Identification of and solution for false D-dimer results.

BACKGROUND: Clinically, D-dimer (DD) levels are mainly used to exclude diseases such as deep venous thrombosis (DVT). In clinical testing, DD assays can be subjected to interference that may cause false results, which directly affect the clinical diagnosis. Our hypothesis was that the 95% confidence intervals (CIs) of the fibrin degradation product (FDP)/DD and fibrinogen (Fib)/DD ratios were used to identify these false results and corrected via multiple dilutions. METHODS: In total, 16 776 samples were divided into three groups according to the DD levels detected by Sysmex CS5100 and CA7000: Group A, DD ≥ 2.0 µg/mL fibrinogen equivalent unit (FEU); group B, 0.5 < DD < 2.0 µg/mL FEU; and group C, DD ≤ 0.5 µg/mL FEU. The 95% CIs of the FDP/DD and Fib/DD ratios were calculated. Six abnormal DD results were found according to the 95% CIs. For verification, we performed multiple dilutions, compared the results with those of other instruments, and tested the addition of heterophilic blocking reagent (HBR). RESULTS: The median and 95% CI of the FDP/DD ratio were 3.76 and 2.25-8.15 in group A, 5.63 and 2.86-10.58 in group B, 10.23 and 0.91-47.71 in groups C, respectively. For the Fib/DD ratio, the 95% CIs was 0.02-2.21 in group A, 0.68-8.15 in group B, and 3.82-55.27 in groups C. Six abnormal results were identified after multiple dilutions, by comparison with other detection systems, and after HBR addition. CONCLUSIONS: The FDP/DD ratio is more reliable for identifying false results. If the FDP/DD ratio falls outside the 95% CI, it should be verified by different methods.

New perspectives on surgical accuracy analysis of image-guided bone tumour resection surgery.

PURPOSE: Image-guided bone tumour resection surgery has been proved in previous literatures to be more accurate than those conventional freehand ones (p < 0.001). However, in this kind of surgery, there are still many procedures depending on manual operations, which will inevitably introduce surgical errors into the surgery. In particular, the negative surgical errors (i.e., errors toward tumour) would increase the risk of tumor recurrence and metastasis. Thus, the first purpose of this study was to evaluate whether the negative surgical errors of image-guided bone tumour resection surgery were statistically significantly great, the second purpose is to evaluate whether the negative surgical errors of image-guided long-bone tumour resection surgery were statistically equivalent to those of pelvis surgery, and the last purpose is to recommend a solution for suppressing these errors when using a navigation system. METHODS: Negative surgical errors of 24 osteotomies in ten pelvis tumour resection operations and 16 osteotomies in ten long-bone surgeries under the image guidance of a navigation system were statistically evaluated and compared with - 2.0 mm. The equivalence of negative surgical errors of pelvis group and those of long-bone group was statistically tested. To suppress these negative surgical errors when using a navigation system, we recommend, based on the obtained statistics, to increase the margins between cut planes and tumour boundary during pre-operatively planning cut planes, by adding an extra margin with the empirical safe margin according to the absolute lower bound of 95% CI of negative surgical errors. RESULTS: Negative surgical errors of the pelvis group and the long-bone group were both significantly less than - 2.0 mm (p < 0.001), but not statistically equivalent (Rg > 1 mm). 95% CI of negative surgical errors were from - 3.95 to - 3.27 mm for the pelvis group, and from - 2.69 to - 2.34 mm for the long-bone group. So, the extra margin added for image-guided pelvis tumour resection surgery should be set as 3.95 mm, and the extra margin added for image-guided long-bone surgery should be set as 2.69 mm. CONCLUSION: The negative surgical errors of image-guided bone resection surgery were statistically significantly less than - 2.0 mm (p < 0.001), thus these errors cannot be safely ignored. Moreover, the negative surgical errors of the pelvis group were not equivalent to those of the long-bone group (Rg > 1.0 mm), thus the solution for image-guided pelvis tumour resection surgery and that for image-guided long-bone tumour resection surgery should be separately determined. In order to suppress these negative surgical errors when using a navigation system, we recommend to add extra 3.95 mm margin with the empirical safe margin for image-guided pelvis tumour resection surgery and to add extra 2.69 mm margin for image-guided long-bone tumour resection surgery during pre-operatively planning cut planes.

Lies, damned lies and statistics: Clinical importance versus statistical significance in research.

Correctly performed and interpreted statistics play a crucial role for both those who 'produce' clinical research, and for those who 'consume' this research. Unfortunately, however, there are many misunderstandings and misinterpretations of statistics by both groups. In particular, there is a widespread lack of appreciation for the severe limitations with p values. This is a particular problem with small sample sizes and low event rates - common features of many published clinical trials. These issues have resulted in increasing numbers of false positive clinical trials (false 'discoveries'), and the well-publicised inability to replicate many of the findings. While chance clearly plays a role in these errors, many more are due to either poorly performed or badly misinterpreted statistics. Consequently, it is essential that whenever p values appear, these need be accompanied by both 95% confidence limits and effect sizes. These will enable readers to immediately assess the plausible range of results, and whether or not the effect is clinically meaningful.

Targeted vaccination programme successful in reducing acute hepatitis B in men having sex with men in Amsterdam, the Netherlands.

BACKGROUND & AIMS: In the Netherlands, transmission of hepatitis B virus occurs mainly within behavioural high-risk groups, such as in men who have sex with men. Therefore, a vaccination programme has targeted these high-risk groups. This study evaluates the impact of the vaccination programme targeting Amsterdam's large population of men who have sex with men from 1998 through 2011. METHODS: We used Amsterdam data from the national database of the vaccination programme for high-risk groups (January 1, 1998 to December 31, 2011). Programme and vaccination coverage were estimated with population statistics. Incidence of acute hepatitis B was analyzed with notification data from the Amsterdam Public Health Service (1992-2011). Mathematical modelling accounting for vaccination data and trends in sexual risk behaviour was used to explore the impact of the programme. RESULTS: At the end of 2011, programme coverage was estimated at 41% and vaccination coverage from 30% to 38%. Most participants (67%) were recruited from the outpatient department for sexually transmitted infections and outreach locations such as saunas and gay bars. Incidence of acute hepatitis B dropped sharply after 2005. The mathematical model in which those who engage most in high-risk sex are vaccinated, best explained the decline in incidence. CONCLUSIONS: Transmission of hepatitis B virus among Amsterdam's men who have sex with men has decreased, despite ongoing high-risk sexual behaviour. Vaccination programmes targeting men who have sex with men do not require full coverage; they may be effective when those who engage most in high-risk sex are reached.

A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C.

BACKGROUND & AIMS: Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC. METHODS: 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003-2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model. RESULTS: Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes. CONCLUSIONS: MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.

High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis.

BACKGROUND & AIMS: Anti-neutrophil cytoplasmic antibodies (ANCA) are a non-uniform family of antibodies recognizing diverse components of neutrophil granulocytes. ANCA formation might be induced by protracted bacterial infections or probably reflect an abnormal immune response to commensal microorganisms. Bacterial infections are common complications in cirrhosis with high incidence of episodes caused by enteric organisms, therefore, we sought to study the presence and clinical importance of ANCA in cirrhosis. METHODS: Sera of 385 patients with cirrhosis of different etiologies were assayed for ANCA of IgG, IgA, IgA1, IgA2, and secretory IgA subtypes by indirect immunofluorescence and ELISAs. The control group comprised 202 patients with chronic liver diseases without cirrhosis and 100 healthy subjects. In cirrhosis, a 2-year follow-up, observational study was conducted to assess a possible association between the presence of ANCA and clinically significant bacterial infections. RESULTS: Prevalence of ANCA IgA was significantly higher in cirrhosis (52.2%) compared to chronic liver diseases (18.6%) or healthy controls (0%, p<0.001 for both). ANCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (46% of total ANCA IgA) and presence of the secretory component concurrently. Presence of ANCA IgA was associated with disease-specific clinical characteristics (Child-Pugh stage and presence of ascites, p<0.001). During a 2-year follow-up period, risk of infections was higher among patients with ANCA IgA compared to those without (41.8% vs. 23.4%, p<0.001). ANCA IgA positivity was associated with a shorter time to the first infectious complication (pLogRank <0.001) in Kaplan-Meier analysis and was identified as an independent predictor in multivariate Cox-regression analysis (HR:1.74, 95% CI: 1.18-2.56, p=0.006). CONCLUSIONS: Presence of IgA type ANCA is common in cirrhosis. Involvement of gut mucosal immune system is in center of their formation and probably reflects sustained exposure to bacterial constituents.

Association of polymorphisms in the MCP-1 and CCR2 genes with the risk of cancer: a meta-analysis.

Studies investigating the impact of polymorphisms on monocyte chemotactic protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) on the risk of cancer have reported inconsistent results. We performed a meta-analysis of 23 eligible studies to summarize the data describing the association between cancer risk and polymorphisms in MCP-1 A2518G and CCR2 V64I. Q-statistics and I(2) statistics were calculated to examine heterogeneity and summary odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated using a random effects model. Potential sources of heterogeneity were investigated via subgroup and sensitivity analyses, and publication biases were estimated. Overall, MCP-1 and CCR2 polymorphisms showed no significant associations with cancer risk (MCP-1-2518A/G, GG + GA vs. AA: OR=0.94, 95% CI=0.76-1.17; CCR2 V64I, AA+AG vs. GG: OR=1.27, 95% CI=0.87-1.86). However, strong evidence of heterogeneity was found among the investigated studies, and subgroup analyses were therefore conducted according to study location, cancer type, source of controls, and presence of deviation from the Hardy-Weinberg equilibrium (HWE). When the data were stratified by study location, the increased risk of cancer among A allele carriers of CCR2 V64I was observed only in studies conducted in Asian countries (AA+AG vs. GG: OR=1.65; 95% CI=1.25-2.18). This meta-analysis suggests that genetic polymorphisms of CCR2 V64I may influence the susceptibility of cancer in Asian countries. Further well-designed studies with larger sample sizes should be conducted.

Determination of a positive response in the Ames Salmonella mutagenicity assay.

Genetic toxicology tests are used to categorize substances as genotoxic and potentially carcinogenic. In general, test results are designated as mutagenic, not mutagenic, or inconclusive and, depending on its potential use and applicable regulations, a mutagenic result can restrict or remove a substance from further development, or assign limits to its use. In these tests, mutation responses form a continuum without a clear delineation between an increase over the background, untreated, mutant frequency and a frequency that would define the test substance as a mutagen and a potential carcinogenic hazard. This situation is illustrated using the Salmonella mutagenicity (Ames) test which is the initial, and often only, test used to characterize substances as mutagenic or nonmutagenic. It has its widest use by industry and regulatory authorities to identify potential carcinogens among chemicals in development. The OECD Test Guideline No. 471 has been adopted by regulatory agencies internationally, and describes the minimum requirements for a negative response, but does not provide a specific approach for evaluating the test data. The most widely used criterion for making yes-or-no mutagenicity decisions is a 2- or 3-fold increase over the background (solvent) mutant frequency. Other approaches rely on formal statistics and/or expert judgment. These approaches and recently proposed modifications are evaluated here. Recommendations are made that are in conformity with the OECD guideline and are based on biological relevance and the biology of the mutagenic response rather than on arbitrary decision points (e.g., ≥2-fold increase or p ≤ .05).

Effect evaluation of case-based learning with situated cognition theory on competence training for student nurses in pediatric surgery.

Objective: The case-based learning with situated cognition theory (CBL-SCT) approach focuses on teaching over learning, making it suited to student nurse education. However, it is rare in student nurse training in pediatric surgery, and some subjective evaluations of the learning effect are still affected by the assessor. This study investigated the effect of the CBL-SCT approach on improving the nursing quality/safety and comprehensive performance of student nurses, and explored a method for analyzing the reliability of subjective evaluations. Methods: Thirty-six student nurses were divided into a control group and an experimental group and received seven days of orientation via conventional and CBL-SCT training, respectively. The learning effect was evaluated via examining their implementation of nursing quality criteria within the following month and their comprehensive clinical performance after six months. Among the evaluation indicators, professional skills, job competency, and professional quality were evaluated by assessors, whose scores were tested for consistency using Cronbach's alpha. Results: Among the 11 nursing quality criteria, the correct implementation of patient identification and communication (t = 2.257, P = 0.031), medication-checking (t = 5.444, P < 0.001), tumbles/bed-falling prevention (t = 3.609, P = 0.001), pressure injury prevention (t = 3.834, P = 0.001), catheter management (t = 3.409, P = 0.002), and nursing record writing (t = 2.911, P = 0.006) in the experimental group were all higher than in the control group. Six months after training, the experimental group was also higher in professional theory (t = 4.889, P < 0.001), professional skills (t = 2.736, P = 0.010), job competency (t = 5.166, P < 0.001), and professional quality (t = 16.809, P < 0.001). Cronbach's alpha test verified that the assessors' evaluations had good internal consistency and reliability for job competency (alpha = 0.847, 95% CI lower limit = 0.769), professional quality (alpha = 0.840, 95% CI lower limit = 0.759), and professional skills (alpha = 0.888, 95% CI lower limit = 0.822). Conclusions: The CBL-SCT method can help student nurses quickly change their nursing role, and Cronbach's alpha test can verify the reliability of subjective evaluations, thus indirectly reflecting the training effect equitably and objectively.

10-Year oncological outcome report after second conservative treatment for ipsilateral breast tumor event.

Purpose: To analyze long-term oncological outcome after 2nd conservative treatment (2ndCT) for patients with ipsilateral 2nd ipsilateral breast tumor event (2ndIBTE). Materials/methods: In this retrospective observational study (N°F20210402152843), patients with 2ndIBTE underwent 2ndCT (lumpectomy + tumor bed re-irradiation). 3rdIBTE (3rdIBTE-FS), regional relapse- (RRFS) and metastatic disease- (MD-FS) free survivals as well as disease-free (DFS), specific (SS) and overall (OS) survival were analyzed. Late toxicity was reported. Results: Between 09/2000 and 04/2022, 244 patients presented a 2ndIBTE and underwent a 2ndCT. Among them, 113 pts with a minimum follow-up of 60 months were analyzed. Median time interval between 1st and 2ndIBTE was 13.5 years [2-35]. Median 2ndIBTE age was 66.2 years [31-85]. 2ndIBTE were adenocarcinomas (77 %). Tumor size was < 20 mm (86.7 %). 2ndIBTE were grade 1/2 (75 %), with positive hormonal receptor (85 %) and clear surgical margins (no ink on tumor, 90.3 %). In the APBI classification, 21 pts were high-risk (18.6 %), while 77 % were Luminal A/BHer2-. With a MFU of 121.5 months [CI95% 111.7-129.6], 10-year 3rdIBTE-FS was 89 % [83-96]. Then-year RRFS, MDFS, DFS, SS and OS were 94 % [89-100], 89 % [83-96], 78 % [70-87], 95 % [91-100] and 94 % [90 -99] respectively. In multivariate analysis, APBI classification (high-risk; HR2.66 [1.01-7.1], p = 0.049) and tumor size (≥20 mm; HR2.64 [1.02-6.8], p = 0.045) were considered independent prognostic factors for DFS.Ninety-seven late complications were observed (fibrosis 64 %) with 6.2 % G ≥ 3 late toxicity. Cosmetic outcome was excellent/good in 91.2 %. Conclusions: With long follow-up, 2ndIBTE managed with 2ndCT allows second breast preservation without oncological outcome compromise and acceptable G ≥ 3 toxicity.

Estimating the global prevalence of hepatitis E virus in swine and pork products.

Zoonotic transmission of hepatitis E virus (HEV), in particular the genotype (GT) 3 and GT4 strains, constitutes a major one health issue. Swine serves as an important reservoir and the processed pork products essentially contribute to foodborne transmission. This study comprehensively estimated HEV prevalence in domestic pigs, wild boars, and pork products. At global level, we found nearly 60% domestic pigs and 27% wild boars have ever encountered HEV infection based seroprevalence rate. Nearly 13% domestic and 9.5% wild swine are actively infected based on HEV RNA positivity. Importantly, about 10% of commercial pork products are HEV RNA positive, although available data are limited in this respect. Our results indicate the high prevalence rate of HEV infection in pigs and widespread contamination in pork products, although there are substantial variations at regional and country levels. These findings are important for better understanding the global epidemiology and clinical burden of HEV infection in human population related to zoonotic transmission.

The effects of acute exercise and inflammation on immune function in early-stage prostate cancer.

Background: The immune system plays a vital role in cancer development and progression. Strategies mobilizing cytotoxic cells of the immune system to combat immunosuppression in cancer may help to improve the treatment response of patients. To this end, we aimed to characterize the anti-cancer effect of acute exercise, including the involvement of inflammatory signals. Patients and methods: Twenty patients with early-stage prostate cancer (PCa) scheduled to undergo prostatectomy performed one bout of acute exercise consisting of a watt-max test and four high-intensity intervals. Natural Killer (NK), NKT-like and T cell phenotype, NK cell cytotoxic activity (NKCA), and NKCA per-cell against cell lines of leukemia (K562) and prostate cancer origin (LNCaP and PC-3) were assessed. Inflammatory markers (TNF-α, IL-6, and CRP) were measured in plasma. Results: Exercise increased NK, NKT-like, and CD8 T cell concentration in the circulation. Furthermore, exercise shifted immune cells towards a mature and cytotoxic phenotype e.g., NK cells exhibited higher CD57 as well as lower NKG2A expression. NKT-like and CD8 cells exhibited elevated CD57, TIGIT and Granzyme-B expression. Exercise significantly improved NKCA against K562 (+16% [5%; 27%]; p = 0.002) and LNCaP (+24% [14%; 34%]; p < 0.001) but not PC-3. NKCA per NK cell decreased during exercise and increased 1-h post exercise compared to baseline in K562, LNCap, and PC-3 cell lines. Baseline IL-6 correlated with lymphocyte, monocyte and T cell concentration pre-exercise and inversely correlated with the fold-change of mobilized lymphocytes and CD8 T cells during exercise. Furthermore, baseline IL-6 and TNF-α inversely correlated with NKCA against PC-3 cells during exercise. Conclusions: Acute exercise mobilized cytotoxic immune cells and improved NKCA in patients with PCa whereas low-grade inflammation might impair the response. Whether the observed improvements impact long-term outcomes warrant further investigation. Clinical trial number: NCT03675529.

RC time (resistance × compliance) is related to residual symptom after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

Background: Right ventricular (RV) afterload is widely assessed by pulmonary vascular resistance (PVR). However, RV afterload is underestimated because PVR does not account for the pulsatile load. The pulsatile load is often evaluated by pulmonary arterial compliance (PAC). The RC (resistance-compliance) time, which is calculated from the product of PVR and PAC, is considered to remain constant under medical therapy. However, little is known on how RC time is affected by invasive therapy in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to evaluate change of RC time in patients underwent pulmonary endarterectomy (PEA). Furthermore, we investigated the clinical relevance of RC time. Methods: We reviewed consecutive 50 patients except for death case underwent PEA. Baseline clinical parameters including RC time before performing PEA and follow-up were evaluated. Patients was classified as decrease or non-decrease according to change of RC time. Furthermore, we classified patients into a NYHA I group who had no symptom after treatment and a residual symptom group in order to investigate the relationship of RC time to residual symptoms. Results: RC time was significantly decreased after PEA (0.54 ± 0.16 to 0.45 ± 0.12 sec, p < 0.001). Residual symptom after PEA of Decrease group were significantly better than that of Non-decrease group in RC time (12 patients, 40% vs. 11 patients, 78.6%, p < 0.02). Furthermore, multivariate analysis revealed that only RC time after PEA was independently associated with residual symptom (OR 1.026, 95% CI 1.005-1.048; p = 0.017). Conclusions: RC time was decreased after PEA, and might be a possible indicator for predicting PEA success.

Utilization of mechanical prostheses and outcomes of surgical aortic valve replacement at safety net hospitals.

Background: Safety-net hospitals care for a high proportion of uninsured/underinsured patients who may lack access to longitudinal care. The present study characterized the use of mechanical valves and clinical outcomes of surgical aortic valve replacement at safety net hospitals. Methods: All adults undergoing surgical aortic valve replacement were abstracted from the 2016-2018 Nationwide Readmissions Database. Hospitals were divided into quartiles based on volume of all Medicaid and uninsured admissions, with the highest quartile defined as safety net hospitals. Multivariable regression was used to determine the association between safety net hospitals and several outcomes including mechanical valve use, perioperative complications, index hospitalization costs, 90-day readmission, and complications at readmission. Results: Of the 94,580 patients undergoing surgical aortic valve replacement, 14.5% of operations were at safety net hospitals. Patients at safety net hospitals more commonly received mechanical valves (20.3% vs 16.9%, P < .01) compared to those at non-safety net hospitals. After adjustment, safety net hospitals remained associated with a greater odds of mechanical aortic valve use (adjusted odds ratio, 1.13, 95% confidence interval 1.05-1.21). However, operation at safety net hospitals was also associated with increased odds of perioperative complications (adjusted odds ratio 1.10, 95% confidence interval 1.03-1.17) and higher hospitalization costs (ß coefficient +$6.15K, 95% confidence interval +$5.26 - +$7.03) despite similar 90-day readmissions. Upon readmission, safety net hospitals patients were more likely to experience mortality (adjusted odds ratio 1.87, 95% confidence interval 1.18-2.98) and stroke (adjusted odds ratio 2.41, 95% confidence interval 1.23-4.70) compared to those at non-safety net hospitals. Conclusion: Hospital safety net status is associated with increased use of mechanical valves for surgical aortic valve replacement despite also being associated with increased perioperative complications, costs, and significant complications upon readmission. Ability to access adequate follow-up care may be an important consideration for surgical aortic valve replacement at safety net hospitals.

Associations of Four sensitization patterns revealed by Latent Class Analysis with Clinical symptoms: A multi-center study of China.

Background: Because of the significant regional differences in the distribution of allergens, the relationship between anaphylaxis and allergic sensitization is complex in China. Using this large-scale epidemiologic survey, we explore the potential patterns of sensitization to common allergens in mainland China and investigate their relationship with various clinical symptoms. Method: The participants were recruited from 13 medical centers in mainland China from October 2019 to June 2021. Skin prick test (SPT) results that cover 18 common allergens were utilized to diagnose atopic sensitization. The demographic characteristics and clinical information were collected through questionnaires during routine medical follow-up. Latent class analysis (LCA) was conducted to determine the optimal sensitization patterns. The logistic regression was used to assess the associations of different sensitization patterns with allergy symptoms. Findings: A total of 1089 patients who had a positive SPT to at least one of 18 allergens were included for formal analysis. An optimal LCA model with 4 classes was obtained in this study, and the corresponding labels were as follows: Class1, house dust mite sensitization; Class2, low pollen sensitization; Class3, middle pollen sensitization; Class4, high pollen sensitization. The prevalence of different classes varied widely in geographical distribution, which was characterized by Class1 being very common in south and east as well as Class2 in north and west of China. Compared with patients in Class1, those in middle and high pollen sensitization clusters had the higher odds ratios (ORs) of allergic rhinitis and allergic conjunctivitis when controlling for other confounders. However, there was no significant difference between low pollen sensitization and house dust mite sensitization groups in the risks for various clinical performances except dermatitis. Additionally, the adjusted ORs (95% confidence interval) of allergic conjunctivitis and dermatitis for participants in pollen sensitization clusters (Class2, 3 and 4) were 1.56 (1.18, 2.06) and 1.43 (1.09, 1.88) respectively compared with those in Class1. Interpretation: In this study, we identified four sensitization clusters with specific risks of various clinical symptoms using common allergens by adopting LCA. Our findings may contribute to improved diagnosis and potential immunotherapy approaches to allergy in mainland China. Funding: This study was supported by the National Natural Science Foundation of China (81802076 and 81871736), the Guangzhou Science and Technology Foundation (202102010327), the Foundation of SKLRD (MS-2019-06 and Z-2022-09), and the Foundation of GYYY (ZH201904) and ZNSA-2020012.

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study.

Purpose: Intensity-modulated radiotherapy (IMRT) is currently used more commonly than 3-dimensional conformal radiation for definitive thoracic radiation. We examined the efficacy profiles of concurrent chemoradiotherapy (CCRT) with IMRT after durvalumab became clinically available. Methods: We reviewed the clinical records of patients with stage III non-small cell lung cancer (NSCLC) treated with CCRT and IMRT at seven centers in Japan and investigated relapse and survival from May 2018 to December 2019. The primary endpoint of this report was progression-free survival (PFS). Results: Among 107 patients enrolled in the study, 87 were sequentially administered durvalumab. From CCRT commencement, patients were followed up for a median period of 29.7 months. The median PFS at the end of the CCRT was 20.7 months. Among the 87 patients, 58 experienced disease relapses, of whom 36 (62.1 %) had distant metastases. Multivariate Cox regression analysis revealed that a favorable response to CCRT, a radiation dose ≥ 62 Gy, and stage IIIA NSCLC were associated with prolonged PFS (all P = 0.04). Multivariate logistic regression by landmark analysis revealed that mortality risk factors were durvalumab treatment duration ≤ 11.7 months, a lower maximum grade of immune-related adverse events, FEV1 < 2805 mL, and radiation dose < 62 Gy (P = 0.01, 0.01, 0.03, and 0.04, respectively). Conclusions: In patients with NSCLC receiving CCRT using IMRT, long PFS was associated with a better response to CCRT, stage IIIA NSCLC, and an increased radiation dose. The duration of durvalumab consolidation also played an essential role in the survival of patients receiving CCRT with IMRT. (250 words).

Pharmacometric characterization of entero-hepatic circulation processes of orally administered formulations of amiodarone under complex binding kinetics.

AIMS: The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations. METHODS: Intravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4. RESULTS: The population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen. CONCLUSIONS: The current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.

Mid-term results of surgical aortic valve replacement with bioprostheses in hemodialysis patients.

Background: Limited studies have assessed the factors affecting prognosis in hemodialysis (HD) patients who undergo surgical aortic valve replacement with a bioprostheses (SAVR-BP). This study aimed to evaluate the outcomes of HD patients who had undergone SAVR-BP for aortic stenosis (AS) and identify the risk factors for mortality. Methods: This retrospective study included 57 HD patients who had undergone SAVR-BP for AS between July 2009 and December 2020. Multivariate logistic regression was used to predict factors associated with mid-term outcomes and death or survival. Kaplan - Meier curves were also generated for mid-term survival. Results: The in-hospital mortality rate was 8.8%, and the 5-year mortality rate was 42.1%. The independent predictors of 5-year mortality were preoperative age (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.175-2.083, p = 0.002), hyperlipidemia (HR, 0.02; 95% CI, 0.002-0.297, p = 0.004), left ventricular diastolic diameter (HR, 1.74; 95% CI, 1.142-2.649, p = 0.010), left ventricular systolic diameter (HR, 0.61; 95% CI, 0.392-0.939, p = 0.025), and Japan SCORE (HR, 1.28; 95% CI, 1.052-1.563, p = 0.014). The postoperative predictors included intensive care unit stay (HR, 1.11; 95% CI, 1.035-1.194, p = 0.004) and albumin level (HR, 0.38; 95% CI, 0.196-0.725, p = 0.003). Conclusions: The 5-year prognosis of HD patients undergoing SAVR may be improved by early diagnosis (before the occurrence of LV hypertrophy/enlargement) and nutritional management with oral intake to alleviate postoperative hypoalbuminemia.Registration number of clinical studies: UMIN000047410.

Severe Acute Respiratory Syndrome by SARS-CoV-2 Infection or Other Etiologic Agents Among Brazilian Indigenous Population: An Observational Study from the First Year of Coronavirus Disease (COVID)-19 Pandemic.

BACKGROUND: Indigenous peoples are vulnerable to pandemics, including to the coronavirus disease (COVID)-19, since it causes high mortality and specially, the loss of elderly Indigenous individuals. METHODS: The epidemiological data of severe acute respiratory syndrome (SARS) by SARS-CoV-2 infection or other etiologic agents (OEA) among Brazilian Indigenous peoples during the first year of COVID-19 pandemic was obtained from a Brazilian Ministry of Health open-access database to perform an observational study. Considering only Indigenous individuals diagnosed with SARS by COVID-19, the epidemiology data were also evaluated as risk of death. The type of sample collection for virus screening, demographic profile, clinical symptoms, comorbidities, and clinical evolution were evaluated. The primary outcome was considered the death in the Brazilian Indigenous individuals and the secondary outcome, the characteristics of Brazilian Indigenous infected by SARS-CoV-2 or OEA, as the need for intensive care unit admission or the need for mechanical ventilation support. The statistical analysis was done using Logistic Regression Model. Alpha of 0.05. FINDINGS: A total of 3,122 cases of Indigenous individuals with SARS in Brazil were reported during the first year of the COVID-19 pandemic. Of these, 1,994 were diagnosed with COVID-19 and 730/1,816 (40.2%) of them died. The death rate among individuals with SARS-CoV-2 was three-fold increased when compared to the group of individuals with OEA. Several symptoms (myalgia, loss of smell, and sore throat) and comorbidities (cardiopathy, systemic arterial hypertension, and diabetes mellitus) were more prevalent in the COVID-19 group when compared to Indigenous individuals with OEA. Similar profile was observed considering the risk of death among the Indigenous individuals with COVID-19 who presented several symptoms (oxygen saturation <95%, dyspnea, and respiratory distress) and comorbidities (renal disorders, cardiopathy, and diabetes mellitus). The multivariate analysis was significant in differentiating between the COVID-19-positive and non-COVID-19 patients [X2 (7)=65.187; P-value<0.001]. Among the patients' features, the following contributed in relation to the diagnosis of COVID-19: age [≥43 years-old [y.o.]; OR=1.984 (95%CI=1.480-2.658)]; loss of smell [OR=2.373 (95%CI=1.461-3.854)]; presence of previous respiratory disorders [OR=0.487; 95%CI=0.287-0.824)]; and fever [OR=1.445 (95%CI=1.082-1.929)]. Also, the multivariate analysis was able to predict the risk of death [X2 (9)=293.694; P-value<0.001]. Among the patients' features, the following contributed in relation to the risk of death: male gender [OR=1.507 (95%CI=1.010-2.250)]; age [≥60 y.o.; OR=3.377 (95%CI=2.292-4.974)]; the need for ventilatory support [invasive mechanical ventilation; OR=24.050 (95%CI=12.584-45.962) and non-invasive mechanical ventilation; OR=2.249 (95%CI=1.378-3.671)]; dyspnea [OR=2.053 (95%CI=1.196-3.522)]; oxygen saturation <95% [OR=1.691 (95%CI=1.050-2.723)]; myalgia [OR=0.423 (95%CI=0.191-0.937)]; and the presence of kidney disorders [OR=3.135 (95%CI=1.144-8.539)]. INTERPRETATION: The Brazilian Indigenous peoples are in a vulnerable situation during the COVID-19 pandemic and presented an increased risk of death due to COVID-19. Several factors were associated with enhanced risk of death, as male sex, older age (≥60 y.o.), and need for ventilatory support; also, other factors might help to differentiate SARS by COVID-19 or by OEA, as older age (≥43 y.o.), loss of smell, and fever. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo (Foundation for Research Support of the State of São Paulo; #2021/05810-7).

Diagnostic accuracy of screening algorithms to identify persons with active pulmonary tuberculosis at prison entry: protocol of a systematic review and network meta-analysis.

Prison inmates are a high-risk group for tuberculosis (TB) infection and disease due to the increasing number of vulnerable fringe groups, risk factors (e.g., alcohol and drug addictions), contagious diseases (HIV, hepatitis), and their high-risk behavior. Compared to the general population, TB incidence and prevalence rates are significantly higher among prison inmates. Early identification of potentially infectious pulmonary TB (PTB) and targeted care of sick inmates are essential to effectively control TB within the prison system. The WHO recommends combining active and passive case-finding in prisons. No study has been published comparing the broad spectrum of screening tools using a diagnostic accuracy network meta-analysis (NMA). We aim to identify the most accurate TB case-finding algorithm at prison entry that is feasible in resource-limited prisons of high-burden TB countries and ensures continuous comprehensive TB detection services in such settings. Evidence generated by this NMA can provide important decision support in selecting the most (cost-) effective algorithms for screening methods for resource-limited settings in the short, medium, and long terms.