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Background: Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)–related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. Methods: Participants were stratified by systolic BP into low- (systolic BP Results: Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. Conclusions: Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.

To determine pressure injury (PI) healing rate and time and identify influencing factors.A prospective cohort research design was used. Data collection was performed between May 2015 and August 2018. The study participants were 77 inpatients who developed at least one PI during their stay in a university hospital. Researchers assessed participants' demographic (age, sex); physical (incontinence, activity of daily living, and nutrition status); physiologic (serum total protein, albumin, and creatinine, blood glucose, and hemoglobin levels); and disease- (diagnosis, number of comorbidities, and cardiovascular comorbidity), wound- (PI stage and size at first detection, and Pressure Ulcer Scale for Healing score), and treatment-related (IV nutrition supply and albumin infusion) factors.Across the 77 patients, 91 PIs developed. Of these, 54 (59.3%) healed with a mean healing time of 17.63 days. The healing rate was better, and the healing time was shorter for stage 2 PIs compared with unstageable or deep-tissue PIs. Factors influencing PI healing rate were number of comorbidities, cardiovascular comorbidity, incontinence, PI stage at first detection, IV nutrition supply, and mean serum creatinine level. Factors influencing PI healing time were number of comorbidities, cardiovascular comorbidity, and PI stage at first detection.To reduce hospital stays, PI-related complications, and mortality, evidence-based management strategies for PIs are needed. The findings of the present study may contribute to the development of such strategies.

Examine the associations of sleep measures with kidney function changes over time among individuals from a community-based study.The sample includes 1657 participants (287 with chronic kidney disease [CKD]) in the Multi-Ethnic Study of Atherosclerosis Sleep Cohort (mean age: 57.7 years, male: 46.0%). We examined associations between a large set of sleep variables (polysomnography, actigraphy, and questionnaires) and cardiovascular disease risk factors and changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio over approximately 5 years using high-dimensional regression. We investigated the modifying effect of sleep on the associations between cardiovascular disease risk factors and kidney function.Sleep metrics predicted kidney function decline only among individuals with baseline CKD. Among this group, eGFR decline was associated with decreased stage N3 sleep (0.32 mL/min/1.73 mReduced deep sleep, daytime napping, increased wake bouts, delayed sleep rhythms, and overnight hypoxemia are associated with longitudinal kidney function decline, with effects most apparent in individuals with CKD. Deep sleep, napping, and sleep timing modified the association between hemoglobin A1C and kidney function.

Background: It is well established that decreased kidney function can increase blood pressure (BP), but it is unproven whether moderately elevated BP causes chronic kidney disease (CKD) or glomerular hyperfiltration. Methods: 311 119 White British UK Biobank participants were included in logistic regression analyses to estimate the odds of CKD (defined as long-term kidney replacement therapy, estimated glomerular filtration rate [eGFR]< 60mL/min/1.73m 2 , or urinary albumin:creatinine ratio ≥3 mg/mmol) associated with higher genetically predicted BP using genetic risk scores comprising 219 systolic and 223 diastolic BP loci. Analyses estimating associations with clinical categories of eGFR and urinary albumin:creatinine ratio were also conducted, with an eGFR ≥120 mL (min·1.73m 2 ) considered evidence of glomerular hyperfiltration. Results: 21 623 participants had CKD: 7781 with reduced eGFR and 15 500 with albuminuria. 1828 participants had an eGFR ≥120 mL/min/1.73m 2 . Each genetically predicted 10 mmHg higher systolic BP and 5 mmHg higher diastolic BP were associated with a 37% (95% CI, 1.29–1.45) and 19% (1.14–1.25) higher odds of CKD, respectively. Associations were evident for both the reduced eGFR and albuminuria components of the CKD outcome. The odds of hyperfiltration (versus an eGFR ≥60 and 2 were 49% higher (95% CI, 1.21–1.84) for each genetically predicted 10 mmHg higher systolic BP. Associations with CKD and hyperfiltration were similar irrespective of preexisting diabetes, vascular disease, or different levels of adiposity. Conclusions: In this general population, genetic epidemiological evidence supports a causal role of life-long differences in BP for decreased kidney function, glomerular hyperfiltration, and albuminuria. Physiological autoregulation may not afford complete renal protection against the moderate BP elevations.

Need for discharge to intermediate care (DCIC) can increase length of stay and be a source of stress to patients. Estimating risk of DCIC would allow earlier involvement of case managers, improve length of stay and patient satisfaction by setting realistic expectations. The aim was to use National Surgical Quality Improvement Program dataset to develop a prediction model for DCIC after undergoing liver metastasectomy.Data were obtained from National Surgical Quality Improvement Program 2011-2018 covering liver metastasectomy. Recursive partitioning narrowed potential predictors and identified thresholds for categorization of continuous variables. Logistic regression identified a predictive model, internally validated by using 200 bootstrap samples with replacement. A risk score was derived using Framingham Study methodology by dividing all regression coefficients by the smallest model coefficient. Receiver operating characteristic analysis identified the score that maximized sensitivity/specificity, defining low/high risk. Finally, recursive partitioning identified categories low/medium/high.The most parsimonious model predicting DCIC area under the curve (, 0.722, 95%CI: 0.705-0.739) identified five independent predictors including age60, procedure type, hypertension requiring medication, albumin3.5 mg/dL and hematocrit30%. Internal validation resulted in expected bias-corrected area under the curve of 0.717, 95% CI: 0.698-0.732. The maximum score was 17.9 and 5.8 maximized sensitivity (sn) and specificity (sp) [sn = 81%, sp = 51%) predicting DCIC. Stratified into three groups, a score ≥9.5 identified highest risk (12.8%), ≥4.3 medium (6.1%) and4.3 lowest risk (1.5%).Determining risk of DCIC benefits shared decision making and patient care. This evidence may enhance discharge planning after liver metastasectomy expediting the process. Age60 contributed the most weight to the score, but the use of additional variables in three groups allowed further discrimination between patients.

The fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio are all prognostic markers in patients with heart failure. Recently, the FAN score, which includes all 3 of these markers, was developed as a useful risk stratification tool in patients with cancer. However, its cut-off values have not been validated for heart failure. We aimed to investigate the optimal cut-off and prognostic values of the FAN score in patients with heart failure. We analyzed 669 consecutive patients hospitalized with heart failure (age, 75.8 ± 11.3 years). Their median values of the fibrosis-4 index, albumin-bilirubin score, and neutrophil-lymphocyte ratio at discharge were 2.12, -2.25, and 2.41, respectively. The FAN score for heart failure (HF-FAN score) was calculated using these median values. The primary outcome was a composite of all-cause death and heart failure rehospitalization. Patients were divided into 4 groups according to HF-FAN scores of 0 (n = 112), 1 (n = 231), 2 (n = 242) and 3 (n = 84). Patients with HF-FAN scores of 3 were older, had higher brain natriuretic peptide levels, and larger inferior vena cava diameters. Kaplan-Meier analysis showed a direct correlation between higher HF-FAN scores and occurrence of the primary endpoint (log-rank P0.001). Cox proportional hazard analysis revealed a higher HF-FAN score was significantly associated with a worse prognosis even after adjustment for possible prognostic factors. Changing from the FAN score to HF-FAN score provided significant continuous net reclassification improvement. In conclusion, the HF-FAN score at discharge was useful for risk stratification in patients hospitalized with heart failure. The HF-FAN score might be more suitable for patients with heart failure than the FAN score.

Isocyanates such as 1,6-hexamethylene diisocyanate (HDI), 4,4'-methylenediphenyl diisocyanate, and toluene diisocyanate are highly reactive compounds that have a variety of commercial applications, including manufacturing polyurethane foam, elastomers, paints, adhesives, coatings, insecticides, and many other products. Their primary route of occupational exposure is through inhalation. Due to their high chemical reactivity, they are toxic and have adverse effects at the cellular and subcellular levels, leading to irritative and immunological reactions associated with lung disease. High concentrations of isocyanates are strong respiratory irritants. Bronchial sensitization and asthma are among the major adverse clinical reactions associated with low-level chronic exposure to isocyanates. Albumin adducts have been linked to the mechanism of occupational asthma caused by isocyanates. Isocyanates react

Assessment of liver reserve function (LRF) is essential for predicting the prognosis of patients with chronic liver disease (CLD) and determines the extent of liver resection in patients with hepatocellular carcinoma.To establish noninvasive models for LRF assessment based on liver stiffness measurement (LSM) and to evaluate their clinical performance.A total of 360 patients with compensated CLD were retrospectively analyzed as the training cohort. The new predictive models were established through logistic regression analysis and were validated internally in a prospective cohort (132 patients).Our study defined indocyanine green retention rate at 15 min (ICGR15) ≥ 10% as mildly impaired LRF and ICGR15 ≥ 20% as severely impaired LRF. We constructed predictive models of LRF, named the mLPaM and sLPaM, which involved only LSM, prothrombin time international normalized ratio to albumin ratio (PTAR), age and model for end-stage liver disease (MELD). The area under the curve of the mLPaM model (0.855, 0.872, respectively) and sLPaM model (0.869, 0.876, respectively) were higher than that of the methods for MELD, albumin-bilirubin grade and PTAR in the two cohorts, and their sensitivity and negative predictive value were the highest among these methods in the training cohort. In addition, the new models showed good sensitivity and accuracy for the diagnosis of LRF impairment in the validation cohort.The new models had a good predictive performance for LRF and could replace the indocyanine green (ICG) clearance test, especially in patients who are unable to undergo ICG testing.

The predicted risk and timeline to progression to liver-related outcomes in the population with NAFLD are not well-characterized. We aimed to examine the risk and time to progression to cirrhosis, hepatic decompensation and death in a contemporary population over a long follow-up period, to obtain information to guide endpoint selection and sample size calculations for clinical trials on NAFLD-related cirrhosis.This is a retrospective study of prospectively collected data in a medical record linkage system, including all adults diagnosed with NAFLD between 1996-2016 by clinical, biochemical and radiological criteria in Olmsted County, Minnesota and followed until 2019. Liver-related outcomes and death were ascertained and validated by individual medical record review. Time and risk of progression from NAFLD to cirrhosis to decompensation and death were assessed using multistate modeling.A total of 5,123 individuals with NAFLD (median age 52 years, 53% women) were followed for a median of 6.4 (range 1-23) years. The risk of progression was as follows: from NAFLD to cirrhosis: 3% in 15 years; compensated cirrhosis to first decompensation: 33% in 4 years (8%/year); first decompensation to ≥2 decompensations: 48% in 2 years. Albumin, bilirubin, non-bleeding esophageal varices and diabetes were independent predictors of decompensation. Among the 575 deaths, 6% were liver related. Therapeutic trials in compensated cirrhosis would require enrolment of a minimum of 2,886 individuals followed for2 years to detect at least a 15% relative decrease in liver-related endpoints.In this population-based cohort with 23 years of longitudinal follow-up, NAFLD was slowly progressive, with liver-related outcomes affecting only a small proportion of people. Large sample sizes and long follow-up are required to detect reductions in liver-related endpoints in clinical trials.For patients with compensated non-alcoholic steatohepatitis-related cirrhosis, the time spent in this state and the risk of progression to decompensation are not well-known in the population. We examined the clinical course of a large population-based cohort over 23 years of follow-up. We identified that adults with compensated cirrhosis spend a mean time of 4 years in this state and have a 10% per year risk of progression to decompensation or death. The risk of further progression is 3-fold higher in adults with cirrhosis and one decompensating event. These results are reflective of placebo arm risks in drug clinical trials and are essential in the estimation of adequate sample sizes.

The aims of this study were to establish a cut-off point by evaluating the usability of the hemato-biochemical indices to determine the severity of inflammation caused by pyometra, and to determine the practical usage of the indices as a diagnostic biomarker in cases of pyometra. Animals that were admitted to Ankara University Veterinary Faculty Obstetrics and Gynecology Clinic were included in the present study. Dogs suffering from pyometra were allocated to two groups according to their SIRS status (SIRS, n = 12; Non-SIRS (NSIRS, n = 16)). Healthy dogs presented for routine ovariohysterectomy were used as the control (n = 13). Blood samples were collected into two tubes containing EDTA for hematological analysis and without anticoagulant for biochemical tests before the beginning of treatment. Hemato-biochemical indices, which are Neutrophil-Lymphocyte Ratio (NLR), Monocyte-Lymphocyte Ratio (MLR), Neutrophil Percentage-Albumin Ratio (NPAR), Platelet-Lymphocyte Ratio and Systemic Immune-Inflammation Index, were calculated. All data were analyzed using the MIXED procedure of the SPSS. Receiver operating characteristics curves were used to determine the dog level threshold for evaluating the SIRS status and used to determine a predicted threshold with hemato-biochemical indices for differentiation between dogs with pyometra (regardless of SIRS status) and the control. Pairwise comparisons were carried out of the area under the curve (AUC) for thresholds of SII, NLR, PLR, MLR, NPAR. White blood cells, lymphocytes, monocyte, neutrophil, ALP, NLR, MLR, and NPAR levels were greater in dogs that suffer from SIRS (P 0.05). Red blood cells and hematocrit levels were significantly higher in the control group (P 0.05). Albumin levels were higher in the control group (P 0.05). Moreover, NLR, MLR and NPAR levels were found to be significantly higher in the SIRS group (P 0.05). Besides, NLR and MLR were the best predictors for diagnosis of the SIRS with the AUC values of 0.936, and 0.966 respectively. Furthermore, NLR, MLR and SII could be a useful diagnostic tool for pyometra with the AUC values of 0.955, 0.931, 0.716. The blood indices could be used as fast, easily accessible, and inexpensive markers for the evaluation of the SIRS status in dogs with pyometra together with diagnosis.

Diabetic foot (DF) is a prevalent metabolic infection. DF wounds are the basis for all cases of nontraumatic lower limb amputations in diabetes. DF care approaches include debridement of wound, pressure relief in the wounded area, proper wound, infection, and ischemia management. However, there is a need for research to develop more effective therapeutic approaches. This study investigated the effectivity and safety of autologous platelet-rich gel combined with conventional treatment and traditional Chinese medicine (TCM) in DF ulcer therapy.Sixty DF ulcer patients were divided into treatment and control groups of 30 patients each. The treatment group involved a combination of autologous platelet-rich gel, conventional treatment, and TCM. The control group was only treated with a combination of conventional therapy and TCM. Laboratory variables, including platelets, hemoglobin (Hb), albumin, and HbA1c, were analyzed and compared between the treatment and the control groups at baseline and endpoint. Healing area, volume, and rates were compared in both groups.Basic patients' data and the wound conditions had no significant difference between the treatment and the control group. The treatment and control groups cure rates were 93.3% vs. 50%, respectively. The healing rate per 2 weeks was significantly higher in the treatment than in the control group (0.78 ± 0.05 vs. 0.43 ± 0.04). There was no statistically significant difference in the platelets, Hb, albumin, and HbA1c levels in the treatment and control groups.Autologous platelet-rich gel combined with conventional treatment and TCM is effective and safe for DF ulcer treatment.

The Memorial Sloan Kettering Cancer Center nomogram, the predictive scoring system of Yamamoto et al, and the 3-point transfusion risk score of Lemke et al are models used to determine the probability of receiving intraoperative blood transfusion in patients undergoing liver resection. However, the external validity of these models remains unknown. The objective of this study was to evaluate their predictive performance in an external cohort of patients with hepatocellular carcinoma. We also aimed to identify predictors of blood transfusion and develop a new predictive model for blood transfusion.Post hoc analysis of our prospective database of 1,081 patients undergoing liver resection for hepatocellular carcinoma from 2001 to 2018. The predictive performance of current prediction models was evaluated using C statistics. Demographic and clinical variables as predictors of blood transfusion were assessed. Using logistic regression, an alternative model was created.The Lemke transfusion risk score performed better than the Memorial Sloan Kettering Cancer Center nomogram (0.69, 95% confidence interval 0.66-0.73 vs 0.66, 95% liver resection 0.62-0.69) (Plt; .001). The model from Yamamoto et al performed comparably with no statistically significant differences found through pairwise comparison. In our alternative model, hemoglobin level, albumin level, liver resection type, and tumor size were independent predictors of blood transfusion. The new HATS model obtained a C statistic of 0.74 (95% confidence interval 0.71-0.78), performing significantly better than the previous 3 models (P ≤ 0.001 for all).The existing Memorial Sloan Kettering Cancer Center, Yamamoto et al, and Lemke et al had nomograms with the suboptimal accuracy of predicting risk of intraoperative blood transfusion in patients undergoing liver resection for hepatocellular carcinoma. The proposed HATS model was more accurate at predicting patients at risk of blood transfusion.

For persons with proteinuria, angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) are treatment mainstays for reducing kidney disease progression. Guidelines for managing hypertension and chronic kidney disease recommend titrating to the maximum ACEi/ARB dose tolerated. Using deidentified national electronic health record data from the Optum Labs Data Warehouse, we examined ACEi/ARB dosing among adults with proteinuria-defined as either a urine albumin to creatinine ratio of 30 mg/g or greater or a protein to creatinine ratio of 150 mg/g or greater-who were prescribed an ACEi/ARB medication between January 1, 2017, and December 31, 2018. Among 100,238 included patients (mean age, 65.1 years; 49,523 [49.4%] female), 29,883 (29.8%) were taking maximal ACEi/ARB doses. Among 74,287 patients without potential contraindications to dose escalation (systolic blood pressure120 mm Hg, estimated glomerular filtration rate15 mL/min per 1.73 m

IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC).We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported.Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4-10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1-8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS.This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.

Abnormal serum calcium concentrations affect the heart and may alter the electrocardiogram (ECG), but the detection of hypocalcemia and hypercalcemia (collectively dyscalcemia) relies on blood laboratory tests requiring turnaround time.The study aimed to develop a bloodless artificial intelligence (AI)-enabled (ECG) method to rapidly detect dyscalcemia and analyze its possible utility for outcome prediction.This study collected 86,731 development, 15,611 tuning, 11,105 internal validation, and 8401 external validation ECGs from electronic medical records with at least 1 ECG associated with an albumin-adjusted calcium (aCa) value within 4 h. The main outcomes were to assess the accuracy of AI-ECG to predict aCa and follow up these patients for all-cause mortality, new-onset acute myocardial infraction (AMI), and new-onset heart failure (HF) to validate the ability of AI-ECG-aCa for previvor identification.ECG-aCa had mean absolute errors (MAE) of 0.78/0.98 mg/dL and achieved an area under receiver operating characteristic curves (AUCs) 0.9219/0.8447 and 0.8948/0.7723 to detect severe hypercalcemia and hypocalcemia in the internal/external validation sets, respectively. Although 20 % variance of ECG-aCa could be explained by traditional ECG features, the ECG-aCa was found to be associated with more complications. Patients with ECG-hypercalcemia but initially normal aCa were found to have a higher risk of subsequent all-cause mortality [hazard ratio (HR): 2.05, 95 % conference interval (CI): 1.55-2.70], new-onset AMI (HR: 2.88, 95 % CI: 1.72-4.83), and new-onset HF (HR: 2.02, 95 % CI: 1.38-2.97) in the internal validation set, which were also seen in external validation.The AI-ECG-aCa may help detecting severe dyscalcemia for early diagnosis and ECG-hypercalcemia also has prognostic value for clinical outcomes (all-cause mortality and new-onset AMI and HF).

It was recently shown that abnormal platelet aggregation (PA) had played a critical role in some adverse pregnancies. Till now reference range for PA in normal pregnancy has not been determined. Furthermore, few study has been conducted to explore the factors related to PA. Our study was performed to assess the reference range of PA in normal pregnancy (150 participants in the second trimester), and to determine whether it differs from that of the controls (38 nonpregnant participants). In addition, this study explored the factors related to PA. The results showed that PA was significantly higher in normal pregnancy than that in the controls (84.40% vs. 80.7%, respectively, P = 0.013). The reference interval for PA in normal pregnancy was 74.75%-94.77%. Hemoglobin (Hb), platelet counts (PLT) and albumin (Alb) were significant lower in normal pregnancy than those in the control group. Moreover, it was found that PA was positively correlated with PLT (r = 0.263, P 0.001), and negatively correlated with platelet distribution width (PDW) (r = -0.342, P 0.001) and mean platelet volume (r = -0.296, P 0.001). Linear correlations between PA and Alb, PDW were proved by linear regression model (LRM). In conclusion, PA was enhanced in normal pregnancy, and Alb and PDW might be the possible contributing factors to PA.

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants and breakthrough infections despite available coronavirus disease 2019 (COVID-19) vaccines calls for antiviral therapeutics. The application of soluble angiotensin converting enzyme 2 (ACE2) as a SARS-CoV-2 decoy that reduces cell bound ACE2-mediated virus entry is limited by a short plasma half-life. This work presents a recombinant human albumin ACE2 genetic fusion (rHA-ACE2) to increase the plasma half-life by an FcRn-driven cellular recycling mechanism, investigated using a wild type (WT) albumin sequence and sequence engineered with null FcRn binding (NB). Binding of rHA-ACE2 fusions to SARS-CoV-2 spike protein subdomain 1 (S1) was demonstrated (WT-ACE2 KD = 32.8 nM and NB-ACE2 KD = 31.7 nM) using Bio-Layer Interferometry and dose-dependent in vitro inhibition of host cell infection of pseudotyped viruses displaying surface SARS-CoV-2 spike (S) protein. FcRn-mediated in vitro recycling was translated to a five times greater plasma half-life of WT-ACE2 (t½ β = 13.5 h) than soluble ACE2 (t½ β = 2.8 h) in humanised FcRn/albumin double transgenic mice. The rHA-ACE2-based SARS-CoV-2 decoy system exhibiting FcRn-driven circulatory half-life extension introduced in this work offers the potential to expand and improve the anti-COVID-19 anti-viral drug armoury. Statement of significance: The COVID-19 pandemic has highlighted the need for rapid development of efficient antiviral therapeutics to combat SARS-CoV-2 and new mutants to lower morbidity and mortality in severe cases, and for people that are unable to receive a vaccine. Here we report a therapeutic albumin ACE2 fusion protein (rHA-ACE2), that can bind SARS-CoV-2 S protein decorated virus-like particles to inhibit viral infection, and exhibits extended in vivo half-life compared to ACE2 alone. Employing ACE2 as a binding decoy for the virus is expected to efficiently inhibit all SARS-CoV-2 mutants as they all rely on binding with endogenous ACE2 for viral cell entry and, therefore, rHA-ACE2 constitutes a versatile addition to the therapeutic arsenal for combatting COVID-19.

Development of a practical point-of-care test for urinalysis is crucial for early diagnosis and treatment of chronic kidney disease (CKD). However, the classical gold standard detection method depends on sophisticated instruments and complicated procedures, impeding them from being utilized in resource-limited settings and daily screening. Herein, we report a rapid point-of-care device for the simultaneous quantification of microalbuminuria and leukocyte using one drop of urine. A luminogen (TTVP) with an aggregation-induced emission property can selectively activate its near-infrared fluorescence in the presence of albumin and leukocyte via hydrophobic or electrostatic interactions. The fluorescence signals from urine albumin and leukocyte could be well-separated combined with the coffee-ring effect. Using a smartphone-based detection device, simultaneous quantification of urine albumin and leukocyte was successfully achieved, which only took 20 min and required one drop of urine. The performance of this system is also verified with 120 clinical samples, which might serve as a simple, low-cost, and rapid tool for CKD screening and disease monitoring at the point of care.

Estimation of the functional reserve of the remnant liver is important to reduce morbidity and mortality.To estimate the functional reserve of the remnant liver in patients with hepatocellular carcinoma (HCC).We reviewed the medical records of 199 patients who underwent resection of HCC. Hepatic clearance of the remnant liver was calculated using fusion images ofTwenty-seven (30%) patients had major complications and 23 (12%) developed PHLF. The incidence of major complications increased with increasing albumin-bilirubin (ALBI) grade. The area under the curve values for hepatic clearance of the remnant liver, liver to heart-plus-liver radioactivity at 15 min (LHL15), and ALBI score predicting PHLF were 0.868, 0.629, and 0.655, respectively. The area under the curve for hepatic clearance of the remnant liver, LHL15, and ALBI score predicting major complications were 0.758, 0.594, and 0.647, respectively. The risk factors for PHLF and major complications were hepatic clearance of the remnant liver and intraoperative bleeding.The measurement of hepatic clearance may predict PHLF and major complications for patients undergoing resection of HCC.

Excess bilirubin accumulates in the bodies of patients suffering from acute liver failure (ALF) to cause much irreversible damage and bring about serious clinical symptoms such as kernicterus, hepatic coma, or even death. Hemoperfusion is a widely used method for removing bilirubin from the blood, but clinically used adsorbents have unsatisfactory adsorption capacity and kinetics. In this study, we prepared four supramolecular organic framework microcrystals

Optimization of peptide stability is essential for the development of peptides as bona fide alternatives to approved monoclonal antibodies. This is clearly the case for the many peptides reported to antagonize proprotein convertase subtilisin-like/kexin type 9 (PCSK9), a clinically validated target for lowering cholesterol. However, the effects of optimization of stability on in vivo activity and particularly the effects of binding to albumin, an emerging drug design paradigm, have not been studied for such peptide leads. In this study, we optimized a PCSK9 inhibitory peptide by mutagenesis and then by conjugation to a short lipidated tag to design P9-alb fusion peptides that have strong affinity to human serum albumin. Although attachment of the tag reduced activity against PCSK9, which was more evident in surface plasmon resonance binding and enzyme-linked immunosorbent competition assays than in cellular assays of activity, activity remained in the nanomolar range (∼40 nM). P9-alb peptides were exceptionally stable in human serum and had half-lives exceeding 48 h, correlating with longer half-lives in mice (40.8 min) compared to the unconjugated peptide. Furthermore, the decrease in in vitro binding was not deleterious to in vivo function, showing that engendering albumin binding improved low-density lipoprotein receptor recovery and cholesterol-lowering activity. Indeed, the peptide P9-albN2 achieved similar functional endpoints as the approved anti-PCSK9 antibody evolocumab, albeit at higher doses. Our study illustrates that optimization of stability instead of binding affinity is an effective way to improve in vivo function.

Background: People with a migration background are underrepresented in dementia research and disfavored in assessment and treatment, and many foreign-born individuals with dementia remain undiagnosed. Objective: The aim of this study was to examine whether there is inequality in the clinical assessment of dementia between native and foreign-born individuals in Sweden. Methods: Information was gathered retrospectively from a cohort of 91 native and 36 foreign-born patients attending four memory clinics in Skåne, Sweden. Data included information on cognitive test results, cerebrospinal fluid biomarkers, scores at structural imaging scales of global cortical atrophy (GCA), medial temporal lobe atrophy (MTA) and the Fazekas scale, laboratory measures of thyroid-stimulating hormone, calcium, albumin, homocysteine, hemoglobin, cobalamin (vitamin B12), and folate (vitamin B9), contact with health care, and treatment. Results: Foreign-born patients had lower educational level and scored lower on Mini-Mental State Examination and Clock Drawing Test (p

Pathological albuminuria (PAU) (urinary albumin creatinine ratio [UACR] ≥30 mg/g) is an independent risk factor of cardiovascular disease. PAU is more prevalent in men than women. We aimed to compare the association of PAU and the early phase of subclinical atherosclerosis (SA) between sexes.1228 subjects aged 50-90 years were stratified by sex and UACR (normal or PAU). SA was defined as mean carotid intima-media thickness ≥75th percentile of the cohort. Demographics and SA prevalence were compared between groups. Multivariate logistic regression was performed to assess the relationship between PAU and SA.Both men and women with PAU had increased prevalence of hypertension, anti-hypertensive therapy, and metabolic syndrome than controls. Men with PAU were older and had greater waist circumference and total body fat percentage. Sex disparity was observed in associations between waist-to-height ratio, total body fat, and UACR. After adjusting for traditional risk factors, multivariate logistic regression disclosed that PAU was independently associated with SA in men (adjusted odds ratio 1.867, 95% CI 1.066-3.210) but not in women.The relationship of PAU and SA differed between sexes. This result may highlight the need for sex-specific risk management strategies to prevent atherosclerosis.

Background Given the increased popularity of flaxseed in meals, several cases of allergy to these seeds have been reported. Little is known about allergens implicated in hypersensitivity reactions to these seeds. The present work aimed to identify the allergens involved in IgE-mediated reactions in five patients with a clinical history of severe systemic symptoms after flaxseed consumption. Methods Proteins susceptible to be allergens with IgE-binding capacity were purified from flaxseed extract by chromatographic techniques. Their identification was achieved via MALDI-TOF mass spectrometry. Immunoassays were performed using the five allergic patient's era either by testing them individually or as a pool. Results Proteins susceptible to be allergens with IgE-binding capacity were purified from flaxseed extract by chromatographic techniques. Their identification was achieved via MALDI-TOF mass spectrometry. Immunoassays were performed using the five allergic patient's era either by testing them individually or as a pool. Results: Four out of five patients recognized a low-molecular-mass protein (around 13kDa) by immunoblotting of the flaxseed extract, while two patients recognized a protein of approximately 55 kDa. They were identified by mass spectrometry as flaxseed 2S albumin, included into WHO/IUIS allergen nomenclature as Lin u 1,and 11S globulin, respectively. Inhibition assays revealed in vitro IgE-cross-reactivity of Lin u 1 with peanut and cashew nut proteins, while IgE recognition of 11S globulin by patients' sera was partially inhibited by several plant-derived sources. Conclusions Seed storage proteins from flaxseed were involved in the development of severe symptoms in five individuals and exhibited cross-reactivity with other allergenic sources. Besides the severity of flaxseed allergy in patients sensitized to 2S albumin, it is the first time that the 11S globulin is identified as a potential allergen. We consider that these data should be taken into account for a more accurate diagnosis of patients.

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a common cancer with poor survival outcomes. Although treatment options are limited, real-world treatment patterns and outcomes are not well understood, particularly beyond first-line treatment. This study described real-world treatment patterns and outcomes for mPDAC in the USA.This retrospective analysis used electronic health record-derived de-identified data of patients with mPDAC diagnosed between January 1, 2014 and June 30, 2021. Treatments were classified into six groups: (1) standard combination chemotherapy; (2) nonstandard combination chemotherapy; (3) single-agent chemotherapy; (4) targeted therapy; (5) clinical study drugs; and (6) off-label therapies. Analyses were descriptive in nature. Treatment utilization and switching, and time on treatment and time to discontinuation, were described by first-line (1LOT) and second-line (2LOT) treatment groups. Median overall survival (mOS) from 1LOT and 2LOT was stratified by treatment group, and for 1LOT on the basis of whether patients received further treatment.1LOT included 6979 patients, 3241 (46%) of whom received further 2LOT. Standard combination chemotherapy was the most common 1LOT (70%) and 2LOT (46%). Nonstandard combination chemotherapy was used more as 2LOT (35%) than 1LOT (11%). First-line time on treatment was generally higher than second-line time on treatment, and time to discontinuation was lower than time on treatment. mOS in days (months) from 1LOT was 271 (8.9), 252 (8.3), 219 (7.2), 170 (5.6), 280 (9.2), and 182 (6.0), and mOS from 2LOT was 202 (6.6), 193 (6.3), 186 (6.1), 193 (6.3), 179 (5.9), and 97 (3.2), for groups 1-6, respectively. Within group 1, mOS from 1LOT was 318 days (10.4 months) for FOLFIRINOX and 241 days (7.9 months) for gemcitabine and nab-paclitaxel.Most patients with mPDAC received 1LOT in line with clinical practice guidelines, yet mOS remains poor. This study highlights the need for novel therapies to demonstrate improved patient survival compared with therapies in current clinical practice guidelines.

Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.

In this study, we aimed to investigate the prognostic value of C-reactive protein (CRP) to albumin ratio (CAR) for predicting restenosis in superficial femoral artery (SFA) lesions and its association with subsequent clinical outcomes in patients undergoing endovascular intervention.The records of 685 consecutive patients who underwent endovascular intervention due to symptomatic peripheral artery disease were analyzed. Patients were divided into 2 groups, based on the CAR values. For each group, technical aspects of procedures and subsequent clinical outcomes were analyzed.According to our study, patients with high CAR values had higher rates of restenosis (30.2% vs. 10.3%, P 0.05) and mortality (31.3% vs. 12.9%, P 0.05). The rate of lower extremity amputations was also significantly higher in patients with high CAR values compared to those with low CAR values (9.1% vs. 3%, P 0.05). With respect to Receiver operating characteristic ROC curves of inflammatory markers, the area under the curve (AUC) value of CAR was statistically significant (AUC: 0.659; 95% confidence interval CI: 0.611-0.706; P 0.01).Our data showed that CAR is an independent predictor of restenosis and poor clinical outcomes in patients undergoing endovascular intervention.

This study aimed to investigate whether the dorsal skeletal muscle area at 12th thoracic level (T12SMA) could be used as a predictor of in-hospital mortality and long-term survival among patients with community-acquired pneumonia (CAP).A retrospective study was conducted on 1701 CAP patients who underwent chest computed tomography (CT) examinations at the First Hospital of Qinhuangdao. The primary outcome was in-hospital mortality. The T12SMA was analyzed. Multivariate regression logistic models were constructed to identify the prognostic markers of hospital mortality. Cox regression logistic models were constructed to identify the risk factors of long-term survival.The multiple logistic regression analysis showed that T12SMA [odds ratio (OR) = 0.946; p = 0.007], CURB-65 (OR = 1.521; p = 0.008), creatinine (OR = 1.003; p = 0.001), albumin (OR = 0.908; p = 0.001) and intensive care unit (ICU) (OR = 2.715; p = 0.007) were independent risk factors for predicting the in-hospital mortality. The cox regression logistic analysis showed that T12SMA (OR = 0.968; p = 0.000), age (OR= 1.036; p = 0.000), sex (OR= 1.435; p = 0.002), CURB-65 (OR = 1.311; p = 0.000), albumin (OR = 0.952; p = 0.000), creatinine (OR = 1.002; p = 0.000) and ICU (OR = 1.606; p = 0.001) were prognostic markers of long-term survival.T12SMA, CURB-65, creatinine, albumin and ICU were independent risk factors for in-hospital mortality among patients with CAP. And low T12SMA affected the in-hospital mortality and long-term survival of patients with CAP.

Here we report the perfusion culture of a multi-layered tissue composed of HepG2 cells (a human hepatoma line) in a pressure-driven microphysiological system (PD-MPS), which we developed previously as a multi-throughput perfusion culture platform. The perfusion culture of multi-layered tissue model was constructed by inserting a modified commercially available permeable membrane insert into the PD-MPS. HepG2 cells were layered on the membrane, and culture medium was perfused both through and below the membrane. The seeded density (number of cells/cm

Although paraquat (PQ) induces oxidative damage and inflammatory responses in the lungs, the mechanism underlying PQ-induced acute kidney injury in patients is unclear. Immunosuppressive therapy with glucocorticoids and the immunosuppressant cyclophosphamide (CP) has been employed to treat patients with PQ poisoning. This study examined whether PQ could concurrently cause renal injury, inflammatory responses, and oxidative damage in the kidneys, and whether CP and dexamethasone (DEX) could suppress PQ-induced alterations. Mice were assigned to eight groups: Control, PQ, DEX, PQ plus DEX, CP, PQ plus CP, DEX plus CP, and PQ plus DEX with CP. DEX, CP, and DEX plus CP reversed PQ-induced renal injury, as indicated by urinary albumin-to-creatinine ratios and urea nitrogen levels in serum. The treatments also attenuated PQ-induced renal infiltration of leukocytes and macrophages and induction of the Il6, Tnf, Icam, Cxcl2, Tlr4, and Tlr9 genes encoding the inflammatory mediators in the kidneys. However, DEX only partially suppressed the macrophage infiltration, whereas DEX plus CP provided stronger protection than DEX or CP alone for the induction of Il6 and Cxcl2. Moreover, through the detection of F

To evaluate the effect of Urinary albumin creatinine ratio (UACR) on diabetic retinopathy (DR) in People with Type 2 diabetes (T2D) and the cut-off value of UACR for predicting DR using receiver operating characteristic curve (ROC).A prospective cohort study of 2490 people with T2D was conducted with follow-up ranging from 3 to 10 years, with a mean follow-up of 7 years. Dilated fundus examination and urine examination were performed annually. Medical history and clinical data were collected and analyzed. Linear mixed effect models with unstructured variance-covariance were carried out to longitudinally assess the influence of UACR and other factors on DR, and ROC curve was drawn to evaluate the value of UACR in early diagnosis of DR.Linear Mixed-effect models revealed that UACR was positively correlated with the development of DR (β = 0.001, 95 %CI: 1.023-1.241, P lt; 0.001). The area under the ROC curve for UACR was 0.634 (95 %CI: 0.605-0.664, P lt; 0.001), cut-off value for early diagnosis of DR was 27.81 mg/g, the sensitivity was 0.586, and the specificity was 0.632.UACR can predict the occurrence of DR in people with T2D, so it can be considered as a preliminary indicator of DR.

To identify predictors of severe adverse events (≥grade 3) in patients with advanced hepatocellular carcinoma treated with lenvatinib.Of 41 patients, 25 and 16 were stratified into the severe and non-severe adverse events groups, respectively. Of these, 19 formed a lactulose-mannitol test subgroup, which was divided into severe adverse events (n=11) and non-severe adverse events (n=8) groups. Severe adverse events were assessed by liver disease etiology and modified albumin-bilirubin grade. Intestinal permeability by lactulose-mannitol test and serum soluble CD163, soluble mannose receptor, and zonulin levels.Severe adverse event incidence rates were higher in patients with advanced hepatocellular carcinoma related to alcoholic liver disease and nonalcoholic fatty-liver disease than in those with advanced hepatocellular carcinoma of other etiologies (p=0.014). The rates were higher for modified albumin-bilirubin grades 2a and 2b compared to modified albumin-bilirubin grade 1 (p=0.0104). Zonulin levels were higher in the severe adverse event group (p=0.0331) and were independently associated with severe adverse events (odds ratio=140, 95% confidence interval=1.66-11800; p=0.029). Patients with high zonulin levels (≥0.518 ng/ml) experienced more severe adverse events than those with low levels (0.518 ng/ml) (p=0.0137). In the lactulose-mannitol test subgroup, the urine lactulose:mannitol ratio was higher in the severe vs. non-severe adverse event group (p=0.0164). Moreover, it was higher in patients with alcoholic liver disease and nonalcoholic fatty-liver disease-related advanced hepatocellular carcinoma compared to those with other advanced hepatocellular carcinoma etiologies (p=0.0108).Serum zonulin levels predict severe adverse events in patients with advanced hepatocellular carcinoma treated with lenvatinib.

Although extracorporeal life support (ECLS) can provide emergency systemic perfusion for acute fulminant myocarditis (AFM), the mortality rate remains extremely high, especially in those undergoing extracorporeal cardiopulmonary resuscitation (ECPR). Temporary ventricular assist device (VAD) can provide a more physiological blood flow direction and better subsequent organ perfusion than ECLS. We investigated temporary VAD efficacy in ECPR-revived AFM patients.During January 2012-May 2019, we retrospectively recruited 22 AFM patients with hemodynamic collapse and ECPR; 11 underwent ECLS only and 11 underwent additional VAD support after ECLS. Systemic perfusion was compared via laboratory biochemistry at post-ECPR days 2 (D2) and 4 (D4). Consciousness and cardiac function were assessed through the Glasgow Coma Scale (GCS) and echocardiography, respectively. All major complications and causes of mortality were recorded; 30-day survival was analyzed and risk factors were predicted.The VAD group had significantly better hemodynamic improvement; more inotropes being tapered at D2 and D4; better data representative of systemic perfusion, including albumin, pH, bicarbonate, and lactate levels at D4; and better 30-day survival (72.7% vs. 27.2%, p = 0.033). The causes of mortality included central failure, multiple organ failure, and bacteremia with sepsis. The risk factors included lethal dysrhythmia before ECLS, GCS5 at D2, and elevated cardiac enzymes at D4.For AFM patients, temporary VAD could provide better systemic perfusion and organ preservation than ECLS. VAD had better survival, including improved recovery and successful transplantation. Hence, temporary VAD should be considered if ECLS cannot revive the sustained cardiogenic shock.

CEND-1 is a novel cyclic peptide that targets αV integrins and neuropilin-1 and enhances tumour delivery of co-administered anticancer drugs. We investigated the safety, tolerability, and biological activity of CEND-1 in patients with metastatic pancreatic ductal adenocarcinoma in combination with nab-paclitaxel and gemcitabine.This open-label, multicentre, phase 1 study, conducted at three hospitals in Australia, enrolled participants aged 18 years or older with histologically confirmed metastatic pancreatic ductal adenocarcinoma who had one or more lesions measurable on MRI or CT, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a life expectancy of at least 3 months. Exclusion criteria included previous chemotherapy and brain metastases or other malignancy (unless receiving curative intent). There was no randomisation or masking. CEND-1 monotherapy was given as an intravenous fluid bolus on day 1 of a run-in phase of 7 days (0·2-3·2 mg/kg) followed by CEND-1 plus intravenous gemcitabine (1000 mg/mBetween Aug 13, 2018, and Nov 30, 2019, 31 patients were enrolled (eight in the dose-escalation phase [cohort 1a] and 23 in the expansion phase [cohort 1b]). Two patients were excluded from the efficacy population. No CEND-1 dose-limiting toxicities were observed in the safety population (n=31). The most common grade 3 or 4 events were neutropenia (17 [55%] patients), anaemia (eight [26%]), leukopenia (five [16%]), and pulmonary embolism (four [13%]). Serious adverse events occurred in 22 (71%) patients, mostly related to disease progression. Ten deaths occurred during the study due to progression of metastatic pancreatic cancer (n=9) and a left middle cerebral artery stroke (n=1). In the efficacy population (n=29), 17 (59%) patients had an objective response, including one complete response and 16 partial responses. After a median follow-up of 26 months (IQR 24-30), median overall survival was 13·2 months (95% CI 9·7-22·5).CEND-1 with nab-paclitaxel and gemcitabine has an acceptable safety profile, with no dose-limiting toxicities and encouraging activity. Adverse events were generally consistent with those seen with nab-paclitaxel and gemcitabine. Further randomised trials to determine the efficacy of CEND-1 are warranted.DrugCendR Australia Pty.

To explore the value of preoperative contrast-enhanced computed tomography (CT) tumour texture characteristics, and clinical and laboratory parameters on the prognosis of curative resection for non-small-cell lung cancer (NSCLC).This retrospective study included 64 patients (34 men and 30 women) with NSCLC who underwent curative resection and were then followed up for 5 years or until death. Preoperative contrast-enhanced CT images, clinical features, and laboratory parameters were collected for these patients. CT texture features of the primary tumour before surgery were extracted from the contrast-enhanced CT images using ImageJ software. Based on the cut-off values determined by X-tile software, the preoperative CT texture features, clinical features, and laboratory parameters were divided into two groups. Kaplan-Meier survival curves and log-rank tests were used to compare the 5-year overall survival (OS) of patients. Multivariate Cox regression analysis was used to determine the independent factors influencing the prognosis.The mean survival was 51.5 months. Tumour volume, entropy, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR) were shown to be significantly associated with 5-year OS (p0.05). Multivariate Cox regression analysis revealed that entropy was the independent factor of prognosis (hazard ratio 4.375, 95% confidence interval [CI]: 1.646-11.620, p=0.003).Entropy is an important and potentially non-invasive imaging biomarker for predicting the prognosis of NSCLC undergoing curative resection.

Preoperative systemic inflammation has been reported to predict survival in patients with various cancer types. In patients with colorectal liver metastasis (CRLM), the prognosis is poor despite therapeutic advances in the field. Here, we aimed to evaluate the prognostic role of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in patients with CRLM after hepatic resection.This retrospective study included 104 patients who underwent hepatic resection for CRLM between October 2010 and 2021 at the National Hospital Organization Fukuyama Medical Center, Hiroshima, Japan. The association between clinicopathological variables, including various inflammatory biomarkers [LCR, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), CRP-to-albumin ratio (CAR), and prognostic nutritional index (PNI)], and overall survival of the patients was investigated using univariate and multivariate analyses.The optimal cut-off values for each biomarker by receiver-operating characteristic analysis were as follows: LCR: 12,720; PLR: 150; NLR: 4; CAR: 0.023; and PNI: 44.8. The 1-, 3-, and 5-year overall survival rates were 97.0%, 71.3%, and 56.8%, respectively. On univariate analysis, LCR12, 720, PLR0.14, body mass index24 kg/mLCR may be an independent prognostic predictor in patients after hepatic resection for CRLM. Therefore, the assessment of LCR as a biomarker may help in treatment planning.

Well-performing survival prediction models (SPMs) help patients and healthcare professionals to choose treatment aligning with prognosis. This retrospective study aims to investigate the prognostic impacts of laboratory data and to compare the performances of Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy (METSSS) model, New England Spinal Metastasis Score (NESMS), and Skeletal Oncology Research Group machine learning algorithm (SORG-MLA) for spinal metastases (SM).From 2010 to 2018, patients who received radiotherapy (RT) for SM at a tertiary center were enrolled and the data were retrospectively collected. Multivariate logistic and Cox-proportional-hazard regression analyses were used to assess the association between laboratory values and survival. The area under receiver-operating characteristics curve (AUROC), calibration analysis, Brier score, and decision curve analysis were used to evaluate the performance of SPMs.A total of 2786 patients were included for analysis. The 90-day and 1-year survival rates after RT were 70.4% and 35.7%, respectively. Higher albumin, hemoglobin, or lymphocyte count were associated with better survival, while higher alkaline phosphatase, white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, or international normalized ratio were associated with poor prognosis. SORG-MLA has the best discrimination (AUROC 90-day, 0.78; 1-year 0.76), best calibrations, and the lowest Brier score (90-day 0.16; 1-year 0.18). The decision curve of SORG-MLA is above the other two competing models with threshold probabilities from 0.1 to 0.8.Laboratory data are of prognostic significance in survival prediction after RT for SM. Machine learning-based model SORG-MLA outperforms statistical regression-based model METSSS model and NESMS in survival predictions.

This work aimed to explore the application value of computed tomography (CT)-based radiomics in predicting changes in tumor regression during radiotherapy for nasopharyngeal carcinoma. In this work, 144 patients with nasopharyngeal carcinoma who underwent concurrent chemoradiotherapy (CCRT) in our hospital from January 2015 to December 2021 were selected. The patients were divided into a radiosensitive group (79 cases) and an insensitive group (65 cases) according to the tumor volume shrinkage during radiotherapy. The 3D Slicer 4.10.2 software was used to delineate the tumor region of interest (ROI), and a total of 1223 radiomics features were extracted using the radiomics module under the software. After between-group and within-group consistency tests, one-way ANOVA, and LASSO dimensionality reduction, three omics features were finally selected for the establishment of predictive models. At the same time, the age, gender, tumor T stage and N stage, hemoglobin, and albumin of the patients were collected to establish a clinical prediction model. The results showed that compared with logistic regression, decision tree, random forest, and AdaBoost models, the SVM model based on CT radiomics features had the best performance in predicting tumor regression changes during tumor radiotherapy (training group area under the receiver operating characteristic curve (AUC): 0.840 (95% confidence interval (CI): 0.764–0.916); validation group: AUC: 0.810 (95% CI: 0.676–0.944)). Compared with the supported vector machine (SVM) prediction model based on clinical features, the SVM model based on radiomics features had better performance in predicting the change of retraction during tumor radiotherapy (training group: omics feature SVM model AUC: 0.84, clinical feature SVM model: 0.78; validation group: omics feature SVM model AUC: 0.8, clinical feature SVM model: 0.58, P = 0.044). Based on the radiomics characteristics and clinical characteristics of patients, a nomo prediction map was established, and the calibration curve shows good consistency, which can be visualized to assist clinical judgment. In this work, the prediction model composed of CT-based radiomic features combined with clinical features can accurately predict withdrawal changes during tumor radiotherapy, ensuring the accuracy of treatment planning, and minimizing the number of CT scans during radiotherapy.

Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1–2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland., This work was supported by the Ministry of Science,Innovation and Universities (MICIU) and AgenciaEstatal de Investigacion (AEI), Spain (co-funded byFEDER funds/Development Fund–a Way to BuildEurope): RTI2018-099098-B-100 to AS/BH andRTI2018-094052-B-100 to AMV; and the RamonAreces Foundation: 20th National Competition forScientific and Technical Research in Life and MatterScience (2020) to IF. NL and JGS were recipients ofresearch assistant contracts linked to grant SAF2015-69145-R and RTI2018-099098-B-100, respectively. CMR was the recipient of a researchcontract (PEJD-2019-POST/BMD-16090) from the Education, Universities, Research and Spokesperson Counseling of the Community of Madrid.

Despite widespread concern about energy imbalance due to tumor and chemotherapy-related side effects, little is known about detailed variations in energy input, metabolic rate, and physical activity. This study explored changes in energy balance components and serum biomarkers of patients with hematologic malignancies undergoing chemotherapy. Our prospective study included 40 patients with hematologic malignancies hospitalized for chemotherapy. We measured energy balance components, physical function, and serum biomarkers at baseline and weekly after chemotherapy for 3 weeks. Significant weight loss, representing negative energy balance, occurred at 2 (p = 0.002) and 3 weeks (p 0.001) post-chemotherapy. Statistically reduced oral intake was observed at 3 weeks post-chemotherapy (p = 0.040), and resting energy expenditure statistically decreased according to Harris-Benedict equation, but not to Penn State University equation. Physical function according to DEMMI score decreased significantly at 3 weeks post-chemotherapy (p = 0.002). Serum biomarker analysis demonstrated significant changes in albumin, total protein, CXCL13, and GDF15, with exception of leptin. Although conventional serum biomarkers (total protein and albumin) did not reach pathological states despite their statistical differences, subgroup analysis showed CXCL13 in weight loss group and GDF15 in reduced oral intake group were significantly changed. Over half of patients (65.0%, n = 26) suffered from energy imbalance associated with weight loss and reduced oral intake during chemotherapy. Serial laboratory results suggested that novel biomarkers (CXCL13, GDF15) could be correlated with cachexic state and reduced food intake. Monitoring clinical and serum biomarkers associated with energy balance together can help identify needs for nutritional support in patients with hematologic malignancies undergoing chemotherapy.

Sodium–glucose cotransporter 2 (SGLT2) occurs in the proximal renal tubule cells. We investigate the hepatic expression of SGLT2 and its related factors in patients with chronic liver disease. This is a retrospective human study. The liver tissues were biopsied from patients with chronic liver disease (n = 30). The expression levels of SGLT2 were evaluated by immunostaining. Furthermore, the undirected graphical model was used to identify factors associated with hepatic expression levels of SGLT2. The SGLT2 expression was observed in not only the kidney, but also the liver in immunostaining (SGLT2 intensity: kidney 165.8 ± 15.6, liver 114.4 ± 49.0 arbitrary units, P

Opinion statementMelanoma is one of the deadliest malignancies. Its incidence has been significantly increasing in most countries in recent decades. Acral melanoma (AM), a peculiar subgroup of melanoma occurring on the palms, soles, and nails, is the main subtype of melanoma in people of color and is extremely rare in Caucasians. Although great progress has been made in melanoma treatment in recent years, patients with AM have shown limited benefit from current therapies and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in this high-risk melanoma subtype represents one of the greatest challenges in the field. The frequency of BRAF mutations in AM is much lower than that in cutaneous melanoma, which prevents most AM patients from receiving treatment with BRAF inhibitors. However, AM has more frequent mutations such as KIT and CDK4/6, so targeted therapy may still improve the survival of some AM patients in the future. AM may be less susceptible to immune checkpoint inhibitors because of the poor immunogenicity. Therefore, how to enhance the immune response to the tumor cells may be the key to the application of immune checkpoint inhibitors in advanced AM. Anti-angiogenic drugs, albumin paclitaxel, or interferons are thought to enhance the effectiveness of immune checkpoint inhibitors. Combination therapies based on the backbone of PD-1 are more likely to provide greater clinical benefits. Understanding the molecular landscapes and immune microenvironment of AM will help optimize our combinatory strategies.

The relationship between albumin corrected anion gap (ACAG) and mortality in acute kidney injury (AKI) patients who received continuous renal replacement therapy (CRRT) has not been investigated in any previous studies. This study aimed to investigate the relationship between ACAG at CRRT initiation and all-cause mortality among these patients in the intensive care unit (ICU). Patients diagnosed with AKI and treated with CRRT in the ICU from the Medical Information Mart for Intensive Care-IV version 1.0 (MIMIC IV) database and Huzhou Central Hospital were retrospectively enrolled. Participants were divided into two groups: the normal ACAG group (12–20 mmol/L) and high ACAG group (> 20 mmol/L). The Kaplan–Meier method and log-rank test were used to compare the survival rate between the two groups. Restricted cubic spine (RCS) and Cox proportional-hazards models were utilized to analyze the relationship between ACAG at CRRT initiation and ICU all-cause mortality of these patients. A total of 708 patients met the inclusion criteria in the study. The all-cause mortality of these patients during ICU hospitalization was 41.95%. Patients in the high ACAG group exhibited significantly higher ICU all-cause mortality rate than patients in the normal ACAG group (all P χ12 = 13.620, χ22 = 12.460, both P 20 mmol/L) levels at the time of CRRT initiation in the MIMIC IV database and Huzhou Central Hospital were significantly correlated with ICU all-cause mortality after adjusting multiple potential confounding factors with hazard ratios of 2.852 (95% CI 1.718–4.734) and 2.637(95% CI 1.584–4.389), respectively. In critically AKI patients who undergo CRRT, higher ACAG (> 20 mmol/L) level at the initiation of CRRT was significantly correlated with ICU all-cause mortality. Therefore, clinicians should pay more attention to those patients with a higher ACAG value.

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported

Background. Silver nanoparticles (AgNPs) utilization is becoming increasingly popular. The existing investigation evaluates the ameliorative impact of eugenol (Eug) against the toxic influences of AgNPs on rats’ liver. Methods. Sixty adult male rats were enrolled equally into control, Eug (100 mg kg-1 orally), AgNPs-low dose (1 mg kg-1 i.p), AgNPs-high dose (2 mg kg-1 i.p), Eug + AgNPs-low dose ( 100 mg k g − 1 orally + 1 mg k g − 1 i . p ), and Eug + AgNPs high dose ( 100 mg k g − 1 orally + 2 mg k g − 1 i . p ). All the groups were treated daily for 30 days, subsequently serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total protein, total albumin, lactate dehydrogenase (LDH), total oxidative capacity (TOC), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), total antioxidant capacity (TAC), and interleukin 6 (IL-6) levels were measured; hepatic tissues superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and glutathione peroxidase (GPx) levels were evaluated; histopathology and histomorphometry were documented in the liver of all groups; and Bcl-2, P53, Caspase-3, and TNF-α reactive proteins were also immunohistochemically detected. Results. AgNPs significantly triggered oxidative stress in hepatic tissues, characterized by elevated levels of AST, ALT, ALP, LDH, TOC, MDA, TNF-α, and IL-6 correlating with considerable decline in total protein, total albumin, TAC, SOD, CAT, GSH, and GPx. These changes were paralleled with histopathological alterations remarkable by devastation of the ordinary hepatic structure, with decrease in the numbers of normal hepatocytes, elevation in the numbers of necrotic hepatocytes, periportal and centrilobular inflammatory cells, deteriorated Kupffer cells, and dilated/congested central and portal veins. Alongside, a marked diminution in Bcl-2 immunoreactivity and a significant elevation in P53, Caspase-3, and TNF-α immunoreactivities were recorded. Supplementation of AgNPs-treated animals with Eug reversed most of the biochemical, histopathological, and immunohistochemical changes. Conclusion. This study proposed that Eug has an ameliorative effect against AgNPs-induced hepatotoxicity.

The triple-negative breast cancer (TNBC) microenvironment makes a feature of aberrant vasculature, high interstitial pressure, and compact extracellular matrix, which combine to reduce the delivery and penetration of therapeutic agents, bringing about incomplete elimination of cancer cells. Herein, employing the tumor penetration strategy of size-shrinkage combined with ligand modification, we constructed a photothermal nanocluster for cascaded deep penetration in tumor parenchyma and efficient eradication of TNBC cells. In our approach, the photothermal agent indocyanine green (ICG) is laded in human serum albumin (HSA), which is cross-linked by a thermally labile azo linker (VA057) and then further modified with a tumor homing/penetrating tLyP-1 peptide (HP), resulting in a TNBC-targeting photothermal-responsive size-switchable albumin nanocluster (ICG@HSA-Azo-HP). Aided by the enhanced permeability and retention effect and guidance of HP, the ca. 149 nm nanoclusters selectively accumulate in the tumor site and then, upon mild irradiation with the 808 nm laser, disintegrate into 11 nm albumin fractions that possess enhanced intratumoral diffusion ability. Meanwhile, HP initiates the CendR pathway among the nutrient-deficient tumor cells and facilitates the transcellular delivery of the nanocluster and its disintegrated fractions for subsequent therapy. By employing this size-shrinkage and peptide-initiated transcytosis strategy, ICG@HSA-Azo-HP possesses excellent penetration capabilities and shows extensive penetration depth in three-dimensional multicellular tumor spheroids after irradiation. Moreover, with a superior photothermal conversion effect, the tumor-penetrating nanocluster can implement effective photothermal therapy throughout the tumor tissue under a second robust irradiation. Both

Hepatic encephalopathy (HE) is a neuropsychiatric disorder that results from either acute or chronic liver failure. CXCR2 plays an essential role in the pathophysiology of liver and brain diseases. In the present study, the potential beneficial effects of SB332235, a selective inhibitor of CXCR2, against HE were evaluated.HE was induced in male rats by thioacetamide injection (200 mg/kg, i.p.) at three alternative days. SB332235 was injected in rats 1 h before TAA at a dose of 1 and 3 mg/kg i.p.SB332235 alleviated oxidative stress as shown by the decreased serum NO and reduced MDA, elevated GSH and SOD levels, and reduced TNF-α and NF-κB levels in both brain and liver tissues of rats. Additionally, SB332235 suppressed brain ASK-1, JNK, IL-8, and caspase-3 expression, and activated PI3K/AKT expression in brain tissues. Markers of brain dysfunction, such as ammonia, and markers of hepatic injury, such as LDH, albumin, bilirubin, γGT, AST, ALT, and ALP, were significantly ameliorated. Also, the protective effect of SB332235 was confirmed by histological examination of both brain and liver tissues.Both doses (1 and 3 mg/kg) of SB332235 revealed significant hepatic/neuroprotective effects due to their anti-inflammatory, antioxidant, and antiapoptotic activities via activation of the PI3K/AKT pathway. Between the two, the 1 mg/kg dose provided significantly improved outcomes.

Objective: Since its development, cumulative evidence has accumulated regarding the prognostic value of the Malnutrition-Inflammation Score (MIS/Kalantar score) prognostic value; however, there is a shortage of recent and large studies with comprehensive statistical methodologies that contribute to support a higher level of evidence and a consensual cutoff. The aim of this study was to assess the strength of MIS association with hospitalization and mortality in a nationwide cohort. Methods: This was a historical cohort study of hemodialysis patients from 25 outpatient centers followed up for 48 months. Univariable and multivariable Cox additive regression models were used to analyze the data. The C-index was estimated to assess the performance of the final model. Results: Two thousand four hundred forty-four patients were analyzed, 59.0% males, 32.0% diabetic, and median age of 71 years (P25 = 60, P75 = 79). During a median period of 45-month follow-up, with a maximum of 48 months (P25 = 31; P75 = 48), 875 patients presented an MIS