Assessment of the glymphatic function in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: Whether the alternation of the glymphatic system exists in neurodevelopmental disease still remains unclear. In this study, we investigated structural and functional changes in the glymphatic system in the treatment-naïve attention-deficit/hyperactivity disorder (ADHD) children by quantitatively measuring the Virchow-Robin spaces (VRS) volume and diffusion tensor image-analysis along the perivascular space (DTI-ALPS). METHODS: Forty-seven pediatric ADHD patients and 52 age- and gender-matched typically developing (TD) children were recruited in this prospective study. The VRS volume was calculated using a semi-automated approach in axial T2-weighted images. Diffusivities along the x-, y-, and z-axes in the projection, association, and subcortical neural fiber areas were measured. The ALPS index, a ratio that accentuated water diffusion along the perivascular space, was calculated. The Mann-Whitney U test was used to compare the quantitative parameters; Pearson's correlation was used to analyze the correlation with clinical symptoms. RESULTS: The cerebral VRS volume (mean, 15.514 mL vs. 11.702 mL) and the VRS volume ratio in the ADHD group were larger than those in the TD group (all p < 0.001). The diffusivity along the x-axis in association fiber area and ALPS index were significantly smaller in the ADHD group vs. TD group (mean, 1.40 vs.1.59, p < 0.05 after false discovery rate adjustment). Besides, the ALPS index was related to inattention symptoms of ADHD (r = - 0.323, p < 0.05). CONCLUSIONS: Our study suggests that the glymphatic system alternation may participate in the pathogenesis of ADHD, which may be a new research direction for exploring the mechanisms of psycho-behavioral developmental disorders. Moreover, the VRS volume and ALPS index could be used as the metrics for diagnosing ADHD. CLINICAL RELEVANCE STATEMENT: Considering the potential relevance of the glymphatic system for exploring the mechanisms of attention deficit/hyperactivity, the Virchow-Robin spaces volume and the analysis along the perivascular space index could be used as additional metrics for diagnosing the disorder. KEY POINTS: • Increased Virchow-Robin space volume and decreased analysis along the perivascular space index were found in the treatment-naïve attention-deficit/hyperactivity disorder children. • The results of this study indicate that the glymphatic system alternation may have a valuable role in the pathogenesis of attention-deficit/hyperactivity disorder. • The analysis along the perivascular space index is correlated with inattention symptoms of attention-deficit/hyperactivity disorder children.

Altered neurovascular coupling in the children with attention-deficit/hyperactivity disorder: a comprehensive fMRI analysis.

The coupling between resting-state cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signals reflects the mechanism of neurovascular coupling (NVC), which have not been illustrated in attention-deficit/hyperactivity disorder (ADHD). Fifty ADHD and 42 age- and gender-matched typically developing controls (TDs) were enrolled. The NVC imaging metrics were investigated by exploring the Pearson correlation coefficients between CBF and BOLD-derived quantitative maps (ALFF, fALFF, DCP maps). Three types of NVC metrics (CBF-ALFF, CBF-fALFF, CBF-DCP coupling) were compared between ADHD and TDs group, and the inner association between altered NVC metrics and clinical variables in ADHD group was further analyzed. Compared to TDs, ADHD showed significantly reduced whole-brain CBF-ALFF coupling (P < 0.001). Among regional level (all PFDR < 0.05), ADHD showed significantly lower CBF-ALFF coupling in bilateral thalamus, default-mode network (DMN) involving left anterior cingulate (ACG.L) and right parahippocampal gyrus (PHG.R), execution control network (ECN) involving right middle orbital frontal gyrus (ORBmid.R) and right inferior frontal triangular gyrus (IFGtriang.R), and increased CBF-ALFF coupling in attention network (AN)-related left superior temporal gyrus (STG.L) and somatosensory network (SSN))-related left rolandic operculum (ROL.L). Furthermore, increased CBF-fALFF coupling was found in the visual network (VN)-related left cuneus and negatively correlated with the concentration index of ADHD (R = - 0.299, PFDR = 0.035). Abnormal regional NVC metrics were at widespread neural networks in ADHD, mainly involved in DMN, ECN, SSN, AN, VN and bilateral thalamus. Notably, this study reinforced the insights into the neural basis and pathophysiological mechanism underlying ADHD.

Disrupted small-world networks in children with drug-naïve atten-tion-deficit/hyperactivity disorder: a DTI-based network analysis.

OBJECTIVES: To explore the alterations in the white matter (WM) structural connectome in children with drug-naïve attention-deficit/hyperactivity disorder (ADHD). METHODS: Forty-nine pediatric ADHD and 51 age- and gender-matched typically developing (TD) children aged 6-14 years old were enrolled. This cross-sectional study applied graph theoretical analysis to assess the white matter organization based on deterministic diffusion tensor imaging (DTI). WM structural connectivity was constructed in 90 cortical and subcor-tical regions, and topological parameters of the resulting graphs were calculated. Networks were compared between two groups. The digit cancellation test (DCT) was taken to evaluate clinical symptom severity in pediatric ADHD, using the concentration index and the total cancellation test scores. Then, a partial correlation analysis was performed to explore the re-lationship between significant topologic metrics and clinical symptom severity. RESULTS: Compared to TDs, ADHD showed an increase in the characteristic path length (Lp), normalized clustering coefficient (γ), small-worldness (σ), and a decrease in the global effi-ciency (Eglob) (all P <0.05). Furthermore, ADHD showed reduced nodal centralities mainly in the regions of default mode (DMN), central executive network (CEN), basal ganglia, and bilateral thalamus (all P <0.05). After performing Benjamini-Hochberg's procedure, only left orbital part of superior frontal gyrus (ORBsup.L) and left caudate (CAU) were statistically significant (P < 0.05, FDR-corrected). In addition, the concentration index of ADHD was negatively correlated with the nodal betweenness of the left orbital part of the middle frontal gyrus (ORBmid.L) (r = -0.302, P = 0.042). CONCLUSIONS: Our findings revealed an ADHD-related shift of WM network topology toward "regularization" pattern, characterized by decreased global network integration, which is also reflected by changed nodal centralities involving DMN, CEN, basal ganglia, and bilateral thalamus. ADHD could be understood by examining the dysfunction of large-scale spatially distributed neural networks.

Gene Variants in Two Families with Inherited Coagulation Factor XI Deficiency and Identification of Mutations.

INTRODUCTION: Mutations in the F11 gene can cause factor XI (FXI) deficiency, leading to abnormal coagulation activity and injury-related bleeding tendency. Therefore, identifying F11 gene mutations and studying the molecular basis will help us understand the pathogenesis of FXI deficiency. METHODS: Coagulation tests and gene sequencing analysis of all members were performed. FXI wild-type and mutant expression plasmids were constructed and transfected into HEK293FT cells. The FXI protein expression level was evaluated by ELISA and Western blot. RESULTS: The FXI activity (FXI:C) and FXI antigen (FXI:Ag) of proband-1 were decreased to 2% and 5%, respectively. FXI:C and FXI:Ag of proband-2 were reduced to 15% and 32%, respectively. Four mutations were found in the two unrelated families, including c.536C>T (p.T179M), c.1556G>A (p.W519*), c.434A>G (p.H145R), and c.1325_1325delT (p.L442Cfs*8). In vitro studies in transiently transfected HEK293FT cells demonstrated that p.T179M, p.W519*, and p.L442Cfs*8 mutations significantly lowered the FXI levels in the culture media. The FXI levels in the culture media and cell lysates of p.H145R mutation were similar to the wild type. CONCLUSION: Our results confirm that the four mutations in the F11 gene are causative in the 2 FXI deficiency families. Moreover, the p.H145R mutation is a cross-reactive material (CRM)-positive phenotype. The other three mutations are CRM-negative phenotypes and lead to FXI protein secretion disorder.

Evaluation of individual-based morphological brain network alterations in children with attention-deficit/hyperactivity disorder: a multi-method investigation.

To investigate the topological organization of individual-based morphological brain networks (MBNs) in attention-deficit/hyperactivity disorder (ADHD) children with different methods. A total of 60 ADHD children and 60 typically developing (TD) controls matched for age and gender were enrolled. Each participant underwent a structural 3D T1-weighted scan. Based on the inter-regional morphological similarity of GM regions, Kullback-Leibler-based similarity (KLS), Multivariate Euclidean Distance (MED), and Tijms's method were used to construct individual-based MBNs, respectively. The between-group difference of global and nodal network topological profiles was estimated, and partial correlation analysis was used for further analysis. According to KLS and MED-based network, ADHD showed a decreased global efficiency (Eglob) and increased characteristic path length (Lp) compared to the TD group, while Tijms's method-based network showed no between-group difference in global and nodal profiles. Nodal profiles were significantly decreased in the bilateral caudate, and nodal efficiency of the bilateral caudate was negatively correlated with clinical symptom severity of ADHD (P < 0.05, FDR-corrected) by the KLS-based network. Nodal betweenness was significantly decreased in the left inferior occipital gyrus and correlated with clinical symptom severity of ADHD (P < 0.05, FDR-corrected) by the MED-based network. ADHD was found to have a significantly less integrated organization and a shift to a "weaker small-worldness" pattern, while abnormal nodal profiles were mainly in the corpus striatum and default-mode networks. Our study highlights the crucial role of abnormal morphological connectivity patterns in understanding the brain maturational effects in ADHD and enriching the insights into MBNs at an individual level.

Quantification of myelination in children with attention-deficit/hyperactivity disorder: a comparative assessment with synthetic MRI and DTI.

Evaluation of myelin content is crucial for attention-deficit/hyperactivity disorder (ADHD). To estimate myelin content in ADHD based on synthetic MRI-based method and compare it with established diffusion tensor imaging (DTI) method. Fifth-nine ADHD and fifty typically developing (TD) children were recruited. Global and regional myelin content (myelin volume fraction [MVF] and myelin volume [MYV]) were assessed using SyMRI and compared with DTI metrics (fractional anisotropy and mean/radial/axial diffusivity). The relationship between significant MRI parameters and clinical variables were assessed in ADHD. No between-group differences of whole-brain myelin content were found. Compared to TDs, ADHD showed higher mean MVF in bilateral internal capsule, external capsule, corona radiata, and corpus callosum, as well as in left tapetum, left superior fronto-occipital fascicular, and right cingulum (all PFDR-corrected < 0.05). Increased MYV were found in similar regions. Abnormalities of DTI metrics were mainly in bilateral corticospinal tract. Besides, MVF in right retro lenticular part of internal capsule was negatively correlated with cancellation test scores (r = - 0.41, P = 0.002), and MYV in right posterior limb of internal capsule (r = 0.377, P = 0.040) and left superior corona radiata (r = 0.375, P = 0.041) were positively correlated with cancellation test scores in ADHD. Increased myelin content underscored the important pathway of frontostriatal tract, posterior thalamic radiation, and corpus callosum underlying ADHD, which reinforced the insights into myelin quantification and its potential role in pathophysiological mechanism and disease diagnosis. Prospectively registered trials number: ChiCTR2100048109; date: 2021-07.

Quantitative susceptibility mapping reveals brain iron deficiency in children with attention-deficit/hyperactivity disorder: a whole-brain analysis.

OBJECTIVES: To quantitatively measure and compare the whole-brain iron deposition between attention-deficit/hyperactivity disorder (ADHD) patients and typically developing (TD) children using the quantitative susceptibility mapping (QSM) technique. METHODS: This study was approved by the institutional review board of our institution (No. [2019]328). Fifty-one patients between 6 and 14 years with clinical diagnosis of ADHD and 51 age- and gender-paired TD children were enrolled. For each participant, the 3D T1 and multi-echo GRE sequence were performed to acquire the whole-brain data with 3.0-T MRI. The QSM maps were calculated using STISuite toolbox. After normalizing the QSM images to MNI space, the voxel-based analysis was used to compare the iron content between the two groups. Pearson's correlation test was used to assess the associations between the iron content and the score of the tablet-PC-based cancellation test, which was done to evaluate the attention concentration level. RESULTS: Iron deficiency was observed in several brain regions in children with ADHD, including bilateral striatums, anterior cingulum, olfactory gyrus, and right lingual gyri. In further correlation analysis, the left anterior cingulum was found to show positive correlation with the symptom severity (r = 0.326, p < 0.05). CONCLUSIONS: Our study demonstrated that the iron deficiency in several brain regions might be related with ADHD, which might be valuable for further studies. And QSM might have the potential efficacy in the auxiliary diagnosis of ADHD. KEY POINTS: • Iron deficiency was observed in several brain regions in children with ADHD, which include bilateral striatums, the critical regions in the dopaminergic transmitter system. • The iron content in the left ACG may have association with the symptom severity of ADHD. • QSM might have the potential efficacy in the auxiliary diagnosis of ADHD.

[Analysis of the molecular pathogenesis of hereditary protein C deficiency due to a p.Gly86Asp variant of the PROC gene].

OBJECTIVE: To explore the molecular pathogenesis of hereditary protein C (PC) deficiency due to a p.Gly86Asp variant of the PROC gene through in vitro expression experiment. METHODS: Wild type and Gly86Asp mutant expression plasmids of PC were constructed and respectively transfected into HEK 293FT cells. Total RNA was extracted from the transfected cells, and the expression of PROC gene was determined by quantitative real-time PCR (qRT-PCR). PC antigen (PC:Ag) in the supernatant of cell culture and cell lysate was determined by enzyme-linked immunosorbent assay (ELISA), and the level of PC protein was detected by Western blotting. RESULTS: qRT-PCR has detected no significant difference in the transcription level of wild-type and mutant-type PC. Compared with the wild type, the level of mutant PC:Ag in the supernatant and cell lysate were 81.3%±2.6% and 110.0%±2.8%, respectively. No difference was detected in the molecular weight between the wild-type and mutant-type PC by Western blotting. The PC content of mutant type was higher than wild-type in cell lysate, while the opposite was found with the cell culture supernatant. CONCLUSION: The impaired secretion by mutant PC may be the molecular mechanism of PC deficiency caused by the p.Gly86Asp variant.

Identifying Performance Outliers for Stroke Care Based on Composite Score of Process Indicators: an Observational Study in China.

BACKGROUND: Variability in the quality of stroke care is widespread. Identifying performance-based outlier hospitals based on quality indicators (QIs) has become a common practice. OBJECTIVES: To develop a tool for identifying performance-based outlier hospitals based on risk-adjusted adherence rates of process indicators. DESIGN: Hospitals were classified into five-level outliers based on the observed-to-expected ratio and P value. The composite quality score was derived by summation of the points for each indicator for each hospital, and associations between outlier status and outcomes were determined. PARTICIPANTS: Patients diagnosed with acute ischemic stroke, January 1, 2011-May 31, 2017. INTERVENTION: N/A MAIN OUTCOME MEASURES: Independence at discharge (the modified Rankin Scale = 0-2). KEY RESULTS: A total of 501,132 patients from 519 hospitals were identified. From 0.39 to 19.65% of hospitals were identified as high outliers according to various QIs. Composite quality scores ranged from - 20 to 16. Providers that were high outliers based on QI2, QI8, QI9, and QI11 had higher independent rates. For composite quality score, each point increase corresponded to an 8% increase in the odds of independent rate. CONCLUSION: Nationwide variation in the quality of acute stroke care exists at the hospital level. Variability in the quality of stroke care can be captured by our proposed quality score. Applying this quality score as a benchmarking tool could provide audit-level feedback to policymakers and hospitals to aid quality improvement.

[Analysis of a Chinese pedigree affected with hereditary factor VII deficiency caused by compound heterozygous variants of F7 gene].

OBJECTIVE: To explore the molecular basis for a Chinese pedigree affected with hereditary coagulation factor VII (FVII) deficiency. METHODS: The coding regions of F7 gene were amplified by PCR and sequenced. Suspected variants were confirmed by reverse sequencing and validated in other members from the pedigree. Pathogenicity of the variants was analyzed with multiple bioinformatic tools. RESULTS: Genetic analysis revealed that the proband has carried compound heterozygous c.985T>C (p.Ser329Pro) and c.1091G>A (p.Arg364Gln) variants in exon 8 of the F7 gene. Her mother, brother and son were heterozygous for c.985T>C (p.Ser329Pro), while her father was heterozygous for c.1091G>A (p.Arg364Gln). Phylogenetic analysis suggested that both p.Ser329 and p.Arg364 are highly conserved among homologous species. Online bioinformatic software predicted both variants to be deleterious. Protein model analysis suggested that the Pro329 side chain may form a new hydrogen bond with Leu333. The Pro benzene ring may clash with Glu325 in the p.Ser329Pro variant model. The p.Arg364Gln variant have two additional hydrogen bonds compared with wild type Arg364. Both variants may lead to alteration of the protein structure. CONCLUSION: The p.Ser329Pro and p.Arg364Gln variants in exon 8 of the F7 gene probably account for the reduced FVII in this pedigree.

Factors analysis on the use of key quality indicators for narrowing the gap of quality of care of breast cancer.

BACKGROUND: There are differences in the quality of care among breast cancer patients. Narrowing the quality differences could be achieved by increasing the utilization rate of indicators. Here we explored key indicators that can improve the quality of care and factors that may affect the use of these indicators. METHODS: A total of 3669 breast cancer patients were included in our retrospective study. We calculated patient quality-of-care composite score based on patient average method. Patients were divided into high- and low-quality groups according to the mean score. We obtained the indicators with large difference in utilization between the two groups. Multilevel logistic regression model was used to analyze the factors influencing quality of care and use of indicators. RESULTS: The mean composite score was 0.802, and the number of patients in the high- and low-quality groups were 1898 and 1771, respectively. Four indicators showed a difference in utilization between the two groups of over 40%. Histological grade, pathological stage, tumor size and insurance type were the factors affecting the quality of care. In single indicator evaluation, besides the above factors, age, patient income and number of comorbidities may also affect the use of these four indicators. Number of comorbidities may have opposite effects on the use of different indicators, as does pathological stage. CONCLUSIONS: Identifying key indicators for enhancing the quality-of-care of breast cancer patients and factors that affect the indicator adherence may provide guides for enhancing the utilization rate of these indicators in clinical practice.

Air-Tolerant Direct Thiol Esterification with Carboxylic Acids Using Hydrosilane via Simple Inorganic Base Catalysis.

Direct thioesterification of carboxylic acids with thiols using nontoxic activation agents is highly desirable. Herein, an efficient and practical protocol using safe and inexpensive industrial waste polymethylhydrosiloxane as the activation agent and K3PO4 with 18-crown-6 as a catalyst is described. Various functional groups on carboxylic acid and thiol substituents can be tolerated by the present system to afford thioesters in yields of 19-100%.

[Genetic analysis and clinical features of a pedigree affected with hereditary coagulation factor â ¦ deficiency caused by compound heterozygotic mutations].

OBJECTIVE: To detect potential mutations of the coagulation factor Ⅶ (F7) gene in a pedigree affected with hereditary FⅦ deficiency and explore its molecular pathogenesis. METHODS: The FⅦ antigen (FⅦ:Ag) was analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Prothrombin time (PT), FⅦ activity (FⅦ:C) and other coagulant parameters were quantified with an one-stage clotting assay. The F7 gene was amplified by PCR and sequenced. Mutational sites were confirmed by reverse sequencing. Impact of amino acid substitution was assessed using SIFT and PolyPhen-2 software. Structure of the mutant protein was analyzed using Swiss-pdb Viewer software based on the three-dimensional structure in the Protein Data Bank. RESULTS: The propositus had prolonged PT (36.3 s), with FⅦ:C and FⅦ:Ag significantly reduced to 2% and 44%, respectively. Her father, mother, younger sister and daughter had slightly prolonged PT and reduced FⅦ:C (86%-120%). The FⅦ:Ag of her father and younger sister were also reduced. DNA sequencing revealed that the propositus has carried compound heterozygous mutations (Lys341Glu and IVS6-1G>A) of the F7 gene. Her father and younger sister were heterozygous for the IVS6-1G>A mutation, while her mother and daughter were heterozygous for the Lys341Glu mutation. Bioinformatics analysis indicated that Lys341Glu mutation may affect the stability and function of the FⅦ protein. CONCLUSION: The Lys341Glu and IVS6-1G>A mutations probably underlie the reduced activity of FⅦ in this pedigree.

[Identification of compound heterozygous mutations of F11 gene in a pedigree affected with heriditary coagulation factor XI deficiency].

OBJECTIVE: To identify potential mutations of F11 gene in a pedigree affected with hereditary coagulation factor XI (FXI) deficiency and explore its molecular pathogenesis. METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), coagulation factor VIII activity (FVIIIC), coagulation factor IX activity (FIXC), coagulation factor XI activity (FXIC), coagulation factor XII activity (FXIIC) and lupus anticoagulation (LA) of the proband and eight family members were determined. FXI antigen (FXIAg) was determined by enzyme-linked immunosorbent assay (ELISA). For the proband, potential mutations in the exons, flanking introns and 5'-, 3'-untranslated regions of the F11 gene were screened by direct DNA sequencing. The results were confirmed by reverse sequencing. Suspected mutations were detected in other family members. ClustalX-2.1-win and four online bioinformatic tools (PolyPhen-2, PROVEAN, SIFT, and Mutation Taster) were used to study the conservation and possible impact of the mutations. The structure of the mutational sites was processed with Swiss-PdbViewer. RESULTS: The propositus had prolonged APTT (69.6 s), whose FXIC and FXIAg were reduced to 6.0% and 10.7%, respectively. Her mother, elder sister, one younger sister, little brother, daughter and son showed slightly prolonged APTT and moderate FXIC and FXIAg levels. Gene sequencing revealed that the propositus carried a heterozygous nonsense mutation c.738G>A (p.Trp228stop) in exon 7 and a heterozygous mutation c.1556G>C (p.Trp501Ser) in exon 13. Her mother, elder sister and daughter were heterozygous for the p.Trp228stop mutation, while one younger sister and little brother and son were heterozygous for p.Trp501Ser. Her husband and the youngest sister were of the wild type. Phylogenetic analysis suggested that Trp501 was highly conserved among all homologous species. The p.Trp501Ser was predicted to be "probably damaging","deleterious", "affect protein function" and "disease causing" corresponding to PolyPhen-2, PROVEAN, SIFT and Mutation Taster. Model analysis demonstrated that the non-polar Trp501 has two benzene rings, forming a hydrogen bond with Gln512 in the wild type. Once substituted by Ser501, the side chain may form another hydrogen bond with the benzene of His396. This may affect the normal space conformation and stability of FXI protein. CONCLUSION: The compound heterozygous mutations of the F11 gene probably accounted for the low FXI concentration in this pedigree.

Long-term effects of neoadjuvant radiotherapy, adjuvant radiotherapy, and chemotherapy-only on survival of locally advanced non-small cell lung Cancer undergoing surgery: a propensity-matched analysis.

BACKGROUND: The optimal timing of radiotherapy (RT) with respect to surgery remains controversial for locally advanced non-small cell lung cancer (LA NSCLC) undergoing surgery and the long-term effect of neoadjuvant RT, adjuvant RT, and chemotherapy-only on survival is unknown. METHODS: A retrospective study with Greedy 5 → 1 Digit propensity score matching technique was performed for locally advanced NSCLC patients identified from the Surveillance, Epidemiology, and End Results (SEER) database during 2004 to 2012. Kaplan-Meier and the log-rank test were conducted to compare NSCLC-specific survival. Cox proportional hazards multivariable regression was performed to assess the impact of different treatment regimens on cancer-specific mortality after adjustment for demographic factors, histology type, tumor grade, tumor size, nodal stage, and extent of resection. RESULTS: One thousand, two hundred and seventy-eight locally advanced NSCLC patients undergoing surgery were identified after propensity matching. Cox regression analyses showed the risk of cancer-specific mortality is not significantly different among neoadjuvant RT, adjuvant RT, and chemotherapy-only. Subgroup analyses showed that for patients with T1/2 & N2/3, the surgery plus chemotherapy-only group showed markedly higher mortality risk (HR = 1.42, 95%CI:1.10-1.83) than the neoadjuvant RT group. Other risk factors include older age, higher tumor grade, larger tumor size, and greater lymph node involvement. CONCLUSIONS: The findings of this study suggest that the benefit of additional neoadjuvant or adjuvant RT to chemotherapy may be linked to a proper selection of LA NSCLC patients who undergo surgery. The timing of radiotherapy should be decided on the premise of fully considering patients' condition and the quality of life after treatment.

The effect of low insurance reimbursement on quality of care for non-small cell lung cancer in China: a comprehensive study covering diagnosis, treatment, and outcomes.

BACKGROUND: The insurance reimbursement rate of medical cost affects the quality and quantity of health services provided in China. The nature of this relationship, however, has not been reliably described in the field of non-small cell lung cancer (NSCLC). The objective of the current study was to examine the impact of low reimbursement rates of medical costs on diagnosis, treatment and outcomes among patients with NSCLC. METHODS: We examined care of 2643 NSCLC patients and we divided the study cohort into a high reimbursement rate group and a low reimbursement rate group. The impact of reimbursement rates of medical costs on quality of care of NSCLC patients were examined using logistic regression and generalized linear models. RESULTS: Compared with patients insured with high reimbursement rate, patients insured through lower reimbursement rate programs were less likely to benefit from early detection and treatment services. Delayed detection was more common in low reimbursement group and they were less likely to be recommended for adjuvant chemotherapy, or to receive adjuvant chemotherapy and postoperative radiation therapy and they had lower odds to receipt chemotherapy response assessment. However, low reimbursement rate group had lower rate of in-hospital mortality and metastases. CONCLUSIONS: Low reimbursement rate mainly negatively influenced the diagnosis and treatment of NSCLC. Reducing the gap in reimbursement rate between the three health insurance schemes should be a focus of equalizing access to care and improving the level of medical compliance and finally improving quality of care of NSCLC.

Short- and long-term effects of clinical pathway on the quality of surgical non-small cell lung cancer care in China: an interrupted time series study.

OBJECTIVE: To examine the short- and long-term effect of clinical pathway for non-small cell lung cancer surgery on the length of stay, the compliance of quality indicators and risk-adjusted post-operative complication rate. DESIGN: A retrospective quasi-experimental study from June 2011 to October 2015. SETTING: A tertiary cancer hospital in China. PARTICIPANTS: Patients diagnosed as non-small cell lung cancer who underwent curative resection. INTERVENTION(S): Clinical pathway was implemented at January 2013. Hence, the study period was divided into three periods: pre-pathway, from June 2011 to December 2012; short-term period, from January 2013 to December 2013; long-term period, from January 2014 to October 2015. MAIN OUTCOME MEASURE(S): Three length of hospital stay indicators, four process performance indicators and one outcome indicator. RESULTS: ITS showed there was a significant decline of 2 days (P = 0.0421) for total length of stay and 2.23 days (P = 0.0199) for post-operative length of stay right after the implementation of clinical pathway. Short-term level changes were found in the compliance rate of required number of lymph node sampling (-8.08%, P = 0.0392), and risk-adjusted complication rate (9.02%, P = 0.0001). There were no statistically significant changes in other quality of care indicators. CONCLUSIONS: The clinical pathway had a positive impact on the length of stay but showed a transient negative effect on complication rate and the quality of lymph node sampling.

Development of quality indicators for non-small cell lung cancer care: a first step toward assessing and improving quality of cancer care in China.

BACKGROUND: Large gap exists between clinical practice and recommended care and large room exists for the improvement of care quality for non-small cell lung cancer (NSCLC) in China. Results of some studies have shown that assessment of care quality can help to make improvement and the development of quality indicators is deemed as the initial and most essential part. Yet there is no such an indicators system specifically suitable for Chinese health care system. The goal of the study is to set up a group of Chinese quality indicators for NSCLC care and make it the first step towards the improvement of NSCLC care quality in China. METHODS: We constructed a new indicator framework based on the characteristics of NSCLC care and the nature of Chinese health care system. Under the new framework, potential indicators were collected and a 3-round modified Delphi process was conducted by a national multi-disciplinary Expert Panel to develop a set of indicators until they reached the final consensus. RESULTS: A new indicator framework (structure, process, communication, management of symptoms or treatment toxicity and outcome) was developed. Seventy four indicators were extracted from guidelines and relevant literatures as potential indicators; 43 indicators plus 1 suggested indicator were remained after the discussion of Round 1; questionnaires of Round 2 were rated by Expert Panel and 19 indicators met the inclusion criteria and entered Round 3; 2 of the eliminated indicators in Round 2 were retrieved by the Expert Panel at the in-person meeting (Round 3). Therefore, 21 indicators got the final consensus of the Expert Panel. CONCLUSIONS: Guided by the new indicator structure, a set of indicators suitable for Chinese healthcare system was developed and can be utilized to measure and improve the care quality of non-small cell lung cancer.

Absolute oral bioavailability of fenofibric acid and choline fenofibrate in rats determined by ultra-performance liquid chromatography tandem mass spectrometry.

Choline fenofibrate is the choline salt of fenofibric acid, which releases free fenofibric acid in the gastrointestinal tract. To estimate the absolute oral bioavailability of fenofibric acid and choline fenofibrate, a novel and sensitive UPLC-MS/MS method with liquid-liquid extraction procedure was developed for the determination of fenofibric acid in rat plasma. The separation was achieved on a Phenomenex Kinetex C18 column (50 × 2.1 mm, 2.6 µm) containing 2 mm ammonium acetate-methanol with a gradient elution program. Validations of this method including specificity, sensitivity (limit of quantification, 5 ng/mL), linearity (0.005-10 µg/mL), accuracy (within ±4.3%), precision (intra- and inter-day coefficient of variation <11.3%), recovery (94.9-105.2% for fenofibric acid), matrix effect, stability and dilution, were all within acceptable limits. This method successfully supported the determination of fenofibric acid and choline fenofibrate. The absolute oral bioavailability was 93.4% for choline fenofibrate and 40.0% for fenofibric acid. These results suggested that choline fenofibrate and fenofibric acid had a better in vivo pharmacokinetic behavior than that of fenofibrate. The two new orally administrated pharmaceuticals, fenofibric acid and choline fenofibrate, can be developed as alternatives to fenofibrate.

Effect of Milk Powder Supplementation with Different Calcium Contents on Bone Mineral Density of Postmenopausal Women in Northern China: A Randomized Controlled Double-Blind Trial.

The objective of this study is to examine the effect of milk powder supplementation with different calcium contents on bone mineral density (BMD) in postmenopausal Chinese women, and to determine a more appropriate dose of calcium supplementation. A 2-year, randomized controlled double-blind trial. Postmenopausal women (n = 210) aged 50-65 years were recruited and assigned randomly into three calcium supplementation groups. All participants received milk powder supplementation with different calcium contents (300, 600, and 900 mg per day for groups A, B, and C, respectively) and all groups received 800 IU of vitamin D per day. During the follow-up period, BMD of the left hip and lumbar spine (as the main indicator) was measured using dual-energy X-ray absorptiometry at the baseline, 1 and 2 years. Both three BMD measures and the changes of BMD over 2 years were used to analyze. Before adjusting for covariates, BMD in group A of the lumbar spine and groups A and B of greater trochanter decreased significantly from the baseline over time but increased significantly in the rest groups of the lumbar spine and greater trochanter and in three groups of Ward's triangle. There were significant differences across the three groups for changes of BMD in the greater trochanter and Ward's triangle. When adjusting for covariates, there were significant decreases with time in group A of the spine (P = 0.001), groups A and B of greater trochanter (P = 0.0002 and P = 0.04, respectively) and increases in groups B and C of Ward's triangle (P = 0.03 and P = 0.004, respectively). BMD change in the greater trochanter was significantly different among three groups. For healthy postmenopausal women, high calcium milk powder supplementation was better in retarding bone loss than medium and low calcium in the greater trochanter. Considering the dietary calcium intake of postmenopausal women in north of China, a dose of 900 mg/day is considered as the most appropriate calcium supplementation for greater trochanter but not for other sites.