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Abstract: Combat casualty care can be complicated by transport times exceeding the "golden hour," with intervention and resuscitation limited to what the medic can carry. Pharmaceutical albumin comes highly saturated with nonesterified fatty acids (NEFAs). We recently showed that treatment with 25% bovine serum albumin (BSA) loaded with oleic acid, but not NEFA-free BSA, improved survival for hours after severe hemorrhage and often eliminated the need for resuscitation in rats. However, it was unknown whether pharmaceutical albumin, derived from human sources and loaded with caprylic acid (CA), would have the same benefits. We compared adjunct treatment with oleic acid-saturated BSA, CA-saturated BSA, pharmaceutical human serum albumin, or a no-albumin control in a similar rat hemorrhagic shock model to determine whether the three NEFA-albumin groups provided the same benefits relative to control. We found almost no significant differences among the NEFA-albumin groups in any measure. Mortality in controls was too low to allow for detection of improvement in survival, but NEFA-albumin groups had significantly improved hemodynamics, lactate clearance, and greatly reduced fluid requirements compared with controls. Contrary to expectations of "dehydration," 25% albumins shifted little additional fluid into the vasculature. Rather, they restored protein to the autotransfusion fluid. Nonesterified fatty acids-albumin did not worsen lung permeability, but we observed a loss of circulating protein suggesting it may have increased overall vascular permeability. Our findings suggest that, though imperfect, 25% human serum albumin could be a solution for resuscitation in austere conditions requiring prolonged field care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.) more...

Rationale & Objective: Rituximab is the first-choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population., Study Design: Case series., Setting & Participants: 7 rituximab-intolerant and 10 rituximab-resistant patients with MN who consented to receive ofatumumab (50-300mg, single intravenous infusion) and were followed at the nephrology unit of Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII (Bergamo, Italy) between September 2015 and January 2019., Findings: Over a median (IQR) follow-up of 5.0 (3.0-9.8) months, all 7 rituximab-intolerant and 3 of the 10 rituximab-resistant patients exhibited complete (proteinuria<0.3g/d) or partial (proteinuria<3.5g/d with≥50% reduction vs baseline) remission of nephrotic syndrome. Circulating B cells were similarly depleted in all patients by 1 week, and serum anti-phospholipase A 2 receptor antibody concentrations decreased to<2.7 relative units/mL in 3 of 4 rituximab-intolerant and 4 of 8 rituximab-resistant patients with phospholipase A 2 receptor-related disease. Ofatumumab significantly reduced 24-hour urinary protein and immunoglobulin G excretion and increased serum albumin and immunoglobulin G levels. These effects were greater in rituximab-intolerant than in rituximab-resistant patients. Measured glomerular filtration rate significantly increased by an average of 13.4% at 24 months compared with baseline (P=0.036) among all patients in the series. There were 14 nonserious infusion-related adverse events in 9 patients that recovered with temporary infusion interruption., Limitations: Retrospective design, limited number of patients., Conclusions: Ofatumumab may represent an effective and safe treatment for rituximab-intolerant cases of MN. Larger prospective studies will be needed to validate these preliminary findings and explore the effectiveness of other second-generation anti-CD20 antibodies in this clinical setting., Plain-Language Summary: Primary membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome (NS) in adults. In this case series, we explored the efficacy of ofatumumab, a fully human second-generation anti-CD20 antibody, in 17 patients with MN and NS who were intolerant or unresponsive to rituximab. All 7 rituximab-intolerant patients exhibited complete or partial clinical remission, compared with only 3 of the 10 rituximab-resistant patients. Autoantibody levels decreased in all patients with phospholipase A 2 receptor-related disease. Ofatumumab achieved a significant reduction in urinary protein and immunoglobulin G excretion while increasing serum albumin and immunoglobulin G levels. Ofatumumab may be a promising option for patients with MN who are rituximab-intolerant. Further investigations are warranted to validate these preliminary findings., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Purpose: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes., Methods: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin., Results: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients., Conclusion: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib. more...

Abstract: Management of heart failure (HF) requires the use of loop diuretics to relieve congestion and improve symptoms. When loop diuretics alone fail to induce adequate diuresis, albumin has been proposed to enhance loop diuretic delivery and promote redistribution of fluid for excretion by the kidneys. Despite the theoretical benefits of albumin, studies suggesting its benefit in HF are scarce and the co-administration of loop diuretics and albumin remains controversial. This retrospective, observational study evaluated patients with HF 18 years or older who received concomitant intravenous loop diuretic and albumin administration. The primary objective was to evaluate the association of serum albumin level with urine output (UOP) in hospitalized patients with HF who received concomitant albumin and loop diuretic therapy. Secondary endpoints included total weight loss after 72 hours, and ICU and hospital lengths of stay. In total, 276 patients were included for analysis. There was no association between initial serum albumin level and 72-hour UOP (coefficient -623.1, 95% confidence interval -1558.6 to 312.4; P = 0.191) or weight difference at 72 hours (coefficient -1.0, 95% confidence interval -2.4 to 0.3; P = 0.131). Lower albumin levels were associated with longer ICU ( P = 0.034) and hospital ( P = 0.039) lengths of stay. Concomitant thiazide diuretic use and increasing loop diuretic doses were associated with increased 72-hour UOP. The results of our study suggests that providers should avoid using baseline albumin levels as guidance for albumin dosing in HF. Given the lack of comparator groups, larger randomized controlled trials should be done to provide a definitive role for albumin to enhance diuresis in patients with HF on intravenous loop diuretics., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.) more...

Objective: To investigate the prognostic value of serum albumin (SA) levels before chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) after receiving chemotherapy., Methods: This is a retrospective study, and 127 patients with DLBCL including 71 males (55.9%) and 56 females (44.1%) were included. Patients' gender, age, Ann Arbor staging, eastern cooperative oncology group (ECOG) score, treatment options, international prognostic index, response rate, overall survival (OS), and progression-free survival (PFS) were obtained for statistical analysis., Results: Univariate analysis showed that SA≤34 g/L, Ann Arbor III-IV, B symptoms, ECOG≥2, and bone marrow involvement suggest a poor prognosis in patients with DLBCL. Patients with persistent SA>34 g/L had significantly longer OS than patients with persistent SA≤34 g/L (P=0.020). Multivariate analysis showed that SA≤34 g/L (HR=0.48, 95% CI=0.26-0.90, P=0.022) and R-CHOP-like treatment regimen (HR=0.43, 95% CI=0.24-0.76, P=0.004) are independent factors that could affect the prognosis of patients with DLBCL., Conclusion: SA can be used as an indicator of prognosis in patients with DLBCL before the first chemotherapy. DLBCL patients with SA≤34 g/L are associated with short OS and poor prognosis, which may potentially provide guidance for the clinician to pay more attention to this population before the first chemotherapy. more...

Backgound: Selinexor is an orally available selective inhibitor of exportin-1 that has offered a new treatment option in relapsed or refractory myeloma (RRMM) either in combination with dexamethasone (Sd) or with bortezomib and dexamethasone (SVd)., Patients-Methods: We evaluated the efficacy and toxicity of selinexor combinations in the real world, post progression therapies and their outcomes. The analysis included 44 patients with RRMM treated with Sd (N = 21, 48%) or SVd (N = 23, 52%)., Results: On intent-to-treat, response rate (ORR) among all treated patients was 29.5% (13/44, of which CR: 2, VGPR: 3, PR:8); ORR was 35% for SVd and 24% for Sd. Median PFS was 3.0 months for all; 6.9 months for responders (≥PR),2.7 months for Sd and 3.4 months for SVd treated patients. In univariate analysis, serum albumin <3.5 g/dl and LDH >ULN were associated with worse PFS (P = .001 and P = .032, respectively).The OS of the whole cohort exceeded one year while serum albumin <3.5 gr/dl and LDH>ULN were associated with worse OS. After progression to Sd/SVd, 20 patients received further therapy; on ITT, the ORR was 40% (8/20) and the subsequent PFS was 3.4 months. The most common adverse events were fatigue, thrombocytopenia and nausea, while the most recorded grade 3 or 4 side effect was thrombocytopenia; 56% (25/44) of patients required dose reduction, however, this was not associated with inferior PFS., Conclusion: In conclusion, selinexor-based therapy provides an additional treatment option in the real word setting and with appropriate dosing and toxicity management a subset of patients may have significant benefit., (Copyright © 2023. Published by Elsevier Inc.) more...

Background: We conducted this animal study to assess the efficacy of the novel hydrogel containing zinc oxide-loaded and minocycline serum albumin nanoparticals (Mino-ZnO@Alb NPs) on peri-implantitis in an experimental mouse model., Material and Methods: Mino-ZnO@Alb NPs was prepared as previously reported. The peri-implantitis model was successfully established in rats, and the rats were divided into three groups randomly: Mino-ZnO@Alb NPs (Mino-ZnO) group, minocycline group, and untreated group. Four weeks later, clinical and radiographic assessments were performed to evaluate soft tissue inflammation and bone resorption level. Histologic analysis was performed to estimate the amount of remaining supporting bone tissue (SBT) around implants. ELISA tests were used to determine the concentration of inflammation factor interleukin-1-beta (IL-1β) and anti-inflammation factor tumor necrosis factor-alpha (TNF-α) around implants., Results: After one month, the Mino-ZnO group showed better results than the other two groups in regards to the results of bleeding on probing, probing pocket depth, bleeding index and gingival index. X-ray showed that SBT at mesial and distal sites around implants in the other two groups was significantly lower compared with that of Mino-ZnO group. The quantity of osteoclasts in peri-implant tissues of the Mino-ZnO group was less than that in the minocycline and untreated groups. IL-1β in the Mino-ZnO group was lower than that in the other two groups. TNF-α level was the opposite., Conclusions: Mino-ZnO@Alb NPs can effectively treat peri-implantitis and promote soft tissue healing, and may act as a promising product. more...

Purpose: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies., Experimental Design: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE)., Results: FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri., Conclusions: These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them., (©2023 American Association for Cancer Research.) more...

Background: Albumin infusion is the primary therapeutic strategy for septic patients with liver cirrhosis. Although recent studies have investigated the efficacy of albumin in the resuscitation stage of septic patients with liver cirrhosis, it remains unclear whether daily albumin administration can improve outcomes. Furthermore, the indications for initiating albumin therapy are not well defined., Methods: Septic patients with liver cirrhosis were obtained from the Medical Information Mart for Intensive Care (MIMIC-IV 2.0) database. Marginal structural Cox models were employed to investigate the association between daily albumin infusion and 28-day mortality. We also aimed to explore under what circumstances enrolled patients could benefit most from albumin administration, based on the clinical parameters collected on the day of albumin infusion, including serum albumin concentration, serum lactate concentration, mean arterial pressure (MAP), and vasopressor dosage., Results: A total of 2265 patients were included in the final analysis, of whom 1093 (48.3%) had received albumin treatment at least once. The overall 28-day mortality was 29.6%. After marginal structural modeling, daily albumin infusion was associated with a reduced risk of 28-day death (hazard ratio, 0.76; 95% CI 0.61-0.94). We found that patients benefit most from albumin infusion when initiated on the day of serum albumin concentration between 2.5 and 3.0 g/dL, serum lactate concentration greater than or equal to 2 mmol/L, MAP less than 60 mmHg, or vasopressor dosage between 0.2 and 0.3 mcg/kg/min (norepinephrine equivalent, NEE)., Conclusions: Albumin infusion is associated with a reduction in mortality in septic patients with liver cirrhosis under specific circumstances. Serum albumin concentration, serum lactate, MAP, and vasopressor dosage were found to be modifiers of treatment effectiveness and should be considered when deciding to initial albumin infusion., (© 2023. The Author(s).) more...

Serum albumin (SA), one of the most abundant proteins in blood plasma, plays essential roles in all living processes and has been used in various biomedical applications. Biomaterials fabricated from SAs (human SA, bovine SA, and ovalbumin) exhibit proper microstructure and hydrophilicity as well as remarkable biocompatibility; this makes them ideal for use in bone regeneration. This review provides a comprehensive overview of the structure, physicochemical properties, and biological features of SAs. SAs can be used to generate a wide array of biomaterials for bone repair because of their flexible structure and diverse functions, which enables us to control structure and morphology as well as modulate the biological responses with host tissue. This review summarizes the material categories, forms, and fabrication methods of SA in bone repair. Finally, concerns for future studies in biomedical fields with SA-derived biomaterials are discussed. more...

Objective: To describe the clinical use of canine-specific albumin (CSA) in critically ill dogs, report adverse events, and evaluate measurable clinical effects of CSA administration., Design: Retrospective case series from 2019 to 2020., Setting: Large, urban, private-practice referral and emergency center., Animals: Consecutive sample of 125 client-owned dogs administered CSA transfusions., Interventions: None., Measurements and Main Results: The conditions most commonly associated with the use of CSA were surgical (32/125) and nonsurgical (20/125) gastrointestinal disease. Both serum albumin and total plasma protein concentrations were significantly increased posttransfusion (P < 0.001), and 16% albumin transfusions produced the greatest magnitude increase in serum albumin (P = 0.0015). Concurrent crystalloid administration did not affect change in albumin. While there was no significant improvement in blood pressure seen in those patients that received albumin, a significant improvement in shock index was identified (P = 0.02). Adverse events were uncommon; however, 8 critically ill dogs died during CSA administration., Conclusions: CSA appears to be a relatively safe alternative to synthetic colloids and complementary to crystalloids in critically ill patients. More concentrated solutions may be more effective in raising serum albumin concentration. Further investigation into the indications for and efficacy of CSA will continue to improve our knowledge of this blood product., (© Veterinary Emergency and Critical Care Society 2023.) more...

The use of cisplatin is severely limited by the risk of developing cardiovascular complications. Sinapic acid may reduce cisplatin's side effects. The anti oxidant, anti-inflammatory, and peroxynitrite-scavenging properties of sinapic acid could provide protection against the cardiotoxicity caused by cisplatin. To induce toxicity in rats, cisplatin was administered for a period of 5 weeks. Animal electrocardiograms were obtained after cisplatin toxicity had taken effect. Blood samples and heart tissues were then harvested from the anesthetized animals. The ELISA technique was used to evaluate the level of proinflammatory cytokines and oxidative and nitrosative stress indicators in the heart tissue and serum. A real-time PCR was used to analyze GPX4 and NF-κB expression in the heart tissue. Hematoxylin-eosin and Masson's trichrome were also utilized. Electrocardiograms data showed an increase in QRS and QT intervals. Biochemically, cisplatin increased oxidative, nitrosative, and proinflammatory cytokine levels. Animals exposed to cisplatin had histopathological findings in the heart tissue, according to the results of histological assessment. Sinapic acid reduced TNF-alpha, interleukin-6, malondialdehyde, and ischemia-modified albumin. Sinapic acid also reduced oxidative and nitrosative stress. Furthermore, Sinapic acid restored lengthy QT and QRS. Cisplatin-treated rats had higher NF-κB activation than controls. This effect was successfully inhibited by sinapic acid. Histopathologically, tissues treated with sinapic acid were less damaged than tissues treated with cisplatin. In conclusion, our results suggest that sinapic acid exhibited a protective effect against the cardiotoxicity induced by cisplatin. These effects may be caused by the overexpression of GPX4 and the downregulation of NF-KB, as well as antioxidant and anti-inflammatory properties., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

Background: The coexistence of Neuromyelitis Optica spectrum disorder (NMOSD) with other autoimmune diseases (AD-NMOSD) presents worse clinical outcomes and healthcare costs than NMOSD alone (NMOSD-only). NMOSD and other autoimmune diseases also have a higher prevalence and morbidity in Black. We aim to compare clinical features and treatment responses in NMOSD patients with and without overlapping autoimmunity in a predominantly Black cohort. We further identify predictors associated with each clinical subtype., Methods: AD-NMOSD (n = 14) and NMOSD-only (n = 27) patients were identified retrospectively. Demographic, clinical, laboratory, imaging, and response to treatment data were examined., Results: Our cohort was predominately Black (82.9%). The prevalence of grouped-comorbidities, history of infections, sensory symptoms, Expanded Disability Status Scale (EDSS) before treatment, double-stranded DNA, antinuclear, ribonucleoprotein, and antiphospholipid antibodies, spinal-cord edema, white matter occipital lesions, and the levels of C-reactive protein, urine protein/creatinine, white blood cell count in cerebrospinal fluid (CSF), were higher in AD-NMOSD patients (p < 0.05 and/or Cramer's V > 30, Cohen's d > 50), whereas the age of males, visual symptoms, serum albumin, platelet count, and optic nerve enhancement were lower. EDSS after treatment improved in both groups being more evident in NMOSD-only patients (p = 0.003, SE = 0.58 vs p = 0.075, SE = 0.51). Other variables had a close to moderate SE, and others did not differ between NMOSD subtypes. A higher frequency of grouped-comorbidities, lower serum albumin, and platelet count were independently associated with a higher risk for AD-NMOSD., Conclusions: Some clinical features between AD-NMOSD and NMOSD-only patients were similar, while others differed. Comorbidities, serum albumin, and platelet count may be independent predictors of AD-NMOSD., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare that are relevant to the content of this article., (Published by Elsevier B.V.) more...

Background: Achieving optimal glycemic targets is the main therapeutic goal in patients with type 2 diabetes (T2D) mellitus. HbA1c is the reference biomarker for monitoring glycemic control; however, in specific conditions affecting erythrocyte turnover or in patients on multiple daily injection (MDI) insulin regimens, the determination of glycated albumin (GA) may be preferable. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a novel class of antidiabetic drugs that lower plasma glucose concentrations quickly, with insulin-independent mechanisms. Herein, we explored the role of GA in predicting the short-term response to SGLT-2 inhibitors as add-on to MDI insulin., Methods: Sixteen patients with long-standing, poorly controlled T2D on MDI insulin starting an SGLT-2 inhibitor were subjected to plasma GA and HbA1c measurements at 30 days intervals for up to 3 months in order to examine the temporal changes of these glycemic biomarkers., Results: At the end of the study, grossly coincident with the life span of erythrocytes, a significant decrease in median HbA1c was observed, (from 8.7 [range: 8.2-9.3%] at baseline to 7.2 [range: 7.0-7.9%]), with the advantage of less insulin dose requirements. However, significant, and incremental reductions in median GA determinations could be already evident after 30 days (-3.5 [range: -7.5, -2.5%]) and 60 days (-6.4 [range: -10.5, -4.7%]) from the start of SGLT-2 inhibitor treatment and persisted for up to 3 months (-8.6 [range: -12.1, 6.1%]). The decrements of HbA1c observed at the 3-month visit were highly correlated with the concurrent absolute reductions of plasma GA (ρ=0.550, P=0.027), whereas a borderline significance could be demonstrated with reference to reductions in plasma GA at 30 and 60 days., Conclusions: Although limited by the small number of participants, these preliminary findings suggest that GA, rather than HbA1c, could represent a useful and reliable biomarker in T2D to monitor the early glucose-lowering effects of antidiabetic drugs with rapid onset of action, such as SGLT-2 inhibitors and MDI insulin. more...

As we look forward to the bright future of immune checkpoint blockade (ICB) therapy, there is still lacking a pharmacokinetic marker to understand the inter-individual differences in ICB response. ICB therapy is based on IgG antibodies that share the same homeostatic pathway with serum albumin. Therefore, serum albumin level could reflect IgG catabolic rate that directly impacts the clearance of therapeutic IgG antibodies. Through interrogating a large, clinically representative pan-cancer cohort of 1,479 ICB-treated patients, this study found that higher baseline albumin levels were significantly associated with stepwise improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) ( p <0.001), with the variability and reproducibility confirmed in 1,000 bootstrap-resampled cohorts. Furthermore, these findings were also confirmed in most subgroups defined by patient demographics, baseline characteristics, treatments, and cancer types, even in those with low ICB-responsive cancer types and low tumor mutation burden (TMB) (TMB≤10 mut/Mb) that most of which have not been approved by the US Food and Drug Administration (FDA) for ICB therapy. In summary, this study highlights the importance of pretreatment pharmacokinetic modeling for predicting ICB treatment outcomes. Based on serum albumin-an inexpensive, non-invasive, and easily accessible biomarker of IgG pharmacokinetics, we could take a step further towards optimizing ICB therapy., Competing Interests: Competing interests: This study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Intravenous administration of crystalloid or colloid solutions is the most common intervention for correcting hypovolemia in intensive care unit patients. In critical illness, especially sepsis and severe trauma, vascular wall permeability increases, and trans-endothelial escape of serum albumin, the major oncotic plasma constituent, contributes to the development of hypoalbuminemia and edema formation. The volume effects of intravenous human albumin solution exceed those of crystalloid solutions. If hypoalbuminemia is an effect moderator, the crystalloid-to-albumin ratio of fluid resuscitation volumes is not well characterized. Randomized controlled trials have confirmed that intravenous administration of human albumin solutions for volume resuscitation results in a lower net fluid balance compared with crystalloids, and smaller infusion volumes may be sufficient for hemodynamic stabilization when human albumin solutions are used. This narrative review summarizes the current evidence and conclusions drawn regarding the role of hypoalbuminemia in volume resuscitation. In the 'Saline versus Albumin Fluid Evaluation' study using 4% human albumin solution or saline, the saline-to-albumin ratio of study fluids was significantly higher in patients with baseline serum albumin concentrations of 25 g/L or less as compared to patients with baseline serum albumin concentrations of more than 25 g/L. In patients receiving renal replacement therapy, intravenous administration of 20-25% human albumin solution reduces intradialytic hypotension and improves fluid removal better than saline if serum albumin levels are similarly reduced. These data suggest that hypoalbuminemia acts as an effect moderator in volume resuscitation and plasma expansion with albumin solution. The volume effectiveness of intravenous human albumin solution in resuscitation appears to be greater when the serum albumin levels are low. In clinical situations, serum albumin concentrations per se may inform when and how to include intravenous albumin in fluid resuscitation if large amounts of crystalloids are needed, which requires further studies. more...

Objectives: Previous studies have compared mycophenolate mofetil and azathioprine as maintenance therapy for lupus nephritis (LN). Leflunomide is an immunosuppressant widely used in the treatment of rheumatoid arthritis. The aim of this investigator-initiated study was to compare the efficacy and safety of leflunomide versus azathioprine as maintenance therapy for LN., Methods: 270 adult patients with biopsy-confirmed active LN from 7 Chinese Rheumatology Centres were enrolled. All patients received induction therapy with 6-9 months of intravenous cyclophosphamide plus glucocorticoids. Patients who achieved complete response (CR) or partial response (PR) were randomised to receive prednisone in combination with leflunomide or azathioprine as maintenance therapy for 36 months. The primary efficacy endpoint was the time to kidney flare. Secondary outcomes included clinical parameters, extrarenal flare and adverse effects., Results: A total of 215 patients were randomly allocated to the leflunomide group (n=108) and azathioprine group (n=107). Kidney flares were observed in 17 (15.7%) leflunomide-treated patients and 19 (17.8%) azathioprine-treated patients. Time to kidney flare did not statistically differ (leflunomide: 16 months vs azathioprine: 14 months, p=0.676). 24-hour proteinuria, serum creatinine, serum albumin, serum C3 and serum C4 improved similarly. Extrarenal flare occurred in two patients from the azathioprine group and one patient from the leflunomide group. The incidence of adverse events was similar in the 2 groups: leflunomide 56.5% and azathioprine 58.9%., Conclusions: The efficacy and safety profile of leflunomide are non-inferior to azathioprine for maintenance therapy of LN. Leflunomide may provide a new candidate for maintenance therapy in patients with LN., Trial Registration Number: NCT01172002., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Objective: To explore the long-term efficacy of low-dose rituximab (RTX) treatment in patients with primary membranous nephropathy (PMN). Methods: Patients with biopsy-proven PMN who received low-dose RTX as initial or second-line regimen from August 2018 to May 2020 in the Department of Nephrology, Tianjin Medical University General Hospital were respectively enrolled. The clinical parameters of patients were urinary protein>3.5 g/24 h, serum albumin<30 g/L and estimated glomerular filtration rate (eGFR)>20 ml·min -1 ·(1.73 m 2 ) -1 . The treatment response of patients with PMN was observed during follow-up, and the remission rate of patients with urinary protein<8 g/24 h or ≥8 g/24 h, anti-PLA2R antibody<150 RU/ml or ≥150 RU/ml, eGFR≥ 60 ml·min -1 ·(1.73 m 2 ) -1 or<60 ml·min -1 ·(1.73 m 2 ) -1 were analyzed, respectively. Results: A total of 40 patients were enrolled, including 26 males and 14 females, aged (53±15) years. There were 14 patients received RTX as initial treatment and 26 patients as second-line therapy. The total median dose of RTX in the first course was 800 (425, 1 075) mg. The overall remission rate at the 1st, 3rd, 6th, 12th and 24th months were 12.5% (5/40), 17.5% (7/40), 47.5% (19/40), 57.5% (23/40), 60% (24/40), respectively. The median overall response time was 6.0 (3.0, 7.5) months. Two cases relapsed. Patients with remission ( n =24) had a higher level of baseline eGFR [(93.9±28.0) vs (62.4±28.1) ml·min -1 ·(1.73 m 2 ) -1 , P =0.001), and a lower level of both urinary protein [5.9 (5.0, 6.5) vs 11.7 (8.6, 15.5) g/24 h, P <0.001] and anti-PLA2R antibody level [73 (29, 132) vs 453 (182, 950) RU/ml, P =0.004] than those without remission ( n =16) 24 month after treatment. There was no statistically significant difference in the remission rate between initial and second-line treatment ( P =0.101). Moreover, patients had a higher remission rate in urinary protein<8 g/24 h group (21/26 vs 3/14, P <0.001), anti-PLA2R antibody<150 RU/ml group (16/19 vs 5/16, P =0.002) and eGFR ≥ 60 ml·min -1 ·(1.73 m 2 ) -1 group (22/29 vs 2/11, P =0.003). Conclusions: Low-dose RTX treatment in PMN is effective during long-term follow-up, and has a lower recurrence rate. The results also suggest that it is more suitable for patients with baseline urinary protein<8 g/24 h, anti-PLA2R antibody<150 RU/ml and eGFR≥ 60 ml·min -1 ·(1.73 m 2 ) -1 . more...

Background: The risk of osteoporosis in patients with rheumatoid arthritis (RA) is frequently overlooked, and investigating a simple indicator in routine care may be beneficial to motivate osteoporosis examination. The aim of this retrospective, case-controlled study was to identify the correlation between serum albumin concentrations and the prevalence of osteoporosis in postmenopausal patients with RA., Methods: This study enrolled 197 patients who underwent dual-energy X-ray absorptiometry of lumbar spine (LS) and proximal femur without osteoporosis treatment [mean age, 67.5 years; disease duration, 12.8 years; Disease Activity Score assessing 28 joints with C-reactive protein, 2.0; prednisolone dose, 4.9 mg/day (usage, 42.6%); and LS T-score, -1.9]. Patients were classified into 2 groups: osteoporosis, defined as ≥ 1 part bone mineral density T-score ≤ -2.5 or history of fragility fracture of the vertebra or proximal femur (121 patients), and non-osteoporosis (76 patients). Groups were then matched by propensity score using clinical backgrounds affecting bone metabolism., Results: In non-matched model, serum albumin concentration was significantly associated with osteoporosis-related factors such as aging, inflammation, physical disability, and glucocorticoid dose. Multivariate logistic regression revealed that serum albumin concentration was independently and significantly associated with osteoporosis risk (odds ratio = 0.22, 95% confidence interval = 0.08, 0.61, p = 0.0033). After propensity score matching, 57 patients for each group showed that in addition to the LS and femoral neck T-scores (p < 0.001), serum albumin concentrations (p = 0.01) remained lower in the osteoporosis group compared to non-osteoporosis group. Receiver operating characteristic curve analysis in non-matched model revealed that when cut-off value of serum albumin concentration for indicating osteoporosis was set at 4.2 g/dl, the area under the curve was 0.69, sensitivity 0.74, and specificity 0.58., Conclusions: Low serum albumin concentration was significantly and independently associated with the prevalence of osteoporosis, which may be considered as one of the osteoporosis-related factors in postmenopausal patients with RA., Competing Interests: Declaration of competing interest KE is affiliated with, and KN supervise the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho. KE has received payments for lectures from Amgen, Asahi-Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Ono, and Pfizer, and received consultant fee from Asahi-Kasei. KE and MH have received research grants from Amgen, Asahi-Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, and Ono. YN has received payments for lectures from Asahi-Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, and Ono. HT has received payments for lectures from Asahi-Kasei, Astellas, Chugai, Eisai, Eli Lilly, and Pfizer, and has received a research grant from Chugai. JH have received payments for lectures from Chugai, and research grants from Astellas, Chugai, and Eisai. HY have received research grants from Astellas, Daiichi Sankyo, Eisai, and MSD. KN has received a research grant from Astellas. SO declare that he has no conflicts of interest., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.) more...

Immune checkpoint inhibitors (ICIs) for treatment of metastatic melanoma (MM) offer lasting overall survival (OS) benefit in a subset of patients. However, outcomes remain poor for non-responders. Clinical predictors of long-term survival remain elusive. We utilized the Alberta Immunotherapy Database to investigate the association of host and disease characteristics, and treatment factors with overall survival (OS) greater than 3 years. We identified patients treated between August 2013 and May 2020 with single-agent anti-PD1 or combination (anti-PD1 and anti-CTLA4) ICI regimens. A logistic regression model was used to assess for independent association between clinical factors captured and survival greater than 3 years. Statistically significant factors on univariable analysis were assessed using multivariable analysis. In total, 284 of 460 patients were identified to have short-term (<1 year) or long-term (>3 years) survival with 186 surviving <1 year and 98 surviving >3 years. The median age was 64 and 18.4% of patients were ECOG ≥ 2. On logistic regression, Breslow's Depth ≤ 4 mm, normal serum LDH, normal serum albumin and M-stage 1a/b were associated with OS > 3 years on univariable and multivariable analysis. ECOG < 2, dNLR ≤ 3, normal hemoglobin were only associated with survival on the univariable analysis but not in the multivariable analysis. The objective response rate in long-term survivors was 83.7% compared to 7.5% in the short-term survivors. Our study identifies four easily accessible predictors of long-term survival in a large real-world MM cohort treated with ICI. more...

The enhanced permeability and retention (EPR) effect has been the gold standard in developing drug delivery systems for passive tumor targeting. Although the importance of this concept remains unchanged, some controversies have arisen. In this review, various strategies for tumor targeting using macromolecules and nanoparticles based on the EPR effect are discussed from the viewpoint of pharmacokinetics. Overall, such strategies seek to retain therapeutic material in the blood circulation, which is a key factor for successful targeting. Strategies using macromolecules, including antibody-drug conjugates, serum albumin-based delivery systems, PEGylated recombinant proteins, and stealth liposomes as well as nanoparticle-based strategies such as those based on lipid nanoparticles, and polymeric micelles, have been discussed. The feasibility of small extracellular vesicles, a new class of nanosized delivery carriers, is also discussed., (Copyright © 2022 Elsevier B.V. All rights reserved.) more...

Purpose: Pegfilgrastim is widely used to prevent chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) in patients with diffuse large B-cell lymphoma (DLBCL). We investigated the predictive factors affecting CIN and FN incidence in patients with DLBCL receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy with pegfilgrastim and conducted experiments to find reason for the occurrence of CIN even when pegfilgrastim was used., Materials and Methods: We reviewed the CIN and FN events of 200 patients with DLBCL. Based on these data, we investigate the association with predictive factor and the levels of granulocyte-colony stimulating factor (G-CSF) receptor signaling pathway markers (pSTAT3, pAKT, pERK1/2, pBAD, and CXCR4) in bone marrow (BM) samples isolated from patients with DLBCL., Results: FN was significantly associated with stage III/IV (hazard ratio [HR], 12.74) and low serum albumin levels (HR, 3.87). Additionally, patients with FN had lower progression-free survival (PFS; 2-year PFS, 51.1 % vs. 74.0%) and overall survival (OS; 2-year OS, 58.2% vs. 85.0%) compared to those without FN. The occurrence of CIN was associated with overexpression of G-CSF receptor signaling pathway markers, and expression levels of these markers were upregulated in BM cells co-cultured with DLBCL cells. The rate of neutrophil apoptosis was also higher in neutrophils co-cultured with DLBCL cells and was further promoted by treatment with doxorubicin., Conclusion: Our findings suggest that high DLBCL burden may alter the BM environment and G-CSF receptor signaling pathway, even in chemotherapy-naïve state, which may increase CIN frequency during R-CHOP chemotherapy. more...

Background: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population., Methods: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year., Results: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM., Conclusion: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A., (© 2022. The Author(s).) more...

Introduction: A good response to initial therapy is key to maximizing survival in patients with diffuse large B-cell lymphoma (DLBCL), but patients with chemorefractory disease and early progression have poor outcomes., Patients and Methods: Data from the GOYA study in patients with DLBCL who received first-line rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were analyzed. Positron emission tomography/computed tomography (PET/CT)-derived characteristics associated with total metabolic tumor volume (TMTV) and clinical risk factors for primary chemorefractory disease and disease progression within 12 months (POD12) were explored., Results: Of those patients fulfilling the criteria for analysis, 108/1126 (10%) were primary chemorefractory and 147/1106 (13%) had POD12. Primary chemorefractory and POD12 status were strongly associated with reduced overall survival. After multivariable analysis of clinical and imaging-based risk factors by backward elimination, only very high TMTV (quartile [Q] 1 vs. Q4 odds ratio [OR]: 0.45; P = .006) and serum albumin levels (low vs. normal OR of 1.86; P = .004) were associated with primary chemorefractoriness. After additionally accounting for BCL2/MYC translocation in a subset of patients, TMTV and BCL2/MYC double-hit status remained as significant predictors of primary chemorefractoriness (Q1 vs. Q4 OR: 0.32, P = .01 and double-hit vs. no-hit OR of 4.47, P = .02, respectively). Risk factors including very high TMTV, high sum of the product of the longest diameters (SPD), geographic region (Asia), short time since diagnosis, extranodal involvement and low serum albumin were retained for POD12., Conclusion: PET-derived TMTV has prognostic value in identifying patients at risk of early treatment failure., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Dear Editor, Scurvy is a nutritional disorder which can develop after prolonged (>1-3 months) severe vitamin C deficiency. Vitamin C is a cofactor in several enzyme reactions involved in collagen synthesis. The defect in collagen causes blood vessel fragility, poor wound healing, mucocutaneous bleedings, hair abnormalities, bone pains, and joint contractures due to periosteal and intraarticular bleeding (1,2). Risk factors for scurvy development are undernutrition, low socioeconomic status, older age, male sex, alcoholism, tobacco smoking, and severe psychiatric illnesses (1-3). The required daily intake for vitamin C is ~60 mg, and this amount of vitamin C can be found in only one medium-sized orange. For this reason, the disease is rarely encountered in developed countries and is often underrecognized by healthcare personnel. Herein, we present an illustrative case of scurvy in order to raise the awareness of this disorder. A 61-year-old Caucasian man was admitted to hospital due to fatigue, hypotension (80/50 mmHg), severe normocytic anemia (hemoglobin 76 g/L), kidney failure (estimated glomerular filtration rate of 6 mL/min/1.73m2) and mild elevation in C-reactive protein (30.9 mg/L). Prior medical history included radical cystoprostatectomy with an ileal conduit performed eight years ago due to a bladder tumor and moderate chronic kidney disease with recurrent urinary tract infections. The patient was also an alcoholic and tobacco smoker, with a very low-income and a poor diet. He did not use any medications. Heteroanamnestically, the current clinical state had developed slowly over several weeks. At admission, the patient was afebrile, lethargic, malnourished, and immobile due to generalized weakness, bone pains, and hip and knee contractures. He had generalized edema, mostly related to kidney failure, as well as severe hypoalbuminemia (serum albumin 19 g/L). There were multiple ecchymoses (Figure 1, a) and perifollicular bleedings (Figure 1, b) in the skin. The teeth were defective, and the patient's facial hair had a "corkscrew" appearance (Figure 1, c). The platelet count was normal, as was the serum fibrinogen level and the prothrombin- and activated partial thromboplastin times. Vancomycin-resistant Enterococcus faecium and multi-drug-resistant Acinetobacter baumanii were isolated from the urine. Therefore, hemodialysis, linezolid, and colistin were started. However, the patient continued to be lethargic, immobile, and with prominent skin bleeding. Medical workup excluded the possibility of an underlying malignancy or an autoimmune disorder. Finally, scurvy was suspected and 500 mg daily of oral vitamin C was introduced into therapy. In the following two weeks, the general condition of the patient significantly improved and he was discharged from the hospital in good condition - mobile and with complete resolution of skin lesions (Figure 1, d and e). Three months later, the patient was still under maintenance hemodialysis and had mild anemia (hemoglobin 123 g/L). Interestingly, scurvy was the first disease in the history of medicine for which a randomized trial found a cure (4). The differential diagnosis of scurvy includes skin infections, hematologic disorders, collagen vascular disorders, and anticoagulant/antiplatelet side-effects (1). Pathognomonic skin findings which may help raise suspicion of scurvy are perifollicular bleedings and "corkscrew" hair. Notably, laboratory testing for vitamin C concentration is not necessary to confirm scurvy as it tends to reflect recent dietary intake of vitamin C (2). Nevertheless, it may be useful to identify less typical cases (2). In our case, rapid clinical improvement with the resolution of skin lesions and joint contractures after the introduction of vitamin C confirmed the clinical diagnosis of scurvy. Additionally, vitamin C deficiency could be, at least partly (besides kidney failure and acute infection), responsible for severe anemia at disease presentation (5). This case serves to remind clinicians not to forget scurvy when treating patients at risk for vitamin C deficiency who present with fatigue, anemia, bone pains, and unexplained mucocutaneous bleedings. In suspected cases, vitamin C should be administered without hesitation. more...

What is the topic of this review? Human serum albumin (HSA) a common factor in COVID-19 vulnerabilities. What advances does it highlight? Understanding of HSA capacity, and systemic vulnerabilities to COVID-19. Raising HSA in COVID-19 patients may alleviate systemic injury caused by diminished native HSA binding. A change in fluid therapy administration into the portal system of the liver is proposed to safely raise HSA levels. ABSTRACT: The specific nature of the vulnerabilities to COVID-19 are an intrinsic part of COVID-19 infection in many patients. This paper proposes that vulnerabilities to COVID-19 may be intensified by a decrease in human serum albumin (HSA) as a ligand carrier for nutrients. A mechanism for COVID-19 vulnerabilities is evident from consideration of ligand carriers such as HSA as intermediaries. We hypothesise that low levels of pool HSA binding, caused for whatever reason, affect the performance of albumin as a carrier protein reducing the availability of nutrients. Hypoalbuminaemia (low HSA) has been implicated as an indicator of COVID-19 and long-COVID-19. The levels of HSA directly affect the immune system and vulnerabilities to age, diabetes and obesity in COVID-19. Any slight reduction in available HSA has profound effects on ligand concentrations in the small capillaries where damage occurs in COVID-19. The clinical implication is that attempts should be made to return HSA to clinical levels to compensate for the additional ligands caused by infection (SARS-CoV-2 virions, antibodies and cellular breakdown products). Therapeutic albumin is usually given peripherally, and usual preparations are unbound to ligands, but we suggest that a clinical trial of HSA therapy via the hepatic portal vein should be considered., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.) more...

Background: While the introduction of immune checkpoint inhibitors (ICI) such as pembrolizumab has significantly improved survival for patients with metastatic non-small cell lung cancer (NSCLC), there remains a need for improved predictive and prognostic biomarkers., Patients and Methods: We conducted a retrospective, 3-center study using electronic medical record data for patients with stage IV NSCLC treated with first-line pembrolizumab, either as monotherapy or in combination with chemotherapy, between 2014 and 2019. We categorized variables as covariates or confounders. Covariates, which were the focus of analysis due to their emerging prognostic value, included pretreatment body mass index (BMI), neutrophil-to-lymphocyte ratio (NLR), albumin, and antibiotic exposure. Confounders, which highlighted characteristics for each patient and their cancer, included sex, age at start of immunotherapy, Programmed death-ligand 1 (PD-L1) expression, performance status (PS), tumor mutational burden and whether pembrolizumab was given as monotherapy or in combination with chemotherapy. The association between these variables with time to treatment failure (TTF) and overall survival (OS) was assessed using Kaplan-Meier method and Cox proportional hazards models., Results: One hundred thirty-six patients were included in our study. Antibiotics usage, serum albumin, and NLR have univariate relationships with TTF. Serum albumin, NLR, and BMI were associated with OS in univariate analyses. In our multivariate analysis, antibiotic usage had a strong negative association with TTF when adjusting for all 6 confounders., Conclusion: Pretreatment usage of antibiotics, as well as albumin, NLR, and BMI have potential to predict treatment outcomes in patients with advanced NSCLC receiving first-line immunotherapy., (Copyright © 2022. Published by Elsevier Inc.) more...

Background: Cancer cachexia exhibits decreased albumin and associates with short overall survival (OS) in patients with non-small cell lung cancer (NSCLC), but whether on-treatment albumin changes associate with OS in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and combination chemoimmunotherapy has not been thoroughly evaluated., Patients and Methods: We conducted a single-center retrospective study of patients with advanced NSCLC who received first-line ICI with or without chemotherapy between 2013 and 2020. The association of pretreatment albumin and early albumin changes with OS was evaluated using Kaplan-Meier method and Cox regression models., Results: A total of 210 patients were included: 109 in ICI cohort and 101 in ICI + Chemo cohort. Within a median of 21 days from treatment initiation, patients with ≥ 10% of albumin decrease had significantly shorter OS compared to patients without albumin decrease in ICI cohort. Pretreatment albumin and albumin decrease within the first or second cycle of treatment were significantly and independently associated with OS in ICI cohort, but not in ICI + Chemo cohort. The lack of association between albumin and OS with the addition of chemotherapy was more pronounced among patients with ≥ 1% PD-L1 expression in subgroup analysis., Conclusion: Pretreatment serum albumin and early albumin decrease in ICI monotherapy was significantly associated with OS in advanced NSCLC. Early albumin change, as a routine lab value tested in clinic, may be combined with established biomarkers to improve outcome predictions of ICI monotherapy. The underlying mechanism of the observed association between decreased albumin and ICI resistance warrants further investigation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Cyclic dinucleotides (CDN) and Toll-like receptor (TLR) ligands mobilize antitumor responses by natural killer (NK) cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy targeting stimulator of interferon genes (STING) protein has yielded mixed results, perhaps because it initiates responses potently but does not provide signals to sustain activation and proliferation of activated cytotoxic lymphocytes. To improve efficacy, we combined CDN with a half life-extended interleukin-2 (IL-2) superkine, H9-MSA (mouse serum albumin). CDN/H9-MSA therapy induced dramatic long-term remissions of the most difficult to treat major histocompatibility complex class I (MHC I)–deficient and MHC I+ tumor transplant models. H9-MSA combined with CpG oligonucleotide also induced potent responses. Mechanistically, tumor elimination required CD8 T cells and not NK cells in the case of MHC I+ tumors and NK cells but not CD8 T cells in the case of MHC-deficient tumors. Furthermore, combination therapy resulted in more prolonged and more intense NK cell activation, cytotoxicity, and expression of cytotoxic effector molecules in comparison with monotherapy. Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA with checkpoint therapy yielded long-term remissions in the majority of the animals, mediated by T cells and NK cells. This combination therapy has the potential to activate responses in tumors resistant to current therapies and prevent MHC I loss accompanying acquired resistance of tumors to checkpoint therapy. more...

Background: The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN., Methods: Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events., Results: There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29)., Conclusions: In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy., Trial Registration: ClinicalTrials.gov Identifier NCT03062813. more...

Background: Repeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities., Methods: Thirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 g/m 2 were used for low-risk patients and 5 g/m 2 for standard/high-risk patients. The Common Terminology Criteria for Adverse Events (V.4.03) was used to report the observed toxicities after HDMTX cycles. Plasma MTX levels were estimated at 24 h (MTX 24 ) from the beginning of HDMTX infusion in the first consolidation cycle. Serum albumin level was determined before HDMTX administration, and pre-infusion hypoalbuminemia was defined when serum albumin was <3.5 g/dL., Results: The patients' age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standard/high risk. Grade 3-4 anemia, grades 3-4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p=0.003, p=0.007, p=0.006, and p=0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p=0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 g/m 2 than the 5 g/m 2 HDMTX cycles (46.7 vs. 26.7%, p=0.023). A significantly longer hospitalization (due to HDMTX toxicity) was observed in the 5 g/m 2 HDMTX cycles (median= 7 days vs. 4 days, p=0.012)., Conclusions: Serum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities., (© 2022. The Author(s).) more...

Objectives: According to recent reports, prophylactic use of antibiotics is not always required in conventional transarterial chemoembolization (c-TACE). However, clinical evidence of prophylactic antibiotics in drug-eluting beads transarterial chemoembolization (DEB-TACE) to prevent postsurgical infection is limited. This study is aimed to evaluate the correlation between the preoperative prophylactic application of antibiotics and postoperative infection in c-TACE or DEB-TACE, especially in a population with a high risk for postsurgical infection., Methods: In this retrospective study, TACE patients diagnosed with hepatic carcinoma (between January 2019 and May 2021) were examined. The case group was given 1.5 g cefuroxime sodium 0.5-1 hour before TACE, while there was no intervention in the control group. The outcomes analyzed were leukocyte count >9.5 × 10 9 /L on the second day after the operation and the diagnosis of infection within one month after the operation. We applied univariate, multivariate logistic regression, trend analysis, and subgroup analysis to find potential risk factors and the necessity of prophylactic antibiotics., Results: Among 142 eligible cases, 72 received antibiotics while 70 were kept as control, 113 cases were treated with c-TACE, and 29 were treated with DEB-TACE. Multivariate analysis showed that the increase in white blood cell count after the operation was related to diabetes (OR 5.112, 95% CI 1.229-21.264, p  = 0.025). The occurrence of postoperative infection was negatively correlated with preoperative albumin value (＜25 g/L) (OR 153.118, 95% CI 1.631-14372.331, p  = 0.030). Trend analysis showed that the risk of postoperative infection increased with a decrease in serum albumin level ( P  < 0.05). Subgroup analysis showed that there were no significant differences in the incidence of increased leukocyte count and postoperative infection between the prophylactic and nonprophylactic treatment groups, in the case of diabetes, preoperative albumin levels, and operation mode ( P  > 0.1)., Conclusions: Prophylactic antibiotic treatment before the c-TACE or DEB-TACE had no significant correlation with postoperative leukocyte increase and postoperative infection. Diabetes history and serum albumin levels were the prominent risk factors associated with an increase in postoperative leukocyte count and postoperative infection. Future large-scale studies and randomized-controlled trials are required to confirm and validate this association., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Baojian Li.) more...

Background: The transcapillary leakage of albumin is increased by inflammation and major surgery, but whether exogenous albumin also disappears faster is unclear., Methods: An intravenous infusion of 3 mL/kg of 20% albumin was given over 30 min to 70 subjects consisting of 15 healthy volunteers, 15 post-burn patients, 15 patients who underwent surgery with minor bleeding, 10 who underwent surgery with major bleeding (mean, 1.1 L) and 15 postoperative patients. Blood Hb and plasma albumin were measured on 15 occasions over 5 h. The rate of albumin disappearance from the plasma was quantitated with population kinetic methodology and reported as the half-life (T 1/2 )., Results: No differences were observed for T 1/2 between volunteers, post-burn patients, patients who underwent surgery with minor bleeding and postoperative patients. The T 1/2 averaged 16.2 h, which corresponds to 3.8% of the amount infused per h. Two groups showed plasma concentrations of C-reactive protein of approximately 60 mg/L and still had a similarly long T 1/2 for albumin. By contrast, patients undergoing surgery associated with major hemorrhage had a shorter T 1/2 , corresponding to 15% of the infused albumin per h. In addition, our analyses show that the T 1/2 differ greatly depending on whether the calculations consider plasma volume changes and blood losses., Conclusion: The disappearance rate of the albumin in 20% preparations was low in volunteers, in patients with moderately severe inflammation, and in postoperative patients., (© 2022. The Author(s).) more...

Repair of bone deficiencies in the craniofacial skeleton remains a challenging clinical problem. The aim of this study was to evaluate and compare the effects of a plasma-derived albumin scaffold, alveolar osteoblasts and synthetic membrane implanted into experimental mandibular defects. Bilateral mandibular defects were created in twelve immunodeficient rats. The bone defect was filled with serum scaffold alone in left sides and scaffold combined with human alveolar osteoblast in right side defects. Implanted areas were closed directly in Group 1 ( n  = 6) and covered by a resorbable polyglycolic-polylactic acid membrane in Group 2 ( n  = 6). Bone regeneration was determined at 12 weeks as measured by and exhaustive multiplanar computed tomography analysis and histological examination. No significant differences in bone density were observed between defects transplanted with scaffold alone or scaffold seeded with osteoblasts. The use of membrane did not result in a determining factor in the grade of bone regeneration between Groups 1 and 2. Based on these results, it could be concluded that the albumin scaffold alone has osteoinductive capacity but presence of seeded ostogenic cells accelerates defect repair without being significantly influenced by covering the defect with a resorbable membrane. more...

Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic plausibility for a causal link between hypoalbuminemia and increased risks of primary and secondary infections. Serum albumin levels have prognostic value for complications in viral, bacterial and fungal infections, and for infectious complications of non-infective chronic conditions. Hypoalbuminemia predicts the development of healthcare-associated infections, particularly with Clostridium difficile . In coronavirus disease 2019, hypoalbuminemia correlates with viral load and degree of acute lung injury and organ dysfunction. Non-oncotic properties of albumin affect the pharmacokinetics and pharmacodynamics of antimicrobials. Low serum albumin is associated with inadequate antimicrobial treatment. Infusion of human albumin solution (HAS) supplements endogenous albumin in patients with cirrhosis of the liver and effectively supported antimicrobial therapy in randomized controlled trials (RCTs). Evidence of the beneficial effects of HAS on infections in hypoalbuminemic patients without cirrhosis is largely observational. Prospective RCTs are underway and, if hypotheses are confirmed, could lead to changes in clinical practice for the management of hypoalbuminemic patients with infections or at risk of infectious complications. more...

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation., (Copyright © 2021 Elsevier Ltd. All rights reserved.) more...

Introduction: Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions., Aim: To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION ® ) in clinical studies and real-world practice., Methods: In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured., Results: In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues., Conclusion: In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.) more...

Objective: To explore the clinical effects of concentrated growth factor (CGF) combined with plasma albumin gel (PAG) in treating facial depressed scar. Methods: From January 2018 to June 2019, 14 patients in the First Affiliated Hospital of Zhengzhou University and 10 patients in Henan NO.3 Provincial People's Hospital with facial depressed scar who met the inclusion criteria were admitted, and their clinical data were retrospectively analyzed by the method of case-control study. Based on the method of treatment, 8 patients (4 males and 4 females) aged 28.50 (25.50, 31.50) years were enrolled in CGF alone group, 8 patients (3 males and 5 females) aged 32.00 (28.50, 35.00) years were enrolled in PAG alone group, and 8 patients (5 males and 3 females) aged 33.50 (29.00, 35.75) years were enrolled in CGF+ PAG group. Suitable amount of CGF, PAG, and CGF+ PAG (mixed at a ratio of 1.0∶1.0-1.0∶1.5) prepared from autologous blood were injected subcutaneously via a single or multiple entrance (s) into the depressed scar of patients in CGF alone, PAG alone, and CGF+ PAG groups respectively to fill up the concavity, once every 4 weeks for a total of 3 times. Before the first treatment (hereinafter referred to as before treatment) and 3 months after the last treatment (hereinafter referred to as after treatment), the Goodman & Baron Acne Scar Grading System was used for scar grading, and the difference was calculated; the Anxiety Self-Rating Scale was used to score anxiety, and the difference was calculated. The Visual Analogue Score was used to score pain immediately after the first treatment. By one, two, and three months after treatment, the patients' satisfaction to scar treatment was scored, and the Global Aesthetic Improvement Scale was used to score the scar improvement. Adverse reaction of patients after treatment was monitored. Data were statistically analyzed with Fisher's exact probability test, Kruskal-Wallis H test, Mann-Whitney U test, Bonferroni correction, and Wilcoxon signed rank sum test. Results: (1) The scars of patients in the three groups were all graded 4.00 (4.00, 4.00) before treatment ( χ (2)<0.001, P >0.05). By three months after treatment, compared with 2.00 (1.25, 2.00) of CGF alone group, the scar grades of patients in PAG alone group and CGF+ PAG group (3.00 (2.00, 3.00) and 1.00 (1.00, 1.00), respectively) had no significant change ( Z =2.199, 2.003, P >0.05). The scar grade of patients in CGF+ PAG group was significantly lower than that in PAG alone group ( Z =3.229, P <0.01). Compared with those before treatment, the scar grades of patients in CGF alone group, PAG alone group, and CGF+ PAG group were significantly reduced three months after treatment ( Z =2.588, 2.598, 2.640, P <0.05 or P <0.01). The difference in scar grade before and after the treatment was significantly higher in CGF+ PAG group than in PAG alone group ( Z =3.229, P <0.01). (2) The anxiety scores of patients in the three groups were similar before treatment and 3 months after ( χ (2)=2.551, 2.768, P >0.05). Compared with those before treatment, the anxiety scores of patients in CGF alone group, PAG alone group, and CGF+ PAG group were significantly reduced three months after treatment ( Z =2.395, 2.527, 2.533, P <0.05). The differences in anxiety score before and after the treatment were similar among the three groups ( χ (2)=1.796, P >0.05). (3) The pain scores of patients in the three groups were similar immediately after the first treatment ( χ (2)=0.400, P >0.05). (4) By one and two month (s) after treatment, the patients' satisfaction scores to scar treatment in the three groups were similar ( χ (2)=2.688, 5.989, P >0.05). By three months after treatment, the patients' satisfaction score to scar treatment in CGF+ PAG group was significantly higher than that in PAG alone group ( Z =2.922, P <0.01). Compared with those one month after treatment within the same group, the patients' satisfaction scores to scar treatment in CGF alone group, PAG alone group, and CGF+ PAG group were significantly increased two and three months after treatment ( Z =1.121, 2.392, 2.000, 2.828, 2.449, 2.598, P <0.05 or P <0.01). Compared with those two months after treatment within the same group, the patients' satisfaction scores to scar treatment in CGF alone group, PAG alone group, and CGF+ PAG group were significantly increased three months after treatment ( Z =2.271, 2.000, 2.646, P <0.05 or P <0.01). (5) One month after treatment, the scar improvement scores of patients in the three groups were similar ( χ (2)=4.438, P >0.05). Two months after treatment, the scar improvement scores of patients in CGF alone group and CGF+ PAG group were 2.00 (2.00, 2.75) and 2.00 (2.00, 2.00) points, respectively, which were significantly higher than 1.00 (1.00, 1.00) point of PAG alone group ( Z =3.303, 3.771, P <0.01). Three months after treatment, the scar improvement score of patients in CGF+ PAG group was 3.00 (3.00, 3.00) points, which was significantly higher than 2.00 (2.00, 2.75) points of CGF alone group and 1.00 (1.00, 2.00) points of PAG alone group ( Z =2.450, 3.427, P <0.05 or P <0.01). Compared with those one month after treatment within the same group, the scar improvement scores of patients were significantly higher in CGF alone group and CGF+ PAG group two and three months after treatment and in PAG alone group three months after treatment ( Z =2.828, 2.828, 2.530, 2.640, 2.121, P <0.05 or P <0.01). Compared with that two months after treatment within the same group, the scar improvement score of patients in CGF+ PAG group was significantly higher three months after treatment ( Z =2.449, P <0.05). (6) After injection, all patients in the three groups had slight redness and swelling at the needle prick point and no other adverse reactions. Conclusions: CGF combined with PAG can reduce the scar grading, anxiety of patients, and enhance patients' satisfaction and scar improvement in the treatment of patients with facial depressed scar. The combined CGF+ PAG injection, without significant adverse reactions, is better than single component injection and is worthy of clinical application. more...

Purpose: This study aimed to validate the safety and effectiveness of percutaneous doxycycline/albumin injection for spinal aneurysmal bone cysts (ABCs) as an alternative to open surgery., Methods: From January 2000 to December 2016, 25 patients who had no/minor neurological deficits (modified Frankel scale D or E) and acceptable local stability (spinal instability neoplastic score < 12) were included in the study, of whom 14 were treated with percutaneous doxycycline/albumin injection (injection group) and 11 were treated with open surgery (surgery group). The demographic and clinical information of the injection and surgery groups were recorded and compared., Results: In the injection group, lesion size was significantly reduced in all 14 patients, all patients showed complete neurological recovery, and 13 patients had complete relief of neck pain; their mean visual analogue scale (VAS) decreased from 3.4 to 0.5. No complication or recurrence was observed during the mean 30.7-month follow-up (range, 24-50 months). In the surgery group, 9 patients had complete neurological recovery and 2 patients had residual slight paresthesia; their mean VAS decreased from 3.4 to 0.5. Two had local recurrence during their follow-up at 66.5 months (range, 50-96 months). Compared with the surgery group, the injection group showed no significant difference in the rate of recurrence (P = 0.14) and complication (P = 0.36)., Conclusions: Percutaneous doxycycline/albumin injection for spinal ABCs can be safely and effectively performed in well-selected cases. It could serve as an alternative treatment, especially for spinal ABCs lesions with acceptable local stability and in patients without severe neurological deficits. These slides can be retrieved under Electronic Supplementary Material. more...

Introduction: Frequent infusions and bleeds can impact on the health-related quality of life (HRQoL) of paediatric haemophilia B patients. rIX-FP (IDELVION ® ) is a fusion protein linking recombinant factor IX with recombinant albumin, and is associated with low bleeding rates with a weekly regimen, which could improve HRQoL., Aims: To measure the effect of rIX-FP prophylaxis on the HRQoL of paediatric patients and treatment satisfaction in their caregivers using the Haemo-QoL and Hemo-SAT P questionnaires, respectively., Methods: At baseline and end-of-study (EOS), patients 4-11 years old participating in the PROLONG-9FP program answered the Haemo-QoL questionnaire and gave information on their socio-demographic data and physical activity. Caregivers completed the Hemo-Sat P . Minimal important differences (MID) (|Cohen's d| > 0.5) between baseline and EOS and the number of responders (patients with meaningful subject-level improvements over time) at EOS were calculated., Results: Twenty patients (age group I: 4-7 years old [n = 12]; age group II: 8-12 years old [n = 8]) completed the Haemo-QoL questionnaire at baseline. MIDs were found in age group I representing improvement for "physical health" (d = -0.547) domain; 60% of patients were responders for "physical health." In age group II, MIDs were seen in most domains; 71.4% patients were responders in "total score." In caregivers, improvements were seen for most domains of the Hemo-Sat P with a small effect size. Fewer patients missed school when treated with rIX-FP and 94.1% patients maintained their physical activity level., Conclusion: Prophylaxis with rIX-FP led to substantial improvements in HRQoL in paediatric patients and treatment satisfaction in caregivers., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.) more...

Acute kidney injury (AKI) is a frequent complication of patients with advanced cirrhosis that it is associated with increased hospital admissions and decreased survival. The definition of AKI in cirrhosis has been recently modified and the new diagnostic criteria are based on small changes in serum creatinine with respect to previous values, occurring within a short period of time. The use of this new definition may lead to an earlier identification of renal impairment and better prognostic stratification. Hepatorenal syndrome (HRS) is a unique form of AKI developing in patients with end-stage liver disease. Systemic circulatory dysfunction and marked kidney vasoconstriction play a key role in the development of HRS. The modification of the definition of AKI has also led to a change in the diagnostic criteria of HRS. The new diagnostic criteria are based on AKI stages and there is no need to reach a specific serum creatinine threshold. According to these new criteria, treatment with vasoconstrictors and albumin for the management of HRS will be started at lower serum creatinine values, with expected higher response rates. Finally, there are consistent data showing that some urine biomarkers, particularly NGAL (neutrophil gelatinase-associated lipocalin), may be useful in daily clinical practice for the differential diagnosis of the cause of AKI in cirrhosis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

Background: Plasma exchange (PE) and double filtration plasmapheresis (DFPP) are known as effective treatment options for hyperviscosity syndrome (HVS) caused by Waldenstrom macroglobulinemia. Nonetheless, few data are available for the relation between the prescribed dose of apheresis and the reduction rate of target molecule immunoglobulin M (IgM), especially in the modality using membrane separation., Objectives: This study was conducted to establish a model to predict the IgM reduction rate by the dose of simple PE and DFPP using membrane separation in patients with HVS and to compare the consumption of albumin between PE and DFPP., Methods: We retrospectively analyzed data of total 17 sessions of PE and DFPP with various therapeutic doses performed for five patients at our institution. We used linear regression analysis to examine the relation between the ratio of processed plasma volume to estimated circulating plasma volume (X) and the reduction rate of IgM (Y)., Results: Regression analysis revealed that Y is expressed by X as the following equation: Y = 0.35X + 0.095. The total usage of albumin for replacement fluid was lower in DFPP than in PE (21.5 g vs 150 g per session), although the treatment efficacies of both modalities are similar., Conclusion: The dose of PE and DFPP using membrane separation can predict IgM reduction rate in the HVS patients. Predicted IgM reduction rates based on our model are lower than those calculated using a known theoretical model. In terms of the amount of use of albumin, DFPP is preferred to PE., (© 2018 Wiley Periodicals, Inc.) more...

Background: Patients undergoing therapeutic plasma exchange (TPE) may present with risks for hemorrhage or thrombosis. Use of replacement fluids devoid of coagulation factors will decrease factor levels and platelet levels. There are no established guidelines for hemostasis management in these situations., Materials and Methods: A survey to evaluate current hemostasis management practice during TPE was conducted using online survey software. One response per institution was analyzed based on a hierarchical algorithm, excluding membrane filtration users, resulting in a maximum of 107 respondents. Descriptive analysis was performed with results reported as the number and frequency (%) of respondents to each question., Results: Apheresis Medicine physicians, alone (59.4%) or jointly with the requesting provider (29.2%), choose the replacement fluid. Based on a theoretical patient case receiving five TPEs approximately every other day, the percent of respondents who would use albumin with or without normal saline was 94.7% with no history of a bleeding or clotting disorder, 1.1% with active bleeding, and 8.8% with hypofibrinogenemia (<100 mg/dL) due to recent TPE. More respondents would use albumin with or without normal saline for replacement fluid when a minor invasive procedure (49.5%) vs a major surgery (8.9%) was performed 1 day before TPE. Replacement fluid selection varied among respondents for several other clinical conditions. The most frequent use for cryoprecipitate by respondents (14.3%) was hypofibrinogenemia., Conclusions: These survey results demonstrate wide interinstitutional variation in replacement fluid selection to manage hemostasis in patients undergoing TPE. Further studies are needed to guide optimal hemostasis management with TPE., (© 2018 Wiley Periodicals, Inc.) more...

Aim: The optimal time to measure serum albumin concentration (SAC) to predict prognosis in cardiac arrest (CA) survivors has not been elucidated. We aimed to compare the relationships between time-related SAC, optic nerve sheath diameter (ONSD), intracranial pressure (ICP), and neurological prognosis in CA survivors., Methods: We undertook a retrospective study examining CA patients treated with target temperature management (TTM). ICP was measured using cerebrospinal fluid (CSF) pressure and ONSD was obtained before TTM. SAC was measured repeatedly at 4-6 h intervals from the hospital arrival time. We analysed CSF pressure, ONSD, and minimum SAC (MSAC) separately, or in combination, to predict poor neurological outcome., Results: Of 83 patients enrolled, the good outcome group comprised 25 (34%) patients. MSAC at 24 h (MSAC24) had a higher area under the receiver operating characteristic curve (AUC) (0.687; 95% confidence interval (CI), 0.668-0.926) than other time points. CSF pressure showed a higher AUC (0.973; 95% CI, 0.911-0.996) than MSAC24 and ONSD (0.677; 95% CI, 0.565-0.776). In contrast to using MSAC24 and ONSD separately, the combination of both modalities resulted in a better AUC, thus improving the prediction of the neurological outcome (0.734; 95% CI, 0.626-0.825) and ICP (0.758; 95% CI, 0.651-0.845) after return of spontaneous circulation (ROSC) from CA., Conclusion: A higher ICP was strongly associated with and seemed predictive of poor outcome. Furthermore, the MSAC24/ONSD combination may be a useful predictor of high ICP and poor neurological outcome. Prospective studies should be conducted to confirm these results., (Copyright © 2018 Elsevier B.V. All rights reserved.) more...

Hepatorenal syndrome (HRS) is a form of kidney function impairment that characteristically occurs in cirrhosis. Recent changes in terminology have led to acute HRS being referred to as acute kidney injury (AKI)-HRS and chronic HRS as chronic kidney disease (CKD)-HRS. AKI-HRS is characterized by a severe impairment of kidney function owing to vasoconstriction of the renal arteries in the absence of substantial abnormalities in kidney histology. Pathogenetic mechanisms involve disturbances in circulatory function due to a marked splanchnic arterial vasodilation, which triggers the activation of vasoconstrictor factors. An intense systemic inflammatory reaction that is characteristic of advanced cirrhosis may also be involved. The main triggering factors of AKI-HRS are bacterial infections, particularly spontaneous bacterial peritonitis. The diagnosis of AKI-HRS is a challenge because of a lack of specific diagnostic tools and mainly involves the differential diagnosis from other forms of AKI, particularly acute tubular necrosis. The prognosis of patients with AKI-HRS is poor, with a median survival of ≤3 months. The ideal treatment for AKI-HRS is liver transplantation in patients without contraindications. Medical therapy consists of vasoconstrictor drugs to counteract splanchnic arterial vasodilation together with volume expansion with albumin. Effective measures to prevent AKI-HRS include early identification and treatment of bacterial infections and the administration of albumin in patients with spontaneous bacterial peritonitis. more...

Hyponatremia is a commonly observed complication that is related to hypoalbuminemia and portal hypertension in patients with advanced liver cirrhosis. Hyponatremia in patients with liver cirrhosis is mostly dilutional hyponatremia and is defined when the serum sodium concentration is below 130 meq/L. The risk of complications increases significantly in cirrhotic patients with hyponatremia, which includes spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic factor before and after liver transplantation. The conventional therapies of hyponatremia are albumin infusion, fluid restriction and loop diuretics, but these are frequently ineffective. This review investigates the pathophysiology and various therapeutic modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with liver cirrhosis. more...

Acute kidney injury (AKI) is common in patients with liver cirrhosis, occurring in 13-20% of patients hospitalized with decompensated cirrhosis, and is significantly associated with the prognosis. The development and progression of AKI is an independent predictive factor for mortality in these patients. If AKI develops, the renal function declines progressively even if AKI is improved later, the patients have a poorer prognosis compared to those who have not developed AKI. In addition, in patients without appropriate treatment or no improvement with the initial treatment, AKI often progress to hepatorenal syndrome (HRS), which is associated with significant morbidity and mortality. Therefore, early detection and appropriate management for the development of AKI is very important in these patients. Recently, there have been significant revisions in the diagnostic criteria and treatment of AKI and HRS; this manuscript reviews these changes. more...

Background: In major abdominal surgery albumin is shifted from the circulation, presumably leaking into the interstitial space, contributing to a 30-40% decrease in plasma albumin concentration. During and after liver transplantation exogenous albumin is infused for volume substitution and to maintain plasma albumin concentration. Here we used liver transplantation as a model procedure for the study of albumin mass balance and kinetics during major abdominal surgery with albumin substitution., Methods: Patients were studied during liver transplantation (n = 16), and until postoperative day 3 (POD 3) (n = 11). Cumulative perioperative albumin shift was assessed by mass balance of albumin and hemoglobin. Synthesis rates of albumin and fibrinogen were estimated by the flooding technique using deuterium-labeled phenylalanine. Albumin distribution was assessed by radioiodinated human serum albumin., Results: At the end of surgery, 37 ± 17 g of albumin (p < 0.0001) had shifted from plasma, and this amount was stable until POD 3 (48 ± 33 g, p = 0.0017 versus baseline). There was 91 ± 37 g exogenous albumin infused peroperatively and another 47 ± 35 g was infused postoperatively until POD 3. Absolute synthesis rates of albumin and fibrinogen on POD 3 were 239 ± 84 mg/kg body weight/day and 33 mg/kg body weight/day (range 5-161), respectively., Conclusions: Albumin net leakage from plasma progressed until the end of surgery, and was then unaltered until POD 3. This is in contrast with the normalization of the cumulative albumin shift identified at day 3 after non-transplant major abdominal surgery. Liver synthesis of export proteins was high compared to reference values at the third postoperative day, suggesting rapid recovery of synthesis capacity., Trial Registration: Swedish Medical Product Agency, EudraCT 2015-002568-18. Registered on 15 July 2015. more...