Incidence Of Elevation Research Articles

Serum creatine kinase elevation following tyrosine kinase inhibitor treatment in cancer patients: Symptoms, mechanism, and clinical management.

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.

Mechanisms leading to peri-procedural myocardial infarction in patients with focal versus diffuse coronary artery disease

Abstract Background PMI are characterized by an elevation in cardiac biomarkers, such as troponin, following PCI. Adherence to the 4th UDMIof PMI necessitates not only elevated cardiac biomarkers but also the presence of ECG changes, new loss of viable myocardium, or angiographic findings indicative of a procedural complication. Understanding the mechanisms underlying PMI and their associated factors is of paramount clinical significance. Our goal was to investigate the specific pathways contributing to the occurrence of PMI in stable patients undergoing PCI. Methods This prospective study was performed at 23 sites and enrolled patients with at least one epicardial lesion with an FFR≤0.80 planned to be treated by PCI. Each patient underwent a standardized physiological protocol, including manual FFR pullbacks with PPG calculation for the characterization of CAD patterns. The median PPG value (0.62) was used to divide patients into predominantly focal or diffuse disease. Troponin levels were measured after PCI, and patients exhibiting an elevation exceeding 5 times the upper limit of normal (ULN) were subject to evaluation by an independent clinical events committee. In addition, patients with large troponin elevation (>70 times above the ULN) were adjudicated as PMI as a standalone criterion. The primary objective was to investigate the mechanism leading to PMI in patients with focal versus diffuse CAD. Results Overall, 855 patients were included in this analysis, with 34.5% (295 patients) exhibiting a troponin elevation exceeding 5 times the ULN. Among these cases, 66 (7.7%) were adjudicated as PMI. The prevalence of secondary criteria for PMI was as follows: ECG changes at 7.6% (5/66), new loss of viable myocardium at 0%, side branch occlusion at 18.2% (12/66), and large troponin elevation at 84.8% (56/66). Diffuse disease (PPG < 0.62) was significantly associated with PMI (OR 1.71, 95% CI 1.03 to 2.88, p-value = 0.038). In the overall population, the occurrence of ECG changes after PCI was 0.7% in focal disease compared to 0.8% in diffuse disease (p-value=1.0). Side branch occlusion after PCI was observed in 0.7% in focal disease vs. 2.5% in diffuse disease (p-value=0.04), and large troponin elevation occurred in 4.8% in focal disease vs. 8.5% in diffuse disease (p-value=0.03). Additionally, PPG was significantly associated with the incidence of side branch occlusion (OR 1.71, 95% CI 1.03 to 2.88, p-value=0.038) and large troponin elevation after PCI (OR 1.83, 95% CI 1.06 to 3.22, p-value=0.038). Conclusion The presence of diffuse atherosclerosis, as defined by PPG, was linked to an increased risk of PMI. The mechanisms leading to PMI differed between patients with focal and diffuse disease. Patients with diffuse disease demonstrated a higher incidence of branch occlusion and large troponin elevation following PCI compared to those with focal CAD. Targeting patients with high PPG may improve outcomes after PCI.MACE by PPG

Reduction in the risk of contrast-induced nephropathy using enhanced external counter-pulsation in patients with chronic kidney disease

Objective To evaluate the efficacy of EECP in the prevention of contrast-induced nephropathy (CIN) in patients with chronic kidney disease (CKD). Methods A prospective trial was undertaken in the participants. A total of 280 patients with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2 who underwent percutaneous coronary artery procedures were enrolled and divided into two groups: the control group (n = 100) and the EECP group (n = 180). All patients received extracellular fluid volume expansion therapy with 0.9% normal saline, and patients in the EECP groups were also treated with EECP. The renal function indexes of the two groups were determined 48–72 h after coronary artery procedures. Results In the EECP group, the BUN and serum creatinine (Scr) after coronary artery procedures were significantly lower than those before coronary artery procedures (BUN: 8.4 ± 3.5 vs. 6.6 ± 2.7 mmol/L, p < 0.001; Scr: 151.9 ± 44.7 vs. 144.5 ± 48.3 μmol/L, p < 0.001), while the eGFR was significantly increased (43.6 ± 11.4 vs. 47.1 ± 13.9 ml/min/1.73 m2, p < 0.001). The degree of Scr elevation was lower in the EECP group than in the control group (12.4 ± 15.0 vs. 20.9 ± 24.8 μmol/L, p = 0.026). Additionally, the EECP group had a lower incidence of post-procedures Scr elevation than the control group (36.5 vs. 48.0%, p = 0.042), a higher incidence of post-procedures eGFR elevation (62.2 vs. 48.0%, p = 0.021), and a lower risk of CIN (1.1 vs. 6.0%, p = 0.019). Conclusion EECP therapy has a protective effect on renal function and can reduce the risk of CIN in patients with CKD.

An evaluation of the empirical vancomycin dosing guide in pediatric cardiology

BackgroundHigher doses of vancomycin are currently prescribed due to the emergence of bacterial tolerance and resistance. This study aimed to evaluate the efficacy and safety of the currently adopted vancomycin dosing guide in pediatric cardiology.MethodsThis was a single-center prospective cohort study with pediatric cardiac patients, younger than 14 years, from June 2020 to March 2021. The patients received intravenous vancomycin (40 mg/kg/day divided every 6–8 h) according to the department’s vancomycin medication administration guide (MAG) for at least three days.ResultsIn total, 88 cardiac patients were included, with a median age of 0.82 years (IQR: 0.25–2.9), and 51 (58%) received cardiopulmonary bypass surgery (CPB). The majority (71.6%, n = 61) achieved a serum vancomycin level within the therapeutic range (7–20 mg/L). Infants, young children, and children exposed to CPB surgery had an increased incidence of subtherapeutic vancomycin levels, [7 (29.2%); P = 0.033], [13 (54.2%); P = 0.01], and [21 (87.5%); P = 0.009] respectively. After the treatment, 8 (10%) patients had an elevated Serum creatinine (SCr) and 2 (2.5%) developed acute kidney injury (AKI). However, no significant difference was found between the patients developing AKI or an elevated SCr and the group who did not, in terms of clinical, therapeutic, and demographic characteristics, except for the decreased incidence of SCr elevation in patients receiving an ACE inhibitor, [4 (36.4%); P = 0.036].ConclusionOur institution followed MAG recommendations; however, subtherapeutic serum concentrations were evident in infants, young children, and CPB patients. Strategies to prevent AKI should be investigated, as the possible causes have not been identified in this study.

A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed/Refractory Hematologic Malignancies.

AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity. The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors. Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.

Norepinephrine mediates heart block during severe hypoglycemia in male rats.

Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia-induced fatal cardiac arrhythmias. To test this hypothesis, adult, non-diabetic Sprague-Dawley rats were subjected to hyperinsulinemic-severe hypoglycemic clamps (3 h, 10-15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5-fold increase in third-degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third-degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia.

Clinical Effectiveness of Drug-Eluting Microsphere Transcatheter Arterial Chemoembolization Combined with First-Line Chemotherapy as the Initial Treatment for Patients with Unresectable Intrahepatic Cholangiocarcinoma

PurposeTo evaluate the safety and effectiveness of the combination of drug-eluting microsphere (DEM) transcatheter arterial chemoembolization (TACE) with those of chemotherapy in treating unresectable intrahepatic cholangiocarcinoma (ICC). Materials and MethodsSeventy patients diagnosed with unresectable ICC between January 2016 and December 2020 were retrospectively included in this study. Of these, 39 patients received DEM-TACE and first-line chemotherapy (TACE+Chemo group) and 31 received chemotherapy alone (Chemo group). Propensity score matching was performed to reduce selection bias between the TACE+Chemo and the Chemo groups. Differences in tumor response, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between 2 groups. ResultsThe patients in the TACE+Chemo group had better median OS (18.6 vs 11.9 months; P = .018), median PFS (11.9 vs 6.9 months, P = .033), and objective response rates (56.8% vs 13.3%; P < .001) than those in the Chemo group. TRAEs showed a higher incidence of transient elevation of transaminase and abdominal pain in the TACE+Chemo group than in the Chemo group (P < .001). ConclusionsCompared with chemotherapy alone, DEM-TACE combined with first-line chemotherapy may be a viable and safe treatment option for unresectable ICC.

Close Cardiovascular Monitoring during the Early Stages of Treatment for Patients Receiving Immune Checkpoint Inhibitors.

Background: There is an unmet medical need for the early detection of immune checkpoint inhibitor (ICI)-induced cardiovascular (CV) adverse events due to a lack of adequate biomarkers. This study aimed to provide insights on the incidence of troponin elevations and echocardiographic dynamics during ICI treatment in cancer patients and their role as potential biomarkers for submyocardial damage. In addition, it is the first study to compare hs-TnT and hs-TnI in ICI-treated patients and to evaluate their interchangeability in the context of screening. Results: Among 59 patients, the mean patient age was 68 years, and 76% were men. Overall, 25% of patients received combination therapy. Although 10.6% [95% CI: 5.0-22.5] of the patients developed troponin elevations, none experienced a CV event. No significant changes were found in 3D left ventricular (LV) ejection fraction nor in global longitudinal strain f (56 ± 6% vs. 56 ± 6%, p = 0.903 and -17.8% [-18.5; -14.2] vs. -17.0% [-18.8; -15.1], p = 0.663) at 3 months. There were also no significant changes in diastolic function and right ventricular function. In addition, there was poor agreement between hs-TnT and hs-TnI. Methods: Here, we present a preliminary analysis of the first 59 patients included in our ongoing prospective clinical trial (NCT05699915) during the first three months of treatment. All patients underwent electrocardiography and echocardiography along with blood sampling at standardized time intervals. This study aimed to investigate the incidence of elevated hs-TnT levels within the first three months of ICI treatment. Elevations were defined as hs-TnT above the upper limit of normal (ULN) if the baseline value was normal, or 1.5 ≥ times baseline if the baseline value was above the ULN. Conclusions: Hs-TnT elevations occurred in 10.6% of the patients. However, no significant changes were found on 3D echocardiography, nor did any of the patients develop a CV event. There were also no changes found in NT-proBNP. The study is still ongoing, but these preliminary findings do not show a promising role for cardiac troponins nor for echocardiographic dynamics in the prediction of CV events during the early stages of ICI treatment.

A Prospective, Randomized, Controlled Clinical Investigation Comparing the Efficacy and Safety of Sodium Hyaluronate-Based Ophthalmical Viscosurgical Devices FIDIAL PLUS and IAL®-F in Cataract Surgery.

Purpose: To protect the corneal endothelium, various ophthalmical viscoelastic devices (OVDs) are used during cataract surgery. In this study, we compared two sodium hyaluronate-based OVD, the bacteria-derived FIDIAL PLUS OVD (test) with the animal-derived IAL®-F OVD (reference) during the surgical procedure. Methods: Fifty patients with bilateral cataract participated in the study: 50 eyes randomly received FIDIAL PLUS and 50 eyes received IAL®-F (ratio 1:1). Noninferior efficacy of FIDIAL PLUS compared with reference OVD (first objective) was evaluated using a paired t-test comparing the mean percent loss of corneal endothelial cells (CECs) with FIDIAL PLUS against the mean percent loss with IAL®-F. Corneal endothelial protection during cataract surgery with FIDIAL PLUS without significant (≥30 mmHg) postoperative intraocular pressure (IOP) increase (main secondary objective) was assessed using a repeated measures logistic model comparing the incidence of significant postoperative IOP elevation between the two groups. Safety, tolerability, and efficacy were also evaluated by assessing secondary endpoints before and after surgery. Results: FIDIAL PLUS showed a statistically noninferior efficacy compared with IAL®-F; there was no significant increase in IOP in either group or different trends of the secondary endpoints were observed between the OVD groups. The safety profile was similar in both OVD groups and no adverse device effects were reported. Conclusions: This study demonstrates the equivalent efficacy, tolerability, and safety of the bacteria-derived FIDIAL PLUS compared with the animal-derived IAL®-F, confirming the clinical value of this product.

Medication use evaluation of tocilizumab implementation in COVID-19 treatment guidelines: A causal inference approach.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Introduction of new medications to health-system formularies is often not accompanied by assessments of their clinical impact on the local patient population. The growing availability of electronic health record (EHR) data and advancements in pharmacoepidemiology methods offer institutions the opportunity to monitor the medication implementation process and assess clinical effectiveness in the local clinical context. In this study, we applied novel causal inference methods to evaluate the effects of a formulary policy introducing tocilizumab therapy for critically ill patients with coronavirus disease 2019 (COVID-19). We conducted a medication use evaluation utilizing EHR data from patients admitted to a large medical center during the 6 months before and after implementation of a formulary policy endorsing the use of tocilizumab for treatment of COVID-19. The impact of tocilizumab on 28-day all-cause mortality was assessed using a difference-in-differences analysis, with ineligible patients serving as a nonequivalent control group, and a matched analysis guided by a target trial emulation framework. Safety endpoints assessed included the incidence of secondary infections and liver enzyme elevations. Our findings were benchmarked against clinical trials, an observational study, and a meta-analysis. Following guideline modification, tocilizumab was administered to 69% of eligible patients. This implementation was associated with a 3.1% absolute risk reduction in 28-day mortality (odds ratio, 0.86; number needed to treat to prevent one death, 32) attributable to the inclusion of tocilizumab in the guidelines and an additional 8.6% absolute risk reduction (odds ratio, 0.65; number needed to treat to prevent one death, 12) linked to its administration. These findings were consistent with estimates from published literature, although the effect estimates from the difference-in-differences analysis exhibited imprecision. Evaluating formulary management decisions through novel causal inference approaches offers valuable estimates of clinical effectiveness and the potential to optimize the impact of new medications on population outcomes.

Evaluation of cyclin-dependent kinase 4/6 inhibitor-induced serum creatinine elevations in patients with hormone receptor positive breast cancer.

e23304 Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have improved the efficacy of endocrine therapy in hormone receptor-positive (HR+)/HER2- breast cancer (BC) and are now used in both early-stage and metastatic disease. In the MONARCH-3 trial, 98% of patients (pts) treated with abemaciclib (abema) experienced elevated serum creatinine (sCr). Chappell et al. reported that abema caused pseudo-elevation in sCr by inhibiting renal tubular secretion. This effect was not evaluated in trials of palbociclib (palbo) and ribociclib (ribo), but case reports suggest that pseudo-sCr elevations are likely a class effect of CDK 4/6i. In this retrospective study, we sought to evaluate the incidence of sCr elevation in pts being treated with CDK4/6i for early and advanced stage BC. Methods: This single-center retrospective analysis included pts aged ≥18 years who received at least one dose of palbo, ribo, or abema for the treatment (tx) of HR+/HER2- BC in the early or advanced setting at the University of Chicago Medicine from January 2015 to August 2023. Pts were categorized into subgroups based on the CDK4/6i received. The primary objective was to evaluate the incidence of pseudo-sCr elevation in the subgroups. sCr elevation was graded according to Common Terminology Criteria for Adverse Events Version 5. CDK4/6i-induced pseudo-sCr elevation was suspected when the sCr elevation could not be fully explained by other causes. Secondary endpoints included the grade, onset, duration, and clinical consequences of pseudo-sCr elevation. Incidence of pseudo-sCr elevation among the three groups were compared using the Chi-squared test. Descriptive statistics were used for pt characteristics and secondary endpoints. Results: In total, 143 pts were analyzed. Pseudo-sCr elevation was suspected in pts treated with palbo, ribo, and abema, with incidences of 16% (8/50), 14% (6/43), and 20% (10/50), respectively. Rates did not significantly differ between agents (p = 0.727). Among pts with CDK4/6i-induced pseudo-sCr elevation, all pts experienced either grade 1 (8.3%) or 2 (91.7%) events, with a median sCr increase from baseline to peak of 0.69 mg/dL (range, 0.39 – 2.9 mg/dL). The median onset from tx initiation to first sCr elevation was 33.5, 42, and 21.5 days, for palbo, ribo, and abema, respectively. Based on available data at study cutoff, 13 of the 24 pts with suspected pseudo-sCr elevation were still on tx with continued sCr elevation. Nine of 24 pts were no longer on CDK4/6i tx; none due to sCr elevation. Three of the 9 pts had sCr returned to baseline within 3 months of tx discontinuation. Conclusions: Pseudo-sCr elevation appears to be a class effect of CDK4/6i, with similar rates of sCr elevation observed across the three CDK4/6i currently FDA approved. Further analyses evaluating differences by age, race, and stage are ongoing.

Postoperative liver injury after sevoflurane or propofol anesthesia in patients undergoing non-cardiac surgery: a retrospective cohort study

Although sevoflurane is generally considered safe, reports suggest that sevoflurane may cause postoperative liver injury more frequently than previously believed. Therefore, we aimed to compare the incidence of clinically significant postoperative liver injury following non-cardiac surgery between patients who underwent sevoflurane anesthesia and propofol-based total intravenous anesthesia. We retrospectively reviewed adult surgical patients from January 2010 to September 2022 who underwent general anesthesia in our center using sevoflurane or propofol over 3 h. After 1:1 propensity score matching, the incidence of postoperative liver injury was compared between the two groups. Out of 58,300 patients reviewed, 44,345 patients were included in the analysis. After propensity score matching, 7767 patients were included in each group. The incidence of postoperative liver injury was 1.4% in the sevoflurane group, which was similar to that in the propofol group (1.6%; p = 0.432). Comparison of the severity of postoperative alanine aminotransferase elevation showed that the incidence of borderline and mild elevation was higher in the sevoflurane group, but there was no difference in the incidence of moderate and severe elevation. In conclusion, sevoflurane anesthesia over 3 h was not associated with a higher incidence of clinically significant postoperative liver injury compared to propofol anesthesia.

Can COVID-19 Increase Platelet in Adult Immune Thrombocytopenia During the TPO-RA Administration? A Real-World Observational Study.

COVID-19 infection has brought new challenges to the treatment of adult patients with immune thrombocytopenia (ITP). In adult ITP patients, there have been no relevant reports exploring the incidence, clinical characteristics, and risk factors of platelet elevation after COVID-19 infection. A total of 66 patients with previously diagnosed ITP from December 2022 to February 2023 in a single-center were collected and analyzed for this real-world clinical retrospective observational study. In the platelet count increased group (n = 19), 13 patients (68.4%) were using thrombopoietin receptor agonists (TPO-RA) treatment at the time of COVID-19 infection; the median platelet count was 52 (2-207) ×109/L at the last visit before infection and 108 (19-453) ×109/L at the first visit after infection. In the platelet count stable group (n = 19) and platelet count decreased group (n = 28), 9 (47.4%) and 8 (28.6%) patients were using TPO-RA at the time of infection, respectively. ITP patients treated with TPO-RA had a significantly higher risk of increased platelet count than those not treated with TPO-RA at the time of infection (platelet count increased group vs platelet count decreased group: OR: 5.745, p = 0.009; platelet count increased group vs the non-increased group: OR: 3.616, p = 0.031). In the platelet count increased group, the median platelet count at 6 months post-infection was 67 (14-235) × 109/L, which was significantly higher than the platelet level at the last visit before infection (p = 0.040). This study showed that some adult ITP patients had an increase in platelet count after COVID-19 infection, and this phenomenon was strongly associated with the use of TPO-RA at the time of infection. Although no thrombotic events were observed in this study, it reminds clinicians that they should be alert to the possibility of thrombotic events in the long-term management of adult ITP patients during the COVID-19 pandemic.

Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. This study provides Class II evidence that among adults with active RRMS and≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

Bimekizumab safety in moderate to severe plaque psoriasis: Rates of hepatic events and changes in liver parameters over 2 years in randomized phase 3/3b trials

Patients with psoriasis are at increased risk of liver function abnormalities. Explore rates of hepatic treatment-emergent adverse events (TEAEs) and changes in liver parameters in bimekizumab-treated patients with psoriasis. Data are reported from 5 phase 3/3b trials over 2years. Hepatic TEAEs, laboratory elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), and changes in clinical markers of liver fibrosis (Fibrosis-4 [FIB-4] Index and AST to Platelet Ratio Index [APRI]) are reported. TEAEs are presented using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). 2186 patients received ≥1 bimekizumab dose. Over 2years, the EAIR of hepatic TEAEs was 3.5/100 PY and did not increase from first to second year. 2-year EAIRs of ALT/AST elevations >3x and >5x the upper limit of normal were 2.3 and 0.6/100 PY; rates were similar to placebo, adalimumab, secukinumab, and ustekinumab during controlled study periods. FIB-4 and APRI scores did not increase through 2years, regardless of fibrosis risk at baseline. Obesity, diabetes, dyslipidemia, chronic alcohol consumption, and medication changes are confounding factors for hepatic dysfunction. Rates of hepatic adverse events (AEs) with bimekizumab were consistent through 2years; incidences of transaminase elevations were similar to comparators during phase 3/3b controlled study periods.

Comparison of efficacy and safety between daptomycin plus β-lactam and daptomycin monotherapy for bloodstream infections due to gram-positive cocci: A systematic review and meta-analysis

ObjectivesWe performed a comprehensive systematic review and meta-analysis to evaluate the clinical or microbiological outcomes and safety of a combination of daptomycin (DAP) and β-lactams compared to DAP monotherapy in patients with blood stream infection (BSI) due to gram-positive cocci (GPC). MethodsWe searched Scopus, PubMed, EMBASE, CINAHL, and Ityuushi databases up to January 30, 2023. Outcomes included all-cause mortality, clinical failure, and creatine phosphokinase (CPK) elevation. ResultsSix cohorts or case-control studies fulfilled the inclusion criteria and were included in the final meta-analysis. Combination therapy of DAP and β-lactams significantly reduced the mortality and clinical failure rate for all BSI due to GPC compared with the DAP monotherapy (mortality, odds ratio [OR] = 0.63, 95 % confidence interval [CI] = 0.41–0.98; clinical failure, OR = 0.42, 95 % CI = 0.22–0.81). In contrast, no significant difference was noted in the incidence of CPK elevation between the two groups (OR = 0.85, 95 % CI = 0.39–1.84). ConclusionAltogether, combination therapy of DAP and β-lactams can improve the prognosis for patients with BSI due to GPC compared with DAP alone. Therefore, it should be considered as an option for the empirical treatment of BSI caused by GPC.

Creatine kinase elevation in chronic hepatitis B patients with telbivudine therapy: influence of telbivudine plasma concentration and single nucleotide polymorphisms of TK2, RRM2B, and NME4.

To study the correlations of genetic variants of telbivudine phosphorylase kinases and telbivudine plasma concentration with creatine kinase elevation in chronic hepatitis B patients who received telbivudine. An observational study was performed in China chronic hepatitis B patients receiving telbivudine therapy at 600mg once daily. Plasma concentration was measured 12h after taking telbivudine using ultra-performance liquid chromatography-tandem mass spectrometry and SNPs located in RRM2B, TK2, and NME4 was detected by MALDI-TOF mass spectrometry. All statistical analyses were performed with R 4.3.1 and all graphs were drawn by Origin 2023b and P value < 0.05 was considered statistically significant. A total of 140 patients receiving telbivudine therapy were recruited with a median plasma concentration of 952.49 (781.07-1238.98) ng/mL. The value of plasma concentration was proportional to the grade of creatine kinase elevation and the best telbivudine plasma concentration threshold to discriminate the grade 3/4 CK elevation was 1336.61ng/mL. Multivariate analysis revealed that plasma concentration and rs3826160 were the independent risk factor of telbivudine-induced creatine kinase elevation. Patients with TC and CC genotype in rs3826160 not only had a higher incidence of creatine kinase elevation but also a higher plasma concentration than TT genotype carriers. Chronic hepatitis B patients with TC and CC genotype in rs3826160 have high telbivudine plasma concentration are at risk of elevated creatine kinase.

Incidence of subclinical and overt hypothyroidism in children treated with [131I]mIBG: a systematic review and meta-analysis.

Treatment with [131I]mIBG is commonly used in pediatric metastatic neuroblastoma (NB); however, unbound [131I]I might be taken up by the thyroid, causing hypothyroidism. To prevent this occurrence, thyroid blockade with iodine salts is commonly used; despite this precaution, thyroid dysfunction still occurs. This review and meta-analysis aim to clarify the mean frequency of hypothyroidism in children with NB treated with [131I]mIBG and to investigate the possible causes. The literature was searched for English-language scientific manuscripts describing the incidence of TSH elevation and overt hypothyroidism in children with NB treated with [131I]mIBG. Preclinical studies, small-case series, and reviews were excluded. A proportion meta-analysis was conducted to test the influence of potentially relevant factors (type and duration of thyroid blockade, year of the study, sample size) on the incidence of TSH elevation/overt hypothyroidism. Eleven studies were included. The pooled percentage of TSH elevation was 0.41 (95% CI: 0.27-0.55); the duration of the thyroid blockade (P=0.004) was inversely correlated with the incidence of TSH elevation. Moreover, a TSH increase was more common in patients treated with potassium iodide (KI) alone than in those managed with a multi-drug thyroid blockade (P<0.001). The pooled percentage of children requiring hormone replacement therapy was 0.33 (95% CI: 0.16-0.49). As in the case of TSH elevation, a longer duration of the thyroid blockade (P=0.006) and a multi-pronged approach (P<0.001) were associated with a lower incidence of overt hypothyroidism. Hypothyroidism appears to occur frequently in children treated with [131I]mIBG, which should be monitored closely after the radionuclide treatment to start hormone replacement therapy as soon as needed. The duration, as well as the type of thyroid blockade, seem to influence the incidence of hypothyroidism; however, more data from prospective evaluations are needed.

Seroprevalence and biochemical parameters among patients with Chikungunya in Adamaoua region, Cameroon: A cross‐sectional study

AbstractBackgroundChikungunya virus (CHIKV) infection is a vector‐borne febrile illness endemic to Africa. In Cameroon, few studies have documented human exposure to CHIKV, especially in the Adamaoua region. This study aimed to assess the CHIKV seroprevalence in Ngaoundere city and analyze likely association with social, clinical, and biochemical determinants.MethodsA cross‐sectional study was conducted at the Ngaoundere Regional Hospital from July to October 2022. The sociodemographic and clinical informations of participants were recorded using a standardized questionnaire. Then, blood tests were performed to determine the CHIKV status, the transaminase, and lipid profiles.ResultsOf the 200 persons surveyed, 21.5% (43) were positive for anti‐CHIKV IgM antibodies. Age, sex, occupation, marital status, level of study, and place of residence were not significantly associated with CHIKV. However, fever (RR = 4.19; 42.86%; p = 0.0124), headaches (RR = 4.89; 50%; p = 0.0007), digestive disorders (RR = 6.52; 66.67%; p = 0.0001), and the presence of at least two clinical symptoms (RR = 2.55; 26.09%; p = 0.009) were significantly correlated with the presence of CHIKV compared with the absence of clinical symptoms (RR = 1, 10.23%). Similarly, cases of CHIKV were significantly more important in subjects with high aspartate aminotransferase (AST) than in those with normal AST (RR = 2.45; 37.50% vs. 15.28%; p = 0.0006). No significant association was found between alanine‐aminotransferase and lipid profile markers.ConclusionNgaoundere populations seem to be commonly infected with CHIKV, increasing the incidence of febrile symptoms and transaminase elevation. Clinical and metabolic monitoring is required.

Postpartum hepatitis flares in mothers with chronic hepatitis B infection.

Postpartum elevation of alanine aminotransferase (ALT) in mothers with chronic hepatitis B (CHB) presents a significant clinical challenge. However, the existing literature demonstrates inconsistencies regarding its incidence and predictors in mothers infected with the hepatitis B virus (HBV). Recent advancements in antiviral prophylaxis against mother-to-child transmission of HBV and postpartum cessation of antiviral therapy further complicate this issue. Our literature review, spanning PubMed, and two Chinese-language databases (CNKI and Wanfang) from 1 January 2000 to 31 December 2023 aimed to consolidate and analyse available data on the frequency and severity of postpartum ALT flares, identify risk factors, and propose a management algorithm. Data from 23 eligible studies involving 8,077 pregnant women revealed an overall incidence of postpartum ALT elevation: 25.7% for mild cases, 4.4% for moderate cases, and 1.7% for severe cases. In the subgroup of mothers who were HBeAg-positive and on antiviral prophylaxis for preventing mother-to-child transmission, postpartum intermediate and severe ALT elevations were reported with pooled rates of 5.9% and 0.8%, respectively. Importantly, none resulted in mortality or necessitated liver transplantation. Identified risk factors for postpartum ALT flares in mothers with CHB included HBV DNA levels, ALT levels during pregnancy, postpartum cessation of antiviral treatment, and HBeAg status. By leveraging this evidence and recent data on predictors of intermediate or severe postpartum ALT flares, we propose a risk-stratified algorithm for managing postpartum ALT elevation and selecting therapy in mothers with CHB, tailoring different approaches for treatment-naive vs treatment-experienced populations. These recommendations aim to provide guidance for clinical decision-making and enhance patient outcomes.