共找到 20 条结果
The journal retracts the article, "Adenine Inhibits the Invasive Potential of DLD-1 Human Colorectal Cancer Cell via the AMPK/FAK Axis" [...].
The journal retracts the article cited above, titled "Design and Evaluation of S-Protected Thiolated-Based Itopride Hydrochloride Polymeric Nanocrystals for Functional Dyspepsia: QbD-Driven Optimization, In Situ, In Vitro, and In Vivo Investigation" [...].
The improper disposal of household pharmaceuticals is a global public health concern, posing risks to both human health and the environment and highlighting the need to raise public awareness. This study aimed to identify individual characteristics associated with the inappropriate disposal of household pharmaceuticals and to determine which individuals may require greater awareness. This cross-sectional study included 310 participants who completed an online questionnaire collecting sociodemographic and clinical information, as well as data regarding the participants' use, storage, and disposal of medications. Most participants were female (74%), single (57%), had a university degree (81%), and were 34 ± 12 years old; 37% had some non-communicable disease (NCD), 85% used some medication, and 62% disposed of pharmaceuticals inappropriately. Having no undergraduate degree (OR = 4.4; 95% CI = 2.01-9.8), an absence of NCDs (OR = 2.5; 95% CI = 1.1-5.6), a lack of knowledge about reverse logistics (OR = 3.6; 95% CI = 1.7-7.6) or environmental risks (OR = 13.5; 95% CI = 1.5-125), and a lack of guidance from healthcare professionals (OR = 3.6; 95% CI = 1.2-10.6) were associated with inappropriate disposal. Although most respondents (88.6%) were aware of the negative environmental impacts of improper disposal, 69.7% did not know what reverse logistics was or where to find collection points (73.5%). These findings highlight the importance of environmental education for the effective implementation of reverse logistics for household pharmaceuticals.
Rapid advancements in biotechnology have enabled biomanufacturing to emerge as a feasible approach for industrial chemical production. By harnessing synthetic biology and metabolic engineering, engineered microbial cell factories can convert renewable resources into valuable chemicals, providing a sustainable alternative to traditional chemical methods. This study focuses on the microbial production of retinal, an important retinoid used in pharmaceuticals, food, and cosmetics. The oleaginous yeast Rhodotorula toruloides NP11 was genetically modified to synthesize retinal by incorporating and optimizing three β-carotene 15,15'-dioxygenase genes from various sources. Several genetic modifications were made to enhance retinal yield, including the overexpression of isopentenyl-diphosphate isomerase (IDI1), geranylgeranyl diphosphate synthase (BTS1), phytoene synthase (CARRP), and phytoene dehydrogenase (CARB), which led to increased β-carotene levels and boosted retinal production. Furthermore, fermentation conditions such as temperature, antioxidants, and extractants were fine-tuned. The engineered strain Rt13 ultimately achieved a maximum retinal concentration of 20.38 mg/L through fed-batch fermentation. This study highlights the potential of R. toruloides as a cell factory for terpenoid biosynthesis, providing valuable insights for future metabolic engineering endeavors.
α-Bisabolol is naturally occurring in many plants and has great potential in health products and pharmaceuticals. However, the current extraction method from natural plants is unsustainable and cannot fulfil the increasing requirement. This study aimed to develop a sustainable strategy to enhance the biosynthesis of α-bisabolol by metabolic engineering. Integration of ERG20 (encoding farnesyl diphosphate synthase) and tHMG1 (encoding truncated 3-hydroxy-3-methylglutaryl-CoA reductase) genes with a constitutive strong promoter into the yeast genome elevated α-bisabolol production from 20.21 mg/L to 98.30 mg/L, representing a 4.86-fold increase. Further optimization of the mevalonate pathway and amplification of ERG20, tHMG1, and OsTPS1 copy numbers enhanced α-bisabolol synthesis to 423.01 mg/L, achieving a 20.93-fold improvement relative to the baseline. This work establishes a reference strategy for high-yield α-bisabolol biosynthesis in engineered yeast.
To examine how changes in metastatic hormone-sensitive prostate cancer (mHSPC) management (e.g. approval of androgen receptor pathway inhibitors [ARPIs] ± docetaxel in combination with androgen deprivation therapy [ADT]) may be impacting metastatic castration-resistant prostate cancer (mCRPC) treatment patterns. This retrospective, observational study analyzed private insurance claims data from the US Komodo Health Healthcare Map database to identify people diagnosed with mCRPC between 1 January 2020 to 31 March 2023, after progressing from mHSPC. Analyses included treatment patterns for mCRPC by line of therapy, with stratification by prior mHSPC therapy and physician specialty. A total of 3,151 people with mCRPC were identified. Median age was 67 years, 46% had bone-only metastases and 31% had bone + visceral metastases; 64% were treated by oncologists and 10% by urologists. Previous treatment for mHSPC included ADT only (68%), ADT + docetaxel (13%), ADT + abiraterone (8%), or ADT + non-abiraterone ARPI (11%; i.e. enzalutamide, apalutamide, or darolutamide). The most common first-line treatment for mCRPC was abiraterone in people who had received ADT alone or ADT + docetaxel for mHSPC (48% each) and chemotherapy in people who had received ADT + abiraterone or ADT + non-abiraterone ARPI for mHSPC (46% and 37%, respectively). mCRPC treatment patterns were heavily influenced by prescribing physician specialty, with oncologists more likely than urologists to prescribe abiraterone, chemotherapy or radiopharmaceuticals, and urologists more likely to prescribe non-abiraterone ARPIs. Despite changes in mHSPC management, ARPIs remain a frequent choice of first-line mCRPC therapy, with back-to-back ARPI use common. Even with the availability of other therapies beyond ARPIs, and the clinical evidence supporting use of agents beyond ARPIs, treatment with these therapies was limited.
Angiotensinogen production represents the rate-limiting step in activation of the renin-angiotensin-aldosterone system. Tonlamarsen is an investigational antisense oligonucleotide directed against hepatic angiotensinogen synthesis; its efficacy and safety among patients with hypertension are unknown. The aim of this study was to assess the safety and efficacy of 90 mg tonlamarsen administered subcutaneously once monthly for 5 months compared with a single dose of tonlamarsen and subsequent placebo. This randomized, placebo-controlled trial enrolled adults with office systolic blood pressure (BP) >135 mm Hg receiving 2 to 5 antihypertensive medications. Participants entered a 3-part treatment period with monthly administration of the study drug, consisting of a 4-week placebo lead-in, followed by 4-week active run-in with a single dose of tonlamarsen and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks. The coprimary endpoints were the between-group differences in the change from baseline to week 20 in plasma angiotensinogen and in office systolic BP. A total of 279 participants received placebo lead-in, 206 received 90 mg tonlamarsen during the active run-in, and 198 were randomized. The mean BP among randomized participants before and after the placebo lead-in was 147/90 and 147/89 mm Hg, respectively. Following active run-in with tonlamarsen, the mean BP was 140/87 mm Hg. Twenty weeks following the first dose of tonlamarsen, least squares (LS) mean percentage changes in plasma angiotensinogen levels were -23.0% (95% CI: -27.8% to -18.2%) with a single dose of tonlamarsen and subsequent placebo and -67.2% (95% CI: -71.9% to -62.4%) with monthly tonlamarsen administration, with a LS mean difference of -44.1% (97.5% CI: -51.9% to -36.4%; P < 0.0001). The LS mean changes in office systolic BP were -6.7 mm Hg (95% CI: -9.8 to -3.5 mm Hg) for participants following a single dose of tonlamarsen and subsequent placebo and -6.7 mm Hg (95% CI: -9.8 to -3.6 mm Hg) for participants treated with monthly tonlamarsen, with a LS mean difference of -0.1 mm Hg (95% CI: -4.5 to -4.4 mm Hg; P = 0.97). Serious adverse events were infrequent and similar between treatment groups. Among individuals with uncontrolled hypertension, monthly tonlamarsen administration was more effective at lowering plasma angiotensinogen compared with a single tonlamarsen dose, but there was no additional BP reduction. (A Study to Investigate Tonlamarsen for the Treatment of Adults With Uncontrolled Hypertension [KARDINAL]; NCT06864104).
For fever in neutropenia (FN) during chemotherapy timely start of antibiotics is recommended. We analyzed time to antibiotics (TTA) and sub-timespans between detection of fever and start of antibiotics in children undergoing chemotherapy for cancer with FN. Specifically, we aimed to assess where delays occur, which variables influence TTA, and whether the order of certain process steps affects TTA. We analyzed 349 FN episodes reported prospectively in 155 Swiss patients from April 2016 to August 2018. In outpatients, the median TTA from fever to the start of antibiotics was 165 minutes, and the median duration from fever to hospital arrival was 80 minutes. For inpatients, the median TTA from fever to the start of antibiotics was 75 minutes. The longest delays were identified for the timespans from phone call to arrival (median, 75 min) and from arrival to decision on treatment (60 min). Known blood counts at recognition of fever, decision to treat FN before arrival at the emergency department, and arrival during office hours contributed to shorter TTA. In conclusion, the time before arrival is relevant and should be considered when optimizing TTA and evaluating its influence on outcomes. Support for transportation, using time to arrive for preparations, and regular blood counts could reduce TTA.
The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated. We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989-2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence. Results demonstrated that the prognostic value of Ki-67 PI differed by subgroups defined by WHO grade and Simpson grade. For patients with the same Simpson grade (1-3), the predictive accuracy of Ki-67 PI for 10-year recurrence risk was stronger in WHO-2 than in WHO-1. Within WHO-1 and WHO-2 meningiomas, the predictive accuracy of Ki-67 PI increased with higher Simpson grade (1-3). However, no predictive value was observed in Simpson grade 4 resections regardless of WHO grade. These findings highlight that Ki-67 PI should be interpreted in the context of both WHO grade and extent of resection, and, if done so, may offer potential value to refine individualized surveillance strategies in meningioma patients with gross total resection in the initial 10-year postoperative timeframe. Findings cannot be extrapolated beyond 10 years, which may be particularly relevant for WHO-1 tumors with low Ki-67 PI and Simpson grade 1 resection.
Ligand design and synthesis for Siglec-8 is important due to its roles in immune responses to allergens, chronic inflammatory disorders and malignancies. Here the synthesis, from readily accessible intermediates, of glycomimetics of Neu5Acα2-3 (6-O-sulfo-Gal), the minimal glycan ligand for Siglec-8, is reported. The mimetics retain Neu5Ac, while replacing the 6-O-sulfo-Gal component by a triazole containing linker presenting either carboxylate or sulfonate groups. Isothermal calorimetry (ITC) measurements showed that the sialyl triazole derivatives were ligands for Siglec-8, with a Kd of 45.5 μM established for the best ligand from the series. The ITC measurements showed that sulfonate was better than carboxylate as a replacement for sulfate, while the incorporation of the naphthylsulfonate group at the Neu5Ac C-9 of the ligands gave affinity improvement, consistent with earlier research. An NMR based binding study supports the conformational change to Siglec-8 to accommodate the 9-naphthylsulfonate group and indicates a similar mode of binding for the highest affinity triazole derivative to previously reported cyclohexane based glycomimetics. The perturbation of NMR signals, docking and binding pose metadynamics support binding of the ligand to the carbohydrate recognition domain. The research provides new Siglec-8 ligands from readily accessible intermediates as a basis for further development.
The treatment paradigm for HER2-positive metastatic breast cancer has evolved from continuous chemotherapy-based regimens to a model of finite chemotherapy induction followed by sustained antibody-driven disease control. The CLEOPATRA trial established dual HER2 blockade with trastuzumab and pertuzumab plus a taxane as the biological and clinical anchor of this approach, demonstrating that chemotherapy is administered for a defined induction period, after which antibody maintains disease suppression. An increasing body of clinical evidence indicates that antibody-based regimens can be combined with targeted agents, including CDK4/6 inhibitors or HER2 tyrosine kinase inhibitors, to achieve durable disease control without the need for continuous chemotherapy. In the PATINA trial, the addition of palbociclib to trastuzumab, pertuzumab, and endocrine therapy was associated with a clinically meaningful improvement in progression-free survival in hormone receptor-positive, HER2-positive metastatic breast cancer. At the same time, quality of life was maintained despite higher rates of hematologic toxicity. More recently, HER2-CLIMB-05 demonstrated that the addition of tucatinib to dual HER2 antibody therapy significantly prolonged progression-free survival, supporting a model of sustained, multi-agent HER2 pathway suppression. The monarcHER trial provided biological proof of concept that antibody plus CDK4/6 inhibition can achieve disease control without chemotherapy in hormone receptor-positive, HER2-positive disease. Collectively, these advances support a translational framework in which antibody therapy serves as a central component of treatment strategies, with targeted partners selected according to tumor biology and prior therapy. This review summarizes the biological basis, clinical evidence, and future perspectives of antibody-driven maintenance in HER2-positive metastatic breast cancer.
Multiple myeloma remains an incurable malignancy in which patients ultimately experience relapses and refractory disease despite therapeutic advances. Triple-class exposed relapsed/refractory MM (TCE/RRMM) patients represent both a population with high unmet clinical needs and a substantial economic burden for the Italian National Health Service (NHS). Recently, BCMA-CD3 bispecific antibodies, including elranatamab and teclistamab, have expanded the treatment options for these patients. This study aimed to evaluate the cost-effectiveness of elranatamab versus teclistamab in adults with TCE/RRMM from the Italian NHS perspective. A partitioned survival model with three health states-progression-free survival, post-progression survival, and death-was developed over a 25-year lifetime horizon, adopting weekly cycles and a 3% annual discount rate. Clinical data for elranatamab were derived from the MagnetisMM-3 trial, while teclistamab outcomes were estimated through matching-adjusted indirect comparisons using MajesTEC-1 data. Direct medical costs included those associated with drug acquisition and administration, disease management, adverse event management, and end-of-life care. Utility values were obtained from EQ-5D-based assessments in MagnetisMM-3. Deterministic and probabilistic sensitivity analyses were performed to test model robustness. Elranatamab yielded 3.31 life-years and 2.33 QALYs per patient, compared with 1.83 life-years and 1.27 QALYs for teclistamab. Total lifetime costs were lower for elranatamab (EUR 153,337) versus teclistamab (EUR 224,610), generating EUR 71,273 in savings. Thus, elranatamab is considered to be dominant, due to its higher efficacy and lower cost. Furthermore, the robustness of these findings was confirmed through sensitivity analyses. From the Italian NHS perspective, elranatamab represents a clinically superior and economically favorable option for patients with TCE/RRMM. The obtained results support its value and sustainability within the national treatment landscape.
Despite recent advances in pharmacological treatment, chronic heart failure (HF) is associated with significant morbidity and mortality, and further treatment options are needed. Intact nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signalling is a prerequisite of cardiovascular health. cGMP produced by NO/NO-sGC acts as a second messenger molecule via various downstream targets, which influence a broad spectrum of critical physiological parameters. Impairment of this cascade in the cardiovascular system is considered an important pathomechanism in HF. This review examines pharmacological therapies that act through the NO-sGC-cGMP signalling pathway. We will focus on the molecular mode(s) of action of NO-independent but haem-dependent sGC stimulators, and will examine evidence from preclinical studies demonstrating cardiovascular benefits of these therapies and their increasing number of effects on other susceptible tissues and organs, which together could contribute to clinical outcomes in HF. The sGC stimulator vericiguat may be considered, in addition to standard therapy, for adults with symptomatic HF with reduced ejection fraction (HFrEF) following a worsening event. The findings from pivotal clinical trials that led to these recommendations will be outlined and classified in terms of their significance for different subpopulations. These include the phase 3 VICTORIA and VICTOR trials. Finally, further research areas and ongoing studies designed to address existing gaps in our knowledge regarding vericiguat and related drugs will be highlighted.
The findings of the prospective, real-world REFINE trial supported the safety and efficacy of regorafenib reported in the phase III RESORCE study, in a broader population of patients with unresectable hepatocellular carcinoma (HCC). This post hoc analysis evaluated patient subgroups based on liver function, liver cancer stage, and prior treatment. Patients were analyzed by subgroups based on liver function [Child-Pugh (CP)-B/B7], prior treatment [prior orthotopic liver transplant (pOLT), transarterial chemoembolization (TACE)/transarterial radioembolization (TARE)], and Barcelona Clinic Liver Cancer (BCLC) stage. The primary objective was to evaluate the safety of regorafenib. Secondary objectives included effectiveness endpoints of overall survival (OS) and duration of treatment. All analyses were descriptive with no adjustment for confounders. A total of 1005 patients were evaluable (overall population). In patients with CP-B (n = 123) compared with the overall population, the incidence of grade ≥3 (28% versus 27%) and serious drug-related treatment-emergent adverse events (TEAEs) was similar (11% versus 9%), whereas TEAEs leading to permanent discontinuation of regorafenib were more common (28% versus 16%). In patients with prior TACE (n = 584), the incidence of TEAEs was generally similar to patients without prior TACE (n = 421) and the overall population (92%, 91%, and 92%, respectively). Median OS was 12.3-19.3 months across all subgroups except CP-B/B7 (6.4/6.7 months). This subgroup analysis of REFINE provides further evidence on the safety and effectiveness of regorafenib demonstrated in RESORCE, in underrepresented subgroups (CP-B, BCLC stage B/C, pOLT) and in those previously treated with TACE/TARE.
In this work, three functionalized hybrid composites, CS/PVA-VAN, CS/PVA-VAN@TiO2 and CS/GO/PVA-VAN@TiO2, were synthesized and applied for adsorption evaluation on two common non-steroidal anti-inflammatory drugs, i.e., diclofenac (DCF) and ketoprofen (KTP). The structural and morphological characteristics of new composites were identified via Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD) and BET techniques. BET analysis demonstrated that the CS/GO/PVA-Van@TiO2 composite has a surface area 64.86 m2/g, which is twice that of CS/PVA-Van. Moreover, adsorption evaluation was achieved at an optimum pH condition (pH 5.0) for both drugs. In addition, the kinetic data fitted better in a pseudo-second-order kinetic model, while the adsorption was heterogeneous and multilayer. The adsorption capacity of CS/GO/PVA-VAN@TiO2 was found to be 114.53 mg/g and 65.20 mg/g for diclofenac and ketoprofen, respectively. Thermodynamic analysis confirmed that the adsorption process was endothermic and spontaneous for all pollutants. Moreover, the kinetic swelling and stability studies demonstrated that graphene oxide contributed to improving the structural compactness and stability of composite. Finally, the adsorption performance of the optimal composite material was investigated in a binary system of non-steroidal anti-inflammatory drugs in various ratios.
In patients with metastatic hormone-sensitive prostate cancer (mHSPC), darolutamide significantly improved radiological progression-free survival versus placebo (hazard ratio [HR] 0·54, 95% CI 0·41-0·71) in the phase 3 ARANOTE study. In addition to survival, symptom control and health-related quality of life (HRQoL) are important factors in treatment decision making; we therefore report pain, HRQoL, and safety outcomes from the ARANOTE trial. ARANOTE is an international, randomised, double-blind, placebo-controlled, phase 3 trial involving men aged 18 years or older, with Eastern Cooperative Oncology Group performance status 0-2 and recurrent or de novo mHSPC, treated at 133 cancer centres in 15 countries. Participants were randomly assigned (2:1) to 600 mg darolutamide or matching placebo orally twice daily, both with investigator's choice of androgen deprivation therapy (ADT; luteinising hormone-releasing hormone agonist or antagonist, or orchiectomy) starting within 12 weeks before randomisation. Randomisation was stratified by presence versus absence of visceral metastases and by previous versus no previous local therapy. Treatment was assigned centrally using an interactive web response system based on a computer-generated permuted block randomisation list with block sizes of six. The investigators, the participants, and the sponsor remained masked to treatment assignment throughout the study. The primary endpoint (reported previously) was radiological progression-free survival. Here, we assessed time to pain progression (≥2-point increase in Brief Pain Inventory-Short Form worst pain score or initiation of opioid for ≥7 days; secondary endpoint) and time to deterioration of overall wellbeing (≥10-point decrease in Functional Assessment of Cancer Therapy-Prostate [FACT-P] total score; prespecified exploratory endpoint). Pain and HRQoL outcomes were analysed in the intention to treat population; safety was analysed in all treated patients according to treatment actually received. The trial, registered at ClinicalTrials.gov, NCT04736199, is ongoing, but no longer recruiting. Between Feb 23, 2021, and June 14, 2022, 669 patients (all male; 376 [56%] White, 209 [31%] Asian, 65 [10%] Black, 19 [3%] other race) were randomly assigned to receive darolutamide (n=446) or placebo (n=223). At the data cutoff date for the primary analysis (June 7, 2024), the median follow-up duration for the analyses presented here was 22·8 months (IQR 12·3-27·4) in the darolutamide group and 20·3 months (11·4-25·2) in the placebo group. Darolutamide delayed time to pain progression (HR 0·72; 95% CI 0·54-0·96) and extended time to deterioration in FACT-P total score (HR 0·76; 0·61-0·94) versus placebo. The most common grade 3-4 adverse events were hypertension (19 [4%] of 445 patients who received darolutamide vs eight [4%] of 221 patients who received placebo), anaemia (14 [3%] vs eight [4%]), and aspartate aminotransferase increase (ten [2%] vs one [<1%]). Serious adverse events occurred in 105 (24%) versus 52 (24%) patients, respectively. One treatment-related grade 5 event occurred, reported as death (not otherwise specified). Along with the known survival benefits, the clinically meaningful delays in pain progression and time to deterioration of overall wellbeing support consideration of darolutamide plus ADT as a standard-of-care treatment option in patients with mHSPC. Bayer and Orion Pharma.
LT-001 evaluated long-term safety/efficacy of onasemnogene abeparvovec (OA) for spinal muscular atrophy (SMA) patients from START (N = 15; NCT02122952). Reported is an interim analysis (5-year totalling up to 10-years post-dose) of long-term follow-up data from START (phase 1, open-label, single-arm, dose-escalation; 2-year follow-up [Nationwide Children's Hospital, Columbus, Ohio] [first patient dosed: May 5, 2014]). Patients (symptomatic SMA type 1, biallelic SMN1 mutations/deletions, two SMN2 copies; full analysis set) received single intravenous OA dose (low [6·7 × 1013 vg/kg] or proposed therapeutic dose [equivalent to 1·1 × 1014 vg/kg]). Safety (primary outcome) and efficacy (alive and independent of permanent ventilatory support [post hoc]) were assessed (NCT03421977 [September 21, 2017-September 17, 2018]). The LT-001 study was initiated on September 21, 2017, and the last patient was enrolled on September 17, 2018. As of July 1, 2024, 13 START patients enrolled in LT-001 (n = 3/13, low-dose; n = 10/13, therapeutic-dose). Mean (SD); min-max age at dosing was 6·3 (0·7); 5·8-7·1 months (low-dose) and 2·8 (1·5); 0·9-5·6 months (therapeutic-dose). Mean (SD); min-max follow-up duration was 9·9 (0·2); 9·8-10·1 years (low-dose) and 8·3 (1·1); 6·8-9·6 years (therapeutic-dose). Most patients (≥70%) received nusinersen/risdiplam post-dosing. Serious adverse events (n = 11/13; 85%) were most frequently acute respiratory failure, dehydration, and pneumonia (none led to study discontinuation or death). Six adverse events (AEs) of special interest (n = 4/13; 31%) included transient thrombocytopenia, cardiac AEs, and new incidence of neurologic disorders (unrelated to treatment). All (n = 13/13) were alive at last visit (n = 5 therapeutic-dose) or data cutoff (n = 8 ongoing). The majority (n = 12/13) were free of permanent ventilation. OA demonstrated a favourable benefit-risk profile and efficacy up to 10 years for START/LT-001 patients, though there are limitations (descriptive analyses, small population, add-on therapy, lack of comparator). Further long-term research may build on phase 3/4 study findings with OA for SMA patients. Novartis Pharma AG.
Chorea is a hallmark of Huntington's disease (HD), yet its clinical assessment is of limited reliability, impairing our ability to sensitively evaluate its progression. We evaluated passive monitoring for estimating the two-year evolution of upper limb chorea in HD. Across four studies, 1025 participants collected smartwatch accelerometer data during their everyday life. We developed a machine learning model anchored to in-clinic upper limb chorea and trained cross-sectionally on disease-relevant features. The final model, selected using nested cross-validation, allowed estimating the longitudinal evolution of chorea. The resulting digital passive monitoring chorea score shows a progression of 0.13 points per year (95% CI: [0.08, 0.17]), and a robust sensitivity to change across studies, avoiding biases related to in-clinic measurements. High-resolution accelerometer data collected passively during daily life can improve the measurement of chorea in HD. Clinical Trial Registry Name: ClinicalTrials.gov; Study IDs: NCT03761849 registered 2018-11-30 and NCT03664804 registered 2018-09-07.
A post-authorisation safety study (PASS) was conducted to assess the impact of LysaKare (2.5% Lysine-Arginine solution) on serum potassium concentrations and its safety/tolerability profile in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) eligible for 177Lu-DOTATATE treatment. In a phase IV, multicentre, single-arm, open-label PASS, adults with somatostatin receptor-positive GEP-NET who were eligible for 177Lu-DOTATATE treatment received 1000 mL of LysaKare (monotherapy) intravenously over 4 h. The primary endpoint was the change in serum potassium levels over the course of 24 h. Secondary endpoints included the incidence of LysaKare-related adverse events (AEs) and changes in laboratory parameters. Forty-one patients were treated (median age, 57 years; 92.7% White and 7.3% Black; 53.7% male) and 40 completed post-treatment follow-up. Mean (standard deviation [SD]) serum potassium was 4.33 (0.397) mmol/L pre-dose, increasing by 0.60 (0.666) mmol/L after 4 h (time to maximum change, range, 2-24 h) before decreasing to around the pre-dose level: the mean (SD) increase after 24 h was 0.07 (0.396) mmol/L. Other electrolytes and blood gas components mostly showed transient changes that lasted ~24 h. A general trend of transient metabolic acidosis was also observed based on laboratory values. Serum potassium grade increased from baseline in 41.5% of patients. By comparison, five patients (12.2%) had a treatment-related AE of hyperkalaemia (grade 3, n = 1); all resolved within 24 h, either without treatment (n = 3) or following intravenous furosemide (n = 2). There were no serious AEs and no AEs leading to treatment discontinuation/interruption. This PASS identified no new safety signals attributable to LysaKare. Trial registration: EudraCT, 2019-004073-76. Registered 20/08/2020.
This pharmacovigilance study drew upon the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) database to compare the reporting patterns of ocular and systemic adverse events (AEs) for the 2 mg (standard-dose [SD]) and 8 mg (high-dose [HD]) formulations of aflibercept given for any ocular indication. Disproportionality analysis, including reporting odds ratios (ROR), was used to compare each dose individually to the background reporting rate for the AE. Statistical significance of the RORs was evaluated using Bonferroni correction, alongside signal detection based on Evans criteria, and Bayesian information components. The Breslow-Day test was used to conduct a head-to-head comparison of RORs between each dose. We identified 953 SD and 314 HD AE reports within the 750-day period after the approval of HD by the U.S. Food and Drug Administration (FDA; 8/18/2023). Compared to SD, HD had a higher ROR for endophthalmitis (HD: ROR 767.56 [95% CI, 466.11-1263.95]; SD: ROR 331.64 [95% CI, 216.71-507.51]), eye inflammation (HD: ROR 118.45 [95% CI, 55.85-251.20]; SD: 43.98 [95% CI, 21.87-88.44]), retinal vasculitis (HD: ROR 769.87 [95% CI, 337.13-1758.04]; SD: ROR 124.80 [95% CI, 39.67-392.63]), and systemic vasculitis (HD: ROR 28.40 [95% CI, 14.63-55.14]; SD: ROR 4.05 [1.52-10.82]). These results, based on FAERS, indicate associations rather than causal relationships. Further studies are needed to quantify the absolute risks and elucidate the mechanisms underlying differences in safety signals, if any.