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Background: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults., Methods and Results: This observational study included adults with sickle cell disease and no history of stroke. Magnetic resonance imaging scans of the brain completed at baseline and >1 year later were reviewed by 3 radiologists for baseline SCIs and new or progressive infarcts on follow-up magnetic resonance imaging. Stroke risk factors were abstracted from the medical chart. Time-to-event analysis was utilized for progressive infarcts. Median age was 24.1 years; 45.3% of 95 participants had SCIs on baseline magnetic resonance imaging. Progressive infarcts were present in 17 participants (17.9%), and the median follow-up was 2.1 years. Incidence of new infarcts was 11.95 per 100 patient-years (6.17-20.88) versus 3.74 per 100 patient-years (1.21-8.73) in those with versus without prior SCI. Multivariable Cox regression showed that baseline SCI predicts progressive infarcts (hazard ratio, 3.46 [95% CI, 1.05-11.39]; P =0.041); baseline hypertension was also associated with progressive infarcts (hazard ratio, 3.23 [95% CI, 1.16-9.51]; P =0.025)., Conclusions: Selecting individuals with SCIs and hypertension for stroke prevention trials in sickle cell disease may enrich the study population with those at highest risk for infarct recurrence.

Objectives: To increase diversity and inclusion in graduate medical education (GME), the Accreditation Council for Graduate Medical Education (ACGME) issued new diversity standards requiring programs to engage in practices that focus on systematic recruitment and retention of a diverse workforce of trainees and faculty. The literature on how program directors (PDs) can incorporate and prepare for this standard is limited., Methods: We developed a diversity, equity, and inclusion (DEI) toolkit for PDs as an example of an institutional GME-led effort to promote inclusive recruitment and DEI awareness among residency and fellowship programs at a large academic center., Results: A survey was sent to 80 PDs before the launch of the toolkit and 6 months afterwards with response rates of 27% (22/80) and 97% (78/80), respectively. At baseline, 45% (10/22) anticipated that the DEI toolkit might provide better resources than those currently available to them and 41% (9/22) perceived that the toolkit might improve recruitment outcomes. At 6 months, 63% (49/78) found the toolkit helpful in the 2021-2022 recruitment season. By contrast, 2% (2/78) of PDs did not find the toolkit helpful, and 33% (26/78) said they did not access the toolkit. When asked if a PD changed their program's recruitment practices because of the toolkit, 31% (24/78) responded yes. Programs that changed recruitment practices started to require unconscious bias training for all faculty and residents involved in the residency interviews and ranking. Others worked on creating a standardized scoring rubric for interviews focused on four main domains: Experiences, Attributes, Competencies, and Academic Metrics., Conclusion: There is a need to support PDs in their DEI journey and their work to recruit a diverse workforce in medicine. Utilizing a DEI toolkit is one option to increase DEI knowledge, skills, awareness, and self-efficacy among PDs and can be adopted by other institutions and leaders in academic medicine., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Sexual trauma is common. Consequences of sexual trauma can include deterioration of mental and physical health and it can also affect future romantic and sexual relationships. Previous studies have identified common healthy and destructive coping mechanisms to recover after experiencing sexual trauma, but few studies have investigated useful strategies to move into a healthy sexual relationship focused on resilience. In-depth semi-structured interviews were conducted with 41 women with a history of sexual trauma who were in a healthy sexual relationship at the time of participation. Participants provided strategies that helped them move beyond the sexually traumatic event(s) toward a healthy sexual relationship. Reflexive thematic analysis identified 5 effective and 6 ineffective strategies reported by the participants. Rich examples of resilience and empowerment were overarching in the effective strategies used for moving toward healthy sexual relationships. Women were also able to reflect on the strategies that were ineffective for them with kindness and understanding for their coping at that time, a normalizing theme for women working through sexual trauma. The results of this study will help therapists and researchers working with women who have experienced sexual trauma learn from their experiences in working beyond trauma toward a healthy sexual relationship., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mark et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although SARS-CoV-2 can cause severe illness and death, a percentage of the infected population is asymptomatic. This, along with other factors, such as insufficient diagnostic testing and underreporting due to self-testing, contributes to the silent transmission of SARS-CoV-2 and highlights the importance of implementing additional surveillance tools. The fecal shedding of the virus from infected individuals enables its detection in community wastewater, and this has become a valuable public health tool worldwide as it allows the monitoring of the disease on a populational scale. Here, we monitored the presence of SARS-CoV-2 and its dynamic genomic changes in wastewater sampled from two metropolitan areas in Arkansas during major surges of COVID-19 cases and assessed how the viral titers in these samples related to the clinical case counts between late April 2020 and January 2022. The levels of SARS-CoV-2 RNA were quantified by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) using a set of TaqMan assays targeting three different viral genes (encoding ORF1ab polyprotein, surface glycoprotein, and nucleocapsid phosphoprotein). An allele-specific RT-qPCR approach was used to screen the samples for SARS-CoV-2 mutations. The identity and genetic diversity of the virus were further investigated through amplicon-based RNA sequencing, and SARS-CoV-2 variants of concern were detected in wastewater samples throughout the duration of this study. Our data show how changes in the virus genome can affect the sensitivity of specific RT-qPCR assays used in COVID-19 testing with the surge of new variants. A significant association was observed between viral titers in wastewater and recorded number of COVID-19 cases in the areas studied, except when assays failed to detect targets due to the presence of particular variants. These findings support the use of wastewater surveillance as a reliable complementary tool for monitoring SARS-CoV-2 and its genetic variants at the community level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Noroviruses are highly diverse viruses that are the major viral cause of acute gastroenteritis in humans. Although these viruses can infect multiple mammalian species, their potential for zoonosis is not well understood, especially within Genogroup IV (GIV), which contains viruses that infect humans, canines, and felines. The study of GIV viruses has been, in part, hindered by the limited number of complete genomes. Here, we developed a full-genome amplicon-based platform that facilitated the sequencing of canine noroviruses circulating in the United States. Eight novel nearly full-length canine norovirus genomes and two nearly complete VP1 sequences, including four GIV.2, three GVI.1, and three GVI.2 viruses, were successfully obtained. Only animal strains exhibited GVI/GIV chimeric viruses, demonstrating restrictions in norovirus recombination. Using genomic, phylogenetic, and structural analyses, we show that differences within the major capsid protein and the non-structural proteins of GIV and GVI noroviruses could potentially limit cross-species transmission between humans, canines, and felines.

Noroviruses (NoV) have enhanced tropism for the gastrointestinal (GI) tract and are the major cause of nonbacterial gastroenteritis in humans. Titanium dioxide (TiO2) nanoparticles (NPs) used as food additives, dietary supplements, and cosmetics accumulate in the GI tract. We investigated the effect anatase TiO2 NPs on NoV replication and host response during virus infection, using murine norovirus (MNV-1) infection of RAW 264.7 macrophages. Pretreatment with 20 μg/ml anatase NPs significantly reduced the viability of macrophages alone or during virus infection, but did not alter virus replication. In contrast, pre-incubation with 2 μg/ml anatase NPs reduced virus replication fivefold at 48 h. The presence of anatase NPs during MNV-1 infection evoked a pro-inflammatory response, as measured by a significant increase in expression of cytokines, including IL-6, IFN-γ, TNFα and the TGFβ1. No genotoxic insults due to anatase TiO2 NPs alone or to their presence during MNV-1 infection were detected. This study highlights important safety considerations related to NP exposure of the GI tract in individuals infected with noroviruses or other foodborne viruses., Competing Interests: Declaration of Interest The authors declare no potential conflict of interest.

Noroviruses (NoV) are the leading cause of nonbacterial gastroenteritis in humans, and replicate extensively in the human gastrointestinal (GI) tract. Silica (also known as silicon dioxide, SiO 2 ) nanoparticles (NPs) used in processed foods, dairy products, and beverages also accumulate in the GI tract. We investigated the effect of silica NPs on NoV replication and host cell response during virus infection, using murine norovirus (MNV-1) infection of RAW 264.7 murine macrophages. Pretreatment with 10 μ g/ml silica significantly reduced the viability of macrophages, but no cumulative effects on viability of macrophages were observed with MNV-1 infection. No difference was observed between exposure to control or silica NPs on either the quantity of viral genome copies or the production of infectious virus in macrophages infected with MNV-1. Silica NPs reduced the ability of macrophages to upregulate genes encoding bone morphogenic proteins (BMPs), chemokine ligands and cytokines for which expression levels were otherwise found to be upregulated in response to MNV-1 infection. Furthermore, silica NPs reduced the levels of proinflammatory cytokines secreted by macrophages in response to MNV infection. Finally, silica NPs with MNV-1 infection produced a genotoxic insult to macrophages. Strikingly, this genotoxic insult was also found to occur as a synergistic effect of silica NPs and feline calicivirus infection in feline kidney epithelial cells. Taken together, our study suggests important safety considerations related to reducing exposure to silica NPs affecting the GI tract in individuals infected with NoVs and possibly other foodborne viruses.

Gastroenteritis caused by bacterial and viral pathogens constitutes a major public health threat in the United States accounting for 35% of hospitalizations. In particular, Salmonella enterica and noroviruses cause the majority of gastroenteritis infections, with emergence of sporadic outbreaks and incidence of increased infections. Although mechanisms underlying infections by these pathogens have been individually studied, little is known about the mechanisms regulating co-infection by these pathogens. In this study, we utilized RAW 264.7 murine macrophage cells to investigate the mechanisms governing co-infection with S. enterica serovar Heidelberg and murine norovirus (MNV). We demonstrate that infection of RAW 264.7 cells with S. enterica reduces the replication of MNV, in part by blocking virus entry early in the virus life cycle, and inducing antiviral cytokines later in the infection cycle. In particular, bacterial infection prior to, or during MNV infection affected virus entry, whereas MNV entry remained unaltered when the virus infection preceded bacterial invasion. This block in virus entry resulted in reduced virus replication, with the highest impact on replication observed during conditions of co-infection. In contrast, bacterial replication showed a threefold increase in MNV-infected cells, despite the presence of antibiotic in the medium. Most importantly, we present evidence that the infection of MNV-infected macrophages by S. enterica blocked MNV-induced apoptosis, despite allowing efficient virus replication. This apoptosis blockade was evidenced by reduction in DNA fragmentation and absence of poly-ADP ribose polymerase (PARP), caspase 3 and caspase 9 cleavage events. Our study suggests a novel mechanism of pathogenesis whereby initial co-infection with these pathogens could result in prolonged infection by either of these pathogens or both together.