Treatment of Relapsed Acute Lymphocytic Leukemia in Adult Patients.

OPINION STATEMENT: For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of novel cellular and immunotherapy approaches - blinatumomab, chimeric antigen receptor (CAR) T therapy, and inotuzumab. For the last several years, research has focused on gaining a better understanding of the effects of specific disease and patient characteristics on long-term outcomes with each of the FDA-approved agents. In combination with the better prevention and management of unique, treatment-specific toxicities, providers can now select the best available treatment option for each individual patient diagnosed with relapsed, adult B-ALL needing therapy. This has allowed more patients to proceed to consolidative hematopoietic stem cell transplant (HSCT), and long-term data has even brought into question the need for HSCT for long-term durable remission for all patients. However, with the adoption of blinatumomab, CAR T therapy, and inotuzumab in front-line treatment regimens, it remains unclear what effects this will have on patients with relapsed B-ALL following exposure to these novel cellular and immunotherapy therapies. Unlike B-ALL, similar advances have unfortunately not yet been realized in T cell-ALL (T-ALL). Currently, new therapeutic approaches are underway to utilize similar targeting strategies that have been successful in B-ALL - monoclonal antibodies, bispecific T-cell engagers (BiTE), and CAR T therapy. Like B-ALL, the only existing approved therapy for relapsed T-ALL, nelarabine, is now used in the upfront treatment setting potentially limiting its utility in relapsed disease. Over the next several years, the hope is for patients diagnosed with T-ALL to experience the drastic improvement in outcomes as has been seen for patients diagnosed with B-ALL over the last decade.

Asociación entre metaplasia, displasia y cáncer de vesícula biliar en una EPS de Bogotá, Colombia / Association between metaplasia, dysplasia and gallbladder cancer in an EPS in Bogotá, Colombia

Introducción. El cáncer de vesícula biliar es el más común en el tracto biliopancreático y una importante causa de mortalidad. La metaplasia y la displasia han sido mencionados como probables precursores relacionados con la secuencia metaplasia-displasia-cáncer. El objetivo de este estudio fue establecer las posibles asociaciones entre estas alteraciones histopatológicas y su relación con la edad y el sexo de los pacientes. Métodos. Estudio observacional retrospectivo descriptivo, con un componente analítico de corte transversal. Se incluyeron los informes de patología de pacientes llevados a colecistectomía laparoscópica electiva y ambulatoria, entre enero de 2015 y diciembre de 2020, con colecistitis crónica, colelitiasis o pólipos vesiculares, mayores de 18 años. Se describieron las características demográficas por sexo y edad utilizando medias, desviaciones estándar y porcentajes. Se emplearon la prueba de chi cuadrado y la prueba exacta de Fisher para evaluar la asociación entre las variables cualitativas. Resultados. Se incluyeron 4871 informes de patología. En esta cohorte se encontró asociación estadísticamente significativa entre metaplasia, displasia y cáncer de vesícula (p<0,05), al igual que con el sexo y la edad de los pacientes. Conclusiones. Los resultados sugieren una asociación entre metaplasia, displasia y cáncer de vesícula biliar en la población estudiada. Se recomienda la realización de investigaciones complementarias para definir la posible causalidad entre metaplasia, displasia y cáncer de vesícula biliar en una población más heterogénea.

Introduction. Gallbladder cancer is the most common cancer in the biliopancreatic tract and an important cause of mortality. Metaplasia and dysplasia have been mentioned as probable precursors related to the metaplasia-dysplasia-cancer sequence. The objective of this study was to establish the possible associations between these histopathological alterations and their relationship with the age and sex of the patients. Methods. Descriptive retrospective observational study, with a cross-sectional analytical component. Pathology reports of patients undergoing elective and outpatient laparoscopic cholecystectomy were included between January 2015 and December 2020, with chronic cholecystitis, cholelithiasis, or gallbladder polyps, over 18 years of age. Demographic characteristics by sex and age was performed using means, standard deviations, and percentages. The chi2 test and Fisher's exact test were used to evaluate the association between the qualitative variables. Results. 4871 pathology reports were included. In this cohort, a statistically significant association was found between metaplasia, dysplasia, and gallbladder cancer (p<0.05), as well as with the sex and age of the patients. Conclusions. The results suggest an association between metaplasia, dysplasia and gallbladder cancer in the study population. Additional research is recommended to define the possible causality between metaplasia, dysplasia, and gallbladder cancer in a more heterogeneous population.

Gaps in Adolescent and Young Adult Cancer Education in Oncology Fellowship Training.

Purpose: Adolescents and young adults (AYAs, 15-39 years) with cancer experience disparities in care and outcomes compared with older/younger patients. AYAs receive care from medical and pediatric oncologists, however, little is known about the extent of training fellows receive. This needs assessment evaluating current AYA oncology (AYA-O) education in pediatric and medical oncology fellowship programs to identify knowledge gaps for curricular development. Methods: An anonymous, cross-sectional, web-based survey developed by pediatric and medical oncologists was sent to medical (n = 178) and pediatric (n = 119) hematology/oncology program directors (PDs) at 251 sites in the United States. PDs were asked to participate and distribute the survey to their fellows. Survey questions addressed current AYA curriculum, provider comfort, and priorities for future AYA educational content. Results: Participants from 69/251 programs responded (program response rate = 27%), including 51 PDs (32 pediatric, 19 medical oncology) and 58 fellows (33 pediatric, 25 medical oncology). Eighty-five percent of PDs (44/51) reported lacking formal AYA curricula. Of these, 80% (35/44) offer some topic-specific lectures, while 20% (9/44) provide little/no education for any topics. For nearly all topics, at least 45% of combined respondents reported little/no education. Respondents believe AYA topics are important for inclusion in future curricula. The most important topics for inclusion reported were oncofertility (82%), survivorship (78%), and communication (77%). Conclusions: There are large and actionable gaps in AYA-O education during fellowship training. Efforts are underway to develop AYA-O curriculum to provide both medical and pediatric oncology fellows with the knowledge and skills required to provide optimal AYA care.

Leveraging health care technology to improve health outcomes and reduce outcome disparities in AYA leukemia.

Significant improvements have occurred for adolescent and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients following the widespread adoption of "pediatric-inspired" treatment regimens for AYA patients cared for in adult oncology settings. However, for AYA patients, aged 15 to 39, an outcomes gap remains in B-ALL, necessitating the incorporation of novel therapies into up-front treatment regimens. As a result, clinical trial enrollment remains the current standard of care for AYA B-ALL across disease subtypes when available and accessible. Currently, several up-front trials are looking to incorporate the use of inotuzumab, blinatumomab, and chimeric antigen receptor T-cell therapy into existing chemotherapy backbones for AYA patients, as well as tyrosine kinase inhibitors for both Philadelphia-positive (Ph+) and Ph-like B-ALL. In addition to ongoing attempts to improve up-front treatments by incorporating immunotherapy and targeted approaches, the increased use of next generation sequencing for measurable residual disease evaluation has led to superior risk-stratification and a decreased need to pursue consolidative hematopoietic stem cell transplantation during the first complete remission for many patients.

Rational social distancing policy during epidemics with limited healthcare capacity.

Epidemics of infectious diseases posing a serious risk to human health have occurred throughout history. During recent epidemics there has been much debate about policy, including how and when to impose restrictions on behaviour. Policymakers must balance a complex spectrum of objectives, suggesting a need for quantitative tools. Whether health services might be 'overwhelmed' has emerged as a key consideration. Here we show how costly interventions, such as taxes or subsidies on behaviour, can be used to exactly align individuals' decision making with government preferences even when these are not aligned. In order to achieve this, we develop a nested optimisation algorithm of both the government intervention strategy and the resulting equilibrium behaviour of individuals. We focus on a situation in which the capacity of the healthcare system to treat patients is limited and identify conditions under which the disease dynamics respect the capacity limit. We find an extremely sharp drop in peak infections at a critical maximum infection cost in the government's objective function. This is in marked contrast to the gradual reduction of infections if individuals make decisions without government intervention. We find optimal interventions vary less strongly in time when interventions are costly to the government and that the critical cost of the policy switch depends on how costly interventions are.

Direct numerical simulations of a microswimmer in a viscoelastic fluid.

This study presents the application of the smoothed profile (SP) method to perform direct numerical simulations for the motion of both passive and active "squirming" particles in Newtonian and viscoelastic fluids. We found that fluid elasticity has a significant impact on both the transient behavior and the steady-state velocity of the particles. Specifically, we observe that the swirling flow generated by the squirmer's surface velocity significantly enhances their swimming speed as the Weissenberg number increases, regardless of the swimming type. Furthermore, we find that pushers outperform pullers in Oldroyd-B fluids, suggesting that the speed of a squirmer depends on the swimmer type. To understand the physical origin of the phenomenon of swirling flow enhancing the swimming speed, we investigate the velocity field and polymer conformation around non-swirling and swirling neutral squirmers in viscoelastic fluids. Our investigation reveals that the velocity field around the neutral swirling squirmers exhibits pusher-like extensional flow characteristics, as well as an asymmetric polymer conformation distribution, which gives rise to this increased propulsion. This is confirmed by the investigation of the force on a fixed squirmer, which revealed that the polymer stress, particularly its diagonal components, plays a critical role in enhancing the swimming speed of swirling squirmers in viscoelastic fluids. Additionally, our results demonstrate that the maximum swimming speeds of swirling squirmers occur at an intermediate value of the fluid viscosity ratio for all swimmer types. These findings have important implications for understanding the behavior of particles and micro-organisms in complex fluids.

Rational social distancing in epidemics with uncertain vaccination timing.

During epidemics people may reduce their social and economic activity to lower their risk of infection. Such social distancing strategies will depend on information about the course of the epidemic but also on when they expect the epidemic to end, for instance due to vaccination. Typically it is difficult to make optimal decisions, because the available information is incomplete and uncertain. Here, we show how optimal decision-making depends on information about vaccination timing in a differential game in which individual decision-making gives rise to Nash equilibria, and the arrival of the vaccine is described by a probability distribution. We predict stronger social distancing the earlier the vaccination is expected and also the more sharply peaked its probability distribution. In particular, equilibrium social distancing only meaningfully deviates from the no-vaccination equilibrium course if the vaccine is expected to arrive before the epidemic would have run its course. We demonstrate how the probability distribution of the vaccination time acts as a generalised form of discounting, with the special case of an exponential vaccination time distribution directly corresponding to regular exponential discounting.

Learning to swim efficiently in a nonuniform flow field.

Microswimmers can acquire information on the surrounding fluid by sensing mechanical queues. They can then navigate in response to these signals. We analyze this navigation by combining deep reinforcement learning with direct numerical simulations to resolve the hydrodynamics. We study how local and nonlocal information can be used to train a swimmer to achieve particular swimming tasks in a nonuniform flow field, in particular, a zigzag shear flow. The swimming tasks are (1) learning how to swim in the vorticity direction, (2) learning how to swim in the shear-gradient direction, and (3) learning how to swim in the shear-flow direction. We find that access to laboratory frame information on the swimmer's instantaneous orientation is all that is required in order to reach the optimal policy for tasks (1) and (2). However, information on both the translational and rotational velocities seems to be required to accomplish task (3). Inspired by biological microorganisms, we also consider the case where the swimmers sense local information, i.e., surface hydrodynamic forces, together with a signal direction. This might correspond to gravity or, for microorganisms with light sensors, a light source. In this case, we show that the swimmer can reach a comparable level of performance to that of a swimmer with access to laboratory frame variables. We also analyze the role of different swimming modes, i.e., pusher, puller, and neutral.

Single-Cell Next-Generation Sequencing to Monitor Hematopoietic Stem-Cell Transplantation: Current Applications and Future Perspectives.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are genetically complex and diverse diseases. Such complexity makes challenging the monitoring of response to treatment. Measurable residual disease (MRD) assessment is a powerful tool for monitoring response and guiding therapeutic interventions. This is accomplished through targeted next-generation sequencing (NGS), as well as polymerase chain reaction and multiparameter flow cytometry, to detect genomic aberrations at a previously challenging leukemic cell concentration. A major shortcoming of NGS techniques is the inability to discriminate nonleukemic clonal hematopoiesis. In addition, risk assessment and prognostication become more complicated after hematopoietic stem-cell transplantation (HSCT) due to genotypic drift. To address this, newer sequencing techniques have been developed, leading to more prospective and randomized clinical trials aiming to demonstrate the prognostic utility of single-cell next-generation sequencing in predicting patient outcomes following HSCT. This review discusses the use of single-cell DNA genomics in MRD assessment for AML/MDS, with an emphasis on the HSCT time period, including the challenges with current technologies. We also touch on the potential benefits of single-cell RNA sequencing and analysis of accessible chromatin, which generate high-dimensional data at the cellular resolution for investigational purposes, but not currently used in the clinical setting.

Absolute lymphocyte count recovery following initial acute myelogenous leukemia therapy: Implications for adoptive cell therapy.

BACKGROUND: An adequate absolute lymphocyte count (ALC) is an essential first step in autologous chimeric antigen receptor (CAR) T-cell manufacturing. For patients with acute myelogenous leukemia (AML), the intensity of chemotherapy received may affect adequate ALC recovery required for CAR T-cell production. We sought to analyze ALC following each course of upfront therapy as one metric for CAR T-cell manufacturing feasibility in children and young adults with AML. PROCEDURE: ALC data were collected from an observational study of patients with newly diagnosed AML between the ages of 1 month and 21 years who received treatment between the years of 2006 and 2018 at one of three hospitals in the Leukemia Electronic Abstraction of Records Network (LEARN) consortium. RESULTS: Among 193 patients with sufficient ALC data for analysis, the median ALC following induction 1 was 1715 cells/µl (interquartile range: 1166-2388), with successive decreases in ALC with each subsequent course. Similarly, the proportion of patients achieving an ALC >400 cells/µl decreased following each course, ranging from 98.4% (190/193) after course 1 to 66.7% (22/33) for patients who received a fifth course of therapy. CONCLUSIONS: There is a successive decline of ALC recovery with subsequent courses of chemotherapy. Despite this decline, ALC values are likely sufficient to consider apheresis prior to the initiation of each course of upfront therapy for the majority of newly diagnosed pediatric AML patients, thereby providing a window of opportunity for T-cell collection for those patients identified at high risk of relapse or with refractory disease.

Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation.

Chimeric antigen receptor T-cells (CART) are active in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), but relapse remains a substantial challenge. Reinfusion with the same CART product (CART2) in patients with suboptimal response or antigen positive relapse following first infusion (CART1) represents a potential treatment strategy, though early experiences suggest limited efficacy of CART2 with CD19 targeting. We report on our experience with CART2 across a host of novel CAR T-cell trials. This was a retrospective review of children and young adults with B-ALL who received reinfusion with an anti-CD19, anti-CD22, or anti-CD19/22 CART construct on one of 3 CAR T-cells trials at the National Cancer Institute (NCT01593696, NCT02315612, NCT0344839) between July 2012 and January 2021. All patients received lymphodepletion (LD) pre-CART (standard LD: 75 mg/m2 fludarabine, 900 mg/m2 cyclophosphamide; or intensified LD: 120 mg/m2 fludarabine, 1200 mg/m2 cyclophosphamide). Primary objectives were to describe response to and toxicity of CART2. Indication for CART2, impact of LD intensity, and CAR T-cell expansion and leukemia antigen expression between CART infusions was additionally evaluated. Eighteen patients proceeded to CART2 due to persistent (n=7) or relapsed antigen positive disease (n=11) following CART1. Seven of 18 (38.9%) demonstrated objective response (responders) to CART2: 5 achieved a minimal residual disease (MRD) negative CR, 1 had persistent MRD level disease, and 1 showed a partial remission, the latter with eradication of antigen positive disease and emergence of antigen negative B-ALL. Responders included four patients who had not achieved a CR with CART1. Limited cytokine release syndrome was seen following CART2. Peripheral blood CART1 expansion was higher than CART2 expansion (p=0.03). Emergence of antigen negative/dim B-ALL in 6 (33.3%) patients following CART2 contributed to lack of CR. Five of seven (71.4%) responders received intensified LD pre-CART2, which corresponded with higher CART2 expansion than in those receiving standard LD (p=0.029). Diminished CAR T-cell expansion and antigen downregulation/loss impeded robust responses to CART2. A subset of patients, however, may derive benefit from CART2 despite suboptimal response to CART1. Intensified LD may be one strategy to augment CART2 responses, though further study of factors associated with CART2 response, including serial monitoring of antigen expression, is warranted.

CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR.

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) may be used to consolidate chimeric antigen receptor (CAR) T cell therapy-induced remissions for patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL), but little is known about the factors impacting overall survival (OS) and event-free survival (EFS) for post-CAR hematopoietic stem cell transplantation (HSCT). The present study's primary objective was to identify factors associated with OS and EFS for consolidative HSCT following CAR-induced complete remission (CR) in transplantation-naïve patients. Secondary objectives included evaluation of OS/EFS, relapse-free survival and cumulative incidence of relapse for all patients who proceeded to HSCT, stratified by first and second HSCT, as well as the tolerability of HSCT following CAR-induced remission. This was a retrospective review of children and young adults enrolled on 1 of 3 CAR T cell trials at the National Cancer Institute targeting CD19, CD22, and CD19/22 (ClinicalTrials.gov identifiers NCT01593696, NCT02315612, and NCT03448393) who proceeded directly to HSCT following CAR T cell therapy. Between July 2012 and February 2021, 46 children and young adults with pre-B ALL went directly to HSCT following CAR therapy. Of these patients, 34 (74%) proceeded to a first HSCT, with a median follow-up of 50.8 months. Transplantation-naïve patients were heavily pretreated prior to CAR T cell therapy (median, 3.5 lines of therapy; range, 1 to 12) with significant prior immunotherapy exposure (blinatumomab, inotuzumab, and/or CAR T cell therapy in patients receiving CD22 or CD19/22 constructs (88%; 15 of /17)). Twelve patients (35%) had primary refractory disease, and the median time from CAR T cell infusion to HSCT Day 0 was 54.5 days (range, 42 to 127 days). The median OS following first HSCT was 72.2 months (95% confidence interval [CI], 16.9 months to not estimable [NE]), with a median EFS of 36.9 months (95% CI, 5.2 months to NE). At 12 and 24 months, the OS was 76.0% (95% CI, 57.6% to 87.2%) and 60.7% (95% CI, 40.8% to 75.8%), respectively, and EFS was 64.6% (95% CI, 46.1% to 78.1%) and 50.9% (95% CI, 32.6% to 66.6%), respectively. The individual factors associated with both decreased OS and EFS in univariate analyses for post-CAR consolidative HSCT in transplantation-naïve patients included ≥5 prior lines of therapy (not reached [NR] versus 12.4 months, P = .014; NR versus 4.8 months, P = .063), prior blinatumomab therapy (NR versus 16.9 months, P = .0038; NR versus 4.4 months, P = .0025), prior inotuzumab therapy (NR versus 11.5 months, P = .044; 36.9 months versus 2.7 months, P = .0054) and ≥5% blasts (M2/M3 marrow) pre-CAR T cell therapy (NR versus 17 months, P = .019; NR versus 12.2 months, P = .035). Primary refractory disease was associated with improved OS/EFS post-HSCT (NR versus 21.9 months, P = .075; NR versus 12.2 months, P = .024). Extensive prior therapy, particularly immunotherapy, and high disease burden each individually adversely impacted OS/EFS following post-CAR T cell consolidative HSCT in transplantation-naïve patients, owing primarily to relapse. Despite this, HSCT remains an important treatment modality in long-term cure. Earlier implementation of HSCT before multiply relapsed disease and incorporation of post-HSCT risk mitigation strategies in patients identified to be at high-risk of post-HSCT relapse may improve outcomes.

Characterization of extramedullary disease in B-ALL and response to CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cells effectively eradicate medullary B-cell acute lymphoblastic leukemia (B-ALL) and can traffic to and clear central nervous system (CNS) involvement. CAR T-cell activity in non-CNS extramedullary disease (EMD) has not been well characterized. We systematically evaluated CAR T-cell kinetics, associated toxicities, and efficacy in B-ALL non-CNS EMD. We conducted a retrospective review of B-ALL patients with non-CNS EMD who were screened for/enrolled on one of three CAR trials (CD19, CD22, and CD19/22) at our institution. Non-CNS EMD was identified according to histology or radiographic imaging at extramedullary sites excluding the cerebrospinal fluid and CNS parenchyma. Of ∼180 patients with relapsed/refractory B-ALL screened across multiple early-phase trials over an 8-year period, 38 (21.1%) presented with isolated non-CNS EMD (n = 5) or combined medullary/non-CNS EMD (n = 33) on 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging. A subset receiving CAR T cells (18 infusions) obtained FDG PET/CT scans preinfusion and postinfusion to monitor response. At best response, 72.2% (13 of 18) of patients showed a medullary minimal residual disease-negative complete remission and complete (n = 7) or partial (n = 6) non-CNS EMD response. Non-CNS EMD responses to CAR T cells were delayed (n = 3), and residual non-CNS EMD was substantial; rarely, discrepant outcomes (marrow response without EMD response) were observed (n = 2). Unique CAR-associated toxicities at non-CNS EMD sites were seen in select patients. CAR T cells are active in B-ALL non-CNS EMD. Still, non-CNS EMD response to CAR T cells may be delayed and suboptimal, particularly with multifocal disease. Serial FDG PET/CT scans are necessary for identifying and monitoring non-CNS EMD.

Cardiovascular risk assessment for patients with serious mental illnesses: An internal review.

Cardiovascular diseases (CVD) are the leading cause of excess premature mortality among patients with serious mental illness (SMI), mainly because of higher cardiovascular risk and metabolic syndrome compared to the general population.1,2 A pertinent contributing factor is second-generation antipsychotics, which further negatively impact the cardiovascular risk burden, amounting to a significant clinical and public health challenge among patients with SMI.3 Qatar has a high metabolic syndrome prevalence of 26%, and the blood pressure of patients with SMI receiving antipsychotics is significantly higher.4 In 2019, the Pharmacy Department of Mental Health Services at Hamad Medical Corporation (HMC) in Doha, Qatar flagged four moderately and one mildly severe cases of adverse drug reaction secondary to antipsychotics. In response to above mentioned incidents, this quality improvement (QI) project was conducted in an acute inpatient male ward from November 2019 to June 2020 in the Psychiatry Hospital of Hamad Medical Corporation to implement a cardiovascular risk assessment for inpatients with SMI. The atherosclerotic cardiovascular disease (ASCVD) risk estimator was used to estimate the 10-year risk of CVD, and inpatients were categorized into low-risk ( < 5%), borderline risk (5%-7.4%), intermediate-risk (7.5%-19.9%), and high risk ( ≥ 20%).5 Patients with SMI above 40 years of age were included. Within 72 hours of admission, the admitting inpatient nurse filled a cardiovascular risk assessment (CVRA) questionnaire, including basic demographics, past and present cardiology and smoking history, laboratory test results such as lipid panel, and renal function tests. This study used an in-depth, semi-structured face-to-face interview as a primary data collection technique. An interview guide was developed to address the purpose. At the end of each assessment, the QI nurse approached the participants again to educate them about the cardiovascular risk result accordingly and explained the required referrals (Cardiology and/or Smoking Cessation). The QI team member calculated the cardiovascular risk by utilizing the ASCVD plus application to determine inpatient cardiovascular risk. Out of 26 inpatients with SMI who underwent CVRA, nine (35%) scored moderate to high risk, and were referred to Cardiology for further intervention. Among these nine patients, two (22%) were started on statin therapy, three (33%) started on aspirin, and the remaining four (44%) received lifestyle modifications advice and counseling. Ten (38%) were referred to a smoking cessation clinic for nicotine replacement therapy and counseling. Table 1 shows the clinical characteristics of patients included in this study. Three inpatient consultations to cardiology were rejected, which shows how health professionals underestimate and stigmatize effective interventions for patient with SMI. In case of comorbidities of two diseases, one of them is known overlooked and this is particularly true for mental illness.6 A cohort study on medical comorbidities in patients with SMIs in Qatar concluded that an evidence of individuals with SMI is less likely to receive standard levels of care for their medical comorbidities.7 Mental health training could help medical health professionals from other specialties improve their understanding on the impact of both psychotropic medications and mental illness in the physical health of people with SMI and address the fear and stigma. Communication improvement between professionals by meaningful discussion of objectives of referral with the patient and contacting the consultant referred to might improve coordination among the referring psychiatrist, physician referred to, and patient.8 Patients who scored high on (ASCVD) assessment and are asymptomatic might benefit from referral to primary health care centers for further assessment by a generalist from whom a referral to other specialty like cardiology might be more easily accepted. From the patients' perspective, physical health education, and most importantly, cardiovascular risk assessment are now significantly invested. All patients above 40 years old with SMI will undergo a CVRA. Besides, their assigned nurse will work jointly with allied health professionals to educate them about the importance of healthy lifestyle, including healthy diet and staying fit. Tailor-made recommendations will be established, taking into consideration the cardiovascular risk status and antipsychotic medications. Close participation with the clinical pharmacist and dietician will ensure constant psychoeducation about the metabolic side effects of antipsychotic medications. Physiotherapists will identify barriers, if any, for patients to participate in physical activities offered by the ward. Simultaneously, facilitators will include one-to-one contact with staff and work on increasing awareness of the positive impact of physical activity at the departmental level. Leadership involvement is crucial to ensure joint agreement with different specialties, particularly those based in other HMC facilities, such as cardiology and smoking cessation clinics, to accept referrals when required.

Infectious complications of CAR T-cell therapy across novel antigen targets in the first 30 days.

Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated among 5 phase 1 CAR T-cell clinical trials. Trials included targeting of CD19, CD22, disialoganglioside (GD2) or B-cell maturation antigen (BCMA). Fifty-three patients (32.7%) had 76 infections between lymphocyte depleting (LD) chemotherapy and day 30 (D30); with the majority of infections (61, 80.3%) occurring between day 0 (D0) and D30. By trial, the highest proportion of infections was seen with CD22 CAR T cells (n = 23/53; 43.4%), followed by BCMA CAR T cells (n = 9/24; 37.5%). By disease, patients with multiple myeloma had the highest proportion of infections (9/24; 37.5%) followed by acute lymphoblastic leukemia (36/102; 35.3%). Grade 4 infections were rare (n = 4; 2.5%). Between D0 and D30, bacteremia and bacterial site infections were the most common infection type. In univariate analysis, increasing prior lines of therapy, recent infection within 100 days of LD chemotherapy, corticosteroid or tocilizumab use, and fever and neutropenia were associated with a higher risk of infection. In a multivariable analysis, only prior lines of therapy and recent infection were associated with higher risk of infection. In conclusion, we provide a broad overview of infection risk within the first 30 days post infusion across a host of multiple targets and diseases, elucidating both unique characteristics and commonalities highlighting aspects important to improving patient outcomes.

Smoothed profile method for direct numerical simulations of hydrodynamically interacting particles.

A general method is presented for computing the motions of hydrodynamically interacting particles in various kinds of host fluids for arbitrary Reynolds numbers. The method follows the standard procedure for performing direct numerical simulations (DNS) of particulate systems, where the Navier-Stokes equation must be solved consistently with the motion of the rigid particles, which defines the temporal boundary conditions to be satisfied by the Navier-Stokes equation. The smoothed profile (SP) method provides an efficient numerical scheme for coupling the continuum fluid mechanics with the dispersed moving particles, which are allowed to have arbitrary shapes. In this method, the sharp boundaries between solid particles and the host fluid are replaced with a smeared out thin shell (interfacial) region, which can be accurately resolved on a fixed Cartesian grid utilizing a SP function with a finite thickness. The accuracy of the SP method is illustrated by comparison with known exact results. In the present paper, the high degree of versatility of the SP method is demonstrated by considering several types of active and passive particle suspensions.

Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.