Durable Effects Research Articles

A Tale of Framing and Screening: How Health Messaging and House Screening Affect Malaria Transmission in Ethiopia

Malaria is a major public health problem in Africa. Traditional methods of controlling malaria no longer provide adequate protection against transmission, and future approaches likely require a combination of technical solutions and behavioral change. We use a cluster randomized controlled trial to study the impacts of an intervention that combines house screening with a behavioral intervention based on health messaging. While house screening provides modest positive benefits, these benefits can be leveraged if it is combined with health messaging. We provide tentative evidence that the impact of messaging varies with the design of the choice architecture: loss-framed health messages seem to do better than gain-based messages––our data suggest they may have larger and more durable effects on behavior and health outcomes.

Health Promotion and the case of social prescription of laughter

Abstract Introduction The use of laughter to change lifestyle and promote active and successful ageing is an area of interest within the scope of health promotion. The positive effects of laughter practices occur throughout the life cycle. That is why “laughing” has been identified and indicated as a human activity of social prescription promoting healthy lifestyles. This communication aims to (1) identify the benefits for health, health promotion, well-being, and healthy lifestyle of using laughter activities and practices, (2) identify “laughing” as a social prescription activity that promotes a healthy lifestyle. Methods This work is structured in a narrative review of the literature and the authors’ lived experience as professionals in the well-being area. Results Studies show that laughing and using laughter-inducing approaches have immediate effects on the person who experiences them (e.g. increased general well-being, reduced cortisol levels) with benefits for the immune system and cardiovascular health. Daily practices that are structured and systematic interventions that induce laughter were revealed to have lasting and durable effects. Studies also highlighted the effectiveness of laughter and its important role in improving communication in healthcare professional-patient encounters. Discussion Several behaviors are associated with well-being, happiness and positive affect, but the one that is accessible to all people and with the most immediate effects is laughter. Daily practices, structured and systematic interventions that induce laughter are part of non-pharmacological approaches that promote health and well-being. The principles underlying laughter practices are aligned with the Sustainable Development Goals, namely goal 3 (Health), goal 4 (Education) and goal 16 (Peace).

Long-term efficacy (at and beyond 1 year) of gastric peroral endoscopic myotomy for refractory gastroparesis: A systematic review and meta-analysis.

Although gastric peroral endoscopic myotomy (G-POEM) has shown substantial efficacy in patients with medically refractory gastroparesis (GP), comprehensive long-term data on its effectiveness are lacking. We conducted a systematic review and meta-analysis including observational studies assessing long-term efficacy after G-POEM in patients with refractory GP. Our primary outcome was the pooled rate of clinical success 1-year after G-POEM. Secondary outcomes included clinical success at 2 and 3 years and the rate of adverse events according to the American Society for Gastrointestinal Endoscopy classification. Thirteen studies, involving 952 patients with refractory GP undergoing G-POEM, were eligible. The pooled 1 year-clinical success was 0.72 (95% confidence interval [CI]: 0.56, 0.85, I2 = 94.9%). The clinical success was 0.67 (95% CI: 0.47, 0.97, I2 = 95.8%) when considering only studies defining success as 1 point decrease in Gastroparesis Cardinal Symptoms Index score and at least 25% decrease in two subscales. For patients who had 1-year success, the pooled clinical success at 2 and 3 years were 0.71 (95% CI: 0.45, 0.92, I2 = 94.9%) and 0.58 (95% CI: 0.19, 0.92, I2 = 97.1%), respectively. The pooled rate of adverse events was 0.08 (95% CI: 0.06, 0.10, I2 = 0%). G-POEM is associated with successful outcomes in about 70% of treated cases after 1 year, with durable long-term effects lasting up to 3 years. In the future, new uniform outcome definitions and strict patient selection criteria are warranted to delineate G-POEM outcomes more accurately.

A Prospective Qualitative Inquiry of Patient Experiences of Cognitive Functional Therapy for Chronic Low Back Pain During the RESTORE Trial.

Cognitive functional therapy (CFT) is a person-centered biopsychosocial physiotherapy intervention that has recently demonstrated large, durable effects in reducing pain and disability in people with chronic low back pain (CLBP). However, exploration of the treatment process from the patients' perspectives, including the process of gaining control and agency over CLBP, is relatively understudied in this patient population. This qualitative study explored the experiences of eight participants from the RESTORE trial through longitudinally following their experiences, including interviews during baseline, mid-treatment, end-treatment, and 12-month follow-up. Data were analyzed according to a narrative approach. Findings described the overarching narrative themes of "The Journey to Self-Management." Within this overarching narrative, four distinct narratives were identified, beginning with "Left High and Dry," capturing the experience of isolation and abandonment with CLBP before commencing CFT, and concluding with three narratives of the experience of CFT from the start of treatment through to the 12-month follow-up. These included "Plain, Smooth Sailing," describing a journey of relative ease and lack of obstacles; "Learning the Ropes and Gaining Sea Legs," capturing an iterative process of learning and negotiating setbacks; and "Sailing Through Headwinds," describing the experience of struggle to gain agency and control over CLBP through CFT. Clinicians treating individuals with CLBP can use these insights to more effectively facilitate self-management, and people living with CLBP may find resonance from the narrative themes to support their journeys.

Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis.

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1β production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1-/- mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.

DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising safety profile and therapeutic efficacy in preclinical small cell lung cancer models

BackgroundDelta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC), one of the most lethal malignancies, but minimally or not in normal tissues, making it an attractive target for SCLC. However, none of the DLL3-targeting antibody-drug conjugates (ADCs) have been approved for SCLC therapy yet. We developed DB-1314, the new anti-DLL3 ADC composed of a novel humanized anti-DLL3 monoclonal antibody (DB131401) conjugated with eight molecules of P1021 (topoisomerase I inhibitor), and described its preclinical profiles.MethodsThe binding epitope for DB131401 and Rovalpituzumab was tested by biolayer interferometry. The binding affinity and specificity of DB-1314 to DLL3 and other homologous proteins were respectively measured by surface plasmon resonance and enzyme-linked immunosorbent assay. Internalization, bystander effects, and antibody-dependent cell-mediated cytotoxicity (ADCC) were assessed by respective assay. DLL3 was quantified by antibodies bound per cell assay and immunohistochemistry. In vitro and in vivo growth inhibition studies were evaluated in SCLC cell lines, and cell line/patient-derived xenograft models. The safety profile was measured in cynomolgus monkeys.ResultsDB-1314 induces potent, durable, and dose-dependent antitumor effects in cells in vitro and in cell/patient-derived xenograft models in vivo. The killing activity of DB-1314 mechanically arises from P1021-induced DNA damage, whereby P1021 is delivered and released within tumor cells through DLL3-specific binding and efficient internalization. Bystander effects and ADCC also contribute to the antitumor activity of DB-1314. DB-1314 displays favorable pharmacokinetic and toxicokinetic profiles in rats and cynomolgus monkeys; besides, DB-1314 is well-tolerated at a dose of up to 60 mg/kg in monkeys.ConclusionsThese results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.

Comparison of Microwave-Based Therapy and Negative-Pressure Suction-Curettage for Axillary Hyperhidrosis and Bromhidrosis: A Retrospective Analysis.

Axillary hyperhidrosis and bromhidrosis are common clinical diseases, affecting the patients' work and life. Negative-pressure suction-curettage is the most popular treatment now, but challenged by a new microwave-based therapy (MiraDry). We intend to compare the safety and efficiency of the 2 treatments. A retrospective analysis of 39 female patients with both primary hyperhidrosis and bromhidrosis was conducted. Seventeen patients were treated with MiraDry, and 22 underwent negative-pressure suction-curettage. The postoperative follow-up program included sweat and odor assessments, satisfaction measurement, safety evaluation, and recurrence assessment at different time points until 12 months. Both treatments showed a significant reduction (P < 0.05) in HDSS score and odor level at 6 and 12 months compared with the baseline. No significant difference in relative reduction was observed between the 2 groups. The satisfaction score of the microwave-based therapy group was higher than that of the negative-pressure suction-curettage group, but no statistical difference was found. The difference in the recurrence rate and complication rate between the groups did not reach significance. Microwave-based therapy is a noninvasive treatment with durable effects, low risks, shorter downtime, good appearance, and high satisfaction for axillary hyperhidrosis and bromhidrosis.

A case for integrating self-compassion interventions targeting shame and self-criticism into eating disorder treatment: Commentary on Paranjothy and Wade.

Paranjothy and Wade's (2024) meta-analysis revealed that disordered eating was robustly and consistently associated with greater self-criticism and lower self-compassion across samples. It is well known that even evidence-based treatments for eating disorders (EDs) do not produce long-lasting effects for many patients. Additionally, it is unclear whether existing "mainstream" evidence-based ED treatments effectively reduce shame and self-criticism and increase self-compassion, even when they intend to do so. In this commentary, we assert that Paranjothy and Wade's (2024) findings should inform the integration of self-compassion interventions within ED treatment. We argue that shame, a related but distinct construct, should be strongly considered as a primary intervention target in ED interventions that seek to reduce self-criticism and increase self-compassion. We hypothesize that directly addressing shame and bolstering self-compassion at the start of ED treatment may foster higher engagement and more durable effects. We introduce the potential for adjunctive self-compassion interventions to reduce shame and self-criticism, and enhance self-compassion, alongside or within existing ED treatments. Because self-criticism and shame are shared correlates of EDs and commonly co-occurring psychopathology, we contend with the possibility that self-compassion interventions may produce transdiagnostic effects. Shame, self-criticism, and self-compassion are important intervention targets to explore in future research.

Exploring biomedical applications with silver and copper nanotechnology

AbstractThe overuse and misuse of antibiotics has accelerated the emergence of bacterial resistance, making the treatment of common infections increasingly difficult and challenging. This has led to a rise in infection rates, worsened patient outcomes, and heightened mortality risks. In response, researchers have been exploring new antimicrobial strategies, with metal nanomaterials of controllable shape and size gaining significant attention for their unique antibacterial properties. Among these, silver (Ag) and copper (Cu) nanomaterials (NMs) stand out for their wide applications in biomedical materials due to their effective antimicrobial mechanisms when used as drugs. Ag and Cu NMs, exemplifying metal biomaterials, showcase broad‐spectrum antibacterial capabilities, durable antimicrobial effects, low toxicity, and reduced likelihood of developing drug resistance. Moreover, they are known to promote angiogenesis, making them exceptionally suitable for biomaterial applications. This review underscores the significance of Ag and Cu NMs in the biomedical sector, detailing their applications and the promising role they play as medical materials. Our aim is to encourage further exploration and utilization of Ag and Cu NMs in biomaterials and industrial production sectors.

A Randomized Controlled Trial Comparing Mentalization-Based Therapy With the Unified Protocol in the Treatment of Psychopathy and Comorbid Borderline + Antisocial Personality Disorders.

Those with cooccurring antisocial personality disorder (ASPD) and borderline personality disorder (BPD) are reported to be highly psychopathic and to represent a severe challenge to treatment efforts. In a sample of such individuals, the effects of two treatments, mentalization-based therapy (MBT) and the unified protocol (UP), were investigated on three outcomes: (i) the psychopathy trait domains of meanness, boldness and disinhibition proposed by the triarchic psychopathy model (TPM); (ii) antisocial and borderline symptom severity; and (iii) the severity of their common features including impulsivity, anger expression and self-harm. Of 163 individuals with BPD + ASPD screened for eligibility, 55 were randomized to MBT treatment and 53 to UP treatment. Outcomes of treatment were assessed at 6-month intervals to 36 months. Short-term reductions were seen following both treatments in traits of psychopathy, antisocial and borderline personality symptom severity, anger dysregulation, impulsivity and self-harm, but both treatment groups showed almost complete relapse of symptoms at the 36-month follow-up. UP had more durable effects than MBT. Despite being a considerably shorter treatment, UP was at least as effective as MBT and in some respects superior. Remission of symptoms was not achieved by either treatment in the long term. Psychopathy and borderline/antisocial comorbidity with which it is associated are to some extent remediable through psychotherapy, but only in the short term. Patients with high levels of impulsivity and disinhibition are likely to relapse following psychotherapy and should be closely monitored after treatment.

The Effect of Developmental Bottom-up Approach Through Perceptual-motor Interventions on Performance of Children With Mild Intellectual Disability

Background and Aims Intellectual disability manifests through defects in cognitive, motor, and perceptual skills as elements affecting learning and acquiring individual skills. Efforts to improve these skills are essential in these children. This study investigated the durable effects of perceptual-motor process-oriented interventions with the Ramon and Johnston protocol on the motor, cognitive, and perceptual performance of children with mild intellectual disability. Methods In this quasi-experimental research, 21 children with mild intellectual disability aged 7 to 12 years were selected using the available sampling method and according to the inclusion criteria. Then, they were assigned to an experimental group of 10 students (10 weeks of perceptual-motor intervention according to the Johnstone and Ramon protocol, two sessions per week) and a control group of 11 students (no intervention) using a simple random method. The participants were evaluated before and 2 months after the intervention with movement assessment battery for children 2nd Edition, Conners’ continuous performance test-II, the working memory test of Wechsler intelligence scale for children fourth edition, and the test of visual perception skills revised. Univariate covariance test was used for data analysis. Results The findings showed a significant difference between the intervention and control groups in general motor performance, aiming and catching, the correct answer in the attention test, visual sequential memory, and visual figure-ground in the delayed post-test stage (P&lt;0.05). Also, no significant difference was seen in other subtests (P&gt;0.05). Conclusion Bottom-up approach interventions through Ramon and Johnston’s comprehensive perceptual-motor training can significantly help improve general and ball motor skills, sustained attention, visual sequential memory, and visual figure-ground in children with mild intellectual disability.

Durable effects of acupuncture for tension-type headache: A systematic review and meta-analysis

BackgroundAcupuncture may be effective in treating tension-type headache (TTH). The durability of its effects after treatment completion remains inconclusive. MethodsWe searched multiple databases and references from previous reviews for randomized controlled trials (RCTs) which investigated the effectiveness of acupuncture for TTH. We assessed the methodological quality of RCTs using the Cochrane Risk of Bias 2.0 (RoB 2) tool. Primary outcome was response rate, defined as the proportion of participants who reported at least a 50% reduction in monthly headache days from baseline after completion of treatment. Secondary outcomes included headache days, headache intensity, and analgesic use. Safety outcomes were also evaluated. ResultsA total of seven RCTs involving 3,221 participants with frequent episodic and chronic TTH were included. Individuals receiving acupuncture reported a significantly higher response rate versus sham acupuncture (SA) immediately and at 1–6 months after completion of treatment (P<0.05). Compared with SA, post-treatment results of headache days and headache intensity appeared consistent on the whole, showing associations favoring acupuncture. However, no significant reduction in analgesic use was found post-treatment. Acupuncture showed no superiority over physical training or relaxation training in headache days and headache intensity. Moreover, no serious adverse events associated with acupuncture were reported. ConclusionLimited evidence suggested that acupuncture might provide durable post-treatment effects in the management of frequent episodic and chronic TTH for up to 6 months compared with SA,with no severe treatment-related adverse events reported.

Comparison of Tecar Therapy and Low-Level Laser Therapy Separately and Simultaneously on Clinical Symptoms and Health-Related Quality of Life in Individuals with Type 2 Diabetes: A 3-Month Follow-up Study

Background: Distal peripheral neuropathy (DPN) is a prevalent issue among patients with type 2 diabetes mellitus. Despite the widespread use of low-level laser therapy (LLLT) and limited use of Tecar therapy in physiotherapy for diabetics, the synergistic effect of these two interventions in a long-term follow-up has not yet been determined. Objectives: This study aimed to compare the effects of Tecar therapy and LLLT separately and simultaneously over a 3-month follow-up period on clinical symptoms and health-related quality of life in individuals with type 2 diabetes and DPN. Methods: In this double-blind, randomized clinical trial, forty-five individuals with type 2 diabetes (30 women and 15 men) with DPN were randomly assigned to three groups of 15 people: Tecar-on + laser-sham, Tecar-on + laser-on, and laser-on + Tecar-sham. The patients received ten treatment sessions and were followed up for 3-months after the last session. Health-related quality of life was assessed using the WHOQOL-BREF Questionnaire, while clinical symptoms, including pain (measured with a Visual Analog Scale), functional balance (evaluated with the timed-up and go test), and neuropathy symptoms (assessed with the Michigan Questionnaire) were also recorded. Results: Inter-group comparison after ten sessions revealed that the Tecar-on + laser-sham and Tecar-on + laser-on groups exhibited significant improvement in neuropathy symptoms compared to the laser-on + Tecar-sham group. Even after the 3-month follow-up, these two groups showed lasting improvement in all variables compared to the laser-on + Tecar-sham group (P &lt; 0.05). The Tecar-on + laser-on group demonstrated a more enduring significant effect on pain scores (P = 0.035) compared to the Tecar-on + laser-sham group after the 3-month follow-up. In intra-group comparison, all three groups showed significant improvement in clinical symptoms and health-related quality of life after ten treatment sessions compared to before treatment (P &lt; 0.05). Moreover, after the 3-month follow-up, both the Tecar-on + laser-sham group and the Tecar-on + laser-on group demonstrated a more lasting significant effect in all variables compared to before treatment (P &lt; 0.05). For the laser-on + Tecar-sham group, a more durable improvement in health-related quality of life (P = 0.000) and neuropathy symptoms (P = 0.011) was reported after the 3-month follow-up compared to before treatment. Conclusions: Although all three groups exhibited significant improvement in clinical symptoms and health-related quality of life in individuals with type 2 diabetes and DPN after ten treatment sessions, the synergistic use of Tecar therapy and LLLT after a long-term follow-up period could lead to more durable therapeutic effects in improving these outcomes for individuals with diabetes.

Abstract 102: Trained Immunity Impairs Inflammation Resolution And Dampens Efferocytosis

Chronic inflammation is a major driver of atherosclerotic cardiovascular disease, and therapeutics that target inflammation reduce clinical cardiac events beyond levels seen with conventional strategies targeting cholesterol alone. Recent findings suggest innate immune cells maintain ‘memory’ of prior exposure to inflammatory stimuli, a phenomenon known as ‘trained immunity’. In response to inflammatory stimuli, macrophages undergo metabolic and epigenetic rewiring that primes them to mount an augmented response upon a second exposure. Oxidized low-density lipoproteins (oxLDL) have recently been shown to be potent triggers of trained immunity. While trained immunity has been shown to promote inflammation, little is known about how immune training impacts efferocytosis. Therefore, we hypothesize that trained immunity in macrophages promotes inflammation by impairing efferocytosis. We treated murine bone marrow progenitors with oxLDL for 24 hours, then washed and differentiated them into macrophages (BMDMs). Upon assessing efferocytosis, trained BMDMs were able to ingest a first apoptotic cell (AC) better than untrained BMDMs yet had an impaired ability to take up additional ACs, reflecting a defect in continual efferocytosis. Using an in vivo approach, we transplanted donor bone marrow from Ldlr -/- mice fed a chow or Western diet into naïve C57BL/6 recipients. After recovery, we elicited peritoneal macrophages to assess efferocytosis and found that recipients receiving marrow from Western diet fed Ldlr -/- mice not only displayed impaired efferocytosis, but also significantly upregulated PGE 2 production, suggesting impaired resolution. To determine whether PGE 2 is a mediator of trained immunity, we primed bone marrow progenitors with PGE 2 and differentiated them into BMDMs. We found that macrophages primed with PGE 2 elaborated higher levels of inflammatory cytokines in response to LPS stimulation than controls. Overall, these findings demonstrate that oxLDL/Western diet-training impinges on the resolution program by impairing efferocytosis and are durable effects that demonstrate heritability. Future directions include determining the impact of these findings on the development of atherosclerosis.

Organ preservation in locally advanced colorectal cancer with microsatellite instability-high after immunotherapy

Neoadjuvant immunotherapy has achieved exciting efficacy with high clinical complete response (cCR) and pathologic complete response (pCR) rates and durable long-term effects. PD-1 checkpoint blockade-based immunotherapy has been highly successful in microsatellite instability high (MSI-H)/mismatch repair deficiency (dMMR) colorectal cancer and has been recommended as the first-line treatment for metastatic colorectal cancer by domestic and international guidelines. Several studies have shown that immunotherapy can be a potentially curable treatment for MSI-H rectal cancer and has even shown promise in organ preservation in colon cancer. In this study, we first clarified the feasibility of the watch-and-wait strategy after PD-1 checkpoint blockade treatment by indirect and direct evidence. Then from the assessment tools (including digital rectal examination, endoscopy, radiology, and lymph node assessment), the viable assessment methods of cCR for immunotherapy and related difficulties are proposed. Finally, the medication choices of immunotherapy, the treatment regimen, and the follow-up strategy are further discussed. We hope that neoadjuvant immunotherapy could be appropriately applied in MSI-H/dMMR colorectal cancer so that more patients can achieve organ preservation.

Cognito’s non-invasive medical device demonstrates durable effects on activities of daily living through OVERTURE open-label extension study. (N2.002)

Cognito’s non-invasive medical device demonstrates durable effects on activities of daily living through OVERTURE open-label extension study. (N2.002)

Percutaneous Vertebral Augmentation and Thermal Ablation in Patients with Spinal Metastases.

Vertebral augmentation and thermal ablation offer radiologists a robust minimally invasive option for treatment of patients with spinal metastases. Such interventions are commonly combined and have proved safe and effective in the management of selected patients with vertebral metastases with durable treatment effects. Special attention to procedure techniques including choice of vertebral augmentation technique, choice of ablation modality, and thermal protection is essential for improved patient outcomes. This article provides a review of the most recent advances in vertebral augmentation and thermal ablation for the treatment of spinal metastases.

Neurofeedback treatment for Attention Deficit Hyperactivity Disorder in adults

IntroductionAttention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopment disorders in the world. Clinical guidelines for ADHD recommend multimodal treatment approaches, with current evidence suggesting that medication, including methylphenidate and various amphetamine formulations, in conjunction with psychosocial treatment are most effective in the short-term and long term. Over the last decade, an increasing number of studies investigating non-pharmacological treatments have been published, such as cognitive therapy, Neurofeedback (NF), Transcranial direct current stimulation with the aim of treating ADHD patients.ObjectivesWe comprehensively reviewed literature searching for studies on the effectiveness and specificity of NF for the treatment of ADHD. The aim of this review is to understand if there is scientific evidence in using of electroencephalogram (EEG)-Neurofeedback for treating patients with ADHD.Methods We did a non systemathic review using pubmed and google schoolar databases in order to analyze the influence and effects of therapy in patients diagnosed with ADHD and under treatment based on EEG Neurofeedback. We analyzed 18 systhematic reviews and metha-analysis and 2 case control studies.Results Accourding to the systhematic reviews results showed positive and significant effects in the visual memory, attention and visual recognition (spatial working memory). EEG also showed improvement in upper alpha activity in a resting state (open-eyed) measured from the occipital area, which similarly indicated improvement in the cognitive domain (attention). Compared to non-active control treatments, NF appears to have more durable treatment effects, for at least 6 months following treatment.Conclusions In conclusion, it is possible to affirm that a neuromodulating effect of the therapy positively influences cognitive processes, mood, and anxiety levels in patients with ADHD and is associated with significant long-term reduction in symptoms. Though limitations exist regarding conclusions about the specific effects of NF, the review documents improvements in school, social, and family environments. However, future efforts should focus on implementing standard neurofeedback protocols, ensuring learning, and optimizing clinically relevant transfer and more studies are needed for a properly powered comparison of follow-up effects between NF and active treatments and to further control for non-specific effects.Disclosure of InterestNone Declared

Can humanity survive to a giant comet impact?

It is well known that giant long period comets originating from the Oort's cloud could be the most threatening celestial bodies. The warning time could indeed be very short, five years, and the kinetic energy could be sufficient for global and durable effects on Earth, killing all life forms on the surface. Humans might nevertheless be able to survive decades in underground shelters. Based on a model used to determine the minimum number of people to survive on another planet, a classification of long terms shelters is proposed, taking all needs into consideration and also the double redundancy principle. Accumulation shelters corresponds to shelters with lots of resources but a weak autonomy, and therefore a well-established limited lifetime around thirty years. Borderline shelters correspond to long term shelters with strong autonomous capacities but little margins and high risks of collapse due to misconceptions, underestimations and insufficient testing. Complete shelters correspond to ideal shelters with double redundancy for every system and also for the working capacity. Thanks to a high resilience, they could last decades, eventually saving humanity from extinction. The limits of the shelters are discussed, as well as uncertainties. Given the short warning time, it is impossible to test any shelter, and, as a consequence to avoid errors in the design of a complete shelter. The risk is indeed high that some problems are underestimated and a slow but unstoppable degradation of life conditions would lead to the death of the survivals, whatever the preparation and motivation of the survivals.

Abstract 4059: Vitokine-2: A TIL-targeting tumor activable engineered IL-2 for cancer treatment

Abstract Background: Interleukin-2 is the first approved immune-oncology (IO) drug to treat multiple metastatic cancers with durable and curative antitumor effects. Yet, its application is restricted due to severe toxicity, short half-life, and a small fraction of response rate. To reduce toxicity and improve efficacy, we developed Vitokine-2, a tumor infiltrating lymphocyte (TIL)-targeting, tumor activable, and precision engineered IL-2 that remains inert systemically but activated in the tumor microenvironment (TME). Methods: Through protein and structure-guided precision engineering, the biological activity of IL-2 was optimized, concealed, guided to exhausted TILs, and activated at TME. The biological activity was determined by measuring proliferation (Ki67) of CD8+ T and NK cells using human peripheral blood mononuclear cells (PBMCs). Pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor efficacy were evaluated in mice, encompassing healthy and multiple syngeneic tumor mouse models. Results: Vitokine-2 was inactive in stimulating CD8+T and NK cell proliferation in vitro. Yet, its biological activity was fully restored following the cleavage and release of the concealing domain. Vitokine-2 displayed a significantly prolonged in vivo pharmacokinetic profile due to half-life extension, concealing and reduction of target sink. Administration of Vitokine-2 in mice resulted in minimal or no detectable activation, proliferation, and expansion of cytotoxic CD8+T and NK cells in the systemic circulation. However, marked CD8+ T cell proliferation and expansion with enhanced expression of granzyme B, a cytotoxic functional biomarker, was observed within the TME. The effect was specific to cytotoxic lymphocytes but not regulatory T cells. Corroborating with the expansion and enhanced functionality of CD8+ T cells in TME, robust antitumor efficacy was observed with Vitokine-2 but not with the non-activable IL-2 counterpart. Furthermore, dose-dependent tumor killing efficacy and complete eradication of tumors were demonstrated in multiple syngeneic tumor models. Vitokine-2 was found to be safe and well tolerated with minimal interferon gamma release and body weight loss even at much higher doses. Conclusion: Vitokine-2 is a TIL-targeting, tumor activable and precision engineered IL-2. It demonstrated robust anti-tumor efficacy with minimal systemic toxicity. It is safe, well tolerated, and permits high dose administration, yielding a widened therapeutic window. Vitokine-2 presents a paradigm-shifting, potentially a first-in-class, highly safe and efficacious IO therapy with an immense potential to address both IO-responsive and unresponsive patient population. Citation Format: Sreerupa V. Challa, Yao-Te Hsieh, Karen Gelinas, Andrea Umana, Wei-chun Weng, Toska Berisha, Cameron Stephens, Yuesheng Li, Jing Xu. Vitokine-2: A TIL-targeting tumor activable engineered IL-2 for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4059.