Chronic Diabetes Research Articles

The prognostic role of the index of global left ventricular function and its companion in patients with chronic heart failure and diabetes mellitus

The index of global left ventricular function (LV IGF) is an imaging marker with pronounced prognostic properties in relation to the development of adverse cardiovascular events and death, determined on the basis of data from both magnetic resonance imaging (MRI) of the heart and echocardiographic examination (EchoCG). Companion indicator (companion) LV IGF (LV IGFC) is a marker obtained from the average quadratic value of the sum of the impact and global LV volume, designed to overcome the limitations of LV IGF due to its calculation formula.The aim. To evaluate the prognostic significance of LV IGF and its companion in patients aged 60 years and older with CHF and type 2 diabetes mellitus observed in outpatient settings.Material and methods. The study included 215 outpatient patients: 110 (51.2%) men and 105 (48.8%) women aged 72 (67; 78) years with CHF IIa–III stage II–IV FC. And LVH (in %) was calculated using the formula: EG LV = (KDO LV–CSR LV)/[0.5=(UP TO LV+CSR LV)+(MMLJ/1.05)]=100. IGFC LJ = {(KDO LJ-CSR LJ)2+[0.5×(BDO LJ+CSR LJ)+(MMLJ/1.05)]2}0.5. The duration of the observation period was 29 (20; 36) months.Results. LV IGF as a whole amounted to 20.6 (16.9; 23.2)%. LV IGF as a whole amounted to 313.8 (262.8; 400.0) ml. Depending on the presence or absence of DM, patients were divided into two groups: 68 patients with DM (group 1); 147 patients without DM (group 2). During the follow–up period of 29 (20; 36) months, 122 (56.7%) patients were hospitalized: in group 1–32 out of 68 (47.1%) patients; in group 2–90 out of 147 (61.2%) patients. The threshold value of LV IGF for predicting hospitalization due to CVD decompensation in group 1 patients was 21.4% or lower (area under the curve [PPK] 0.677±0.065, 95% CI 0.549–0.805, p=0.012; sensitivity 68.8%, specificity 61.1%); LV IGFC – 300.3 ml or more (PPK 0.666±0.067, 95% CI 0.535–0.797, p=0.019; sensitivity 62.5%, specificity 61.1%). There was a high rate of hospitalization due to CVD decompensation in group 1 with LV IGF of 21.4% or less (among patients with LV IGF of ≤21.4%, 59.5% of patients were hospitalized, more than 21.4% –32.3%) (OR 3.08, p<0.05); with LV IGFC of 300.3 ml or more (among patients with LV IGFC ≥300.3 ml, 58.8% of patients were hospitalized, less than 300.3 ml – 35.3%) (OR 2.62, p>0.05).Conclusion. The threshold value of LV IGF for predicting decompensation of cardiovascular disease with subsequent hospitalization in patients 60 years and older with CHF and DM was ≤21.4%; LV IGF was ≥300.3 ml. The data obtained allow us to consider LV IGF, LV IGFC, as well as their combination as markers of an unfavorable prognosis in older patients with CHF and DM at the outpatient stage.

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review).

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low‑density lipoprotein‑cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti‑PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.

Integrating Genome-Wide Polygenic Risk Scores With Nongenetic Models to Predict Surgical Site Infection After Total Knee Arthroplasty Using United Kingdom Biobank Data

BackgroundPrediction of the risk of developing surgical site infection (SSI) in patients following total knee arthroplasty (TKA) is of clinical importance. Genetic susceptibility is involved in developing TKA-related SSI. Previously reported models for predicting SSI were constructed using nongenetic risk factors without incorporating genetic risk factors. To address this issue, we performed a genome-wide association study (GWAS) using the UK Biobank database. MethodsAdult patients who underwent primary TKA (n = 19,767) were analyzed and divided into SSI (n = 269) and non-SSI (n = 19,498) cohorts. Nongenetic covariates, including demographic data and preoperative comorbidities, were recorded. Genetic variants associated with SSI were identified by GWAS and included to obtain standardized polygenic risk scores (zPRS, an estimate of genetic risk). Prediction models were established through analyses of multivariable logistic regression and the receiver operating characteristic curve. ResultsThere were 4 variants (rs117896641, rs111686424, rs8101598, and rs74648298) achieving genome-wide significance that were identified. The logistic regression analysis revealed 7 significant risk factors: increasing zPRS, decreasing age, men, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, and peripheral vascular disease. The areas under the receiver operating characteristic curve were 0.628 and 0.708 when zPRS (model 1) and nongenetic covariates (model 2) were used as predictors, respectively. The areas under the receiver operating characteristic curve increased to 0.76 when both zPRS and nongenetic covariates (model 3) were used as predictors. A risk-prediction nomogram was constructed based on model 3 to visualize the relative effect of statistically significant covariates on the risk of SSI and predict the probability of developing SSI. Age and zPRS were the top 2 covariates that contributed to the risk, with younger age and higher zPRS associated with higher risks. ConclusionsOur GWAS identified 4 novel variants that were significantly associated with susceptibility to SSI following TKA. Integrating genome-wide zPRS with nongenetic risk factors improved the performance of the model in predicting SSI.

Risk Factors for Hydroxychloroquine Retinopathy and Its Subtypes

ImportanceThe major toxic effect of hydroxychloroquine is retinopathy. Thus, current guidelines recommend limiting the dose and screening annually for retinopathy among all long-term users, but individual patient factors may be associated with retinopathy risk.ObjectiveTo identify risk factors beyond hydroxychloroquine dose and duration of use for hydroxychloroquine retinopathy.Design, Setting, and ParticipantsThis cohort study of 4677 patients in the Kaiser Permanente Northern California integrated health network who initiated hydroxychloroquine, continued treatment, and underwent retinopathy screening after 5 years of use was conducted from July 1, 1997, to December 31, 2020, with up to 15 years of follow-up. Statistical analysis was performed in August 2023.ExposureCandidate risk factors included age at hydroxychloroquine initiation, sex, race and ethnicity, indications, chronic kidney disease (CKD), liver disease, diabetes, tamoxifen use, and medications that interact with hydroxychloroquine metabolism. Hydroxychloroquine dose was assessed from pharmacy dispensing records.Main Outcome and MeasuresIncident hydroxychloroquine retinopathy was adjudicated from masked review of guideline-recommended screening studies and classified as parafoveal or pericentral pattern. Multivariable Cox proportional hazards regression was used to assess potential risk factors for hydroxychloroquine retinopathy within 15 years of initiation.ResultsOf 4677 long-term hydroxychloroquine users (mean [SD] age at initiation, 52.4 [14.1] years; 3877 women [82.9%]), 125 patients developed hydroxychloroquine retinopathy within 15 years (102 parafoveal, 23 pericentral). Older age at time of hydroxychloroquine initiation was associated with retinopathy risk, with adjusted hazard ratios (HRs) of 2.48 (95% CI, 1.28-4.78) for those aged 45 to 54 years, 3.82 (95% CI, 2.05-7.14) for those aged 55 to 64 years, and 5.68 (95% CI, 2.99-10.79) for those aged 65 years or older compared with those younger than 45 years. The risk of retinopathy was higher among females than males (HR, 3.83 [95% CI, 1.86-7.89]), among patients with CKD stage 3 or greater (HR, 1.95 [95% CI, 1.25-3.04]), and among individuals with tamoxifen use (HR, 3.43 [95% CI, 1.08-10.89]). The likelihood of pericentral retinopathy was higher among Asian patients (HR, 15.02 [95% CI, 4.82-46.87]) and Black patients (HR, 5.51 [95% CI, 1.22-24.97]) compared with non-Hispanic White patients.Conclusions and RelevanceThis study suggests that increasing age, female sex, CKD stage 3 or greater, and tamoxifen use were associated with a higher risk of hydroxychloroquine retinopathy, whereas being younger than 45 years at hydroxychloroquine initiation and male sex were associated with a lower risk. Race and ethnicity were also associated with the pattern of retinopathy. These factors should be incorporated into hydroxychloroquine dosing decisions.

Intravenous angiotensin II as an add-on to standard of care vasopressors in patients with refractory shock on mechanical circulatory support: a single centre retrospective case series

Abstract Funding Acknowledgements None. Background Refractory shock is life-threatening condition characterized by hypotension with mean arterial pressure (MAP) less than 65 mmHg and end-organ dysfunction, despite volume resuscitation and high doses of vasopressors. Mortality rates in refractory shock exceeds 90%. Angiotensin II (Ang II) is a non-catecholamine vasopressor that targets the renin-angiotensin-aldosterone system by agonism of the angiotensin type 1 receptors. Ang II has been studied in settings of vasodilatory shock, however there is paucity of data regarding the usage of Ang II in patients with preexisting heart failure or in patients requiring mechanical circulatory support (MCS), either short term such as venoarterial extracorporeal membrane oxygenation (VA-ECMO) or long term such as left ventricular assist device (LVAD) (1,2). Purpose This report is aimed to analyse baseline characteristics of patients who have received Ang II from the moment it became available in our institution (January 2023). Methods Five patients were included in this retrospective analyses. Demographic, clinical and laboratory parameters as well as hourly changes of vasopressors doses, MAP, lactates, and diuresis were collected and analysed. Results Median age of 5 included patients, 4 of whom were male, was 53 years old (range 18-57). The most common comorbidities were chronic kidney disease (n=3), diabetes mellitus (n=3) and arterial hypertension (n=3), treated with valsartan as chronic therapy. All patients presented with severe shock. 4 patients were on VA-ECMO support, 1 had additionally implanted Impella for left ventricular unloading and 2 had implanted LVAD. All patients had severely reduced left ventricular ejection fraction (median 15%, range 10-25%). In 4 cases vasopressors were initiated due to sepsis and in 1 case during cardiopulmonary resuscitation. Median values prior to administration of Ang II were as following: MAP 51 mmHg (range 41-56 mmHg), lactates 6.7 mmol/L (range 2.4-10.7 mmol/L) and Sequential Organ Failure Assessment (SOFA) score 9 (range 5-11). Four hours following administration of Ang II median MAP was 61 mmHg (range 54-77 mmHg). Patient who ultimately survived had better response to Ang II, with median rise of MAP of 22 mmHg (range 12-22 mmHg). In contrast, patients who ultimately died didn’t respond to Ang II, with rise of MAP of only 2.5 mmHg. Median duration of Ang II administration was 52 h (range 20-96 h). 60% of patients are alive up to the present day. Complete patient data are shown in Table 1. Hourly changes of vasopressor doses and MAP are shown in Figure 1. Conclusion Ang II is an effective vasopressor with rapid effect. This case series suggests that it may be considered as salvage treatment option in patients on MCS with refractory shock. Patients who responded to Ang II had better survival, similar to previous findings. Therefore, Ang II should be considered in earlier phases of shock when maximum doses of vasopressors have not yet been reached.

Polyvascular disease is common in patients undergoing carotid endarterectomy and lower extremity bypass and is associated with worse outcomes

BackgroundPolyvascular disease is strongly associated with increased risk of cardiovascular morbidity and mortality. However, its prevalence in patients undergoing carotid and lower extremity surgical revascularization and its impact on outcomes are unknown. MethodsThe Vascular Quality Initiative was queried for carotid endarterectomy (CEA) or infrainguinal lower extremity bypass (LEB), 2013-2019. Polyvascular disease was defined as presence of atherosclerotic occlusive disease in more than one arterial bed: carotid, coronary, and infrainguinal. Primary outcomes were (1) composite perioperative myocardial infarction (MI) or death and (2) 5-year survival. Patient characteristics and perioperative outcomes were evaluated using the χ2 test and multivariable logistic regression. Survival was analyzed using Kaplan-Meier method and Cox proportional hazards multivariable models. ResultsPolyvascular disease was identified in 47% of CEA (39.0% in 2 arterial beds, 7.6% in 3 arterial beds; n = 93,736) and 47% of LEB (41.0% in 2 arterial beds, 5.7% in 3 arterial beds; n = 25,223). For both CEA and LEB, patients with polyvascular disease had more comorbidities including hypertension, congestive heart disease, chronic obstructive pulmonary disease, smoking, diabetes mellitus, and end-stage renal disease (P < .0001). Perioperative MI/death rates increased with increasing number of vascular beds affected following CEA (0.9% in 1 bed vs 1.5% in 2 beds vs 2.7% in 3 beds; P < .001) and LEB (2.2% in 1 bed vs 5.3% in 2 beds vs 6.6% in 3 beds; P < .001). Polyvascular disease was associated independently with perioperative MI/death after CEA (odds ratio, 1.59; 95% confidence interval [CI], 1.40-1.81;P < .0001) and LEB (odds ratio, 1.78; 95% CI, 1.52-2.08; P < .0001). Five-year survival was decreased in patients with polyvascular disease after CEA (82% in 3 beds vs 88% in 2 beds vs 92% in 1 bed; P < .01) and LEB (72% in 3 beds vs 75% in 2 beds vs 84% in 1 bed; P < .01) in a dose-dependent manner, with the lowest 5-year survival observed in those with three arterial beds involved. Polyvascular disease was independently associated with 5-year mortality after CEA (hazard ratio, 1.33; 95% CI, 1.24-1.40; P = .0001) and LEB (hazard ratio, 1.30; 95% CI, 1.20-1.41; P = .0001). ConclusionsPolyvascular disease is common in patients undergoing CEA and LEB and is associated with a higher risk of perioperative MI/death and decreased long-term survival. After revascularization, patients with polyvascular disease should be considered for more aggressive cardioprotective medications and closer follow-up.

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation

BackgroundDiabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism.Methods and resultsMice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα).ConclusionThese findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Complications associated with HCV-related liver cirrhosis and their relationship with diabetic control. A tertiary care center study in Peshawar, Pakistan.

Objective: To determine the frequencies of liver cirrhosis-associated complications in patients with HCV+ diabetic patients and its association with HbA1C. Study Design: Observational Cross-sectional study. Setting: Medical Wards of Khyber Teaching Hospital. Period: October 2019 to November 2020. Methods: After approval from the hospital ethical committee, all HCV positive diabetic patients were enrolled in the study. Informed consent was obtained and relevant examination was performed. Hematemesis was diagnosed clinically, while venous blood was sent for all routine and relevant specialized investigations. Twenty-four-hour urinary output was calculated. Abdominal ultrasounds and Triphasic CT abdomen were done where required. Data were collected on structurally designed proforma. All data were entered into SPSS version 22. Results: A total of 62 patients were enrolled. The mean age was 49. 23 years ± 11.72 SD. Twenty-three patients (37.1%) were males, while 39 patients (62.9%) were females. Forty-nine patients (79%) were PCR-positive for HCV. Most patients (58.1%) had less than five years duration of HCV. Frequency of SBP was 16.1%, hepatic encephalopathy was 22.6%, ascites was 40.3%, hematemesis was 11.3%, portal vein hypertension was 45.2%, and HCC 3.2%. On post-stratification, significant associations emerged with age, where SBP (p &lt;0.01), hepatic encephalopathy (p&lt;0.001), and ascites (p&lt;0.0001), increased with advancing age, while hematemesis (p&lt;0.04) and portal vein hypertension (p&lt;0.04) were more pronounced in younger patients. Conclusion: In conclusion, individuals with both chronic HCV and diabetes mellitus exhibit an increased risk of cirrhosis-related complications. The most common complication was portal vein hypertension followed by ascites and hepatic encephalopathy. The complications like SBP, Hepatic encephalopathy and ascites associated with increasing age.

Comparative Cardiovascular Risks of Febuxostat and Allopurinol in Patients with Diabetes Mellitus and Chronic Kidney Disease.

BACKGROUND Hyperuricemia, which is common in chronic kidney disease and diabetes mellitus patients, raises health concerns. Febuxostat, a first-line urate-lowering agent, prompts cardiovascular risk questions, especially in high-risk patients. This study compared the effects of febuxostat and allopurinol on cardiovascular risk in diabetes mellitus and chronic kidney disease patients. MATERIAL AND METHODS This retrospective observational cohort study, conducted using Taiwan's National Health Insurance Research Database, focused on patients diagnosed with chronic kidney disease and diabetes between January 2012 and December 2017. The study population was divided into 2 groups: allopurinol users (n=12 901) and febuxostat users (n=2997). We performed 1: 1 propensity score matching, resulting in subgroups of 2997 patients each. The primary outcomes were assessed using a competing risk model, estimating hazard ratios (HR) for long-term outcomes, including the risks of all-cause hospitalization, hospitalization for heart failure, and hospitalization for cardiovascular interventions. RESULTS Febuxostat users, compared to allopurinol users, had higher all-cause hospitalization (HR: 1.33; 95% confidence interval [CI]: 1.25 to 1.42; P<.001), hospitalization for heart failure (HR: 1.62; 95% CI: 1.43 to 1.83; P<.001), and hospitalization for cardiovascular interventions (HR: 1.51; 95% CI: 1.32 to 1.74; P<.001). Moreover, the adverse effects of febuxostat on cardiac health were consistent across most subgroups. CONCLUSIONS Use of febuxostat in patients with diabetes mellitus and chronic kidney disease is associated with higher cardiovascular risks compared to allopurinol. Prudent evaluation is essential when recommending febuxostat for this at-risk group.

EXERCISE PRESCRIPTION TO SUPPORT THE MANAGEMENT OF OSTEOPOROSIS: AN EXPERT STATEMENT FOR EXERCISE PHYSIOLOGISTS

INTRODUCTION &amp; AIMS Low bone density, which includes osteopenia and osteoporosis, leads to roughly 183,000 fractures annually in Australia, with associated direct costs of $2.59B. Osteoporosis is underdiagnosed. Exercise is effective therapy but is underutilised due to a lack of knowledge and unfounded concerns about risk of injury. The aim of the newly developed Exercise Prescription for the Prevention of Osteoporosis Fracture National Statement is to provide clear, actionable, evidence-based exercise advice to improve the bone health of people living with osteopenia and osteoporosis. The project was led and supported by Healthy Bones Australia with funding awarded by the Australian Government Department of Health, Public Health and Chronic Disease Program Osteoporosis – Education and Prevention. METHODS An expert working group (scientists, AEP, physiotherapist, endocrinologist and orthopaedic resident) and advisory committee (practising AEPs and physiotherapists) reviewed current evidence and existing guidelines to formulate recommendations for a national statement in the Australian context. A National Exercise Roundtable was convened, including consumers and stakeholders across multiple disciplines, to adapt the recommendations for clinical practice and consumer acceptability. RESULTS The final statement is presented as an evidence-based document, and a 2-page user summary. The Statement outlines the general principles of osteogenic loading and falls prevention, then presents a comprehensive exercise prescription based on those principles, along with special considerations for comorbid conditions. Level A consensus was achieved on five summary statements. CONCLUSION Bone health is an essential part of general health. While exercise prescription for other chronic diseases, such as, heart health and diabetes, is quite well established, there is a care gap for bone which we have addressed. Our National Statement, informed by high level evidence and expert insight, delivers best practice for prescribing exercise for osteoporosis to achieve best patient outcomes. We will present the document to the intended end users – exercise physiologists.

PULSE PRESSURE DYNAMICS: UNRAVELING THE IMPACT ON TARGET ORGAN DAMAGE, INDEPENDENT OF MEAN ARTERIAL PRESSURE

Objective: As individuals age, pulse pressure (PP) naturally increases due to arteriosclerosis and diffuse vascular stiffening. In the absence of an identifiable cause, a wide PP signals target organ damage (TOD) and adverse clinical outcomes. While hypertension is endemic in South Asia, there is paucity of data regarding determinants of PP and relationship with TOD in this region. We therefore aimed to explore the determinants of PP in an ambulatory patient population. Design and method: We analysed electronic medical records of subjects (n=8,362, 64% females 64%) attending a Medicine outpatient Department (OPD) at Shalamar Hospital, a tertiary care hospital, in Lahore, Pakistan during the period September 1st, 2021 to September 30th, 2023. Haemodynamic data included single measure of systolic and diastolic BP and heart rate. HTN was defined according to ESH and ACC guidelines. History of CVD included ishaemic heart disease and stroke. Relationshp between variables was analysed using univariate and multivariate analysis. Pp was analysed both as a continuous and categorical variable (&gt;50, mm Hg). Results: Of the 8,362 subjects attending the OPD, 62% and 100% had a diagnosis of HTN as per ESH and ACC guidelines, respectively. PP&gt;50, mm Hg was present in 56% and 45% of HTN as defined by ESH and ACC respectively. PP&gt;50, mm Hg was associated with age (OR=2.7), female gender (OR=1.46), chronic kidney disease (CKD, OR= 3.6), CVD (OR=1.47) and diabetes mellitus (DM, OR=1.54). In a stepwise regression model, age, gender, heart rate, DM, CKD and CVD were associated with PP, independent of mean arterial pressure (R2=0.45, p&lt;0.0001). Conclusions: To the best of our knowledge, this is the first large study, exploring the determinants of PP in Pakistan. While the study is retrospective, using single office BP measurements, it highlights the importance of PP as an independent predictor of TOD. Prospective studies are the need of the hour to elucidate the pathophysiology and outcome of high PP in this population.

Upregulation of the Urotensin II System in Diabetic Kidney Disease Includes Urotensin II-Related Peptide

The urotensin II (UII) system consists of endogenous ligands UII and its paralog urotensin II-related peptide (URP) and their receptor, UT. Originally isolated from the rat brain, URP is conserved across all vertebrates and shares the same cyclic hexapeptide core sequence with UII. However, UII and URP exhibit different N-terminal amino acid sequences. Beyond the central nervous system, UII and URP are functionally expressed in peripheral tissues. Alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been associated with cardiovascular, pulmonary, and kidney dysfunctions, including hypertension, chronic heart failure, pulmonary hypertension, glomerulonephritis, and diabetes, making the UII system a potential therapeutic target for cardiovascular and kidney disease. The skeletal muscle and plasma levels of UII are increased in diabetic mice. Increased kidney tissue expression levels of UII and UT have also been demonstrated in humans and animals with diabetic kidney disease (DKD). Our recent work showed that UT is functionally expressed in cultured mouse glomerular mesangial cells (GMCs). Activation of UT by UII contributes to Ca2+-dependent GMC proliferation and extracellular matrix protein accumulation under high glucose conditions. We have also shown that DKD is attenuated in UT knockout mice. Despite the structural homology between UII and URP, studies have shown that the peptides may exhibit differential central and peripheral expression and pathophysiological function. However, whether URP is dysregulated in DKD remains unclear. Here, we examined whether URP production and kidney expression levels are altered in a hyperglycemic milieu and associated with DKD. Using a streptozotocin (STZ)-induced diabetes model, we examined the kidney tissue, plasma, and urinary levels of UII peptides. We also tested the hypothesis that, like UII, URP stimulates GMC proliferation and matrix protein synthesis. Our data show that protein and mRNA expression levels of both UII and URP were increased in the kidneys of hyperglycemic mice that developed albuminuria. Urinary and plasma UII and URP concentrations were also elevated in the mice. Although both UII and URP stimulated proliferation and type IV collagen production in cultured mouse GMCs by activating UT, the effect of UII was greater. Our data suggests that changes in the UII system in DKD are not limited to UII and UT but include the less-studied URP. GMC proliferation and extracellular matrix accumulation driven by UII and URP may contribute to DKD. NHLBI: R01 HL151735. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prevalence and predictors of polypharmacy in elderly patients discharged from a tertiary care teaching hospital in Swat, Pakistan: A retrospective cross-sectional study

Background: The use of polypharmacy in the elderly has been the subject of much consideration in recent years. However, its prevalence and risk factors are yet to be properly investigated in Pakistan. Objective: The study investigated the prevalence and risk factors of polypharmacy at discharge in Pakistan. Method: A retrospective cross-sectional study of elderly patients' medical profiles for the year 2021 was performed, and the profiles that met the inclusion criteria were included. Results: The total sample size was 800, and 51.9% of patients received polypharmacy at discharge. The authors found that the female gender (OR = 0.469) has comparatively less risk of receiving polypharmacy. Furthermore, patients with an increased length of stay and increased medication use in the hospital (OR 1.1295, OR = 17.189, respectively) have a high risk of receiving polypharmacy at discharge. Furthermore, patients diagnosed with peripheral vascular disease (OR = 4.689), cerebrovascular accident (OR = 2.764), chronic obstructive pulmonary disease (OR = 3.748), asthma (OR = 2.321), and diabetes mellitus (OR = 2.754) had higher risks of receiving polypharmacy. Conclusion: The study found a high prevalence of polypharmacy at discharge in Pakistan and identified several risk factors that could help to reduce polypharmacy by targeting vulnerable groups.

Clinical and epidemiological risk factors associated with hospitalization and mortality rate of COVID-19 patients in Banja Luka County: A retrospective observational cohort study on 40,000 patients.

Since beginning of the coronavirus disease (COVID-19) it became clear that severe forms of this infection have primarily affected patients with chronic conditions. The aim of the study was to explore clinical and epidemiological characteristics associated with COVID 19 outcomes. The retrospective observational study included 40,692 citizens of Banja Luka County, Bosnia and Herzegovina, who were confirmed as reverse transcriptase polymerase chain reaction (RT-PCR) positive on COVID-19 at a primary healthcare centre from March 2020 to September 2022. Epidemiological data were obtained from Web-Medic medical records of patients. The COVID-19 data were obtained from COVID-19 data sheets comprised of patients' RT-PCR testing forms, surveillance forms for severe acute respiratory syndrome coronavirus-2 status, and a map of their positive and isolated contacts. Differences regarding the distributions of patients between groups were analysed using the Pearson chi-square test and Mantel-Haenszel chi-square test for trends, while differences in mean values were compared using an independent sample t-test. The average age of hospitalised patients was significantly higher compared to the age of non-hospitalised patients (P < 0.001). The average age of patients with lethal outcomes was nearly twice as high in comparison to patients with non-lethal outcomes (P < 0.001). Male patients had a higher hospitalization and mortality rate (P < 0.001). The highest hospitalization rate was in patients with chronic renal failure (CRF), diabetes and cardiovascular diseases (CVDs), while the death rate was the highest among patients with CRF and hearth comorbidities. Patients with fatigue and appetite loss had a higher percentage of lethal outcomes. Vaccinated patients had a significantly lower rate of lethal outcome. Clinical symptoms, signs and outcomes, are posing as predictive parameters for further management of COVID-19. Vaccination has an important role in the clinical outcomes of COVID-19.

Abstract 146: Phosphodiesterase 10A Mediates Arterial Calcification Through A P38/MAPK-MMP3 Signaling

Background: Vascular calcification is prevalent in patients with atherosclerosis, chronic kidney disease (CKD), diabetes, and peripheral artery disease (PAD). When located in the arterial media, it is strongly associated with increased cardiovascular morbidity and mortality. The cyclic nucleotides cAMP and cGMP play important regulatory roles in a variety of human diseases that are controlled by distinct phosphodiesterase (PDE) isozymes. We have recently found that PDE10A is the most highly induced isoform in a rodent model of arterial calcification. The function and underlying mechanisms of PDE10A in medial artery calcification, however, remain unknown. Methods: Vascular smooth muscle cell (VSMC) calcification was mediated by a high phosphate media. Medial artery calcification was induced by vitamin D 3 injection and 5/6 nephrectomy calcification models. Vascular calcification was assessed by calcium assay and Von Kossa staining. Results: PDE10A was markedly increased in calcifying VSMCs in vitro , calcified arteries in vivo , and calcified human tibial arteries from patients with PAD. Knockdown or inhibition of PDE10A markedly attenuated phosphate-induced VSMC osteogenic transformation and calcification in VSMCs. Conversely, overexpression of PDE10A increased VSMC calcification. Deficiency and inhibition of PDE10A significantly decreased arterial calcification in vivo . Several labs including our own have demonstrated that matrix metallopeptidases (MMPs) are involved in vascular calcification. Using bioinformatics analysis and loss-of-function strategy, we found that MMP-3 could be regulated by PDE10A in calcifying VSMCs. Our further mechanistic studies showed that knockdown or inhibition of PDE10A decreased activated p38 MAPK and that inhibition of p38 MAPK attenuated MMP-3 upregulation under a calcifying condition. These data suggest that PDE10A mediates arterial calcification through a p38 MAPK-MMP-3 signaling pathway. Conclusion: PDE10A is a key regulator in the development of medial artery calcification. Our findings provide insight into the use of PDE10A inhibition strategies to reduce arterial calcification in patients with CKD and PAD.

Utility of the ACD-GENE-CLI Score in Asian Patients with Critical Limb Ischemia Undergoing Endovascular Interventions.

Critical limb ischemia (CLI) is an emerging public health threat and lacks a reliable score for predicting the outcomes. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD-GENE) risk score helps identify patients with coronary artery disease who have cytochrome P450 2C19 (CYP2C19) polymorphism-related drug resistance and are at risk for cardiovascular adverse events. However, its application to CLI remains unknown. In this study, we aim to validate a modified ACD-GENE-CLI score to improve the prediction of major adverse limb events (MALEs) in patients with CLI receiving clopidogrel. Patients with CLI receiving clopidogrel post-endovascular intervention were enrolled prospectively in two medical centers. Amputation and revascularization as MALEs were regarded as the outcomes. A total of 473 patients were recruited, with a mean follow-up duration of 25 months. Except for obesity, old age, diabetes, chronic kidney disease (CKD), and CYP2C19 polymorphisms were significantly associated with MALEs. Using bootstrap regression analysis, we established a modified risk score (ACD-GENE-CLI) that included old age (≥ 65 years), diabetes, CKD, and CYP2C19 polymorphisms. At a cutoff value of 8, the ACD-GENE-CLI score was superior to the CYP2C19 deficiency only, and the conventional ABCD-GENE score in predicting MALEs (area under the curve: 0.69 vs. 0.59 vs. 0.67, p=0.01). The diagnostic ability of the ACD-GENE-CLI score was consistent in the external validation. Also, Kaplan-Meier curves showed that in CYP2C19 deficiency, the ABCD-GENE and ACD-GENE-CLI scores could all differentiate patients with CLI who are free from MALEs. The modified ACD-GENE-CLI score could differentiate patients with CLI receiving clopidogrel who are at risk of MALEs. Further studies are required to generalize the utility of the score.

Current State and Future Perspective of Diabetic Wound Healing Treatment: Present Evidence from Clinical Trials.

Diabetes is a chronic metabolic condition that is becoming more common and is characterised by sustained hyperglycaemia and long-term health effects. Diabetes-related wounds often heal slowly and are more susceptible to infection because of hyperglycaemia in the wound beds. The diabetic lesion becomes harder to heal after planktonic bacterial cells form biofilms. A potential approach is the creation of hydrogels with many functions. High priority is given to a variety of processes, such as antimicrobial, pro-angiogenesis, and general pro-healing. Diabetes problems include diabetic amputations or chronic wounds (DM). Chronic diabetes wounds that do not heal are often caused by low oxygen levels, increased reactive oxygen species, and impaired vascularization. Several types of hydrogels have been developed to get rid of contamination by pathogens; these hydrogels help to clean up the infection, reduce wound inflammation, and avoid necrosis. This review paper will focus on the most recent improvements and breakthroughs in antibacterial hydrogels for treating chronic wounds in people with diabetes. Prominent and significant side effects of diabetes mellitus include foot ulcers. Antioxidants, along with oxidative stress, are essential to promote the healing of diabetic wounds. Some of the problems that can come from a foot ulcer are neuropathic diabetes, ischemia, infection, inadequate glucose control, poor nutrition, also very high morbidity. Given the worrying rise in diabetes and, by extension, diabetic wounds, future treatments must focus on the rapid healing of diabetic wounds.

Clusters from chronic conditions in the Danish adult population.

Multimorbidity, the presence of 2 or more chronic conditions in a person at the same time, is an increasing public health concern, which affects individuals through reduced health related quality of life, and society through increased need for healthcare services. Yet the structure of chronic conditions in individuals with multimorbidity, viewed as a population, is largely unmapped. We use algorithmic diagnoses and the K-means algorithm to cluster the entire 2015 Danish multimorbidity population into 5 clusters. The study introduces the concept of rim data as an additional tool for determining the number of clusters. We label the 5 clusters the Allergies, Chronic Heart Conditions, Diabetes, Hypercholesterolemia, and Musculoskeletal and Psychiatric Conditions clusters, and demonstrate that for 99.32% of the population, the cluster allocation can be determined from the diagnoses of 4-5 conditions. Clusters are characterized through most prevalent conditions, absent conditions, over- or under-represented conditions, and co-occurrence of conditions. Clusters are further characterized through socioeconomic variables and healthcare service utilizations. Additionally, geographical variations throughout Denmark are studied at the regional and municipality level. We find that subdivision into municipality levels suggests that the Allergies cluster frequency is positively associated with socioeconomic status, while the subdivision suggests that frequencies for clusters Diabetes and Hypercholesterolemia are negatively correlated with socioeconomic status. We detect no indication of association to socioeconomic status for the Chronic Heart Conditions cluster and the Musculoskeletal and Psychiatric Conditions cluster. Additional spatial variation is revealed, some of which may be related to urban/rural populations. Our work constitutes a step in the process of characterizing multimorbidity populations, leading to increased comprehension of the nature of multimorbidity, and towards potential applications to individual-based care, prevention, the development of clinical guidelines, and population management.

Earthing Method as a Lifestyle Medicine to Accelerate the Healing of Chronic Diabetic Wounds

Diabetes mellitus (DM) type 2 is a non-communicable disease that causes death number 6 worldwide. Caused by resistance to insulin, accompanied by many complications, including neuropathy (peripheral nerve damage), diabetic ulcers, heart disease, kidney failure, hypertension, retinopathy (damage to the retina in the eyes), blindness, leg amputation, stroke, and death. Diabetic wounds do not heal because of microbial infections in the wounds, accompanied by high blood sugar levels. This study aims to analyze the effect of earthing/grounding on chronic diabetes wound healing. This research was conducted in June-December 2023 in Karanganyar Regency, Central Java. The population in this study were clients with type 2 diabetes mellitus. Earthing intervention was carried out for 1 hour every day for 30 days. The sample size was 21 respondents taken by the purposive sampling method. Statistical analysis shows a P value of 0.000&lt;0.000 and a Z-score of -4.032. Shows the significant effect of earthing/grounding therapy on accelerating diabetes mellitus wound healing. It is highly recommended for clients with type 2 DM to apply earthing/grounding as part of Lifestyle Medicine, which is integrated into life habits to cure infections and speed up wound healing, thereby preventing amputations.

Transplantation and Pregnancy

Transplantation is becoming increasingly widespread worldwide as a life-saving treatment for patients with end-stage organ failure. While the woman's quality of life improves rapidly after transplantation, the improvement of the endocrine system helps to regain fertility. The success of conception and successful pregnancy rates are quite low compared to the general population. Particular attention should be paid to obstetric complications such as hypertension, preeclampsia, fetal growth restriction, and preterm delivery during pregnancy. Ideally, preconception counseling should begin in the period before transplantation. Initiating contraception immediately after transplantation is ideal and long-acting reversible methods such as intrauterine devices and subcutaneous implants may be preferable. Factors that influence pregnancy outcomes in women undergoing organ transplantation include good general health within two years of transplantation, no evidence of organ rejection in the last year, stable graft conditions, absence of acute infections affecting the fetus, and adequate doses of immunosuppression drugs. However, factors that may adversely affect pregnancy include the etiology of the disease requiring transplantation, chronic allograft dysfunction, renal failure, cardiopulmonary diseases, hypertension, diabetes, obesity, and infections such as hepatitis B, hepatitis C, and Cytomegalovirus (CMV). Postponing pregnancy for at least 1 year after transplantation is very important to optimize pregnancy outcomes. Pregnancy in the early post-transplant period increases the risk of acute rejection, infection risk, and graft-related problems. In general, transplanted women can have successful pregnancies and live birth rates are above 70% on average. Although perinatal morbidity and mortality rates are high, most newborns are healthy and develop normally. Specific criteria such as pre-pregnancy serum creatinine levels and blood pressure control, as well as adherence to immunosuppressive therapy, significantly influence pregnancy success in transplant patients. In this review, optimizing pregnancy outcomes often involves addressing maternal and fetal risks, regular graft monitoring to detect potential complications such as organ rejection, and regulation of transplant medications to ensure safety and efficacy during pregnancy. Successful management relies on a multidisciplinary approach with contributions from obstetricians, neonatologists, nephrologists, hepatologists, and transplant surgeons.