expression between tumors treated with FEC + oHSV-1 versus untreated tumors. In this work, we uncovered a therapeutically driven switch of the myeloid phenotype and a gene signature driving increased tumor cell killing.

In the event of the current COVID-19 pandemic and in preparation for future pandemics, open science can support mission-oriented research and development, as well as commercialization. Open science shares skills and resources across sectors; avoids duplication and provides the basis for rapid and effective validation due to full transparency. It is a strategy that can adjust quickly to reflect changing incentives and priorities, because it does not rely on any one actor or sector. While eschewing patents, it can ensure high-quality drugs, low pricing, and access through existing regulatory mechanisms. Open science practices and partnerships decrease transaction costs, increase diversity of actors, reduce overall costs, open new, higher-risk/higher-impact approaches to research, and provide entrepreneurs freedom to operate and freedom to innovate. We argue that it is time to re-open science, not only in its now restricted arena of fundamental research, but throughout clinical translation. Our model and attendant recommendations map onto a strategy to accelerate discovery of novel broad-spectrum anti-viral drugs and clinical trials of those drugs, from first-in-human safety-focused trials to late stage trials for efficacy. The goal is to ensure low-cost and rapid access, globally, and to ensure that Canadians do not pay a premium for drugs developed from Canadian science.

Introduction This paper describes the adoption of an electronic health record-based social determinants of health screening tool in a national network of more than 100 community health centers. Methods In 2016, a screening tool with questions on 7 social determinants of health domains was developed and deployed in the electronic health record, with technical instructions on how to use the tool and suggested clinical workflows. To understand adoption patterns, the study team extracted electronic health record data for any patient with a community health center visit between June 2016 and May 2018. Patients were considered “screened” if a response to at least 1 social determinants of health domain was documented in the electronic health record tool. Results A total of 31,549 patients (2% of those with a visit in the study period) had a documented social determinants of health screening. The number of screenings increased over time, time; 71 community health centers (67%) conducted at least one screening, but almost 50% took place in only 4 community health centers. Over half (55%) of screenings only included responses for only 1 domain. Screening was most likely to occur during an office visit with an established patient and documented in the electronic health record by a medical assistant. Conclusions Screening documentation patterns varied widely across the network of community health centers. Despite the growing national emphasis on the importance of screening for social determinants of health, these findings suggest that simply activating electronic health record tools for social determinants of health screening does not lead to widespread adoption. Potential barriers to screening adoption and implementation should be explored further. Supplement information This article is part of a supplement entitled Identifying and Intervening on Social Needs in Clinical Settings: Evidence and Evidence Gaps, which is sponsored by the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services, Kaiser Permanente, and the Robert Wood Johnson Foundation.

Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder that is diagnosed based solely on clinical findings. Rarely, central lesions can present with positional vertigo and nystagmus, mimicking BPPV. Recognised red flags that may help distinguish central mimics from BPPV include the presence of additional neurological symptoms and signs, atypical nystagmus patterns, and the absence of a sustained response to repositioning manoeuvres. We present seven cases that illustrate how heuristic bias may affect the detection of these features in practice. Furthermore, our cases suggest that isolated downbeat positional nystagmus (simulating anterior canal BPPV) and apogeotropic horizontal nystagmus on the supine roll test (simulating horizontal canal BPPV) should be considered additional red flags.

The aim of this study is to explore how offsite fabrication (OSF) can be tightly coupled with production and assembly on-site. Prefabrication is a production method that has potential to yield significant productivity and sustainability improvements in the construction industry. Failure to synchronise production in the factory with on-site production can lead to financial losses for the client/owner, main contractor and subcontractors as well as to delays in the construction schedule. The study draws on two case-studies and the authors’ experiences in the context of a critical review of literature on the concepts of flow and Just-in-time (JIT) construction delivery. The findings show the value of a buffer between suppliers, fabricators and the site as a way to help the whole supply team create production flow and more environmentally friendly results. A buffer can help while the team is learning to use collaborative short-term planning to create predictable production. The paper recommends ways to synchronise OSF with on-site production. The paper provides practitioners with ideas to reduce both work waiting for workers (or robots) and workers (or robots) waiting for work – and it contributes to theory by raising more questions for further research.

Background: Globally, male involvement in reproductive, maternal, newborn, and child health (RMNCH) is associated with increased benefits for women, their children, and their communities. Between 2016 and 2020, the Aga Khan University implemented the Access to Quality of Care through Extending and Strengthening Health Systems (AQCESS), project funded by the Government of Canada and Aga Khan Foundation Canada (AKFC). A key component of the project was to encourage greater male engagement in RMNCH in rural Kisii and Kilifi, two predominantly patriarchal communities in Kenya, through a wide range of interventions. Toward the end of the project, we conducted a qualitative evaluation to explore how male engagement strategies influenced access to and utilization of RMNCH services. This paper presents the endline evaluative study findings on how male engagement influenced RMNCH in rural Kisii and Kilifi.Methods: The study used complementing qualitative methods in the AQCESS intervention areas. We conducted 10 focus group discussions (FGDs) with 82 community members across four groups including adult women, adult men, adolescent girls, and adolescent boys. We also conducted 11 key informant interviews (KIIs) with facility health managers, and sub-county and county officials who were aware of the AQCESS project.Results: Male engagement activities in Kisii and Kilifi counties were linked to improved knowledge and uptake of family planning (FP), spousal/partner accompaniment to facility care, and defeminization of social and gender roles.Conclusion: This study supports the importance of male involvement in RMNCH in facilitating decisions on women and children's health as well as in improving spousal support for use of FP methods.

Saltmarsh is a coastal ecosystem providing crucial ecosystem services, and its continued degradation and fragmentation has drawn increasing attention. However, how to effectively restore the connectivity between fragmented saltmarsh patches remains an open challenge. In this study, we developed a metric and modelling framework that prioritised saltmarsh patches for restoration. To demonstrate our approach, we simulated spatially explicit restoration schedules for Suaeda salsa patches at the Yellow River Delta National Nature Reserve, China, using three strategies: increasing-patch-area, increasing-number-of-patches and a benchmark unrestrictive prioritization strategy. We prioritised patches for restoration based on a number of widely used graph-theoretic landscape connectivity and metapopulation capacity metrics. Our simulation results suggested the rank connectivity-importance of extant patches was correlated within the group of graph-theoretic connectivity metrics or metapopulation capacity metrics, but unrelated across group. The unrestrictive prioritization strategy clearly outperformed the strategies of increasing-patch-area and increasing-number-of-patches which returned comparable connectivity restoration outcomes. For the more effective unrestrictive prioritization strategy, there were substantial differences in the simulated priority patches between metrics that considered stepping stone effects and those did not. While the former resulted in corridor-building priority patches that led to a more connected landscape throughout the region, the latter led to local clustering. We recommend use of the total probability of connectivity (PC) among the metrics we tested due to similarity of results to other metrics and its simulation efficiency. The proposed framework is readily applicable to prioritise areas for connectivity conservation and restoration in any monospecific ecosystem at the regional scale.

Safe and effective vaccines are needed to end the COVID-19 pandemic caused by SARS-CoV-2. Here we report the preclinical development of a lipid nanoparticle (LNP) formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern (VOCs), including the B.1.1.7, B.1.351 and P.1 lineages. No adverse effects were induced by PTX-COVID19-B in both mice and hamsters. These preclinical results indicate that PTX-COVID19-B is safe and effective. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 1 clinical trial ongoing (ClinicalTrials.govnumber:NCT04765436).One Sentence SummaryPTX-COVID19-B is a SARS-CoV-2 mRNA vaccine that is highly immunogenic, safe, and effective in preventing SARS-CoV-2 infection in mice and hamsters and is currently being evaluated in human clinical trials.

Programmed cell death protein 1 (PD-1), a receptor on T cells, and its ligand, PD-L1, have been a topic of much interest in cancer research. Both tumour and virus-infected cells can upregulate PD-L1 to suppress cytotoxic T-cell killing. Research on the PD-1/PD-L1 axis has led to the development of anti-PD-1/PD-L1 immune checkpoint blockades (ICBs) as promising cancer therapies. Although effective in some cancer patients, for many, this form of treatment is ineffective due to a lack of immunogenicity in the tumour microenvironment (TME). Despite the development of therapies targeting the PD-1/PD-L1 axis, the mechanisms and pathways through which these proteins are regulated are not completely understood. In this review, we discuss the latest research on molecules of inflammation and innate immunity that regulate PD-L1 expression, how its expression is regulated during viral infection, and how it is modulated by different cancer therapies. We also highlight existing research on the development of different combination therapies with anti-PD-1/PD-L1 antibodies. This information can be used to develop better cancer immunotherapies that take into consideration the pathways involved in the PD-1/PD-L1 axis, so these molecules do not reduce their efficacy, which is currently seen with some cancer therapies. This review will also assist in understanding how the TME changes during treatment, which will provide further rationale for combination therapies.

OBJECTIVE: To identify predictors of medication-placebo differences in double-blind placebo-controlled antidepressant trials in children and adolescents with anxiety and depression. METHODS: Clinical trials in patients

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

The Ngorongoro Conservation Area (NCA) is a protected area and UNESCO World Heritage Site and part of the Serengeti‐Ngorongoro Biosphere reserve in northern Tanzania. It is famous for its large volcanic caldera, unique cultural heritage, early hominid fossils and significant wildlife populations. NCA has been managed as a multiple land‐use area since 1959, a designation intended to foster a harmonious coexistence between indigenous residents and wildlife (Goldstein, 2004).

Background: Diabetic retinopathy is the leading cause of blindness among adults, but vision loss is preventable through regular screening. Urban areas in Canada have large numbers of unscreened individuals and teleophthalmology programs have been used to improve access and uptake of screening. The purpose of this study was to test different patient engagement approaches to expand teleophthalmology program to team-based primary care clinic in the city of Toronto, Canada.Methods: A teleophthalmology program was set up in a large urban academic team-based primary care practice. Patients over 18 years of age, with type 1 or type 2 diabetes were randomized to one of four engagement strategies: a phone call, a letter, a letter plus phone call, or usual care. Outreach was conducted by administrative staff within the clinic. The primary outcome was booking an appointment for diabetic retinopathy screening through a teleophthalmology program at the time of the call or within one week for the mail intervention. Results: A total of 23 patients in the phone, 28 in the mail, 32 in the mail and phone, and 27 in the control (usual care) were included in the analysis. After the intervention, 88% of patients in the phone intervention, 11% of patients in the mail group, and 100% in the mail and phone group booked an appointment with the teleophthalmology program compared to 0% in the control group. Phoning patients positively predicted patients booking a teleophthalmology appointment (p< .0001), while sending a letter had no effect. Conclusions: Patient engagement to book diabetic retinopathy screening via teleophthalmology in an urban academic team-based primary care practice using telephone calls was much more effective than letters or usual care. Practices that have access to a local DR screening programs and have the required resources to undertake such engagement strategies should consider using them as a means in improving their DR screening rates.

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells., Vito et al. investigated the effects of combination therapy in a TNBC tumor model and reported increased tumor-infiltrating lymphocytes that contributed to an improved response to immune checkpoint blockade. By depletion of circulating B cells prior to therapy, the authors showed a loss of therapeutic efficacy and simultaneous expansion of myeloid-derived suppressor cells.

Simple Summary Despite great advances in cancer therapy, tumor heterogeneity continues to be a great barrier for the successful treatment of cancer. It has long been established that tumor heterogeneity is prevelant in most cancer patients and is a major driver of acquired resistance to all forms of cancer therapy. In the case of immunotherapy, the response of the immune system against specific tumor antigens can drive selective pressure towards antigen-negative cells, which is a common cause of relapse in the clinic. In this review we summarize the mechanisms in which tumor heterogeity can arise. Furthermore, we discuss recent advances in the field of oncology that can be used to better identify, study, and overcome tumor heterogeneity. Abstract Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase selective pressure towards subpopulations with acquired resistance. This phenomenon is often the cause of relapse in previously responsive patients, drastically changing the expected outcome of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes more affordable and accessible, researchers continue to deepen their understanding of the factors that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to various treatments and review the strategies currently being employed to overcome this challenging clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better understanding of tumor heterogeneity and develop appropriate solutions.

Context Early integrated palliative care improves quality of life, but palliative care programs are underutilized. Psychoeducational interventions explaining palliative care may increase patients' readiness for palliative care. Objectives To 1) collaborate with stakeholders to develop the EMPOWER 2 intervention explaining palliative care, 2) examine acceptability, 3) evaluate feasibility and preliminary efficacy. Methods The research was conducted at a North American cancer center and involved 21 stakeholders and 10 patient-participants. Investigators and stakeholders iteratively developed the intervention. Stakeholders rated acceptability of the final intervention. Investigators implemented a pre-post trial to examine the feasibility of recruiting 10 patients with metastatic cancer within one month and with a ≥50% consent rate. Preliminary efficacy outcomes were changes in palliative care knowledge and attitudes. Results Using feedback from four stakeholder meetings, we developed a multimedia intervention tailored to three levels of health-literacy. The intervention provides knowledge and reassurance about the purpose and nature of palliative care, addressing cognitive and emotional barriers to utilization. Stakeholders rated the intervention and design process highly acceptable (3.78/4.00). The pilot met a priori feasibility criteria (10 patients enrolled in 14 days; 83.3% consent rate). The intervention increased palliative care knowledge by 83.1% and improved attitudes by 18.9 points on a 0 to 51 scale (Ps Conclusions This formative research outlines the development of a psychoeducational intervention about palliative care. The intervention is acceptable, feasible, and demonstrated promising pilot test results. This study will guide clinical teams in improving patients’ readiness for palliative care and inform the forthcoming EMPOWER 3 randomized clinical trial.

Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming. Here we show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors., Workenhe et al. show in mice that a combination of oncolytic HSV-1 virus and Mitomycin-C activates an inflammatory response, through necroptosis induction, that renders tumours susceptible to immune checkpoint inhibitors. These findings informs on the potential role of necroptosis in immunotherapy approaches.

Background: Short-term ambient fine particulate matter has been associated with exacerbations of psychiatric disorders in children and adolescents as measured by psychiatric emergency department ut...

BackgroundEvidence shows that 30% of healthcare services are unnecessary and unlikely to benefit patients and may even be harmful. Choosing Wisely (CW) is a physician-initiated, international campaign (with campaigns in at least 20 countries) aimed at addressing unnecessary medical care through the provision of evidence-based resources and clinical guidance. Our objectives were to evaluate the sustainability potential of CW across four Ontario community hospitals and affiliated family health teams (FHT). MethodsWe recruited CW implementation teams across Ontario hospitals and their affiliated primary care family health teams (FHTs) to participate in a mixed-methods study to identify and respond to their CW implementation and sustainability challenges. The study involved the administration of a validated sustainability Survey at baseline, 6- and 12-months follow-up, and participation in two focus groups (at baseline and 6 months) to discuss identified successes and opportunities for improvement, and to respond to implementation and sustainability challenges through a team exercise involving the co-creation and implementation of an action plan to directly address them.ResultsFifteen CW implementation teams across five Ontario community hospitals and affiliated FHTs participated in the study. Three CW de-adoption priority areas were investigated by teams: de-prescribing of proton pump inhibitors (PPIs), and reducing Pre-Op testing and BUN/Urea lab testing. All 15 teams achieved a baseline sustainability team score that was well above the threshold of what is considered a potentially sustainable innovation (i.e., >55%). We observed steady improvements in sustainability scores over three time points across all primary care teams, which is a strong indication that CW is sustainable in these settings. Regardless of site or priority area, facilitators that were common across all teams were fit with existing processes and workflows, leadership support, and optimized team communication. Common challenges were: lack of awareness and buy-in, lack of leadership engagement or a champion, and lack of fit with existing workflow and culture. All teams identified at least one challenge (during the baseline focus groups) for which they co-designed and implemented a plan to address them aimed at maximizing the sustainability potential of their CW priority areas. ConclusionsEvaluating the sustainability potential of an innovation such as Choosing Wisely is critical to ensuring that they have the best potential for impact. Our work highlights that implementation teams can be empowered to influence their implementation efforts, and to realize positive outcomes for their healthcare services and patients.

A Zika self-amplifying mRNA vaccine delivered by a flexible bedside mixing formulation induces protective immunity in NHPs., Zika virus (ZIKV) is the cause of a pandemic associated with microcephaly in newborns and Guillain-Barre syndrome in adults. Currently, there are no available treatments or vaccines for ZIKV, and the development of a safe and effective vaccine is a high priority for many global health organizations. We describe the development of ZIKV vaccine candidates using the self-amplifying messenger RNA (SAM) platform technology delivered by cationic nanoemulsion (CNE) that allows bedside mixing and is particularly useful for rapid responses to pandemic outbreaks. Two immunizations of either of the two lead SAM (CNE) vaccine candidates elicited potent neutralizing antibody responses to ZIKV in mice and nonhuman primates. Both SAM (CNE) vaccines protected these animals from ZIKV challenge, with one candidate providing complete protection against ZIKV infection in nonhuman primates. The data provide a preclinical proof of concept that a SAM (CNE) vaccine candidate can rapidly elicit protective immunity against ZIKV.

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02818751.

Background Accumulating evidence suggests that breastfeeding exclusivity and duration are positively associated with child cognition. This study investigated whether DNA methylation, an epigenetic mechanism modified by nutrient intake, may contribute to the link between breastfeeding and child cognition. The aim was to quantify the relationship between global DNA methylation and cognition and behavior at 4 years of age. Methods Child behavior and cognition were measured at age 4 years using the Wechsler Preschool and Primary Scale of Intelligence, third version (WPPSI‐III), and Child Behavior Checklist (CBC). Global DNA methylation (%5‐methylcytosines (%5mC)) was measured in buccal cells at age 4 years, using an enzyme‐linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. Results Data were collected from 73 children recruited from the Women and Their Children's Health (WATCH) study. No statistically significant associations were found between global DNA methylation levels and child cognition or behavior (p > .05), though the estimates of effect were consistently negative. Global DNA methylation levels in males were significantly higher than in females (median %5mC: 1.82 vs. 1.03, males and females, respectively, (p, This study quantified the relationship between global DNA methylation and cognition and behavior at 4 years of age. Data were collected from 73 children indicated no statistically significant associations were found between global DNA methylation levels and child cognition or behavior (p > .05). Global DNA methylation levels in males were significantly higher than in females (median %5mC: 1.82 vs. 1.03, males and females, respectively, (p

Variants in RORB have been reported in eight individuals with epilepsy, with phenotypes ranging from eyelid myoclonia with absence epilepsy to developmental and epileptic encephalopathies. We identified novel RORB variants in 11 affected individuals from four families. One was from whole genome sequencing and three were from RORB screening of three epilepsy cohorts: developmental and epileptic encephalopathies (n = 1021), overlap of generalized and occipital epilepsy (n = 84), and photosensitivity (n = 123). Following interviews and review of medical records, individuals' seizure and epilepsy syndromes were classified. Three novel missense variants and one exon 3 deletion were predicted to be pathogenic by in silico tools, not found in population databases, and located in key evolutionary conserved domains. Median age at seizure onset was 3.5 years (0.5-10 years). Generalized, predominantly absence and myoclonic, and occipital seizures were seen in all families, often within the same individual (6/11). All individuals with epilepsy were photosensitive, and seven of 11 had cognitive abnormalities. Electroencephalograms showed generalized spike and wave and/or polyspike and wave. Here we show a striking RORB phenotype of overlap of photosensitive generalized and occipital epilepsy in both individuals and families. This is the first report of a gene associated with this overlap of epilepsy syndromes.

Numerous candidate vaccines against cytomegalovirus (CMV) infection and disease are in development. Whereas the previous article [1] provides background and opinions about the issues relating to vaccination, this article provides specifics about the vaccines in active development, as reported at a National Institutes of Health-sponsored meeting in Bethesda on September 4–6, 2018. Here, vaccine developers provide synopses of their candidate vaccines to immunize women to protect against congenital CMV disease and to prevent the consequences of CMV disease in recipients of transplanted organs or hematopoietic stem calls. The projects are presented here roughly in the descending order of their stage of development in the opinion of the first author.

In many industries, meeting the needs of customers can mean the difference between thriving and going out of business. In the last century, manufacturers started to use and refine methods to reliably make products that offered a better customer experience at lower cost, by reducing defects and waste.1 These methods, introduced to healthcare almost 30 years ago2, are now part of the routine operations of many hospitals and large physician organisations. They have contributed to improvements in patient experience, reductions in hospital acquired infections and fewer readmissions.3 Customer-focused companies have not stood still during this time, creating an abundance of new products and services.4 5Many of these were made by technology startups and firms adapting industrial design methods like ‘human-centred design’ to create better experiences by understanding and responding to unspoken or unmet needs of customers.6 Embracing methods to create new products and services can augment current efforts to improve existing products and services and has potential to make health systems more responsive to patient’s needs. While the financial pressure to improve the user experience is less in healthcare than other service industries, the rise of value-based financing in many health systems creates an incentive to explore new models of care that offer a better patient experience and better health outcomes at lower cost. The broad goal of improving value and delivering a better experience can be pursued using established methods like Lean and Six-Sigma that are relatively well established in healthcare.7 However, these methods may not be as well suited to generating novel services. Methods less familiar to healthcare like design thinking (first introduced by some healthcare organisations in the last 15 years or so),8 9 and Lean Startup (introduced within the last 5 years)10 may confer advantages on …

BACKGROUND AND PURPOSE Sensory neuronopathy is a cardinal feature of cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS). Having observed that two patients with CANVAS had small median and ulnar nerves on ultrasound, we set out to examine this finding systematically in a cohort of patients with CANVAS, and compare them with both healthy controls and a cohort of patients with axonal neuropathy. We have previously reported preliminary findings in seven of these patients with CANVAS and seven healthy controls. METHODS We compared the ultrasound cross-sectional area of median, ulnar, sural and tibial nerves of 14 patients with CANVAS with 14 healthy controls and 14 age- and gender-matched patients with acquired primarily axonal neuropathy. We also compared the individual nerve cross-sectional areas of patients with CANVAS and neuropathy with the reference values of our laboratory control population. RESULTS The nerve cross-sectional area of patients with CANVAS was smaller than that of both the healthy controls and the neuropathy controls, with highly significant differences at most sites (P < 0.001). Conversely, the nerve cross-sectional areas in the upper limb were larger in neuropathy controls than healthy controls (P < 0.05). On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one patient with CANVAS. DISCUSSION Small nerves in CANVAS probably reflect nerve thinning from loss of axons due to ganglion cell loss. This is distinct from the ultrasound findings in axonal neuropathy, in which nerve size was either normal or enlarged. Our findings indicate a diagnostic role for ultrasound in CANVAS sensory neuronopathy and in differentiating neuronopathy from neuropathy.

Objectives:Health-related quality of life (HRQoL) data generated by generic, preference-based instruments (i.e., EQ-5D) are highly demanded in health policy decision making, because they allow for direct comparisons of HRQoL outcomes between disease areas. We aimed to quantify HRQoL outcomes in breast cancer (BC), rheumatoid arthritis (RA), multiple sclerosis (MS), rare cancers (RC), and rare disease (RD) patients and understand the patterns that differentiate HRQoL outcomes between these disease areas, and more specifically between rare and more common disease population groups.Methods:An international, Web survey of patients measured HRQoL (EQ-5D-5L), self-perceived health (EQ-5D-5L Visual Analogue Scale), and additional QoL dimensions, such as patient disability level.Results:We received 675 completed responses. Average utility loss was 53.5 percent, 32.5 percent, and 33.3 percent for RD, RA, and MS patients, respectively, in contrast to 18.6 percent for BC and RC patients. Statistically significant differences (p < .05) were observed between disease groups in all EQ-5D-5L domain outcomes, apart from that of “Anxiety/Depression.” Severe and/or extreme problems were reported in performing usual activities for RD and RC (34 percent and 13 percent of overall problems reported respectively), mobility for MS (18 percent), pain/discomfort for RA (13 percent), and anxiety/depression for BC (7 percent) patients.Conclusions:We demonstrated significant differences in the dimensions that drive HRQoL outcomes between rare and more common diseases and showcased that the same EQ-5D utility may reflect very different severities depending on the patient population under investigation. Future research should examine whether outcomes in other, critical HRQoL domains not included in generic measures also highlight significant differences across disease areas.

The acute vestibular syndrome is common and usually has a benign cause. Sometimes, however, even experienced neurologists can find it difficult to determine the cause clinically. Furthermore, neuroimaging is known to be insensitive.We describe two cases of acute vestibular syndrome where conflicting clinical findings contributed to a delay in making the correct diagnosis. The first patient with symptomatic vertigo had signs consistent with horizontal benign paroxysmal positional vertigo but also had an abnormal horizontal head impulse test, superficially suggesting acute vestibular neuritis but later accounted for by the finding of a vestibular schwannoma (acoustic neuroma). The second patient also had an abnormal horizontal head impulse test, with skew deviation suggesting stroke as the cause. However, later assessment identified that a long-standing fourth nerve palsy was the true cause for her apparent skew. We discuss potential errors that can arise when assessing such patients and highlight ways to avoid them.

INTRODUCTION Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. METHODS The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. RESULTS The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P

The International MultiPlE Sclerosis Study (IMPrESS) studied the significant impact of multiple sclerosis (MS) on the health and well-being of both people with the disease and their caregivers, along with its broader socioeconomic impact. Results confirmed that there is an urgent need to achieve better outcomes for people with MS. This paper uses results from the IMPrESS to present new international evidence on the socioeconomic burden of MS and discuss the merits of a likely paradigm shift in the management of MS towards the use of better (and more accurate) diagnostic follow-up to monitor disease progression and the earlier use of disease-modifying treatments (DMTs) to achieve better clinical, quality-of-life and socioeconomic results for individuals.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged to cause widespread infections in humans SARS-CoV-2 infections have been reported

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation. ispartof: JOURNAL FOR IMMUNOTHERAPY OF CANCER vol:8 issue:1 ispartof: location:England status: published