CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

Predictive nomograms based on gamma-glutamyl transpeptidase to prealbumin ratio for prognosis of hepatocellular carcinoma patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) presents a significant threat to individuals and healthcare systems due to its high recurrence rate. Accurate prognostic models are essential for improving patient outcomes. Gamma-glutamyl transpeptidase (GGT) and prealbumin (PA) are biomarkers closely related to HCC. This study aimed to investigate the predictive value of the GGT to PA ratio (GPR) and to construct prognostic nomograms for HCC patients without microvascular invasion. METHODS: We retrospectively analyzed data from 355 HCC patients who underwent radical hepatectomy at Shengjing Hospital of China Medical University between December 2012 and January 2021. Patients were randomly assigned to a training cohort (n = 267) and a validation cohort (n = 88). The linearity of GPR was assessed using restricted cubic spline (RCS) analysis, and the optimal cut-off value was determined by X-tile. Kaplan-Meier survival curves and log-rank tests were used to investigate the associations between GPR and both progression-free survival (PFS) and overall survival (OS). Cox multivariate regression analysis identified independent risk factors, enabling the construction of nomograms. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the accuracy of the nomograms. Decision curve analysis (DCA) assessed the predictive value of the models. RESULTS: Patients were categorized into GPR-low and GPR-high groups based on a GPR value of 333.33. Significant differences in PFS and OS were observed between the two groups (both P < 0.001). Cox multivariate analysis identified GPR as an independent risk factor for both PFS (OR = 1.80, 95% CI: 1.24-2.60, P = 0.002) and OS (OR = 1.87, 95% CI: 1.07-3.26, P = 0.029). The nomograms demonstrated good predictive performance, with C-index values of 0.69 for PFS and 0.76 for OS. Time-dependent ROC curves and calibration curves revealed the accuracy of the models in both the training and validation cohorts, with DCA results indicating notable clinical value. CONCLUSIONS: GPR emerged as an independent risk factor for both OS and PFS in HCC patients without microvascular invasion. The nomograms based on GPR demonstrated relatively robust predictive efficiency for prognosis.

Predictive significance of systemic immune-inflammation index combined with prealbumin for postoperative pneumonia following lung resection surgery.

BACKGROUND: We aimed to determine whether systemic immune-inflammation index (SII) combined with prealbumin can provide better predictive power for postoperative pneumonia in patients undergoing lung resection surgery. METHODS: We identified eligible patients undergoing lung resection surgery at the Affiliated Hospital of Nantong University from March 2021 to March 2022. Demographic characteristics, clinical data, and laboratory information were collected and reviewed from the electronic medical records of the patients. To test the effect of the combined detection of SII and prealbumin, we made an equation using logistic regression analysis. The receiver operating characteristic curve (ROC) was plotted to evaluate the predictive powers, sensitivity, and specificity of prealbumin, SII, and SII combined with prealbumin. Decision curve analysis (DCA) was used to determine the clinical validity and net benefit of different methods of detection. RESULTS: Totally 386 eligible patients were included with a median age of 62.0 years (IQR: 55.0, 68.0), and 57 (14.8%) patients presented with postoperative pneumonia within 7 days after surgery. The multivariate regression analysis showed that preoperative SII as continuous variable was associated with an increased risk of postoperative pneumonia (OR: 1.38, 95% CI: 1.19-2.83, P = 0.011), whereas the prealbumin as continuous variable remained as an independent protective predictor of postoperative pneumonia in the adjusted analysis (OR: 0.80, 95% CI: 0.37-0.89, P = 0.023). Compared to SII or prealbumin, the combined detection of preoperative SII and prealbumin showed a higher predictive power with area under curve of 0.79 (95% CI: 0.71-0.86, P < 0.05 for all). Additionally, DCA indicated that the combined detection was superior over preoperative SII or prealbumin alone in clinical validity and net benefit. CONCLUSION: Both preoperative SII and prealbumin are independent influencing factors for postoperative pneumonia after lung resection surgery. The combined detection of preoperative SII and prealbumin can significantly improve prediction capability to identify potential postoperative pneumonia-susceptible patients, facilitating early interventions to improve postoperative quality of life for surgical lung resection patients.

High fibrinogen-prealbumin ratio (FPR) predicts stroke-associated pneumonia.

OBJECTIVES: Although numerous factors had been found to be associated with stroke-associated pneumonia (SAP), the underlying mechanisms of SAP remain unclear. Fibrinogen-prealbumin ratio (FPR) is a novel indicator that could balance the effects of inflammation and nutrition, which might reflect biological status of patients more comprehensively than other biomarkers. To date, FPR has not been explored in acute ischemic stroke patients. This study aims to explore the relationship between FPR and SAP. MATERIALS AND METHODS: 900 stroke patients participated in this retrospective study and 146 healthy controls were recruited. Fibrinogen and prealbumin were measured within 24 hours on admission. FPR was calculated after dividing fibrinogen (g/L) by prealbumin (mg/L) × 1000. SAP was defined according to the modified Centers for Disease Control criteria. RESULTS: 121 patients were diagnosed with SAP. Log10FPR was higher in stroke patients than healthy controls. In logistic regression analysis, log10FPR was independently associated with SAP (OR 15.568; 95% CI: 3.287-73.732; P=0.001). Moreover, after using ROC curve, the predictive power of "current standard"(defined as A2DS2 plus leukocyte count and log10hs-CRP) plus log10FPR (0.832[0.804-0.857]) was higher than "current standard" (0.811[0.782-0.837], P=0.0944) and A2DS2 plus log10FPR (0.801[0.772-0.828], P=0.0316). No significant difference was found between the predictive power of A2DS2 plus log10FPR and "current standard" (P =0.6342). CONCLUSION: Higher FPR was observed in stroke patients compared with healthy controls and was significantly associated with SAP. FPR might provide useful clues for timely identification and treatment of SAP.

Rare c.302C>T TTR Variant Associated with Transthyretin Amyloidosis.

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by pathogenic variants in the transthyretin (TTR) gene. More than 140 different disease-causing variants in TTR have been reported. Only a few individuals with a rare TTR variant, c.302C>T, p.(Ala101Val) (historically known as p.(Ala81Val)), primarily associated with cardiac ATTRv, have been described. Therefore, our aim was to analyze the clinical characteristics of individuals with the identified c.302C>T TTR variant at our center. Materials and Methods: We analyzed data from individuals with ATTRv who were diagnosed and treated at Vilnius University Hospital Santaros Klinikos. ATTRv was confirmed by negative hematological analysis for monoclonal protein, positive tissue biopsy or bone scintigraphy and a pathogenic TTR variant. Results: During 2018-2021, the TTR NM_000371.3:c.302C>T, NP_000362.1:p.(Ala101Val) variant was found in one individual in a homozygous state and in three individuals in a heterozygous state. The age of onset of symptoms ranged from 44 to 74 years. The earliest onset of symptoms was in the individual with the homozygous variant. A history of carpal tunnel syndrome was identified in two individuals. On ECG, three individuals had low QRS voltage in limb leads. All individuals had elevated NT-proBNP and hsTroponine I levels on baseline laboratory tests and concentric left ventricular hypertrophy on transthoracic echocardiography. The individual with the homozygous c.302C>T TTR variant had the most pronounced polyneuropathy with tetraparesis. Other patients with the heterozygous variant had more significant amyloid cardiomyopathy. When screening family members, the c.302C>T TTR variant was identified in two phenotypically negative relatives at the ages of 33 and 47 years. Conclusions: c.302C>T is a rare TTR variant associated with ATTRv cardiomyopathy. The homozygous state of this variant was not reported before, and is associated with earlier disease onset and neurological involvement compared to the heterozygote state.

Role of specific nutritional biomarkers in predicting post-operative complications among patients undergoing elective abdominal surgery.

PURPOSE: Nutritional biomarkers like serum prealbumin, transferrin, retinol-binding protein (RBP), C-reactive protein (CRP), leptin, and insulin-like growth factor 1 (IGF1) have the inherent ability to diagnose undernutrition objectively before it is clinically manifested. The primary objective of the study was to evaluate the diagnostic efficacy of the specific nutritional biomarkers in predicting post-operative complications. METHODS: A prospective cohort study was conducted in the department of surgery and included all patients aged 18 years and above who underwent elective abdominal surgery. Demographic details and clinical and surgical details were documented from the case records. Nutritional biomarker assay was done at admission. The post-operative complications occurring until discharge were graded using the Clavien-Dindo classification. The diagnostic accuracy of the specific nutritional biomarkers in predicting post-operative complications was assessed. RESULTS: A total of 320 patients were included in the study. Of these, 126 (39.38%) developed post-operative complications. Major complications accounted for 19.05% of the complications, while 80.95% were minor complications. Patients with blood prealbumin level less than 17.287 mg/dL had a higher incidence of complications (p < 0.001). Serum transferrin levels less than 168.04 mg/dL and IGF1 levels less than < 44.51 ng/ml showed increased incidence of complications (p < 0.001). The AUC was found to be the highest for serum IGF1 with 0.7782. Sensitivity was equally high for IGF1 and serum transferrin, with 76.98% for the former and 76.19% for the latter. CONCLUSION: Specific nutritional biomarkers, like serum prealbumin and transferrin, were efficient in predicting postoperative complications of patients before undergoing elective abdominal surgeries even after adjusting for confounders. This can facilitate preoperative corrective measures to lower the overall postoperative complications.

TTR exon-humanized mouse optimal for verifying new therapies for FAP.

Familial amyloidotic polyneuropathy (FAP) is caused by a mutation in the transthyretin (TTR) gene. In addition, deposition of wild-type TTR can cause senile systemic amyloidosis (SSA). To date, we have produced several transgenic mouse models for FAP and SSA by introducing TTR genes with different promoters or mutations. However, mouse TTR can associate with human TTR to produce hybrid tetramers in transgenic mice. Thus, these transgenic mice cannot be used to test the efficacy of a new therapy. In this study, we attempted to construct an optimized mouse model to verify a new therapy. The TTR gene consists of 4 exons and 3 introns. We prepared two gRNAs, one for the exon 1 and the other for exon 4, and a single donor vector carrying the whole TTR gene in which mouse exons were replaced with human exons. Using these vectors, we produced a TTR exon-humanized mouse with human exons and mouse introns using genome editing technology. These TTR exon-humanized mice showed normal TTR expression patterns in terms of serum TTR level and spatial specificity. These TTR exon-humanized mice will be useful for devising new treatment methods for FAP, including gene therapy.

Transferrin and Prealbumin Identify Esophageal Cancer Patients with Malnutrition and Poor Prognosis in Patients with Normal Albuminemia: A Cohort Study.

In this study, we aimed to analyze whether serum prealbumin and transferrin have a higher sensitivity than albumin for detecting malnutrition and predicting survival in esophageal cancer patients. A total of 212 patients were prospectively enrolled. Serum albumin, prealbumin, and transferrin were analyzed by enzyme-linked immunosorbent assays. The association of nutritional markers with survival was analyzed. We found that malnutrition was presented in 44.5% of the patients, while 56.6% were unaware of their body weight change. The area under the curve for diagnosing malnutrition was largest for prealbumin, followed by transferrin and albumin, with optimal breakpoints of 21 mg/dL, 206 mg/dL, and 4.3 g/dL, respectively, for diagnosing malnutrition. The diagnostic sensitivity for malnutrition was 34.1-63.4% with a single marker and this increased to 80.5% with all 3 markers. In patients with normal albuminemia (≥ 4.3 g/dL), a low level of prealbumin and/or transferrin predicted malnutrition and poor prognosis. Multivariate Cox regression analysis confirmed that a low level of the nutritional marker was an independent poor prognostic factor. In conclusion, serum prealbumin and transferrin outperformed albumin in identifying esophageal cancer patients with malnutrition and poor prognosis. Checking all three markers will help with the early diagnosis of malnutrition and enable timely intervention.

C-reactive protein to prealbumin ratio: a useful inflammatory and nutritional index for predicting prognosis after curative resection in esophageal squamous cell carcinoma patients.

PURPOSE: Although C-reactive protein to prealbumin ratio (CPR) can predict the outcomes of several types of cancer surgeries, little is known about the implication of CPR in patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC). METHODS: Between 2009 and 2018, 682 consecutive ESCC patients who underwent curative esophagectomy were enrolled. The clinicopathological factors and prognoses were compared between the groups stratified by preoperative CPR levels. A logistic regression model was used to determine the risk factors of postoperative pneumonia. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to elucidate prognostic factors. RESULTS: There were more elderly patients, more males, and more advanced clinical T and N categories in the high CPR group than in the low CPR group. Also, the incidence of postoperative pneumonia was significantly higher in the high CPR group than in the low CPR group (32.4% vs. 20.3%, p < 0.01). In multivariate analyses, high CPR was one of the independent predictive factors for postoperative pneumonia (OR, 1.71; 95% CI, 1.15-2.54; p < 0.03). Moreover, high CPR was an independent prognostic factor for overall, cancer-specific, and recurrence-free survivals (HR 1.62; 95% CI 1.18-2.23; p < 0.01, HR 1.57; 95% CI 1.08-2.32; p = 0.02, HR 1.42; 95% CI 1.06-1.90; p = 0.02). CONCLUSION: Preoperative CPR was found to be a useful inflammatory and nutritional indicator for predicting the occurrence of pneumonia and prognosis in patients with ESCC undergoing esophagectomy.

Transthyretin and retinol-binding protein as discriminators of diabetic retinopathy in type 1 diabetes mellitus.

PURPOSE: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM), which is still a major reason for blindness. Transthyretin (TTR) and retinol-binding protein (RBP) are thought to be related to the pathogenesis both in T2DM and T1DM. We aimed to investigate the association between serum levels of TTR, RBP, RBP/TTR ratio, and DR. METHODS: This retrospective study involved 188 T1DM inpatients divided into two groups: patients with DR (n = 95) and patients without DR (n = 93). Data of serum levels on lipids and inflammation were collected. Multiple logistic regression analysis was performed to research the association between TTR, RBP, RBP/TTR, and diabetic retinopathy in T1DM. RESULTS: Compared with patients without DR, those with DR have a higher level of TTR (207 versus 195 mg/L, p = 0.034) and RBP4 (36.85 versus 25.68 mg/L, p < 0.001). Significant differences were also observed between two groups with respect to body mass index (BMI), blood pressure (BP), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), homocysteine, apolipoprotein B (APOB), leucocyte, monocyte, neutrophil, and uric acid (p < 0.05 for all). TTR, RBP, and RBP/TTR were positively correlated with BP, BMI, TG, LDL, homocysteine, APOB, and uric acid. A multivariate logistic regression model revealed individuals with RBP4 level in the highest quartile had 58.95 times higher risk of developing diabetic retinopathy than those in the lowest quartile. CONCLUSIONS: In conclusion, TTR, RBP, and RBP/TTR ratio are risk factors of DR in T1DM. They are potential markers and targets for diagnosis and treatment of DR.

Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).

SARS-CoV-2 respiratory viral loads and association with clinical and biological features.

To determine the distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) respiratory viral loads (VL) during the acute phase of infection and their correlation with clinical presentation and inflammation-related biomarkers. Nasopharyngeal swabs from 453 adult SARS-CoV-2-infected patients from the Department of Infectious Diseases, Besançon, France, were collected at the time of admission or consultation for reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Clinical information and concentrations of biological parameters (C-reactive protein [CRP], fibrinogen, lactate dehydrogenase [LDH], prealbumin) were noticed. Mean respiratory VL homogeneously decreased from 7.2 log10 copies/ml (95% confidence interval [CI]: 6.6-7.8) on the first day of symptoms until 4.6 log10 copies/ml (95% CI: 3.8-5.4) at day 10 (slope = -0.24; R2 = .95). VL were poorly correlated with COVID-19 symptoms and outcome, excepted for dyspnea and anosmia, which were significantly associated with lower VL (p < .05). CRP, fibrinogen, and LDH concentrations significantly increased over the first 10 days (median CRP concentrations from 36.8 mg/L at days 0-1 to 99.5 mg/L at days 8-10; p < .01), whereas prealbumin concentrations tended to decrease. Since SARS-CoV-2 respiratory VL regularly decrease in the acute phase of infection, determining the level of VL may help predicting the onset of virus shedding in a specific patient. However, the role of SARS-CoV-2 VL as a biomarker of severity is limited.

A quinoline derived D-A-D type fluorescent probe for sensing tetrameric transthyretin.

Nowadays, with an upward trend in the prevalence of intracerebral amyloidosis, it is of great significance to use fluorescent probes for early diagnosis in vitro. In this study, a quinoline-derived D-A-D type chemosensor was rationally designed and synthesized as a probe for the sensitive detection of tetrameric transthyretin (WT-TTR).

Prediction of risk factors of bronchial mucus plugs in children with Mycoplasma pneumoniae pneumonia.

BACKGROUND: Recently, many cases of pneumonia in children with Mycoplasma pneumoniae infection have been shown to have varying degrees of intrabronchial mucus plug formation. The clinical, laboratory, radiological characteristics, and treatment of patients with Mycoplasma infection are analyzed in this study. The risk factors for M. pneumoniae pneumonia (MPP) mucus plug formation in children are explored, and a risk factor scoring system is established. METHODS: MPP patients treated with bronchoscopy were retrospectively enrolled in the study from February 2015 to December 2019. The children were divided into a mucus plug group and a control group according to the presence or absence of mucus plug formation. The clinical, laboratory, radiological characteristics, and treatment of the two groups of children were compared. Univariate and multivariate logistic regression models were used to identify the risk factors for MPP mucus plug formation. The receiver operating characteristic (ROC) curve was drawn to evaluate the regression model and establish the MPP mucous plug risk factor scoring system. RESULTS: A univariate analysis showed that the children in the mucous group were older and had a longer fever duration, longer hospital stay, higher fever peak, more cases of wheezing symptoms and allergies, and azithromycin or corticosteroids were administered later. In addition, neutrophil, C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer (DD), sputum MP-DNA copy number, and total immunoglobulin A (IgA) levels were higher, while prealbumin (PA) levels were lower. The ROC curve analysis showed that children with MPP had PA ≤144.5 mg/L, had used corticosteroids during the course of the illness of ≥4.5 days, CRP ≥12.27 mg/L, an LDH ≥ 462.65 U/L, and there was a possibility of intra-airway mucus formation. The independent risk factors were scored according to their odds ratio (OR) value. Among the 255 children with MPP, the high-risk group had 44 (83.02%) mucus plugs out of 53; the middle-risk group had 35 (34.3%) mucus plugs out of 102; and the low-risk group had 11 (11%) mucus plugs out of 100. CONCLUSIONS: PA levels, timing of corticosteroid use (use in the first few days), CRP levels, and LDH levels were independent risk factors for MPP mucus plug formation. This provides a basis for the early identification of MPP in children combined with mucus plug formation.

Distribution of amyloidosis subtypes based on tissue biopsy site - Consecutive analysis of 729 patients at a single amyloidosis center in Japan.

This study was performed to elucidate the distribution of amyloidosis subtypes based on tissue biopsy site. Samples obtained from 729 consecutive patients with amyloidosis were analyzed by immunohistochemical staining (IHC) and supplemental mass spectrometry (MS). The correlations between the type of organs from which samples were obtained and amyloidosis subtypes were investigated retrospectively. Among the patients, 95.1% were diagnosed by IHC and 4.9% were diagnosed by MS. The distribution of amyloidosis subtypes was as follows: AL, 59.1%; ATTR, 32.9%; AA, 4.0%; AH, 1.4%; Aß2M, 0.8%; and others, 0.9%. AL was the most common subtype in most organs, including the liver, lung, kidney, lower urinary tract, bone marrow, gastrointestinal tract, and skin/subcutaneous tissue. ATTR was the most common subtype in the heart, carpal tunnel, and peripheral nerves. AH was the second most common subtype in renal biopsy. Three or more amyloidosis subtypes were detected in each organ. In conclusion, AL was the most common subtype in most biopsy sites except the heart, carpal tunnel, and peripheral nerve, in which ATTR was more common. Because several types of amyloidogenic protein were detected in each organ, amyloid typing must be pursued, no matter the site from where biopsy was obtained.

Comparative evaluation of methods to determine intra-individual reference ranges in nutrition support team (NST)-related tests.

BACKGROUND: The intra-individual reference range is generally narrower than the commonly used reference range. Consequently, close monitoring of changes in the laboratory test results of individuals based on the inter-individual reference range remains challenging. METHODS: We examined the determination of individual reference ranges using four indicators of nutritional conditions: transferrin (TRF), albumin (ALB), retinol-binding protein (RBP), and transthyretin (TTR). The subjects comprised 20 healthy individuals and blood samples were collected and tested five times at 2-week intervals. We used the measurement results for the four indicators and examined individual reference ranges using four methods, including calculation methods based on the reference change value and Bayesian inference. RESULTS: The resulting intra-individual reference ranges were narrower than the currently used inter-individual reference range for all measurements using four methods. Furthermore, the intra-individual coefficient of variation [CV (intra)] was smaller than the inter-individual coefficient of variation [CV (inter)] for TRF, RBP, and TTR for all 20 subjects. The means CV (intra) for the four indicators were also lower than the corresponding CV (inter). CONCLUSIONS: The intra-individual reference range can be used to validate the standard deviation and coefficient of variation for currently used indicators. Moreover, Bayesian methods are speculated to be the most versatile.

Laboratory markers associated with COVID-19 progression in patients with or without comorbidity: A retrospective study.

OBJECTIVES: To investigate laboratory markers for COVID-19 progression in patients with different medical conditions. METHODS: We performed a multicenter retrospective study of 836 cases in Hubei. To avoid the collinearity among the indicators, principal component analysis (PCA) followed by partial least squares discriminant analysis (PLS-DA) was performed to obtain an overview of laboratory assessments. Multivariable logistic regression analysis and multivariable Cox proportional hazards regression analysis were respectively used to explore risk factors associated with disease severity and mortality. Survival analysis was performed in patients with the most common comorbidities. RESULTS: Lactate dehydrogenase (LDH) and prealbumin were associated with disease severity in patients with or without comorbidities, indicated by both PCA/PLS-DA and multivariable logistic regression analysis. The mortality risk was associated with age, LDH, C-reactive protein (CRP), D-dimer, and lymphopenia in patients with comorbidities. CRP was a risk factor associated with short-term mortality in patients with hypertension, but not liver diseases; additionally, D-dimer was a risk factor for death in patients with liver diseases. CONCLUSIONS: Lactate dehydrogenase was a reliable predictor associated with COVID-19 severity and mortality in patients with different medical conditions. Laboratory biomarkers for mortality risk were not identical in patients with comorbidities, suggesting multiple pathophysiological mechanisms following COVID-19 infection.

Plasma Exosome Profile in ST-Elevation Myocardial Infarction Patients with and without Out-of-Hospital Cardiac Arrest.

The identification of new biomarkers allowing an early and more accurate characterization of patients with ST-segment elevation myocardial infarction (STEMI) is still needed, and exosomes represent an attractive diagnostic tool in this context. However, the characterization of their protein cargo in relation to cardiovascular clinical manifestation is still lacking. To this end, 35 STEMI patients (17 experiencing resuscitated out-of-hospital cardiac arrest (OHCA-STEMI) and 18 uncomplicated) and 32 patients with chronic coronary syndrome (CCS) were enrolled. Plasma exosomes were characterized by the nanoparticle tracking analysis and Western blotting. Exosomes from STEMI patients displayed a higher concentration and size and a greater expression of platelet (GPIIb) and vascular endothelial (VE-cadherin) markers, but a similar amount of cardiac troponin compared to CCS. In addition, a difference in exosome expression of acute-phase proteins (ceruloplasmin, transthyretin and fibronectin) between STEMI and CCS patients was found. GPIIb and brain-associated marker PLP1 accurately discriminated between OHCA and uncomplicated STEMI. In conclusion, the exosome profile of STEMI patients has peculiar features that differentiate it from that of CCS patients, reflecting the pathophysiological mechanisms involved in STEMI. Additionally, the exosome expression of brain- and platelet-specific markers might allow the identification of patients experiencing ischemic brain injury in STEMI.