Addressing Structural Racism Through Public Policy Advocacy: A Policy Statement From the American Heart Association.

During the COVID-19 pandemic, the American Heart Association created a new 2024 Impact Goal with health equity at its core, in recognition of the increasing health disparities in our country and the overwhelming evidence of the damaging effect of structural racism on cardiovascular and stroke health. Concurrent with the announcement of the new Impact Goal was the release of an American Heart Association presidential advisory on structural racism, recognizing racism as a fundamental driver of health disparities and directing the American Heart Association to advance antiracist strategies regarding science, business operations, leadership, quality improvement, and advocacy. This policy statement builds on the call to action put forth in our presidential advisory, discussing specific opportunities to leverage public policy in promoting overall well-being and rectifying those long-standing structural barriers that impede the progress that we need and seek for the health of all communities. Although this policy statement discusses difficult aspects of our past, it is meant to provide a forward-looking blueprint that can be embraced by a broad spectrum of stakeholders who share the association's commitment to addressing structural racism and realizing true health equity.

Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity.

Dopaminergic neurons of the substantia nigra exist in a persistent state of vulnerability resulting from high baseline oxidative stress, high-energy demand, and broad unmyelinated axonal arborisations. Impairments in the storage of dopamine compound this stress because of cytosolic reactions that transform the vital neurotransmitter into an endogenous neurotoxicant, and this toxicity is thought to contribute to the dopamine neuron degeneration that occurs Parkinson's disease. We have previously identified synaptic vesicle glycoprotein 2C (SV2C) as a modifier of vesicular dopamine function, demonstrating that genetic ablation of SV2C in mice results in decreased dopamine content and evoked dopamine release in the striatum. Here, we adapted a previously published in vitro assay utilising false fluorescent neurotransmitter 206 (FFN206) to visualise how SV2C regulates vesicular dopamine dynamics and determined that SV2C promotes the uptake and retention of FFN206 within vesicles. In addition, we present data indicating that SV2C enhances the retention of dopamine in the vesicular compartment with radiolabelled dopamine in vesicles isolated from immortalised cells and from mouse brain. Further, we demonstrate that SV2C enhances the ability of vesicles to store the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) and that genetic ablation of SV2C results in enhanced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced vulnerability in mice. Together, these findings suggest that SV2C functions to enhance vesicular storage of dopamine and neurotoxicants and helps maintain the integrity of dopaminergic neurons.

Impact of an evidence-based bundle on incontinence-associated dermatitis prevalence in hospital patients: A quasi-experimental translational study.

The study aimed to evaluate the effect of an intervention on the prevalence and severity of incontinence-associated dermatitis (IAD) in six hospitals in one state in Australia. This quasi-experimental pre-and post-study, conducted in 18 wards, was part of a larger implementation science study on incontinence-associated dermatitis. Skin and incontinence assessments were conducted on patients during February and March 2020 (pre-intervention) and July and August 2021 (post-intervention). The intervention comprised continence assessment and management, an education brochure for patients, family and caregivers on IAD, the Ghent Global IAD Categorisation Tool (GLOBIAD) and a skin care regime with patient skin protection measures (three-in-one barrier cream cloths, minimisation of bed protection layers, use of appropriate continence aid). A total of 1897 patients were assessed (pre-intervention = 964, post-intervention = 933). A total of 343 (35.6%) pre-intervention patients and 351 (37.6%) post-intervention patients had incontinence. The prevalence of hospital-acquired IAD was 6.71% in the pre-intervention group and 4.27% in the post-intervention group; a reduction of 36.3% (p = 0.159) despite higher patient acuity, prevalence of double incontinence and the COVID-19 pandemic in the post-intervention group compared with the pre-intervention group. Our multisite best practice IAD prevention and treatment intervention was able to reduce the prevalence and severity of hospital-acquired IAD, suggesting enduring effectiveness of the intervention.

with Rare Kidney Disease.

Chronic kidney disease (CKD) affects more than 35 million people in the United States, many of whom are undiagnosed. Included in this number are individuals with many types of rare kidney diseases, affecting 20,000 to 200,000 individuals nationwide. There is a major need to educate these individuals on the disease and its progression, especially since many individuals are not aware they have the disease. Descriptive correlational research was conducted in a nationwide sample of adult individuals living with rare glomerular kidney disease. Patient activation and quality of life were the concepts studied across the five CKD stages. New findings included statistically significant differences between participants' self-reported mental health quality of life and CKD Stage 1, with CKD Stages 4 and 5 in the rare kidney disease population. Nurses are essential for educating and supporting patients with rare kidney disease to preserve kidney function and slow disease progression.

xenoGI 3: using the DTLOR model to reconstruct the evolution of gene families in clades of microbes.

To understand genome evolution in a group of microbes, we need to know the timing of events such as duplications, deletions and horizontal transfers. A common approach is to perform a gene-tree / species-tree reconciliation. While a number of software packages perform this type of analysis, none are geared toward a complete reconstruction for all families in an entire clade. Here we describe an update to the xenoGI software package which allows users to perform such an analysis using the newly developed DTLOR (duplication-transfer-loss-origin-rearrangement) reconciliation model starting from genome sequences as input.

Proximity-based labeling reveals DNA damage-induced phosphorylation of fused in sarcoma (FUS) causes distinct changes in the FUS protein interactome.

Accumulation of cytoplasmic inclusions containing fused in sarcoma (FUS), an RNA/DNA-binding protein, is a common hallmark of frontotemporal lobar degeneration and amyotrophic lateral sclerosis neuropathology. We have previously shown that DNA damage can trigger the cytoplasmic accumulation of N-terminally phosphorylated FUS. However, the functional consequences of N-terminal FUS phosphorylation are unknown. To gain insight into this question, we utilized proximity-dependent biotin labeling via ascorbate peroxidase 2 aired with mass spectrometry to investigate whether N-terminal phosphorylation alters the FUS protein-protein interaction network (interactome), and subsequently, FUS function. We report the first analysis comparing the interactomes of three FUS variants: homeostatic wildtype FUS (FUS WT), phosphomimetic FUS (FUS PM; a proxy for N-terminally phosphorylated FUS), and the toxic FUS proline 525 to leucine mutant (FUS P525L) that causes juvenile amyotrophic lateral sclerosis. We found that the phosphomimetic FUS interactome is uniquely enriched for a group of cytoplasmic proteins that mediate mRNA metabolism and translation, as well as nuclear proteins involved in the spliceosome and DNA repair functions. Furthermore, we identified and validated the RNA-induced silencing complex RNA helicase MOV10 as a novel interacting partner of FUS. Finally, we provide functional evidence that N-terminally phosphorylated FUS may disrupt homeostatic translation and steady-state levels of specific mRNA transcripts. Taken together, these results highlight phosphorylation as a unique modulator of the interactome and function of FUS.

Glutamine-dependent effects of nitric oxide on cancer cells subjected to hypoxia-reoxygenation.

Limited O2 availability can decrease essential processes in energy metabolism. However, cancers have developed distinct metabolic adaptations to these conditions. For example, glutaminolysis can maintain energy metabolism and hypoxia signaling. Additionally, it has been observed that nitric oxide (NO) possesses concentration-dependent, biphasic effects in cancer. NO has potent anti-tumor effects through modulating events such as angiogenesis and metastasis at low physiological concentrations and inducing cell death at higher concentrations. In this study, Ewing Sarcoma cells (A-673), MIA PaCa, and SKBR3 cells were treated with DetaNONOate (DetaNO) in a model of hypoxia (1% O2) and reoxygenation (21% O2). All 3 cell types showed NO-dependent inhibition of cellular O2 consumption which was enhanced as O2-tension decreased. L-Gln depletion suppressed the mitochondrial response to decreasing O2 tension in all 3 cell types and resulted in inhibition of Complex I activity. In A-673 cells the O2 tension dependent change in mitochondrial O2 consumption and increase in glycolysis was dependent on the presence of L-Gln. The response to hypoxia and Complex I activity were restored by α-ketoglutarate. NO exposure resulted in the A-673 cells showing greater sensitivity to decreasing O2 tension. Under conditions of L-Gln depletion, NO restored HIF-1α levels and the mitochondrial response to O2 tension possibly through the increase of 2-hydroxyglutarate. NO also resulted in suppression of cellular bioenergetics and further inhibition of Complex I which was not rescued by α-ketoglutarate. Taken together these data suggest that NO modulates the mitochondrial response to O2 differentially in the absence and presence of L-Gln. These data suggest a combination of metabolic strategies targeting glutaminolysis and Complex I in cancer cells.

Pressure injury prevention practice in Australian intensive care units: A national cross-sectional survey.

INTRODUCTION: Pressure injury (PI) is an ongoing problem for patients in intensive care units (ICUs). The aim of this study was to explore the nature and extent of PI prevention practices in Australian adult ICUs. MATERIALS AND METHODS: An Australian multicentre, cross-sectional study was conducted via telephone interview using a structured survey instrument comprising six categories: workplace demographics, patient assessment, PI prevention strategies, medical devices, skin hygiene, and other health service strategies. Publicly funded adult ICUs, accredited with the College of Intensive Care Medicine, were surveyed. Data were analysed using descriptive statistics and chi-square tests for independence to explore associations according to geographical location. RESULTS: Of the 75 eligible ICUs, 70 responded (93% response rate). PI was considered problematic in two-thirds (68%) of all ICUs. Common PI prevention strategies included risk assessment and visual skin assessment conducted within at least 6 h of admission (70% and 73%, respectively), a structured repositioning regimen (90%), use of barrier products to protect the skin (94%), sacrum or heel prophylactic multilayered silicone foam dressings (88%), regular PI chart audits (96%), and PI quality improvement projects (90%). PI prevention rounding and safety huddles were used in 37% of ICUs, and 31% undertook PI research. Although most ICUs were supported by a facility-wide skin integrity service, it was more common in metropolitan ICUs than in rural and regional ICUs (p < 0.001). Conversely, there was greater involvement of occupational therapists in PI prevention in rural or regional ICUs than in metropolitan ICUs (p = 0.026). DISCUSSION AND CONCLUSION: This is the first study to provide a comprehensive description of PI prevention practices in Australian ICUs. Findings demonstrate that PI prevention practices, although nuanced in some areas to geographical location, are used in multiple and varied ways across ICUs.

The Cure VCP Scientific Conference 2021: Molecular and clinical insights into neurodegeneration and myopathy linked to multisystem proteinopathy-1 (MSP-1).

The 2021 VCP Scientific Conference took place virtually from September 9-10, 2021. This conference, planned and organized by the nonprofit patient advocacy group Cure VCP Disease, Inc. (https://www.curevcp.org), was the first VCP focused meeting since the 215th ENMC International Workshop VCP-related multi-system proteinopathy in 2016 (Evangelista et al., 2016). Mutations in VCP cause a complex and heterogenous disease termed inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), or multisystem proteinopathy 1 (MSP-1) Kimonis (n.d.), Kovach et al. (2001), Kimonis et al. (2000). In addition, VCP mutations also cause other age-related neurodegenerative disorders including amyptrophic lateral sclerosis (ALS), Parkinsonism, Charcot-Marie type II-B, vacuolar tauopathy among others (Korb et al., 2022). The objectives of this conference were as follows: (1) to provide a forum that facilitates sharing of published and unpublished information on physiological roles of p97/VCP, and on how mutations of VCP lead to diseases; (2) to bolster understanding of mechanisms involved in p97/VCP-relevant diseases and to enable identification of therapeutics to treat these conditions; (3) to identify gaps and barriers of further discoveries and translational research in the p97/VCP field; (4) to set a concrete basic and translational research agenda for future studies including crucial discussions on biomarker discoveries and patient longitudinal studies to facilitate near-term clinical trials; (5) to accelerate cross-disciplinary research collaborations among p97/VCP researchers; (6) to enable attendees to learn about new tools and reagents with the potential to facilitate p97/VCP research; (7) to assist trainees in propelling their research and to foster mentorship from leaders in the field; and (8) to promote diversity and inclusion of under-represented minorities in p97/VCP research as diversity is critically important for strong scientific research. Given the range of topics, the VCP Scientific Conference brought together over one hundred and forty individuals representing a diverse group of research scientists, trainees, medical practitioners, industry representatives, and patient advocates. Twenty-five institutions with individuals from thirteen countries attended this virtual meeting. In this report, we summarize the major topics presented at this conference by a range of experts.

Infants at risk for physical disability may be identified by measures of postural control in supine.

BACKGROUND: Early detection of delay or impairment in motor function is important to guide clinical management and inform prognosis during a critical window for the development of motor control in children. The purpose of this study was to investigate the ability of biomechanical measures of early postural control to distinguish infants with future impairment in motor control from their typically developing peers. METHODS: We recorded postural control from infants lying in supine in several conditions. We compared various center of pressure metrics between infants grouped by birth status (preterm and full term) and by future motor outcome (impaired motor control and typical motor control). RESULTS: One of the seven postural control metrics-path length-was consistently different between groups for both group classifications and for the majority of conditions. CONCLUSIONS: Quantitative measures of early spontaneous infant movement may have promise to distinguish early in life between infants who are at risk for motor impairment or physical disability and those who will demonstrate typical motor control. Our observation that center of pressure path length may be a potential early marker of postural instability and motor control impairment needs further confirmation and further investigation to elucidate the responsible neuromotor mechanisms. IMPACT: The key message of this article is that quantitative measures of infant postural control in supine may have promise to distinguish between infants who will demonstrate future motor impairment and those who will demonstrate typical motor control. One of seven postural control metrics-path length-was consistently different between groups. This metric may be an early marker of postural instability in infants at risk for physical disability.

Tibial Intraosseous Administration of Epinephrine Is Effective in Restoring Return of Spontaneous Circulation in a Pediatric Normovolemic But Not Hypovolemic Cardiac Arrest Model.

OBJECTIVE: We compared the efficacy of tibial intraosseous (TIO) administration of epinephrine in a pediatric normovolemic versus hypovolemic cardiac arrest model to determine the incidence of return of spontaneous circulation (ROSC) and plasma epinephrine concentrations over time. METHODS: This experimental study evaluated the pharmacokinetics of epinephrine and/or incidence of ROSC after TIO administration in either a normovolemic or hypovolemic pediatric swine model. RESULTS: All subjects in the TIO normovolemia cardiac arrest group experienced ROSC after TIO administration of epinephrine. In contrast, subjects experiencing hypovolemia and cardiac arrest were significantly less likely to experience ROSC when epinephrine was administered TIO versus intravenous (TIO hypovolemia: 14% [1/7] vs IV hypovolemia: 71% [5/7]; P = 0.031). The TIO hypovolemia group exhibited significantly lower plasma epinephrine concentrations versus IV hypovolemia at 60, 90, 120, and 150 seconds (P < 0.05). Although the maximum concentration of plasma epinephrine was similar, the TIO hypovolemia group exhibited significantly slower time to maximum concentration times versus TIO normovolemia subjects (P = 0.004). CONCLUSIONS: Tibial intraosseous administration of epinephrine reliably facilitated ROSC among normovolemic cardiac arrest pediatric patients, which is consistent with published reports. However, TIO administration of epinephrine was ineffective in restoring ROSC among subjects experiencing hypovolemia and cardiac arrest. Tibial intraosseous-administered epinephrine during hypovolemia and cardiac arrest may have resulted in a potential sequestration of epinephrine in the tibia. Central or peripheral intravascular access attempts should not be abandoned after successful TIO placement in the resuscitation of patients experiencing concurrent hypovolemia and cardiac arrest.

Development and Psychometric Testing of a Knowledge Instrument on Incontinence-Associated Dermatitis for Clinicians: The Know-IAD.

PURPOSE: The purpose of this study was to describe the development and evaluation of the psychometric properties of an instrument used to assess clinician knowledge of Incontinence-associated dermatitis (IAD). DESIGN: The instrument was developed in three phases: Phase 1 involved item development; Phase 2 evaluated content validity of the instrument by surveying clinicians and stakeholders within a single state of Australia and, Phase 3 used a pilot multisite cross-sectional survey design to determine composite reliability and evaluate scores of the knowledge tool. SUBJECTS AND SETTINGS: In Phase 1, the instrument was developed by five persons with clinical and research subject expertise in the area of IAD. In Phase 2, content validity was evaluated by a group of 13 clinicians (nurses, physicians, occupational therapists, dietitians, and physiotherapists) working in acute care across one Australian state, New South Wales, along with two consumer representatives. In Phase 3, clinicians, working across six hospitals in New South Wales and on wards with patients diagnosed with incontinence-associated dermatitis, participated in pilot-testing the instrument. METHODS: During Phase 1, a group of local and international experts developed items for a draft tool based on an international consensus document, our prior research evaluating incontinence-associated dermatitis knowledge, and agreement among an expert panel of clinicians and researchers. Phase 2 used a survey design to determine content validity of the knowledge tool. Specifically, we calculated item- and scale-level content validity ratios and content validity indices for all questions within the draft instrument. Phase 3 comprised pilot-testing of the knowledge tool using a cross-sectional survey. Analysis involved confirmatory factor analysis to confirm the hypothesized model structure of the knowledge tool, as measured by model goodness-of-fit. Composite reliability testing was undertaken to determine the extent of internal consistency between constituent items of each construct. RESULTS: During Phase 1, a draft version of the Barakat-Johnson Incontinence-Associated Dermatitis Knowledge tool (Know-IAD), comprising 19 items and divided into three domains of IAD-related knowledge: 1) Etiology and Risk, 2) Classification and Diagnosis, and 3) Prevention and Management was developed. In Phase 2, 18 of the 19 items demonstrated high scale content validity ratios scores on relevance (0.75) and clarity (0.82); and high scale-content validity indices scores on relevance (0.87) and clarity (0.91). In Phase 3, the final 18-item Know-IAD tool demonstrated construct validity by a model goodness-of-fit. Construct validity was excellent for the Etiology and Risk domain (root mean squared error=0.02) and Prevention and Management domain (root mean squared error=0.02); it was good for the Classification and Diagnosis domain (root mean squared error=0.04). Composite reliability (CR) was good in the Etiology and Risk domain (CR=0.76), Prevention and Management domains (CR=0.75), and adequate in the Classification and Diagnosis domain (CR=0.64). Respondents had good understanding of etiology and risk (72.6% correct responses); fairly good understanding of prevention and management of IAD (64.0% correct responses) and moderate understanding of classification and diagnosis (40.2% correct responses). CONCLUSIONS: The Know-IAD demonstrated good psychometric properties and provides preliminary evidence that it can be applied to evaluate clinician knowledge on IAD.

Clinician Knowledge of Incontinence-Associated Dermatitis: A Multisite Survey of Healthcare Professionals in Acute and Subacute Settings.

PURPOSE: This study examined clinicians' knowledge of incontinence-associated dermatitis (IAD) using the Barakat-Johnson Incontinence-Associated Dermatitis Knowledge Tool (Know-IAD). DESIGN: A cross-sectional multicenter survey. SUBJECTS AND SETTING: The setting was 6 hospitals across 5 health districts in New South Wales, Australia. The participants were nurses (registered nurses and enrolled nurses), physicians, allied health (occupational therapists, dietitians, and physiotherapists), and students (nursing and allied health). METHODS: Data about IAD knowledge were collected from November 2019 to January 2020. The Know-IAD, an 18-item validated instrument that measures knowledge of IAD in 3 domains (etiology and risk, classification and diagnosis, and prevention and management), was administered to a cross section of eligible clinicians. The participants anonymously completed hard copy surveys. Descriptive and exploratory analyses were conducted to quantify clinicians' knowledge about the etiology and risk, classification and diagnosis, and prevention and management of IAD. A mean knowledge score of 70% was considered to be satisfactory. RESULTS: Four hundred twelve respondents completed the survey. One hundred twenty nine respondents (31.3%) achieved 70% correct responses and greater for the entire set of items. For the etiology and risk domain, 348 respondents (84.5%) obtained a score of 70% correct responses and greater, 67 respondents (16.3%) achieved 70% correct responses and greater for the classification and diagnosis domain, and 84 respondents (20.4%) achieved 70% correct responses and greater for the prevention and management domain. CONCLUSION: Clinicians tend to have low knowledge and recognition of IAD, particularly in the areas of classification and diagnosis along with prevention and management. They tend to have higher knowledge of how IAD is caused and the risk factors. This study has identified knowledge gaps for further education that can improve assessment, prevention, and management of IAD.

Reshaping wound care: Evaluation of an artificial intelligence app to improve wound assessment and management amid the COVID-19 pandemic.

Wound documentation is integral to effective wound care, health data coding and facilitating continuity of care. This study evaluated the usability and effectiveness of an artificial intelligence application for wound assessment and management from a clinician-and-patient user perspective. A quasi-experimental design was conducted in four settings in an Australian health service. Data were collected from patients in the standard group (n = 166, 243 wounds) and intervention group (n = 124, 184 wounds), at baseline and post-intervention. Clinicians participated in a survey (n = 10) and focus group interviews (n = 13) and patients were interviewed (n = 4). Wound documentation data were analysed descriptively, and bivariate statistics were used to determine between-group differences. Thematic analysis of interviews was conducted. Compared with the standard group, wound documentation in the intervention group improved significantly (more than two items documented 24% vs 70%, P < .001). During the intervention, 101 out of 132 wounds improved (mean wound size reduction = 53.99%). Positive evaluations identified improvements such as instantaneous objective wound assessment, shared wound plans, increased patient adherence and enhanced efficiency in providing virtual care. The use of the application facilitated remote patient monitoring and reduced patient travel time while maintaining optimal wound care.

The viability and acceptability of a Virtual Wound Care Command Centre in Australia.

The objective of this study was to assess the viability and acceptability of an innovative Virtual Wound Care Command Centre where patients in the community, and their treating clinicians, have access to an expert wound specialist service that comprises a digitally enabled application for wound analysis, decision-making, remote consultation, and monitoring. Fifty-one patients with chronic wounds from 9 centres, encompassing hospital services, outpatient clinics, and community nurses in one metropolitan and rural state in Australia, were enrolled and a total of 61 wounds were analysed over 7 months. Patients received, on average, an occasion of service every 4.4 days, with direct queries responded to in a median time of 1.5 hours. During the study period, 26 (42.6%) wounds were healed, with a median time to healing of 66 (95% CI: 56-88) days. All patients reported high satisfaction with their wound care, 86.4% of patients recommended the Virtual Wound Care Command Centre with 84.1% of patients reporting the digital wound application as easy to use. Potential mean travel savings of $99.65 for rural patients per visit were recognised. The data revealed that the Virtual Wound Care Command Centre was a viable and acceptable patient-centred expert wound consultation service for chronic wound patients in the community.

Pressure injury prevalence in Australian intensive care units: A secondary analysis.

BACKGROUND: Pressure injuries (PIs) are an enduring problem for patients in the intensive care unit (ICU) because of their vulnerability and numerous risk factors. METHOD: This study reports Australian data as a subset of data from an international 1-day point prevalence study of ICU-acquired PI in adult patients. Patients aged 18 years or older and admitted to the ICU on the study day were included. The outcome measure was the identification of a PI by direct visual skin assessment on the study day. Data collected included demographic data and clinical risk factors, PI location and stage, and PI prevention strategies used. Descriptive statistics were used to describe PI characteristics, and odds ratios (ORs) were used to identify factors associated with the development of a PI. RESULTS: Data were collected from 288 patients from 16 Australian ICUs. ICU-acquired PI prevalence was 9.7%, with 40 PIs identified on 28 patients. Most PIs were of stage 1 and stage 2 (26/40, 65.0%). Half of the ICU-acquired PIs were found on the head and face. The odds of developing an ICU-acquired PI increased significantly with renal replacement therapy (OR: 4.25, 95% confidence interval [CI]: 1.49-12.11), impaired mobility (OR: 3.13, 95% CI: 1.08-9.12), fastest respiratory rate (OR: 1.05 [per breath per minute], 95% CI: 1.00-1.10), longer stay in the ICU (OR: 1.04 [per day], 95% CI: 1.01-1.06), and mechanical ventilation on admission (OR: 0.36, CI: 0.14-0.91). CONCLUSION: This study found that Australian ICU-acquired PI prevalence was 9.7% and these PIs were associated with many risk factors. Targeted PI prevention strategies should be incorporated into routine prevention approaches to reduce the burden of PIs in the Australian adult ICU patient population.

ZKSCAN3 in severe bacterial lung infection and sepsis-induced immunosuppression.

The mortality rates among patients who initially survive sepsis are, in part, associated with a high risk of secondary lung infections and respiratory failure. Given that phagolysosomes are important for intracellular killing of pathogenic microbes, we investigated how severe lung infections associated with post-sepsis immunosuppression affect phagolysosome biogenesis. In mice with P. aeruginosa-induced pneumonia, we found a depletion of both phagosomes and lysosomes, as evidenced by decreased amounts of microtubule associated protein light chain 3-II (LC3-II) and lysosomal-associated membrane protein (LAMP1). We also found a loss of transcription factor E3 (TFE3) and transcription factor EB (TFEB), which are important activators for transcription of genes encoding autophagy and lysosomal proteins. These events were associated with increased expression of ZKSCAN3, a repressor for transcription of genes encoding autophagy and lysosomal proteins. Zkscan3-/- mice had increased expression of genes involved in the autophagy-lysosomal pathway along with enhanced killing of P. aeruginosa in the lungs, as compared to wild-type mice. These findings highlight the involvement of ZKSCAN3 in response to severe lung infection, including susceptibility to secondary bacterial infections due to immunosuppression.

Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that are thought to exist on a clinical and pathological spectrum. FTD and ALS are linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) and neuropathology, such as inclusions of ubiquitinated, misfolded proteins (e.g. TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes that cause FTD or ALS when mutated encode proteins that localize to the lysosome or modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, lysosomal acidification, autophagy, or TFEB activity. In this review, we summarize evidence that lysosomal dysfunction, caused by genetic mutations (e.g. C9orf72, GRN, MAPT, TMEM106B) or toxic-gain of function (e.g. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS. Further studies into the normal function of many of these proteins are required and will help uncover the mechanisms that cause lysosomal dysfunction in FTD and ALS. Mutations or polymorphisms in genes that encode proteins important for endosome-lysosome function also occur in other age-dependent neurodegenerative diseases, including Alzheimer's (e.g. APOE, PSEN1, APP) and Parkinson's (e.g. GBA, LRRK2, ATP13A2) disease. A more complete understanding of the common and unique features of lysosome dysfunction across the spectrum of neurodegeneration will help guide the development of therapies for these devastating diseases.

Understanding Skin Failure: A Scoping Review.

OBJECTIVE: To map the use of the term "skin failure" in the literature over time and enhance understanding of this term as it is used in clinical practice. DATA SOURCES: The databases searched for published literature included PubMed, Embase, the Cumulative Index for Nursing and Allied Health Literature, and Google Scholar. The search for unpublished literature encompassed two databases, Open Gray and ProQuest Dissertation and Theses. STUDY SELECTION: Search terms included "skin failure," "acute skin failure," "chronic skin failure," and "end stage skin." All qualitative and quantitative research designs, editorial, opinion pieces, and case studies were included, as well as relevant gray literature. DATA EXTRACTION: Data collected included author, title, year of publication, journal name, whether the term "skin failure" was mentioned in the publication and/or in conjunction with other skin injury, study design, study setting, study population, sample size, main focus of the publication, what causes skin failure, skin failure definition, primary study aim, and primary outcome. DATA SYNTHESIS: Two main themes of skin failure were identified through this scoping review: the etiology of skin failure and the interchangeable use of definitions. CONCLUSIONS: Use of the term "skin failure" has increased significantly over the past 30 years. However, there remains a significant lack of empirical evidence related to skin failure across all healthcare settings. The lack of quality research has resulted in multiple lines of thinking on the cause of skin failure, as well as divergent definitions of the concept. These results illustrate substantial gaps in the current literature and an urgent need to develop a globally agreed-upon definition of skin failure, as well as a better understanding of skin failure etiology.

Implementing best available evidence into practice for incontinence-associated dermatitis in Australia: A multisite multimethod study protocol.

AIMS: Incontinence-associated dermatitis (IAD) is an insidious and under-reported hospital-acquired complication which substantially impacts on patients' quality of life. A published international guideline and the Ghent Global IAD Categorisation Tool (GLOBIAD) outline the best available evidence for the optimal management of IAD. This study aims to implement theguideline and the GLOBIAD tool and evaluate the effect on IAD occurrences and sacral pressure injuries as well as patient, clinician and cost-effectiveness outcomes. MATERIALS AND METHODS: The study will employ a multi-method design across six hospitals in five health districts in Australia, and will be conducted in three phases (pre-implementation, implementation and post-implementation) over 19 months. Data collection will involve IAD and pressure injury prevalence audits for patient hospital admissions, focus groups with, and surveys of, clinicians, patient interviews, and collection of the cost of IAD hospital care and patient-related outcomes including quality of life. Eligible participants will be hospitalised adults over 18 years of age experiencing incontinence, and clinicians working in the study wards will be invited to participate in focus groups and surveys. CONCLUSION: The implementation of health district-wide evidence-based practices for IAD using a translational research approach that engages key stakeholders will allow the standardisation of IAD care that can potentially be applicable to a range of settings. Knowledge gained will inform future practice change in patient care and health service delivery and improve the quality of care for patients with IAD. Support at the hospital, state and national levels, coupled with a refined stakeholder-inclusive strategy, will enhance this project's success, sustainability and scalability beyond this existing project.