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Excessive water consumption is an extremely rare and potential asthma risk factor with very few cases reported in the literature. Common triggers of asthma include genetic factors, smoking, allergens, and viral respiratory infections. The adult patient with asthma reportedly drank too much water and was unable to get relief from his asthma while hospitalized. The patient's asthma was better controlled with the use of diuretics and control of the patient's fluid intake and output. This case explores asthma induced by excessive drinking of water. [ABSTRACT FROM AUTHOR]

Background: Low immune function after laparoscopic total gastrectomy puts patients at risk of infection-related complications. Low-dose naloxone (LDN) can improve the prognosis of patients suffering from chronic inflammatory diseases or autoimmune diseases. The use of LDN during perioperative procedures may reduce perioperative complications. The purpose of this study was to examine the effects of LDN on endogenous immune function in gastric cancer patients and its specific mechanisms through a randomized controlled trial. Methods: Fifty-five patients who underwent laparoscopic-assisted total gastrectomy were randomly assigned to either a naloxone group (n = 23) or a nonnaloxone group (n = 22). Patients in the naloxone group received 0.05 µg/kg-1.h− 1naloxone from 3 days before surgery to 5 days after surgery via a patient-controlled intravenous injection (PCIA) pump, and patients in the nonnaloxone group did not receive special treatment. The primary outcomes were the rates of postoperative complications and immune function assessed by NK cell, CD3+ T cell, CD4+ T cell, CD8+ T cell, WBC count, neutrophil percentage, and IL-6 and calcitonin levels. The secondary outcomes were the expression levels of TLR4 (Toll-like receptor), IL-6 and TNF-α in gastric cancer tissue. Results: Compared with the nonnaloxone group, the naloxone group exhibited a lower incidence of infection (in the incision, abdomen, and lungs) (P < 0.05). The numbers of NK cells and CD8+ T cells in the naloxone group were significantly greater than those in the nonnaloxone group at 24 h after surgery (P < 0.05) and at 96 h after surgery (P < 0.05). Compared with those in the nonnaloxone group, the CD3 + T-cell (P < 0.05) and CD4 + T-cell (P < 0.01) counts were significantly lower in the naloxone group 24 h after surgery. At 24 h and 96 h after surgery, the WBC count (P < 0.05) and neutrophil percentage (P < 0.05) were significantly greater in the nonnaloxone group. The levels of IL-6 (P < 0.05) and calcitonin in the nonnaloxone group were significantly greater at 24 h after surgery. At 24 h following surgery, the nonnaloxone group had significantly greater levels of IL-6 (P < 0.05) and calcitonin than did the naloxone group. Compared with those in the naloxone group, the expression levels of TLR4 (P < 0.05) in gastric cancer tissue in the naloxone group were greater; however, the expression levels of IL-6 (P < 0.01) and TNF-α (P < 0.01) in the naloxone group were greater than those in the nonnaloxone group. Conclusion: Laparoscopic total gastrectomy patients can benefit from 0.05 ug/kg− 1. h− 1 naloxone by reducing their risk of infection. It is possible that LDN alters the number of cells in lymphocyte subpopulations, such as NK cells, CD3 + T cells, and CD4 + T cells, and the CD4+/CD8 + T-cell ratio or alters TLR4 receptor expression in immune cells, thereby altering immune cell activity. Trial registration: The trial was registered at the Chinese Clinical Trial Registry on 24/11/2023 (ChiCTR2300077948). [ABSTRACT FROM AUTHOR]

Background: Medullary thyroid carcinoma (MTC) is a malignant tumor with low incidence. Currently, most studies have focused on the prognostic risk factors of MTC, whatever, time kinetic and risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) are yet to be elucidated. Methods: A retrospective study was conducted for 190 MTC patients. Risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) were analyzed. The predictors of calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BPT) were identified. Further, the prognostic roles of CNT and BPT were also demonstrated. Results: The 5- and 10-year DFS were 86.7% and 70.2%, respectively. The 5- and 10-year OS were 97.6% and 78.8%, respectively. CN was achieved in 120 (63.2%) patients, whereas BP was presented in 76 (40.0%) patients at the last follow up. After curative surgery, 39 (32.5%) and 106 (88.3%) patients achieved CN within 1 week and 1 month. All patients who failed to achieve CN turned to BP over time and 32/70 of them developed structural recurrence. The median time of CNT and BPT was 1 month (1 day to 84 months) and 6 month (3 day to 63months), respectively. LNR > 0.23 and male gender were independent predictors for CN and BP. LNR > 0.23 (Hazard ratio (HR), 0.24; 95% CI,0.13–0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42–0.99; P = 0.045) were independent predictors for longer CNT. LNR > 0.23 (HR,5.10; 95% CI,2.15–12.11; P < 0.01) was still the strongest independent predictor followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29–4.25; P = 0.005) for shorter BPT. In survival analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17–27.61; P = 0.031) and multifocality (HR, 3.10; 95% CI, 1.45–6.65; P = 0.004) were independent predictor of DFS. Conclusion: Early changes of Ctn after curative surgery can predict the long-term risks of biochemical and structural recurrence, which provide a useful real-time prognostic information. LNR significantly affect the time kinetic of biochemical prognosis. Tumor burden and CNT play a crucial role in MTC survival, the intensity of follow-up must be tailored accordingly. [ABSTRACT FROM AUTHOR]

Study Design: Systematic review and meta-analysis. Objective: There is some controversy about the effects of calcitonin (CT) on lumbar spinal stenosis (LSS). This systematic review and meta-analysis is to assess the strength of the evidence supporting the use of CT in the treatment of patients with LSS. Material and Method: We performed an electronic search depicting randomized controlled trials (RCTs) through 4 databases from the date of database creation to January 2023. 3 different researchers conducted independent literature screening, data extractions, and quality assessments. The outcome measures included visual analogue scale (VAS), walking distance, and oswestry disability index (ODI). Meta-analysis and trial sequence analysis (TSA) were carried out using RevMan 5.4, Stata 16.0, and TSA 0.9. GRADE 3.6 was used to evaluate the evidence quality. Results: We accepted 9 studies with 496 participants. The meta-analysis revealed that CT offered no significant improvement in VAS, walking distance, or ODI in patients with LSS. Conclusion: There is no evidence that CT has a benefit in patients with LSS, either alone or in combination with other treatments, or depending on the route of administration, according to the systematic review and meta-analysis of relevant RCTs. [ABSTRACT FROM AUTHOR]

Introduction: Coronavirus disease 2019 (COVID-19) can lead to secondary bacterial infections, particularly among critically ill patients. Differentiating between viral and bacterial infections is crucial for timely and appropriate antibiotic treatment. This study aimed to assess the predictive value of procalcitonin (PCT), C-reactive protein-to-mean platelet volume ratio (CRP-to-MPV ratio), and neutrophil-to-lymphocyte ratio (NLR) for secondary bacterial infections in COVID-19 patients. Methods: A retrospective analysis was conducted on COVID-19 patients admitted to RSUP dr. Sardjito between April 2020 and April 2021. Clinical data, procalcitonin levels, CRP-to-MPV ratio, NLR, culture results, and antibiotic susceptibility tests were analyzed. Statistical tests, including chi-square, t-tests and Mann-Whitney tests, were employed, with significance set at p<0.05. Receiver operating characteristic (ROC) analysis was performed to determine optimal cutoff values. Multivariate analysis was performed using logistic regression to ascertain the effects of multiple factors on the likelihood of developing secondary bacterial infections in COVID-19 patients. Results: Among 328 COVID-19 patients, 98 met the inclusion criteria. PCT had limited predictive value (AUC=0.535, p=0.638) with a sensitivity of 18.18% and specificity of 97.37% at a cutoff of 3.59. The CRP-to-MPV ratio showed slightly better predictive ability (AUC=0.587, p=0.198) with a sensitivity of 77.27% and specificity of 48.68% at the same cutoff value. The NLR demonstrated a higher predictive value (AUC=0.674, p=0.002) with a sensitivity of 90.91% and specificity of 44.74% at a cutoff of 3.64. Patients with an NLR of ≤3.64 exhibited an 8.01- fold elevated risk in the multivariate model. Conclusion: In COVID-19 patients hospitalized for up to seven days, an NLR greater than 3.64 can serve as a predictor of secondary bacterial infections. The use of NLR as a prognostic tool may aid in early identification and appropriate management of bacterial infections in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Sepsis-associated acute kidney injury (SA-AKI) is a critical condition with significant clinical implications, yet there is a need for a predictive model that can reliably assess the risk of its development. This study is undertaken to bridge a gap in healthcare by creating a predictive model for SA-AKI with the goal of empowering healthcare providers with a tool that can revolutionize patient care and ultimately lead to improved outcomes. Methods: A cohort of 615 patients afflicted with sepsis, who were admitted to the intensive care unit, underwent random stratification into 2 groups: a training set (n = 435) and a validation set (n = 180). Subsequently, a multivariate logistic regression model, imbued with nonzero coefficients via LASSO regression, was meticulously devised for the prognostication of SA-AKI. This model was thoughtfully rendered in the form of a nomogram. The salience of individual risk factors was assessed and ranked employing Shapley Additive Interpretation (SHAP). Recursive partition analysis was performed to stratify the risk of patients with sepsis. Results: Among the panoply of clinical variables examined, hypertension, diabetes mellitus, C-reactive protein, procalcitonin (PCT), activated partial thromboplastin time, and platelet count emerged as robust and independent determinants of SA-AKI. The receiver operating characteristic curve analysis for SA-AKI risk discrimination in both the training set and validation set yielded an area under the curve estimates of 0.843 (95% CI: 0.805 to 0.882) and 0.834 (95% CI: 0.775 to 0.893), respectively. Notably, PCT exhibited the most conspicuous influence on the model's predictive capacity. Furthermore, statistically significant disparities were observed in the incidence of SA-AKI and the 28-day survival rate across high-risk, medium-risk, and low-risk cohorts (P <.05). Conclusion: The composite predictive model, amalgamating the quintet of SA-AKI predictors, holds significant promise in facilitating the identification of high-risk patient subsets. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To show the procalcitonin (PCT) test demand from an emergency department (ED) over several years, to decrease PCT measurement via a computerized algorithm based on C-reactive protein (CRP) value, and to evaluate the subsequent economic savings. STUDY DESIGN: A cross-sectional study was performed from January 1, 2018, to May 31, 2019, to evaluate an intervention to avoid PCT measurement in the ED of Hospital Universitario San Juan in Alicante in Spain, when CRP values are low. METHODS: A PCT result of at least 1.5 ng/mL was agreed upon with ED providers in our study as the value for clinical decision-making, with values less than 1.5 ng/mL considered negative. We retrospectively reviewed all PCT and CRP values for ED patients and calculated the diagnostic indicators for PCT at 4 different CRP cutoffs using the PCT quantification as the gold standard. From July 1, 2019, to April 30, 2021, the agreed-upon strategy was implemented, and we counted the PCT tests avoided and calculated the savings. RESULTS: PCT was not measured when CRP values were less than the selected CRP cutoff of 0.8 mg/dL, at which false-negative results were 1% and the 99th percentile of PCT was 1.5 ng/mL. In the postintervention period, 1091 PCT values were not measured and $11,553.69 was saved. CONCLUSIONS: An intervention to decrease PCT measurement in the ED designed by the clinical laboratory staff in consensus with requesting clinicians and based on CRP values decreased PCT testing and generated significant economic savings. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. METHODS: We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants #90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. RESULTS: We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. CONCLUSIONS: The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules. [ABSTRACT FROM AUTHOR]

Objective: Sepsis often prompts clinicians to start empirical antibiotics in suspected neonates while awaiting diagnosis. The next-generation testing with point-of-care (POC) techniques offers a lead-time advantage that could bridge the gap by providing a timely diagnosis. Materials and Methods: We conducted a prospective diagnostic study in 82 neonates enrolled between May and October 2022 in a level III neonatal intensive care unit. All neonates with a new episode of clinically suspected sepsis were included. Diagnostic accuracy of POC testing of C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) with standard laboratory methods was performed. Results: The mean gestation age and birth weight of the neonates were 33.17 ± 4.25 weeks and 1,695.4 ± 700.74 grams, respectively. Most neonates were preterm (75%) with nearly equal proportions of early (51.22%) and late-onset (48.78%) sepsis. The POC CRP correlated well with standard CRP (r = 0.8001, 95% CI: 0.706–0.867, p < 0.0001). Among the three biomarkers, CRP had the maximum diagnostic accuracy (area under the curve [AUC] – 0.73) followed by PCT (AUC – 0.65) and IL-6 (0.55). There was no significant difference in the diagnostic accuracy of CRP (p = 0.46), PCT (p = 0.29), and IL-6 (p = 0.60) in early- and late-onset sepsis. The mean time for POC estimation of IL-6, PCT, and CRP was 12 ± 3 min which was significantly less compared to 366 ± 61 min for standard techniques (p < 0.001). Conclusion: POC CRP correlates well with standard techniques of estimation, and CRP alone and in combination with PCT has good diagnostic accuracy in neonatal sepsis. Highlights of the Study: Point-of-care (POC) C-reactive protein (CRP) levels correlate well with standard laboratory estimation. CRP alone and in combination with procalcitonin (PCT) has maximum diagnostic accuracy in neonatal sepsis. POC testing can be used in both early- and late-onset sepsis with similar diagnostic accuracy. The mean time required for POC estimation of interleukin-6, PCT, and CRP is nearly 12 min which is significantly less than standard techniques. [ABSTRACT FROM AUTHOR]

Background: Procalcitonin (PCT) has been used as a biomarker to guide antibiotic therapy in various patient populations. However, its role in optimizing antibiotic use in COVID-19 patients has not been well studied to date. Thus, we aimed to evaluate the use of serial PCT monitoring as an antimicrobial stewardship tool for COVID-19 patients. Methods: This retrospective study included 240 COVID-19 patients who were admitted to a tertiary medical institution in Saudi Arabia between January 2020 and February 2022. Patients who received empiric antibiotic therapy for community-acquired pneumonia (CAP) and had serial procalcitonin levels were included. The patients were divided into two groups: the normal procalcitonin arm (PCT level < 0.5 ng/mL) and the elevated PCT arm (PCT level > 0.5 ng/mL). The primary and secondary outcomes were the effect of PCT monitoring on the duration of antibiotic exposure and the length of hospital stay, respectively. To measure the accuracy of PCT, the receiver-operating characteristic area under the curve (ROC-AUC) was determined. Results: Among the included patients, 142 were in the normal procalcitonin arm (median PCT, 0.12 ng/mL), and 78 were in the elevated PCT arm (median PCT, 4.04 ng/mL). The baseline characteristics were similar between the two arms, except for the higher prevalence of kidney disease in the elevated PCT arm. There was no statistically significant difference in the duration of antibiotic exposure between the normal and elevated PCT arms (median duration: 7 days in both arms). However, the length of hospital stay was significantly shorter in the normal PCT arm (median stay, 9 days) than in the elevated PCT arm (median stay, 13 days; p = 0.028). The ROC-AUC value was 0.54 (95% CI: 0.503–0.595). Conclusions: Serial PCT monitoring did not lead to a reduction in the duration of antibiotic exposure in COVID-19 patients. However, it was associated with a shorter hospital stay. These findings suggest that PCT monitoring may be useful for optimizing antibiotic use and improving outcomes in COVID-19 patients. While PCT-guided algorithms have the potential to enable antibiotic stewardship, their role in the context of COVID-19 treatment requires further investigation. [ABSTRACT FROM AUTHOR]

Background: The most frequent cause of coronary artery aneurysm in children is Kawasaki disease (KD). Recently, limited studies on procalcitonin (PCT) were performed to find a biomarker for the diagnosis or prognosis of children with KD. Objectives: This study aimed to compare serum PCT levels between complete and incomplete KD and testify to the predictive validity of PCT for intravenous immunoglobulin (IVIG) resistance and predicting coronary artery lesions (CALs). Methods: This cross-sectional study was conducted at Namazi hospital in Shiraz, Iran, in 2019. All KD patients admitted to the hospital were included, with parental consent obtained. Kawasaki disease patients were categorized as complete KD (cKD) or incomplete KD (iKD). Two-dimensional echocardiography was performed, and peripheral venous blood was examined for PCT levels and other markers. All patients received IVIG and aspirin as standard treatment. The presence of coronary artery abnormalities (CAAs) was determined based on coronary artery size and morphology. We used Stata software version 14.0 for data analysis. Logistic regression models identified predictive factors for coronary complications. This study determined the optimal PCT cut-off point for predicted coronary complications using receiver operating characteristic (ROC) curve analysis. Approval was obtained from the Research Ethics Committees of Shiraz University of Medical Sciences. Results: Procalcitonin values in 38 children hospitalized with acute KD ranged from 0.2 ng/mL to 10 ng/mL, with a mean of 2.65 ng/m. There was no correlation of PCT with patients' age or gender, incomplete KD, or IVIG resistance. The serum PCT concentration was higher in patients with CAL (P = 0.009). The best PCT cut-off value for CAL prediction was 2.5 ng/mL (corresponding sensitivity = 81.8% and specificity = 68.7%), considering CAL prevalence as the studied group. Conclusions: Supplementary research is needed to determine the sensitivity and specificity of PCT for the diagnosis and prognosis of KD. Procalcitonin might be of value in predicting which children are at increased risk for CALs to intensify therapy. [ABSTRACT FROM AUTHOR]

Objective: To compare calcitonin gene–related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). Background: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. Methods: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. Results: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta‐analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of −1.64 (−1.99 to −1.28) MMD, which is compatible with small effect size (Cohen's d −0.25 [−0.34 to −0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD −1.45 [−1.52 to −1.38] and −1.65 [−2.30 to −1.00], respectively; Cohen's d −1.25 [−2.47 to −0.03] and −0.48 [−0.67 to −0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta‐analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD −0.19 [−0.56 to 0.17]) or divalproex (0.01 [−0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [−0.45 to 0.86]). Conclusions: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first‐line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first‐line treatment. Plain Language Summary: Insurance companies often do not approve calcitonin gene–related peptide monoclonal antibodies (CGRP mAbs) for the treatment of migraine until patients have tried other medicines first. We reviewed and summarized data from studies that reported how well different migraine medications worked, including CGRP mAbs, and found evidence that CGRP mAbs are more effective than placebo and just as effective as other migraine drugs. This suggests that CGRP mAbs should be offered as a first‐line preventive therapy at the discretion of the clinician and the individual patient. Answer questions and earn CME credit: https://wileyhealthlearning.com/#/online‐courses/d524dd0e‐d6b3‐4fd3‐b298‐230b74599848 [ABSTRACT FROM AUTHOR]

Aim: The diagnosis of early‐onset neonatal sepsis (EOS) remains difficult. The main aim was to study the effect of a new algorithm for EOS, which includes the level of procalcitonin in umbilical cord blood, on the exposure to antibiotic therapy of premature newborn infants. Methods: This was a monocentric, observational and retrospective study with before‐and‐after design. The duration and dose of antibiotic therapy provided as well as the morbidity and mortality were compared in two groups, one included 01 May 2015–30 November 2015 when procalcitonin was not used, and one after the change 01 November 2016–30 May 2017 when procalcitonin was used in a hospital setting in Nice, France. Results: Sixty newborn infants were included in the before group and 54 in the after group. Antibiotic therapy was stopped after 24 h for 18 newborn infants in the after group and four in the before group, and after 48 h for 26 newborn infants in the after group and 10 in the before group. Conclusion: The implementation of a new decision‐making algorithm including early procalcitonin assay of premature newborn infants significantly reduced exposure to antibiotics without modifying mortality or morbidity. [ABSTRACT FROM AUTHOR]

Background: Neuropeptides play a critical role in regulating pain and inflammation. Despite accumulating evidence has further uncovered the novel functions and mechanisms of different neuropeptides in orofacial pain sensation and transmission, there is deficient systematic description of neuropeptides' pain modulation in the orofacial region, especially in the trigeminal system. Objectives: The present review aims to summarise several key neuropeptides and gain a better understanding of their major regulatory roles in orofacial inflammation and pain. Methods: We review and summarise current studies related to calcitonin gene‐related peptide (CGRP), substance P (SP), opioid peptide (OP), galanin (GAL) and other neuropeptides' functions and mechanisms as well as promising targets for orofacial pain control. Results: A number of neuropeptides are clearly expressed in the trigeminal sensory system and have critical functions in the transduction and pathogenesis of orofacial pain. The functions, possible cellular and molecular mechanisms have been introduced and discussed. Neuropeptides and their agonists or antagonists which are widely studied to be potential treatment options of orofacial pain has been evaluated. Conclusions: Various neuropeptides play important but distinct (pro‐nociceptive or analgesic) roles in orofacial pain with different mechanisms. In summary, CGRP, SP, NPY, NKA, HK‐1, VIP mainly play proinflammatory and pro‐nociceptive effects while OP, GAL, OXT, OrxA mainly have inhibitory effects on orofacial pain. [ABSTRACT FROM AUTHOR]

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non‐sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non‐sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non‐sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4–6), p = 0.008]. The serum levels of d‐lactate (p = 0.033), intestinal fatty acid‐binding protein (p = 0.005), interleukin‐6 (p = 0.001), white blood cells (p = 0.007), C‐reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non‐sivelestat group. The sivelestat group also demonstrated longer ICU‐free days [18 (0–22) vs. 13 (0–17), p = 0.004] and ventilator‐free days [22 (1–24) vs. 16 (1–19), p = 0.002] compared with the non‐sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients. [ABSTRACT FROM AUTHOR]

Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by the loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. The Cyp24a1+/− mice were mated to create pregnancies with wildtype, Cyp24a1+/− , and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1+/− fetuses only), with 3.5-fold increased calcitriol, 4-fold increased fibroblast growth factor 23 (FGF23), and unchanged parathyroid hormone. The quantitative RT-PCR confirmed the absence of Cyp24a1 and 2-fold increases in S100g , sodium–calcium exchanger type 1, and calcium-sensing receptor in null placentas but not in fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45Ca and 32P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum procollagen 1 intact N-terminal propeptide and bone expression of sclerostin and Blgap were reduced while calcitonin receptor was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, and increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in the skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Migraines are a common comorbidity and source of disability in patients with chronic inflammatory diseases like multiple sclerosis (MS). Recently, therapeutic agents for episodic and chronic migraine known as calcitonin gene-related peptide (CGRP) inhibitors have shown to effectively control migraine attacks and improve quality of life in the general population. This study explored the use of these novel agents in individuals with comorbid MS. METHODS: This was a retrospective, population-based cohort study at the University of South Florida's neurology clinic; it evaluated individuals with both MS and migraine. RESULTS: A total of 27 individuals with MS and chronic or episodic migraine who received treatment with a CGRP monoclonal antibody were identified. Of these, 63% reported a reduction in their migraine frequency of greater than 75%. Concurrent use of a disease-modifying therapy (DMT) for MS occurred in 82% of patients, and in 37% of these, the DMT used was also a monoclonal antibody. Adverse effects from CGRP monoclonal antibodies were mild and occurred in only 11% of patients, and no patient experienced worsening of their MS symptoms during cotreatment over the duration of the study. CONCLUSIONS: Our study showed a significant reduction in migraine frequency and a favorable adverse event profile for individuals with comorbid MS who took CGRP monoclonal antibodies and experienced no worsening of MS symptoms. In individuals with MS, CGRP monoclonal antibodies seem to be a safe and effective therapy for episodic or chronic migraine. [ABSTRACT FROM AUTHOR]

Introduction: Over the last four years, COVID-19 has caused more than 3 million deaths around the world. This phenomenon led to the search for diagnostic markers for COVID-19. Considering that the clinical applicability of specific biomarkers for the prediction of the severity of COVID-19 is still debatable, this study analyses the clinical applicability of NT-proCNP, presepsin, SuPAR, Crp, procalcitonin, interleukin-6 and D-dimers in patients who died and survived COVID-19 to establish cross-relevance between the outcome of COVID-19 and markers level. Material and methods: The study sample comprised 84 deceased patients (62 men, 21 women) and 72 survivors (40 men, 32 women). Various immunological techniques were employed to analyse the concentration of specific biomarkers. Statistical analysis was performed using the Student's t-test or the Mann-Whitney test according to the distribution of the sample studied. Results: This study revealed that the levels of NT-proCNP, presepsin, SuPAR, procalcitonin, and IL-6 increase due to COVID-19. Thus, nonsurvivors are defined by the higher levels of those markers than the survivors. Conclusions: The study revealed the potential application of NT-proCNP, presepsin, SuPAR, CRP, procalcitonin, IL-6, and D-dimers as markers of progression of the COVID-19-D. However, considering the physiological mechanism of a dimension of a response of the studied markers as a function of disease progress, it may not be concluded that they are singularly unique for the progress of the COVID-19-D. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening condition that affects 1.2 million children annually. Although there are several criteria for diagnosing this condition, signs are often nonspecific, and identifying sepsis is challenging. In this context, presepsin (P-SEP) seems to be a promising new biomarker since its plasma levels increase earlier than other sepsis-related proteins and its measurement is faster. We enrolled 157 minors who presented to the Pediatric Emergency Department of Agostino Gemelli Hospital with fever and suspected sepsis. Biochemical, anamnestic, and clinical data were collected. Viral agents were identified as the causative factor in 64 patients, who had an average P-SEP value of 309.04 pg/mL (SD ± 273.2), versus an average P-SEP value of 526.09 pg/mL (SD ± 657) found in 27 bacterial cases (p value: 0.0398). Four cases of overt sepsis had an average P-SEP value of 3328.5 pg/mL (SD ± 1586.6). The difference in P-SEP levels in viral versus bacterial infections was found to be statistically significant; therefore, P-SEP may have a central role in the evaluation of febrile children, helping clinicians distinguish between these two etiologies. Furthermore, amongst the cases of confirmed sepsis, P-SEP was always greater than 2000 pg/mL, while C-reactive protein and procalcitonin values appeared lower than what was considered significant. [ABSTRACT FROM AUTHOR]

Ventilator-associated pneumonia (VAP) is common in Pediatric Intensive Care Units. Although early detection is crucial, current diagnostic methods are not definitive. This study aimed to identify lung ultrasound (LUS) findings and procalcitonin (PCT) values in pediatric patients with VAP to create a new early diagnosis score combined with the Clinical Pulmonary Infection Score (CPIS), the CPIS-PLUS score. Prospective longitudinal and interventional study. Pediatric patients with suspected VAP were included and classified into VAP or non-VAP groups, based on Centers of Disease Control (CDC) criteria for the final diagnosis. A chest-X-ray (CXR), LUS, and blood test were performed within the first 12 h of admission. CPIS score was calculated. A total of 108 patients with VAP suspicion were included, and VAP was finally diagnosed in 51 (47%) patients. CPIS-PLUS showed high accuracy in VAP diagnosis with a sensitivity (Sn) of 80% (95% CI 65–89%) and specificity (Sp) of 73% (95% CI 54–86%). The area under the curve (AUC) resulted in 0.86 for CPIS-PLUS vs. 0.61 for CPIS. In conclusion, this pilot study showed that CPIS-PLUS could be a potential and reliable tool for VAP early diagnosis in pediatric patients. Internal and external validations are needed to confirm the potential value of this score to facilitate VAP diagnosis in pediatric patients. [ABSTRACT FROM AUTHOR]

Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both. [ABSTRACT FROM AUTHOR]

Objectives. Procalcitonin level is generally undetectable from blood sample under normal physiological condition. However, its production can be greatly stimulated by the presence of various inflammatory responses, especially those caused by bacterial infection. We aimed to determine if postoperative procalcitonin level could be used to predict bacterial infection more promptly than bacterial culture results. Materials and Methods. We performed a retrospective case-control study by collecting postoperative procalcitonin as well as white blood cell level of patients undergoing cardiac surgery using cardiopulmonary bypass from electronic medical records of Ramathibodi Hospital between 1st January 2019 and 30th June 2023. Patients with pre-existing inflammatory syndromes or proven bacterial infection, who had been receiving preoperative treatment-dose antibiotics or steroids, who underwent non-elective surgery, and whose medical record data were lost or insufficiently recorded were excluded. Demographic data and operative details were also collected and reviewed. Results. From a total of 146 patients in our study, 42 patients developed proven postoperative bacterial infection. The level of procalcitonin with greatest association to postoperative bacterial infection from our study was 4.13 ng/dl on postoperative day 7. White blood cell level, however, was less predictive of bacterial infection. Conclusions. Procalcitonin level, when utilized alongside clinical presentation, proved to be useful as a predictor of bacterial infection during postoperative day 7. A larger, prospective trial of our continuing series would further strengthen our results. [ABSTRACT FROM AUTHOR]

PURPOSE: Medullary thyroid carcinoma (MTC) in MEN2B syndrome is associated with germline RET mutation. Patients harboring de novo mutations are usually diagnosed at more advanced disease stages. We present a young woman with Met918Th mutation diagnosed with stage IV MTC at age 10 years. METHODS: The disease progressed despite total thyroidectomy and multiple surgical interventions for cervical lymph node recurrences, leading to distant metastases in the fifth year after the initial diagnosis. Subsequently, she underwent five different types of tyrosine kinase inhibitor (TKI) treatments. The 17-year disease course was divided into periods defined by four surgical interventions and sequential treatment intervals with four multikinase (sunitinib, vandetanib, cabozantinib, and lenvatinib) and one RET-selective TKI (selpercatinib). Tumor growth for different phases of spontaneous development and drug treatment intervals was characterized by changes in serial log-transformed calcitonin measurements (n = 114). RESULTS: Three operations (one for calcitonin-producing adrenal pheochromocytoma) were associated with drops in calcitonin levels. All of the nonselective TKIs were stopped due to adverse effects. As reflected by the negative calcitonin doubling rate, the best treatment response was observed with selpercatinib, which was associated with an initial large drop followed by a decreasing calcitonin trajectory over 514 days without any major side effects. CONCLUSION: This case of MEN2B medullary thyroid cancer with long-term survival presents how the effectiveness of different treatment modalities can be estimated using log-transformed calcitonin levels. Furthermore, our experience supports the view that serial calcitonin measurements may be more sensitive than radiological follow-up in advanced MTC. Our patient also represents a new case of rarely reported calcitonin-producing pheochromocytomas. Case report by Zs. Reti et al from @semmelweishu on MEN2B-related advanced MTC highlights the superiority of serial calcitonin measurements over imaging to monitor responses to TKIs over 17 years. [ABSTRACT FROM AUTHOR]

Intoduction/Aim. Agreement or disagreement of inflammatory parameters becomes important for making diagnosis when disparate values are encountered in a patient with suspected sepsis. The aim of our study was to test the agreement between the four commonly used tests for diagnosing systemic infection: white blood cell count (WBC), serum levels of C-reactive protein (CRP), procalcitonin and presepsin. This cross-sectional study included 479 adult patients hospitalized in the Clinical Center Kragujevac during 2019, who were suspected to have systemic infection and whose microbiological analyses were positive. Results. In a sample of hospital patients with isolated bacteria from the sites of suspected infection, the parameters of inflammation showed low agreement when used for diagnosing systemic infection. Only presepsin serum levels showed significant level of agreement with CRP and procalcitonin (Cohen's kappa = 0,257, p = 0,000Cohen's kappa = 0,169, p = 0,000, respectively, but also with low kappa values, while the agreement between CRP and procalcitonin was insignificant, as well as between the white cell count and the remaining three parameters. Conclusions. When disparate values of parameters of inflammation are encountered in a patient with suspected sepsis, a decision about antibiotic therapy should be based on either of the two pairs of parameters, presepsin/C-reactive protein or presepsin/procalcitonin. Keywords: sepsis, presepsin, procalcitonin, C-reactive protein, white blood cell count. [ABSTRACT FROM AUTHOR]

Background: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated. Methods: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1β, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C. Results: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2. Conclusions: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis, a syndrome of organ dysfunction caused by an unregulated host response to infection. This study aimed to develop a novel sepsis diagnostic model of hematological parameters and evaluate its effectiveness in the early identification and prognosis of sepsis in emergency departments. Methods: A retrospective study was conducted in Emergency Department. Cell population data parameters related to monocytes and neutrophils were obtained using the Mindary BC‐6800 plus hematology analyzer. Receiver operating characteristic (ROC) curve analysis, logistic regression analysis was performed to assess the performance of the parameters and establish a diagnostic and prognostic model of sepsis, which was then verified with a validation cohort. Results: Mon_XW exhibited the best diagnostic performance (area under the ROC curve [AUC] = 0.848, 95% confidence interval [CI]: 0.810–0.885, p < 0.001), followed by Neu_Y and Neu_YW (AUC = 0.777 95% CI: 0.730–0.824, p < 0.001). Logistic regression analysis identified Mon_XW and Neu_Y as independent predictors, which were used to establish a diagnostic model named hematological parameter for sepsis (HPS). HPS demonstrated the best diagnostic performance with an AUC of 0.862 (95% CI: 0.826–0.898, p < 0.001), sensitivity of 70.0%, and specificity of 87.1%, compared to C‐reactive protein (CRP) and procalcitonin (PCT). The validation cohort also found that the positive predictive value of HPS was 70.4% and the negative predictive value was 92.2%. Conclusion: The developed HPS model showed promising diagnostic efficacy for sepsis in the emergency department, which outperformed CRP and PCT in terms of sensitivity and specificity. By enabling early identification and prognosis of sepsis, that contributes to reducing sepsis‐related mortality. [ABSTRACT FROM AUTHOR]

Background: Neonatal sepsis has remained a major cause of neonatal morbidity and mortality. Despite advances in neonatal diagnostics, its diagnosis has remained challenging majorly because its symptoms are vague and blood culture which remains the gold standard for diagnosis is cumbersome and has poor yield and other forms of sepsis are usually not sought for (anaerobes, viral fungal). The search for newer diagnostic methods is still on going and procalcitonin has shown some promise. Aim/ Objective: The aim of the study is to examine the role procalcitonin plays in neonatal sepsis. Materials and Methods: A total of 248 neonates with suspicion of sepsis were enrolled and had their samples taken for blood culture, full blood count, C-reactive and procalcitonin assay based on which the neonates were classified as proven, suspected and clinical sepsis. Result: The behaviour of procalcitonin in the different sepsis groups (more elevated in proven and suspected than clinical), ages (to accommodate the physiologic variation seen in the first 72hours of life) and according to isolates (more elevated in gram negative than gram positive sepsis). The diagnostic value of procalcitonin was also determined and found have sensitivity 74.5%, specificity 38.3%, positive predictive value 42.4% and negative predictive value 71.1%, which were better after >72hours of life. Conclusion: For now, procalcitonin should continue to serve as a supportive marker for sepsis as its levels are affected by age of the neonate, sepsis mimics, and type of offending organism causing the infection. [ABSTRACT FROM AUTHOR]

Introduction: Longitudinal biomarkers in patients with community-acquired pneumonia (CAP) may help in monitoring of disease progression and treatment response. The metabolic host response could be a potential source of such biomarkers since it closely associates with the current health status of the patient. Objectives: In this study we performed longitudinal metabolite profiling in patients with CAP for a comprehensive range of metabolites to identify potential host response biomarkers. Methods: Previously collected serum samples from CAP patients with confirmed Streptococcus pneumoniae infection (n = 25) were used. Samples were collected at multiple time points, up to 30 days after admission. A wide range of metabolites was measured, including amines, acylcarnitines, organic acids, and lipids. The associations between metabolites and C-reactive protein (CRP), procalcitonin, CURB disease severity score at admission, and total length of stay were evaluated. Results: Distinct longitudinal profiles of metabolite profiles were identified, including cholesteryl esters, diacyl-phosphatidylethanolamine, diacylglycerols, lysophosphatidylcholines, sphingomyelin, and triglycerides. Positive correlations were found between CRP and phosphatidylcholine (34:1) (cor = 0.63) and negative correlations were found for CRP and nine lysophosphocholines (cor = − 0.57 to − 0.74). The CURB disease severity score was negatively associated with six metabolites, including acylcarnitines (tau = − 0.64 to − 0.58). Negative correlations were found between the length of stay and six triglycerides (TGs), especially TGs (60:3) and (58:2) (cor = − 0.63 and − 0.61). Conclusion: The identified metabolites may provide insight into biological mechanisms underlying disease severity and may be of interest for exploration as potential treatment response monitoring biomarker. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies suggest that alterations in blood parameters, such as changes in platelet, lymphocyte, hemoglobin, eosinophil, and basophil counts; increased neutrophil counts; and elevated neutrophil/lymphocyte and platelet/lymphocyte ratios, signal COVID-19 infection and predict worse outcomes. Leveraging these insights, our study seeks to create a predictive mortality model by assessing age and crucial laboratory markers. Materials and Methods: Patients were categorized into two groups based on their hospital outcomes: 130 survivors who recovered from their Intensive Care Unit (ICU) stay (Group 1) and 74 who died (Group 2). We then developed a predictive mortality model using patients' age, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), procalcitonin levels, and ferritin lactate (FL) index results. Results: A total of 204 patients were included. Patients in Group 2 had a notably higher mean age compared to those in Group 1 (76 ± 11 vs. 66 ± 15 years) (p < 0.001). Using specific cut-off values, our analysis revealed varying effectiveness in predicting COVID-19 mortality: Those aged over 73 years showed 74% sensitivity and 60% specificity, with an area under the curve (AUC) of 0.701. Procalcitonin levels above 0.35 ng/mL balanced true-positive and -negative identifications well, achieving an AUC of 0.752. The FL index, with a threshold of 1228 mg/dL, had 68% sensitivity and 65% specificity with an AUC of 0.707. A PLR higher than 212 resulted in 48% sensitivity and 69% specificity, with an AUC of 0.582. An NLR higher than 5.8 resulted in 55% sensitivity and 63% specificity, with an AUC of 0.640, showcasing diverse predictive accuracies across parameters. The statistical analysis evaluated the effects of age (>73), procalcitonin levels (>0.35), FL > 1228, PLR > 212, and NLR > 5.8 on mortality variables using logistic regression. Ages over 73 significantly increased event odds by 2.1 times (p = 0.05), procalcitonin levels above 0.35 nearly quintupled the odds (OR = 5.6, p < 0.001), high FL index levels more than tripled the odds (OR = 3.5, p = 0.003), a PLR > 212 significantly increased event odds by 3.5 (p = 0.030), and an NLR > 5.8 significantly increased event odds by 1.6 (p = 0.043). Conclusions: Our study highlights significant predictors of mortality in COVID-19 ICU patients, including advanced age, elevated procalcitonin, FL index levels, the PLR, and the NLR. [ABSTRACT FROM AUTHOR]

Objective: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene‐related peptide (CGRP) for the prevention of migraine. Background: All migraine preventive therapies previously considered to be first‐line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine‐specific therapies have been developed based on a broad foundation of pre‐clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP‐targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first‐line approaches. Methods: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo‐controlled clinical trials, post hoc analyses and open‐label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. Results: The evidence for the efficacy, tolerability, and safety of CGRP‐targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP‐targeting treatments and is corroborated by extensive "real‐world" clinical experience. The data indicates that the efficacy and tolerability of CGRP‐targeting therapies are equal to or greater than those of previous first‐line therapies and that serious adverse events associated with CGRP‐targeting therapies are rare. Conclusion: The CGRP‐targeting therapies should be considered as a first‐line approach for migraine prevention along with previous first‐line treatments without a requirement for prior failure of other classes of migraine preventive treatment. [ABSTRACT FROM AUTHOR]

Background: Pneumonia is a major public health problem with an impact on morbidity and mortality. Its management still represents a challenge. The aim was to determine whether a new diagnostic algorithm combining lung ultrasound (LUS) and procalcitonin (PCT) improved pneumonia management regarding antibiotic use, radiation exposure, and associated costs, in critically ill pediatric patients with suspected bacterial pneumonia (BP). Methods: Randomized, blinded, comparative effectiveness clinical trial. Children < 18y with suspected BP admitted to the PICU from September 2017 to December 2019, were included. PCT was determined at admission. Patients were randomized into the experimental group (EG) and control group (CG) if LUS or chest X-ray (CXR) were done as the first image test, respectively. Patients were classified: 1.LUS/CXR not suggestive of BP and PCT < 1 ng/mL, no antibiotics were recommended; 2.LUS/CXR suggestive of BP, regardless of the PCT value, antibiotics were recommended; 3.LUS/CXR not suggestive of BP and PCT > 1 ng/mL, antibiotics were recommended. Results: 194 children were enrolled, 113 (58.2%) females, median age of 134 (IQR 39–554) days. 96 randomized into EG and 98 into CG. 1. In 75/194 patients the image test was not suggestive of BP with PCT < 1 ng/ml; 29/52 in the EG and 11/23 in the CG did not receive antibiotics. 2. In 101 patients, the image was suggestive of BP; 34/34 in the EG and 57/67 in the CG received antibiotics. Statistically significant differences between groups were observed when PCT resulted < 1 ng/ml (p = 0.01). 3. In 18 patients the image test was not suggestive of BP but PCT resulted > 1 ng/ml, all of them received antibiotics. A total of 0.035 mSv radiation/patient was eluded. A reduction of 77% CXR/patient was observed. LUS did not significantly increase costs. Conclusions: Combination of LUS and PCT showed no risk of mistreating BP, avoided radiation and did not increase costs. The algorithm could be a reliable tool for improving pneumonia management. Clinical Trial Registration: NCT04217980. [ABSTRACT FROM AUTHOR]

Introduction: Medullary thyroid carcinoma (MTC) is an aggressive cancer that is often caused by driver mutations in RET. Splice site variants (SSV) reflect changes in mRNA processing, which may alter protein function. RET SSVs have been described in thyroid tumors in general but have not been extensively studied in MTC. Methods: The prevalence of RET SSVs was evaluated in 3,624 cases with next generation sequence reports, including 25 MTCs. Fisher exact analysis was performed to compare RET SSV frequency in cancers with/without a diagnosis of MTC. Results: All 25 MTCs had at least one of the two most common RET SSVs versus 0.3% of 3,599 cancers with other diagnoses (p < 0.00001). The 11 cancers with non-MTC diagnoses that had the common RET SSVs were 4 neuroendocrine cancers, 4 non-small cell lung carcinomas, 2 non-MTC thyroid cancers, and 1 melanoma. All 25 MTCs analyzed had at least one of the two most common RET SSVs, including 4 with no identified mutational driver. Discussion: The identification of RET SSVs in all MTCs, but rarely in other cancer types, demonstrates that these RET SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these RET SSVs play a pathogenic role in MTC. [ABSTRACT FROM AUTHOR]

Copyright of Turkish Journal of Trauma & Emergency Surgery / Ulusal Travma ve Acil Cerrahi Dergisi is the property of KARE Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Balikesir Health Sciences Journal / Balıkesir Sağlık Bilimleri Dergisi is the property of Balikesir Health Sciences Journal (BAUN Health Sci J) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: To investigate the relation between thyroid-stimulating-hormone (TSH) and metabolic tumor volume (MTV) in patients with advanced medullary thyroid cancer. Methods: Ga-68-DOTA-TATE-PET/CT findings such whole-body somatostatin receptor-expressing metabolic tumor volume (SSR-E MTV) and total lesion volume (SSR-E TLV) were calculated, and correlation analysis was performed for TSH and whole-body SSR-E MTV and SSR-E TLV. Results: Totally twenty-eight patients were included in the study. The median TSH level was 2.90 mU/L and median free T4 was 2.70 ng/L. The median calcitonin level was 6671.6 pg/mL and the median carcinoembryonic antigen level was 202.8 ng/mL. Median whole-body SSR-E MTV was calculated as 37.2 cm3 and median SSR-E TLV was calculated 198.6 cm3. There was a significantly positive correlation between TSH and whole-body SSR-E MTV and SSR-E TLV (rho=0.739, p<0.001 and rho=0.595, p=0.006). In the linear regression analysis, only calcitonin was found as a significant factor in terms of correlated with for SSR-E MTV (p<0.001). there were found that calcitonin and TSH were statistically significant factors in terms of correlated with SSR-E TLV (p<0.001 and p=0.005, respectively). Conclusion: This is the first study shown that a positive correlation between TSH and SSR-E MTV in patients with advanced medullary thyroid cancer. [ABSTRACT FROM AUTHOR]

The early detection of procalcitonin (PCT) is crucial for diagnosing bacterial infections due to its high sensitivity and specificity. While colloidal gold colorimetric and immune-chemiluminescence methods are commonly employed in clinical detection, the former lacks sensitivity, and the latter faces challenges with a brief luminescence process and an elevated background. Here, we introduce a novel approach for the quantitative analysis of PCT using surface-enhanced Raman spectroscopy (SERS), leveraging the enhanced properties of metal nanoparticles. Simultaneously, we employed a magnetic nanoparticle coating and surface biofunctionalization modification to immobilize PCT-trapping antibodies, creating the required immune substrates. The resulting magnetic nanoparticles and antibody complexes, acting as carriers and recognition units, exhibited superparamagnetism and the specific recognition of biomarkers. Then, this complex efficiently underwent magnetic separation with an applied magnetic field, streamlining the cumbersome steps of traditional ELISA and significantly reducing the detection time. In conclusion, the exploration of immunomagnetic bead detection technology based on surface-enhanced Raman spectroscopy holds crucial practical significance for the sensitive detection of PCT. [ABSTRACT FROM AUTHOR]

Diabetic Foot Ulcers (DFUs) are a major complication of diabetes, often leading to amputation. Understanding the relationship between haematological inflammatory markers and the incidence of amputation in DFU patients with infectious complications is crucial for improving management and outcomes. This retrospective study, conducted from May 2020 to October 2022, involved 109 patients with DFUs, categorised into amputation (AM) and non‐amputation (NAM) groups. Patients were evaluated for various factors, including demographic data, DFU duration, and blood parameters such as haemoglobin A1c (HbA1c), haemoglobin (Hb), albumin (ALB), white blood cell count (WBC), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), C‐reactive protein (CRP), platelet‐to‐lymphocyte ratio (PLR), neutrophil‐to‐lymphocyte ratio (NLR), and lymphocyte‐to‐monocyte ratio (LMR). Statistical analyses were performed using independent sample t‐tests, Mann–Whitney U test and logistic regression. The univariate analysis showed no significant difference in BMI, DM duration or DFU duration between groups. However, significant differences were noted in PCT, Hb, ESR, ALB, HbA1c and WBC levels, and in inflammatory ratios (NLR, PLR and LMR). Multivariate logistic regression identified CRP, NLR and PLR as independent risk factors for amputation. The study highlights CRP, PLR and NLR as key independent risk factors for amputation in patients with DFUs. These easily obtainable markers from routine blood tests can effectively aid in predicting the risk of osteomyelitis and amputation, enhancing clinical decision making and patient care strategies. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess a potential organ protective effect of volatile sedation in a scenario of severe inflammation with an early cytokine storm (in particular IL-6 elevation) in patients suffering from COVID-19-related lung injury with invasive mechanical ventilation and sedation. Methods: This is a small-scale pilot multicenter randomized controlled trial from four tertiary hospitals in Switzerland, conducted between April 2020 and May 2021. 60 patients requiring mechanical ventilation due to severe COVID-19-related lung injury were included and randomized to 48-hour sedation with sevoflurane vs. continuous intravenous sedation (= control) within 24 h after intubation. The primary composite outcome was determined as mortality or persistent organ dysfunction (POD), defined as the need for mechanical ventilation, vasopressors, or renal replacement therapy at day 28. Secondary outcomes were the length of ICU and hospital stay, adverse events, routine laboratory parameters (creatinine, urea), and plasma inflammatory mediators. Results: 28 patients were randomized to sevoflurane, 32 to the control arm. The intention-to-treat analysis revealed no difference in the primary endpoint with 11 (39%) sevoflurane and 13 (41%) control patients (p = 0.916) reaching the primary outcome. Five patients died within 28 days in each group (16% vs. 18%, p = 0.817). Of the 28-day survivors, 6 (26%) and 8 (30%) presented with POD (p = 0.781). There was a significant difference regarding the need for vasopressors (1 (4%) patient in the sevoflurane arm, 7 (26%) in the control one (p = 0.028)). Length of ICU stay, hospital stay, and registered adverse events within 28 days were comparable, except for acute kidney injury (AKI), with 11 (39%) sevoflurane vs. 2 (6%) control patients (p = 0.001). The blood levels of IL-6 in the first few days after the onset of the lung injury were less distinctly elevated than expected. Conclusions: No evident benefits were observed with short sevoflurane sedation on mortality and POD. Unexpectedly low blood levels of IL-6 might indicate a moderate injury with therefore limited improvement options of sevoflurane. Acute renal issues suggest caution in using sevoflurane for sedation in COVID-19. Trial registration: The trial was registered on ClinicalTrials.gov (NCT04355962) on 2020/04/21. [ABSTRACT FROM AUTHOR]

To investigate the incidence, characteristics and risk factors for hypoactive delirium in patients with nontraumatic acute respiratory distress syndrome (ARDS) and to explore the independent risk factors associated with hypoactive delirium and provide new ideas for early prediction and treatment. Hypoactive delirium is a known serious complication in ARDS patients, and currently, there are no effective early detection models or clinical prediction tools, and there is a lack of clinical treatment. This study included nontraumatic ARDS patients who stayed in the intensive care unit (ICU) for more than 24 h and were older than 18 years. A total of 205 ARDS patients admitted to the ICU of Gansu Provincial People's Hospital between December 2021 and February 2023 were selected. Demographic data, clinical characteristics and laboratory test results were collected within 24 h after the patients entered the ICU. Multivariate logistic regression analysis was used to investigate risk factors, evaluate the clinical prediction effect of the model and construct a nomogram for visual display. The incidence of hypoactive delirium among the patients included in the study was 41%. Patients with hypoactive delirium had hypertension; diabetes mellitus; Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ≥ 15; and increased procalcitonin, C-reactive protein (CRP), lactic dehydrogenase and interleukin-6 (IL-6) levels compared with those without hypoactive delirium. Logistic regression analysis revealed that diabetes mellitus (OR 3.305, 95% CI: 1.866–12.616; p = 0.047), CRP level (OR 1.002, 95% CI: 1.001–1.023; p = 0.044), and IL-6 level (OR 1.045, 95% CI: 1.017–1.063; p = 0.001) were independent risk factors for hypoactive delirium. After receiver operating characteristic (ROC) curve analysis, calibration plot and decision curve analysis (DCA) confirmed that the clinical prediction ability of this study model was satisfactory, and a nomogram was drawn for visual display. Hypoactive delirium is a common serious complication in nontraumatic ARDS patients. Our logistic regression model not only effectively predicts hypoactive delirium early but also reveals potential clinical therapeutic targets. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder affecting women in their reproductive years. Emerging evidence suggests that the maternal-fetal immune system is crucial for proper pregnancy. However, whether immune function is altered at the end of pregnancy in PCOS women and the underlying molecular mechanisms is currently unexplored. Herein, the basic maternal immune system was investigated (n = 136 in the control group; n = 103 in the PCOS group), and whole-transcriptome sequencing was carried out to quantify the mRNAs, miRNAs, and lncRNAs expression levels in fetal side placental tissue of women with PCOS. GO, KEGG, and GSEA analysis were employed for functional enrichment analysis. The process of identifying hub genes was conducted utilizing the protein-protein interaction network. CIBERSORT and Connectivity Map were deployed to determine immune cell infiltration and predict potential drugs, respectively. A network of mRNA-miRNA-lncRNA was constructed and then validated by qRT-PCR. First, red blood cell count, neutrophil count, lymphocyte count, hypersensitive C-reactive protein, and procalcitonin were significantly elevated, while placental growth factor was hindered in PCOS women. We identified 308 DEmRNAs, 77 DEmiRNAs, and 332 DElncRNAs in PCOS samples. Functional enrichment analysis revealed that there were significant changes observed in terms of the immune system, especially the chemokine pathway. Eight genes, including FOS, JUN, EGR1, CXCL10, CXCR1, CXCR2, CXCL11, and CXCL8, were considered as hub genes. Furthermore, the degree of infiltration of neutrophils was dramatically decreased in PCOS tissues. In total, 57 ceRNA events were finally obtained, and immune-related ceRNA networks were validated. Some potential drug candidates, such as enalapril and RS-100329, could have a function in PCOS therapy. This study represents the inaugural attempt to evaluate the immune system at the end of pregnancy and placental ceRNA networks in PCOS, indicating alterations in the chemokine pathway, which may impact fetal and placental growth, and provides new therapy targets. [ABSTRACT FROM AUTHOR]

Over the last years non-alcoholic fatty liver disease (NAFLD) has grown into the most common chronic liver disease globally, affecting 17-38% of the general population and 50-75% of patients with obesity and/or type 2 diabetes mellitus (T2DM). NAFLD encompasses a spectrum of chronic liver diseases, ranging from simple steatosis (non-alcoholic fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH; or metabolic dysfunction-associated steatohepatitis, MASH) to fibrosis and cirrhosis with liver failure or/and hepatocellular carcinoma. Due to its increasing prevalence and associated morbidity and mortality, the disease-related and broader socioeconomic burden of NAFLD is substantial. Of note, currently there is no globally approved pharmacotherapy for NAFLD. Similar to NAFLD, osteoporosis constitutes also a silent disease, until an osteoporotic fracture occurs, which poses a markedly significant disease and socioeconomic burden. Increasing emerging data have recently highlighted links between NAFLD and osteoporosis, linking the pathogenesis of NAFLD with the process of bone remodeling. However, clinical studies are still limited demonstrating this associative relationship, while more evidence is needed towards discovering potential causative links. Since these two chronic diseases frequently co-exist, there are data suggesting that anti-osteoporosis treatments may affect NAFLD progression by impacting on its pathogenetic mechanisms. In the present review, we present on overview of the current understanding of the liver-bone cross talk and summarize the experimental and clinical evidence correlating NAFLD and osteoporosis, focusing on the possible effects of antiosteoporotic drugs on NAFLD. [ABSTRACT FROM AUTHOR]

Background: Urinary tract infections (UTIs) are a leading bacterial infection in the emergency department (ED). Diagnosing UTIs in the ED can be challenging due to the heterogeneous presentation; therefore, fast and precise tests are needed. We aimed to evaluate the diagnostic precision of procalcitonin (PCT), soluble urokinase plasminogen activator receptors (suPARs), and C-reactive protein (CRP) in diagnosing UTIs, grading the severity of UTIs, and ruling out bacteremia. Methods: We recruited adults admitted to three Danish EDs with suspected UTIs. PCT, suPAR, and CRP were used in index tests, while blood cultures, expert panel diagnosis, and severity grading were used in the reference tests. Logistic regression and area under the receiver operator characteristic curves (AUROCs) were utilized to evaluate the models and determine the optimal cut-offs. Results: We enrolled 229 patients. PCT diagnosed UTI with an AUROC of 0.612, detected severe disease with an AUROC of 0.712, and ruled out bacteremia with an AUROC of 0.777. SuPAR had AUROCs of 0.480, 0.638, and 0.605, while CRP had AUROCs of 0.599, 0.778, and 0.646. Conclusions: The diagnostic performance of PCT, suPAR, or CRP for UTIs or to rule out severe disease was poor. However, PCT can safely rule out bacteremia in clinically relevant numbers in ED patients suspected of UTI. [ABSTRACT FROM AUTHOR]

Background: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have greatly changed migraine treatment options. In Japan, although CGRPmAb guidelines (≥ 4 monthly migraine days (MMDs) and ≥ 1 previous preventive failure) are well-acknowledged, the actual use of CGRPmAbs and the circumstances of the related headache care are unknown. Methods: We conducted an online survey of Japanese Headache Society members, inquiring about the physicians' experience with CGRPmAbs and how they make decisions related to their use. Results: Of the 397 respondents, 320 had prescribed CGRPmAbs. The threshold number of previous preventive failures for recommending a CGRPmAb was two for the majority of the respondents (n = 170, 54.5%), followed by one (n = 64, 20.5%). The MMD threshold was ≥ 4 for 71 respondents (22.8%), ≥ 6 for 68 (21.8%), ≥ 8 for 76 (24.4%), and ≥ 10 for 81 (26.0%). The respondents tended to assess treatment efficacy after 3 months (episodic migraine: n = 217, 69.6%, chronic migraine: n = 188, 60.3%). The cost of CGRPmAbs was described by many respondents in two questions: (i) any request for a CGRPmAb (27.7%), and (ii) the most frequently reported reason for responders to discontinue CGRPmAbs (24.4%). Conclusions: Most of the respondents recommended CGRPmAbs to patients with ≥ 2 preventive failures, followed by ≥ 1. The MMD threshold ranged mostly from ≥ 4 to ≥ 10. The concern for costs was raised as a major limiting factor for prescribing CGRPmAbs. [ABSTRACT FROM AUTHOR]

Background: The upper cervical dorsal root ganglia (DRG) are important for the transmission of sensory information associated with the back of the head and neck, contributing to head pain. Calcitonin receptor (CTR)-based receptors, such as the amylin 1 (AMY1) receptor, and ligands, calcitonin gene-related peptide (CGRP) and amylin, have been linked to migraine and pain. However, the contribution of this system to nociception involving the cervical DRG is unclear. Therefore, this study aimed to determine the relative distribution of the CTR, CGRP, and amylin in upper cervical DRG. Methods: CTR, CGRP, and amylin immunofluorescence was examined relative to neural markers in C1/2 DRG from male and female mice, rats, and human cases. Immunofluorescence was supported by RNA-fluorescence in situ hybridization examining amylin mRNA distribution in rat DRG. Results: Amylin immunofluorescence was observed in neuronal soma and fibres. Amylin mRNA (Iapp) was also detected. Amylin and CGRP co-expression was observed in 19% (mouse), 17% (rat), and 36% (human) of DRG neurons in distinct vesicle-like neuronal puncta from one another. CTR immunoreactivity was present in DRG neurons, and both peptides produced receptor signalling in primary DRG cell cultures. CTR-positive neurons frequently co-expressed amylin and/or CGRP (66% rat; 84% human), with some sex differences. Conclusions: Amylin and CGRP could both be local peptide agonists for CTR-based receptors in upper cervical DRG, potentially acting through autocrine and/or paracrine signalling mechanisms to modulate neuron function. Amylin and its receptors could represent novel pain targets. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a malignancy of bad prognosis, and advances in early detection and treatment are needed. GBM is heterogenous, with varieties differing in malignancy within a tumor of a patient and between patients. Means are needed to distinguish these GMB forms, so that specific strategies can be deployed for patient management. We study the participation of the chaperone system (CS) in carcinogenesis. The CS is dynamic, with its members moving around the body in extracellular vesicles (EVs) and interacting with components of other physiological systems in health and disease, including GBM. Here, we describe the finding of high amounts of Hsp70 (HSPA1A) and the calcitonin receptor protein (CTR) in EVs in patients with GBM. We present a standardized protocol for collecting, purifying, and characterizing EVs carrying Hsp70 and CTR in plasma-derived EVs from patients with GBM. EVs from GBM patients were obtained just before tumor ablative surgery (T0) and 7 days afterwards (T1); Hsp70 was highly elevated at T0 and less so at T1, and CTR was greatly increased at T0 and reduced to below normal values at T1. Our results encourage further research to assess Hsp70 and CTR as biomarkers for differentiating tumor forms and to determine their roles in GBM carcinogenesis. [ABSTRACT FROM AUTHOR]

Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes. Plain Language Summary: Impact of peptides from the gut on bone health in obesity and diabetes mellitus Obesity and related type 2 diabetes (T2D) are prevalent diseases. Unfortunately, there is now a clear link between obesity and related T2D and poor bone health, leading to increased bone fracture risk. However, we know that peptides derived from the gut following a meal can possess positive effects on bone health and reduce bone fracture risk. These peptides are called glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). Moreover, some of these peptides, GLP-1 and GIP, are already being used to treat obesity and T2D, whilst GLP-2 is used to treat people with short bowel syndrome. In other words, drugs that mimic the action of GLP-1, GLP-2 and GIP are available for human use. This current review article aims to provide an initial appraisal of the relationship between obesity, diabetes and bone health, with a focus on the positive impact of peptide hormones like GLP-1, GLP-2 and GIP for bone health in obesity/diabetes. The take home message is that drugs engineered to promote GIP, GLP-1 and GLP-2 action may have potential to offer therapeutic promise for improving bone health in obesity and diabetes. [ABSTRACT FROM AUTHOR]

Background: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene–related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. Methods: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). Results: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. Conclusions: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. Trial registration: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309). [ABSTRACT FROM AUTHOR]

Background: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. Methods: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. Results: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. Conclusions: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine. [ABSTRACT FROM AUTHOR]