Demining Research Articles

Landmine Clearance and Peacebuilding: Evidence from Somaliland

The mine action sector has struggled to demonstrate the socioeconomic benefits of mine clearance. Previous academic studies have made important contributions but have been limited in offering in-depth discussions of causal pathways. This paper seeks to fill that gap. It proposes a new framework, the Mine Clearance and Peacebuilding Synergies (MPS) framework that combines the Humanitarian Mine Action Peacebuilding Palette, the Mine Action- Sustainable Development Goals (SDGs) framework and theoretical considerations from the Infrastructure as Peacebuilding framework to interrogate this interaction. Using Somaliland's post-conflict reconstruction as a case study, we analyze qualitative and quantitative data to map both the direct and indirect benefits of mine clearance in relation to infrastructure development. We find that mine clearance can influence both economic and physical reconstruction through its impact on dominant economic sectors as well as critical strategic infrastructure, including ports and roads, and demonstrate the synergies therein with an array of SDGs.

Safety of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis (HLH): Relationship to Treatment Exposure

▪Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which interferon gamma (IFNγ) is considered a key cytokine. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only curative therapy so far. Current conventional therapy for HLH is based on immunochemotherapies, namely etoposide and glucocorticoids; this treatment, however, is associated with opportunistic infections and severe myelotoxicity. Emapalumab, a fully human, anti-IFNγ monoclonal antibody that neutralizes IFNγ, is the only FDA-approved treatment for primary HLH patients with refractory, recurrent or progressive disease, or intolerance to conventional HLH therapy. In patients with primary HLH, the pharmacokinetics (PK) of emapalumab is highly influenced by body weight, and also by IFNγ production due to target-mediated drug disposition. In the pivotal trial (Locatelli et al NEJM 2020;382:1811-22), treatment of primary HLH patients with emapalumab was associated with a favorable safety and tolerability profile, with no unexpected safety concerns.Objective: To describe prespecified exploratory exposure-safety analyses that were performed on data from patients with primary HLH receiving emapalumab in the pivotal trial.Methods: Data from a multicenter, open-label, pivotal phase 2/3 study (NCT01818492) and its long-term follow-up study (NCT02069899) were included in this analysis. The safety of emapalumab was assessed in 34 patients (27 treatment experienced; 7 treatment naïve) with active primary HLH. Emapalumab was initiated at a dose of 1 mg/kg administered intravenously every 3 days, on a background of dexamethasone 5-10 mg/kg/day. Subsequent doses could be increased to 3, 6 and 10 mg/kg, if required, based on predefined laboratory and clinical response parameters. Treatment duration was up to 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to time of transplantation if needed. Exploratory graphical analyses were performed to determine the incidence of adverse events (AEs) as a function of the exposure parameters at the time of the AE. The relationship between emapalumab exposure and the incidence of treatment-emergent AEs, serious AEs, severe AEs, and AEs related to infections and infusion-related reactions (IRRs) was explored by logistic regression analyses. Selected parameters of renal (creatine clearance [CRCL]) and liver (total bilirubin [TBIL] and alanine aminotransferase [ALT]) function were explored graphically. Exposure parameters were obtained from the population PK/pharmacodynamic (PD) data file that was used for the population PK and PK/PD analyses. Observed individual concentration-time data were used to derive the individual exposure parameters as a function of time. The analyses considered AEs that emerged after the start of the first infusion until last infusion and prior to initiation of HSCT conditioning.Results: Exploratory graphical exposure-safety analyses did not reveal any apparent relationship between the number of AEs and exposure to emapalumab. Logistic exposure-safety regression analyses using the observed exposure to emapalumab at the time of an AE for patients experiencing an event and the highest observed exposure to emapalumab for those patients experiencing no AE, indicated that the incidence of AEs did not increase as a function of increasing emapalumab concentration. In fact, a statistically significant decrease in the incidence of severe AEs and the incidence of AEs related to IRRs was observed. No multivariate effects were identified in the multivariate regression analyses. No clear trend was observed for TBIL, ALT or CRCL as a function of the duration of emapalumab treatment. The exposure of emapalumab did not appear to influence the levels of TBIL, ALT or CRCL in individual patients during treatment.Conclusion: In this study, the exposure-safety evaluation did not reveal any significant relationships between exposure to emapalumab and observed incidence rates of AEs, serious AEs, infections, or IRRs. These findings support the primary evidence of a favorable benefit-risk profile of emapalumab across the dose range used in this fragile patient population. DisclosuresJordan: Sobi: Consultancy. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Jacqmin: Sobi: Consultancy. Laveille: Sobi: Consultancy. Snoeck: Sobi: Consultancy. de Min: Sobi: Consultancy, Ended employment in the past 24 months.

Macrophage Activation Syndrome (MAS) in Systemic Juvenile Idiopathic Arthritis (sJIA): Treatment with Emapalumab, an Anti-Interferon Gamma (IFNγ) Monoclonal Antibody

▪Introduction: MAS is a severe, life-threatening complication of rheumatic diseases that occurs most frequently in patients with sJIA. The mainstay of treatment for MAS is high dose glucocorticoids (GCs); however, GCs do not always provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morbidity and mortality remain high. Data from animal models of MAS and from observational studies in patients suggest that overproduction of IFNγ is a driver of the hyperinflammation observed in MAS; neutralization of IFNγ has been shown to revert the signs and symptoms of MAS in murine models, and high IFNγ levels are strongly correlated with laboratory parameters of disease severity in patients.Objective: To assess the efficacy and safety of intravenous (IV) infusions of emapalumab, a fully human anti-IFNγ monoclonal antibody, in patients with MAS associated with sJIA.Methods: This was a pilot, open-label, single-arm, phase 2 study (NCT03311854) that included patients with MAS (2016 ACR/EULAR criteria) associated with sJIA and who had not responded adequately to high dose IV GC and other treatments. Emapalumab was initiated at a dose of 6 mg/kg on Day 0 and continued at 3 mg/kg every 3 days until Day 15, and then twice weekly for an additional 2 weeks (i.e. until Day 28). As per protocol, 10 infusions were planned over the 4 weeks; however, treatment could be shortened if MAS remission was achieved earlier, or extended if required to achieve response. All patients were followed up for 4 weeks after the last emapalumab infusion and were offered to enter a long-term, follow-up study.Results: We report preliminary results from 14 patients with a median age of 11 (range 2-25) years who were enrolled in the trial (11 in Europe and 3 in the USA). All patients had failed high-dose GC; in addition, several patients had received cyclosporine A and/or anakinra within 10 days of being enrolled in the study. Treatment with emapalumab resulted in rapid IFNγ neutralization, as demonstrated by a decrease in the levels of the IFNγ-induced chemokine (C-X-C motif) ligand 9 (CXCL9), and subsequent deactivation of T cells, as indicated by the decrease in soluble interleukin-2 receptor levels. A progressive improvement in all clinical and laboratory parameters of MAS was observed. Emapalumab infusions were well tolerated by all patients, with no discontinuations. A cytomegalovirus reactivation was reported in 1 patient as a serious event related to emapalumab and resolved with antiviral therapy. During the study, GC doses were tapered in all patients. Administration of anakinra for the treatment of underlying sJIA was maintained/introduced during the study, as required.Conclusion: Emapalumab administration led to rapid neutralization of IFNγ, as indicated by a rapid decrease in CXCL9 levels, and was efficacious in controlling MAS in all patients. Emapalumab was well tolerated and had a favorable safety profile. These results support the pathogenic role of IFNγ in MAS/sJIA and the therapeutic value of IFNγ neutralization in MAS patients who have failed high-dose GCs and other treatments. DisclosuresDe Benedetti: Novimmune: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Grom: AB2 Bio: Consultancy; Novartis: Consultancy. Brogan: Sobi: Consultancy; Novartis: Consultancy; Roche: Consultancy; UCB: Consultancy. Eleftheriou: Sobi: Speakers Bureau. Papadopoulou: Sobi: Speakers Bureau. Quartier: Pfizer: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Chugai-Roche: Consultancy, Speakers Bureau; Lilly: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Antón: Sobi: Consultancy; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy; GSK: Consultancy; AbbVie: Consultancy. Frederiksen: Sobi: Current Employment. Asnaghi: Sobi: Current Employment. Ballabio: Sobi: Consultancy, Ended employment in the past 24 months. de Min: Sobi: Consultancy, Ended employment in the past 24 months. OffLabel Disclosure:Emapalumab is an IFN-y blocking antibody indicated for the treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.

Development of mine-blast trauma severity score for lower extremities in men

This study presented the results of the analysis of existing approaches to the assessment of the severity of lower extremity injuries protected with explosion-proof shoes in case of mine-explosive ammunition explosion. An increasing number of mine explosives are used in modern local wars and armed conflicts. At present, more than 110 million mines are planted and activated. Every year, nearly 10 thousand individuals are killed by explosive demolitions, and more than 20 thousand civilians sustain injuries. The necessity to clear minefields and to destroy located ammunition increases the risks of mine clearance specialists to mine-blast trauma of the lower extremities. To reduce the likelihood of severe trauma in this population, developing effective blast protective equipment, such as anti-mine boots, is necessary. The effectiveness evaluation of protective boots requires special methodology that should comprise relevant methods of mine-blast trauma severity estimation. Mine-blast trauma is a special type of surgical pathology where the injured individual has extremity avulsion or multiple injuries to extremity tissues accompanied by severe impairment of body functions. Almost all available domestic classifications of mine-explosive wounds have a pronounced clinical orientation, and foreign ones have terminologies that are not accepted in Russia and cannot be fully used for assessment purposes. The modified working classification, in the form of a rating scale, showed not only the characteristics of a given blast trauma but also the criteria of trauma severity estimation and feasibility of exposure to blast trauma. The results of the study demonstrated the potential for its use to estimate the protective features of mine clearance specialist boots when exposed to charge explosion, as well as recommendations to include this classification in documenting the science and technology that deal with the general specifications of protective equipment for specialists at the project stage.

IOT based Land Mine Detection Robot

Such equipment is usually automatically blasted through pressure when a target steps on it or drives on it. Demining or mine clearance is the process of removing land mines from an area, while minesweeping describes the task of locating mines. Landmines are generally easy to lay and difficult and dangerous. They are harmful due to their unknown positions and are often difficult to detect. Although dimming has been given the highest priority, currently my clearing operation is a labor-intensive, slow, very dangerous, expensive and low technology operation. The current rate of human quarry is about 100 thousand per year. The idea is to build and develop an automated robot capable of detecting buried landmines and taking them from their locations, enabling the operator to control the robot from afar. The buried quarry is detected using metal detectors as most land mines have metal components. The robot will travel in a straight line route. The system allows the operator to stay at a safe distance by enabling the robot to safely control. Wireless control is for the safety of the operator, designed robots must be able to operate remotely, and is equipped with wireless data transmission capabilities.

ПОВЫШЕНИЕ ПОИСКОВЫХ ВОЗМОЖНОСТЕЙ АВТОНОМНЫХ НЕОБИТАЕМЫХ ПОДВОДНЫХ АППАРАТОВ ЗА СЧЕТ ПРИМЕНЕНИЯ МНОГОКАНАЛЬНЫХ МАГНИТОМЕТРИЧЕСКИХ СИСТЕМ

The article substantiates the relevance of solving the problems of searching for unexplodedordnance, as well as archaeological and geological surveys in the waters of inland waters andcoastal zones of the Russian Federation. Using examples of mine clearance operations in the BalticSea and a detailed magnetometric survey of the Phanagoria water area, the extensive capabilitiesof modern equipment for localization of objects covered by bottom sediments and visuallyinvisible on the bottom surface are shown. The advantages of using autonomous uninhabited underwatervehicles for the method of searching for ferromagnetic objects based on the registrationof spatially distributed magnetic anomalies are considered. The directions of development of multichannelmagnetometric search tools are shown. The potential capabilities of multichannelmagnetometric systems for identifying search objects are revealed. Using the example of the existingtechnology of diving search, it is shown that the rate of exploration provided in this way isextremely low even under the most favorable conditions: the best visibility, a gentle slope of thebottom with a solid base. At the same time, the time for exploration of a section of the water areaby diving along one shore will be about 5 hours in favorable conditions, and, therefore, this methodcannot be used when examining large water areas. Taking into account the level of technologyachieved at the present stage, it is proposed to use autonomous uninhabited underwater vehicleswith a multi-channel magnetometric system installed as a target load for automating underwateroperations. In addition to automating the process of performing tasks, the use of uninhabited underwatervehicles will either completely eliminate or significantly reduce the dangerous impact onhumans of measures to search for unexploded ordnance and harmful factors of deep-sea operations,as well as reduce material and time costs by reducing operations for servicing divingequipment. Processing the survey results and creating a map of magnetic anomalies will allow youto identify structures whose geomagnetic properties are markedly different from the natural magneticbackground. Such a technique can significantly increase the information content and reliabilityof the results of the survey of water areas, providing the identification of visually invisibleobjects that have their own magnetic field. Based on the theory of the electromagnetic field andmagnetostatics, a method for calculating the parameters and efficiency of the multichannelmagnetometric system for uninhabited underwater vehicles has been developed. The method isdesigned to evaluate the parameters and capabilities for detecting ferromagnetic objects and tomake a preliminary assessment of the search efficiency. As a criterion (achieving a positive resultof evaluating the parameters and efficiency of the multi-channel magnetometric system), in accordancewith the IMAS Mine Action Standards, the following condition is accepted: detection ofan object of a certain type at a given depth. The influence of the above data on the solution of theproblem was evaluated as a result of computer simulation in the software environment of the computer-aided design system MathCAD with further visualization of the results.

Retention of Military Divers in The Royal Malaysian Navy Diving Organisation

The RMN military divers are specifically trained to supplement the naval operation. They are capable to dive up to 60 meters, and perform specialized diving such as Mine Clearance Diving, Un-exploded Bomb Removal and Search and Rescue. According to the data from the year 2013 to 2018, the attrition rate of military divers is a major concern for the organisation. A total of 61 out of 100 divers retired early within this period. To make matters worse, retired divers were not replaced accordingly. Only 70 recruits joined this department, leaving the organization with a shortage of military divers. This study employed a Qualitative Descriptive Case Study to understand factors that influence early turnover and retention among the RMN military divers. The study suggests practical solutions and retention strategies to retain the current personnel so that they continue to serve until compulsory retirement. These solutions may also be beneficial in attracting new personnel. The research will use the Institutional Theory as the theoretical lens to explore the factors influencing military divers’ intention to stay. The findings will be used to boost the retention rate of the military divers in the RMN.

Structural design and gait research of a new bionic quadruped robot

Quadruped bionic robot has a strong adaptability to the environment, compared with wheeled and tracked robots, it has superior motion performance, and has a wide range of application prospects in rescue and disaster relief, ground mine clearance, mountain transportation, so it has become a research hotspot all over the world. Leg structure is an important embodiment of the superior performance of quadruped robot, and it is also the key and difficult point of design. This article proposes a novel quadruped robot with waist structure, which can complete a variety of gait forms. Based on the theory of linkage mechanism, a novel leg structure is designed with anti-parallelogram mechanism, which improves the strength and stiffness of the robot. Using D-H description method, the kinematics analysis of this quadruped robot single leg is carried out. On this basis, in order to ensure the foot contact with the ground and achieve zero impact, polynomial programming is used to plan the foot trajectory of swing phase and support phase. Based on the static stability margin, the optimal static gait of the quadruped robot is planned. A co-simulation study has been carried out to investigate further the validity and effectiveness of the quadruped robot on gait. The simulation results clearly show the robot can walk steadily and its input and output meet the expected requirements. The solid prototype platform is built, and the trajectory planning experiment of single leg is carried out, and the foot trajectory of single leg is obtained by using laser tracker. The gait planning algorithm is applied to the whole robot, and the results show that the robot can walk according to the scheduled gait, which proves the effectiveness of the proposed algorithm.

Forced Labor of the Population under the Nazi Occupation of 1941–1944 (Based on the Materials of the Border Territory of Belarus and the North-West of Russia)

The article investigates features of forced labor in the border territory of Belarus and the North-West of Russia during Nazi occupation of 1941–1944. The Wehrmacht used forced labor both in Germany by hijacking Soviet citizens there, and in industrial enterprises and in agriculture of the occupied territories. The civilian population was involved in the performance of certain work in favor of the occupation authorities. Peasants, in addition to traditional agricultural work and payment of in-kind taxes, were often forcibly involved in performing horse — drawn duties, peat and logging, railway protection, and mine clearance. Citizens were actively used by the occupying authorities to construct defensive structures and to work at industrial enterprises. Refusal to work was punishable by a fine, deprivation of ration cards, corporal punishment, and sentencing to a labor camp or shooting. Forced to work in enterprises, institutions, and agriculture, the population received meager wages and food rations, and the vast majority of workers lived below the poverty line. A special place among the crimes of Nazism in the territory of the North-West of Russia and Belarus, where the occupation went on the longest, is occupied by the forcible deportation of the population to Germany. From some settlements, the occupation authorities sent entire local populations to Germany without regard to age, health, or family circumstances. To provide the Nazi economy with labor, the occupation authorities paid considerable attention to propaganda among the population and the organization of recruitment campaigns. However, this did not contribute to raising the number of volunteers; instead, local residents in the occupied regions sabotaged the orders of the German-fascist command.

ОСОБЛИВОСТІ КОНСТРУКЦІЇ ТА ЗНЕШКОДЖЕННЯ ВИБУХОВИХ ПРИСТРОЇВ

The article provides a general analysis of explosives, discloses the concepts of an explosion and its characteristics, gives a description of explosives. Features of the design and destruction of modern explosive devices during mine clearance and the organization of these works are disclosed. The necessity of observing international standards in matters of mine action, which after its ratification became part of Ukrainian national legislation, is examined. In accordance with international standards and the experience of other countries, the main responsibility lies with the National Mine Action Authority The factors that complicate the clearing of the terrain and the destruction of explosive objects are disclosed. Limitations are formulated that are imposed on the ways of clearing settlements located near historical and cultural monuments (churches, cemeteries, etc.) and industrial objects that pose a great danger when they are destroyed, a list of improvised explosive objects is proposed, their unmasking factors are disclosed when they are detected using special equipment and specially trained dogs, in open areas, in rooms and vehicles. Separately investigated issues of localization and destruction of improvised explosive devices. Keywords: explosive objects, explosive, basic properties, terrain clearance, improvised explosive device, explosion classification, international standards.

Role of Profound Knowledge in Improving the Performance of Teamwork - A Case Study on Al – Fahad Company Ltd for Mine Survey and Clearance

The current research aimed at analyzing two dimensions of profound knowledge and teamwork activities to form perceptions about the impact of profound knowledge on the performance of Al-Fahd company teams to remove limited mines. The problem was embodied by questions looking at whether or not the existence of perceptions about Profound knowledge with the management of the company in question, and looking for activities, the work teams and their performance measurement indicators to answer a third question related to the contribution of profound knowledge to the performance of the teams. To answer these questions, the research adopted a comparative study method for historical data and a checklist as two main methods for collecting data and completing the practical side. The questionnaire included nine experts who represented the leaders of the company and the leaders of the teams working in it. Supported by interviews with the concerned managers to complete the checklist and ensuring the accuracy of the data derived from it, the list was analyzed by adopting the appropriate statistical tools through the statistical program (spss 22). The two researchers reached a set of conclusions, perhaps the most important of which existence of the two dimensions in-profound knowledge and teams contexts in a good and very good direction, respectively. The two research also concluded that the management of Al-Fahd Company is working on understanding the concepts of quality management and developing its beliefs in order to present the procedures and instructions necessary for the work of individuals within the organization. The two researchers also presented proposals for managing the company, perhaps the most prominent of which is increasing the company's management interest in the contents of the profound knowledge and quality issues, to know first-hand the quality philosophy, and its tools because this contributes to enhancing the quality culture in a way that contributes to enhancing the company's ability to compete. The two researchers also suggested the need to increase interest in the management of the company and all its employees from technical and administrative resources in the concept of cooperation and teamwork and all that would enhance the team work style. Role of Profound Knowledge in Improving the Performance of Teamwork - A Case Study on Al – Fahad Company Ltd for Mine Survey and Clearance

Sensitivity Analysis of Overall Response Rate (ORR) with Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis (HLH)

Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation, the only curative therapy. Conventional HLH therapy comprises immunotherapies (namely, dexamethasone and etoposide), which, unfortunately, predispose patients to infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. In the pivotal study of emapalumab in primary HLH, objective response criteria were used to define the primary endpoint of overall response (Locatelli et al NEJM 2020). These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria (Henter et al Pediatr Blood Cancer 2007), clinical considerations from the study's Scientific Steering Committee, and available experience reported with conventional HLH treatments. We now report on findings of a sensitivity analysis of overall response rate (ORR) to emapalumab using various assessment criteria. Methods: The open-label pivotal study included patients aged ≤18 years with a diagnosis of primary HLH and active disease (NCT01818492; Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 10 mg/kg if required, based on predefined laboratory and clinical response parameters, for a treatment duration of 8 weeks. In addition to emapalumab, all patients received dexamethasone, and a protocol amendment allowed for concomitant use of other HLH treatments if deemed appropriate by the investigator. ORR at end of treatment was analyzed as per the protocol definition in the 27 patients previously treated with conventional therapies. In addition, several pre-specified and post hoc sensitivity analyses were performed to pressure test the data; including: (i) a pre-specified analysis using a more conservative approach where any patient who received concomitant HLH therapies during the study was imputed as non-responder; (ii) a pre-specified analysis with physician-reported response rates recorded by the study investigators, based on their clinical judgement and previous experience in treating patients with primary HLH; and (iii) a post hoc sensitivity analysis using a previously published definition of overall response (Henter et al Pediatr Blood Cancer 2007). Results: 63% (95% confidence interval [CI], 0.42, 0.81) of 27 treatment-experienced patients had a response according to the pivotal study protocol definition of ORR (Fig. 1). A pre-specified sensitivity analysis on the primary endpoint where any patient who received concomitant HLH therapy and imputed as non-responders showed a magnitude of response similar to that observed in the protocol-defined primary analysis (59.3%; 95% CI 0.39, 0.78; n=22). Use of the response criteria defined by Marsh et al (Pediatr Blood Cancer 2013) in a retrospective analysis of 27 patients with primary HLH also resulted in a similar ORR to the protocol-defined primary endpoint in treatment-experienced patients (70.4%; 95% CI 0.50, 0.86). When platelet count was added to this analysis, the percentage of responders to emapalumab increased to 74.1% (95% CI 0.54, 0.89). The pre-specified analysis of physician-reported response rates was also in line with the primary analysis, with 70.4% (95% CI 0.50, 0.86) of 27 treatment-experienced patients deemed to have a response to emapalumab. Conclusion: The current analyses using different definitions of treatment response support the primary analysis results by having a numerically comparable point estimate to the primary endpoint, therefore confirming the positive benefit of emapalumab in patient's refractory or intolerant to conventional HLH therapies. Taken together, these findings also suggest that the clinically objective ORR, utilized in the pivotal emapalumab trial, may be used as a primary endpoint in primary HLH. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board; Novartis: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding; Novartis Pharma: Research Funding; Pfizer: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding. Grom:Sobi: Consultancy; Novartis Pharma: Consultancy; AB2Bio: Consultancy. Stoltenberg:Sobi: Current Employment. Vågerö:Sobi: Consultancy. de Min:Sobi: Consultancy.

Population Pharmacokinetic Analysis of Emapalumab, a Fully Human, Anti-Interferon Gamma Monoclonal Antibody, in Children with Primary Hemophagocytic Lymphohistiocytosis

Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by pathologic immune activation and hyperinflammation. It typically manifests during infancy and is invariably fatal if untreated. Interferon gamma (IFNy) is considered a key contributor to the hyperinflammation of HLH. Thus, neutralization of IFNy could help control the disease until haematopoietic stem cell transplantation, the only curative treatment. Emapalumab, a fully human, anti-IFNy monoclonal antibody, binds to and neutralizes IFNy. Emapalumab is the first and only approved (FDA) treatment for primary HLH. It is indicated for the treatment of adult and pediatric patients with HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy. Objective: To develop a population pharmacokinetic (PK) model to describe the PK profile of emapalumab. Methods: PK data were obtained from patients with primary HLH administered emapalumab intravenously during an open-label, single-group, phase 2/3 clinical trial (NCT01818492) and as part of a compassionate use program. A population PK analysis was performed using nonlinear mixed effects modeling (NONMEM® version 7.3.0). Predictive performance of the model was assessed using a visual predictive check. Results: The PK of emapalumab was adequately described by a two-compartment model. All model parameters were estimated with good precision. Central and peripheral volumes of distribution were 0.059 and 0.079 L/kg, respectively. Exploratory graphical analysis showed that (i) IFNy production varied significantly between and within patients as a function of time; (ii) the higher the IFNy production, the faster the elimination of emapalumab due to target-mediated drug disposition; and (iii) the higher the IFNy production, the higher the dose of emapalumab required to reach the neutralizing concentration of IFNy (evidenced by a higher target-mediated clearance of emapalumab). Of the parameters examined, only body weight and total IFNy (free and bound) levels were found to significantly influence the PK of emapalumab. The allometric exponents of body weight for the volume of distribution and clearance were 1 (fixed) and 0.886 (95% confidence interval 0.68, 1.09), respectively. These values support the bodyweight-based dosing of emapalumab (i.e. mg/kg). At values of total IFNy from 103 to 106 pg/mL, the total clearance (linear + target mediated) of emapalumab ranged from 0.0012 to 0.0140 L/h for a bodyweight of 5 kg, with corresponding terminal half-lives from 17.5 to 2.3 days. This wide variance in clearances and half-lives partly explains the emapalumab dose adaptations that are required for treating primary HLH patients. Conclusion: The population PK model reliably predicted serum concentrations of emapalumab in patients with primary HLH. The central and peripheral volumes of distribution were low, clearance was slow, and the terminal half-life long. The expected dynamic of the biology of IFNy was confirmed and included in the population PK model. Simulations using this model supported the proposed dosing scheme of emapalumab in patients with primary HLH. Disclosures Laveille: Sobi: Consultancy. Jacqmin:Sobi: Consultancy. de Min:Sobi: Consultancy.

Safety of Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis: Results of the Primary Analysis of the Pivotal Phase 2/3 Study

Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, interferon gamma (IFNy) is considered to be the key player driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Current conventional therapy for HLH is based on the combined use of dexamethasone and etoposide, and, although effective in many patients, these drugs may promote the development of opportunistic infections and tissue toxicity, and are associated with high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease, or intolerance with conventional HLH therapy. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study (Locatelli et al. NEJM 2020) and investigate the relationship of adverse events (AE) to dose and duration of treatment. Methods: Due to the rare and life-threatening nature of the disease, the efficacy and safety of emapalumab was assessed in an open-label pivotal study (NCT01818492) which included patients aged ≤18 years with a diagnosis of primary HLH and active disease (Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 3, 6 and 10 mg/kg if required, based on predefined laboratory and clinical response parameters. Treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of HSCT if needed. Analysis was performed on 34 patients at a database cut-off date of July 2017 (Locatelli et al NEJM 2020). The relationship of AE to emapalumab treatment was reported by the study investigator. The impact of treatment duration on AE or infection occurrence was measured by the number of events with onset in a predefined time interval from emapalumab initiation. The impact of the dosing scheme on AE and infection occurrence was assessed by the number of AEs or infections in a predefined dose range. Results: Overall, 29% of patients had at least one AE deemed related to emapalumab use. Most (90%) of these events were infusion-related reactions, all of which were mild to moderate and resolved. No severe or serious hypersensitivity reactions were reported. Infections caused by pathogens potentially favored by IFNy neutralization occurred in 1 patient during emapalumab treatment (disseminated histoplasmosis) and resolved with appropriate treatment. There was no increase in AE frequency or the number of viral, bacterial, or fungal infections with increased dose or duration of emapalumab treatment. Conclusion: Neutralization of IFNy with emapalumab in this very fragile population of patients with active primary HLH was associated with a favorable and manageable safety profile across all doses and treatment durations assessed, allowing for flexible and tailored use based on patient clinical response. In addition, 102 patients have been treated in the US following FDA approval, and post-marketing surveillance has not revealed any additional safety concerns with the use of emapalumab in primary HLH (cutoff date 19 May 2020). Taken together, these safety results suggest that emapalumab may offer an additional advantage over conventional HLH therapies. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Novartis: Other: Advisory Board; Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Pfizer: Research Funding; Novartis Pharma: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding; Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding. Grom:Novartis Pharma: Consultancy; Sobi: Consultancy; AB2Bio: Consultancy. de Min:Sobi: Consultancy.

Detection of buried explosives with immobilized bacterial bioreporters.

The unchecked dispersal of antipersonnel landmines since the late 19th century has resulted in large areas contaminated with these explosive devices, creating a substantial worldwide humanitarian safety risk. The main obstacle to safe and effective landmine removal is the identification of their exact location, an activity that currently requires entry of personnel into the minefields; to date, there is no commercialized technology for an efficient stand-off detection of buried landmines. In this article, we describe the optimization of a microbial sensor strain, genetically engineered for the remote detection of 2,4,6-trinitrotoloune (TNT)-based mines. This bioreporter, designed to bioluminescence in response to minute concentrations of either TNT or 2,4-dinitotoluene (DNT), was immobilized in hydrogel beads and optimized for dispersion over the minefield. Following modifications of the hydrogel matrix in which the sensor bacteria are encapsulated, as well as their genetic reporting elements, these sensor bacteria sensitively detected buried 2,4-dinitrotoluene in laboratory experiments. Encapsulated in 1.5mm 2% alginate beads containing 1% polyacrylic acid, they also detected the location of a real metallic antipersonnel landmine under field conditions. To the best of our knowledge, this is the first report demonstrating the detection of a buried landmine with a luminescent microbial bioreporter.

The War Damage on Archaeological Heritage after the War: Archaeological Heritage and Landmines

ABSTRACT War is an invasive spatial practice and naturally, these practices are detrimental for archaeological heritage. However, a form of war-related damage to archaeological heritage is hitherto unrecognised. This paper represents a first attempt to define, quantify and estimate the extent of war damage to archaeological heritage caused by deployment, placement and removal of landmines and various other explosive remnants of war (ERW). Three case studies from Croatia each demonstrate that estimated figures are staggering and that archaeological heritage is indeed gravely affected. We suggest that adequate reaction from various stakeholders is missing. This is unfortunate because the case studies also demonstrate that the loss of archaeological potential could be mitigated and controlled. Deployment and removal of explosive devices are activities which must be recognised managed as a form of war damage. Archaeological community should take a keener interest in the subject and become a relevant stakeholder in mine action.

The Influence of the Flushing Method on the Stable Oxygen Content in the Scr1 Crabe Breathing Loop in the Decompression Phase

Abstract Maintaining a stable oxygen content in the breathing loop of the diving apparatus with a semi-closed respiratory circuit is essential for the safety of underwater mine clearance operations. This article discusses the influence of modified methods of flushing the breathing apparatus on the quality of the breathing loop ventilation process. The problem of flushing an apparatus is presented in light of the Polish Naval Academy’s change from statistical to deterministic decompression schedules, based on the model of apparatus ventilation, oxygen toxicity hazard and decompression. The examination and determination utilising the required accuracy of the method used for flushing the breathing loop of the device allowed to assess the stable oxygen content during the decompression phase. The assumptions were verified based on a system for measuring oxygen content in the breathing loop.

Search and Rescue Algorithm using a Cooperative Robot System

Cooperative robotics is very different from working on a single robot before. Cooperative robots can perform tasks that were previously impossible with a single robot. This robot research can be applied in computer science, artificial intelligence, and electrical engineering. This research aims to deal with tasks that are difficult or impossible to perform with a single robot. For this purpose, we propose a Se-Re (Search-and-Rescue) algorithm. In addition, the proposed algorithm is designed to allow multiple robots to collaborate in the area of work. Robots use wireless communication to collaborate and are organized in groups, which create environmental maps and share data with each other. The robot uses the shared area map to create a global map. Using this information, the robot does not revisit the previously visited area. The proposed algorithm can be applied both indoors and outdoors. Indoors can be used in general buildings as well as livestock housing, and outdoors can be used for landmine removal, human search, and rescue.

Глобальна проблема розмінування: стан та підходи до розв’язання

В останні роки міжнародне співтовариство все глибше усвідомлює масштаби і гостроту проблем, породжуваних наземними мінами та вибухонебезпечними залишками війни, у тому числі боєприпасами, що не розірвалися, поступово погоджуючись з тим, що мова йде про глобальну проблему, яка вимагає узгоджених заходів у відповідь на міжнародному рівні. При цьому ООН покликана зіграти ключову роль у формулюванні цих глобальних заходів у відповідь, а також у забезпеченні необхідної міжнародної підтримки і створенні відповідних координаційних механізмів. Як показує аналіз, жоден з розроблених раніше методів виявлення мін за своїми основними параметрами (чутливість, вибірковість, швидкодія) не відповідає ні вимогам стандартів ООН з гуманітарного розмінування, ні загальному завданню глобального розмінування планети. Метою статті є визначення сучасних підходів до розв’язання проблеми розмінування. На теперішній час зарубіжні країни розробили та використовують сучасні мобільні робототехнічні комплекси (далі – РТК) для розмінування і продовжують фінансувати роботи з розширення функціональних можливостей для їхнього застосування у нових напрямах за рахунок створення нових конструктивних схем або використання уніфікованих підсистем міжтипового призначення. Досвід експлуатації мобільних РТК у цьому випадку розглядається в якості базової основи для перспективних розробок. Разом з тим, одним з актуальних у світі напрямів розробки РТК, у зв’язку з розвитком різноманітних безпілотних літальних апаратів, стала активізація ідеї щодо застосування БПЛА для ведення розвідки мінної обстановки, виявлення мін і дистанційного їх знищення. Подальші дослідження можуть відбуватися за такими напрямами: розробка чи закупівля готових безпілотних авіаційних комплексів, здатних виконувати завдання розвідки мінної обстановки, виявлення мін і дистанційного їх знищення; дослідження можливостей застосування спектрозональної чи багатоспектральної апаратури на борту безпілотника для підвищення достовірності та забезпечення повноти інформації про мінну обстановку; створення спеціалізованих підрозділів у складі безпосередніх користувачів, діяльність яких буде пов’язана з використанням безпілотних авіаційних комплексів для розвідки мінної обстановки, виявлення мін і дистанційного їх знищення тощо.

Правові аспекти роззброєння України відповідно до Конвенції про заборону протипіхотних мін

Автор досліджує суспільні відносини у сфері роззброєння, зокрема протимінної діяльності в сучасних умовах, а також аналізує результати Оглядової конференції з питань розмінування, що відбулася 25–29 листопада 2019 року в Осло. У статті розкрито зміст прийнятих Плану дій Осло та Проекту декларації Осло про світ, вільний від мін. Відзначено причини невиконання Україною статті 5 Оттавської конвенції. Висвітлено оцінки критеріїв здатності України до проведення розмінування.
 Обґрунтовується зміна змісту виконання міжнародних зобов’язань України із роззброєння до 2014 року, що зумовило сьогодні перегляд правових підходів до забезпечення розмінування. Відзначається, що сфера протимінної діяльності становить самостійний предмет правового регулювання, а також достатність підстав для прийняття окремого закону та подальшого розвитку законодавства у цій сфері.
 Метою статті є наукове обґрунтування та визначення правових аспектів роззброєння України, зокрема у сфері протимінної діяльності, шляхом висвітлення положень Конвенції про заборону застосування, накопичення запасів, виробництва і передачі протипіхотних мін та про їхнє знищення 1997 року, а також аналізу стану її виконання Україною у контексті постановки завдань розвитку національного законодавства з означених питань.
 Наукова новизна дослідження полягає у представленні автором обґрунтованих результатів та висновків самостійного дослідження стану виконання Україною міжнародних зобов’язань за Оттавською конвенцією, використання яких у законотворчій практиці сприятиме забезпеченню створення адекватного правового регулювання протимінної діяльності на національному рівні, з урахуванням притаманних лише Україні особливостей.
 Висновки. Перед Україною постали нові виклики законодавчого оновлення регулювання роззброєння як в цілому, так і з урахуванням фактору воєнної агресії з боку РФ, що триває з 2014 року. На загальному рівні перспективним вбачається розвиток досліджень стану виконання міжнародних зобов’язань із роззброєння з огляду на необхідність забезпечення захисту державного суверенітету. Констатовано відсутність національного стратегічного плану щодо протимінної діяльності, консолідації національної інформаційної системи протимінної діяльності, гендерної політики у цій сфері та відповідних програм, точної інформації щодо площі і місць знаходження протипіхотних мін та звітів про це. Україна поки не встала на шлях реалізації положень Оттавської конвенції.