Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

Functional exploration of copy number alterations in a Drosophila model of triple-negative breast cancer.

Accounting for 10-20% of breast cancer cases, triple-negative breast cancer (TNBC) is associated with a disproportionate number of breast cancer deaths. One challenge in studying TNBC is its genomic profile: with the exception of TP53 loss, most breast cancer tumors are characterized by a high number of copy number alterations (CNAs), making modeling the disease in whole animals challenging. We computationally analyzed 186 CNA regions previously identified in breast cancer tumors to rank genes within each region by likelihood of acting as a tumor driver. We then used a Drosophila p53-Myc TNBC model to identify 48 genes as functional drivers. To demonstrate the utility of this functional database, we established six 3-hit models; altering candidate genes led to increased aspects of transformation as well as resistance to the chemotherapeutic drug fluorouracil. Our work provides a functional database of CNA-associated TNBC drivers, and a template for an integrated computational/whole-animal approach to identify functional drivers of transformation and drug resistance within CNAs in other tumor types.

Comparing Mediators and Moderators of Mental Health Outcomes from the Implementation of Group Problem Management Plus (PM+) among Venezuelan Refugees and Migrants and Colombian Returnees in Northern Colombia.

Colombia hosts the largest number of refugees and migrants fleeing the humanitarian emergency in Venezuela, many of whom experience high levels of displacement-related trauma and adversity. Yet, Colombian mental health services do not meet the needs of this population. Scalable, task-sharing interventions, such as Group Problem Management Plus (Group PM+), have the potential to bridge this gap by utilizing lay workers to provide the intervention. However, the current literature lacks a comprehensive understanding of how and for whom Group PM+ is most effective. This mixed methods study utilized data from a randomized effectiveness-implementation trial to examine the mediators and moderators of Group PM+ on mental health outcomes. One hundred twenty-eight migrant and refugee women in northern Colombia participated in Group PM+ delivered by trained community members. Patterns in moderation effects showed that participants in more stable, less marginalized positions improved the most. Results from linear regression models showed that Group PM+-related skill acquisition was not a significant mediator of the association between session attendance and mental health outcomes. Participants and facilitators reported additional possible mediators and community-level moderators that warrant future research. Further studies are needed to examine mediators and moderators contributing to the effectiveness of task-shared, scalable, psychological interventions in diverse contexts.

U-CAN-seq: A Universal Competition Assay by Nanopore Sequencing.

RNA viruses quickly evolve subtle genotypic changes that can have major impacts on viral fitness and host range, with potential consequences for human health. It is therefore important to understand the evolutionary fitness of novel viral variants relative to well-studied genotypes of epidemic viruses. Competition assays are an effective and rigorous system with which to assess the relative fitness of viral genotypes. However, it is challenging to quickly and cheaply distinguish and quantify fitness differences between very similar viral genotypes. Here, we describe a protocol for using reverse transcription PCR in combination with commercial nanopore sequencing services to perform competition assays on untagged RNA viruses. Our assay, called the Universal Competition Assay by Nanopore Sequencing (U-CAN-seq), is relatively cheap and highly sensitive. We used a well-studied N24A mutation in the chikungunya virus (CHIKV) nsp3 gene to confirm that we could detect a competitive disadvantage using U-CAN-seq. We also used this approach to show that mutations to the CHIKV 5' conserved sequence element that disrupt sequence but not structure did not affect the fitness of CHIKV. However, similar mutations to an adjacent CHIKV stem loop (SL3) did cause a fitness disadvantage compared to wild-type CHIKV, suggesting that structure-independent, primary sequence determinants in this loop play an important role in CHIKV biology. Our novel findings illustrate the utility of the U-CAN-seq competition assay.

Adjuvant-dependent effects on the safety and efficacy of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Inactivated whole virus SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide (Alum) are among the most widely used COVID-19 vaccines globally and have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous virus infection in healthy recipients, the emergence of novel SARS-CoV-2 variants and the presence of large zoonotic reservoirs provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes including vaccine-associated enhanced respiratory disease (VAERD). To evaluate this possibility, we tested the performance of an inactivated SARS-CoV-2 vaccine (iCoV2) in combination with Alum against either homologous or heterologous coronavirus challenge in a mouse model of coronavirus-induced pulmonary disease. Consistent with human results, iCoV2 + Alum protected against homologous challenge. However, challenge with a heterologous SARS-related coronavirus, Rs-SHC014-CoV (SHC014), up to at least 10 months post-vaccination, resulted in VAERD in iCoV2 + Alum-vaccinated animals, characterized by pulmonary eosinophilic infiltrates, enhanced pulmonary pathology, delayed viral clearance, and decreased pulmonary function. In contrast, vaccination with iCoV2 in combination with an alternative adjuvant (RIBI) did not induce VAERD and promoted enhanced SHC014 clearance. Further characterization of iCoV2 + Alum-induced immunity suggested that CD4+ T cells were a major driver of VAERD, and these responses were partially reversed by re-boosting with recombinant Spike protein + RIBI adjuvant. These results highlight potential risks associated with vaccine breakthrough in recipients of Alum-adjuvanted inactivated vaccines and provide important insights into factors affecting both the safety and efficacy of coronavirus vaccines in the face of heterologous virus infections.

Health Services in Huntington Disease: A Systematic Literature Review.

Purpose of Review: Clinical trials for Huntington disease (HD) have primarily focused on managing chorea and, more recently, the development of disease-modifying therapies (DMTs). Nonetheless, understanding health services among patients with HD is essential for assessing new therapeutics, development of quality metrics, and overall quality of life of patients and families with HD. Health services assess health care utilization patterns, outcomes, and health care-associated costs, which can help shape the development of therapeutics and aid in policies that affect patients with a specific condition. In this systematic literature review, we analyze data of published studies looking at causes of hospitalization, outcomes, and health care costs in HD. Recent Findings: The search yielded 8 articles published in the English language and comprising data from the United States, Australia, New Zealand, and Israel. The most common cause of hospitalization among patients with HD was dysphagia or dysphagia-related complications (e.g., aspiration pneumonia or malnutrition), followed by psychiatric or behavioral symptoms. Patients with HD had more prolonged hospitalizations than non-HD patients, and it was most prominent among those with advanced disease. Patients with HD were more likely to be discharged to a facility. A small percentage received inpatient palliative care consultation, and behavioral symptoms were a primary cause of discharge to another facility. Interventions such as gastrostomy tube placement had associated morbidity, and it was common among patients with HD with a diagnosis of dementia. Palliative care consultation and specialized nursing care were associated with more routine discharges and fewer hospitalizations. In terms of cost, patients with HD with private and public insurances had the highest expenditure with more advanced disease, and expenses were associated with hospitalization and medication costs. Summary: In addition to DMTs, HD clinical trial development should also consider the leading causes of hospitalization, morbidity, and mortality in patients with HD, including dysphagia and psychiatric disease. No research study, to our knowledge, has systematically reviewed health services research studies in HD. Evidence from health services research is needed to evaluate the efficacy of pharmacologic and supportive therapies. This type of research is also critical in understanding health care costs associated with the disease and to better advocate and shape policies that can benefit this patient population.

Epidemiology of Coronavirus Disease 2019 at a County Jail-Alameda County, California, March 2020-March 2021.

CONTEXT: Coronavirus disease 2019 (COVID-19) incidence rates are 2- to 5-fold higher among persons incarcerated in the United States than in the general population. PROGRAM OR POLICY: We describe an outbreak investigation of COVID-19 at a jail (jail A) in Alameda County during March 2020-March 2021. IMPLEMENTATION: To prevent COVID-19 cases among incarcerated persons and employees, staff at jail A and the county public health department worked to develop and recommend infection control measures implemented by jail A including, but not limited to, face covering use among incarcerated persons and staff; cohorting incarcerated persons at a higher risk of severe COVID-19 in dedicated housing units; quarantining all newly detained individuals for 14 days; and offering testing for all symptomatic incarcerated persons, newly incarcerated persons at day 2 and day 10, and all persons who resided in a housing unit where a COVID-19 case was detected. EVALUATION: A total of 571 COVID-19 cases were detected among incarcerated persons at jail A during March 2020-March 2021, which represented a total incidence of 280 per 1000 population, 5 times higher than the rate in Alameda County. Of the 571 cases among incarcerated persons, 557 (98%) were male; 415 (73%) were aged 18 to 40 years; 249 (44%) were Latino; and 180 (32%) were African American; 354 (62%) were not symptomatic; and 220 (39%) had no comorbidities. Less than 2% of infected incarcerated persons were hospitalized, and no deaths were reported. DISCUSSION: COVID-19 disproportionately impacted persons incarcerated at jail A, with higher numbers among Latinos and African Americans. Implementation of COVID-19 infection control and testing measures, and collaboration between public health, law enforcement, and health care providers may have, in part, led to reductions in morbidity and mortality associated with COVID-19 at jail A.

In the post-COVID-19 era, is the illegal wildlife trade the most serious form of trafficking?

Despite the immense impact of wildlife trafficking, comparisons of the profits, costs, and seriousness of crime consistently rank wildlife trafficking lower relative to human trafficking, drug trafficking and weapons trafficking. Using the published literature and current events, we make the case, when properly viewed within the context of COVID-19 and other zoonotic diseases transmitted from wildlife, that wildlife trafficking is the most costly and perhaps the most serious form of trafficking. Our synthesis should raise awareness of the seriousness of wildlife trafficking for humans, thereby inducing strategic policy decisions that boost criminal justice initiatives and resources to combat wildlife trafficking.

Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer.

OBJECTIVE: Surveillance tools for early cancer detection are suboptimal, including hepatocellular carcinoma (HCC), and biomarkers are urgently needed. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumour initiation and metastasis; however, most extracellular RNA (exRNA) blood-based biomarker studies are limited to annotated genomic regions. DESIGN: EVs were isolated with differential ultracentrifugation and integrated nanoscale deterministic lateral displacement arrays (nanoDLD) and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking and deconvolution analysis. Genome-wide sequencing of the largely unexplored small exRNA landscape, including unannotated transcripts, identified and reproducibly quantified small RNA clusters (smRCs). Their key genomic features were delineated across biospecimens and EV isolation techniques in prostate cancer and HCC. Three independent exRNA cancer datasets with a total of 479 samples from 375 patients, including longitudinal samples, were used for this study. RESULTS: ExRNA smRCs were dominated by uncharacterised, unannotated small RNA with a consensus sequence of 20 nt. An unannotated 3-smRC signature was significantly overexpressed in plasma exRNA of patients with HCC (p<0.01, n=157). An independent validation in a phase 2 biomarker case-control study revealed 86% sensitivity and 91% specificity for the detection of early HCC from controls at risk (n=209) (area under the receiver operating curve (AUC): 0.87). The 3-smRC signature was independent of alpha-fetoprotein (p<0.0001) and a composite model yielded an increased AUC of 0.93. CONCLUSION: These findings directly lead to the prospect of a minimally invasive, blood-only, operator-independent clinical tool for HCC surveillance, thus highlighting the potential of unannotated smRCs for biomarker research in cancer.

Simultaneous Superiorly Based Pharyngeal Flap and Tonsillectomy: Evaluation of Speech and Pain Outcomes.

ABSTRACT: Controversy remains whether to perform a pharyngeal flap simultaneously with a tonsillectomy in patients with velopharyngeal insufficiency. The aim of this study is to revisit the speech outcomes and complications associated with the combined superiorly based pharyngeal flap and tonsillectomy procedure, while comparing pain outcomes. We hypothesize that the combined procedure will improve speech outcomes with minimal complications, but patients will experience more pain in the combined procedure.A 5-year retrospective review of registry data from Boys Town National Research Hospital was conducted from 2014 to 2019. Data collection included age, surgeries performed, length of stay, pain medication administration occurrences, immediate postoperative complications, postoperative speech outcomes specifically related to articulation (audible nasal airway emissions) and resonance (hypernasality).Eighty-eight patients had a superiorly based pharyngeal flap over this 5-year period. Eighteen patients (20%) had a simultaneous procedure performed. There were no patients who had immediate postoperative complications such as upper airway obstruction or bleeding complications that necessitated a reoperation. One of the patients had a pharyngeal flap dehiscence that required a revision pharyngeal flap in the combined group. Nasal airway emissions and hypernasality were eliminated in 58.3% and 75%of the combined patients, respectively. The total number of narcotic administration occurrences were significantly higher in the combined group than the pharyngeal flap only group (9.0 versus 7.0; P = 0.03).A number of velopharyngeal patients will present with hypertrophied tonsils. We believe that it is safe and beneficial to perform the combined procedure in the same setting.

Personality traits and male vulnerability to commercial sexual exploitation victimisation.

BACKGROUND: There has been little research into whether personality traits increase vulnerability to serious forms of recurring victimisation, such as commercial sexual exploitation of young people. AIMS: To investigate whether impulsivity, emotional dysregulation or high psychopathy scale scores indicative of personality traits increase vulnerability to commercial sexual exploitation. METHODS: Data were used from the longitudinal Pathways to Desistance Study 1170 justice-involved men who were aged 14-19 at baseline data collection. Ninety-eight (8%) reported having been commercially sexually exploited during adolescence or young adulthood. We investigated whether personality traits measured at baseline were related to such victimisation. RESULTS: Results of binomial logistic regression among the young men in this sample indicated that Factor 1 scores on the Psychopathy Checklist-Youth Version (PCL-YV), reflecting affective and interpersonal features, are associated with having been commercially sexually exploited, while impulsivity, emotional dysregulation and Factor 2 PCL-YV, reflecting antisocial activities, were not. Having been a victim of other violence and being a member of a cultural or ethnic minority group were also independently related to being exploited. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Our findings show that individual differences in personality, such as fearless temperament and boredom susceptibility, could differentially disadvantage young people, and put them at greater risk of commercial sexual exploitation. This knowledge could be beneficial to prevention efforts supporting male adolescents at risk for victimisation by commercial sexual exploitation, and to shed new light on the theoretical understanding of vulnerability to it.

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies.

Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.

modEnrichr: a suite of gene set enrichment analysis tools for model organisms.

High-throughput experiments produce increasingly large datasets that are difficult to analyze and integrate. While most data integration approaches focus on aligning metadata, data integration can be achieved by abstracting experimental results into gene sets. Such gene sets can be made available for reuse through gene set enrichment analysis tools such as Enrichr. Enrichr currently only supports gene sets compiled from human and mouse, limiting accessibility for investigators that study other model organisms. modEnrichr is an expansion of Enrichr for four model organisms: fish, fly, worm and yeast. The gene set libraries within FishEnrichr, FlyEnrichr, WormEnrichr and YeastEnrichr are created from the Gene Ontology, mRNA expression profiles, GeneRIF, pathway databases, protein domain databases and other organism-specific resources. Additionally, libraries were created by predicting gene function from RNA-seq co-expression data processed uniformly from the gene expression omnibus for each organism. The modEnrichr suite of tools provides the ability to convert gene lists across species using an ortholog conversion tool that automatically detects the species. For complex analyses, modEnrichr provides API access that enables submitting batch queries. In summary, modEnrichr leverages existing model organism databases and other resources to facilitate comprehensive hypothesis generation through data integration.

The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation.

Vitamin B12 deficiency is common in older individuals. Circulating vitamin B12 concentration can be used to diagnose deficiency, but this test has substantial false positive and false negative rates. We conducted genome-wide association studies (GWAS) in which we resolved total serum vitamin B12 into the fractions bound to transcobalamin and haptocorrin: two carrier proteins with very different biological properties. We replicated reported associations between total circulating vitamin B12 concentrations and a common null variant in FUT2. This allele determines the secretor phenotype in which blood group antigens are found in non-blood body fluids. Vitamin B12 bound to haptocorrin (holoHC) remained highly associated with FUT2 rs601338 (p.Trp154Ter). Transcobalamin bound vitamin B12 (holoTC) was not influenced by this variant. HoloTC is the bioactive the form of the vitamin and is taken up by all tissues. In contrast, holoHC is only taken up by the liver. Using holoHC from individuals with known FUT2 genotypes, we demonstrated that FUT2 rs601338 genotype influences the glycosylation of haptocorrin. We then developed an experimental model demonstrating that holoHC is transported into cultured hepatic cells (HepG2) via the asialoglycoprotein receptor (ASGR). Our data challenge current published hypotheses on the influence of genetic variation on this clinically important measure and are consistent with a model in which FUT2 rs601338 influences holoHC by altering haptocorrin glycosylation, whereas B12 bound to non-glycosylated transcobalamin (i.e. holoTC) is not affected. Our findings explain some of the observed disparity between use of total B12 or holoTC as first-line clinical tests of vitamin B12 status.

Interpreter training for medical students: pilot implementation and assessment in a student-run clinic.

BACKGROUND: Trained medical interpreters are instrumental to patient satisfaction and quality of care. They are especially important in student-run clinics, where many patients have limited English proficiency. Because student-run clinics have ties to their medical schools, they have access to bilingual students who may volunteer to interpret, but are not necessarily formally trained. METHODS: To study the feasibility and efficacy of leveraging medical student volunteers to improve interpretation services, we performed a pilot study at the student-run clinic at the Icahn School of Medicine at Mount Sinai. In each fall semester in 2012-2015, we implemented a 6-h course providing didactic and interactive training on medical Spanish interpreting techniques and language skills to bilingual students. We then assessed the impact of the course on interpreter abilities. RESULTS: Participants' comfort levels, understanding of their roles, and understanding of terminology significantly increased after the course (p < 0.05), and these gains remained several months later (p < 0.05) and were repeated in an independent cohort. Patients and student clinicians also rated participants highly (averages above 4.5 out of 5) on these measures in real clinical encounters. CONCLUSIONS: These findings suggest that a formal interpreter training course tailored for medical students in the setting of a student-run clinic is feasible and effective. This program for training qualified student interpreters can serve as a model for other settings where medical students serve as interpreters.

Electrophoretic Transport of Na(+) and K(+) Ions Within Cyclic Peptide Nanotubes.

One of the most important applications of cyclic peptide nanotubes (CPNTs) is their potential to be used as artificial ion channels. Natural ion channels are large and complex membrane proteins, which are very expensive, difficult to isolate, and sensible to denaturation; for this reason, artificial ion channels are an important alternative, as they can be produced by simple and inexpensive synthetic chemistry paths, allowing manipulation of properties and enhancement of ion selectivity properties. Artificial ion channels can be used as component in molecular sensors and novel therapeutic agents. Here, the electrophoretic transport of Na(+) and K(+) ions within cyclic peptide nanotubes is investigated by using molecular dynamic simulations. The effect of electric field in the stability of peptide nanotubes was studied by calculating the root mean square deviation curves. Results show that the stability for CPNTs decreases for higher electric fields. Selective transport of cations within the hydrophilic tubes was observed and the negative Cl(-) ions did not enter the peptide nanotubes during the simulation. Radial distribution functions were calculated to describe structural properties and coordination numbers and changes in the first and second hydration shell were observed for the transport of Na(+) and K(+) inside of cyclic peptide nanotubes. However, no effect on coordination number was observed. Diffusion coefficients were calculated from the mean square deviation curves and the Na(+) ion showed higher mobility than the K(+) ion as observed in equivalent experimental studies. The values for diffusion coefficients are comparable with previous calculations in protein channels of equivalent sizes.

Breast cancer prevention.

Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women.

Clinical implications of the obese-asthma phenotypes.

The concomitant increase in obesity and asthma in recent years has led to the classification of two obese-asthma phenotypes, characterized by the age of asthma onset and atopy. Asthma tends to be more severe, harder to control, and more resistant to standard medications among members of these two groups. Because of the limited effectiveness of inhaled corticosteroids, dietary changes and weight loss measures must be considered in the management of these patients. Furthermore, comorbidities such as depression and obstructive sleep apnea must be addressed to provide optimal care for this group of difficult-to-control asthmatics.

Thermo-mechanical stability and strength of peptide nanostructures from molecular dynamics: self-assembled cyclic peptide nanotubes.

Peptide nanostructures present a wide range of opportunities for applications in biomedicine and bionanotechnology; hence experimental and theoretical studies aiming at determination of thermo-mechanical stability of peptide-based nanostructures are critical for the design and development of their technological applications. Here, we present a homogeneous deformation method combined with the finite elasticity theory and molecular dynamics simulations (MD) for the calculation of second-order anisotropic elastic constants for a membrane model made up of self-assembled cyclic peptide nanotubes. We have computed the values of all anisotropic elastic constants at 300 K. The value of the engineering Young's modulus (in the z direction) is 19.6 GPa. We observed a yield behavior in the z direction for a strain value of 6%. Furthermore, we also report calculated heat capacity, thermal expansion coefficient and isothermal compressibility of the system under study.

The pull of magnetism: a look at the standards and the experience of a western academic medical center hospital in achieving and sustaining Magnet status.

Many hospitals are working to improve the work environment for their staff. Research has indicated a linkage between work environment characteristics and patient outcomes and this research along with the nursing shortage has been the impetus for focusing on improving the work environment. The authors described the experience of an academic medical center hospital in achieving Magnet hospital status. The process and the required resources and support are discussed. Outcome data from staff nurses regarding their perception of the work environment in a Magnet hospital are presented.