Understanding pathways from implementation to sustainment: a longitudinal, mixed methods analysis of promising practices implemented in the Veterans Health Administration.

BACKGROUND: The Veterans Health Administration (VHA) is the United States largest learning health system. The Diffusion of Excellence (DoE) program is a large-scale model of diffusion that identifies and diffuses evidence-informed practices across VHA. During the period of 2016-2021, 57 evidence-informed practices were implemented across 82 VHA facilities. This setting provides a unique opportunity to understand sustainment determinants and pathways. Our objective was to characterize the longitudinal pathways of practices as they transition from initial implementation to long-term sustainment at each facility. METHODS: A longitudinal, mixed-methods evaluation of 82 VHA facilities. Eighty-two facility representatives, chosen by leadership as points-of-contact for 57 DoE practices, were eligible for post-implementation interviews and annual sustainment surveys. Primary outcomes (implementation, sustainment), and secondary outcomes (institutionalization, effectiveness, anticipated sustainment) at four time-points were collected. We performed descriptive statistics and directed content analysis using Hailemariam et al.'s factors influencing sustainment. RESULTS: After approximately five years post-implementation (e.g., 2021 sustainment outcomes), of the 82 facilities, about one-third fully sustained their practice compared to one-third that did not fully sustain their practice because it was in a "liminal" stage (neither sustained nor discontinued) or permanently discontinued. The remaining one-third of facilities had missing 2021 sustainment outcomes. A higher percentage of facilities (70%) had inconsistent primary outcomes (changing over time) compared to facilities (30%) with consistent primary outcomes (same over time). Thirty-four percent of facilities with sustained practices reported resilience since they overcame implementation and sustainment barriers. Facilities with sustained practices reported more positive secondary outcomes compared to those that did not sustain their practice. Key factors facilitating practice sustainment included: demonstrating practice effectiveness/benefit, sufficient organizational leadership, sufficient workforce, and adaptation/alignment with local context. Key factors hindering practice sustainment included: insufficient workforce, not able to maintain practice fidelity/integrity, critical incidents related to the COVID-19 pandemic, organizational leadership did not support sustainment of practice, and no ongoing support. CONCLUSIONS: We identified diverse pathways from implementation to sustainment, and our data underscore that initial implementation outcomes may not determine long-term sustainment outcomes. This longitudinal evaluation contributes to understanding impacts of the DoE program, including return on investment, achieving learning health system goals, and insights into achieving high-quality healthcare in VHA.

Validation of the Klinrisk chronic kidney disease progression model in the FIDELITY population.

Background: Chronic kidney disease (CKD) affects >800 million individuals worldwide and is often underrecognized. Early detection, identification and treatment can delay disease progression. Klinrisk is a proprietary CKD progression risk prediction model based on common laboratory data to predict CKD progression. We aimed to externally validate the Klinrisk model for prediction of CKD progression in FIDELITY (a prespecified pooled analysis of two finerenone phase III trials in patients with CKD and type 2 diabetes). In addition, we sought to identify evidence of an interaction between treatment and risk. Methods: The validation cohort included all participants in FIDELITY up to 4 years. The primary and secondary composite outcomes included a ≥40% decrease in estimated glomerular filtration rate (eGFR) or kidney failure, and a ≥57% decrease in eGFR or kidney failure. Prediction discrimination was calculated using area under the receiver operating characteristic curve (AUC). Calibration plots were calculated by decile comparing observed with predicted risk. Results: At time horizons of 2 and 4 years, 993 and 1795 patients experienced a primary outcome event, respectively. The model predicted the primary outcome accurately with an AUC of 0.81 for 2 years and 0.86 for 4 years. Calibration was appropriate at both 2 and 4 years, with Brier scores of 0.067 and 0.115, respectively. No evidence of interaction between treatment and risk was identified for the primary composite outcome (P = .31). Conclusions: Our findings demonstrate the accuracy and utility of a laboratory-based prediction model for early identification of patients at the highest risk of CKD progression.

Total Intravenous Anesthesia with Propofol Reduces Discharge Times Compared with Inhaled General Anesthesia in Shoulder Arthroscopy: A Randomized Controlled Trial.

BACKGROUND: Shoulder arthroscopy is commonly performed at ambulatory surgical centers (ASCs) with use of an interscalene block and inhaled general anesthesia (IGA). However, an alternative option known as total intravenous anesthesia with propofol (TIVA-P) has shown promising results in reducing recovery time for other surgeries. The objective of this study was to assess whether there is a clinically meaningful difference in post-anesthesia care unit phase-I (PACU-I) time following shoulder arthroscopy between patients receiving an interscalene block with IGA and those receiving an interscalene block with TIVA-P. METHODS: Patients who underwent shoulder arthroscopy performed by a single surgeon at the ASC of our institution between 2020 and 2023 were enrolled. Enrollment was conducted in blocks, with up to 3 planned interim analyses. After 2 blocks, enrollment was halted because the study arms demonstrated a significant difference in the primary outcome measure, PACU-I time. A total of 96 patients were randomized into the TIVA-P and IGA groups; after patient withdrawals, the groups comprised 42 and 40 patients, respectively. Patients underwent shoulder arthroscopy with use of the anesthesia method corresponding to their assigned group. Pain, satisfaction, antiemetic use, perioperative interventions, surgical time, PACU-II time, postoperative care time, and total time until discharge were recorded and were analyzed with use of chi-square and Mann-Whitney U tests with a significance cutoff of 0.0167 to account for the interim analyses. RESULTS: Across groups, 81.7% of patients were non-Hispanic White and 58.5% were male. Significant differences were observed between the TIVA-P and IGA groups with respect to median PACU-I time (0.0 minutes [interquartile range (IQR), 0.0 to 6.0 minutes] versus 25.5 minutes [IQR, 20.5 to 32.5 minutes]; p < 0.001) and median total time until discharge (135.5 minutes [IQR, 118.5 to 156.8 minutes] versus 148.5 minutes [IQR, 133.8 to 168.8 minutes]; p = 0.0104). The TIVA-P group had a 9.1% quicker discharge time, primarily as a result of bypassing PACU-I (66.7% of patients) and spending 25.5 fewer minutes there overall. The TIVA-P group also had a lower rate of antiemetic use than the IGA group (59.5% versus 92.5% of patients; p = 0.0013). No significant differences were detected between the TIVA-P and IGA groups in terms of median pain improvement (1.0 [IQR, 0.0 to 2.0] versus 1.0 [IQR, 0.0 to 2.0]; p = 0.6734), perioperative interventions (78.6% versus 77.5% of patients, p = 1.0000), or median patient satisfaction (4.0 [IQR, 4.0 to 4.0] versus 4.0 [IQR, 3.8 to 4.0]; p = 0.4148). CONCLUSIONS: TIVA-P showed potential to improve both PACU-I time and the total time until discharge while reducing antiemetic use without impacting pain or satisfaction. TIVA-P thus warrants consideration by orthopaedic surgeons for use in shoulder arthroscopy performed at ASCs. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Investigating antimicrobial resistance genes in Kenya, Uganda and Tanzania cattle using metagenomics.

Antimicrobial resistance (AMR) is a growing problem in African cattle production systems, posing a threat to human and animal health and the associated economic value chain. However, there is a poor understanding of the resistomes in small-holder cattle breeds in East African countries. This study aims to examine the distribution of antimicrobial resistance genes (ARGs) in Kenya, Tanzania, and Uganda cattle using a metagenomics approach. We used the SqueezeMeta-Abricate (assembly-based) pipeline to detect ARGs and benchmarked this approach using the Centifuge-AMRplusplus (read-based) pipeline to evaluate its efficiency. Our findings reveal a significant number of ARGs of critical medical and economic importance in all three countries, including resistance to drugs of last resort such as carbapenems, suggesting the presence of highly virulent and antibiotic-resistant bacterial pathogens (ESKAPE) circulating in East Africa. Shared ARGs such as aph(6)-id (aminoglycoside phosphotransferase), tet (tetracycline resistance gene), sul2 (sulfonamide resistance gene) and cfxA_gen (betalactamase gene) were detected. Assembly-based methods revealed fewer ARGs compared to read-based methods, indicating the sensitivity and specificity of read-based methods in resistome characterization. Our findings call for further surveillance to estimate the intensity of the antibiotic resistance problem and wider resistome classification. Effective management of livestock and antibiotic consumption is crucial in minimizing antimicrobial resistance and maximizing productivity, making these findings relevant to stakeholders, agriculturists, and veterinarians in East Africa and Africa at large.

Visceral Leishmaniasis in a Twin Pregnancy: A Case Report and Review of the Literature.

Visceral leishmaniasis (VL), often referred to as kala-azar, is quite rare in developed countries during pregnancy. Only few studies have evaluated its impact on perinatal outcome. It is caused primarily by Leishmania donovani or Leishmania infantum and presents with a wide spectrum of clinical manifestations from cutaneous ulcers to multisystem disease. Differential diagnosis is challenging as symptoms and signs are insidious, mimicking other diseases. Misdiagnosis can result in severe adverse perinatal outcomes, even maternal/neonatal death. Early treatment with liposomal amphotericin-B (LAmB) is currently the first choice with adequate effectiveness. We report a rare case of VL in a twin pregnancy with onset at the second trimester, presenting with periodic fever with rigors, right flank pain, and gradual dysregulation of all three cell lines. The positive rK39 enzyme-linked immunosorbent assay test confirmed the diagnosis. Treatment with LAmB resulted in clinical improvement within 48 h and in the delivery of two late-preterm healthy neonates with no symptoms or signs of vertical transmission. The one-year follow-up, of the mother and the neonates, was negative for recurrence. To our knowledge, this is the first reported case of VL in a twin pregnancy, and consequently treatment and perinatal outcome are of great importance.

Effects of a Global Rab27a Null Mutation on Murine PVAT and Cardiovascular Function.

BACKGROUND: RAB27A, a modulator of secretion, is expressed within vessels and perivascular adipose tissue. We hypothesized that loss of RAB27A would alter cardiovascular function. METHODS: Body weight of Rab27aash mice was measured from 2 to 18 months of age, along with glucose resorption at 6 and 12 months of age and glucose sensitivity at 18 months of age. Body weight and cellular and molecular features of perivascular adipose tissue and aortic tissue were examined in a novel C57BL/6J Rab27a null strain. Analyses included morphometric quantification and proteomic analyses. Wire myography measured vasoreactivity, and echocardiography measured cardiac function. Comparisons across ages and genotypes were evaluated via 2-way ANOVA with multiple comparison testing. Significance for myography was determined via 4-parameter nonlinear regression testing. RESULTS: Genome-wide association data linked rare human RAB27A variants with body mass index and glucose handling. Changes in glucose tolerance were observed in Rab27aash male mice at 18 months of age. In WT (wild-type) and Rab27a null male mice, body weight, adipocyte lipid area, and aortic area increased with age. In female mice, only body weight increased with age, independent of RAB27A presence. Protein signatures from male Rab27a null mice suggested greater associations with cardiovascular and metabolic phenotypes compared with female tissues. Wire myography results showed Rab27a null males exhibited increased vasoconstriction and reduced vasodilation at 8 weeks of age. Rab27a null females exhibited increased vasoconstriction and vasodilation at 20 weeks of age. Consistent with these vascular changes, male Rab27a null mice experienced age-related cardiomyopathy, with severe differences observed by 21 weeks of age. CONCLUSIONS: Global RAB27A loss impacted perivascular adipose tissue and thoracic aorta proteomic signatures, altered vasocontractile responses, and decreased left ventricular ejection fraction in mice.

Commercially available mouthguards: Unearthing trace elements for the first time.

The use of mouthguards is advocated by the American Dental Association for orofacial injury prevention and teeth protection. However, the chemical environment in the mouth may cause harmful substances within the mouthguard's polymer material to leach out and be absorbed by the user. Considering this, the present study for the first time analyzed commercially available mouthguards and disclosed the presence of trace elements. Specifically, an analytical method was developed based on closed-vessel microwave-assisted digestion and plasma-based atomic spectrometry for determining toxic trace elements in mouthguard samples. Initially, 75 elements were assessed and, thereafter, quantified cadmium (Cd), copper (Cu) and lead (Pb) in each sample by inductively coupled plasma mass spectrometry (ICP-MS). Method validation was carried out by analyzing a certified reference material of Low-Density Polyethylene, and by addition and recovery experiments. Results for copper were further validated by ICP optical emission spectrometry (ICP-OES). While most samples exhibited elemental levels beneath the method's limit of quantification, Cd, Cu and Pb were detected in four samples. Remarkably, one sample had Cu levels exceeding safe limits by 109 times, highlighting potential toxicity risks. This initial research underscores the need for stricter contamination control in mouthguard materials to minimize potentially health hazards.

Kinase signalling adaptation supports dysfunctional mitochondria in disease.

Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.

The inner membrane protein YhiM links copper and CpxAR envelope stress responses in uropathogenic E. coli.

Urinary tract infection (UTI) is a ubiquitous infectious condition, and uropathogenic Escherichia coli (UPEC) is the predominant causative agent of UTI. Copper (Cu) is implicated in innate immunity, including against UPEC. Cu is a trace element utilized as a co-factor, but excess Cu is toxic due to mismetalation of non-cognate proteins. E. coli precisely regulates Cu homeostasis via efflux systems. However, Cu import mechanisms into the bacterial cell are not clear. We hypothesized that Cu import defective mutants would exhibit increased resistance to Cu. This hypothesis was tested in a forward genetic screen with transposon (Tn5) insertion mutants in UPEC strain CFT073, and we identified 32 unique Cu-resistant mutants. Transposon and defined mutants lacking yhiM, which encodes a hypothetical inner membrane protein, were more resistant to Cu than parental strain. Loss of YhiM led to decreased cellular Cu content and increased expression of copA, encoding a Cu efflux pump. The CpxAR envelope stress response system was activated in the ΔyhiM mutant as indicated by increased expression of cpxP. Transcription of yhiM was regulated by CueR and CpxR, and the CpxAR system was essential for increased Cu resistance in the ΔyhiM mutant. Importantly, activation of CpxAR system in the ΔyhiM mutant was independent of NlpE, a known activator of this system. YhiM was required for optimal fitness of UPEC in a mouse model of UTI. Our findings demonstrate that YhiM is a critical mediator of Cu homeostasis and links bacterial adaptation to Cu stress with the CpxAR-dependent envelope stress response in UPEC.IMPORTANCEUPEC is a common bacterial infection. Bacterial pathogens are exposed to host-derived Cu during infection, including UTI. Here, we describe detection of genes involved in Cu homeostasis in UPEC. A UPEC mutant lacking YhiM, a membrane protein, exhibited dramatic increase in resistance to Cu. Our study demonstrates YhiM as a nexus between Cu stress and the CpxAR-dependent envelope stress response system. Importantly, our findings establish NlpE-independent activation of CpxAR system during Cu stress in UPEC. Collectively, YhiM emerges as a critical mediator of Cu homeostasis in UPEC and highlights the interlinked nature of bacterial adaptation to survival during Cu and envelope stress.

Reconstructing colonization dynamics to establish how human activities transformed island biodiversity.

Drivers and dynamics of initial human migrations across individual islands and archipelagos are poorly understood, hampering assessments of subsequent modification of island biodiversity. We developed and tested a new statistical-simulation approach for reconstructing the pattern and pace of human migration across islands at high spatiotemporal resolutions. Using Polynesian colonisation of New Zealand as an example, we show that process-explicit models, informed by archaeological records and spatiotemporal reconstructions of past climates and environments, can provide new and important insights into the patterns and mechanisms of arrival and establishment of people on islands. We find that colonisation of New Zealand required there to have been a single founding population of approximately 500 people, arriving between 1233 and 1257 AD, settling multiple areas, and expanding rapidly over both North and South Islands. These verified spatiotemporal reconstructions of colonisation dynamics provide new opportunities to explore more extensively the potential ecological impacts of human colonisation on New Zealand's native biota and ecosystems.

Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model.

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes. Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4). Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs. Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.

Development of opioid analgesic tolerance in rat to extended-release buprenorphine formulated for laboratory subjects.

Buprenorphine in an extended-release formulation intended for use in laboratory subjects is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine may persist in serum once extended-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of extended-release buprenorphine intended for use in laboratory subjects in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg extended-release buprenorphine, analgesic efficacy did not persist for the expected 72 hours. No changes were observed in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to extended-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or extended-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1-3 mg/kg). Rats previously given extended-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in male rats after exposure to the extended-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.

Social determinants of health and treatment center affiliation: analysis from the sickle cell disease implementation consortium registry.

BACKGROUND: Adults with sickle cell disease (SCD) suffer early mortality and high morbidity. Many are not affiliated with SCD centers, defined as no ambulatory visit with a SCD specialist in 2 years. Negative social determinants of health (SDOH) can impair access to care. HYPOTHESIS: Negative SDOH are more likely to be experienced by unaffiliated adults than adults who regularly receive expert SCD care. METHODS: Cross-sectional analysis of the SCD Implementation Consortium (SCDIC) Registry, a convenience sample at 8 academic SCD centers in 2017-2019. A Distressed Communities Index (DCI) score was assigned to each registry member's zip code. Insurance status and other barriers to care were self-reported. Most patients were enrolled in the clinic or hospital setting. RESULTS: The SCDIC Registry enrolled 288 Unaffiliated and 2110 Affiliated SCD patients, ages 15-45y. The highest DCI quintile accounted for 39% of both Unaffiliated and Affiliated patients. Lack of health insurance was reported by 19% of Unaffiliated versus 7% of Affiliated patients. The most frequently selected barriers to care for both groups were "previous bad experience with the healthcare system" (40%) and "Worry about Cost" (17%). SCD co-morbidities had no straightforward trend of association with Unaffiliated status. The 8 sites' results varied. CONCLUSION: The DCI economic measure of SDOH was not associated with Unaffiliated status of patients recruited in the health care delivery setting. SCDIC Registrants reside in more distressed communities than other Americans. Other SDOH themes of affordability and negative experiences might contribute to Unaffiliated status. Recruiting Unaffiliated SCD patients to care might benefit from systems adopting value-based patient-centered solutions.

Reframing the Morbidity and Mortality Conference: The Impact of a Just Culture.

ABSTRACT: Morbidity and mortality (M&M) conferences are prevalent in all fields of medicine. Historically, they arose out a desire to improve medical care. Nevertheless, the goals of M&M conferences are often poorly defined, at odds with one another, and do not support a just culture. We differentiate among the various possible goals of an M&M and review the literature for strategies that have been shown to achieve these goals. Based on the literature, we outline an ideal M&M structure within the context of just culture: The process starts with robust adverse event and near miss reporting, followed by careful case selection, excluding cases solely attributable to individual error. Prior to the M&M, the case should be openly discussed with involved members and should be reviewed using a selected framework. The goal of the M&M should be selected and clearly defined, and the presentation format and rules of conduct should all conform to the selected presentation goal. The audience should ideally be multidisciplinary and multispecialty. The M&M should conclude with concrete tasks and assigned follow-up. The entire process should be conducted in a peer review protected format within an environment promoting psychological safety. We conclude with future directions for M&Ms.