The Maternal Omega-3 Long-Chain Polyunsaturated Fatty Acid Concentration in Early Pregnancy and Infant Neurodevelopment: The ECLIPSES Study.

Omega-3 Long-Chain Polyunsaturated Fatty Acids (n-3 LCPUFAs) play a key role in early neurodevelopment, but evidence from observational and clinical studies remains inconsistent. This study investigates the association between maternal n-3 LCPUFA, Docosahexaenoic Acid (DHA), and eicosapentaenoic acid (EPA) concentrations during pregnancy and infant development functioning at 40 days. This study includes 348 mother-infant pairs. Maternal serum concentrations were assessed in the first and third trimesters alongside sociodemographic, clinical, nutritional, psychological, and obstetrical data. At 40 days, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was administered. An adjusted analysis revealed that lower first-trimester n-3 LCPUFA and DHA concentrations are associated with better infant motor development. These results underscore the potential significance of the maternal n-3 LCPUFA status in early pregnancy for influencing fetal neurodevelopment. However, the complexity of these associations necessitates further investigation, emphasizing the urgent need for additional studies to comprehensively elucidate the nuanced interplay between the maternal n-3 LCPUFA status and infant neurodevelopment.

Trends in Serum Per- and Polyfluoroalkyl Substance (PFAS) Concentrations in Teenagers and Adults, 1999-2018 NHANES.

Some types of per- and poly-fluoroalkyl substances (PFAS) have been banned over the last two decades, but millions of Americans continue to have exposure to the compounds through drinking water and consumer products. Therefore, understanding the changes in serum PFAS concentrations after their limited use is necessary to protect public health. In this study, we evaluated trends of serum PFAS compounds (PFOS, PFOA, PFHxS, PFDA, and PFNA) to determine their distribution among the United States general population. We analyzed serum concentrations of PFAS measured from random subsamples of the National Health and Nutrition Examination Survey (NHANES) participants. The study results demonstrated that demographic factors such as race/ethnicity, age, and sex may influence the levels of serum PFAS over time. Adults, males, Asians, Non-Hispanic Blacks, and Non-Hispanic Whites had high risks of exposure to the selected PFAS. Overall, serum PFAS levels declined continuously in the studied population from 1999 to 2018. Among the studied population, PFOS and PFDA were the most and least prevalent PFAS in blood serum, respectively. Serum levels of PFDA, PFOA, and PFHxS showed upward trends in at least one racial/ethnic group after 2016, which underscores the need for continuous biomonitoring of PFAS levels in humans and the environment.

Neonatal Serum Gentamicin Concentrations and Outcomes Following Maternal Once-Daily Gentamicin Dosing.

OBJECTIVE: This study evaluated newborn gentamicin serum concentrations after birth and the effects on the newborn after extended interval gentamicin dosing in peripartum mothers. METHODS: This was a single-center, retrospective chart review of neonates born to mothers that received peripartum once-daily gentamicin dosing of approximately 5 mg/kg within 12 hours of delivery. A gentamicin serum concentration was obtained immediately after birth in the newborn. The primary outcome was initial neonatal gentamicin serum concentration after birth. Several secondary outcomes were evaluated including nephrotoxicity and ototoxicity. A subgroup analysis comparing baseline demographics of mother-newborn dyads with birth neonatal serum concentrations of less than 2 mcg/mL versus 2 mcg/mL or greater was performed. RESULTS: A total of 32 mother-newborn dyads were included. Newborns had a median gestational age of 39.4 weeks and median birth weight of 3.4 kg. The mean initial gentamicin serum concentration was elevated at 3.1 ± 1.9 mcg/mL among all newborns. The median maternal dose based on actual body weight in newborns with gentamicin serum concentrations less than 2 mcg/mL was 3.5 (IQR, 3.3-4.8) mg/kg versus 4.8 (IQR, 4.3-5.2) mg/kg in those that had serum concentrations of 2 mcg/mL or greater (p = 0.025). All newborn gentamicin serum concentrations were less than 2 mcg/mL for maternal doses given less than 1 hour prior to delivery (n = 8). There were no significant differences in nephrotoxicity or ototoxicity. CONCLUSIONS: Peripartum once daily dosing of gentamicin administered between 1 to 12 hours of birth may lead to clinically significant serum concentrations in newborns.

The Relationship between Thyrotropin Serum Concentrations and Thyroid Carcinoma.

Thyroid Stimulating Hormone (TSH) is a hormone secreted by the pituitary gland and plays a role in regulating the production and secretion of thyroid hormones by the thyroid gland. This precise feedback loop is essential for maintaining a harmonious balance of thyroid hormones in the body, which are vital for numerous physiological processes. Consequently, TSH serves as a significant marker in assessing thyroid function, and deviations from normal TSH levels may indicate the presence of a thyroid disorder. Thyroid cancer (TC) is the malignant tumor within the endocrine system. In recent years, numerous experts have dedicated their efforts to discovering efficacious biomarkers for TC. These biomarkers aim to improve the accurate identification of tumors with a poor prognosis, as well as facilitate active monitoring of tumors with a more favorable prognosis. The role of TSH in the thyroid gland underscores its potential influence on the occurrence and progression of TC, which has garnered attention in the scientific community. However, due to the limited scope of clinical research and the dearth of high-quality foundational studies, the precise impact of TSH on TC remains unclear. Consequently, we present a comprehensive review of this subject, aiming to offer a valuable reference for future research endeavors.

Investigating the Role of Serum and Plasma IL-6, IL-8, IL-10, TNF-alpha, CRP, and S100B Concentrations in Obstructive Sleep Apnea Diagnosis.

Obstructive sleep apnea (OSA) is a prevalent and underdiagnosed condition associated with cardiovascular diseases, depression, accidents, and stroke. There is an increasing need for alternative diagnostic tools beyond overnight sleep studies that measure the Apnea/Hypopnea Index (AHI). In this single-center, case-control study, we evaluated serum and plasma concentrations of IL-6, IL-8, IL-10, TNF-α, CRP, and S100B in 80 subjects, including 52 OSA patients (27 moderate [15 ≤ AHI ˂ 30], 25 severe [AHI ≥ 30]) and 28 non-OSA controls (AHI 0-5). Participants with OSA showed approximately 2 times higher median concentrations of CRP in plasma, and IL-6 in serum, as well as 1.3 to 1.7 times higher concentrations of TNF-α and IL-8 in plasma compared with the control group. Receiver Operator Characteristic (ROC) curve analysis was performed to evaluate the predictive capabilities of these serum and plasma biomarkers in distinguishing between the OSA and control groups, revealing varying sensitivity and specificity. In summary, in this study, serum and plasma biomarkers CRP, S100B, IL-6, TNF-α, and IL-8 have been shown to be elevated in patients with OSA, correlated positively with disease severity, age, and BMI. These results support the potential role of these biomarkers in diagnosing OSA, supplementing traditional methods such as overnight sleep studies.

Determinants of exposure to polychlorinated biphenyls in the Italian population in the last decades.

Polychlorinated biphenyls (PCBs) are industrial products extensively used in the past. Because of their widespread presence and toxic effects, the international community adopted control measures to reduce their release into the environment. Currently, PCB concentrations are decreasing, but humans are still exposed. In this paper, we reported the results of a study concerning PCB concentrations in human serum samples collected in Italy over two decades. The aim of the study was to investigate the trend of major determinants of PCB human exposure, several decades after the end of their production. PCB concentrations ranged over three orders of magnitude (from 0.4 to 958 ng/g lipid), with a median value of 85 ng/g lipid. We identified age, sampling year, body mass index, sex, and living near hot spots or being occupationally exposed as relevant factors in determining body burden. Our results can give indications to refine regulatory policies on PCBs in Italy, with particular attention to the disposal of residue PCB-containing products. To improve control measures can further decrease the exposure of citizens to PCBs, limit health implications, and improve citizens' perception about chemical risk management.

Osteoprotegerin, Chitinase 3-like Protein 1, and Cardiotrophin-1 as Potential Biomarkers of Obstructive Sleep Apnea in Adults-A Case-Control Study.

Obstructive sleep apnea (OSA) is a prevalent, underdiagnosed disease and is considered a risk factor for cardiovascular diseases, depression, accidents, and stroke. Recent clinical practice guidelines for OSA expressed the need for a new clinical tool that establishes the Apnea-Hypopnea Index (AHI) to determine the disease burden. The serum and plasma concentrations of Osteoprotegerin (OPG), Chitinase 3-like protein 1 (YKL-40), and Cardiotrophin-1 (CT-1) in 80 subjects-52 OSA patients, 27 moderate (15 ≤ AHI ˂ 30) and 25 severe (AHI ≥ 30), and 28 non-OSA controls (AHI 0-5)-were determined. Moreover, the Total Oxidative Status (TOS), Total Antioxidative Status (TAS), and Oxidative Stress Index (OSI) were assessed in the serum and plasma to evaluate whether the severity of OSA and the concentrations of OPG, YKL-40, and CT-1 correlate with the oxidative/reductive status. The serum and plasma concentrations of YKL-40 and CT-1 were higher in the OSA group, whereas the serum and plasma concentrations of OPG were lower compared to the control group. The concentrations of OPG, YKL-40, and CT-1 in the serum and plasma correlated with AHI; however, a better correlation of the concentrations was obtained for the above-mentioned proteins in the plasma. The concentrations of YKL-40 and CT-1 in the serum and OPG in the plasma show better diagnostic capabilities for moderate and severe OSA than the concentrations of YKL-40 and CT-1 in the plasma and the concentrations of OPG in the serum.

Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations.

BACKGROUND: There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. OBJECTIVES: We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. METHODS: We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016-2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. RESULTS: When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: -2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (-0.50; -4.59, 3.59; 0.810). CONCLUSIONS: Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.

Differences in serum concentration with valproate oral solution versus delayed-release divalproex in an adherent patient.

Background: Several different formulations of valproic acid derivatives are available in the United States. Although these formulations have different absorption characteristics, they are believed to be interchangeable, with the exception of the extended-release product. Case Report: A 31-year-old African American man with schizoaffective disorder was started on fluphenazine concentrate and valproate oral solution on admission to an inpatient unit. A 12-hour steady-state concentration, drawn on 1000 mg/day, resulted in 40.8 mg/L, and the dose continued to be titrated. Despite increasing doses, confirmed medication adherence, and accurate lab sampling, his concentrations remained low: 60.3 and 60.1 mg/L on 1500 mg/day, and 65.6 mg/L on 1750 mg/day. He was switched to divalproex delayed-release tablets, and his dose was increased to 2000 mg/day. Follow-up 12-hour steady-state concentrations were significantly higher, at 126.6 and 113.8 mg/L. It is theorized that the formulation of divalproex/valproic acid is what contributed to these differences in concentrations. Discussion: Valproic acid formulations are considered to be interchangeable, and several studies have demonstrated that chronic psychiatric inpatients stabilized on delayed-release divalproex may be safely switched to valproate oral solution without changes in psychiatric stability. This case demonstrates a significant difference in serum drug concentrations when switching from valproate oral solution to divalproex delayed-release tablets.

Dose-response analysis of aripiprazole in patients with schizophrenia in Taiwan.

Background: Aripiprazole is a third-generation antipsychotic agent with acceptable efficacy and a good safety profile. Previous studies have indicated the therapeutic serum concentration of aripiprazole to be 100 to 350 ng/ml; however, most of these studies examined a Western population. Patients with schizophrenia from Tungs' Taichung MetroHarbor Hospital in central Taiwan were recruited to analyze the dose-response relationship of aripiprazole in the Chinese population. Objective: We aimed to investigate whether a serum concentration of aripiprazole higher than the current suggested range leads to higher response rates. Design: A prospective cohort study was designed to investigate the response rates in different studied cohorts grouped by serum concentration of aripiprazole. Data Sources and Methods: Data of 64 patients who presented to a single medical center in central Taiwan and who received therapeutic drug monitoring (TDM) were obtained. Serum concentrations of aripiprazole were correlated with the clinical response of patients by using the Clinical Global Impressions (CGI) scores. Results: The mean concentration of aripiprazole was 432.1 ± 275.1 ng/ml in the study cohort. Among the much-improved patients, the mean serum concentration of aripiprazole was 494 ± 273 ng/ml (25th-75th percentiles 264-666 ng/ml), which was higher than the current recommended therapeutic target of 100-350 ng/ml for aripiprazole. The response rate in the severe group (baseline CGI score of 6 or 7) was significantly higher than in the moderate group (baseline CGI score of 4 or 5; 86.7% versus 55.9%, p = 0.007). Conclusion: A significantly higher response rate was observed in the study cohort with serum aripiprazole concentrations over 300 ng/ml. Therefore, dosing higher than the current recommended range may potentially improve the treatment efficacy in the Chinese population. Because the serum concentration varies among patients due to multiple intrinsic and extrinsic factors, TDM, especially in outpatients, is recommended if the clinical response is limited.

Ustekinumab Therapeutic Drug Monitoring-Impact on Clinical Practice: A Multicenter Cross-Sectional Observational Trial.

BACKGROUND AND AIMS: The value of ustekinumab (UST) therapeutic drug monitoring (TDM) in clinical practice remains unclear. This study examined the impact of UST TDM on clinical decision making in patients with Crohn's disease (CD). METHODS: A total of 110 consecutive UST-treated CD patients were enrolled in this multicenter, single-arm cross-sectional study. During a single study visit, clinical decisions, disease characteristics, and serum and fecal samples were obtained. The primary outcome was congruency of the actual and two hypothetical clinical decisions based on provision of UST TDM (with and without fecal calprotectin [FCP]) to participating clinicians. Decisions were compared against those of a review panel. A sub-study retrospectively measured the associations of clinical outcomes at the next follow-up visit with serum UST concentration [UST]. RESULTS: No differences in the pattern of decisions by clinicians were observed before and after provision of UST TDM (P = 1.0) or UST TDM + FCP (P = 0.86). However, 39% (TDM) and 50% (TDM + FCP) of hypothetical decisions differed from the initial decisions. The review panel's decisions differed with the addition of TDM + FCP (P = 0.0006), but not TDM alone (P = 0.16). The sub-study (n = 53) failed to detect an association between therapeutic serum [UST] at the initial study visit and clinical outcomes at the next visit. CONCLUSIONS: In consecutive CD patients treated with UST, the addition of TDM into routine clinical practice did not significantly impact clinical decisions and there was no association between short-term clinical outcomes and serum [UST]. Further studies are warranted before clinicians routinely implement UST TDM into clinical practice.

Study of the fluctuation of serum vitamin D concentration with time during the same day and night on a random sample of healthy adults.

BACKGROUND AND AIMS: A common practice in the assessment of vitamin D is to measure its blood level in the morning after overnight fasting. The aim of this study was to measure vitamin D during different times of the day and night for a random sample of healthy individuals, to see if there are significant changes throughout the day and night. METHODS: A cross sectional study was carried out on a total of 52 randomly selected Jordanian healthy volunteers (26 women and 26 men) aged between 18 and 45 years. Six blood samples were taken from each participant on the same study day; 7:30 AM (at fasting), 10:30 AM, 1:30 PM, 4:30 PM, 7:30 PM and at 10:30 PM. An extra 7th blood sample was taken next morning at 7:30 AM (after fasting overnight). RESULTS: There was a significant difference (P < 0.05) between mean serum vitamin D level at 7:30 AM (19.64 ± 0.26 ng/ml) and 1:30 PM (20.60 ± 0.26 ng/ml), and 4:30 PM (20.61 ± 0.26 ng/ml), P-value 0.0096 and 0.0090, respectively. When taken into consideration the effect of exposure to the sun and the time, there was a significant difference (P ˂ 0.05) between the two groups (group 1: sun protected group, and group 2: sun exposure group) at different times on the same day and the morning of the second day (P-value = 0.0113). CONCLUSION: The serum vitamin D concentrations vary during different times of the day, night and next morning, and that its concentration at fasting does not represent its true value.

Case Report: Predicting the Range of Lamotrigine Concentration Using Pharmacokinetic Models Based on Monte Carlo Simulation: A Case Study of Antiepileptic Drug-Related Leukopenia.

Lamotrigine (LTG), a wide-spectrum antiepileptic drug, is frequently associated with cutaneous side-effects, whereas hematological side-effects such as leukopenia have rarely been reported for it. We report the case of a 15-year-old Chinese female epileptic patient weighing 60 kg who developed combined asymptomatic leukopenia after receiving concomitant therapy with LTG and valproate acid (VPA). In this case report, antiepileptic drug-related leukopenia may have occurred in definite relation to an increase in LTG concentration and reversed with the discontinuation of VPA. Monte Carlo (MC) simulations were performed to estimate the steady-state serum concentrations (C ss ) of LTG for different dosing regimens in adolescent Chinese epileptic patients weighing the same as the patient considered in the case study, based on pharmacokinetic (PK) models published in past research. Adjustments to the dosage of LTG for the patient were analyzed to illustrate the application of MC simulations and verify the results. The predicted LTG concentrations within a prediction interval between the 10th and 90th percentiles that represented 80% of the simulated populations, could adequately capture the measured LTG concentrations of the patient, indicating that MC simulations are a useful tool for estimating drug concentrations. Clinicians may benefit from the timely probabilistic predictions of the range of drug concentration based on an MC simulation that considers a large sample of virtual patients. The case considered here highlights the importance of therapeutic drug monitoring (TDM) and implementing model-informed precision dosing in the course of a patient's individualized treatment to minimize adverse reactions.

Determination of serum tumor necrosis factor-alpha (TNF-α) levels in metabolic syndrome patients from Saudi population.

OBJECTIVES: To detect the relationship between serum tumor necrosis factor-alpha (TNF-α) and metabolic syndrome (MetS) components in patients of the Saudi population. METHODS: This cross-sectional study was carried out at Jouf University Saudi Arabia from September 2019 to August 2020 and comprised of 183 individuals (91 cases and 92 controls). The blood samples were drawn from the patients visiting two tertiary care settings of Al Jouf province. Biochemical analysis was conducted on various instruments, and serum TNF-α was measured by the ELISA method. RESULTS: The levels of serum glucose fasting, lipid profile, HbA1c and body mass index (BMI) were raised significantly in cases of MetS than controls (p = 0.001). Serum TNF-α was significantly higher in patients (58.04 ± 15.44) than controls (48.81 ± 10.30). It was correlated with the BMI, blood HbA1c, serum fasting glucose (SFG) and serum high density lipoprotein (HDL). The weak positive correlation was found with BMI (r = 0.18; p = 0.01), serum glucose (r = 0.21; p = 0.007) and HbA1c (r = 0.14; p = 0.04), but found negative association with serum HDL (r = -0.18; p = 0.01). CONCLUSION: The serum TNF-α was raised in metabolic syndrome patients than the healthy controls. It was positively associated with high BMI, serum fasting glucose, and HbA1c and found linked and negatively linked to low HDL levels in MetS patients in the Saudi population.

Identification of Potential Distinguishing Markers for the Use of Cannabis-Based Medicines or Street Cannabis in Serum Samples.

Increasing prescription numbers of cannabis-based medicines raise the question of whether uptake of these medicines can be distinguished from recreational cannabis use. In this pilot study, serum cannabinoid profiles after use of cannabis-based medicines were investigated, in order to identify potential distinguishing markers. Serum samples after use of Sativex®, Dronabinol or medical cannabis were collected and analyzed for 18 different cannabinoids, using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Analytes included delta-9-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabicyclol, tetrahydrocannabivarin, cannabidivarin, tetrahydocannabinolic acid A, cannabidiolic acid, cannabinolic acid, cannabigerolic acid, cannabichromenic acid, cannabicyclolic acid, tetrahydrocannabivarinic acid and cannabidivarinic acid. Cannabinoid profiles of study samples were compared to profiles of street cannabis user samples via principal component analysis and Kruskal-Wallis test. Potential distinguishing markers for Dronabinol and Sativex® intake were identified, including 11-hydroxy-tetrahydrocannabinol/delta-9-tetrahydrocannabinol ratios ≥1 and increased concentrations of 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol or cannabichromene. Larger quantities of minor cannabinoids suggested use of cannabis. Use of medical and street cannabis could not be distinguished, except for use of a cannabidiol-rich strain with higher cannabidiol/delta-9-tetrahydrocannabinol and cannabichromene/delta-9-tetrahydrocannabinol ratios. Findings of the study were used to classify forensic serum samples with self-reported use of cannabis-based medicines.

Evaluation of Factors Impacting the Efficacy of Single or Combination Therapies of Valproic Acid, Carbamazepine, and Oxcarbazepine: A Longitudinal Observation Study.

Objective: This study aimed to determine the efficacy and clinical factors related to the pharmacodynamics of single or combination therapies of valproic acid (VPA), carbamazepine (CBZ), and oxcarbazepine (OXC), three commonly used anti-epileptic drugs (AEDs) in China. Methods: The study evaluated the records of 2027 outpatients in a Changsha hospital, located in China, from December 23, 2015 to October 28, 2019. The baseline seizure frequency was assessed during the first visit. AED efficacy was determined based on the reduction in seizures from baseline at the subsequent visits. Multivariable ordinal regression analysis was used to determine the association between the clinical factors (demographic characteristics, clinical features, and medication situation) and AED efficacy. For validation, the clinical efficacies of AEDs were compared as both single agents and in combinations. Differences in adverse effect (AEs) categories were analyzed by Chi-square between AED groups. Results: Records of patients receiving VPA, CBZ, and OXC were evaluated. Serum concentrations of VPA and CBZ is significantly correlated with efficacy (OR 1.030 [1.024-1.037], p < 0 0.0001; OR 1.250 [1.146-1.63], p < 0.0001, respectively) and OXC efficacy correlated to the serum concentration of the metabolite 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) serum concentrations (OR 1.060 [1.031-1.089], p < 0.0001). Significant differences existed between females and males in VPA efficacy (OR 1.318 [1.033-1.682], p = 0.027). After validation, VPA, in combination with OXC (OR 1.93 [1.38-2.70], p<0.001), or with VGB (Vigabatrin) (OR 2.36 [1.38-2.70], p = 0.002), showed significantly better efficacy than as a single agent. OXC efficacy was also affected by the duration of epilepsy (OR 0.965 [0.946-0.984], p < 0.001). Additionally, the efficacies of OXC and VPA were also affected by the seizure type. Seizure reduction improved significantly with an increasing number of pharmacists' educations in the first three visits period. There were no differences in AEs incidence among these 3 AEDs except for Psychiatric (0.02) and nervous system disorders (0.0001). Conclusion: Serum concentrations of VPA and CBZ may positively affect their efficacies, while OXC efficacies are correlated to MHD serum concentrations. The efficacy of VPA was higher in females compared to males. VPA-OXC and VPA-VGB combinations had higher efficacies compared to monotherapy. Besides, OXC efficacy is probably reducing by the duration of epilepsy. Additionally, VPA efficacy for focal or generalized seizures is superior to mixed-type seizures. OXC was more effective for focal seizures compared to mixed-type ones. Education provided by pharmacists improved the seizures to some extent, and there were no significant differences between most categories of adverse effects for the investigated AEDs.

Maternal vitamin D status and risk of gestational diabetes mellitus: A systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: No earlier systematic review and meta-analysis have been done on the association between maternal serum vitamin D status and risk of GDM among prospective studies. The current study was done to systematically review prospective cohort studies (with several years of follow-up) on the association between maternal serum vitamin D deficiency or insufficiency and risk of GDM. METHODS: Relevant papers published up to January 2020 were searched through PubMed, MEDLINE, SCOPUS, EMBASE, and Google Scholar using suitable keywords. All prospective cohort studies reporting Hazard Ratios (HRs) or Relative Risks (RRs) and 95% Confidence Intervals (CI) for GDM across categories of maternal serum vitamin D status were included. RESULTS: A total of 29 prospective and nested case-control studies were included in the current systematic review, of which 27 studies had sufficient data for the meta-analysis. Individuals with vitamin D deficiency had a 26% greater risk of developing GDM than those with normal serum vitamin D concentrations (OR: 1.26; 95% CI: 1.13, 1.41). In addition, a significant positive association was seen between combined vitamin D insufficiency and deficiency and risk of developing GDM (OR: 1.23; 95% CI: 1.11, 1.35). Dose-response analysis showed a significant U-shaped non-linear association between serum vitamin D concentrations and risk of developing GDM (P < 0.001), such that those with serum vitamin D concentrations between 40 and 90 nmol/L had significantly reduced risk of GDM. CONCLUSIONS: We found a significant association between vitamin D deficiency and an increased risk of GDM. The lowest risk of GDM was found among those with a serum vitamin D levels of 40-90 nmol/L. Further studies, including randomized clinical trials, are needed to confirm our findings. REGISTRATION: PROSPERO (ID: 180722), https://www.crd.york.ac.uk/prospero/.

Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway.

BACKGROUND: There is little evidence-based guidance on how to optimize methadone dosages among patients with opioid addiction undergoing methadone maintenance treatment (MMT). This study aims to investigate whether self-perceived opioid withdrawal symptoms, adverse effects, and self-reported substance use in patients on MMT are related to serum methadone concentrations and the role that these variables could play in clinical decisions on dose adjustments. METHODS: This naturalistic prospective cohort study included clinical and laboratory measurements from 83 patients undergoing MMT in outpatient clinics in Bergen, Norway, from May 2017 to January 2020. Information on age, gender, methadone daily doses and serum concentrations, subjective opioid withdrawal symptoms using 16 items Subjective Opioid Withdrawal Scale (SOWS) questionnaire, self-reported adverse effects, and substance use was obtained. Linear mixed modelling was used for analyzing the data. RESULTS: The mean age of the participants was 45 years, and 33% were women. Almost half reported mild to moderate subjective opioid withdrawal symptoms, and all had experienced at least one subjective adverse effect. The use of at least one substance was reported by 88% of the participants. Serum concentration-to-dose ratios were lower among those who had reported subjective opioid withdrawal symptoms (p) = 0.039). The total SOWS score (p < 0.001); the specific subjective withdrawal symptoms of anxiety (p = 0.004), bone and muscle aches (p = 0.003), restlessness (p = 0.017), and (slightly) shaking (p = 0.046), also use of heroin (p = 0.015) and alcohol (p = 0.011) were associated with lower methadone concentrations. Cannabis use was slightly related to higher methadone concentrations (p = 0.049). CONCLUSIONS: The findings suggest that the patient's self-perceived symptoms and current clinical condition are related to the serum concentrations of methadone. This interpretation supports dose adjustments based on patient-reported symptoms. In some aberrant cases, measurement of serum concentrations together with other individual assessments may be considered to support the clinical decision.

Effect and tolerability of perampanel in patients with drug-resistant epilepsy.

OBJECTIVE: Perampanel is one of the most recently approved antiseizure medications. The aim of the present study was to assess clinical efficacy and tolerability, in combination with pharmacokinetic variability, of perampanel treatment in patients at a tertiary referral center for epilepsy. METHODS: We performed a retrospective observational study of patients given perampanel as adjunctive treatment in the period January 2013 - February 2019 at the National Center for Epilepsy at Oslo University Hospital, Norway. RESULTS: Clinical data were available for 175 mainly adult patients with drug-resistant epilepsy with mean treatment duration of 16.1 months. We found that 23% (40 patients) were responders (i.e., achieving more than 50% reduction in seizure frequency), four of whom became seizure free, 29% (51 patients) experienced a modest effect, whereas for 29% (50 patients) perampanel had no seizure-reducing effect. A paradoxical effect, with seizure aggravation, was reported in 9% (15 patients). The responder rate was significantly higher in those with slow vs. fast dosage titration. Logistic regression analysis showed better efficacy among those with generalized vs. those with focal epilepsy. Adverse effects were reported by 135 patients (77%), ranging from mild (34%), to moderate (41%) and severe (2%). In 55 patients (41%), these adverse effects resulted in discontinuation of treatment with perampanel. The most frequent adverse effects were psychiatric symptoms (34%), dizziness (31%), and sleepiness (26%). Of the 31 patients for whom serum concentration measurements were available, the mean daily perampanel dose was 6.3 mg (SD 3.0), with a mean serum concentration at steady state of 1.03 µmol/L (range: 0.15-3.59 µmol/L). There were pronounced differences between patients, as demonstrated by a 12-fold variability in the range of concentration/dose (C/D)-ratios (0.06 to 0.69 µmol/L/mg), where enzyme inducers contributed. CONCLUSION: Our results demonstrate that perampanel had a modest seizure-reducing effect in this very treatment-resistant patient group. Predictors of treatment success were generalized epilepsy and slow dosage titration. In patients without a history of psychiatric problems, clinicians could consider increasing dose of perampanel beyond 6 mg daily, taking co-medication and serum concentrations into account.

Poor Correlation between Meropenem and Piperacillin Plasma Concentrations and Delivered Dose of Continuous Renal Replacement Therapy.

There is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT). In this prospective observational study, we explored the variability in plasma concentrations of meropenem and piperacillin in critically ill patients treated with CRRT and the correlation between concentrations and CRRT intensity. Antibiotic concentrations were measured at the middle and end of the dosing interval and repeated after 2 to 3 days when feasible. Measured concentrations were compared to the clinical susceptible breakpoints for Pseudomonas aeruginosa, 16 and 2 mg/liter for piperacillin and meropenem, respectively. CRRT intensity was estimated by delivered, time-averaged, total effluent flow (Qeff), corrected for predilution. Concentrations were also compared between patients with different residual diuresis. We included 140 meropenem concentrations from 98 patients and 47 piperacillin concentrations from 37 patients. Concentrations at the middle of the dosing interval were above target at all occasions for both antibiotics. For meropenem, 6.5% of trough concentrations were below target, and for piperacillin, 22%. Correlations between Qeff and antibiotic concentrations or the concentration half-life (t1/2) were either statistically not significant or weak. Meropenem concentrations and t1/2 values differed between patients with different residual diuresis. Thus, when treating intensive care patients with CRRT and recommended doses of meropenem or piperacillin, both low, suboptimal plasma concentrations and unnecessarily high, potentially toxic, plasma concentrations are common. Plasma concentrations cannot be predicted from CRRT intensity. Residual diuresis is associated with lower meropenem concentrations, but the correlation is weak. Concentration measurement is probably the most useful approach to avoid suboptimal treatment.