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Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
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PURPOSE: Medical errors may be occasionally explained by inattentional blindness (IB), i.e., failing to notice an event/object that is in plain sight. We aimed to determine whether age/experience, restfulness/fatigue, and previous exposure to simulation education may affect IB in the anesthetic/surgical setting. METHODS: In this multicentre/multinational study, a convenience sample of 280 anesthesiologists watched an attention-demanding video of a simulated trauma patient undergoing laparotomy and (independently/anonymously) recorded the abnormalities they noticed. The video contained four expected/common abnormalities (hypotension, tachycardia, hypoxia, hypothermia) and two prominently displayed unexpected/rare events (patient's head movement, leaky central venous line). We analyzed the participants' ability to notice the expected/unexpected events (primary outcome) and the proportion of expected/unexpected events according to age group and prior exposure to simulation education (secondary outcomes). RESULTS: Anesthesiologists across all ages noticed fewer unexpected/rare events than expected/common ones. Overall, younger anesthesiologists missed fewer common events than older participants did (P = 0.02). There was no consistent association between age and perception of unexpected/rare events (P = 0.28), although the youngest cohort (< 30 yr) outperformed the other age groups. Prior simulation education did not affect the proportion of misses for the unexpected/rare events but was associated with fewer misses for the expected/common events. Self-perceived restfulness did not impact perception of events. CONCLUSION: Anesthesiologists noticed fewer unexpected/rare clinical events than expected/common ones in an attention-demanding video of a simulated trauma patient, in keeping with IB. Prior simulation training was associated with an improved ability to notice anticipated/expected events, but did not reduce IB. Our findings may have implications for understanding medical mishaps, and efforts to improve situational awareness, especially in acute perioperative and critical care settings.
RéSUMé: OBJECTIF: Les erreurs médicales peuvent parfois s'expliquer par la cécité d'inattention, soit le fait de ne pas remarquer un événement/objet qui est à la vue de tous et toutes. Notre objectif était de déterminer si l'âge/l'expérience, le repos/la fatigue et l'exposition antérieure à l'enseignement par simulation pouvaient affecter la cécité d'inattention dans le cadre de l'anesthésie/chirurgie. MéTHODE: Dans cette étude multicentrique/multinationale, un échantillon de convenance de 280 anesthésiologistes ont visionné une vidéo exigeant l'attention portant sur un patient de trauma simulé bénéficiant d'une laparotomie et ont enregistré (de manière indépendante/anonyme) les anomalies qu'ils et elles ont remarquées. La vidéo contenait quatre anomalies attendues/courantes (hypotension, tachycardie, hypoxie, hypothermie) et deux événements inattendus/rares bien en vue (mouvement de la tête du patient, fuite du cathéter veineux central). Nous avons analysé la capacité des participant·es à remarquer les événements attendus/inattendus (critère d'évaluation principal) et la proportion d'événements attendus/inattendus selon le groupe d'âge et l'exposition antérieure à l'enseignement par simulation (critères d'évaluation secondaires). RéSULTATS: Les anesthésiologistes de tous âges ont remarqué moins d'événements inattendus/rares que d'événements attendus/courants. Globalement, les anesthésiologistes plus jeunes ont manqué moins d'événements courants que leurs congénères plus âgé·es (P = 0,02). Il n'y avait pas d'association constante entre l'âge et la perception d'événements inattendus ou rares (P = 0,28), bien que la cohorte la plus jeune (< 30 ans) ait surpassé les autres groupes d'âge. La formation antérieure par simulation n'a pas eu d'incidence sur la proportion d'inobservation des événements inattendus ou rares, mais a été associée à moins de cécité d'inattention envers les événements attendus ou courants. Le repos perçu n'a pas eu d'impact sur la perception des événements. CONCLUSION: Les anesthésiologistes ont remarqué moins d'événements cliniques inattendus/rares que d'événements attendus/courants dans une vidéo exigeant l'attention portant sur la simulation d'un patient traumatisé, ce qui s'inscrit dans la cécité d'inattention. La formation préalable par simulation était associée à une meilleure capacité à remarquer les événements anticipés/attendus, mais ne réduisait pas la cécité d'inattention. Nos résultats peuvent avoir des implications pour la compréhension des accidents médicaux et les efforts visant à améliorer la conscience situationnelle, en particulier dans les contextes de soins périopératoires aigus et de soins intensifs.
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The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age, and discovered the heterogeneous mSV landscapes of hematopoietic stem and progenitor cells. While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional somatic structural variants, including megabase-scale segmental aneuploidies. Capitalizing on comprehensive single-cell micrococcal nuclease digestion with sequencing reference data, we conducted high-resolution cell-typing for eight hematopoietic stem and progenitor cells. Clonally expanded mSVs disrupt normal cellular function by dysregulating diverse cellular pathways, and enriching for myeloid progenitors. Our findings underscore the contribution of mSVs to the cellular and molecular phenotypes associated with the aging hematopoietic system, and establish a foundation for deciphering the molecular links between mSVs, aging and disease susceptibility in normal tissues.
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Células Madre Hematopoyéticas , Mosaicismo , Humanos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Persona de Mediana Edad , Adulto , Análisis de la Célula Individual/métodos , Anciano , Femenino , Masculino , Envejecimiento/genética , Anciano de 80 o más Años , Células Madre/metabolismo , Variación GenéticaRESUMEN
PURPOSE: Point-of-care ultrasound (POCUS) allows for rapid bedside assessment and guidance of patient care. Recently, POCUS was included as a mandatory component of Canadian anesthesiology training; however, there is no national consensus regarding the competencies to guide curriculum development. We therefore aimed to define national residency competencies for basic perioperative POCUS proficiency. METHODS: We adopted a Delphi process to delineate relevant POCUS competencies whereby we circulated an online survey to academic anesthesiologists identified as POCUS leads/experts (n = 25) at all 17 Canadian anesthesiology residency programs. After reviewing a list of competencies derived from the Royal College of Physicians and Surgeons of Canada's National Curriculum, we asked participants to accept, refine, delete, or add competencies. Three rounds were completed between 2022 and 2023. We discarded items with < 50% agreement, revised those with 50-79% agreement based upon feedback provided, and maintained unrevised those items with ≥ 80% agreement. RESULTS: We initially identified and circulated (Round 1) 74 competencies across 19 clinical domains (e.g., basics of ultrasound [equipment, nomenclature, clinical governance, physics]; cardiac [left ventricle, right ventricle, valve assessment, pericardial effusion, intravascular volume status] and lung ultrasound anatomy, image acquisition, and image interpretation; and clinical applications [monitoring and serial assessments, persistent hypotension, respiratory distress, cardiac arrest]). After three Delphi rounds (and 100% response rate maintained), panellists ultimately agreed upon 75 competencies. CONCLUSION: Through national expert consensus, this study identified POCUS competencies suitable for curriculum development and assessment in perioperative anesthesiology. Next steps include designing and piloting a POCUS curriculum and assessment tool(s) based upon these nationally defined competencies.
RéSUMé: OBJECTIF: L'échographie ciblée (POCUS) permet une évaluation rapide au chevet des patient·es et l'orientation des soins aux patient·es. Récemment, l'échographie ciblée a été incluse en tant que composante obligatoire de la formation en anesthésiologie au Canada; cependant, il n'y a pas de consensus national sur les compétences qui guideront l'élaboration des programmes d'études. Nous avons donc cherché à définir les compétences à inclure dans les programmes de résidence nationaux pour acquérir des compétences de base en échographie ciblée périopératoire. MéTHODE: Nous avons adopté un processus Delphi pour délimiter les compétences pertinentes en échographie ciblée, processus dans le cadre duquel nous avons fait circuler un sondage en ligne auprès d'anesthésiologistes universitaires identifié·es comme des responsables/expert·es en échographie ciblée (n = 25) dans les 17 programmes canadiens de résidence en anesthésiologie. Après avoir examiné une liste de compétences tirées du programme d'études national du Collège royal des médecins et chirurgiens du Canada, nous avons demandé aux participant·es d'accepter, de peaufiner, de supprimer ou d'ajouter des compétences. Trois rondes ont été complétées entre 2022 et 2023. Nous avons écarté les éléments ayant < 50 % d'accord, révisé ceux avec 50 à 79 % d'accord en fonction des commentaires fournis, et maintenu sans révision les éléments obtenant ≥ 80 % d'accord. RéSULTATS: Nous avons d'abord identifié et diffusé (ronde 1) 74 compétences dans 19 domaines cliniques (p. ex., les bases de l'échographie [équipement, nomenclature, gouvernance clinique, physique]; anatomie échographique cardiaque [ventricule gauche, ventricule droit, évaluation valvulaire, épanchement péricardique, état du volume intravasculaire] et pulmonaire [acquisition et interprétation d'images]; et applications cliniques [surveillance et évaluations en série, hypotension persistante, détresse respiratoire, arrêt cardiaque]). Après trois rondes Delphi (et un taux de réponse de 100 % maintenu), les panélistes se sont finalement mis·es d'accord sur 75 compétences. CONCLUSION: Grâce à un consensus d'expert·es au pays, cette étude a permis d'identifier les compétences en échographie ciblée adaptées à l'élaboration et à l'évaluation de programmes d'études en anesthésiologie périopératoire. Les prochaines étapes comprennent la conception et la mise à l'essai d'un programme d'études et d'outils d'évaluation en échographie ciblée basés sur ces compétences définies à l'échelle nationale.
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Anestesiología , Competencia Clínica , Curriculum , Técnica Delphi , Sistemas de Atención de Punto , Ultrasonografía , Anestesiología/educación , Humanos , Canadá , Ultrasonografía/métodos , Internado y Residencia , Anestesiólogos/educación , Encuestas y CuestionariosRESUMEN
PURPOSE: Rib fracture(s) is a common and painful injury often associated with significant morbidity (e.g., respiratory complications) and high mortality rates, especially in the elderly. Risk stratification and prompt implementation of analgesic pathways using a multimodal analgesia approach comprise a primary endpoint of care to reduce morbidity and mortality associated with rib fractures. This narrative review aims to describe the most recent evidence and care pathways currently available, including risk stratification tools and pharmacologic and regional analgesic blocks frequently used as part of the broadly recommended multimodal analgesic approach. SOURCE: Available literature was searched using PubMed and Embase databases for each topic addressed herein and reviewed by content experts. PRINCIPAL FINDINGS: Four risk stratification tools were identified, with the Study of the Management of Blunt Chest Wall Trauma score as most predictive. Current evidence on pharmacologic (i.e., acetaminophen, nonsteroidal anti-inflammatory drugs, gabapentinoids, ketamine, lidocaine, and dexmedetomidine) and regional analgesia (i.e., thoracic epidural analgesia, thoracic paravertebral block, erector spinae plane block, and serratus anterior plane block) techniques was reviewed, as was the pathophysiology of rib fracture(s) and its associated complications, including the development of chronic pain and disabilities. CONCLUSION: Rib fracture(s) continues to be a serious diagnosis, with high rates of mortality, development of chronic pain, and disability. A multidisciplinary approach to management, combined with appropriate analgesia and adherence to care bundles/protocols, has been shown to decrease morbidity and mortality. Most of the risk-stratifying care pathways identified perform poorly in predicting mortality and complications after rib fracture(s).
RéSUMé: OBJECTIF: Les fractures des côtes sont des blessures courantes et douloureuses souvent associées à une morbidité importante (p. ex., complications respiratoires) et à des taux de mortalité élevés, surtout chez les personnes âgées. La stratification des risques et la mise en Åuvre rapide de voies analgésiques à l'aide d'une approche d'analgésie multimodale constituent un critère d'évaluation principal des soins visant à réduire la morbidité et la mortalité associées aux fractures des côtes. Ce compte rendu narratif a pour objectif de décrire les données probantes les plus récentes et les parcours de soins actuellement disponibles, y compris les outils de stratification des risques et les blocs analgésiques pharmacologiques et régionaux fréquemment utilisés dans le cadre de l'approche analgésique multimodale largement recommandée. SOURCES: La littérature disponible a été recherchée à l'aide des bases de données PubMed et Embase pour chaque sujet abordé dans le présent compte rendu et examinée par des expert·es en contenu. CONSTATATIONS PRINCIPALES: Quatre outils de stratification des risques ont été identifiés, le score de l'Étude de la prise en charge des traumatismes contondants de la paroi thoracique (Study of the Management of Blunt Chest Wall Trauma) étant le plus prédictif. Les données probantes actuelles sur les techniques d'analgésie pharmacologiques (c.-à-d. acétaminophène, anti-inflammatoires non stéroïdiens, gabapentinoïdes, kétamine, lidocaïne et dexmédétomidine) et d'analgésie régionale (c.-à-d. analgésie péridurale thoracique, bloc paravertébral thoracique, bloc du plan des muscles érecteurs du rachis et bloc du plan du muscle grand dentelé) ont été examinées, de même que la physiopathologie de la ou des fractures des côtes et de leurs complications associées, y compris l'apparition de douleurs chroniques et d'incapacités. CONCLUSION: Les fractures des côtes continuent d'être un diagnostic grave, avec des taux élevés de mortalité, de développement de douleurs chroniques et d'invalidité. Il a été démontré qu'une approche multidisciplinaire de la prise en charge, combinée à une analgésie appropriée et à l'adhésion aux ensembles et protocoles de soins, réduit la morbidité et la mortalité. La plupart des parcours de soins de stratification des risques identifiés sont peu performants pour prédire la mortalité et les complications après une ou plusieurs fractures de côtes.
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Analgesia Epidural , Analgesia , Dolor Crónico , Fracturas de las Costillas , Humanos , Anciano , Fracturas de las Costillas/complicaciones , Fracturas de las Costillas/terapia , Manejo del Dolor/métodos , Analgesia/métodos , Analgésicos/uso terapéutico , Analgesia Epidural/métodosRESUMEN
Gastrostomy tubes (G-tubes) are the gold standard for feeding assistance for children with feeding dysfunction. Current G-tubes pose complications that interrupt the delivery of feed, including tube displacement and difficulty of at-home use. This study details an alternative, spoke-based, double-lumen G-tube design and preliminary validation of its function and usability. Pull force testing was performed on spoke G-tube models across three sizes and two classifications (hard/soft). Preliminary models were evaluated against market standards. Though the pull force of the spoke model was found to be lower than that of both market standards, hard modifications to the spoke model improved retentive force. Ease of use was tested amongst users unfamiliar with G-tube placement. The spoke design required 12.3 ± 4.7 s to deploy, less than half the time required for market standards. However, balloon G-tubes were still perceived to be easiest to use by 70% of participants, with indications that a spoke design may be easier to use if sized similarly to current G-tubes, with auxiliary improvements to factors such as grip. While there is a need for improvements in the material properties and manufacturing of the proposed design, this study provides early validation of the potential to address complications of existing G-tubes.
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PURPOSE OF REVIEW: To summarize the mechanism of action, clinical outcomes, and perioperative implications of glucagon-like peptide-1 receptor agonists (GLP-1-RAs). Specifically, this review focuses on the available literature surrounding complications (primarily, bronchoaspiration) and current recommendations, as well as knowledge gaps and future research directions on the perioperative management of GLP-1-RAs. RECENT FINDINGS: GLP-1-RAs are known to delay gastric emptying. Accordingly, recent case reports and retrospective observational studies, while anecdotal, suggest that the perioperative use of GLP-1-RAs may increase the risk of bronchoaspiration despite fasting intervals that comply with (and often exceed) current guidelines. As a result, guidelines and safety bulletins have been published by several Anesthesiology Societies. SUMMARY: While rapidly emerging evidence suggests that perioperative GLP-1-RAs use is associated with delayed gastric emptying and increased risk of bronchoaspiration (particularly in patients undergoing general anesthesia and/or deep sedation), high-quality studies are needed to provide definitive answers with respect to the safety and duration of preoperative drug cessation, and optimal fasting intervals according to the specific GLP-1-RA agent, the dose/duration of administration, and patient-specific factors. Meanwhile, clinicians must be aware of the potential risks associated with the perioperative use of GLP-1-RAs and follow the recommendations put forth by their respective Anesthesiology Societies.
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Vaciamiento Gástrico , Agonistas Receptor de Péptidos Similares al Glucagón , Atención Perioperativa , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ayuno , Vaciamiento Gástrico/efectos de los fármacos , Agonistas Receptor de Péptidos Similares al Glucagón/efectos adversos , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéuticoRESUMEN
Stem cells are regulated not only by biochemical signals but also by biophysical properties of extracellular matrix (ECM). The ECM is constantly monitored and remodeled because the fate of stem cells can be misdirected when the mechanical interaction between cells and ECM is imbalanced. A well-defined ECM model for bone marrow-derived human mesenchymal stem cells (hMSCs) based on supramolecular hydrogels containing reversible host-guest crosslinks is fabricated. The stiffness (Young's modulus E) of the hydrogels can be switched reversibly by altering the concentration of non-cytotoxic, free guest molecules dissolved in the culture medium. Fine-adjustment of substrate stiffness enables the authors to determine the critical stiffness level E* at which hMSCs turn the mechano-sensory machinery on or off. Next, the substrate stiffness across E* is switched and the dynamic adaptation characteristics such as morphology, traction force, and YAP/TAZ signaling of hMSCs are monitored. These data demonstrate the instantaneous switching of traction force, which is followed by YAP/TAZ signaling and morphological adaptation. Periodical switching of the substrate stiffness across E* proves that frequent applications of mechanical stimuli drastically suppress hMSC proliferation. Mechanical stimulation across E* level using dynamic hydrogels is a promising strategy for the on-demand control of hMSC transcription and proliferation.
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Hidrogeles , Células Madre Mesenquimatosas , Humanos , Hidrogeles/farmacología , Hidrogeles/química , Transducción de Señal , Matriz Extracelular , Módulo de ElasticidadRESUMEN
BACKGROUND: Breast reconstruction is an integral part of breast cancer care. There are 2 main types of breast reconstruction: alloplastic (using implants) and autologous (using the patient's own tissue). The latter creates a more natural breast mound and avoids the long-term need for surgical revision-more often associated with implant-based surgery. The deep inferior epigastric perforator (DIEP) flap is considered the gold standard approach in autologous breast reconstruction. However, complications do occur with DIEP flap surgery and can stem from poor flap tissue perfusion/oxygenation. Hence, the development of strategies to enhance flap perfusion (eg, goal-directed perioperative fluid therapy) is essential. Current perioperative fluid therapy is traditionally guided by subjective criteria, which leads to wide variations in clinical practice. OBJECTIVE: The main objective of this trial is to determine whether the use of minimally invasive cardiac output (CO) monitoring for guiding intravenous fluid administration, combined with low-dose dobutamine infusion (via a treatment algorithm), will increase tissue oxygenation in patients undergoing DIEP flap surgery. METHODS: With appropriate institutional ethics board and Health Canada approval, patients undergoing DIEP flap surgery are randomly assigned to receive CO monitoring for the guidance of intraoperative fluid therapy in addition to a low-dose dobutamine infusion (which potentially improves flap oxygenation) versus the current standard of care. The primary outcome is tissue oxygenation measured via near-infrared spectroscopy at the perfusion zone furthest from the perforator vessels 45 minutes after vascular reanastomosis of the DIEP flap. Low dose (2.5 µg/kg/hr) dobutamine infusion continues for up to 4 hours postoperatively, provided there are no associated complications (ie, persistent tachycardia). Flap oxygenation, hemodynamic parameters, and any medication-associated side effects/complications are monitored for up to 48 hours postoperatively. Complications, rehospitalizations, and patient satisfaction are also collected until 30 days postoperatively. RESULTS: Funding and regulatory approvals were obtained in 2019, but the study recruitment was interrupted by the COVID-19 pandemic. As of October 4, 2023, 34 participants have been recruited. Because of the significant delays associated with the pandemic, the expected completion date was extended. We expect the study to be completed and ready for potential news release (as appropriate) and publication by July 2024. No patients have suffered any adverse effects/complications from participating in this study, and none have been lost to follow-up. CONCLUSIONS: CO-directed fluid therapy in combination with a low-dose dobutamine infusion via a treatment algorithm has the potential to improve DIEP flap tissue oxygenation and reduce complications following DIEP flap breast reconstruction surgery. However, given that the investigators remain blinded to group randomization, no comment can be made regarding the efficacy of this intervention for improving tissue oxygenation at this time. Nevertheless, no patients have been withdrawn for safety concerns thus far, and compliance remains high. TRIAL REGISTRATION: Clinicaltrials.gov NCT04020172; https://clinicaltrials.gov/study/NCT04020172.
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During central nervous system (CNS) development, a precisely patterned vasculature emerges to support CNS function. How neurons control angiogenesis is not well understood. Here, we show that the neuromodulator dopamine restricts vascular development in the retina via temporally limited production by an unexpected neuron subset. Our genetic and pharmacological experiments demonstrate that elevating dopamine levels inhibits tip-cell sprouting and vessel growth, whereas reducing dopamine production by all retina neurons increases growth. Dopamine production by canonical dopaminergic amacrine interneurons is dispensable for these events. Instead, we found that temporally restricted dopamine production by retinal ganglion cells (RGCs) modulates vascular development. RGCs produce dopamine precisely during angiogenic periods. Genetically limiting dopamine production by ganglion cells, but not amacrines, decreases angiogenesis. Conversely, elevating ganglion-cell-derived dopamine production inhibits early vessel growth. These vasculature outcomes occur downstream of vascular endothelial growth factor receptor (VEGFR) activation and Notch-Jagged1 signaling. Jagged1 is increased and subsequently inhibits Notch signaling when ganglion cell dopamine production is reduced. Our findings demonstrate that dopaminergic neural activity from a small neuron subset functions upstream of VEGFR to serve as developmental timing cue that regulates vessel growth.
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Dopamina , Factor A de Crecimiento Endotelial Vascular , Dopamina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Retina , Células Ganglionares de la Retina/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www. CLINICALTRIALS: gov as NCT03676504.
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Síndromes de Neurotoxicidad , Humanos , Adulto , Leucaféresis , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19/uso terapéuticoAsunto(s)
Obstrucción de las Vías Aéreas , Obstrucción Nasal , Humanos , Dióxido de Carbono , Cánula , Intubación , Hipoxia/etiologíaRESUMEN
Home-based photobiomodulation is a popular treatment modality for patients seeking non-invasive aesthetic treatment. Studies demonstrate that photobiomodulation is effective for skin rejuvenation, which is aimed at improving the overall appearance of the skin by reducing fine lines and wrinkles and improving skin texture, skin tone, and dyspigmentation. Most current skin rejuvenation research focuses on treatments in women. However, men's aesthetics remains an underserved market. A combined red light (RL) and near-infrared (NIR) light-emitting diode (LED) has been designed specifically to target male skin, which may have different physiological and biophysical properties compared to female skin. Herein, the safety and efficacy of a commercially available RL and NIR (633, 830, and 1072 nm) LED array designed to be worn as a face mask was assessed. Primary outcomes included adverse events and facial rejuvenation as determined by participant-reported satisfaction scales and quantitative digital skin photography and computer analysis after 6 weeks of treatment. The participants reported overall favorable results and improvements in all individual categories, were satisfied with the treatment, and would recommend the product to others. The participants perceived the greatest improvement in fine lines and wrinkles, skin texture, and youthful appearance. Photographic digital analysis demonstrated favorable improvements in wrinkles, UV spots, brown spots, pores, and porphyrins. These results support the use of RL and NIR to treat male skin. Advantages of the LED facemask include its safety, efficacy, convenient home-based use, minimal associated downtime, simple operation, non-invasiveness, and appreciable results in as few as 6 weeks.