Identification of blood metabolic biomarkers associated with diabetic distal symmetric sensorimotor polyneuropathy in patients with type 2 diabetes mellitus.

BACKGROUND: Distal symmetric sensorimotor polyneuropathy (DSPN) is a common neurologic complication of type 2 diabetes mellitus (T2DM), but the underlying mechanisms and changes in serum metabolites remain largely undefined. This study aimed to characterize the plasma metabolite profiles of participants with T2DM using targeted metabolomics analysis and identify potential biomarkers for DSPN. METHODS: A combined liquid chromatography MS/MS and direct flow injection were used to quantify plasma metabolite obtained from 63 participants with T2DM, 81 with DSPN, and 33 nondiabetic control participants. A total of 130 metabolites, including amino acids, biogenic amines, sphingomyelins (SM), phosphatidylcholines, carnitines, and hexose, were analyzed. RESULTS: A total of 16 plasma metabolites and 3 cholesterol-related laboratory parameters were found to have variable importance in the projection score >1.0 and false discovery rate <5.0% between control, T2DM, and DSPN. Among these variables, five serum metabolites, including phenylalanine (AUC = 0.653), alanine (AUC = 0.630), lysine (AUC = 0.622) tryptophan (AUC = 0.620), and SM C16:0 (AUC = 0.630), are potential biomarkers (all p < .05) in distinguishing T2DM with DSPN from those without (AUC = 0.720). CONCLUSIONS: In this cross-sectional study, derangement of several metabolites in the plasma was observed in T2DM with and without DSPN, and these metabolites may be potential biomarkers for predicting DSPN. Longitudinal studies are warranted.

Cost-effectiveness evaluation of mammography screening program in Taiwan: Adjusting different distributions of age and calendar year for real world data.

BACKGROUND/PURPOSE: We estimated loss-of-life expectancy (LE) and lifetime medical expenditures (LME) stratified by stages to evaluate the cost-effectiveness of breast cancer (BC) screening in Taiwan. METHODS: We interlinked four national databases- Cancer Registry, Mortality Registry, National Health Insurance Claim, and Mammography Screening. A cohort of 123,221 BC was identified during 2002-2015 and followed until December 31, 2017. We estimated LE and loss-of-LE by rolling extrapolation algorithm using age-, sex-, and calendar-year-matched referents simulated from vital statistics. LME was estimated by multiplying monthly cost with survival probability and adjusted for annual discount rate. We calculated incremental cost-effectiveness ratio (ICER) by comparing the loss-of-LE of those detected by screening versus non-screening after accounting for administration fees and radiation-related excess BC. RESULTS: The LEs of stages I, II, III, and IV were 31.4, 27.2, 20.0, and 5.2 years, respectively, while the loss-of-LEs were 1.2, 4.9, 11.7, and 25.0 years with corresponding LMEs of US$ 73,791, 79,496, 89,962, and 66,981, respectively. The difference in LE between stages I and IV was 26.2 years while that of loss-of-LE was 23.8 years, which implies that a potential lead time bias may exist if diagnosis at younger ages for earlier stages were not adjusted for. The ICER of mammography seemed cost-saving after the coverage exceeded half a million. CONCLUSION: Mammography could detect BC early and be cost-saving after adjustment for different distributions of age and calendar year of diagnosis. Future studies exploring healthcare expenditure and impaired quality of life for false-positive cases are warranted.

QALYs and medical costs saved from prevention of a cancer: Analysis of nation-wide real-world data of Taiwan with lifetime horizon.

BACKGROUND/PURPOSE: To quantify savings of loss-of-QALE (quality-adjusted life expectancy) and lifetime medical costs from prevention of different cancers. METHODS: We collected nation-wide data on 808,700 new cancer cases of 14 different organ systems and followed them from 1998 to 2014 in Taiwan. We also collected 13,005 cancer patients from a medical center and 47,320 repeated measurements of quality of life (QoL) of EQ-5D to obtain utility values and multiplied them with the corresponding survival rates to calculate QALE. With Kaplan-Meier estimation to survival function to the end of follow-up, we extrapolated to lifetime through a rolling over algorithm on the logit transform of the survival ratio between the index cohort and age-, sex, and calendar year matched referents simulated from vital statistics. Lifetime costs for each cancer were estimated by multiplying survival with average monthly costs after adjustment with annual discount rate. The loss-of-QALE was estimated by the difference in QALE between the index cancer cohort and corresponding referents. RESULTS: The dynamic changes and weighted averages of the QoL utility values of 14 different cancers ranged from 0.82 to 0.95. Successful prevention of liver, lung, esophagus, or nasopharynx cancer would save more than 10 quality-adjusted life years and more than 21,000 USD per case for both genders. Since the saving of loss-of-QALE was adjusted for different age, sex, and calendar-year distributions, it could be used in cost effectiveness evaluation. CONCLUSION: Savings of loss-of-QALE and lifetime costs could be used for comparison of prevention, diagnosis, treatment and rehabilitation from a lifetime horizon.

Metabolomics study in severe extracranial carotid artery stenosis.

BACKGROUND: Significant genetic association has been found in patients with severe carotid artery stenosis (CAS). The present study wished to investigate if metabolites may also act as biomarkers for CAS. METHODS: Consecutive patients with at least one carotid artery stenosis > = 60% on cerebral angiography were prospectively recruited from May 2007 to January 2016. Normal controls were recruited from outpatient clinic who had no stroke and coronary artery disease (CAD) history, and the brain magnetic resonance or computed tomographic angiography showed bilateral CAS < 30%. Risk factor profile, clinical characteristics, age, and clinical features were recorded. All subjects were male, and none had diabetes. 1H-NMR spectroscopy-based metabolomics analysis was carried out for plasma samples. RESULTS: Totally, 130 male subjects were recruited. Age had no significant difference between the controls and CAS group (60.2 ± 5.9 vs. 63.3 ± 6.0, p = 0.050). The CAS group had significantly higher frequency of CAD, hypertension, smoking and alcohol but lower body mass index than the controls (p < 0.05). The laboratory tests showed CAS group had significantly higher level of homocysteine but lower levels of cholesterol, high-density lipoprotein and hemoglobin than the controls (p < 0.05). The 1H-NMR based plasma metabolomics analysis indicated that choline was significantly lower in CAS patients. The VIP values of lipids were greater than 1.0, which were considered significantly different. CONCLUSIONS: Our results suggest homocysteine, choline and lipids in association with traditional risk factors may be involved in the pathogenesis of CAS. Diet adjustment to control homocysteine, choline and lipids may be helpful for the prevention of CAS.

Serum indoxyl sulfate predicts adverse cardiovascular events in patients with chronic kidney disease.

BACKGROUND/PURPOSE: Indoxyl sulfate (IS) is a protein-binding molecule that exhibits cardiovascular (CV) toxicity. This study determined whether the serum IS level can be used to predict the risk of major adverse CV events (MACEs) in patients with chronic kidney disease (CKD). METHODS: We studied 147 patients with CKD stage 1-5 over a 3-year follow-up period. IS was measured through mass spectrometry. Patients' demographics were collected and analyzed to predict outcomes by using multivariable Cox regression. RESULTS: Forty-seven (32.0%) patients had MACEs. IS remained significantly associated with MACEs after multivariable regression analysis. The area under the receiver operating characteristic curve for IS levels was 0.708 (95% confidence interval: 0.618-0.798). CONCLUSION: IS may have a critical role in the prediction of CV disease in patients with CKD. Further large-scale investigations are warranted and suggested.

A modified developmental care bundle reduces pain and stress in preterm infants undergoing examinations for retinopathy of prematurity: A randomised controlled trial.

AIMS AND OBJECTIVES: To determine the comparative efficacy of developmental care versus standard care for reducing pain and stress in preterm infants during examinations for retinopathy of prematurity (ROP). BACKGROUND: ROP examinations are routinely performed in neonatal intensive care units to detect these lesions. Pain scores recorded during and after eye examinations have revealed physiological and behavioural manifestations of pain and stress. DESIGN: A randomised crossover trial was conducted. METHODS: Fourteen preterm infants were evaluated. The modified developmental care bundle included environmental modifications, positioning and containment, oxygen supplementation, interaction and approach and cue-based individual care, which were applied before, during and after the ROP examination. The primary outcomes were obtained from pain and stress scores using the premature infant pain profile-revised (PIPP-R) and a behavioural evaluation. The secondary outcomes were recovery time to the baseline of the vital signs and oxygen saturation. RESULTS: Statistical significances were found in the care type comparison (p = 0.013), time comparison (p < 0.001) and type-by-time interaction (p = 0.005) in the PIPP-R, and also in the care type comparison (p < 0.001), time comparison (p < 0.001) and type-by-time interaction (p = 0.001) in the behavioural evaluation scores using a generalised estimating equation (GEE) analysis. Recovery time for the developmental care (N = 13, mean = 8.6 ± 11.5 min, 95% CI = 1.68-15.57) was significantly shorter than for the standard care (N = 11, mean = 25.5 ± 20.8 min, 95% CI = 11.45-39.46), which was found to be statistically significant according to the Wilcoxon signed-rank test (N = 11, p = 0.003). CONCLUSIONS: A bundled developmental care intervention significantly reduced pain and stress responses and the time needed for infants to recover their physiological status following the procedure. RELEVANCE TO CLINICAL PRACTICE: Since the results show the benefits of developmental care in an ROP examination, it can be the practical evidence basis by which to develop a standard of procedure or guideline for clinical practice.

The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection.

BACKGROUND: Highly pathogenic influenza viruses cause high levels of morbidity, including excessive infiltration of leukocytes into the lungs, high viral loads and a cytokine storm. However, the details of how these pathological features unfold in severe influenza infections remain unclear. Accumulation of Gr1 + CD11b + myeloid cells has been observed in highly pathogenic influenza infections but it is not clear how and why they accumulate in the severely inflamed lung. In this study, we selected this cell population as a target to investigate the extreme inflammatory response during severe influenza infection. RESULTS: We established H1N1 IAV-infected mouse models using three viruses of varying pathogenicity and noted the accumulation of a defined Gr1 + CD11b + myeloid population correlating with the pathogenicity. Herein, we reported that CCR2+ inflammatory monocytes are the major cell compartments in this population. Of note, impaired clearance of the high pathogenicity virus prolonged IFN expression, leading to CCR2+ inflammatory monocytes amplifying their own recruitment via an interferon-α/ß receptor 1 (IFNAR1)-triggered chemokine loop. Blockage of IFNAR1-triggered signaling or inhibition of viral replication by Oseltamivir significantly suppresses the expression of CCR2 ligands and reduced the influx of CCR2+ inflammatory monocytes. Furthermore, trafficking of CCR2+ inflammatory monocytes from the bone marrow to the lung was evidenced by a CCR2-dependent chemotaxis. Importantly, leukocyte infiltration, cytokine storm and expression of iNOS were significantly reduced in CCR2-/- mice lacking infiltrating CCR2+ inflammatory monocytes, enhancing the survival of the infected mice. CONCLUSIONS: Our results indicated that uncontrolled viral replication leads to excessive production of inflammatory innate immune responses by accumulating CCR2+ inflammatory monocytes, which contribute to the fatal outcomes of high pathogenicity virus infections.

Comparing Survival Extrapolation within All-Cause and Relative Survival Frameworks by Standard Parametric Models and Flexible Parametric Spline Models Using the Swedish Cancer Registry.

BACKGROUND: In health technology assessment, restricted mean survival time and life expectancy are commonly evaluated. Parametric models are typically used for extrapolation. Spline models using a relative survival framework have been shown to estimate life expectancy of cancer patients more reliably; however, more research is needed to assess spline models using an all-cause survival framework and standard parametric models using a relative survival framework. AIM: To assess survival extrapolation using standard parametric models and spline models within relative survival and all-cause survival frameworks. METHODS: From the Swedish Cancer Registry, we identified patients diagnosed with 5 types of cancer (colon, breast, melanoma, prostate, and chronic myeloid leukemia) between 1981 and 1990 with follow-up until 2020. Patients were categorized into 15 cancer cohorts by cancer and age group (18-59, 60-69, and 70-99 y). We right-censored the follow-up at 2, 3, 5, and 10 y and fitted the parametric models within an all-cause and a relative survival framework to extrapolate to 10 y and lifetime in comparison with the observed Kaplan-Meier survival estimates. All cohorts were modeled with 6 standard parametric models (exponential, Weibull, Gompertz, log-logistic, log-normal, and generalized gamma) and 3 spline models (on hazard, odds, and normal scales). RESULTS: For predicting 10-y survival, spline models generally performed better than standard parametric models. However, using an all-cause or a relative survival framework did not show any distinct difference. For lifetime survival, extrapolating from a relative survival framework agreed better with the observed survival, particularly using spline models. CONCLUSIONS: For extrapolation to 10 y, we recommend spline models. For extrapolation to lifetime, we suggest extrapolating in a relative survival framework, especially using spline models. HIGHLIGHTS: For survival extrapolation to 10 y, spline models generally performed better than standard parametric models did. However, using an all-cause or a relative survival framework showed no distinct difference under the same parametric model.Survival extrapolation to lifetime within a relative survival framework agreed well with the observed data, especially using spline models.Extrapolating parametric models within an all-cause survival framework may overestimate survival proportions at lifetime; models for the relative survival approach may underestimate instead.

Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Long-term management and treatment of acute intermittent porphyria with recurring attacks using pharmacological prophylaxis.

BACKGROUND: There is no definitive guidance on whether patients with acute intermittent porphyria (AIP) with recurrent attacks need pharmacological prophylactic treatment. METHODS: The management strategies for patients with frequent (defined as ≥4 annualized attack rate (AAR) and less frequent attacks (<4 AAR), including treatment for acute attacks and duration of prophylaxis (weekly heme arginate 3 mg/kg body weight and/or investigational drug, givosiran), were summarized. The AAR for the following periods were presented: the first 2 years after diagnosis, before/after prophylaxis, and the most recent 2 years. RESULTS: A total of 29 patients with AIP were included, 19 (34.5%) had <4 AAR and 10 (65.6%) had ≥4 AAR in the first 2 years after diagnosis. All patients experienced reduced attacks during the treatment course, 23 (79.3%) were attack-free during the most recent 2 years. Among the 9 patients who received prophylaxis (7 heme arginate; 1 givosiran, 1 heme arginate followed by givosiran), 5 (55.6%) were attack-free in the most recent 2-year period and prophylaxis was discontinued because there had been no attacks for >1 year. For patients without prophylaxis (n = 20), 18 (90.0%) were attack-free in the most recent 2-year period and 15 (75.0%) experienced attacks only in the first 2 years after diagnosis. CONCLUSIONS: Prophylaxis could be considered for patients with AIP with ≥4 biochemically confirmed attacks/year after routine treatment of 1-2 years, during which the severity and frequency of attacks should be closely monitored to determine the necessity of pharmacologic prophylaxis. More studies are needed to reach a consensus on the use of pharmacological prophylaxis and treatment of AIP.

Association between serum carcinoembryonic antigen and cardiometabolic risks: Implication for cardiometabolic prevention.

Background: Serum carcinoembryonic antigen (CEA) is a biomarker commonly used to detect colorectal cancer. CEA levels are affected by many factors, including cardiometabolic diseases, such as cardiovascular diseases (CVDs) and diabetes. Cardiometabolic diseases and cancer share a similar pathological inflammatory pathway, which correlates with an unhealthy lifestyle. Hence, establishing an adequate CEA cut-off value might be a valuable reference for developing precision healthcare programs for cardiometabolic disease prevention. This study aimed to investigate the association between cardiometabolic risks and serum CEA and the underlying factors. Methods: A community-based, cross-sectional study was conducted between March and December 2021 on the western coast of Taiwan. Lifestyle data were assessed using a structured questionnaire. The cardiometabolic biomarkers, serum CEA, urine malondialdehyde, and 1-hydroxypyrene were quantified by the central laboratory of the collaborating hospital. Chi-square and binary multivariable logistic regression implemented in R version 4.0.2 were used to identify factors defining the risk of high serum CEA levels. Results: A total of 6,295 adult residents without cancer-related diseases completed the study. The mean age was 48.6 (SD = 16.4) years, 56% were female, 32% had metabolic syndrome, and 23% and 10% had CVDs and diabetes, respectively. Multivariate logistic regression showed that age ≥ 65 years, male sex, alcohol consumption, smoking, infrequent use of dental floss, fewer remaining teeth, CVDs, diabetes, and oxidative stress were significantly associated with serum CEA ≥ 3 ng/mL. The discriminatory performance of the area under the receiver operating characteristic curve was 0.75 (0.73-0.76), showing that this model was suitable for distinguishing high CEA levels. Conclusion: Our findings highlight the importance of understanding cardiometabolic diseases, unhealthy lifestyles, and oxidative stress, which contribute to high serum CEA. This study demonstrates that CEA, a well-known tumor marker, can help the early detection and prevention of cardiometabolic diseases via personalized lifestyle modification.

Dynamic changes in quality of life, psychological status, and body image in women who underwent a mastectomy as compared with breast reconstruction: an 8-year follow up.

BACKGROUND: Surgical decisions and methods of surgery highly influence long term QoL for breast cancer (BC) survivors. This study is aimed towards an exploration of the dynamic changes in quality of life (QoL), anxiety/depression status, and body image (BI) among women with BC who received a mastectomy compared with those receiving breast reconstruction (BR) within an 8-year follow-up period. METHODS: Women with major BC surgeries were invited to complete the World Health Organization Quality of Life-Brief (WHOQOL-BREF), the European quality of life five dimensions questionnaire (EQ-5D), and a body image scale within 8 years of surgery. Kernel smoothing methods were applied to describe dynamic changes in QoL, anxiety/depression, and BI at different time points. Linear mixed effects models were constructed to identify the interaction between time, different types of surgery, and the determinants of QoL in these patients. RESULTS: After 1:10 propensity score matching, a total of 741 women who had undergone a BR and mastectomy were included. The BR group exhibited a high WHOQOL QoL score one to five years after surgery with some fluctuations. The mastectomy group had comparatively stable QoL scores on WHOQOL items and were less depressed/anxious. The BR group generally showed fluctuating, higher BI scores two years after surgery, but they exhibited more anxiety/depression during follow up for 8 years. Medical comorbidities, the status of anxiety/depression, and BI were the major factors influencing all domains and items of the WHOQOL BREF among women with BC. CONCLUSION: The mastectomy group showed a decreased trend toward depression in patients with BC. The BR group showed a significant improvement in QoL in the first 5 years with massive fluctuations. These findings should be considered and discussed in patient participatory decision-making and promotion of QoL for breast cancer survivors.

Clinical impact of therapeutic drug monitoring for newer anti-seizure medications in patients with epilepsy: A real-world observation study.

BACKGROUND: The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy. METHODS: We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM request, test results, interpretation, and impact on patient management. RESULTS: A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visit showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%). CONCLUSIONS: These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

[Feeding preterm infants: application of developmental care].

Developmental care is the core concept of the preterm infant caring model. It is characterized by interaction, individualization, and evolving process. In order to enhance family competency with regard to preterm infant care, health professionals should include parents as team members when preterm infants are hospitalized so that parents can provide care helpful to facilitate preterm infant adaptation to external environmental stimulation. The preterm infant's 6-8 feedings per day represent the most frequent daily activity and an activity in which safety is essential. Potential adverse feeding responses in preterm infants such as tachypnea, cyanosis, and fatigue may stress the mother. This is a particular risk when the mother tries to increase her infant's intake volume by over-stimulating oral-motor activity. Theories and guidelines for feeding preterm infants in western societies have been evolving since the 1980s. However, little has been done in this area in Taiwan. This article addresses preterm infant feeding characteristics and cues, the application of developmental care in feeding infants, and proposes guidelines for feeding preterm infants. Healthcare professionals may reference our suggestions in feeding preterm infants and educating parents.

Factors Associated with Urinary 1-Hydroxypyrene and Malondialdehyde among Adults near a Petrochemical Factory: Implications for Sex and Lifestyle Modification.

BACKGROUND: The association between the biomarkers of environmental exposure, oxidative stress, and health-related behaviors in community residents living in an endemic viral hepatitis area and near petrochemical industrial complexes remains unclear. From a health promotion perspective, healthcare providers must know what to do for residents concerned about their health and living environment, especially for individual-level and modifiable risk factors. Therefore, we aimed to explore the factors associated with urinary 1-hydroxypyrene (1-OHP) and malondialdehyde (MDA). METHODS: A community-based, cross-sectional study was conducted between July 2018 and February 2019 in western coastal Yunlin County, Taiwan. All participants lived within a 10 km radius of a large petrochemical complex and did not work in the factory. This study was conducted with the local hospital through annual community health screening. Biological samples were collected and biomarkers determined and quantified in the central laboratory of the collaborating hospital. RESULTS: A total of 6335 adult residents completed the study. The mean age was 47.7 (SD = 16) years. Out of the total population, 56.4% were female, 30.1% had metabolic syndrome (MetS), and 16.8% and 14.3% had hepatitis B virus antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) positivity, respectively. The median 1-OHP and MDA level was 0.11 and 0.9 µg/g creatinine with an interquartile range of 0.07-0.18, and 0.4-1.5, respectively. The MDA levels correlated with specific diseases. The multivariable ordinal logistic regression model revealed that female sex, smoking, betel nut use, HBsAg, and anti-HCV positivity were associated with higher 1-OHP levels. In men, MetS was associated with higher 1-OHP levels and regular exercise with lower 1-OHP levels. High MDA levels were associated with smoking, betel nut users, HBsAg, and anti-HCV positivity. CONCLUSIONS: The findings highlight the importance of initiating individualized health promotion programs for residents near petrochemical factories, especially for adults with substance-use and cardiometabolic risk factors. Furthermore, it is crucial to provide further treatment to patients with viral hepatitis.

Identification of Metabolomics Biomarkers in Extracranial Carotid Artery Stenosis.

The biochemical identification of carotid artery stenosis (CAS) is still a challenge. Hence, 349 male subjects (176 normal controls and 173 stroke patients with extracranial CAS ≥ 50% diameter stenosis) were recruited. Blood samples were collected 14 days after stroke onset with no acute illness. Carotid plaque score (≥2, ≥5 and ≥8) was used to define CAS severity. Serum metabolites were analyzed using a targeted Absolute IDQ®p180 kit. Results showed hypertension, diabetes, smoking, and alcohol consumption were more common, but levels of diastolic blood pressure, HDL-C, LDL-C, and cholesterol were lower in CAS patients than controls (p < 0.05), suggesting intensive medical treatment for CAS. PCA and PLS-DA did not demonstrate clear separation between controls and CAS patients. Decision tree and random forest showed that acylcarnitine species (C4, C14:1, C18), amino acids and biogenic amines (SDMA), and glycerophospholipids (PC aa C36:6, PC ae C34:3) contributed to the prediction of CAS. Metabolite panel analysis showed high specificity (0.923 ± 0.081, 0.906 ± 0.086 and 0.881 ± 0.109) but low sensitivity (0.230 ± 0.166, 0.240 ± 0.176 and 0.271 ± 0.169) in the detection of CAS (≥2, ≥5 and ≥8, respectively). The present study suggests that metabolomics profiles could help in differentiating between controls and CAS patients and in monitoring the progression of CAS.

The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases.

Pieces of evidence support the view that the accumulation of uremic toxins enhances oxidative stress and downstream regulation of signaling pathways, contributing to both endothelial microangiography and cell dysfunction. This study is to address the impact of protein-binding uremic toxins on the severity of peripheral nerve function in patients with chronic kidney disease (CKD). Fifty-four patients with CKD were included in the Toronto Clinical Neuropathy Score (TCNS), nerve conduction study (NCS), and laboratory studies including protein-binding uremic toxin (indoxyl sulfate [IS] and p-cresyl sulfate [PCS]), oxidative stress (Thiol and thiobarbituric acid reacting substances [TBARS]), and endothelial dysfunction (serum intercellular adhesion molecule 1 [sICAM-1] and serum vascular adhesion molecule 1 [sVCAM-1]) at enrollment. We used composite amplitude scores (CAS) to analyze the severity of nerve conductions on peripheral nerve function. TCNS and CAS were higher in the diabetic CKD group (p = 0.02 and 0.01, respectively). The NCS revealed the compound muscle action potential of ulnar and peroneal nerves and the sensory nerve action potential of ulnar and sural nerves (p = 0.004, p = 0.004, p = 0.004, and p = 0.001, respectively), which was found to be significantly low in the diabetic group. CAS was significantly correlated with age (r = 0.27, p = 0.04), urine albumin-creatinine ratio (UACR) (r = 0.29, p = 0.046), free-form IS (r = 0.39, p = 0.009), sICAM-1 (r = 0.31, p = 0.02), sVCAM-1 (r = 0.44, p < 0.0001), TBARS (r = 0.35, p = 0.002), and thiols (r = −0.28, p = 0.045). Linear regression revealed that only TBARS and free-form IS were strongly associated with CAS. The mediation analysis shows that the sVCAM-1 level serves as the mediator between higher IS and higher CAS. IS and oxidative stress contribute to the severity of peripheral nerve dysfunction in patients with CKD, and chronic glycemic impairment can worsen the conditions.

Prophylactic Heme Arginate Infusion for Acute Intermittent Porphyria.

Objectives: This study aimed to evaluate the efficacy of long-term weekly prophylactic heme arginate (HA) infusions in reducing attack frequency and severity in female AIP patients. Methods: We report the results of five female AIP patients with frequent recurrent attacks (>9/year) before and after institution of weekly prophylaxis with heme arginate (3 mg/kg body weight). All five cases had confirmed disease-associated mutations in the porphobilinogen deaminase gene, and all had received genetic and clinical counseling about AIP. Results: In the five included patients, average annual attack rate (AAR) in the year prior to HA prophylaxis was 11.82 (range 9.03-17.06), and average total HA usage was 32.60 doses (range: 13.71-53.13). After 2.58-14.64 years of HA prophylaxis, average AAR was reduced to 2.23 (range 0.00-5.58), and attack severity (i.e., doses required per attack) was reduced from 2.81 to 1.39 doses/attack. Liver and renal function remained stable during weekly administration of HA prophylaxis. The most common complications were port-A catheter-related events. No other complications or safety concerns occurred with long-term use of HA prophylaxis. Conclusion: Our study demonstrated women with AIP receiving weekly prophylactic HA infusions resulted in fewer episodes that required acute HA treatment while maintaining stable renal and liver function. Weekly prophylactic HA infusions effectively prevent frequent porphyric attacks and reduce attack severity.

Profiling of Serum Metabolites of Acute Intermittent Porphyria and Asymptomatic HMBS Mutation Carriers.

This study aims to present the serum metabolite profiles of patients with acute intermittent porphyria (AIP) and identify specific metabolites that could potentially discriminate between AIP, asymptomatic HMBS mutation carriers, and healthy individuals. The study cohort included 46 female participants: 21 AIP patients, 5 asymptomatic carriers, and 20 'normal' participants (without HMBS gene mutation). Serum samples were analyzed for 157 selected metabolites or clinical variables using an assay combining liquid chromatography MS/MS and direct flow injection. AUC analysis was used to distinguish unique variables between the three groups. A total of 15 variables differed significantly between the AIP and normal control group (VIP score > 1.0 and p < 0.05 with FDR correction). In AIP patients, the levels tyrosine, valine, and eGFR were significantly lower, and the levels of sphingomyelin C16:0, C24:0, C24:1, phosphatidylcholine diacyl C32:1, C36:1, C36:3, ornithine, sarcosine, citrulline, blood urea nitrogen AST, and ALT were significantly higher. The AUC of these 15 variables in discriminating between normal and AIP patients ranged between 0.73 and 0.94 (p < 0.05). In conclusion, serum metabolic profiles differ between normal individuals and patients carrying the HMBS mutation. The unique metabolites associated with AIP identified in this study may be useful for monitoring the development of AIP symptoms.

Efficacy and safety of perampanel in refractory and super-refractory status epilepticus: cohort study of 81 patients and literature review.

BACKGROUND: The effective dose of perampanel in status epilepticus (SE), refractory SE (RSE), and super-refractory SE (SRSE) in humans is unknown, and the potential of perampanel in treating SE has not been evaluated in a large cohort. METHODS: Data of intensive care patients with RSE and SRSE treated with perampanel were retrospectively reviewed and analyzed. RESULTS: Eighty-one patients received perampanel, including 39 females with median age 64 [17-91] years, perampanel responders (n = 27), and non-responders (n = 54). The initial perampanel dose was positively associated with treatment response in patients with RSE or SRSE (OR = 1.27, 95% CI 1.03-1.57, p = 0.025), while the maximum dose was negatively associated with treatment response (OR = 0.74, 95% CI 0.58-0.96, p = 0.022). Hypoxia caused seizures in six patients; five died in hospital and one had severe disability. A statistically non-significant tendency toward better response was found in patients with unique SE type and cause, particularly in nonconvulsive status epilepticus (NCSE) without coma (NCSE without coma vs. generalized tonic-clonic seizure: OR = 4.14, 95% CI 0.98-17.47, p = 0.053). In the high-dose (≥ 16 mg/day) groups, although distributions of modified Rankin Scale (mRS) scores were similar between perampanel responders and non-responders at discharge, a greater proportion of perampanel responders had less change in mRS scores from baseline than did perampanel non-responders (median mRS: 0 vs 4, p = 0.064). No cardiorespiratory adverse events or laboratory abnormalities were noted with perampanel treatment. CONCLUSIONS: Perampanel is effective and has a satisfactory safety profile in the emergency treatment of established RSE and SRSE.