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Interferon-epsilon, an estrogen-induced type I interferon, is uniquely exploited by Neisseria gonorrhoeae via effects on sialic acid metabolism
Get PDFThe female genital mucosa expresses the hormone-dependent type I interferon (IFN), IFN-epsilon (IFN-ε), which protects against chlamydia and herpes infection. Surprisingly, we found that IFN-ε knockout (Ifnε) mice and type I IFN receptor knockout (Ifnar1) mice exhibited enhanced clearance of Neisseria gonorrhoeae (Ng). This result was phenocopied using blocking anti-IFNAR monoclonal antibody (mAb). Ng colonization of the Ifnε urogenital tract was restored by exogenous recombinant IFN-ε or IFN-β. Clearance of Ng in anti-IFNAR-treated mice required the expression of the cathelicidin mCRAMP. Ng deploys a unique mechanism to evade cathelicidins and other innate defenses by sialylating its lipooligosaccharide (LOS) using host-derived cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-Neu5Ac or CMP-sialic acid). Ifnε mice expressed reduced levels of CMP-sialic acid synthetase mRNA in genital tissues. Accordingly, Ng recovered from IFN-deficient mice were hyposialylated. In conclusion, Ng exploits type I IFNs to obtain CMP-sialic acid for LOS sialylation, resulting in innate immune evasion and enhanced colonization.No embarg
Training medical providers to serve diverse deaf patients: Age-based intervention effects in a randomized trial
No full textBACKGROUND: Deaf American Sign Language users are severely underserved in the U.S. healthcare system. To address longstanding inaccessibility and mistrust, our Deaf community-led team produced a film to train providers to better serve Deaf patients - Vital Signs.
OBJECTIVE: We conducted a two-arm randomized controlled trial to evaluate preliminary efficacy of Vital Signs among healthcare providers and health professions students.
METHODS: Participants were randomly assigned to review Vital Signs or intervention as usual - standard written guidance about working with Deaf patients. Intervention completers were invited to participate in a simulation with a Deaf standardized patient. Three Deaf team members were trained to review simulation recordings and complete validated patient self-report measures of provider behavior: Healthcare Provider Cultural Competency; Ask, Understand, and Remember Assessment; and Wake Forest Physician Trust Scale.
RESULTS: Of 208 enrolled participants, 52 completed all study components and were included in final analyses. A clear pattern of results emerged - participant age influenced learning and behavior change in response to different training strategies. Participants aged 33+ who viewed Vital Signs scored higher on content knowledge compared to same-aged peers who reviewed training as usual, but worse across measures of cultural competency, communication skill, and trust-building. An opposite pattern emerged for participants younger than 33 years - those who watched Vital Signs exhibited greater cultural competence, communication skill, and trust-building abilities than same-aged peers who reviewed standard written guidance.
CONCLUSION: Future steps include an implementation trial of various Vital Signs training configurations, evaluating strategies for training health professions students versus experienced providers.No embarg
miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression
No full textAcetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the FDA-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) and demonstrated its potent protection in a murine model of APAP overdose-induced ALF. Slc16a2, Cyb5b, and Acsl5 were identified as critical targets acting synergistically to mitigate toxicity. Liver transcriptome revealed that miR-375 overexpression or silencing of the targets of miR-375 increased Gstm3 expression in mice. AAV8-mediated Gstm3 expression protects against APAP-ALF, and the protection was further enhanced by disrupting the expression of Cyp2e1. Additionally, CYP2E1 and GSS, which contribute to APAP detoxification, were down- and upregulated by miR-375, respectively. These findings suggest that miR-375 prevents APAP-ALF by orchestrating the expression of pharmacogenes and enhancing glutathione synthesis. We conclude that miR-375 and its targets are promising therapeutic targets for APAP-ALF.No embarg
PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors
Get PDFImmunotherapy modalities have revolutionized cancer treatment for a number of metastatic and treatment-refractory tumor types. Still, many malignancies that lack T cell infiltration and are termed immunologically "cold" fail to respond to these modalities. One approach to increase tumor immunogenicity has been to induce stimulator of interferon gene (STING) and downstream interferon signaling that is often dysregulated in cold tumors. Despite some early success of STING agonists in preclinical cancer models, these approaches have not been successful in the clinic due to poor tumor penetrance and systemic toxicities. Here, we performed a genome-wide CRISPR screen to uncover therapeutic targets to activate STING expression in human tumors. We identified the lysosomal hydrolase Palmitoyl Protein Thioesterase1 (PPT1) as a negative regulator of STING highly expressed in cold ovarian and prostate tumors. Genetic or pharmacological PPT1 suppression increased STING protein stability and its downstream activation of interferon and inflammatory cytokine signaling to enhance T cell migration. Treatment of preclinical prostate and ovarian cancer models expressing low levels of STING with the small molecule PPT1 inhibitor GNS561 enhanced STING expression and activation, leading to infiltration and activation of cytotoxic T cells that turned these tumors "hot" and reduced tumor growth, fibrosis, and dissemination without toxicity. Further analysis demonstrated that PPT1 is associated with reduced STING expression, CD8 T cell numbers, overall survival, and immunotherapy outcomes in ovarian and prostate cancer patients. Thus, PPT1 inhibition may be a promising approach to activate STING and potentiate the effects of immunotherapy in cold tumors.No embarg
FAVOR 2.0: A reengineered functional annotation of variants online resource for interpreting genomic variation
Get PDFThe Functional Annotation of Variants Online Resource (FAVOR), http://favor.genohub.org, is a whole genome variant annotation database and portal that provides comprehensive variant functional annotations of all possible variants across the genome. It can facilitate the analysis of whole-genome sequencing studies, support the interpretation of variant functional impacts, and help prioritize causal variants of diseases or traits. To support the growing popularity and expand the scope of FAVOR, we present here a substantial platform update. The new release features dramatically expanded annotations, a completely redesigned infrastructure powered by a newly implemented application programming interface (FAVOR-API), and a revamped web interface with advanced data-visualization capabilities and enhanced query performance. Key expansions include much more comprehensive variant annotations, including global, tissue- and cell-type-specific variant annotations; gene and protein annotations; support for both hg38 and hg19 reference genomes; and an interactive genome-browser for visualization of multi-faceted variant annotations. The updated platform also includes FAVOR-GPT, a large language model-powered interface for navigating the FAVOR database and interpreting results. FAVOR continues to evolve to keep pace with advances in research on interpreting the functional and phenotypic impact of genomic variation.No embarg
Potential for Increasing Physical Activity through an e-Bike Pilot Program to Reduce Greenhouse Gas Emissions
Get PDFActive transportation such as walking, bicycling, scootering, or using a wheelchair has direct physical and mental health benefits. Electric bicycles (e-bikes) have great potential as a form of active transportation. The Massachusetts Clean Energy Center partnered with the Massachusetts Bicycle Coalition (MassBike) to develop and pilot test a program to provide free pedal assist e-bikes with implementation support for income-eligible residents in Worcester, MA as a strategy to reduce greenhouse gas emissions that contribute to climate change. MassBike received program funding over two years to provide 100 free e-bicycles to income-eligible individuals who live or work in Worcester utilizing a community-engaged approach. The e-bike pilot program took place from August 2022-May 2024. Overall, 64% of the 96 participants regularly reported their e-bike usage during the first 13 months of deployment. Per month, participants who reported their usage on average made 17 trips, rode 65 miles, and were physically active for 20 minutes per trip using their e-bike. Program results demonstrated high aggregate levels as well as strong start-up levels with a return to similar results when weather became milder after winter dips. Lessons learned include the time needed for behavior shifts and retention and reporting challenges. These preliminary results offer a glimpse of the opportunities for increased physical activity possible with a climate change mitigation strategy of active transportation.No embarg
Prevalence and Co-Detection Rates of SARS-CoV-2, Influenza, and Respiratory Syncytial Virus: A Retrospective Analysis
No full textIn late 2022, there was a significant increase in the prevalence of RSV in the northeastern United States. This surge occurred concurrently with the beginning of the traditional influenza season and the ongoing circulation of SARS-CoV-2. We retrospectively analyzed respiratory testing data at a regional reference laboratory from September 2022 to April 2024 to characterize the prevalence and incidence of co-detection of RSV, influenza A, influenza B, and SARS-CoV-2 in the northeastern United States. The positivity rates were found to be 16.68% for SARS-CoV-2, 11.66% for influenza A, 0.83% for influenza B, and 9.11% for RSV during the study period. Co-detections were observed in 0.49% of samples, with SARS-CoV-2/influenza A co-detection being the most common. Co-detections occurred less frequently than expected based on individual positivity rates. During the study period, influenza B positivity increased over 10-fold, SARS-CoV-2 positivity decreased by 60%, and co-detection was more prevalent in the pediatric population.No embarg
Developing a real-time registry to track breast cancer patients across the city of Boston
Get PDFObjectives: Patient navigation is designed to identify and address patients' needs throughout their cancer treatment. In the context of a clinical trial designed to deliver a standardized patient navigation protocol, a registry was needed to allow users from across multiple health systems to input patient data, track navigation outreach, and coordinate cancer care in real time. To design a registry to allow patient navigators (PNs) at 6 medical centers across 4 health systems to track breast cancer patients determined to be most at risk for delays in treatment.
Materials and methods: A multi-disciplinary team chose REDCap to host the registry. The aim was to develop a platform that would (1) manage a caseload of patients who are most vulnerable for delays; (2) track patients through the continuum of cancer care in real time; (3) allow PNs to prioritize certain patients; (4) facilitate inter-system communication; and (5) allow the research team to monitor navigators' activities (in context of a research study, for supervision and feedback).
Results: The registry was built through collaboration with clinical providers, PNs, informatics specialists, and expert developers from the REDCap team, using the software standard features and incorporating additional functionality using SAS programming.
Conclusion: REDCap provided an accessible and modifiable platform for hosting a registry to track patients in real time. However, it did not streamline PNs' workflows or reduce data entry burdens as intended. A major barrier was the lack of interoperability with pre-existing systems navigators use, which led to redundancy and increased the burden of documentation.No embarg
A community-engaged implementation mapping approach to increase SNAP participation in a diverse Latine community
Get PDFBackground: The Supplemental Nutrition Assistance Program (SNAP) is an underutilized program. SNAP uptake is limited in Latine households in particular due to concerns about immigration eligibility, even when there are SNAP-eligible household members. Implementation strategies are urgently needed to increase SNAP participation rates among those who are eligible.
Purpose: We used collaborative planning and implementation mapping to design implementation strategies to increase SNAP participation.
Methods: Collaborative planning and implementation mapping included: (i) identify a shared priority; (ii) review relevant data to identify determinants of SNAP participation; (iii) design strategies to accomplish the priority goal; (iv) reach consensus and pilot-chosen strategies and workflows; and (v) evaluate implementation success based on chosen outcomes. Using the Practical Robust Implementation and Sustainability Model, we identified two implementation strategies, a community and a policy strategy, to pilot from January to December 2023.
Results: The community strategy leveraged an existing food program to identify participants who were not already enrolled in SNAP. This resulted in 69 referrals and 4 new SNAP enrollees. The policy strategy leveraged the existing policy context to link SNAP enrollment with Medicaid insurance reenrollment at the end of the COVID-19 public health emergency protections. This resulted in an unknown number of referrals due to data workflow barriers.
Conclusions: Despite considering context in the design and piloting of two implementation strategies, success was limited. Future success will require including the perspectives of those with lived experience to inform processes to identify eligible individuals without creating additional stigma or furthering distrust among those who may be ineligible.No embarg
Violence in the Workplace: Preparedness, Prevention, Response, and Recovery Strategies for Acute and Critical Care Nurses
No full textBackground: Workplace violence has been increasing in hospitals and has been associated with employee turnover and decreased productivity and quality of care.
Objective: To identify interventions acute and critical care nurses can employ to address workplace violence among patients and visitors.
Methods: The methods of Whittemore, Knafl, and Torraco informed this integrative review. Ovid MEDLINE, CINAHL, Scopus, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were searched for publications related to hospital workplace violence.
Results: Of 951 articles retrieved, 47 were included. Only 2 articles (4%) were specific to critical care, 5 (11%) were generic to hospital settings, and 40 (85%) focused on emergency departments. The highest level of evidence was in 1 randomized controlled trial; 46 articles (98%) had level 6 or 7 evidence. The evidence revealed 3 themes: preparedness/prevention, response to violence, and recovery. Preparedness/ prevention was the most prevalent theme. Assessment and screening, communication, education, leadership, and infrastructure were subthemes.
Discussion: Nurses can engage in efforts to promote a safe and healthy work environment. With increasing prevalence of workplace violence in health care, acute and critical care nurses must be prepared to prevent and manage violence. Focused education, including simulations and drills, are essential.
Conclusion: Bedside nurses and leadership teams should collaborate to reduce workplace violence in their environments. Further research focusing on workplace violence in acute and critical care areas is needed to define the most effective interventions.No embarg