Development and Evaluation of Surveillance System for Identifying Jail-Associated COVID-19 Cases in Minnesota, USA, 2022.

Confinement facilities are high-risk settings for the spread of infectious disease, necessitating timely surveillance to inform public health action. To identify jail-associated COVID-19 cases from electronic laboratory reports maintained in the Minnesota Electronic Disease Surveillance System (MEDSS), Minnesota, USA, the Minnesota Department of Health developed a surveillance system that used keyword and address matching (KAM). The KAM system used a SAS program (SAS Institute Inc., https://www.sas.com) and an automated program within MEDSS to identify confinement keywords and addresses. To evaluate KAM, we matched jail booking data from the Minnesota Statewide Supervision System by full name and birthdate to the MEDSS records of adults with COVID-19 for 2022. The KAM system identified 2,212 cases in persons detained in jail; sensitivity was 92.40% and specificity was 99.95%. The success of KAM demonstrates its potential to be applied to other diseases and congregate-living settings for real-time surveillance without added reporting burden.

Genomic Epidemiology of Human Respiratory Syncytial Virus, Minnesota, USA, July 2023-February 2024.

We recently expanded the viral genomic surveillance program in Minnesota, USA, to include human respiratory syncytial virus. We performed whole-genome sequencing of 575 specimens collected at Minnesota healthcare facilities during July 2023-February 2024. Subgroups A and B differed in their genomic landscapes, and we identified 23 clusters of genetically identical genomes.

Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas.

Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

Delayed graft rejection in autoimmune islet transplantation via biomaterial immunotherapy.

The induction of operational immune tolerance is a major goal in beta-cell replacement strategies for the treatment of type 1 diabetes. Our group previously reported long-term efficacy via biomaterial-mediated programmed death ligand 1 (PD-L1) immunotherapy in islet allografts in nonautoimmune models. In this study, we evaluated autoimmune recurrence and allograft rejection during islet transplantation in spontaneous nonobese diabetic (NOD) mice. Graft survival and metabolic function were significantly prolonged over 60 days in recipients of syngeneic islets receiving the biomaterial-delivered immunotherapy, but not in control animals. The biomaterial-mediated PD-L1 immunotherapy resulted in delayed allograft rejection in diabetic NOD mice compared with controls. Discrimination between responders and nonresponders was attributed to the enriched presence of CD206+ program death 1+ macrophages and exhausted signatures in the cytotoxic T cell compartment in the local graft microenvironment. Notably, draining lymph nodes had similar remodeling in innate and adaptive immune cell populations. This work establishes that our biomaterial platform for PD-L1 delivery can modulate immune responses to transplanted islets in diabetic NOD mice and, thus, can provide a platform for the development of immunologic strategies to curb the allo- and autoimmune processes in beta-cell transplant recipients.

Creating a quadruple aim model for nursing education.

Baccalaureate nursing education is moving to adopt the new American Association of Colleges of Nursing Essentials for Professional Nursing Education. As identified in two of the six domains of the essentials, graduates need to be prepared to address population health and utilize informatics and healthcare technologies. Community/public health nursing also has eight domains for generalist nurses linked to population health which will help prepare a skilled nursing workforce for the 21st century. The Institute for Healthcare Improvement's Triple Aim which evolved into the Quadruple Aim is focused on improving health outcomes within healthcare delivery. Through a literature review, a need for a Quadruple Aim model for nursing education was identified. Mirroring the Institute for Healthcare Improvement's Triple Aim for healthcare delivery, a Quadruple Aim for Nursing Education Model was developed. The model dimensions include (1) Population-focused Care, (2) Maximize Student Learning Experience, (3) Cost-effective Pedagogy, and (4) Nurse Educator Well-being. The Quadruple Aim for Nursing Education Model supports nursing education to prepare future nurses effectively and efficiently bridging population health concepts and issues with nursing informatics. Nurse educators are encouraged to utilize the model to transform nursing education.

Evolving beyond antiracism: Reflections on the experience of developing a cultural safety curriculum in a tertiary education setting.

There is an inextricable link between cultural and clinical safety. In Australia high-profile Aboriginal deaths in custody, publicised institutional racism in health services and the international Black Lives Matter movement have cemented momentum to ensure culturally safe care. However, racism within health professionals and health professional students remains a barrier to increasing the number of Aboriginal and Torres Strait Islander Health professionals. The Australian Health Practitioner Regulation Agency's Aboriginal and Torres Strait Islander Health Strategy's objective to 'eliminate racism from the health system', and the recent adoption of the Aboriginal and Torres Strait Islander peoples led cultural safety definition, has instigated systems level reflections on decolonising practice. This article explores cultural safety as the conceptual antithesis to racism, examining its origins, and contemporary evolution led by Aboriginal and Torres Strait Islander peoples in Australia, including its development in curriculum innovation. The application of cultural safety is explored using in-depth reflection, and the crucial development of integrating critical consciousness theory, as a precursor to culturally safe practice, is discussed. Novel approaches to university curriculum development are needed to facilitate culturally safe and decolonised learning and working environments, including the key considerations of non-Indigenous allyship and collaborative curriculum innovations and initiatives.

Evaluating the Presence of Replication-Competent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From Nursing Home Residents With Persistently Positive Reverse Transcription Polymerase Chain Reaction (RT-PCR) Results.

Replication-competent virus has not been detected in individuals with mild to moderate coronavirus disease 2019 (COVID-19) more than 10 days after symptom onset. It is unknown whether these findings apply to nursing home residents. Of 273 specimens collected from nursing home residents >10 days from the initial positive test, none were culture positive.

Hydrolytically Degradable Microgels with Tunable Mechanical Properties Modulate the Host Immune Response.

Hydrogel microparticles (microgels) are an attractive approach for therapeutic delivery because of their modularity, injectability, and enhanced integration with the host tissue. Multiple microgel fabrication strategies and chemistries have been implemented, yet manipulation of microgel degradability and its effect on in vivo tissue responses remains underexplored. Here, the authors report a facile method to synthesize microgels crosslinked with ester-containing junctions to afford tunable degradation kinetics. Monodisperse microgels of maleimide-functionalized poly(ethylene-glycol) are generated using droplet microfluidics crosslinked with thiol-terminated, ester-containing molecules. Tunable mechanics are achievable based on the ratio of degradable to nondegradable crosslinkers in the continuous phase. Degradation in an aqueous medium leads to microgel deformation based on swelling and a decrease in elastic modulus. Furthermore, degradation byproducts are cytocompatible and do not cause monocytic cell activation under noninflammatory conditions. These injectable microgels possess time-dependent degradation on the order of weeks in vivo. Lastly, the evaluation of tissue responses in a subcutaneous dorsal pocket shows a dynamic type-1 like immune response to the synthetic microgels, driven by interferon gamma (IFN-γ ) expression, which can be moderated by tuning the degradation properties. Collectively, this study demonstrates the development of a hydrolytic microgel platform that can be adapted to desired host tissue immune responses.

Transmission Dynamics of Severe Acute Respiratory Syndrome Coronavirus 2 in High-Density Settings, Minnesota, USA, March-June 2020.

Coronavirus disease has disproportionately affected persons in congregate settings and high-density workplaces. To determine more about the transmission patterns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in these settings, we performed whole-genome sequencing and phylogenetic analysis on 319 (14.4%) samples from 2,222 SARS-CoV-2-positive persons associated with 8 outbreaks in Minnesota, USA, during March-June 2020. Sequencing indicated that virus spread in 3 long-term care facilities and 2 correctional facilities was associated with a single genetic sequence and that in a fourth long-term care facility, outbreak cases were associated with 2 distinct sequences. In contrast, cases associated with outbreaks in 2 meat-processing plants were associated with multiple SARS-CoV-2 sequences. These results suggest that a single introduction of SARS-CoV-2 into a facility can result in a widespread outbreak. Early identification and cohorting (segregating) of virus-positive persons in these settings, along with continued vigilance with infection prevention and control measures, is imperative.

Energy drink intake is associated with insomnia and decreased daytime functioning in young adult females.

OBJECTIVE: To investigate the association between energy drink (ED) use and sleep-related disturbances in a population-based sample of young adults from the Raine Study. DESIGN: Analysis of cross-sectional data obtained from self-administered questionnaires to assess ED use and sleep disturbance (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire (FOSQ-10) and the Pittsburgh Sleep Symptoms Questionnaire-Insomnia (PSSQ-I)). Regression modelling was used to estimate the effect of ED use on sleep disturbances. All models adjusted for various potential confounders. SETTING: Western Australia. PARTICIPANTS: Males and females, aged 22 years, from Raine Study Gen2-22 year follow-up. RESULTS: Of the 1115 participants, 66 % were never/rare users (i.e. once/month to

Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing.

Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair.

"Unless you overdose or something you're not going to get help": What do adolescent experiences reveal about the mental health system in Perth, Western Australia?

ISSUES ADDRESSED: To explore adolescents' experiences of access to and continued use of mental health services, and identify factors influencing their perceived satisfaction with their care. This paper focusses on the role of organisational and policy-level factors in the mental health system. METHOD: Qualitative semi-structured face-to-face interviews with 22 adolescents aged 14-18 years living in Perth, Western Australia. RESULTS: Adolescents identified key policy, systemic and service-based factors which influenced their access to and continued use of mental health services. These were strongly related to the processes of service intake, level of orientation towards person-centred care and adequacy of service resourcing and funding. Areas of concern for adolescents included, complex service intake procedures, suboptimal mental health service environments, lack of client-centred care and the quality of mental health support provided in school settings. CONCLUSIONS: Our research has identified a wide spectrum of factors influencing mental health service access and use amongst adolescents. The findings further support the growing national consensus for major reform to address the mental health needs of this age group. The current strengths within mental health services and the system identified by adolescents need to be supported and extended. SO WHAT?: Although there have been numerous recommendations on ways to improve mental health service access and ongoing engagement for Australian adolescents, a number of the major challenges faced by this high-risk population have shown little improvement. The findings of this research indicate the importance of now moving towards implementing meaningful plans for action.

Summer Outbreak of Severe RSV-B Disease, Minnesota, 2017 Associated with Emergence of a Genetically Distinct Viral Lineage.

BACKGROUND: Respiratory syncytial virus (RSV) typically causes winter outbreaks in temperate climates. During summer 2017, the Minnesota Department of Health received a report of increased cases of severe RSV-B infection. METHODS: We compared characteristics of summer 2017 cases with those of 2014-2018 summers. To understand the genetic relatedness among viruses, we performed high-throughput sequencing of RSV from patients with a spectrum of illness from sites in Minnesota and Wisconsin. RESULTS: From May to September 2017, 58 RSV cases (43 RSV-B) were reported compared to 20-29 cases (3-7 RSV-B) during these months in other years. Median age and frequency of comorbidities were similar, but 55% (24/43) were admitted to the ICU in 2017 compared to 12% in preceding 3 years (odds ratio, 4.84, P < .01). Sequencing was performed on 137 specimens from March 2016 to March 2018. Outbreak cases formed a unique clade sharing a single conserved nonsynonymous change in the SH gene. We observed increased cases during the following winter season, when the new lineage was the predominant strain. CONCLUSIONS: We identified an outbreak of severe RSV-B disease associated with a new genetic lineage among urban Minnesota children during a time of expected low RSV circulation.

Identifying Vaccine-associated Rash Illness Amidst a Large Measles Outbreak: Minnesota, 2017.

Characteristics of vaccine-associated rash illness (VARI) and confirmed measles cases were compared during a measles outbreak. Although some clinical differences were noted, measles exposure and identification of the vaccine strain were helpful for public health decision-making. Rapid, vaccine strain-specific diagnostic assays will more efficiently distinguish VARI from measles.

Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer.

BACKGROUND: Unlike other breast cancer subtypes that may be treated with a variety of hormonal or targeted therapies, there is a need to identify new, effective targets for triple-negative breast cancer (TNBC). It has recently been recognized that membrane potential is depolarized in breast cancer cells. The primary objective of the study is to explore whether hyperpolarization induced by opening potassium channels may provide a new strategy for treatment of TNBC. METHODS: Breast cancer datasets in cBioPortal for cancer genomics was used to search for ion channel gene expression. Immunoblots and immunohistochemistry were used for protein expression in culture cells and in the patient tissues. Electrophysiological patch clamp techniques were used to study properties of BK channels in culture cells. Flow cytometry and fluorescence microscope were used for cell viability and cell cycle studies. Ultrasound imaging was used to study xenograft in female NSG mice. RESULTS: In large datasets of breast cancer patients, we identified a gene, KCNMA1 (encoding for a voltage- and calcium-dependent large-conductance potassium channel, called BK channel), overexpressed in triple-negative breast cancer patients. Although overexpressed, 99% of channels are closed in TNBC cells. Opening BK channels hyperpolarized membrane potential, which induced cell cycle arrest in G2 phase and apoptosis via caspase-3 activation. In a TNBC cell induced xenograft model, treatment with a BK channel opener significantly slowed tumor growth without cardiac toxicity. CONCLUSIONS: Our results support the idea that hyperpolarization induced by opening BK channel in TNBC cells can become a new strategy for development of a targeted therapy in TNBC.

Serial Testing for SARS-CoV-2 and Virus Whole Genome Sequencing Inform Infection Risk at Two Skilled Nursing Facilities with COVID-19 Outbreaks - Minnesota, April-June 2020.

SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), can spread rapidly in high-risk congregate settings such as skilled nursing facilities (SNFs) (1). In Minnesota, SNF-associated cases accounted for 3,950 (8%) of 48,711 COVID-19 cases reported through July 21, 2020; 35% of SNF-associated cases involved health care personnel (HCP*), including six deaths. Facility-wide, serial testing in SNFs has been used to identify residents with asymptomatic and presymptomatic SARS-CoV-2 infection to inform mitigation efforts, including cohorting of residents with positive test results and exclusion of infected HCP from the workplace (2,3). During April-June 2020, the Minnesota Department of Health (MDH), with CDC assistance, conducted weekly serial testing at two SNFs experiencing COVID-19 outbreaks. Among 259 tested residents, and 341 tested HCP, 64% and 33%, respectively, had positive reverse transcription-polymerase chain reaction (RT-PCR) SARS-CoV-2 test results. Continued SARS-CoV-2 transmission was potentially facilitated by lapses in infection prevention and control (IPC) practices, up to 12-day delays in receiving HCP test results (53%) at one facility, and incomplete HCP participation (71%). Genetic sequencing demonstrated that SARS-CoV-2 viral genomes from HCP and resident specimens were clustered by facility, suggesting facility-based transmission. Residents and HCP working in SNFs are at risk for infection with SARS-CoV-2. As part of comprehensive COVID-19 preparation and response, including early identification of cases, SNFs should conduct serial testing of residents and HCP, maximize HCP testing participation, ensure availability of personal protective equipment (PPE), and enhance IPC practices† (4-5).

Pyrvinium Pamoate Use in a B cell Acute Lymphoblastic Leukemia Model of the Bone Tumor Microenvironment.

PURPOSE: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia. METHODS: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness. RESULTS: PP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP's cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. CONCLUSION: We have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC50 value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1-induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.

A mixed methods randomised control trial to evaluate the effectiveness of the journey to social inclusion - phase 2 intervention for chronically homeless adults: study protocol.

BACKGROUND: Chronic homelessness is a problem characterised by longstanding inability to attain or maintain secure accommodation. Longitudinal research with homeless populations is challenging, and randomised controlled trials that evaluate the effectiveness of intensive, case management interventions aimed at improving housing and health-related outcomes for chronically homelessness people are scant. More research is needed to inform programmatic design and policy frameworks in this area. This study protocol details an evaluation of the Journey to Social Inclusion - Phase 2 program, an intervention designed to reduce homelessness and improve outcomes in chronically homeless adults. METHODS/DESIGN: J2SI Phase 2 is a three-year, mixed methods, multi-site, RCT that enrolled 186 participants aged 25 to 50 years between 07 January 2016 and 30 September 2016 in Melbourne. The intervention group (n = 90 recruited) receives the J2SI Phase 2 program, a trauma-informed intervention that integrates intensive case management and service coordination; transition to housing and support to sustain tenancy; and support to build social connections, obtain employment and foster independence. The comparison group (n = 96 recruited) receives standard service provision. Prior to randomisation, participants completed a baseline survey. Follow-up surveys will be completed every six months for three years (six in total). In addition to self-report data on history of homelessness and housing, physical and mental health, substance use, quality of life, social connectedness and public service utilisation, linked administrative data on participants' public services utilisation (e.g., hospitalisation, justice system) will be obtained for the three-year period pre- and post-randomisation. Semi-structured, qualitative interviews will be conducted with a randomly selected subset of participants and service providers at three time-points to explore changes in key outcome variables and to examine individual experiences with the intervention and standard service provision. An economic evaluation of the intervention and associated costs will also be undertaken. DISCUSSION: Results of this trial will provide robust evidence on the effectiveness of J2SI Phase 2 compared to standard service provision. If the intervention demonstrates effectiveness in improving housing, health, quality-of-life, and other social outcomes, it may be considered for broader national and international dissemination to improve outcomes among chronically homeless adults. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000162415 (retrospectively registered 10-February-2016).

Feasibility of describing community strengths relative to Omaha system concepts.

OBJECTIVES: The purpose was to determine the feasibility of using a standardized language, the Omaha System, to describe community-level strengths. The objectives were: (a) to evaluate the feasibility of using the Omaha System at the community level to reflect community strengths and (b) to describe preliminary results of community strengths observations across international settings. DESIGN AND SAMPLE: A descriptive qualitative design was used. The sample was a data set of 284 windshield surveys by nursing students in 5 countries: Mexico, New Zealand, Norway, Turkey, and the United States. MEASURES: An online survey included a checklist and open-ended questions on community strengths for 11 concepts of the Omaha System Problem Classification Scheme: Income, Sanitation, Residence, Neighborhood/workplace safety, Communication with community resources, Social contact, Interpersonal relationship, Spirituality, Nutrition, Substance use, and Health care supervision. Themes were derived through content analysis of responses to the open-ended questions. RESULTS: Feasibility was demonstrated: Students were able to use the Omaha System terms and collect data on strengths. Common themes were described among the five countries. CONCLUSIONS: The Omaha System appears to be useful in documenting community-level strengths. Themes and exemplar quotes provide a first step in developing operational definitions of strengths at a more granular level.