Effect of PERLA®, a new cold-storage solution, on oxidative stress injury and early graft function in rat kidney transplantation model.

BACKGROUND: The composition of organ preservation solutions is crucial for maintaining graft integrity and early graft function after transplantation. The aim of this study is to compare new organ preservation solution PERLA® with the gold standard preservation solution University of Wisconsin (UW) regarding oxidative stress and early graft injury. METHODS: In order to assess oxidative stress after cold storage, kidney grafts have been preserved for 18 h at 4° C in either UW solution or PERLA® solution and then assessed for oxidative stress injury (protocol 1). To assess kidney injuries and oxidative stress after reperfusion, rat kidneys were harvested, stored in cold UW or in PERLA® solutions for 18 h at 4 °C and then transplanted heterotopically for 6 h (protocol 2). PERLA® is a high Na+/low K+ solution including PEG-35 (1 g/L), trimetazidine (1 µM), carvedilol (10 µM) and tacrolimus (5 µM). RESULTS: Our results showed that preservation of kidneys in PERLA® solution significantly attenuates oxidative stress parameters after cold storage and reperfusion. We found a significant decrease in oxidative damage indicators (MDA, CD and CP) and a significant increase in antioxidant indicators (GPx, GSH, CAT, SOD and PSH). Moreover, PERLA® solution decreased kidney injury after reperfusion (creatinine, LDH and uric acid). CONCLUSION: PERLA® solution was more effective than UW storage solution in preserving rat's kidney grafts.

Seascape genomics of the pink abalone (Haliotis corrugata): An insight into a cross-border species in the northeast Pacific coast.

Seascape genomics gives insight into the geographic and environmental factors shaping local adaptations. It improves the understanding of the potential effects of climate change, which is relevant to provide the basis for the international management of fishery resources. The pink abalone (Haliotis corrugata) is distributed from California, United States to Baja California Sur, Mexico, exposed to a latitudinal environmental gradient in the California Current System. Management of the pink abalone contrasts between Mexico and the United States; Mexico has an active fishery organized in four administrative areas, while the United States has kept the fishery in permanent closure since 1996. However, the impact of environmental factors on genetic variation along the species distribution remains unknown, and understanding this relationship is crucial for effective spatial management strategies. This study aims to investigate the neutral and adaptive genomic structure of H. corrugata. A total of 203 samples from 13 locations were processed using ddRADseq, and covering the species' distribution. Overall, 2,231 neutral, nine potentially adaptive and three genomic-environmental association loci were detected. The neutral structure identified two groups: 1) California, United States and 2) Baja California Peninsula, México. In addition, the adaptive structure analysis also detected two groups with genetic divergence observed at Punta Eugenia. Notably, the seawater temperature significantly correlated with the northern group (temperate) and the southern (warmer) group. This study is a valuable foundation for future research and conservation initiatives, emphasizing the importance of considering neutral and adaptive genetic factors when developing management strategies for marine species.

Associations between abrupt transition, dialysis-requiring AKI, and early mortality in ESKD among U.S. veterans.

BACKGROUND: Mortality is high within the first few months of starting chronic dialysis. Pre-ESKD trajectory of kidney function has been shown to be predictive of early death after dialysis initiation. We aim to better understand how two key aspects of pre-dialysis kidney function-an abrupt transition pattern and an episode of dialysis-requiring AKI (AKI-D) leading directly to ESKD-are associated with early mortality after dialysis initiation. METHODS: We extracted national data from U.S. Veterans Health Administration cross-linked with the United States Renal Data System (USRDS) to identify patients who initiated hemodialysis during 2009-2013. We defined abrupt transition as having a mean outpatient eGFR ≥ 30 ml/min/1.73m2 within 1 year prior to ESKD. AKI-D was identified using inpatient serum creatinine measurements (serum Cr increase by at least 50% from baseline) along with billing codes for inpatient receipt of dialysis for AKI within 30 days prior to the ESKD start date. We used multivariable proportional hazards models to examine the association between patterns of kidney function prior to ESKD and all-cause mortality within 90 days after ESKD. RESULTS: Twenty-two thousand eight hundred fifteen patients were identified in the final analytic cohort of Veterans who initiated hemodialysis and entered the USRDS. We defined five patterns of kidney function decline. Most (68%) patients (N = 15,484) did not have abrupt transition and did not suffer an episode of AKI-D prior to ESKD (reference group). The remaining groups had abrupt transition, AKI-D, or both. Patients who had an abrupt transition with (N = 503) or without (N = 3611) AKI-D had the highest risk of early mortality after ESKD onset after adjustment for demographics and comorbidities (adjusted HR 2.10, 95% CI 1.66-2.65 for abrupt transition with AKI-D; adjusted HR 2.10, 95% CI 1.90-2.33 for abrupt transition without AKI-D). In contrast, patients who experienced AKI-D without an abrupt transition pattern (N = 2141 had only a modestly higher risk of early death (adjusted HR 1.19, 95% CI 1.01-1.40). CONCLUSIONS: An abrupt decline in kidney function within 1 year prior to ESKD occurred in nearly 1 in 5 incident hemodialysis patients (18%) in this national cohort of Veterans and was strongly associated with higher early mortality after ESKD onset.

NO-IL-6/10-IL-1ß axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats.

Introduction: Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). Material and methods: Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. Results: BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1ß, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1ß only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1ß inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1ß only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1ß effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1ß action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1ß regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1ß seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1ß, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1ß levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. Conclusion: Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1ß in non-steatotic livers and NO-IL-10-IL-1ß in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.

A Case Report of Primary Hepatic Tuberculosis

This case report presents an incidental finding of primary tuberculosis in the liver of a 54-year-old female patient who had a history of multiple hospital admissions due to abdominal pain, jaundice, persistent fever, nausea with vomiting, weight loss, and asthenia. The evaluation involved considering differential diagnoses of cholangiocarcinoma, Caroli's disease, hepatocellular carcinoma, and hepatic tuberculosis based on the patient's history, imaging studies, and laboratory tests. The aim of this report is to provide healthcare professionals with a new diagnostic perspective when encountering patients with this ambiguous presentation, even in regions with low epidemiological incidence. Hepatic tuberculosis should be included in the differential diagnosis of patients with focal intrahepatic lesions or liver abscesses who have a history of recurrent hospitalizations and evidence on imaging studies.

Se trata de un hallazgo incidental de tuberculosis primaria en el hígado en una paciente femenina de 54 años con historia de múltiples ingresos por síntomas de dolor abdominal, ictericia, fiebre persistente, náuseas acompañadas de vómitos de contenido gástrico, pérdida de peso y astenia. A la evaluación se consideraron los diagnósticos diferenciales de colangiocarcinoma, enfermedad de Caroli, carcinoma hepatocelular y tuberculosis hepática, basados en anamnesis, estudios de imágenes y pruebas de gabinete. Este reporte de caso brinda una nueva perspectiva diagnóstica para el personal de salud que reciba pacientes con esta presentación ambigua, aun en el contexto de baja incidencia epidemiológica. La tuberculosis hepática debe ser considerada en el diagnóstico diferencial de pacientes con lesiones focales a nivel intrahepático o abscesos hepáticos con hospitalizaciones recurrentes y evidencia de imágenes.

Effect of the Non-steroidal Anti-inflammatory Drug Diclofenac on Ischemia-Reperfusion Injury in Rat Liver: A Nitric Oxide-Dependent Mechanism.

Ischemia/reperfusion injury (IRI) is an inevitable complication of liver surgery and transplantation. The purpose of this study was to examine the beneficial effects of diclofenac on hepatic IRI and the mechanism behind it. Wistar rats' livers were subjected to warm ischemia for 60 min followed by 24 h of reperfusion. Diclofenac was administered intravenously 15 min before ischemia at 10, 20, and 40 mg/kg body weight. To determine the mechanism of diclofenac protection, the NOS inhibitor L-Nitro-arginine methyl ester (L-NAME) was administered intravenously 10 min after diclofenac injection (40 mg/kg). Liver injury was evaluated by aminotransferases (ALT and AST) activities and histopathological analysis. Oxidative stress parameters (SOD, GPX, MPO, GSH, MDA, and PSH) were also determined. Then, eNOS gene transcription and p-eNOS and iNOS protein expressions were evaluated. The transcription factors PPAR-γ and NF-κB in addition to the regulatory protein IκBα were also investigated. Finally, the gene expression levels of inflammatory (COX-2, IL-6, IL-1ß, IL-18, TNF-α, HMGB-1, and TLR-4) and apoptosis (Bcl-2 and Bax) markers were measured. Diclofenac, at the optimal dose of 40 mg/kg, decreased liver injury and maintained histological integrity. It also reduced oxidative stress, inflammation, and apoptosis. Its mechanism of action essentially depended on eNOS activation rather than COX-2 inhibition, since pre-treatment with L-NAME abolished all the protective effects of diclofenac. To our knowledge, this is the first study demonstrating that diclofenac protects rat liver against warm IRI through the induction of NO-dependent pathway. Diclofenac reduced oxidative balance, attenuated the activation of the subsequent pro-inflammatory response and decreased cellular and tissue damage. Therefore, diclofenac could be a promising molecule for the prevention of liver IRI.

Systolic blood pressure, antihypertensive treatment, and cardiovascular and mortality risk in VA nursing home residents.

BACKGROUND: Optimal systolic BP (SBP) control in nursing home residents is uncertain, largely because this population has been excluded from clinical trials. We examined the association of SBP levels with the risk of cardiovascular (CV) events and mortality in Veterans Affairs (VA) nursing home residents on different numbers of antihypertensive medications. METHODS: Our study included 36,634 residents aged ≥65 years with a VA nursing home stay of ≥90 days from October 2006-June 2019. SBP was averaged over the first week after admission and divided into categories. Cause-specific hazard ratios (HRs) of SBP categories with CV events (primary outcome) and all-cause mortality (secondary outcome) were examined using Cox regression and multistate modeling stratified by the number of antihypertensive medications used at admission (0, 1 or 2, and ≥3 medications). RESULTS: More than 76% of residents were on antihypertensive therapy and 20% received ≥3 medications. In residents on antihypertensive therapy, a low SBP < 110 mmHg (compared with SBP 130 ~ 149 mmHg) was associated with a greater CV risk (adjusted HR [95% confidence interval]: 1.47 [1.28-1.68] in 1 or 2 medications group, and 1.41 [1.19-1.67] in ≥3 medications group). In residents on no antihypertensives, both low SBP < 110 mmHg and high SBP ≥ 150 mmHg were associated with higher mortality; while in residents receiving any antihypertensives, a low SBP was associated with higher mortality and the highest point estimates were for SBP < 110 mmHg (1.36 [1.28-1.45] in 1 or 2 medications group, and 1.47 [1.31-1.64] in ≥3 medications group). CONCLUSIONS: The associations of SBP with CV and mortality risk varied by the intensity of antihypertensive treatment among VA nursing home residents. A low SBP among those receiving antihypertensives was associated with increased CV and mortality risk, and untreated high SBP was associated with higher mortality. More research is needed on the benefits and harms of SBP lowering in long-term care populations.

Improving chronic kidney disease detection and treatment in the United States: the chronic kidney disease cascade of care (C3) study protocol.

BACKGROUND: There are major gaps in the implementation of guideline-concordant care for persons with chronic kidney disease (CKD). The CKD Cascade of Care (C3) initiative seeks to improve CKD care by improving detection and treatment of CKD in primary care. METHODS: C3 is a multi-modal initiative deployed in three major academic medical centers within the Department of Veterans Affairs (VA) Health Care System: San Francisco VA, San Diego VA, and Houston VA. The main objective of the first phase of C3 described in this protocol is to establish the infrastructure for universal CKD detection among primary care patients at high-risk for CKD with a triple-marker screen comprising cystatin C, creatinine, and albuminuria. Across the three sites, a comprehensive educational intervention and the integration of primary care-based clinical champions will be employed with the goal of improving CKD detection and treatment. The San Francisco VA will also implement a practice-facilitation intervention leveraging telehealth and health informatics tools and capabilities for enhanced CKD detection. Parallel formative evaluation across the three sites will assess the feasibility and acceptability of integrating cystatin C as part of routine CKD detection in primary care practice. The effectiveness of the interventions will be assessed using a pre-post observational design for change in the proportion of patients tested annually for CKD. Secondary outcomes will assess change in the initiation of cardio-kidney protective therapies and in nephrology referrals of high-risk patients. DISCUSSION: The first phase of C3 is a multi-facility multi-modal initiative that aims to improve CKD care by implementing a triple-marker screen for enhanced CKD detection in primary care.

A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation.

The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs.

Association of Race and Ethnicity With Prescription of SGLT2 Inhibitors and GLP1 Receptor Agonists Among Patients With Type 2 Diabetes in the Veterans Health Administration System.

Importance: Novel therapies for type 2 diabetes can reduce the risk of cardiovascular disease and chronic kidney disease progression. The equitability of these agents' prescription across racial and ethnic groups has not been well-evaluated. Objective: To investigate differences in the prescription of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) among adult patients with type 2 diabetes by racial and ethnic groups. Design, Setting, and Participants: Cross-sectional analysis of data from the US Veterans Health Administration's Corporate Data Warehouse. The sample included adult patients with type 2 diabetes and at least 2 primary care clinic visits from January 1, 2019, to December 31, 2020. Exposures: Self-identified race and self-identified ethnicity. Main Outcomes and Measures: The primary outcomes were prevalent SGLT2i or GLP-1 RA prescription, defined as any active prescription during the study period. Results: Among 1 197 914 patients (mean age, 68 years; 96% men; 1% American Indian or Alaska Native, 2% Asian, Native Hawaiian, or Other Pacific Islander, 20% Black or African American, 71% White, and 7% of Hispanic or Latino ethnicity), 10.7% and 7.7% were prescribed an SGLT2i or a GLP-1 RA, respectively. Prescription rates for SGLT2i and GLP-1 RA, respectively, were 11% and 8.4% among American Indian or Alaska Native patients; 11.8% and 8% among Asian, Native Hawaiian, or Other Pacific Islander patients; 8.8% and 6.1% among Black or African American patients; and 11.3% and 8.2% among White patients, respectively. Prescription rates for SGLT2i and GLP-1 RA, respectively, were 11% and 7.1% among Hispanic or Latino patients and 10.7% and 7.8% among non-Hispanic or Latino patients. After accounting for patient- and system-level factors, all racial groups had significantly lower odds of SGLT2i and GLP-1 RA prescription compared with White patients. Black patients had the lowest odds of prescription compared with White patients (adjusted odds ratio, 0.72 [95% CI, 0.71-0.74] for SGLT2i and 0.64 [95% CI, 0.63-0.66] for GLP-1 RA). Patients of Hispanic or Latino ethnicity had significantly lower odds of prescription (0.90 [95% CI, 0.88-0.93] for SGLT2i and 0.88 [95% CI, 0.85-0.91] for GLP-1 RA) compared with non-Hispanic or Latino patients. Conclusions and Relevance: Among patients with type 2 diabetes in the Veterans Health Administration system during 2019 and 2020, prescription rates of SGLT2i and GLP-1 RA medications were low, and individuals of several different racial groups and those of Hispanic ethnicity had statistically significantly lower odds of receiving prescriptions for these medications compared with individuals of White race and non-Hispanic ethnicity. Further research is needed to understand the mechanisms underlying these differences in rates of prescribing and the potential relationship with differences in clinical outcomes.

Prescription Patterns of Cardiovascular- and Kidney-Protective Therapies Among Patients With Type 2 Diabetes and Chronic Kidney Disease.

OBJECTIVE: To assess the prevalence and correlates of prescription of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and/or glucagon-like peptide 1 receptor agonists (GLP1-RA) in individuals with type 2 diabetes mellitus (T2DM) with and without chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: This was a cross-sectional analyses of SGLT2i and GLP1-RA prescriptions from 1 January 2019 to 31 December 2020 in the Veterans Health Administration System. The likelihood of prescriptions was examined by the presence or absence of CKD and by predicted risks of atherosclerotic cardiovascular disease (ASCVD) and end-stage kidney disease (ESKD). RESULTS: Of 1,197,880 adults with T2DM, SGLT2i and GLP1-RA were prescribed to 11% and 8% of patients overall, and to 12% and 10% of those with concomitant CKD, respectively. In adjusted models, patients with severe albuminuria were less likely to be prescribed SGLT2i or GLP1-RA versus nonalbuminuric patients with CKD, with odds ratios (ORs) of 0.91 (95% CI 0.89, 0.93) and 0.97 (0.94, 1.00), respectively. Patients with a 10-year ASCVD risk >20% (vs. <5%), had lower odds of SGLT2i use (OR 0.66 [0.61, 0.71]) and GLP1-RA prescription (OR 0.55 [0.52, 0.59]). A 5-year ESKD risk >5%, compared with <1%, was associated with lower likelihood of SGLT2i prescription (OR 0.63 [0.59, 0.67]) but higher likelihood of GLP1-RA prescription (OR 1.53 [1.46, 1.61]). CONCLUSIONS: Among a large cohort of patients with T2DM, prescription of SGLT2i and GLP1-RA was low in those with CKD. We observed a "risk-treatment paradox," whereby patients with higher risk of adverse outcomes were less likely to receive these therapies.

Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial.

BACKGROUND: Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail. METHODS: We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables. RESULTS: Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function. CONCLUSIONS: Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR.

The Role of Neuregulin-1 in Steatotic and Non-Steatotic Liver Transplantation from Brain-Dead Donors.

BACKGROUND: Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). METHODS: NRG1 pathways were characterized after surgery. RESULTS: NRG1 and p21-activated kinase 1 (PAK1) levels increased in steatotic and non-steatotic grafts from DBDs. The abolishment of NRG1 effects reduced PAK1. When the effect of either NRG1 nor PAK1 was inhibited, injury and regenerative failure were exacerbated. The benefits of the NRG-1-PAK1 axis in liver grafts from DBDs were associated with increased vascular endothelial growth factor-A (VEGFA) and insulin growth factor-1 (IGF1) levels, respectively. Indeed, VEGFA administration in non-steatotic livers and IGF1 treatment in steatotic grafts prevented damage and regenerative failure resulting from the inhibition of either NRG1 or PAK-1 activity in each type of liver. Exogenous NRG1 induced greater injury than BD induction. CONCLUSIONS: This study indicates the benefits of endogenous NRG1 in liver grafts from DBDs and underscores the specificity of the NRG1 signaling pathway depending on the type of liver: NRG1-PAK1-VEGFA in non-steatotic livers and NRG1-PAK1-IGF1 in steatotic livers. Exogenous NRG1 is not an appropriate strategy to apply to liver grafts from DBD.

Trends in blood pressure diagnosis, treatment, and control among VA nursing home residents, 2007-2018.

BACKGROUND: Inadequate treatment of high blood pressure (BP) can lead to preventable adverse events in nursing home residents, while excessive treatment can lead to associated harms. METHODS: Data were extracted from the VA electronic health record and Bar Code Medication Administration system on 40,079 long-term care residents aged ≥65 years from October 2006 through September 2018 (FY2007-2018). Hypertension prevalence at admission was identified by ICD code(s) in the year prior, and antihypertensive medication use was defined as administration ≥50% of days. BP measures were averaged over 2-year epochs. RESULTS: The age-standardized prevalence of hypertension diagnosis at admission increased from 75.2% in FY2007-2008 to 85.1% in FY2017-2018 (p-value for trend <0.001). Rates of BP treatment and control among residents with hypertension at admission declined slightly over time (p-values for trend <0.001) but remained high (80.3% treated in FY2017-2018, 80.1% with average BP <140/90 mmHg). The age-adjusted prevalence of chronic low BP (average <90/60 mmHg) also declined from 11.1% in FY2007-2008 to 4.7% in FY2017-2018 (p-value for trend <0.001). Persons identified as Black race or Hispanic ethnicity and those with a history of diabetes, stroke, and renal disease were less likely to have an average BP <140/90 mmHg. CONCLUSIONS: Hypertension is well controlled in VA nursing homes, and recent trends of less intensive BP control were accompanied by a lower prevalence of chronic low BP. Nonetheless, some high-risk populations have average BP levels >140/90 mmHg. Future research is needed to better understand the benefits and harms of BP control in nursing home residents.

Association of Antihypertensives and Cognitive Impairment in Long-Term Care Residents.

BACKGROUND: Certain classes of antihypertensive medication may have different associations with cognitive impairment. OBJECTIVE: To examine the association between prevalent use of antihypertensive medications that stimulate (thiazides, dihydropyridine calcium channel blockers, angiotensin type I receptor blockers) versus inhibit (angiotensin-converting enzyme inhibitors, beta-blockers, non-dihydropyridine calcium channel blockers) type 2 and 4 angiotensin II receptors on cognitive impairment among older adults residing in Veterans Affairs (VA) nursing homes for long-term care. METHODS: Retrospective cohort study. Long-term care residents aged 65 + years admitted to a VA nursing home from 2012 to 2019 using blood pressure medication and without cognitive impairment at admission. Main exposure was prevalent use of angiotensin II receptor type 2 and 4-'stimulating' (N = 589), 'inhibiting' (N = 3,219), or 'mixed' (N = 1,715) antihypertensive medication regimens at admission. Primary outcome was any cognitive impairment (Cognitive Function Scale). RESULTS: Over an average of 5.4 months of follow-up, prevalent use of regimens containing exclusively 'stimulating' antihypertensives was associated with a lower risk of any incident cognitive impairment as compared to prevalent use of regimens containing exclusively 'inhibiting' antihypertensives (HR 0.83, 95% CI 0.74-0.93). Results for the comparison between 'mixed' versus 'inhibiting' regimens were in the same direction but not statistically significant (HR 0.96, 95% CI 0.88-1.06). CONCLUSION: For residents without cognitive impairment at baseline, prevalent users of regimens containing exclusively antihypertensives that stimulate type 2 and 4 angiotensin II receptors had lower rates of cognitive impairment as compared to prevalent users of regimens containing exclusively antihypertensives that inhibit these receptors. Residual confounding cannot be ruled out.

Exploring the Dynamics of Week-to-Week Blood Pressure in Nursing Home Residents Before Death.

BACKGROUND: Aging is accompanied by an overall dysregulation of many dynamic physiologic processes including those related to blood pressure (BP). While year-to-year BP variability is associated with cardiovascular events and mortality, no studies have examined this trend with more frequent BP assessments. Our study objective is to take the next step to examine week-to-week BP dynamics-pattern, variability, and complexity-before death. METHODS: Using a retrospective study design, we assessed BP dynamics in the 6 months before death in long-term nursing home residents between 1 October 2006 and 30 September 2017. Variability was characterized using SD and mean squared error after adjusting for diurnal variations. Complexity (i.e., amount of novel information in a trend) was examined using Shannon's entropy (bits). Generalized linear models were used to examine factors associated with overall BP variability. RESULTS: We identified 17,953 nursing home residents (98.0% male, 82.5% White, mean age 80.2 years, and mean BP 125.7/68.6 mm Hg). Despite a slight trend of decreasing systolic week-to-week BP over time (delta = 7.2 mm Hg), week-to-week complexity did not change in the 6 months before death (delta = 0.02 bits). Average weekly BP variability was stable until the last 3-4 weeks of life, at which point variability increased by 30% for both systolic and diastolic BP. Factors associated with BP variability include average weekly systolic/diastolic BP, days in the nursing home, days in the hospital, and changes to antihypertensive medications. CONCLUSIONS: Week-to-week BP variability increases substantially in the last month of life, but complexity does not change. Changes in care patterns may drive the increase in BP variability as one approaches death.

Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models. APPROACH AND RESULTS: Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations. CONCLUSIONS: Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.

Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection.

Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.