Author Correction: BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.

In Extended Data Fig. 1a of this Letter, the flow cytometry plot depicting the surface phenotype of AML sample DD08 was a duplicate of the plot for AML sample DD06. Supplementary Data 4 has been added to the Supplementary Information of the original Letter to clarify the proteome data acquisition and presentation. The original Letter has been corrected online.

Competencies for proficiency in basic point-of-care ultrasound in anesthesiology: national expert recommendations using Delphi methodology.

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.

Analgesia for rib fractures: a narrative review.

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 œuvre 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.

Identifying intraoperative events in a simulated laparotomy video: a multinational study of inattentional blindness among anesthesiologists.

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.

Perioperative management of patients on glucagon-like peptide-1 receptor agonists.

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.

Impact of trisomy 19 on outcome according to genetic makeup in patients with acute myeloid leukemia.

We retrospectively studied 97 acute myeloid leukemia patients with trisomy 19 (median age at diagnosis 57 years; range, 17- 83 years) treated between 2001 and 2019 within two multicenter study groups. Trisomy 19 occurred alone in ten (10.5%) patients, with additional abnormalities being present in non-complex karyotypes in eight (8%) patients and in complex karyotypes in 79 (82%) patients. Altogether, karyotypes characterized by trisomies only were present in 27 (28%) patients. Data on response and outcome of intensively treated patients were available for 92 cases. The median follow-up was 6.4 years (95% confidence interval [95% CI]: 2.9-9.0 years). The complete remission (CR) rate after induction therapy was 52% (48 patients); the early death rate was 10% (n=9). Notably, patients with trisomy 19 as the sole abnormality had a CR rate of 89%. Allogeneic hematopoietic stem cell transplantation (allo-HCT) was performed in 34 (35%) patients (CR, n=19; active disease, n=15). Five-year relapse-free and overall survival rates were 26% (95% CI: 16-43%) and 20% (95% CI: 13-31%), respectively. Overall survival rates were significantly higher in patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only (P=0.05). An Andersen-Gill model including allo-HCT as a time-dependent covariable on overall survival revealed that trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only was a favorable factor (hazard ratio [HR]=0.47; P=0.021); higher age at diagnosis had an adverse impact (10 years difference; HR=1.29; P=0.002), whereas allo-HCT did not have a beneficial impact (odds ratio=1.45; P=0.21). In our cohort, patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only had a high CR rate and better clinical outcome.

Characteristics and outcome of patients with acute myeloid leukemia and trisomy 4.

We retrospectively studied 125 patients with acute myeloid leukemia and trisomy 4 (median age at diagnosis, 58 years; range, 16-77 years) treated between 2000 and 2019 within a multicenter study. Trisomy 4 was the sole abnormality in 28 (22%) patients and additional abnormalities were present in 97 (78%) patients. Twenty-two (22%) and 15 (15%) of 101 tested patients harbored NPM1 and FLT3-ITD mutations. Two (3%) of 72 tested patients had double CEBPA mutations. Data on response to intensive anthracycline-based induction therapy were available for 119 patients. Complete remission was achieved in 67% (n=80) and the early death rate was 5% (n=6). Notably, patients with trisomy 4 as sole abnormality had a complete remission rate of 89%. Allogeneic hematopoietic cell transplantation was performed in 40 (34%) patients, of whom 19 were transplanted in first complete remission. The median follow-up of the intensively treated cohort was 5.76 years (95% confidence interval [95% CI]: 2.99-7.61 years). The 5-year overall survival and relapse-free survival rates were 30% (95% CI: 22-41%) and 27% (95% CI: 18-41%), respectively. An Andersen-Gill regression model on overall survival revealed that favorable-risk according to the European LeukemiaNet classification (hazard ratio [HR]=0.34; P=0.006) and trisomy 4 as sole abnormality (HR=0.41; P=0.01) were favorable factors, whereas age with a difference of 10 years (HR=1.15; P=0.11), female gender (HR=0.74; P=0.20) and allogeneic hematopoietic cell transplantation (HR=0.64; P=0.14) did not have an significant impact. In our cohort, patients with trisomy 4 as their sole abnormality had a high complete remission rate and favorable clinical outcome. Allogeneic hematopoietic cell transplantation did not seem to improve overall survival.

BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.

The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mut AML. Gene sets characteristic for IDHmut AML were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1high AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.

Introducing the fragility index-A case study using the Term Breech Trial.

The fragility index (FI) is a sensitivity analysis of the statistically significant result of a clinical study. It is the number of hypothetical changes in the primary event of one of the two cohorts in a 1-to-1 comparative trial to render the statistically significant result non-significant (ie, to alter the P-value from ≤0.05 to >0.05). The FI can be compared with the patient drop-out rates and protocol violations, which, if much higher than the FI, may arguably suggest less robustness/stability of the trial's results. To illustrate the concept, we have chosen the Term Breech Trial (TBT) as a case study. The TBT results favor planned cesarean birth, as opposed to planned vaginal delivery, in the term singleton fetus with breech presentation. Our analysis shows that the FI of the TBT is 21, which is small in comparison to the number (hundreds) of protocol violations present. Some experts have suggested the inclusion of the FI in data analysis and subsequent discussion of clinical trial data. Routine use of such a metric may be valuable in encouraging readers to maintain a healthy degree of skepticism, especially when interpreting trial results which may directly influence clinical practice.

Systemic Heparinization After Neuraxial Anesthesia in Vascular Surgery: A Retrospective Analysis.

OBJECTIVES: The American Society of Regional Anesthesia and Pain Medicine's guidelines recommend a 1-hour interval after neuraxial anesthesia (NA) before systemic heparinization to mitigate the risk of spinal hematoma (SH). The study authors aimed to characterize the time interval between NA and systemic heparinization in vascular surgery patients (primary outcome). The secondary outcomes included the historic incidence of SH, and risk estimation of the SH formation based on available data. Heparin dose, length of surgery, difficulty and/or the number of NA attempts, and patient demographics were recorded. DESIGN: A retrospective analysis between April 2012 and April 2022. SETTING: A single (academic) center. PARTICIPANTS: Vascular surgery patients. INTERVENTIONS: Intravenous heparin administration. MEASUREMENTS AND MAIN RESULTS: All (N = 311) vascular patients were reviewed, of whom 127 (5 femoral-femoral bypass, 67 femoral-popliteal bypass, and 55 endovascular aneurysm repairs [EVAR]) received NA and were included in the final analysis. Patients receiving general anesthesia alone (N = 184) were excluded. Neuraxial anesthesia included spinal (N = 119), epidural (N = 4), or combined spinal-epidural (N = 4) blocks. The average time between NA and heparin administration was 42.8 ± 22.1 minutes, with 83.7% of patients receiving heparin within 1 hour of NA. The time between NA and heparin administration was 40.4 ± 22.3, 50.1 ± 23.4, and 31.3 ± 12.5 minutes for femoral-femoral bypass, femoral-popliteal bypass, and EVAR, respectively. Heparin was administered after 1 hour of NA in 20% of femoral-femoral bypass, 27% of femoral-popliteal bypass, and 3.9% of EVAR patients. No SHs were reported during the study period. CONCLUSIONS: The vast majority of vascular surgery patients at the authors' center received heparin within 1 hour of NA. Further studies are required to assess if their findings are consistent in other vascular surgery settings and/or centers.

Quantitative proteomics reveals specific metabolic features of acute myeloid leukemia stem cells.

Acute myeloid leukemia is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Because this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus information about posttranscriptionally regulated genes and associated networks is lacking. Here, we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provide strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA-processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts, and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.

Outcome of relapsed or refractory acute B-lymphoblastic leukemia patients and BCR-ABL-positive blast cell crisis of B-lymphoid lineage with extramedullary disease receiving inotuzumab ozogamicin.

Acute lymphoblastic leukemia (ALL) can relapse in the extramedullary compartment, with or without medullary involvement. Response to treatment may be individual. We evaluated response to inotuzumab ozogamicin in 31 patients with relapsed/refractory B-ALL with extramedullary disease. Median age was 31 years (range, 19-81). All patients were heavily pretreated, including allogeneic hematopoietic stem cell transplantation (HSCT; n=18). Overall response rate after two cycles of inotuzumab ozogamicin was 84% (complete remission, 55%; partial remission, 29%; resistant disease, 13%; early death, 3%). The median follow-up was 29 months and median overall survival was 12.8 months. One-year and 2-year overall survival rates were 53% (95% CI: 37-76%) and 18% (95% CI: 8-43%), respectively. Age had no impact on overall survival when assessed as a continuous variable or dichotomized at 60 years. Twelve patients proceeded to allogeneic HSCT (complete remission, n=6; partial remission, n=3; resistant disease, n=3). Prior to allogeneic HSCT, eight patients received two or fewer cycles and four patients received three or four cycles of inotuzumab ozogamicin. Sinusoidal obstruction syndrome was reported in three patients, including one after transplantation. Allogeneic HSCT, evaluated as a time-dependent variable, had no impact on overall survival. Inotuzumab ozogamicin seems to be effective as a debulking strategy in relapsed/refractory ALL with extramedullary disease. However, inotuzumab ozogamicin followed by allogeneic HSCT seems not to be effective in maintaining long-term disease control.

Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study.

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.

The extracellular matrix proteins type I collagen, type III collagen, fibronectin, and laminin 421 stimulate migration of cancer cells.

For metastasis formation, individual cells from a primary tumor must migrate toward other tissues. The aim of this study was to determine if mesenchymal stromal cells (MSCs) from human bone marrow are able to emit signals that induce this migratory activity in cancer cells. We separated the supernatant of MSCs derived from human bone marrow by size-exclusion and ion-exchange chromatography and have subsequently studied the migratory behavior of the prostate cancer cell line PC3 and the breast cancer cell line MDA-MB-231 toward the respective fractions in a transwell migration assay. We identified the extracellular matrix (ECM) proteins type I collagen, type III collagen, fibronectin, and laminin 421 as potential drivers of cancer cell migration. These results could be reproduced using the corresponding isolated or recombinant ECM proteins. Knockdown of the gene encoding beta 1 integrin, an important cell surface receptor for fibronectin, has led to inhibition of cancer cell migration. This supports the hypothesis that beta 1 integrin signaling represents an initial event that leads to metastasis, and that signaling is triggered by binding of integrin heterodimers to ECM molecules. Further characterization of signaling factors and their respective receptors will have implications for anticancer drug development.

A Study of Postoperative Complications Occurring at Home With Pediatric Gastrostomy Feeding Tubes.

OBJECTIVE: Gastrostomy tubes (G-tubes) provide long-term feeding assistance to children with severe feeding dysfunction. Although there are a host of complications that occur at home with current pediatric G-tube feeding, their prevalences and outcomes remain relatively unstudied. This study aims to identify and describe such complications. METHODS: A dual-round survey was administered to 98 participants through the Feeding Tube Awareness Foundation, a 501(c)(3) organization that supports parents and caretakers of G-tube-fed children. Information was collected broadly regarding G-tube complications, causes, and attitudes toward such complications. RESULTS: Infection (56%), itching/irritation/redness (52%), and leakage (51%) were the leading G-tube related complications. The average time that G-tubes were replaced was 3.4 ± 1.2 months as compared to the typical recommended period of up to 6 months. Of the caretakers who had not experienced G-tube displacement, 7.9% wanted to see a change in current G-tubes to address the issue, compared with 75% of those who had experienced displacement. This 67.1% differential in caretakers' attitudes toward G-tubes based on their prior experience with a particular complication was the largest gap among all other listed complications. CONCLUSIONS: G-tube complications are prevalent and varied. A sizable portion of G-tube users experience complications severe enough to require intervention. Of these, G-tube displacement is particularly critical and frequently precedes other prevalent complications, namely gastric leakage, infection, and tissue granulation.

Retrospective Review of Time to Uterotonic Administration and Maternal Outcomes After Postpartum Hemorrhage.

OBJECTIVE: Despite advances in health care and ample resources, post-partum hemorrhage (PPH) rates are increasing in high income countries. Although guidelines recommend therapeutic uterotonics, timing of administration is open to judgement and most often based on (inherently inaccurate) visual estimates of blood loss. With severe hemorrhage, every minute of delay can have significant consequences. Our objective was to examine the timing of uterotonic administration and its impact upon maternal outcomes. We hypothesized that increased time to uterotonic administration following the identification of PPH would be associated with a greater decline in hemoglobin (Hb) and higher odds of hypotension and transfusion. METHODS: We reviewed all cases of PPH that occurred at an academic centre between June 2015 and September 2017. All cases of primary PPH (i.e., those declared within 24 h of delivery with estimated blood loss [EBL] >500 mL for vaginal and >1000 mL for cesarean deliveries) were analyzed. Patient records were excluded if they were missing information regarding time of PPH declaration, uterotonic administration, and/or Hb measures, or if a pre-existing medical condition could have contributed to PPH. RESULTS: Of 4397 births, there were 259 (5.9%) cases of primary PPH, of which 128 were included in this analysis. For these patients, each 5-minute delay in uterotonic treatment was associated with 26% higher odds of hypotension following delivery of any type. For vaginal deliveries (n = 86), each 5-minute delay was associated with 31% and 34% higher odds of hypotension and transfusion, respectively. CONCLUSION: In this study, delay in administration of therapeutic uterotonics was associated with a higher incidence of hypotension and transfusion in primary PPH patients.

Perceptions of cervical cancer care among Ethiopian women and their providers: a qualitative study.

BACKGROUND: Cervical cancer is the second most commonly diagnosed cancer among Ethiopian women, killing an estimated 4700 women each year. As the government rolls out the country's first national cancer control strategy, information on patient and provider experiences in receiving and providing cervical cancer screening, diagnosis, and treatment is critical. METHODS: This qualitative study aimed to assess the availability of cervical cancer care; explore care barriers and sources of delay; and describe women's and providers' perceptions and experiences of care. We analyzed data from 45 informants collected at 16 health centers, district hospitals and referral hospitals in East Gojjam Zone and a support center in Addis Ababa. Thirty providers and ten women receiving care were interviewed, and five women in treatment or post-treatment participated in a focus group discussion. Deductive and inductive codes were used to thematically analyze data. RESULTS: Providers lacked equipment and space to screen and treat patients and only 16% had received in-service cervical cancer training. Consequently, few facilities provided screening or preventative treatment. Patients reported low perceptions of risk, high stigma, a lack of knowledge about cervical cancer, and delayed care initiation. All but one patient sought care only when she became symptomatic, and, pre-diagnosis, only half of the patients knew about cervical cancer. Even among those aware of cervical cancer, many assumed they were not at risk because they were not sexually active. Misdiagnosis was another common source of delay experienced by half of the patients. Once diagnosed, women faced multiple-month waits for referrals, and, once in treatment, broken equipment and shortages of hospital beds resulted in additional delays. Barriers to therapeutic treatment included a lack of housing and travel funds. Patient-provider communication of cancer diagnosis was often lacking. CONCLUSIONS: In-service provider training should be intensified and should include discussions of cervical cancer symptoms. Better distribution of screening and diagnostic supplies to lower-level facilities and better maintenance of treatment equipment at tertiary facilities are also a priority. Expanded cervical cancer health education should focus on stigma reduction and emphasize a broad, wide-spread risk of cervical cancer.

Cervical cancer is the second most commonly diagnosed cancer among Ethiopian women, killing an estimated 4700 women each year. This study aimed to assess patient and provider experiences in receiving and providing cervical cancer screening, diagnosis, and treatment. We interviewed 30 midlevel providers and ten women receiving care and held a focus group discussion with five women who were receiving treatment or who had recently completed treatment. Patients reported bottlenecks and delays at each stage of care. Low perception of risk, high stigma, and a lack of knowledge about cervical cancer among both providers and patients, were significant sources of delay in initiating care. Few patients had been aware of cervical cancer before they were diagnosed and of those who were aware, many assumed that they were not at risk because they were not sexually active. Misdiagnosis was another common source of delay. Once diagnosed correctly, women faced multiple-month delays after referrals, and, once in treatment, broken equipment and a shortage of hospital beds resulted in additional delays. The most frequently mentioned barriers to care were a lack of housing and travel funds while receiving treatment in the capital. Patient-provider communication of cancer diagnosis was often poor. Our findings suggest the need to intensify in-service training for providers, focusing initially on alerting them to cervical cancer symptoms. Better distribution of screening and diagnostic supplies to lower-level facilities and better maintenance of treatment equipment at tertiary facilities should also be a priority.

Update on surgical repair in functional mitral regurgitation.

BACKGROUND: Functional mitral regurgitation (FMR) is common in patients with myocardial infarction or dilated cardiomyopathy, and portends a poor prognosis despite guideline-directed medical therapy (GDMT). Surgical or transcatheter mitral repair for FMR from recent randomized clinical trials showed disappointing or conflicting results. AIMS: To provide an update on the role of surgical repair in the management of FMR. MATERIALS AND METHODS: A literature search was conducted utilizing PubMed, Ovid, Web of Science, Embase, and Cochrane Library. The search terms included secondary/FMR, ischemic mitral regurgitation, mitral repair, mitral replacement, mitral annuloplasty, transcatheter mitral repair, and percutaneous mitral repair. Randomized clinical trials over the past decade were the particular focus of the current review. RESULTS: Recent data underlined the complexity and poor prognosis of FMR. GDMT and cardiac resynchronization, when indicated, should always be applied. Accurate assessment of the interplay between ventricular geometry and mitral valve function is essential to differentiate proportionate FMR from the disproportionate subgroup, which could be helpful in selecting appropriate transcatheter intervention strategies. Surgical repair, most commonly performed with an undersized ring annuloplasty, remains controversial. Adjunctive valvular or subvalvular repair techniques are evolving and may produce improved results in selected FMR patients. CONCLUSION: FMR resulted from complex valve-ventricular interaction and remodeling. Distinguishing proportionate FMR from disproportionate FMR is important in exploring their underlying mechanisms and to guide medical treatment with surgical or transcatheter interventions. Further studies are warranted to confirm the clinical benefit of appropriate surgical repair in selected FMR patients.

A simple technique to assess postoperative epidural functionality.

To describe an alternative method of measuring the Epidural Waveform Analysis (EWA), a technique through which anesthesiologists can confirm the position of a needle and/or catheter tip in the epidural space. EWA consists of epidural catheter transduction with a pressure system typically used for invasive arterial blood pressure monitoring which generates a characteristic oscillatory waveform (provided the catheter tip is within the epidural space) in synchrony with the pulsatile epidural circulation. The technique requires a double-male connector, a 3-way stopcock and an arterial pressure extension tubing along with the patient's existing arterial line setup while ensuring a meticulously sterile technique to mitigate the risks of neuraxial infection. The technique described herein has been successfully and routinely applied within our institution to measure EWA with the advantage of being potentially less wasteful. EWA allows anesthesiologists to confirm the correct position of an epidural needle/catheter. We describe a method of successfully measuring EWA while reducing wastefulness.

Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells.

Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis. This is in addition to deregulations found in murine transcriptomics studies, such as an increased differentiation bias towards the myeloid lineage, alterations in DNA repair, and a decrease in lymphoid development. The increase in glycolytic enzyme activity is caused by the expansion of a more glycolytic HSPC subset. We therefore developed a method to isolate HSPC into three distinct categories according to their glucose uptake (GU) levels, namely the GUhigh, GUinter and GUlow subsets. Single-cell transcriptomics studies showed that the GUhigh subset is highly enriched for HSPC with a differentiation bias towards myeloid lineages. Gene set enrichment analysis (GSEA) demonstrated that the gene sets for cell cycle arrest, senescence-associated secretory phenotype, and the anti-apoptosis and P53 pathways are significantly upregulated in the GUhigh population. With this series of studies, we have produced a comprehensive proteomics and single-cell transcriptomics atlas of molecular changes in human HSPC upon aging. Although many of the molecular deregulations are similar to those found in mice, there are significant differences. The most unique finding is the association of elevated central carbon metabolism with senescence. Due to the lack of specific markers, the isolation and collection of senescent cells have yet to be developed, especially for human HSPC. The GUhigh subset from the human HSPC compartment possesses all the transcriptome characteristics of senescence. This property may be exploited to accurately enrich, visualize, and trace senescence development in human bone marrow.