10 research outputs found
Organisational and methodological challenges of CAR-T manufacturing in the Russian Federation
No full textDespite their widespread clinical implementation, chimeric antigen receptor T-cell (CAR-T) therapy products, including those manufactured by industrial processes, are still not legally available or used in the Russian Federation.The aim of the study was to describe the current challenges associated with specific aspects of CAR-T manufacturing in the Russian Federation and the potential ways to overcome them.This article discusses the regulatory, legal, organisational, and methodological challenges of CAR-T manufacturing. It analyses differences in the interpretation of CAR-T therapy products under national and supranational law. According to Russian Federal Law No. 180-FZ “On Biomedical Cell Products” of 23 June 2016, CAR-T therapy products are considered biomedical cell products. However, according to Decision No. 78 of the Council of the Eurasian Economic Commission “On the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use” of 3 November 2016, CAR-T therapy products are considered advanced therapy medicinal products (ATMPs). This article provides a detailed overview of the difficulties in obtaining starting biological materials (i.e. the inability to consider the patient as a donor) and transferring the materials for CAR-T manufacturing (i.e. the inapplicability of national law). In addition, this article describes export aspects specific to biological materials. The authors reckon that CAR-T therapy products should be categorised as ATMPs and that the corresponding active pharmaceutical ingredients, genetically modified autologous lymphocytes, should be defined as starting materials. Therefore, genetically modified autologous lymphocytes should be regulated under the requirements for starting materials for the manufacturing of active pharmaceutical ingredients that are set forth in Decision No. 77 of the Council of the Eurasian Economic Commission “On the Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union” of 3 November 2016. In conclusion, the authors recognise the need for national and supranational law harmonisation. For this task, it is necessary to establish expert groups that will include clinicians, legal experts, and representatives from the relevant authorities and the pharmaceutical industry
Организационно-методические проблемы производства CAR-T в Российской Федерации
No full textDespite their widespread clinical implementation, chimeric antigen receptor T-cell (CAR-T) therapy products, including those manufactured by industrial processes, are still not legally available or used in the Russian Federation.The aim of the study was to describe the current challenges associated with specific aspects of CAR-T manufacturing in the Russian Federation and the potential ways to overcome them.This article discusses the regulatory, legal, organisational, and methodological challenges of CAR-T manufacturing. It analyses differences in the interpretation of CAR-T therapy products under national and supranational law. According to Russian Federal Law No. 180-FZ “On Biomedical Cell Products” of 23 June 2016, CAR-T therapy products are considered biomedical cell products. However, according to Decision No. 78 of the Council of the Eurasian Economic Commission “On the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use” of 3 November 2016, CAR-T therapy products are considered advanced therapy medicinal products (ATMPs). This article provides a detailed overview of the difficulties in obtaining starting biological materials (i.e. the inability to consider the patient as a donor) and transferring the materials for CAR-T manufacturing (i.e. the inapplicability of national law). In addition, this article describes export aspects specific to biological materials. The authors reckon that CAR-T therapy products should be categorised as ATMPs and that the corresponding active pharmaceutical ingredients, genetically modified autologous lymphocytes, should be defined as starting materials. Therefore, genetically modified autologous lymphocytes should be regulated under the requirements for starting materials for the manufacturing of active pharmaceutical ingredients that are set forth in Decision No. 77 of the Council of the Eurasian Economic Commission “On the Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union” of 3 November 2016. In conclusion, the authors recognise the need for national and supranational law harmonisation. For this task, it is necessary to establish expert groups that will include clinicians, legal experts, and representatives from the relevant authorities and the pharmaceutical industry.Несмотря на широкое внедрение в клиническую практику терапии Т-клетками с химерным антигенным рецептором (chimeric antigen receptor T-cell, CAR-T), на территории Российской Федерации данные препараты до сих пор официально не представлены и не используются, в том числе и произведенные промышленным (индустриальным) способом.Цель работы — описание текущих проблем, связанных с особенностями производства CAR-T в Российской Федерации, и потенциальных путей их решения.Рассмотрены трудности, связанные c регуляторными, юридическими и организационно-методическими аспектами производства CAR-T. Проанализированы расхождения в трактовке понятия CAR-T в национальном и наднациональном праве: как биомедицинского клеточного продукта согласно Федеральному закону от 23.06.2016 № 180-ФЗ «О биомедицинских клеточных продуктах» и как высокотехнологического лекарственного препарата (ВТЛП) согласно Решению Совета Евразийской экономической комиссии от 03.11.2016 № 78 «О Правилах регистрации и экспертизы лекарственных средств для медицинского применения». Подробно рассмотрены трудности на этапе получения исходного биологического материала (невозможность рассматривать пациента как донора биологического материала); на этапе передачи биологического материала для производства CAR-T (невозможность применения национального права); особенности экспорта биологического материала. По мнению авторов статьи, CAR-T следует относить к ВТЛП, активной фармацевтической субстанцией (АФС) которых являются генетически модифицированные аутологичные лимфоциты, а последние должны быть определены как «исходный материал», и к ним должны применяться требования как к исходному материалу для производства АФС, указанные в Решении Совета Евразийской экономической комиссии от 03.11.2016 № 77 «Об утверждении Правил надлежащей производственной практики Евразийского экономического союза». Сделано заключение о необходимости гармонизации национального и наднационального права, что требует формирования экспертных групп, объединяющих врачей-клиницистов, специалистов в области права, представителей профильных ведомств и фармацевтической индустрии
Evaluating energy financing considerations and sustainable energy innovation with the role of financial development and energy development
No full text[EN] The purpose of the study is to test the role of energy development in energy financing considerations for sustainable energy innovation and financial development. To achieve the study objective, a fuzzy decision-making modeling technique is applied. The results revealed that bank loans are now the main source of financing for innovation and creativity in Chinese business entities. Project-based financing might be replaced with collaborative and sustainable energy innovation (CSI), warranting energy development. Moreover, green financing loan schemes invest both public and private funds in sustainable energy innovation to capitalize on financial development through sustainable energy innovation. The consideration and application of financial consideration for sustainable energy innovation-financing projects or companies are limitless. Providing for screening energy development cooperation proposals with small financial payback hurdle rates might have large opportunity costs. There may be a case for governments to increase industrial growth, improve resource efficiency, and increase factor productivity while tackling climate change. Economic growth in China may have an even greater influence on environmental sustainability than in other countries. On such points, there is a need to pay the attention. If the suggested policy suggestions are implemented successfully, they would help to enhance the scope of financing considerations for sustainable energy innovation to uplift financial development through energy development mechanisms at the corporate level.The research is partially funded by the Ministry of Science and Higher Education of the Russian Federation under the strategic academic leadership program "Priority 2030" (Agreement. 075-152021-1333 dd 30.09.2021).Barykin, SE.; Sergeev, SM.; Mottaeva, AB.; De La Poza, E.; Baydukova, NV.; Gubenko, AV. (2022). Evaluating energy financing considerations and sustainable energy innovation with the role of financial development and energy development. Environmental Science and Pollution Research. 30:6849-6863. https://doi.org/10.1007/s11356-022-22576-xS6849686330Abdullah R, Selamat MH, Sahibudin S, Alias RA (2005) A framework for knowledge management system implementation in energy development for higher learning institution. 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Identification and localization of layers in the ionosphere using the eikonal and amplitude of radio occultation signals
No full textBy using the CHAllenge Minisatellite Payload (CHAMP) radio occultation (RO) data, a description of different types of the ionospheric impacts on the RO signals at the altitudes 30–90 km of the RO ray perigee is given and compared with the results of measurements obtained earlier in the satellite-to-Earth communication link at frequency 1.5415 GHz. An analytical model is introduced for describing propagation of radio waves in a stratified medium consisting of sectors with spherically symmetric refractivity distribution. This model gives analytical expressions for the phase, bending angle, and refractive attenuation of radio waves and is applied to the analysis of radio wave propagation phenomena along an extended path including the atmosphere and two parts of the ionosphere. The model explains significant amplitude and phase variations at altitudes 30–90 km of the RO ray perigee and attributes them to inclined ionospheric layers. Based on this analytical model, an innovative technique is introduced to locate layers in the atmosphere and ionosphere. A necessary and sufficient criterion is obtained for a layer to be located at the RO ray perigee. This criterion gives both qualitative and quantitative estimation of the displacement of an ionospheric and/or atmospheric layer from the RO ray perigee. This is important, in particular, for determining the location of wind shears and directions of the internal wave propagation in the lower ionosphere, and, possibly, in the atmosphere
Identification and localization of layers in the ionosphere using the eikonal and amplitude of radio occultation signals
No full textAbstract. Conditions for communication, navigation, and remote sensing in the ionosphere and atmosphere depend strongly on the ionospheric impact on the radio waves propagation. By use of the CHAllenge Minisatellite Payload (CHAMP) radio occultation (RO) data a description of different types of the ionospheric contributions to the RO signals at the altitudes 30–90 km of the RO ray perigee is introduced and compared with results of measurements obtained earlier in the communication link satellite-to-Earth at frequency 1.5415 GHz. An analytical model is introduced for description of the radio waves propagation in a stratified medium consisting of sectors having the spherically symmetric distributions of refractivity. Model presents analytical expressions for the phase path and refractive attenuation of radio waves. Model is applied for analysis of the radio waves propagation effects along a prolonged path including the atmosphere and two parts of the ionosphere. Model explains significant amplitude and phase variations at the altitudes 30–90 km of the RO ray perigee as connected with influence of the inclined ionospheric layers. An innovative eikonal acceleration technique is described and applied for the identification of the inclined ionospheric layers contributions and their location. Possibility to separate the influence of layered structures from contributions of irregularities and turbulence is analyzed.</jats:p
Ultrashort-pulse generation from quantum-dot semiconductor diode lasers
No full textIn this thesis, novel regimes of mode locking in quantum dot semiconductor laser diodes have been investigated by exploiting the unique features offered by quantum dots. Using an unconventional approach, the role of excited state transitions in the quantum dots was exploited as an additional degree of freedom for the mode locking of experimental quantum dot lasers.
For the first time, passive mode locking via ground (1260nm) or excited state (1190nm) was demonstrated in a quantum dot laser. Picosecond pulses were generated at a repetition rate of 21GHz and 20.5GHz, for the ground and excited states respectively, with average powers in excess of 25mW. Switching between these two states in the mode-locking regime was achieved by changing the electrical biasing conditions, thus providing full control of the operating spectral band.
A novel regime for mode locking in a quantum-dot laser was also investigated, where the simultaneous presence of cw emission in the excited-state band at high injection current levels, dramatically reduced the duration of the pulses generated via the ground state, whilst simultaneously boosting its peak power. This represents a radically different trend from the one typically observed in mode-locked lasers. From this investigation, it was concluded that the role of the excited state can not be neglected in the generation of ultrashort pulses from quantum-dot lasers.
Stable passive mode locking of a quantum-dot laser over an extended temperature range (from 20ºC to 80ºC) was also demonstrated at relatively high output average powers. It was observed that the pulse duration and the spectral width decreased significantly as the temperature was increased up to 70ºC. The process of carrier escape in the absorber was identified as the main contributing factor that led to a decrease in the absorber recovery time as a function of increasing temperature which facilitated a decrease in the pulse durations. These results are shown to open the way for the ultimate deployment of ultra stable and uncooled mode-locked semiconductor diode lasers
Планирование программы клинических исследований препаратов прямого противовирусного действия для лечения хронического вирусного гепатита С
No full textScientific relevance. Direct-acting antivirals have significantly improved the effectiveness of treatment for hepatitis C. However, Russia and the Eurasian Economic Union lack recommendations for the clinical development of medicinal products from this pharmacotherapeutic group.Aim. The study aimed to analyse the requirements and recommendations for planning safety and efficacy clinical trials of direct-acting antivirals for chronic viral hepatitis C, outlined in the regulatory documents of the European Union and the United States.Discussion. Upon analysing the requirements and recommendations, the authors explained the reasons behind choosing the target population and the design for the efficacy and confirmatory studies. The article covers the clinical development of direct-acting antivirals in special populations, including patients with hepatitis C and HIV co-infection, a liver transplant, and prior treatment experience. According to the authors, patients who achieved a sustained virological response should be followed up for a full year after the end of treatment in order to confirm the durability of their response. A dose-finding study should first identify a suitable dose range for monotherapy and, subsequently, for combined therapy. Current treatment regimens should be optimised, and studies should be conducted to reduce treatment duration.Conclusions. The authors outlined the main approaches and a methodology for clinical trial programmes that should take into account the degree of correlation between the efficacy of direct-acting antivirals and the genotype/subtype of hepatitis C virus.Актуальность. Разработка и применение препаратов прямого противовирусного действия существенно повысили эффективность лечения пациентов с инфекцией гепатита С. Однако рекомендации по клинической разработке данной группы препаратов в России и странах Евразийского экономического союза на данный момент отсутствуют.Цель. Анализ требований и рекомендаций к планированию клинических исследований эффективности и безопасности противовирусной терапии хронического гепатита С препаратами прямого противовирусного действия на основании нормативной документации регуляторных органов Европейского союза и США.Обсуждение. В результате проведенного анализа обоснован выбор целевой популяции пациентов и дизайна клинических исследований эффективности и подтверждающих исследований, а также особенности разработки на клиническом этапе в особых группах пациентов, в том числе с коинфекцией гепатитом С и вирусом иммунодефицита человека, пациентов с трансплантатом печени и наличием предшествующего опыта лечения. Отмечено, что за пациентами, достигшими устойчивого вирусологического ответа, требуется наблюдение в течение одного полного года после завершения терапии для подтверждения длительности эффекта. В исследованиях по подбору дозы рекомендовано сначала изучить достаточный диапазон доз в режиме монотерапии, а затем проводить исследования комбинированного применения препарата. Показана необходимость совершенствования существующих схем лечения и изучения возможности сокращения продолжительности курса лечения.Выводы. Сформулированы основные подходы и определена методология программы клинических исследований с учетом высокой степени корреляции эффективности указанных препаратов с генотипом и подтипом вируса гепатита С, которым инфицирован пациент
Numerical simulation and design of semiconductor quantum dot-based lasers and amplifiers
No full textNumerical simulation and design of semiconductor quantum dot-based lasers and amplifier
Ubiquitous nanoperforator aleatoric loco-regional (UNAL) flaps: case series
No full textilustraciones, fotografías, graficasContexto: Los colgajos Keystone son colgajos de perforantes en isla fundamentados en el concepto vascular de angiotoma. Mediante la introducción de modificaciones que incluyen la introducción de los conceptos de área pedicular y diseño libre, se presenta el concepto de colgajos de nanoperforantes ubicuas de localización aleatoria, siendo colgajos en isla pediculados a partir de áreas pequeñas de localización aleatoria en cualquier región anatómica, vascularmente seguros, con arcos de movilidad amplios, y técnicamente sencillos.
Métodos: Se presenta el concepto de colgajos de nanoperforantes ubicuas de localización aleatoria a través de una serie de casos retrospectiva de 150 pacientes, sin restricción de edad, ni localización anatómica, tratados entre 2012 y 2021. Se realiza una descripción de la técnica quirúrgica y se evalúan perfil demográfico, presentación clínica, características de los colgajos, procedimientos adicionales y desenlaces posoperatorios.
Resultados: Se realizaron 211 colgajos en 184 defectos. Las etiologías más comunes de los defectos fueron tumores (30,4%) y trauma (23,3%). La mayoría de los colgajos se realizaron en cabeza y cuello (31%) y miembro inferior (30,4%). El área pedicular promedio de los colgajos fue de 33%, y el 82% de los colgajos fueron entre 1 y 2 veces el tamaño del defecto. Los movimientos más frecuentes fueron los tipos 1A y 4. El 35% de los colgajos presentó alguna complicación, las más frecuentes fueron las dehiscencias (18,5%), necrosis parcial o total (10,9%) y trastornos de cicatrización (6,6%). Hubo necrosis completa en 1,9% de los colgajos. Sólo 27% de las complicaciones requirieron reintervenciones, las más frecuentes consistieron en desbridamientos (28%) y avance de los colgajos (21%).
Conclusiones: Con base en la presunción de existencia de nanoperforantes de forma universal, se presenta el concepto de colgajos de nanoperforantes ubicuas de localización aleatoria. En este estudio se demuestra no sólo la seguridad de la técnica, llegando a tener tasas de necrosis inferiores a la transferencia de tejido libre aun con áreas pediculares pequeñas, sino su inigualable versatilidad, lo cual los hace ideales para resolver todo tipo de problemas reconstructivos complejos. (Texto tomado de la fuente)Background: Keystone flaps, are island perforator flaps based on the vascular concept of
angiotome. Through a series of modifications that include the introduction of the concepts
of pedicle area and free design, the concept of Ubiquitous Nanoperforator Aleatoric Locoregional (UNAL) Flap is presented, being island flaps pedicled from small areas of random
location in any anatomical region, vascularly safe, with wide arches of movement, and
technically simple.
Methods: The concept of Ubiquitous Nanoperforator Aleatoric Loco-regional flap is
presented through a retrospective case series of 150 patients, without age or anatomical
location restriction, treated between 2012 and 2021. A description of the surgical technique
is made and demographic profile, clinical presentation, flap characteristics, additional
procedures and postoperative outcomes are evaluated.
Results: 211 flaps were performed in 184 defects. The most common etiologies were
tumors (30.4%) and trauma (23.3%). Most flaps were performed on the head and neck
(31%) and lower limb (30.4%). The average pedicle area of the flaps was 33%, and 82%
of the flaps were between 1 and 2 times the size of the defect. The most frequent
movements were types 1A and 4. 35% of the flaps presented some complication, the most
frequent were dehiscences (18.5%), partial or total necrosis (10.9%) and healing disorders
(6.6%). Complete necrosis occurred in 1.9% of flaps. Only 27% of complications required
re-interventions, the most frequent consisted of debridement (28%) and flap advancement
(21%) Conclusions: Based on the presumption of universal existence of nanoperforators, the
concept of Ubiquitous Nanoperforator Aleatoric Loco-regional flap is presented. This study
demonstrates not only the safety of the technique, reaching necrosis rates lower than free
tissue transfer, even with small pedicle areas, but its unparalleled versatility, which makes
them ideal for solving all kinds of complex reconstructive problems.Especialidades MédicasEspecialista en Cirugía PlásticaSe realizó una búsqueda en bases de datos personales de los autores para identificar pacientes adultos sometidos a cobertura de cualquier defecto con colgajos de nanoperforantes de localización aleatoria. Se incluyeron pacientes de cualquier edad, operados entre los años 2012 y 2022, con un tiempo mínimo de seguimiento de 2 meses, con defectos por cualquier etiología, y en cualquier localización.
Se revisaron los registros de historia clínica y descripciones quirúrgicas, se extrajeron los datos relevantes para establecer un perfil demográfico (edad, género, comorbilidades), la presentación clínica inicial (número, etiología y localización de los defectos, tiempo de seguimiento, tratamientos previos) , las características de los colgajos (número de colgajos por defecto, área pedicular, relación de tamaño entre el colgajo y el defecto, tipo de movimiento), procedimientos adicionales requeridos, y los desenlaces postoperatorios (complicaciones mayores y menores, reintervenciones y estancia hospitalaria). Se utilizó estadística descriptiva para presentar las variables cuantitativas.
Este estudio se adhiere a las guías STROBE, y a los principios éticos de la Declaración de Helsinki, contando con la aprobación del comité de ética de nuestra institución, a través del acta No. 005-041. No se utilizaron consentimientos para uso de fotografías en tanto no se utilizaron fotografías que revelen la identidad de los pacientes; se obtuvo consentimiento verbal para utilizar las fotografías incluidas.Colgajos de nanoperforante
Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
No full textInternational audienceBACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. METHODS: In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98). CONCLUSIONS: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.)
