Safety Studies Research Articles

Automated Geographic-Information-System-Based Framework for Detecting Crosswalk Changes from Bi-Temporal High-Resolution Aerial Images

Identifying changes in pavement markings has become crucial for infrastructure monitoring, maintenance, development, traffic management, and safety. Automated extraction of the roadway geometry is critical in helping with this, given the increasing availability of high-resolution images and advancements in computer vision and object detection. Specifically, because of the substantial volume of satellite and high-resolution aerial images captured at different time instances, change detection has become a viable solution. In this study, an automated framework is developed to detect changes in crosswalks in Orange, Osceola, and Seminole counties in Florida, utilizing data extracted from high-resolution images obtained at various time intervals. Specifically, for Orange County, crosswalk changes between 2019 and 2021 were manually extracted, verified, and categorized as either new or modified crosswalks. For Seminole County, the developed model was used to automatically extract crosswalk changes between 2018 and 2021, while for Osceola County, changes between 2019 and 2020 were extracted. Findings indicate that Orange County witnessed approximately 2,094 crosswalk changes, with 314 occurring on state roads. In Seminole and Osceola counties, on the other hand, 1,040 and 1,402 crosswalk changes were observed on both local and state roads, respectively. Among these, 340 and 344 were identified on state roads in Seminole and Osceola, respectively. Spatiotemporal changes observed in crosswalks can be utilized to regularly update the existing crosswalk inventories, which is essential for agencies engaged in traffic and safety studies. Data extracted from these crosswalk changes can be combined with traffic and crash data to provide valuable insights to policymakers.

Interim analysis of the multinational, post-authorization safety study (NISSO) to assess the long-term safety of sonidegib in patients with locally advanced basal cell carcinoma.

Following the pivotal phase II trial BOLT, the Hedgehog (Hh) inhibitor sonidegib was approved in the EU to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiotherapy. We report safety data from the interim analysis of the real-world NISSO study. NISSO is an ongoing non-interventional, multinational, post-authorization safety study (NCT04066504). Patients with laBCC are treated with sonidegib 200mg orally once daily and followed for 3years. Dose modifications were allowed according to the local prescribing information. Between May 6, 2019, and March 15, 2022, 321 patients with laBCC were enrolled at 46 European sites (data cut-off: June 22, 2023). Treatment was discontinued in 241 (75.1%) patients, with the main reasons being the patient/guardian decision (n = 69, 28.6%), treatment success (n = 40, 16.6%) and the physician decision (n = 35, 14.5%). The median duration of sonidegib exposure was 8.8months (4.4-13.7months). Overall, 284 (88.5%) patients had ≥ one treatment-emergent adverse event (TEAE). Most TEAEs were ≤ grade 2 and the most common were muscle spasms (n = 141; 43.9%), dysgeusia (n = 119; 37.1%), and alopecia (n = 97; 30.2%). After 3months of treatment, the cumulative rates of muscle spasms, dysgeusia, and alopecia were 21.8%, 16.2%, and 3.7%, respectively. TEAEs led to treatment discontinuation in 59 (18.4%) patients, while 149 (46.4%) patients had at least one TEAE leading to dose reduction or interruption. Serious drug-related TEAEs were reported in 13 (4.1%) patients. These results confirm the safety profile previously observed. Most patients experienced the onset of common TEAEs after 3months of treatment, and the cumulative incidence of most common TEAEs was 10-20% lower compared to the BOLT study, except for dysgeusia and fatigue that had a similar incidence. The percentage of patients experiencing TEAEs requiring interruption or dose reduction was similar to the BOLT study, while the proportion of patients with TEAE leading to discontinuation of sonidegib was lower. This study demonstrates that the tolerability of sonidegib is manageable in routine clinical practice. NCT04066504.

Phase Ib study of the oral PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

Patients with advanced solid tumors have a suboptimal prognosis. This study investigated the safety and feasibility of linperlisib, a selective phosphatidylinositol 3-kinase delta isoform (PI3Kδ) inhibitor, for treating patients with advanced solid tumors. In this phase Ib, single-arm, open-label, multi-center clinical trial, patients with histologically confirmed advanced solid tumors from eight centers in China were enrolled to receive oral linperlisib (80mg/day). The primary endpoint was safety. Between August 2019 and June 2022, 94 patients were enrolled in the trial and received the study treatment. The most common (≥ 20%) treatment emergent adverse events (TEAEs) of all grades irrespective of causality were increased aspartate aminotransferase (AST) (26.6%), proteinuria (26.6%), decreased appetite (25.5%), increased alanine aminotransferase (ALT) (22.3%), weight loss (21.3%), and anemia (21.3%). The most common grade ≥ 3 TEAEs were diarrhea (4.3%), increased AST (3.2%), increased ALT (3.2%), neutropenia (3.2%), anemia (3.2%), increased blood alkaline phosphatase (3.2%). The objective response rate (ORR) was 1.1% (95% confidence interval [CI] 0.0-5.8), and the disease control rate (DCR) was 37.2% (95% CI 27.5-47.8). As of the data cutoff, the median follow-up time was 4.2months (95% CI 2.8-6.9). The median progression-free survival (PFS) was 1.85months (95% CI 1.79-1.88). The median overall survival (OS) was not reached. Linperlisib showed an acceptable safety profile and preliminary clinical benefit in patients with a range of advanced solid tumors. Further studies of linperlisib safety and efficacy are warranted.

Abstract 4134630: Focal Delivery of Antiplatelet Therapy to Prevent Post-Stent Bleeding in High-Risk Patients

Background: Over 3 million percutaneous coronary interventions (PCI) are performed yearly to treat coronary artery stenosis. Stent thrombosis is a catastrophic complication associated with high morbidity and mortality, and its prevention requires the use of prolonged dual antiplatelet therapy (DAPT), which increases bleeding risk. Within the first 30 days after PCI, the mortality of DAPT-associated major bleeding is on par with recurrent myocardial infarction. Research question: No stent system that provides focal antiplatelet activity to prevent stent thrombosis exists, eliminating the need for systemic DAPT and subsequent bleeding risk. Aim: To address this unmet need, we have developed such a stent, termed “the ticagrelor coated stent” (TCS). Methods: Self-assembled monolayers (SAMs) of 12-aminododecylphosphonic acid (ADPA) were formed on cobalt-chromium stents. The amine tail group of ADPA was used to link the ticagrelor molecule through a Mitsunobu reaction and confirmed via infrared spectroscopy. Coating uniformity was validated via atomic force microscopy. In an ex-vivo porcine arterio-venous fistula model, the ticagrelor-coated stents (TCS) were placed in alternating series adjacent to uncoated bare metal stents (BMS). Similarly, TCS and everolimus-eluting stents were placed in the porcine left circumflex arteries for acute (7 days) and chronic (35 days) studies. Results: ( Figure 1 ): Grossly, no thrombus was seen on the TCS compared to the BMS. Platelet and micro-thrombi adherence were significantly reduced on TCS. Notably, inflammation, measured by neutrophil and monocyte adherence, was also reduced by approximately 10-fold on the TCS vs the BMS. Angiography, optical coherence tomography (OCT), and histopathology results show the TCS widely patent without systemic DAPT. Conclusion: These findings show that TCS prevents stent thrombosis through focal anti-platelet action and may reduce the bleeding risk associated with prolonged use of systemic DAPT. Long-term safety and efficacy studies are underway.

Negotiations of responsibility for community and personal care: Emotional coping, leisure, and restoration for uniformed first responders

ABSTRACT Uniformed public safety personnels (PSPs) are the first line of care on scenes of distress, where they are put into positions to negotiate the responsibilities of community and personal care. This work helps expose the oppressive nature that systems governing community safety have on bodies that are uniformed. Using critical, narrative approaches, 11 public safety personnel participants were recruited to participate in focus groups and interviews. Conversations with PSPs centred on how they navigate relations of power and adhere to militant cultural norms to perform the expectations of the ‘uniform.’ We interpretively analyzed the data to describe three threads that make up the uniform and to create reflections on the potentials of leisure as a means of resistance and healing under capitalism. The intent of this paper is to create a stronger rationale for more work in the study of community safety and care, addressing a gap in services for PSPs.

CTIM-06. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)

Abstract BACKGROUND Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma. METHODS Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores ≥70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion. RESULTS Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 years and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing. CONCLUSIONS Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.

Photothermally Active Quantum Dots in Cancer Imaging and Therapeutics: Nanotheranostics Perspective.

Cancer is becoming a global threat, as the cancerous cells manipulate themselves frequently, resulting in mutants and more abnormalities. Early-stage and real-time detection of cancer biomarkers can provide insight into designing cost-effective diagnostic and therapeutic modalities. Nanoparticle and quantum dot (QD)-based approaches have been recognized as clinically relevant methods to detect disease biomarkers at the molecular level. Over decades, as an emergent noninvasive approach, photothermal therapy has evolved to eradicate cancer. Moreover, various structures, viz., nanoparticles, clusters, quantum dots, etc., have been tested as bioimaging and photothermal agents to identify tumor cells selectively. Among them, QDs have been recognized as versatile probes. They have attracted enormous attention for imaging and therapeutic applications due to their unique colloidal stability, optical and physicochemical properties, biocompatibility, easy surface conjugation, scalable production, etc. However, a few critical concerns of QDs, viz., precise engineering for molecular imaging and sensing, selective interaction with the biological system, and their associated toxicity, restrict their potential intervention in curing cancer and are yet to be explored. According to the U.S. Food and Drug Administration (FDA), there is no specific regulation for the approval of nanomedicines. Therefore, these nanomedicines undergo the traditional drug, biological, and device approval process. However, the market survey of QDs is increasing, and their prospects in translational nanomedicine are very promising. From this perspective, we discuss the importance of QDs for imaging, sensing, and therapeutic usage pertinent to cancer, especially in its early stages. Moreover, we also discuss the rapidly growing translational view of QDs. The long-term safety studies and cellular interaction of these QDs could enhance their visibility and bring photothermally active QDs to the clinical stage and concurrently to FDA approval.

CTNI-29. A PHASE 1B STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND OBJECTIVE RESPONSE OF LP-184 ALONE AND IN COMBINATION WITH SPIRONOLACTONE IN IDH WILD TYPE GLIOBLASTOMA AT FIRST PROGRESSION

Abstract LP-184 is a fully synthetic small molecule alkylator of the acylfulvene therapeutics class that induces DNA double-strand breaks and improves survival in orthotopic GBM xenograft models. In preclinical studies, LP-184 is brain penetrant with a brain tumor/plasma concentration ratio of 0.2. DNA damage induced by acylfulvenes is repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes. GBM with intrinsic or pharmacologically induced DNA Damage Repair deficiency (dDDR) may preferentially respond to LP-184, independent of MGMT status. LP-184 is currently under investigation in a first-in-human Phase 1a dose-escalation safety study (NCT05933265) in adult patients with advanced solid tumors including GBM, with no dose-limiting toxicities to date at dose level 6. Following determination of the Maximum Tolerated Dose and/or Recommended Phase 2 Dose from Phase 1a, the selected expansion dose will be assessed in a Phase 1b study to evaluate the safety, pharmacokinetics, and objective response of LP-184 alone and in combination with spironolactone in IDH wild type glioblastoma at first progression. Spironolactone is a brain penetrant FDA approved agent that proteolytically degrades the TC-NER component ERCC3, thereby creating dDDR. Two rGBM cohorts will be enrolled according to a Simon’s 2-stage optimal design: (i) LP-184 alone (days 1 and 8 in a 21-day cycle, as intravenous infusion over 30 minutes) and (ii) combination of LP-184 and spironolactone (200 mg orally daily in conjunction and before the LP-184 infusion). In the first stage, 10 response evaluable subjects will be enrolled. If 1 or more of the first 10 response evaluable subjects achieve an objective response, 19 further subjects may be accrued in the second stage. In each cohort, at least 5 subjects will undergo planned tumor resection and will be treated with LP-184 or the combination the day prior to surgery to evaluate PK/PD.

Repeated inhalation of GM-CSF by nonhuman primates induces bronchus-associated lymphoid tissue along the lower respiratory tract

BackgroundRepeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear.MethodsIn this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim.ResultsAll the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro.ConclusionLong-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab.

Novel application of metabolic imaging of early embryos using a light-sheet on-a-chip device: a proof-of-concept study.

Is it feasible to safely determine metabolic imaging signatures of nicotinamide adenine dinucleotide [NAD(P)H] associated auto-fluorescence in early embryos using a light-sheet on-a-chip approach? We developed an optofluidic device capable of obtaining high-resolution 3D images of the NAD(P)H autofluorescence of live mouse embryos using a light-sheet on-a-chip device as a proof-of-concept. Selecting the most suitable embryos for implantation and subsequent healthy live birth is crucial to the success rate of assisted reproduction and offspring health. Besides morphological evaluation using optical microscopy, a promising alternative is the non-invasive imaging of live embryos to establish metabolic activity performance. Indeed, in recent years, metabolic imaging has been investigated using highly advanced microscopy technologies such as fluorescence-lifetime imaging and hyperspectral microscopy. The potential safety of the system was investigated by assessing the development and viability of live embryos after embryo culture for 67 h post metabolic imaging at the two-cell embryo stage (n = 115), including a control for culture conditions and sham controls (system non-illuminated). Embryo quality of developed blastocysts was assessed by immunocytochemistry to quantify trophectoderm and inner mass cells (n = 75). Furthermore, inhibition of metabolic activity (FK866 inhibitor) during embryo culture was also assessed (n = 18). The microstructures were fabricated following a standard UV-photolithography process integrating light-sheet fluorescence microscopy into a microfluidic system, including on-chip micro-lenses to generate a light-sheet at the centre of a microchannel. Super-ovulated F1 (CBA/C57Bl6) mice were used to produce two-cell embryos and embryo culture experiments. Blastocyst formation rates and embryo quality (immunocytochemistry) were compared between the study groups. A convolutional neural network (ResNet 34) model using metabolic images was also trained. The optofluidic device was capable of obtaining high-resolution 3D images of live mouse embryos that can be linked to their metabolic activity. The system's design allowed continuous tracking of the embryo location, including high control displacement through the light-sheet and fast imaging of the embryos (<2 s), while keeping a low dose of light exposure (16 J · cm-2 and 8 J · cm-2). Optimum settings for keeping sample viability showed that a modest light dosage was capable of obtaining 30 times higher signal-noise-ratio images than images obtained with a confocal system (P < 0.00001; t-test). The results showed no significant differences between the control, illuminated and non-illuminated embryos (sham control) for embryo development as well as embryo quality at the blastocyst stage (P > 0.05; Yate's chi-squared test). Additionally, embryos with inhibited metabolic activity showed a decreased blastocyst formation rate of 22.2% compared to controls, as well as a 47% reduction in metabolic activity measured by metabolic imaging (P < 0.0001; t-test). This indicates that the optofluidic device was capable of producing metabolic images of live embryos by measuring NAD(P)H autofluorescence, allowing a novel and affordable approach. The obtained metabolic images of two-cell embryos predicted blastocyst formation with an AUC of 0.974. N/A. The study was conducted using a mouse model focused on early embryo development assessing illumination at the two-cell stage. Further safety studies are required to assess the safety and use of 405 nm light at the blastocyst stage by investigating any potential negative impact on live birth rates, offspring health, aneuploidy rates, mutational load, changes in gene expression, and/or effects on epigenome stability in newborns. This light-sheet on-a-chip approach is novel and after rigorous safety studies and a roadmap for technology development, potential future applications could be developed for ART. The overall cost-efficient fabrication of the device will facilitate scalability and integration into future devices if full-safety application is demonstrated. This work was partially supported by an Ideas Grant (no 2004126) from the National Health and Medical Research Council (NHMRC), by the Education Program in Reproduction and Development (EPRD), Department Obstetrics and Gynaecology, Monash University, and by the Department of Mechanical and Aerospace Engineering, Faculty of Engineering, Monash University. The authors E.V-O, R.N., V.J.C., A.N., and F.H. have applied for a patent on the topic of this technology (PCT/AU2023/051132). The remaining authors have nothing to disclose.

Safety of Rimegepant in Adults with Migraine and Anxiety, Depression, or Using Antidepressants: Analysis of a Multicenter, Long-Term, Open-Label Study.

Anxiety and depression are frequently associated with migraine, and antidepressant use can complicate treatment. These analyses assessed the safety and tolerability of rimegepant in participants with migraine and anxiety and/or depression, or using selective serotonin reuptake inhibitors (SSRIs) and/or other antidepressants. Data were from a phase II/III safety study of rimegepant for the acute treatment of migraine. Participants with a history of 2-14 migraine attacks per month of moderate or severe pain intensity self-administered rimegepant 75mg as needed up to once daily for up to 52weeks. These post hoc subgroup analyses assessed safety according to self-reported history of anxiety (yes or no) or depression (yes or no), and current use of SSRIs (yes or no) or other antidepressants (yes or no). Of 1800 treated participants, 23.2% (n = 417) had a self-reported history of anxiety, 23.7% (n = 426) had a self-reported history of depression, and 11.2% (n = 202) reported both anxiety and depression. A total of 10.1% (n = 181) of participants were using an SSRI, 10.8% (n = 195) were using other antidepressants, and 1.8% (n = 32) were using both. Across the subgroups with anxiety, without anxiety, with depression, without depression, using SSRIs, not using SSRIs, using other antidepressants, and not using other antidepressants, respectively, similar proportions of participants reported adverse events (67.1%, 58.4%, 62.0%, 60.0%, 64.1%, 60.0%, 66.2%, 59.8%), serious adverse events (3.6%, 2.3%, 2.8%, 2.5%, 3.3%, 2.5%, 5.1%, 2.3%), and discontinuation of rimegepant due to adverse events (4.1%, 2.2%, 3.1%, 2.5%, 5.0%, 2.4%, 3.1%, 2.6%). Numerical improvements in a variety of participant-reported outcomes were also observed at weeks 12 and 52. Rimegepant showed favorable safety and tolerability in adults with migraine and a history of anxiety and/or depression and with SSRI and/or other antidepressant use. Clinicaltrials.gov: NCT03266588.

Pharmacokinetics and Safety of Endotracheal Lidocainefor Endotracheal Intubation in Critically Ill Children.

Critically ill pediatric patients are endotracheally intubated in pediatric intensive care units for a variety of illnesses and indications. Management of an endotracheal tube (ETT) requires suctioning to remove patient secretions and prevent occlusion, but this practice can be associated with adverse events, such as hemodynamic deterioration or increases in intracranial pressure. Instillation of lidocaine into the ETT before suctioning may be beneficial in preventing these events. The purpose of this phase I, fixed-dose, open-label pharmacokinetic and safety study, conducted in endotracheally intubated and mechanically ventilated infants and children requiring ETT suctioning, was to determine the serum concentrations and safety of lidocaine after ETT administration. A total of 21 infants and children meeting inclusion criteria received a single dose of ETT lidocaine per institutional protocol. Blood samples were obtained pre-dose and at 5, 10, 30, and 120 minutes after administration for serum concentration analysis. Lidocaine dosing was driven by weight and age, with infants and children aged > 38 weeks' estimated gestational age and <3 years receiving 0.5 mg/kg/dose (maximum: 20 mg/dose) and children aged 3-18 years receiving 1mg/kg/dose (maximum: 100 mg/dose). No subjects aged <3 years had detectable serum lidocaine concentrations. Four subjects in the group aged ≥ 3 years had detectable serum lidocaine concentrations at 5, 10, and/or 30 minutes, but no serum concentrations were within the toxic range. No adverse effects, such as cough, bronchospasm, seizure activity, or clinically significant depression of cardiac or respiratory function, were noted in any subjects. Pharmacokinetic sampling showed that only 4 of 21 subjects had detectable serum lidocaine concentrations and none were within the toxic range. The safety of ETT administration of lidocaine in endotracheally intubated infants and children requiring ETT suctioning was demonstratedat the doses used in this study. The study was conducted at Norton Children's Hospital. The research team confirmed that this study was not registered with clinicaltrials.gov.

RVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai proches)

BackgroundZaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralisation, and reactogenicity following vaccination.MethodsIn this prospective cohort study, 2115 consenting close contacts (“proches”) of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralisation.ResultsTen percent were seropositive at baseline. At day 28, IgG in baseline seronegative (GMT 0.106 IU/ml, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p < 0.0001). There was strong correlation between antibody titres and virus neutralisation in day 28 samples (Spearman’s rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles to those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% in children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. No EVD survivors tested positive for Ebolavirus by RT-PCR.ConclusionsThese data add further evidence of rVSV-ZEBOV safety and immunogenicity, including in people with pre-existing antibodies from suspected natural ZEBOV infection whose state does not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required.

Dual-Fluoroscopy vs. Single-Fluoroscopy in Balloon Kyphoplasty: A Study of Efficiency and Safety.

Background: Vertebral compression fractures (VCFs) are the most prevalent type of osteoporotic fractures, often causing significant pain, morbidity, and mortality. Vertebral augmentation procedures like balloon kyphoplasty (BK) are effective in treating VCFs. These procedures are typically performed using a single fluoroscopy machine (SF) for anteroposterior (AP) and lateral views. We have implemented a dual-fluoroscopy (DF) technique to reduce procedure time and radiation exposure. The goal of this study was to determine whether dual-fluoroscopy could optimize surgical efficiency without compromising safety, offering a more effective alternative to traditional single-fluoroscopy methods. Methods: This retrospective study included 126 patients who underwent BK with either SF (n = 74, 58.7%) or DF (n = 52, 41.3%) between 2020 and 2024. We collected data on procedure duration per pedicle (PDPP), radiation exposure (reference air kerma and dose-area product [DAP]), and radiation duration. A sub-analysis of post-learning phase cases was performed. Results: A learning curve was identified for the first 24 cases and 15 cases using the SF technique and DF technique, respectively, which was followed by a stabilization in procedure duration per pedicle (Levene's statistic = 10.623, p = 0.002 for SD difference, p < 0.001 for mean PDPP difference). After the completion of the learning phase for both techniques, the DF group demonstrated a significantly shorter PDPP (11.83 ± 4.3 vs. 14.03 ± 5.57 min, p = 0.049). No significant differences were found in radiation exposure, including radiation duration (p = 0.577), reference air kerma, or DAP. Conclusions: Dual-fluoroscopy significantly reduces procedure time after the learning curve is overcome, improving efficiency without increasing radiation exposure. This technique holds promise for optimizing kyphoplasty workflow and safety, supporting broader clinical adoption.

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy

Globally, nearly half of all pregnancies are unintended, ~1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy against two highly prevalent sexually transmitted infections (STIs).

Preclinical ex vivo IL2RG gene therapy using autologous hematopoietic stem cells as an effective and safe treatment for X-linked severe combined immunodeficiency disease

X-linked severe combined immunodeficiency disease (X-SCID) is a rare inherited disease caused by mutations in the interleukin 2 receptor subunit gamma gene (IL2RG), which encodes the common γ chain protein, a subunit of the receptor for lymphocytes. X-SCID is characterized by profound defects in T-cell, B-cell, and natural killer cell function. Here, we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations. Among those, the two adolescent patients carrying missense mutation with an atypical immunotype were confirmed by further analyzing IL-2-JAK-STAT5 signaling, T cell proliferation, and T cell receptor excision circles (Trecs). Interestingly, Bacillus Calmette-Guérin (BCG) disease occurred commonly in this cohort. Although allogeneic hematopoietic stem-cell transplantation is curative for the disease, it is not available to all patients due to the lack of suitable matched donors. Autologous gene therapy using a self-inactivating lentiviral vector (SIN-LV) technology, developed in recent decades has provided an alternative therapy for treating such mono-genetic diseases. Here, we performed the pre-clinical studies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG and CD34+ stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID. This work is done complied with the established "Good Manufacturing Practice" (GMP) used in the clinical trials. In addition, a safety study is performed using the transduced CD34+ cells implanted into the axilla of nude mice in vivo. Overall, our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV, which paves the way for conducting X-SCID gene therapy clinical trials in China in the near future.

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Clinical efficacy evaluation and safety study of Qishen Tongmai Yin I combined with moxibustion therapy on ASO: A retrospective study.

This study aimed to assess the therapeutic efficacy of moxibustion assisted therapy in combination with Qishen Tongmai Yin No. 1 on arteriosclerosis obliterans (ASO) patients. The impact on clinical symptoms, sign scores, foot dorsum temperature, foot dorsum artery blood flow, and overall clinical efficacy were analyzed. Sixty-three ASO patients from Beijing Xiaotangshan Hospital and Beijing Shijitan Hospital (January 2020-December 2021) were divided into 3 groups: a Qi Shen Tong Mai Yin I-only group, a moxibustion-only group, and a combined treatment group receiving both moxibustion and Qi Shen Tong Mai Yin No. 1. The treatment group took Qi Shen Tong Mai Yin No. 1 orally 3 times daily for 1 month. Moxibustion, employing a mild method, was applied once daily for 35 minutes over a month. Key acupoints included bilateral kidney Shu, Guan Yuan, Ming Men, Zu San Li, Wei Zhong, San Yin Jiao, and Yao Yang Guan. Posttreatment, clinical symptom scores, and dorsum foot parameters were measured, including foot temperature and dorsum foot artery blood flow. Total effective and cure rates were calculated. Pretreatment, no significant differences existed among the 3 groups (P > .05). Posttreatment, the clinical efficacy, dorsalis pedis temperature, dorsalis pedis artery blood flow, and symptom scores significantly improved in all groups (P < .05). Differences in these indicators were also significant among the 3 groups (P < .05). Moxibustion assisted therapy combined with Qishen Tongmai Yin No. 1 enhances total effective and cure rates in ASO patients, improving foot temperature, blood flow, microcirculation, and overall clinical efficacy. Additionally, this combination reduces scores for intermittent claudication, pain, skin temperature, soreness, skin color, and numbness, mitigating disease progression. Safety evaluation indicated no adverse events during treatment, demonstrating the safety of the combined therapy.

Tofacitinib Safety and Effectiveness in Canadian Patients with Rheumatoid Arthritis by Cardiovascular Risk Enrichment: Subanalysis of the CANTORAL Study.

ORAL Surveillance, a post-authorisation safety study of patients with rheumatoid arthritis (RA) enriched for cardiovascular (CV) risk, demonstrated increased risk of major adverse CV events (MACE) and malignancies (excluding non-melanoma skin cancer [NMSC]) for tofacitinib versus tumour necrosis factor inhibitors (TNFi). This analysis of a real-world Canadian observational study evaluated tofacitinib safety/effectiveness in patients meeting or not meeting CV risk criteria. CANTORAL included patients with moderate-to-severe RA initiating tofacitinib (10/2017-07/2020; N = 504). Interim data (data-cut: 07/2021) were stratified as CV risk-enriched (CV+ ; patients ≥ 50 years with ≥ 1 additional CV risk factor) or not CV risk-enriched (CV-; ≥ 50years without additional CV risk factors and 18-49 years with/without CV risk factors). Safety and persistence were evaluated to month (M) 36. Effectiveness outcomes to M18 included Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA)/remission (CANTORAL co-primary endpoints) and Disease Activity Score in 28 joints, C-reactive protein (DAS28-4[CRP]) < 3.2/ < 2.6. Overall, 272/232 patients were included in CV+ /CV- cohorts (full analysis set) (435/356 patient-years [safety analysis set]). Incidence rates (events/100 patient-years) in CV+ /CV- cohorts were 138.5/112.5 for treatment-emergent adverse events (AEs); 17.0/5.6for serious AEs; 1.2/0.3for deaths; 5.5/1.7 for serious infections; 1.4/1.1 for herpes zoster; 1.6/0.0for MACE; 2.1/0.3for malignancies (excluding NMSC); 0.7/0.6 for NMSC; 0.5/0.0 for venous thromboembolic events. Persistence was generally comparable between cohorts. In CV+ /CV- cohorts, at M6, CDAI LDA and remission rates were 51.5%/54.6% and 12.0%/19.6%; DAS28-4(CRP) < 3.2/ < 2.6 rates were 44.0%/39.3% and 31.5%/28.8%, respectively; effectiveness was generally maintained to M18. In concordance with studies of background risk, AEs were more common in patients with CV risk enrichment, particularly those aged ≥ 65 years. Tofacitinib effectiveness/persistence were generally similar regardless of CV risk enrichment. These findings support individualised treatment benefit-risk assessment, including CV assessment/management, to optimise RA outcomes.

Systematic review of cognitive impairment in drivers through mental workload using physiological measures of heart rate variability.

The intricate interplay between driver cognitive dysfunction, mental workload (MWL), and heart rate variability (HRV) provides a captivating avenue for investigation within the domain of transportation safety studies. This article provides a systematic review and examines cognitive hindrance stemming from mental workload and heart rate variability. It scrutinizes the mental workload experienced by drivers by leveraging data gleaned from prior studies that employed heart rate monitoring systems and eye tracking technology, thereby illuminating the correlation between cognitive impairment, mental workload, and physiological indicators such as heart rate and ocular movements. The investigation is grounded in the premise that the mental workload of drivers can be assessed through physiological cues, such as heart rate and eye movements. The study discovered that HRV and infrared (IR) measurements played a crucial role in evaluating fatigue and workload for skilled drivers. However, the study overlooked potential factors contributing to cognitive impairment in drivers and could benefit from incorporating alternative indicators of cognitive workload for deeper insights. Furthermore, investigated driving simulators demonstrated that an eco-safe driving Human-Machine Interface (HMI) significantly promoted safe driving behaviors without imposing excessive mental and visual workload on drivers. Recommendations were made for future studies to consider additional indicators of cognitive workload, such as subjective assessments or task performance metrics, for a more comprehensive understanding.