Emergency Events Research Articles

Surufatinib combined with TAS-102 as a late-line therapy in patients with metastatic pancreatic cancer (mPDAC): Updated results of a single-arm, phase II trial.

739 Background: Patients (pts) with mPDAC recurrent after FOLFIRINOX and AG chemotherapies have few treatment options. Previous reports of NCT05481463 showed promising clinical benefits of surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus TAS-102 (combination of trifluridine and tipiracil hydrochloride) in recurrent mPDAC pts. Here, we report the updated results. Methods: This is a single-arm, phase II trial (NCT05481463). Eligible pts with histologically confirmed mPDAC, who had progressed after ≥ 2 lines of previous therapies were treated with surufatinib (250mg, qd, po, q4w) and TAS-102 (35 mg/m 2 , bid, po, days 1–5 and 8–12, q4w). The primary endpoint was progression-free survival (PFS). Key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: Up to Sep 18, 2024, 20 pts were enrolled (median age 58 years, male 70.0%, TNM stage IV 100.0%, ECOG PS 1 100.0%, liver metastasis 50.0%, peritoneum metastasis 50.0%). Median baseline CA19-9 level of the 20 pts was 996.7u/ml, with a range from 2u/ml to 16612u/ml. 40.0% of pts had received 3L prior therapies before enrollment and 70.0% with primary site on pancreatic body and tail. All pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 15.0% (3 PRs), DCR was 30.0% (3 PRs, 3SDs). 35.0% pts had stable or shrinking tumors. Median PFS was 2.35m (95% CI 1.91-3.94). Median OS was 6.44m (95% CI 3.81-NR). In subgroup analysis, significantly longer PFS&OS were observed in pts without liver metastasis (mPFS: 3.42m vs 2.01m, p=0.049; mOS: 9.92m vs 3.70m, p=0.026), or with ≤ 2 metastatic organs (mPFS: 3.94m vs 1.91m, p=0.005; mOS: 10.09m vs 3.81m, p=0.003). Additionally, OS was significantly prolonged in pts with baseline CA19-9 level ≤ 996.7u/ml, in contrast with those with baseline CA19-9 level more than 996.7u/ml (9.92m vs 3.70m, p=0.008). All pts experienced treatment emergent adverse events (TEAEs). Most common (≥ 10%) TEAEs (any grade) were anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%). Grade ≥ 3 TEAEs included neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%). Conclusions: Surufatinib plus TAS-102 showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory mPDAC, especially in patients without liver metastasis, with ≤ 2 metastatic organs, or with baseline CA19-9 level ≤ 996.7u/ml. The results warrant further investigations in a large cohort. Clinical trial information: NCT05481463 .

Efficacy and safety of albumin-bound docetaxel vs. docetaxel in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma: A multicenter, randomized, phase II study.

333 Background: Docetaxel has demonstrated promising activity in gastric cancer, both as monotherapy and in combination with other agents. Albumin-bound docetaxel (HB1801) is a new kind of taxane and has many advantages compared with docetaxel. Previous phase I study has demonstrated that HB1801 showed preliminary efficacy in patients with gastric cancer. Methods: In this phase II study, eligible patients were aged 18-75 years with histologically confirmed gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, who progressed on at least first line of combined chemotherapy of platinum and fluorouracil. Patients were randomized (1:1) to receive HB1801 (100 mg/m 2 ) or docetaxel (Taxotere, 75 mg/m 2 ) administered every 3 weeks by intravenous infusion. Stratified factors included previous treatment with immunotherapy (yes or no) and ECOG PS (0 or 1). Primary endpoint was progression free survival (PFS). Results: As of June 25, 2024, 128 patients were randomized to the HB1801 group ( n =65) or the docetaxel group ( n =63). The two groups were comparable on baseline characteristics. Overall, the median age was 59.0 (range 27-75) years, 106 (82.8%) patients had ECOG PS of 1. 76 (59.4%) patients had received previous treatment with immunotherapy. 76 (59.4%) patients had ≥ 2 metastatic sites. Median PFS was 4.0 months (95%CI 2.8-4.2) with HB1801 versus 2.7 months (95%CI 1.8-3.0) with docetaxel, HR = 0.81(95%CI 0.53, 1.21). Objective response rate and disease control rate were 21.5% (1CR and 13 PRs, 95%CI 12.3-33.5) and 56.9% (20 SDs, 95%CI 44.0-69.2) in the HB1801 group, compared with 14.3% (1 CR and 8 PRs, 95%CI 6.8-25.4) and 42.9% (17 SDs, 95%CI 30.5-56.0) in the docetaxel group. Median overall survival was 11.3 months with HB1801 versus 7.8 months with docetaxel (HR = 0.59 [95%CI 0.35, 1.01], p=0.025). Treatment-related adverse events (TRAEs) occurred in 93.8% of patients receiving HB1801, and 93.7% of patients receiving docetaxel. Alopecia (46.2% vs. 39.7%), fatigue (43.1% vs 23.8%), anemia (40.0% vs 39.7%), hypoalbuminemia (29.2% vs 12.7%), decreased appetite (21.5% vs 12.7%), peripheral edema (16.9% vs 12.7%) and nausea (15.4% vs 19.0%) were the most common TRAEs in the HB1801 group and the docetaxel group. 20 patients (30.8%) in the HB1801 group and 19 patients (30.2%) in the docetaxel group experienced ≥grade 3 TRAEs, with the most common being anemia and fatigue. 3 patients in the docetaxel group experienced treatment emergent adverse events (TEAEs) leading to death, which one was considered to be treatment-related. No patients in the HB1801 group had TEAEs leading to death. No new safety signal was observed in HB1801 group. Conclusions: Compared with Taxotere, HB1801 results in 41% reduction in risk of death with a manageable safety profile in patients with previously treated advanced G/GEJ cancer. Clinical trial information: NCT05705635 .

Occupational health impacts of climate-related emergency events on health system workers in British Columbia

Occupational health impacts of climate-related emergency events on health system workers in British Columbia

A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome

BackgroundPreclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.DesignThis was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6–12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.MethodsParticipants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity.ResultsTwenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019–11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine.ConclusionsShort-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT.Trial registrationRegistered at clinicaltrials.gov NCT03633058.

Effects of a New Enzymatic Debrider (SN514-066b) on Eschar Protein Digestion, Burn Wound Debridement, and Healthy Skin Irritation.

Objective: SN514 is a thermolysin-like enzyme under development as a debrider. Preclinical and non-clinical studies supported a first in human healthy volunteer study to predict the need for protection of periwound skin. Approach: Pharmacologic activity testing compared in vitro digestion of collagen, fibrin, and elastin with relevant enzymes. A Yorkshire pig model of burn injury was used to evaluate debridement over 10 days and effects on intact skin. A human 21-day cumulative irritation study using Webril patches taped to the backs of 38 healthy adult volunteers compared four enzyme concentrations (0.10%, 0.20%, 0.40%, and 0.80% w/w) with the hydrogel vehicle, saline (low irritant control), and 0.2% sodium lauryl sulfate (positive irritant control) using randomized placements and blinded evaluation. Results: SN514 showed excellent digestion of fibrin, elastin, and collagen in vitro. Burn wound studies in Yorkshire pigs showed efficient eschar debridement with minimal periwound erythema. Direct treatment on intact porcine skin for 5 days produced no to limited erythema. The preclinical findings of minimal irritation with SN514 were verified by a Phase 1 first-in-human 21-day cumulative skin irritation test. Irritation was observed to increase stepwise by concentration, confirming formulation accuracy. Each enzyme concentration was found to be "possibly mild in use" (Berger and Bowman method). No treatment emergent adverse events were observed during the study. Innovation: A fast-acting enzyme with a favorable irritation profile, prepared as a stable, ready to use hydrogel formulation, overcomes many recognized shortcomings of enzyme debriders. Conclusion: The overall findings support clinical dose range testing for tolerance and preliminary efficacy.

First-in-Human Phase 1 study of a CD16A bispecific innate cell engager, AFM24, targeting EGFR-expressing solid tumors.

Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on natural killer (NK) cells/macrophages and EGFR on tumor cells, redirecting antitumor activity towards tumors. The safety and tolerability of AFM24 was evaluated in this Phase 1/2a dose escalation/dose expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR. The main objective in Phase 1 was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints included the incidence of treatment emergent adverse events and pharmacokinetics. In the dose escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a DLT of Grade 3 infusion-related reaction (IRR). IRRs were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics were dose-proportional and CD16A receptor occupancy on NK cells approached saturation between 320-480 mg. Paired tumor biopsies demonstrated activation of innate and adaptive immune responses within the tumor. Best objective response was stable disease in 10/35 patients; four had stable disease for 4.3-7.1 months. AFM24 was well tolerated with 480 mg established as the RP2D. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.

DOP098 Development of BEN8744, a phase 2 ready, peripherally restricted PDE10 inhibitor targeting a new mechanism of action for the treatment of ulcerative colitis.

Abstract Background To identify novel therapeutic targets for ulcerative colitis (UC), a disease-agnostic Knowledge Graph1, comprising multi-modal data sources was used as input to a machine learning gene/protein prioritisation model2. Following in-depth target assessment, phosphodiesterase 10 (PDE10) was selected as a promising novel target for further investigation. Methods Our aim was to develop a novel therapeutic target for UC that will have not just anti-inflammatory properties but improve barrier function. PDE10 hydrolyses both cAMP and cGMP. In UC patients, reduced cAMP levels promote inflammation, while guanylate cyclase-C and its endogenous activators are downregulated in the colon, with lower levels correlating to higher disease severity. Our transcriptional analysis revealed that PDE10 is upregulated in UC patients’ colonic mucosa, correlating with disease severity, suggesting that PDE10 inhibition could potentially restore normal cyclic nucleotide signalling. Following successful experimental target validation, we developed BEN8744 a potent, selective, peripherally restricted oral PDE10 inhibitor. Supporting its therapeutic potential, BEN8744 significantly reduced TNFα, IL-6, and IL-8 in ex vivo inflamed UC patient colonic mucosa biopsy samples, and improved barrier integrity in an in vitro intestinal epithelial cell model. In a Phase 1, randomised, double-blind, placebo-controlled trial with 74 healthy subjects, we assessed the safety, tolerability, pharmacokinetics (PK), and food effect of BEN8744 (NCT06118385). The trial was in 3 parts: Part A investigated single ascending oral doses of BEN8744; Part B was a 2-way crossover assessment of the effect of food on the PK of BEN8744; and Part C investigated multiple ascending oral doses of BEN8744 for 14 days. Results All treatment emergent adverse events (TEASs) were mild or moderate in severity with no clinically significant findings in physical examination, laboratory variables, ECGs, OAAS/S or VAS results, during the study. No class effects previously seen with centrally active PDE10 inhibitors were observed in the present trial. Neither were there any dose dependent nervous system related TEAEs. Conclusion BEN8744 is a potent, peripherally restricted, well tolerated Phase 2 ready PDE10 inhibitor targeting a novel mechanism of action for the treatment of UC. The Phase 1 study showed a favourable safety, tolerability, and PK profile for BEN8744, supporting its further development. We are now planning a study in patients with moderate to severely active ulcerative colitis.

P0813 Integrated summary of safety of obefazimod for patients with moderately to severely active ulcerative colitis

Abstract Background Obefazimod is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC across 4 clinical studies: two placebo-controlled Phase 2 induction trials, and two subsequent open-label maintenance (OLM) studies [2, 3]. Here we report an integrated safety analysis of those studies in the UC clinical program. Methods Exposure-adjusted incidence rates (EAIRs per patients-years [PY]) of treatment emergent adverse events (TEAEs) were examined among patients from the induction trials (NCT03093259, NCT03760003), and the OLM studies (NCT03368118, NCT04023396). Patients received one of three obefazimod doses (25mg, 50mg or 100mg QD) or placebo during induction, and all patients received 50 mg QD during OLM studies. Results Demographics and disease characteristics were similar among treatment groups. Exposure for all obefazimod-treated patients (N=274) was 440.1 PY including induction and maintenance periods. EAIR of TEAEs per PY was 1.40 in obefazimod-treated patients and 2.40 in placebo-treated patients (N=73), with TEAEs occurring in 78.5% and 47.9% of patients, respectively (Table 1). The most common TEAEs (EAIR per PY ≥ 0.05) in all obefazimod-treated patients included headache, Covid-19, ulcerative colitis, nasopharyngitis, and nausea. For each of these TEAEs, the incidence per PY was numerically lower in the group of all obefazimod-treated patients relative to placebo. Conclusion This integrated safety analysis of the 4 completed studies in the obefazimod UC clinical program indicates that exposure-adjusted incidence rates of TEAEs were generally numerically lower among patients treated with obefazimod relative to placebo. Integrated safety data further support a favorable safety and tolerability profile.

Scenarios for the emergence of new miRNA genes in the plant Arabidopsis halleri.

MicroRNAs (miRNAs) are central players of the regulation of gene expression in Eukaryotes. The repertoires of miRNA genes vary drastically even among closely related species, indicating that they are evolutionarily labile. However, the processes by which they originate over the course of evolution and the nature of their progenitors across the genome remain poorly understood. Here we analyzed miRNA genes in Arabidopsis halleri, a plant species where we recently documented a large number of species-specific miRNA genes, likely to represent recent events of emergence. Analysis of sequence homology across the genome indicates that a diversity of sources contributes to the emergence of new miRNA genes, including inverted duplications from protein-coding genes, rearrangements of transposable element sequences and duplications of preexisting miRNA genes. Our observations indicate that the origin from protein-coding genes was less common than was previously considered. In contrast, we estimate that almost half of the new miRNA genes likely emerged from transposable elements. Miniature inverted transposable elements (MITE) seem to be particularly important contributors to new miRNA genes, with the Harbinger and Mariner transposable element superfamilies representing disproportionate sources for their emergence. We further analyzed the recent expansion of a miRNA family derived from MuDR elements, and the duplication of miRNA genes formed by two hAT transposons. Overall, our results illustrate the rapid pace at which new regulatory elements can arise from the modification of preexisting sequences in a genome, and highlight the central role of certain categories of transposable elements in this process.

Exploring Emergency Decision-Making: A Bibliometric Review of Existing Literature

In recent years, we have witnessed an increase in emergency and catastrophic events. It is now crucial for professionals involved in emergency management to stay updated on issues and statistics related to decision-making in emergency situations. Emergency Decision-Making (EDM) has emerged as a strategic field of study, guiding the training and education of those responsible for managing and responding to emergencies, making it a critical area for national security. This original work advances the study of EDM by offering key insights into research trends over the years, the geographical distribution of scientific output, the methodologies employed, yearly statistics, and the spread of key terms and the most-explored topics. The main findings of this study on EDM literature from 1977 to 2023 highlight the dominant role of China and the USA in scientific productivity in the field. Moreover, a significant absolute increase in scientific productivity has been observed from 2020 to the present.

Twitter User Geolocation Based on Location Feature Enhancement

User location discovery from social media is crucial for location-based services like emergency awareness and event monitoring. Existing approaches generally integrate user-generated text features and social relationships, but insufficiently explore location-specific features and geographically proximate relationships, leading to suboptimal accuracy. In this paper, we propose a Twitter user geolocation method based on location feature enhancement, to better capture the location characteristics in users’ tweets and social relationships. Specifically, a user tweet representation algorithm based on location feature separation (TwLS) is designed. By leveraging words’ location-aware weight matrix and pre-trained embeddings, TwLS calculates a tweet representation for each user in every location, explicitly indicating the relevance between users and various locations. Additionally, we develop the local celebrity discovery method (LocCel) to construct social networks by identifying and preserving geographically concentrated high-degree nodes while filtering noise. Thereby LocCel enhances local relationships and strengthens location-proximate connections within the user social network. Experiments on two real-world datasets show that our method outperforms seven baselines, improving user geolocation accuracy by 3.1% ∼ 8.1% and 1.8% ∼ 8.8%, while reducing median error by 22.2% ∼ 52.8% and 19.4% ∼ 50.7%, respectively.

Lebrikizumab Improves Atopic Dermatitis in Adult and Adolescent Patients With Skin of Color: 16-Week Results From the ADmirable Study

Introduction: Lebrikizumab is a novel monoclonal antibody that binds with high affinity and a slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL13 with high potency. ADmirable (NCT05372419) is an ongoing, open-label, Phase 3b clinical trial of lebrikizumab in patients with moderate-to-severe atopic dermatitis (AD) and skin of color (SoC). These are the first primary results of any Phase 3 clinical trial studying patients with AD and SoC, a historically underrepresented patient population. Methods: At baseline and Week 2, patients received 500-mg lebrikizumab loading doses followed by 250-mg every 2 weeks through Week 16. Concomitant topical therapy was allowed. Patients receiving protocol-defined rescue therapy were discontinued. Key eligibility criteria included: ≥12 years of age, self-reported race other than White, Fitzpatrick Phototype IV-VI, and moderate-to-severe AD. This study includes new objective measures of pigment such as PDCA-Derm™. Endpoints are summarized as observed (primary analysis) and using non-responder imputation/multiple imputation (NRI/MI; supporting analysis). Results: At baseline (N=90), patients had a mean (SD) age of 40.7 (19.6) years, AD disease duration of 19.7 (16.1) years, Eczema Area and Severity Index (EASI) of 26.4 (12.2), and Pruritus Numeric Rating Scale (NRS) of 7.0 (2.2). Forty-three percent of patients were female and 16% were adolescent. Most patients had an Investigator’s Global Assessment (IGA) of 3 (69%). Patients self-reported their race as Black/African American (78%), Asian (11%), American Indian/Alaskan Native (7%), and Native Hawaiian or Other Pacific Islander (4%). Patients had Fitzpatrick Phototypes of IV (43%), V (24%), and VI (32%). At Week 16, 69.2% (54/78) of patients achieved a 75% improvement in EASI (NRI/MI, 66.9%), 44.9% (35/78) achieved a 90% improvement in EASI (NRI/MI, 42.5%), 44.9% (35/78) achieved an IGA 0/1 with ≥2-point improvement (NRI/MI, 44.1%), and 58.1% (36/62) reported ≥4-point Pruritus NRS improvement (NRI/MI, 55.4%). Approximately 50% of patients reported itch improvement within 6 weeks. Using PDCA-Derm™, hypopigmentation and hyperpigmentation improved in 33.3% (4/12) and 63.0% (29/46) of patients, respectively (as observed). Most treatment emergent adverse events (TEAE) were mild-to-moderate in severity. No TEAEs lead to discontinuation and no cases of treatment-related conjunctivitis were reported. No serious adverse events were observed. Conclusion: Lebrikizumab improved signs and symptoms of disease, including post-inflammatory pigment discoloration, in patients with AD and SoC and demonstrated a favorable safety profile.

Health Emergency Challenges and Support Strategies: A Qualitative Study on Healthcare Workers

The purpose of this article is to explore the health emergency related challenges (HECs) faced by healthcare workers (HCWs) during COVID-19. Additionally, the study also examines the various practices and support strategies that have helped HCWs deal with HECs. In this qualitative thematic study, the participants were selected using snowball and purposive sampling techniques. Semi-structured telephone interviews were conducted to understand the subjective evaluations of health emergency (HE) events. Themes covering different areas of challenge and coping mechanisms were identified. Inductive thematic analysis yielded six themes. This study presents possible HECs that can affect HCWs, and there is convincing evidence that support from different agencies can effectively help HCWs in dealing with HECs. These findings are important and can contribute to policymakers in drawing guidelines for managing and supporting HCWs in future HEs.

Pre-hospital emergency: analyzing the status of medication and equipment in pre-hospital emergency bases.

Pre-hospital emergency care is a comprehensive system that responds to the medical needs of injured patients outside of health care centers. The right equipment and facilities are necessary to provide proper and satisfactory services. Due to the increase in pre-hospital emergency services and the high prevalence of emergency events, the present study was conducted to investigate the status of medication and equipment in pre-hospital emergency bases and compare it with national standards. This descriptive-analytical study was conducted in Iran in 2022-2023. Sampling was done in 46 urban and road bases using the census method. Data collection was done using two checklists. The first checklist, in 17 sections, was based on the latest edition of the instructions for medication and equipment of Iran's pre-hospital emergency organization. The second checklist included the specifications of the base. The collected data were analyzed using descriptive and analytical statistics and SPSS25 software. Of the 46 bases included in the study, 41.3% were urban bases and the rest were road bases. The mean age for building the bases was 13.76±9.47 years (the minimum was one year and the maximum was 45 years). The mean score of the status of medication and equipment in the bases was 224.34 ± 32.05 (minimum score 155 and maximum 322), which was 56.09% of the total score. The highest score was obtained in the medication section of the patient cabin (81.88%) and the lowest score was in the CBRNe bag equipment section (4.55%). The results showed that the status of the medication and equipment of the pre-hospital emergency bases is far from the standards. This long distance can affect the quality of pre-hospital emergency services. Resolving deficiencies and reaching standards requires more attention.

INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease.

Soluble species of multimeric amyloid-beta including globular amyloid-beta oligomers (AβOs) and linear amyloid-beta protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against globular species of soluble AβO, that has over 650-fold greater binding affinity for AβOs over monomers and appears to have relatively little binding to amyloid plaque. To assess safety, pharmacokinetics, and exploratory measures including target engagement, biomarker effects, and clinical efficacy of sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment and mild dementia due to AD). Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study. Fifteen study centers in the United States. Sixty-five participants with early symptomatic AD. Participants received one infusion of sabirnetug 2 mg/kg, 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part A) or three infusions of sabirnetug 10 mg/kg, 25 mg/kg, 60 mg/kg, or placebo (Part B). Safety, tolerability, serum pharmacokinetics, and central target engagement of single and multiple doses of sabirnetug, cerebrospinal fluid (CSF) concentrations of sabirnetug, and amyloid plaque load, as determined by positron emission tomography. Sabirnetug was generally well tolerated. A larger percentage of participants receiving sabirnetug (56.3%) versus placebo (42.9%) had at least one treatment emergent adverse event, with approximately 29% in each group considered related to study drug. Most events were mild-to-moderate in severity. Of 48 participants given sabirnetug, five developed amyloid related imaging abnormalities - edema/effusion, including one instance that was mildly symptomatic in a participant who had received one dose sabirnetug 60 mg/kg. Notably, none of the six apolipoprotein E Ɛ4 homozygotes who received sabirnetug developed amyloid related imaging abnormalities - edema/effusion or - hemorrhage/hemosiderin deposition. Infusion reactions, such as rash, pain, or erythema, were not frequent (6.3% for sabirnetug versus 0.0% for placebo). Sabirnetug exposure was dose proportional in both serum and CSF. Target engagement, defined as drug bound to AβOs in CSF, was shown to be dose and exposure dependent. Over three months, approximately 25% and 20% reduction in amyloid plaques, respectively, were observed in participants receiving three infusions of sabirnetug 60 mg/kg every four weeks and 25 mg/kg every two weeks. The Phase 1 INTERCEPT-AD study provided safety, tolerability, dosing, and target engagement data that supported the design of the ongoing ALTITUDE-AD study (NCT06335173).

Mapping hotspots of zoonotic pathogen emergence: an integrated model-based and participatory-based approach.

An increase in pandemics of zoonotic origin has led to a growing interest in using statistical prediction to identify hotspots of zoonotic emergence. However, the rare nature of pathogen emergence requires modellers to impose simplifying assumptions, which limit the model's validity. We present a novel approach to hotspot mapping that aims to improve validity by combining model-based insights with expert knowledge. We conducted a systematic literature review to identify predictors for zoonotic emergence events in three priority virus families (Filoviridae, Coronaviridae, and Paramyxoviridae). We searched PubMed, Web of Science, Agricola, medRxiv, bioRxiv, Embase, CAB Global Health, and Google Scholar on Oct 14-28, 2021, with no restrictions on language or the date of publication. Articles suggested by subject matter experts and those identified by a review of reference lists were also included. We used regularised regression to fit a model to the data extracted from the literature and produced maps of ranked risk. In a series of workshops in five countries (Kenya, Peru, Senegal, Thailand, and Viet Nam), experts in zoonotic diseases produced qualitative hotspot maps based on their expertise, which were compared with the model-derived maps. 425 articles were analysed, from which 19 predictors and 1068 outcome events were identified. The in-sample misclassification error was 0·365, and 89% of participant-selected zones were ranked as moderate or high risk by the model. Participant-selected zones were too large to be actionable without further refinement. Discordance was probably due to missing predictors for which no valid data exist, and homogeneity imposed by our global model. Concordance between the two sets of maps supports the validity of each. Because model-based and participatory strategies have non-overlapping limitations, the results can be harmonised to minimise bias, and model-based results could be used to refine participant-selected zones. This approach shows potential for refining deployment of countermeasures to prevent future pandemics. US Agency for International Development.

Strategy Deduction for Improving Aviation Emergency Rescue Capability from the Perspective of Public Safety

Aviation emergency rescue plays a crucial role in the emergency management of various emergency events. Consequently, the processes of identifying relevant constraints of aviation emergency rescue ability, analyzing the interactive relationship among factors, and putting forward an economical and effective improvement strategy for aviation emergency rescue capabilities have become widely popular among scholars. To greatly improve the economic input efficiency of aviation emergency rescue capabilities, 18 relevant influencing factors were screened and identified from four perspectives: system institutionalization, technological advancement, rescuer professionalism, and operation safety. Then, the causal relationship among the influencing factors and the feedback mechanism were analyzed via the system dynamics (SD) method, and the influencing factor weights were calculated via the entropy weight method. Then, the equations of state variables and constants among the influencing factors were determined, and an SD model of aviation emergency rescue was built. Finally, a case study based on a practical construction condition of an aviation emergency rescue in Henan Province, China was analyzed. The variation trend of rescue ability was predicted from the temporal dimension, and the optimal economic input strategy for effectively improving the rescue ability was determined. Results demonstrate that the efficacy level of aviation emergency rescue ability in Henan Province is 44.97. The aviation rescue ability level on the 49th month can be improved to 90 if the monthly input into the aviation emergency rescue is raised to 3 million RMB. Additionally, the aviation rescue project can be significantly improved if the input proportions of operation safety, rescuer professionalism, system institutionalization, and technological advancement are 0.4, 0.2, 0.2, and 0.2, respectively. This work can provide an economic decision reference for building and perfecting public safety systems.

Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukaemia arising from a prior myeloproliferative neoplasm.

Acute myeloid leukaemia (AML) arising from a myeloproliferative neoplasm (MPN) is more aggressive and less responsive to therapies compared to de novo AML. Olutasidenib, an oral small-molecule inhibitor of mutated IDH1 (mIDH1), showed encouraging and durable responses in a phase 1/2 study of adults with post-MPN mIDH1 AML. Patients received olutasidenib 150 mg BID monotherapy or in combination with azacitidine. Primary end-points: safety and best response defined as complete remission (CR), CR with partial haematological recovery or morphological leukaemia-free state (MLFS). Analysis included 15 patients with post-MPN mIDH1 AML; 10 had relapsed or refractory AML and five had newly diagnosed AML. Six were treated with olutasidenib monotherapy and nine in combination with azacitidine. Treatment emergent adverse events occurred in 15 patients, three of whom discontinued therapy. CR: 40% (n = 6/15); median duration of response: 15.6 months (range: 1.7-44.3); CR with incomplete haematological recovery: 13% (n = 2/15); MLFS: 7% (n = 1/15); composite complete remission (CRc): 53% (n = 8/15); and overall response rate (ORR): 60% (9/18). Median duration of CRc and ORR: 13.15 (range: 2.4-48.7) and 14.3 months (range: 2.4-48.7), respectively, and median overall survival: 13.8 months (95% confidence interval: 3.70-23.7). Olutasidenib demonstrated encouraging response rates with a manageable safety profile for patients with post-MPN mIDH1 AML.

Associations between extreme weather events and child undernutrition: evidence from sub-Saharan Africa, 2010–2019

BackgroundExtreme weather events, or natural disasters, present a large and increasing threat to human health, infrastructure and food security, including in sub-Saharan Africa (SSA), where the burden of undernutrition is...

A novel recommender framework with chatbot to stratify heart attack risk

Cardiovascular diseases are a major cause of mortality and morbidity. Fast detection of life-threatening emergency events and an earlier start of the therapy would save many lives and reduce successive disabilities. Understanding the specific risk factors associated with heart attack and the degree of association is crucial in the clinical diagnosis. Considering the potential benefits of intelligent models in healthcare, many researchers have developed a variety of machine learning (ML)-based models to identify patients at risk of a heart attack. However, the common problem of previous works that used ML concepts was the lack of transparency in black-box models, which makes it difficult to understand how the model made the prediction. In this study, an automated smart recommender system (Explainable Artificial Intelligence) for heart attack prediction and risk stratification was developed. For the purpose, the CatBoost classifier was applied as the initial step. Then, the SHAP (SHapley Additive exPlanation) explainable algorithm was employed to determine reasons behind high or low risk classification. The recommender system can provide insights into the reasoning behind the predictions, including group-based and patient-specific explanations. In the final step, we integrated a Large Language Model (LLM) called BioMistral for chatting functionally to talk to users based on the model output as a digital doctor for consultation. Our smart recommender system achieved high accuracy in predicting a patient risk level with an average AUC of 0.88 and can explain the results transparently. Moreover, a Django-based online application that uses patient data to update medical information about an individual’s heart attack risk was created. The LLM chatbot component would answer user questions about heart attacks and serve as a virtual companion on the route to heart health, our system also can locate nearby hospitals by applying Google Maps API and alert the users. The recommender system could improve patient management and lower heart attack risk while timely therapy aids in avoiding subsequent disabilities.