Application of peripheral blood routine parameters in the diagnosis of influenza and Mycoplasma pneumoniae.

OBJECTIVES: Influenza and Mycoplasma pneumoniae infections often present concurrent and overlapping symptoms in clinical manifestations, making it crucial to accurately differentiate between the two in clinical practice. Therefore, this study aims to explore the potential of using peripheral blood routine parameters to effectively distinguish between influenza and Mycoplasma pneumoniae infections. METHODS: This study selected 209 influenza patients (IV group) and 214 Mycoplasma pneumoniae patients (MP group) from September 2023 to January 2024 at Nansha Division, the First Affiliated Hospital of Sun Yat-sen University. We conducted a routine blood-related index test on all research subjects to develop a diagnostic model. For normally distributed parameters, we used the T-test, and for non-normally distributed parameters, we used the Wilcoxon test. RESULTS: Based on an area under the curve (AUC) threshold of ≥ 0.7, we selected indices such as Lym# (lymphocyte count), Eos# (eosinophil percentage), Mon% (monocyte percentage), PLT (platelet count), HFC# (high fluorescent cell count), and PLR (platelet to lymphocyte ratio) to construct the model. Based on these indicators, we constructed a diagnostic algorithm named IV@MP using the random forest method. CONCLUSIONS: The diagnostic algorithm demonstrated excellent diagnostic performance and was validated in a new population, with an AUC of 0.845. In addition, we developed a web tool to facilitate the diagnosis of influenza and Mycoplasma pneumoniae infections. The results of this study provide an effective tool for clinical practice, enabling physicians to accurately diagnose and differentiate between influenza and Mycoplasma pneumoniae infection, thereby offering patients more precise treatment plans.

Effects of different blood pressures and their long-term variability on the development of diabetic kidney disease in patients with type 2 diabetes mellitus.

AIM: To explore the relationship between long-term variabilities in different blood pressure variables and diabetic kidney disease (DKD) in patients with type 2 diabetes. DESIGN: A retrospective study. METHODS: This study included 3050 patients with type 2 diabetes whose metabolic parameters were regularly checked. Intrapersonal means and standard deviations (SDs) of all recorded systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) measurements were calculated. Subjects were divided into four groups: Q1 (SBP-Mean < 130, SBP-SD < 11.06); Q2 (SBP-Mean < 130, SBP-SD ≥ 11.06); Q3 (SBP-Mean ≥ 130, SBP-SD < 11.06); Q4 (SBP-Mean ≥ 130, SBP-SD ≥ 11.06). Similarly, based on whether the PP-Mean was higher or lower than 80 mmHg (average PP-Mean) and the PP-SD was higher or lower than 6.48 mmHg (average PP-SD), the involved patients were redivided into Q1'~ Q4' groups. RESULTS: Adjusted for age, sex and diabetes duration, results revealed that the SBP-Mean, SBP-SD, PP-Mean and PP-SD were risk factors for DKD. Meanwhile, patients in the Q4 group had the highest DKD prevalence (HR = 1.976, p < .001), while Q1 group had the lowest. In addition, patients in the Q3 group (HR = 1.614, P < .001) had a higher risk of DKD than those in the Q2 group (HR = 1.408, P < .001). After re-stratification by PP-Mean and PP-SD, patients in the Q4' group had the highest risk of DKD (HR = 1.370, p < .001), while those in the Q1' group had the lowest risk. Patients in the Q3' group (HR = 1.266, p < .001) had a higher risk of DKD than those in the Q2' group (HR = 1.212, p < .001).

The Impact of Systolic Blood Pressure, Pulse Pressure, and Their Variability on Diabetes Retinopathy among Patients with Type 2 Diabetes.

Objectives: To evaluate the effects of variations in systolic blood pressure (SBP) and pulse pressure (PP) on diabetic retinopathy (DR) in patients with type 2 diabetes. Methods: A total of 3275 type 2 diabetes patients without DR at Taiwan Lee's United Clinic from 2002 to 2014 were enrolled in the study. The average age of the patients was 65.5 (±12.2) years, and the follow-up period ranged from 3 to 10 years. Blood pressure variability was defined as the standard deviation (SD) of the average blood pressure values over the entire study period and was calculated for each patient. The mean SD for SBP was 11.16, and a SBP ≥ 130 mmHg (1 mmHg = 0.133 kPa) was defined as high SBP. Based on these data, patients were divided into four groups as follows: group 1 (G1, mean SBP < 130 mmHg, SD of SBP < 11.16 mmHg), group 2 (G2, mean SBP < 130 mmHg, SD ≥ 11.16 mmHg), group 3 (G3, mean SBP ≥ 130 mmHg, SD of SBP < 11.16 mmHg), and group 4 (G4, mean SBP ≥ 130 mmHg, SD ≥ 11.16 mmHg). Based on a mean PP of 80 mmHg with a pulse pressure SD of 6.53 mmHg, the patients were regrouped into four groups designated G1'-G4'. Results: After adjusting for patient age, sex, and disease course, Cox regression showed that the mean and SD of SBP, pulse pressure, and their SDs were risk factors for DR. After stratifying the patients based on the mean and SD of the SBP, we found that the patients in the G4 group had the highest risk of DR (hazard ratio (HR) = 1.980, 95% CI: 1.716~2.285, P < 0.01) and patients in the G1 group had the lowest risk. Patients in the G3 group (HR = 1.409, 95% CI: 1.284~1.546, P < 0.01) had a higher risk of DR compared to those in the G2 group (HR = 1.353, 95% CI: 1.116~1.640, P < 0.01). After the restratification of patients based on the mean and SD of the pulse pressures, it was found that patients in the G2' group had the highest risk of DR (HR = 2.086, 95% CI: 1.641~2.652, P < 0.01), whilst patients in the G1' group had the lowest risk. Also, the risk of DR in the G4' group (HR = 1.507, 95% CI: 1.135~2.000, P < 0.01) was higher than that in the G3' group (HR = 1.289, 95% CI: 1.181~1.408, P < 0.01). Conclusions: Variability in SBP and PP are risk factors for DR in patients with type 2 diabetes. The variability of PP was better able to predict the occurrence of DR than mean pulse pressure.

Abnormal functional connectivity of the frontostriatal circuits in type 2 diabetes mellitus.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with an increased incidence of cognitive and emotional disorders. Previous studies have indicated that the frontostriatal circuits play a significant role in brain disorders. However, few studies have investigated functional connectivity (FC) abnormalities in the frontostriatal circuits in T2DM. Objective: We aimed to investigate the abnormal functional connectivity (FC) of the frontostriatal circuits in patients with T2DM and to explore the relationship between abnormal FC and diabetes-related variables. Methods: Twenty-seven patients with T2DM were selected as the patient group, and 27 healthy peoples were selected as the healthy controls (HCs). The two groups were matched for age and sex. In addition, all subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological evaluation. Seed-based FC analyses were performed by placing six bilateral pairs of seeds within a priori defined subdivisions of the striatum. The functional connection strength of subdivisions of the striatum was compared between the two groups and correlated with each clinical variable. Results: Patients with T2DM showed abnormalities in the FC of the frontostriatal circuits. Our findings show significantly reduced FC between the right caudate nucleus and left precentral gyrus (LPCG) in the patients with T2DM compared to the HCs. The FC between the prefrontal cortex (left inferior frontal gyrus, left frontal pole, right frontal pole, and right middle frontal gyrus) and the right caudate nucleus has a significant positive correlation with fasting blood glucose (FBG). Conclusion: The results showed abnormal FC of the frontostriatal circuits in T2DM patients, which might provide a new direction to investigate the neuropathological mechanisms of T2DM.

Annual decline in ß-cell function in patients with type 2 diabetes in China.

BACKGROUND: The aim of this study was to investigate the annual decline of ß-cell function correlated with disease duration in patients with type 2 diabetes in China. METHODS: This cross-sectional study included 4792 adults with type 2 diabetes who were recruited from four university hospital diabetes clinics between April 2018 and November 2018. Baseline data were collected from electric medical records. Participants were divided into 21 groups with 1-year diabetes duration interval to assess the decline rate of ß-cell function. Homeostatic model assessment model (HOMA 2) model was applied to assess ß-cell function. Multiple linear regression model was used to evaluate the association between biochemical and clinical variables and ß-cell function. RESULTS: In Chinese patients with type 2 diabetes, ß-cell function declined by 2% annually. Using angiotensin receptor blockade (ARB) (ß = .048; P = .011), metformin (ß = .138; P = .021), or insulin (ß = .142; P = .018) was associated with increased ß-cell function. However, increased BMI (ß = -.215; P = .022), alcohol consumption (ß = -.331; P < .001), haemoglobin A1c (ß = -.104; P = .027), or increased diabetes duration (ß = -.183; P = .003) was significantly and negatively associated with ß-cell function. CONCLUSIONS: We determined that the annual rate of the ß-cell function decline was 2% in patients with type 2 diabetes in China. Moreover, we confirmed a positive relationship between ARB treatment and ß-cell function, while BMI and alcohol consumption were significantly and negatively associated with the ß-cell function.

Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the highest incidences in cancers; however, traditional chemotherapy often suffers from low efficiency caused by drug resistance. Herein, we report an arsenite-loaded dual-drug (doxorubicin and arsenic trioxide, i.e., DOX and ATO) nanomedicine system (FeAsOx@SiO2-DOX, Combo NP) with significant drug synergy and pH-triggered drug release for effective treatment of DOX resistant HCC cells (HuH-7/ADM). This nano-formulation Combo NP exhibits the synergistic effect of DNA damage by DOX along with DNA repair interference by ATO, which results in unprecedented killing efficiency on DOX resistant cancer cells. More importantly, we explored the possible mechanism is that the activity of PARP-1 is inhibited by ATO during the treatment of Combo NP, which finally induces apoptosis of HuH-7/ADM cells by poly (ADP-ribosyl) ation suppression and DNA lesions accumulation. This study provides a smart drug delivery strategy to develop a novel synergistic combination therapy for effectively overcome drug- resistant cancer cells.

Anemia rather than hypertension contributes to cerebral hyperperfusion in young adults undergoing hemodialysis: A phase contrast MRI study.

Cerebral hyperperfusion, anemia and hypertension are common in patients with end-stage renal disease (ESRD). Young ESRD adults might afford a better hemodynamic tolerance; however, their cerebral vascular disorders are often overlooked. This phase-contrast MRI study investigated relationships between cerebral blood flow (CBF), anemia and hypertension in young adults undergoing hemodialysis (HD). Blood flows, velocities, and cross-sectional areas of bilateral internal carotid arteries and vertebral arteries were quantified on phase maps in 33 patients and 27 healthy controls. Cerebral oxygen delivery (COD) and vascular resistance were (CVR) were computed based on CBF, hemoglobin and mean arterial pressure (MAP). We found strong correlations among hemoglobin, MAP and CBF. Hemoglobin rather than MAP was directly related to CBF. COD was negatively related to MAP, while CVR was positively related to hemoglobin. The cross-sectional areas of arteries were increased which were directly associated with hemoglobin rather than MAP. HD patients were of elevated CBF, decreased COD and unchanged CVR. Although elevated CBF compensated anemia-induced hypoxia, COD of these patients was still lower. Anemia directly contributed to elevated CBF and hypertension affected CBF through anemia. Unaffected CVR of young patients probably indicated that they could maintain basic functions of cerebral circulation under multiple risk factors.

A facile route to core-shell nanoparticulate formation of arsenic trioxide for effective solid tumor treatment.

Arsenic trioxide has achieved great clinical success in the treatment of acute promyelocytic leukemia (APL). However, it is difficult to replicate the success in other cancers, such as solid tumors, in part because of the rapid renal clearance and dose-limiting toxicity. Nanotechnology is expected to overcome these disadvantages through altering its pharmacokinetics and concentrating the drug at the desired sites. Herein, we report a "one-pot" method to develop arsenic-based nanodrugs by in situ coating the as-prepared arsenic nanocomplexes with porous silica shells. This process can be easily reproduced and scaled up because no complicated synthesis and purification steps are involved. This core-shell embedding method endows nanodrugs with high loading capacity (57.9 wt%) and a prolonged pH-responsive releasing profile, which is crucial to increase the drug concentration at tumor sites and improve the drug efficacy. Based on these unique features, the nanodrugs significantly inhibit the growth of solid tumors without adverse side effects. Therefore, we anticipate that the arsenic-based nanodrugs generated by this facile synthetic route may be a powerful and alternative strategy for solid tumor therapy.

Geometrically confined ultrasmall gadolinium oxide nanoparticles boost the T(1) contrast ability.

High-performance magnetic resonance imaging (MRI) contrast agents and novel contrast enhancement strategies are urgently needed for sensitive and accurate diagnosis. Here we report a strategy to construct a new T1 contrast agent based on the Solomon-Bloembergen-Morgan (SBM) theory. We loaded the ultrasmall gadolinium oxide nanoparticles into worm-like interior channels of mesoporous silica nanospheres (Gd2O3@MSN nanocomposites). This unique structure endows the nanocomposites with geometrical confinement, high molecular tumbling time, and a large coordinated number of water molecules, which results in a significant enhancement of the T1 contrast with longitudinal proton relaxivity (r1) as high as 45.08 mM(-1) s(-1). Such a high r1 value of Gd2O3@MSN, compared to those of ultrasmall Gd2O3 nanoparticles and gadolinium-based clinical contrast agents, is mainly attributed to the strong geometrical confinement effect. This strategy provides new guidance for developing various high-performance T1 contrast agents for sensitive imaging and disease diagnosis.

Elevated global cerebral blood flow, oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease: an MRI study.

OBJECTIVES: To noninvasively assess global cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in young adults with end-stage renal disease (ESRD). METHODS: Thirty-six patients and 38 healthy volunteers were included and took part in MR examinations, blood and neuropsychological tests. CBF and OEF were measured by phase-contrast and T2-relaxation-under-spin-tagging MRI techniques, respectively. CMRO2 was computed from CBF, OEF and hematocrit according to Fick's principle. Correlations were performed between MR measurements, blood biochemistry measurements and neuropsychological test scores. RESULTS: Compared with controls, ESRD patients had elevated CBF (72.9 ± 12.5 vs. 63.8 ± 8.5 ml min(-1) 100 g(-1), P < 0.001), elevated OEF (47.2 ± 10.2 vs. 35.8 ± 5.4 %, P < 0.001), but unaffected CMRO2 (199.5 ± 36.4 vs. 193.8 ± 28.6 µmol O2 min(-1) 100 g(-1), P = 0.879). Hematocrit negatively correlated with CBF (r = -0.640, P < 0.001) and OEF (r = -0.701, P < 0.001), but not with CMRO2. Altered neuropsychological test scores of ESRD patients were associated with OEF and CBF, but not with CMRO2. There were weak relationships between eGFR and hematocrit (r = 0.308, P = 0.068) or CBF (r = 0.318, P = 0.059). CONCLUSION: Our findings suggested that anaemic young adults with ESRD may afford higher CBF and OEF to maintain a normal CMRO2. Despite this compensatory process, however, cognitive function was still impaired and its severity was correlated with their CBF and OEF abnormality. KEY POINTS: • Anaemic young adults with ESRD may afford higher CBF and OEF. • Anaemic young adults with ESRD maintain a normal CMRO 2 . • Cognitive function was still impaired in young ESRD adults. • The severity of cognitive dysfunction correlated with CBF and OEF changes.

Efficacy of nonvenous medications for acute convulsive seizures: A network meta-analysis.

OBJECTIVE: This is a network meta-analysis of nonvenous drugs used in randomized controlled trials (RCTs) for treatment of acute convulsive seizures and convulsive status epilepticus. METHODS: Literature was searched according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for RCTs examining treatment of acute convulsive seizures or status epilepticus with at least one of the study arms being a nonvenous medication. After demographic and outcome data extraction, a Bayesian network meta-analysis was performed and efficacy results were summarized using treatment effects and their credible intervals (CrI). We also calculated the probability of each route-drug combination being the most clinically effective for a given outcome, and provided their Bayesian hierarchical ranking. RESULTS: This meta-analysis of 16 studies found that intramuscular midazolam (IM-MDZ) is superior to other nonvenous medications regarding time to seizure termination after administration (2.145 minutes, 95% CrI 1.308-3.489), time to seizure cessation after arrival in the hospital (3.841 minutes, 95% CrI 2.697-5.416), and time to initiate treatment (0.779 minutes, 95% CrI 0.495-1.221). Additionally, intranasal midazolam (IN-MDZ) was adjudged most efficacious for seizure cessation within 10 minutes of administration (90.4% of participants, 95% CrI 79.4%-96.9%), and persistent seizure cessation for ≥1 hour (78.5% of participants, 95% CrI 59.5%-92.1%). Paucity of RCTs produced evidence gaps resulting in small networks, routes/drugs included in some networks but not others, and some trials not being connected to any network. CONCLUSIONS: Despite the evidence gaps, IM-MDZ and IN-MDZ exhibit the best efficacy data for the nonvenous treatment of acute convulsive seizures or status epilepticus.

Shared and discrepant susceptibility for carotid artery and aortic arch calcification: A genetic association study.

Genome-wide association studies (GWASs) have identified several risk loci for coronary artery calcification. Four single-nucleotide polymorphisms (SNPs, rs1537370, rs1333049, rs2026458 and rs9349379) were associated with coronary artery calcification with P values less than 5 × 10(-8) in GWASs. It is unclear if these associations exist in other vascular beds. Thus, we evaluated the impacts of these four SNPs on carotid artery and aortic arch calcification in this study. Computed tomography was applied to quantify the calcification of carotid artery and aortic arch. 860 patients with stroke completed calcification quantification and genotype testing were included in data analysis. Each SNP was evaluated for the association with carotid artery calcification, and with aortic arch calcification using generalized linear model. Among the four tested SNPs, rs2026458 was associated with calcification in both carotid artery (ß = 0.31, 95% confidence interval [CI] 0.10-0.52, P = 0.003) and aortic arch (ß = 0.32, 95% CI 0.10-0.54, P = 0.004), while rs1333049 was only associated with carotid artery calcification (ß = 0.28, 95% CI 0.06-0.50, P = 0.011). In gender-stratified analyses, rs2026458 had significant impacts on carotid artery (P = 0.003) and aortic arch calcification (P = 0.008) in male, but not in female patients; while rs1537370 was significantly associated with carotid artery calcification in female (P = 0.013), but not in male patients. In conclusion, SNPs associated with coronary artery calcification may also increase the risk of calcification in other arteries such as carotid artery and aortic arch.

Comparison of Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging and Arterial Spin Labeling MR Imaging in Gliomas.

Gliomas grading is important for treatment plan; we aimed to investigate the application of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in gliomas grading, by comparing with the three-dimensional pseudocontinuous arterial spin labeling (3D pCASL). 24 patients (13 high grade gliomas and 11 low grade gliomas) underwent IVIM DWI and 3D pCASL imaging before operation; maps of fast diffusion coefficient (D (∗)), slow diffusion coefficient (D), fractional perfusion-related volume (f), and apparent diffusion coefficient (ADC) as well as cerebral blood flow (CBF) were calculated and then coregistered to generate the corresponding parameter values. We found CBF and D (∗) were higher in the high grade gliomas, whereas ADC, D, and f were lower (all P < 0.05). In differentiating the high from low grade gliomas, the maximum areas under the curves (AUC) of D (∗), CBF, and ADC were 0.857, 0.85, and 0.902, respectively. CBF was negatively correlated with f in tumor (r = -0.619, P = 0.001). ADC was positively correlated with D in both tumor and white matter (r = 0.887, P = 0.000 and r = 0.824, P = 0.000, resp.). There was no correlation between CBF and D (∗) in both tumor and white matter (P > 0.05). IVIM DWI showed more efficiency than 3D pCASL but less validity than conventional DWI in differentiating the high from low grade gliomas.

Pathological uncoupling between amplitude and connectivity of brain fluctuations in epilepsy.

Amplitude and functional connectivity are two fundamental parameters for describing the spontaneous brain fluctuations. These two parameters present close coupling in physiological state, and present different alteration patterns in epilepsy revealed by functional MRI (fMRI). We hypothesized that the alteration of coupling between these two imaging parameters may be underpinned by specific pathological factors of epilepsy, and can be employed to improve the capability for epileptic focus detection. Forty-seven patients (26 left- and 21 right-sided) with mesial temporal lobe epilepsy (mTLE) and 32 healthy controls underwent resting-state fMRI scans. All patients were detected to have interictal epileptic discharges on simultaneous electroencephalograph (EEG) recordings. Amplitude-connectivity coupling was calculated by correlating amplitude and functional connectivity density of low-frequency brain fluctuations. We observed reduced amplitude-connectivity coupling associated with epileptic discharges in the mesial temporal regions in both groups of patients, and increased coupling associated with epilepsy durations in the posterior regions of the default-mode network in the right-sided patients. Moreover, we proposed a new index of amplitude subtracting connectivity, which elevated imaging contrast for differentiating the patients from the controls. The findings indicated that epileptic discharges and chronic damaging effect of epilepsy might both contribute to alterations of amplitude-connectivity coupling in different pivotal regions in mTLE. Investigation on imaging coupling provides synergistic approach for describing brain functional changing features in epilepsy.

Real-time monitoring of arsenic trioxide release and delivery by activatable T(1) imaging.

Delivery of arsenic trioxide (ATO), a clinical anticancer drug, has drawn much attention to improve its pharmacokinetics and bioavailability for efficient cancer therapy. Real-time and in situ monitoring of ATO behaviors in vivo is highly desirable for efficient tumor treatment. Herein, we report an ATO-based multifunctional drug delivery system that efficiently delivers ATO to treat tumors and allows real-time monitoring of ATO release by activatable T1 imaging. We loaded water-insoluble manganese arsenite complexes, the ATO prodrug, into hollow silica nanoparticles to form a pH-sensitive multifunctional drug delivery system. Acidic stimuli triggered the simultaneous release of manganese ions and ATO, which dramatically increased the T1 signal (bright signal) and enabled real-time visualization and monitoring of ATO release and delivery. Moreover, this smart multifunctional drug delivery system significantly improved ATO efficacy and strongly inhibited the growth of solid tumors without adverse side effects. This strategy has great potential for real-time monitoring of theranostic drug delivery in cancer diagnosis and therapy.

Correlation between cerebral microbleeds and S100B/RAGE in acute lacunar stroke patients.

BACKGROUND AND PURPOSE: S100B and its scavenger, soluble receptor for advanced glycation end products (sRAGE), participate in various acute and chronic brain disorders. However, their impact on hemorrhage-prone small vessel disease represented by cerebral microbleeds (CMBs) is unclear. The purpose of this study was to investigate the relationship of CMBs with plasma S100B and sRAGE. METHODS: A cohort of 147 consecutive patients with first-ever acute lacunar stroke was prospectively enrolled. We collected demographic, clinical, and laboratory data, including plasma levels of S100B and sRAGE, and presence and number of CMBs using susceptibility-weighted imaging (SWI). Associations between plasma S100B, sRAGE levels and the presence, number, and location of CMBs were determined. RESULTS: CMBs were present in 58 patients (39.5%). Each 1SD-increase in S100B and sRAGE levels was significantly associated with presence of CMBs (adjusted odds ratio [OR], 3.06; 95% confidence interval [CI], 1.81-5.17 and adjusted OR, 0.29; 95% CI, 0.16-0.53; respectively) and number of CMBs (adjusted relative risk [RR], 4.07; 95% CI, 3.60-5.65 for S100B and RR 0.34; 95% CI, 0.25-0.46 for sRAGE). When stratified by location, plasma S100B and sRAGE levels were similarly associated with presence of deep CMBs (adjusted OR, 3.65; 95% CI, 1.99-6.69 and adjusted OR, 0.23; 95% CI, 0.12-0.46; respectively), but not with strictly lobar CMBs. CONCLUSIONS: Higher levels of S100B and lower levels of sRAGE are independently associated with presence and number of CMBs in patients with first-ever acute lacunar stroke, particularly in those with deep CMBs.

Multipopulation Tailoring Clinical Trials: Design, Analysis, and Inference Considerations.

Several recent publications have focused on statistical considerations that arise in multipopulation tailoring clinical trials that evaluate treatment effect in an overall patient population as well as one or more predefined subpopulations. This paper presents a decision-making framework applicable to these trials and evaluates the operating characteristics of this framework versus one based solely on the results of primary hypothesis tests. The operating characteristics are presented as rates of applicable errors, known as influence errors and interaction errors.

Structural and functional abnormalities of default mode network in minimal hepatic encephalopathy: a study combining DTI and fMRI.

BACKGROUND AND PURPOSE: Live failure can cause brain edema and aberrant brain function in cirrhotic patients. In particular, decreased functional connectivity within the brain default-mode network (DMN) has been recently reported in overt hepatic encephalopathy (HE) patients. However, so far, little is known about the connectivity among the DMN in the minimal HE (MHE), the mildest form of HE. Here, we combined diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) to test our hypothesis that both structural and functional connectivity within the DMN were disturbed in MHE. MATERIALS AND METHODS: Twenty MHE patients and 20 healthy controls participated in the study. We explored the changes of structural (path length, tracts count, fractional anisotropy [FA] and mean diffusivity [MD] derived from DTI tractography) and functional (temporal correlation coefficient derived from rs-fMRI) connectivity of the DMN in MHE patients. Pearson correlation analysis was performed between the structural/functional indices and venous blood ammonia levels/neuropsychological tests scores of patients. All thresholds were set at P<0.05, Bonferroni corrected. RESULTS: Compared to the healthy controls, MHE patients showed both decreased FA and increased MD in the tract connecting the posterior cingulate cortex/precuneus (PCC/PCUN) to left parahippocampal gyrus (PHG), and decreased functional connectivity between the PCC/PCUN and left PHG, and medial prefrontal cortex (MPFC). MD values of the tract connecting PCC/PCUN to the left PHG positively correlated to the ammonia levels, the temporal correlation coefficients between the PCC/PCUN and the MPFC showed positive correlation to the digital symbol tests scores of patients. CONCLUSION: MHE patients have both disturbed structural and functional connectivity within the DMN. The decreased functional connectivity was also detected between some regions without abnormal structural connectivity, suggesting that the former may be more sensitive in detecting the early abnormalities of MHE. This study extends our understanding of the pathophysiology of MHE.

Selective impairments of resting-state networks in minimal hepatic encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) is a neuro-cognitive dysfunction characterized by impairment in attention, vigilance and integrative functions, while the sensorimotor function was often unaffected. Little is known, so far, about the exact neuro-pathophysiological mechanisms of aberrant cognition function in this disease. METHODOLOGY/PRINCIPAL FINDINGS: To investigate how the brain function is changed in MHE, we applied a resting-state fMRI approach with independent component analysis (ICA) to assess the differences of resting-state networks (RSNs) between MHE patients and healthy controls. Fourteen MHE patients and 14 age-and sex-matched healthy subjects underwent resting-state fMRI scans. ICA was used to identify six RSNs [dorsal attention network (DAN), default mode network (DMN), visual network (VN), auditory network (AN), sensorimotor network (SMN), self-referential network (SRN)] in each subject. Group maps of each RSN were compared between the MHE and healthy control groups. Pearson correlation analysis was performed between the RSNs functional connectivity (FC) and venous blood ammonia levels, and neuropsychological tests scores for all patients. Compared with the healthy controls, MHE patients showed significantly decreased FC in DAN, both decreased and increased FC in DMN, AN and VN. No significant differences were found in SRN and SMN between two groups. A relationship between FC and blood ammonia levels/neuropsychological tests scores were found in specific regions of RSNs, including middle and medial frontal gyrus, inferior parietal lobule, as well as anterior and posterior cingulate cortex/precuneus. CONCLUSIONS/SIGNIFICANCE: MHE patients have selective impairments of RSNs intrinsic functional connectivity, with aberrant functional connectivity in DAN, DMN, VN, AN, and spared SMN and SRN. Our fMRI study might supply a novel way to understand the neuropathophysiological mechanism of cognition function changes in MHE.

Altered resting-state brain activity at functional MR imaging during the progression of hepatic encephalopathy.

PURPOSE: To explore the spatial patterns of the amplitude of low-frequency fluctuation (ALFF) in patients with hepatic encephalopathy (HE) of varying severity and to correlate these fluctuations with clinical markers of HE. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all participants. Twenty-nine patients with HE (15 with overt and 14 with minimal HE) and 17 healthy control subjects underwent resting-state functional magnetic resonance (MR) imaging. The ALFF, an index reflecting the amplitudes of spontaneous brain activity, was compared among patients with overt HE, patients with minimal HE, and control subjects with analysis of variance tests and t tests between each pair. Pearson correlation analysis was performed between the ALFF and the venous blood ammonia level and Child-Pugh score of all patients with HE. RESULTS: Compared with control subjects, patients with overt and minimal HE showed decreased ALFF mainly in regions within the default-mode network (DMN) and increased ALFF in the cerebellum and middle temporal gyrus. Compared with patients with minimal HE, those with overt HE showed decreased ALFF in DMN regions and increased ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). Both the venous blood ammonia levels and Child-Pugh scores of individual patients with HE showed negative correlation with ALFF within some DMN regions, whereas they showed positive correlation with ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). CONCLUSION: Patients with HE have diffuse abnormalities in intrinsic brain activity. The levels of decreased ALFF in the DMN and increased ALFF in the posterior insular cortex are dependent on the severity of HE, suggesting continuous impairment of the DMN and a compensatory role of the insula during the progression of HE. Resting-state functional MR imaging with ALFF analysis may be a noninvasive modality with which to detect the progression of HE.