Post-transplantation cyclophosphamide and cyclosporine A versus methotrexate and cyclosporine A for graft-versus-host disease prophylaxis after allogeneic peripheral stem cell transplantation in adult acute myeloid leukemia patients.

BACKGROUND: Different prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors. METHODS: The 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared. RESULTS: The cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, p = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, p = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (p < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, p = 0.470), overall survival (79.1% vs 77.3%, p = 0.986), non-relapse mortality (16.5% vs 16.8%, p = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, p = 0.478) did not differ statistically at 1-year. CONCLUSION: PT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.

Pulmonary function is a strong predictor of 2-year overall survival and non-relapse mortality after allogenic hematopoietic cell transplantation.

OBJECTIVES: The purpose of the study was to assess the validity of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and of pulmonary comorbidity prior to HCT in terms of predicting non-relapse mortality (NRM) and overall survival (OS). METHODS: In this retrospective single-center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low-risk, intermediate-risk, and high-risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT-CI. RESULTS: In univariate analysis, the HCT-CI and the PCS were associated with OS after transplantation when comparing patients in high-risk groups with patients in low-risk groups. Using the PCS, the hazard ratios (HRs) of the 2-year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (p < .001) and 3.27 (p < .001), respectively, whereas the HRs using the HCT-CI were 1.83 (p < .001) and 2.57 (p = .002). The 2-year NRM incidence in the three risk-groups in the entire population was significant using both indexes. In the MAC group, the 2-year NRM was significant using the PCS (p = .003), but not using the HCT-CI (p = .23). CONCLUSIONS: Our study suggest that pulmonary function alone is a strong predictor of 2-year OS and NRM after HCT.

Cytomegalovirus infection is associated with rapid NK differentiation and reduced incidence of relapse in HLA matched sibling donor transplant patients.

The effect of cytomegalovirus (CMV) infection on leukemia relapse and the potential mechanism remains controversial. In this retrospective study, we evaluated the association among CMV infection, NK reconstitution and clinical outcomes in consecutive patients with hematologic malignancy who underwent HLA matched sibling donor transplantation (MST). In total, 228 patients were enrolled in the study between January 2010 and December 2011. The cumulative incidence of CMV infection on day 100 post-HSCT was 13.6 ± 4.9%. The probabilities of OS and DFS were 45.4% vs. 71.7% (P = 0.004) and 43.9% vs. 64.2% (P = 0.050) in the patients with CMV infection and without CMV infection, respectively. The cumulative incidence of treatment-related mortality (TRM) and relapse at 5 years was 48.6 ± 9.6% vs. 11.5 ± 2.9% (P < 0.001) and 6.2 ± 4.3% vs. 29.2 ± 3.9% (P = 0.024) in the patients with CMV infection and without CMV infection, respectively. In the multivariate analysis, CMV infection was associated with higher TRM, lower OS, and lower DFS. In addition, we found that CMV infection may promote the recovery of the absolute number of NK cells and promote the differentiation of NK cells post-MST. In conclusion, CMV infection may promote the recovery and differentiation of NK cells and was correlated with a lower relapse rate post-MST.

Cytomegalovirus Viral Load Kinetics Predict Cytomegalovirus End-Organ Disease and Mortality After Hematopoietic Cell Transplant.

BACKGROUND: We investigatedthe association between time-averaged area under the curve (AAUC) of cytomegalovirus (CMV) viral load (VL) by day 100 and overall survival (OS) at 1-year after hematopoietic cell transplantation (HCT). METHODS: In a retrospective cohort study, including patients receiving HCT between June 2010 and December 2017 from Memorial Sloan Kettering Cancer Center, AAUC was calculated for patients with detected VL. Patients were categorized into non-controllers (Q4) and controllers (Q1-Q3) using the highest AAUC quartile as cutoff. Cox models were used to estimate the association between AAUC and OS. Patients with non-detected CMV VL were categorized into elite-controllers (recipient+ [R+] or R-/donor+ [D+]) and R-/D-. RESULTS: The study (N = 952) included 282 controllers, 93 non-controllers, 275 elite-controllers, and 302 R-/D-. OS was 80.1% and 58.1% for controllers and non-controllers, respectively. In multivariable models, non-controllers had worse OS versus controllers (adjusted hazard ratio [HR] = 2.65; 95% confidence interval [CI], 1.71-4.12). In landmark analyses, controllers had similar OS as elite-controllers (HR = 1.26; 95% CI, .83-1.91) or R-/D- (HR = 0.98; 95% CI, .64-1.5). CONCLUSIONS: Non-controllers had worse OS 1-year post-HCT. Controllers had similar OS as elite-controllers or R-/D-. Future studies are needed to validate our AAUC cutoff across different cohorts and CMV management strategies.

Measurement properties of the project-level Women's Empowerment in Agriculture Index.

Women's empowerment is a process that includes increases in intrinsic agency (power within); instrumental agency (power to); and collective agency (power with). We used baseline data from two studies-Targeting and Realigning Agriculture for Improved Nutrition (TRAIN) in Bangladesh and Building Resilience in Burkina Faso (BRB)-to assess the measurement properties of survey questions operationalizing selected dimensions of intrinsic, instrumental, and collective agency in the project-level Women's Empowerment in Agricultural Index (pro-WEAI). We applied unidimensional item-response models to question (item) sets to assess their measurement properties, and when possible, their cross-context measurement equivalence-a requirement of measures designed for cross-group comparisons. For intrinsic agency in the right to bodily integrity, measured with five attitudinal questions about intimate partner violence (IPV) against women, model assumptions of unidimensionality and local independence were met. Four items showed good model fit and measurement equivalence across TRAIN and BRB. For item sets designed to capture autonomy in income, intrinsic agency in livelihoods activities, and instrumental agency in: livelihoods activities, the sale or use of outputs, the use of income, and borrowing from financial services, model assumptions were not met, model fit was poor, and items generally were weakly related to the latent (unobserved) agency construct. For intrinsic and instrumental agency in livelihoods activities and for instrumental agency in the sale or use of outputs and in the use of income, items sets had similar precision along the latent-agency continuum, suggesting that similar item sets could be dropped without a loss of precision. IRT models for collective agency were not estimable because of low reported presence and membership in community groups. This analysis demonstrates the use of IRT methods to assess the measurement properties of item sets in pro-WEAI, and empowerment scales generally. Findings suggest that a shorter version of pro-WEAI can be developed that will improve its measurement properties. We recommend revisions to the pro-WEAI questionnaire and call for new measures of women's collective agency.

Hematopoietic Cell Transplantation-Specific Comorbidity Index Predicts Morbidity and Mortality in Autologous Stem Cell Transplantation.

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score is a useful tool to assess the risk for nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation. Although the HCT-CI has been investigated in autologous stem cell transplantation (ASCT), its use is limited. To improve on the current use of the HCT-CI score on the morbidity and mortality after ASCT, we assessed the 100-day morbidity defined as orotracheal intubation (OTI), dialysis or shock (vasopressors need), 100-day NRM, early composite morbidity-mortality (combined endpoint that included any previous endpoints), and long-term NRM. We retrospectively reviewed a cohort of 1730 records of adult patients who received an ASCT in Argentinean center's between October 2002 and August 2016. Median follow-up was 1.15 years, and median age was 53 years. Diseases were multiple myeloma (48%), non-Hodgkin lymphoma (27%), and Hodgkin lymphoma (17%); 51% were in complete or partial remission; and 13% received ≥ 3 chemotherapy lines before transplant (heavily pretreated). Early NRM (100-day) was 2.7%, 5.4% required OTI, 4.5% required vasopressors, and 2.1% dialysis, with an early composite morbidity-mortality of 6.8%. Long-term (1 and 3 years) NRM was 4% and 5.2% and overall survival 89% and 77%, respectively. High-risk HCT-CI patients had a significant increase in 100-day NRM compared with intermediate and low risk (6.1% versus 3.4% versus 1.8%, respectively; P = .002), OTI (11% versus 6% versus 4%, P = .001), shock (8.7% versus 5.8% versus 3%, P = .001), early composite morbidity-mortality (13% versus 9 % versus 4.7%, P < .001), and long-term NRM (1 year, 7.7% versus 4% versus 3.3%; and 3 years, 10.8% versus 4% versus 4.8%, respectively; P = .002). After multivariate analysis these outcomes remained significant: early composite morbidity-mortality (odds ratio [95% confidence interval] compared with low risk: intermediate risk 2.1 [1.3 to 3.5] and high risk 3.3 [1.9 to 5.9]) and NRM (hazard ratio [95% confidence interval] compared with low risk: intermediate risk .97 [.8 to 2.4] and high risk 3.05 [1.3 to 4.5]). No significant impact was observed in overall survival. Other than comorbidities, significant impact was observed for heavily pretreated patients, age ≥ 55 years, non-Hodgkin lymphoma, and bendamustine-etoposide-citarabine-melphalan conditioning. We confirmed that the HCT-CI had a significant impact on NRM after ASCT, and these findings are mainly due to early toxicity express as 100-day NRM and the 3 main morbidity outcomes as well as the composite endpoint.

Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes Demonstrates Long Term Survival, Results from Australia and New Zealand Transplant and Cellular Therapies.

There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow-derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.

Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

From clones to immunopeptidomes: New developments in the characterization of permissive HLA-DP mismatches in hematopoietic cell transplantation.

Mismatching at the HLA-DPB1 locus occurs frequently in hematopoietic cell transplantation with unrelated donors. Despite this, HLA-DPB1 allelic mismatches have traditionally not been considered in patient-donor matching. A T-cell epitope (TCE) model for the functional assessment of permissive mismatches at this locus has nevertheless been adopted in clinical practice. While initially based on a hierarchical immunogenicity elucidated from allorecognition by T-cell clones isolated from a patient, newer developments in the understanding of this model's biological basis, including a central role for immunopeptidome divergence between mismatched allotypes, have prompted changes in the assignment of permissiveness, providing the opportunity for a more granular evaluation of graft-versus-host disease and relapse risks according to the nature and directionality of permissive mismatches. How these advances impact the assessment of permissiveness at HLA-DPB1 and potentially the intelligent selection of donors according to the main clinical goal for different patients is the subject of the present review.

The degree of HLA matching determines the incidence of cytokine release syndrome and associated nonrelapse mortality in matched related and unrelated allogeneic stem cell transplantation with post-transplant cyclophosphamide.

Cytokine release syndrome (CRS) occurs frequently after haplo-identical allogeneic stem cell transplantation (alloSCT) with post-transplant cyclophosphamide (PTCy), increasing nonrelapse mortality (NRM) and decreasing survival. Data on CRS in HLA-matched alloSCT are limited and effects of specific HLA-mismatches on CRS development unknown. We hypothesized that in HLA-matched alloSCT increasing degrees of HLA-mismatching influence CRS incidence, NRM and survival. Retrospective analysis of 126 HLA-matched PTCy-alloSCT patients showed that higher degrees of HLA-mismatching significantly increased CRS incidence (26%, 75% and 90% CRS with 12/12, 10/10 and 9/10 matched donors, respectively). Maximum temperature during CRS increased with higher HLA-mismatch. Specific associations between HLA-mismatches and CRS could be determined. Grade 2 CRS and CRS-induced grade 3 fever were associated with significantly increased NRM (p < 0.001 and p = 0.003, respectively) and inferior survival (p < 0.001 and p = 0.005, respectively). NRM was mainly caused by disease conditions that may be considered CRS-induced inflammatory responses (encephalopathy, cryptogenic organizing pneumonia and multi-organ failure).

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches.

Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease.

Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory.

Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla.

Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant.

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. Methods: A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. Results: The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). Conclusions: Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

Disease Outcomes of COVID-19 in Diabetic and Hypertensive Patients During the Hospital Stay.

Background A single-stranded RNA genome-encapsulated virus known as severe acute respiratory syndrome coronavirus 2 is known to cause severe acute respiratory syndrome in humans. People with diabetes and hypertension are often more susceptible to developing coronavirus disease 2019 (COVID-19) and experience a disproportionately higher rate of morbidity and death compared to the general population. The COVID-19 pandemic has become an urgent worldwide issue. Therefore, the main goal of this study is to assess how diabetes and hypertension, both separately and together, affect clinical outcomes in terms of morbidity and mortality in patients hospitalized with COVID-19. This study aimed to evaluate the disease outcomes in hypertensive and diabetic patients hospitalized with COVID-19. Methodology This descriptive, cross-sectional study was conducted from June 2022 to November 2022. Using purposive selective sampling, a total of 90 known hypertensive and diabetic patients with COVID-19 aged 18-90 years admitted in COVID-19 isolation wards and intensive care units (ICUs) of Mayo Hospital Lahore were recruited in this study after obtaining informed consent and IRB approval from the Institutional Review Board of King Edward Medical University, Lahore. Patients who did not provide consent, patients whose positive polymerase chain reaction reports for COVID-19 were not available, pregnant females, and patients with other comorbidities were excluded from the study. Data were collected from the COVID-19 isolation medical wards and ICUs from patient charts containing age, the status of hypertension and diabetes, disease status, severity, and levels of inflammatory markers, i.e., D-dimers, serum lactate dehydrogenase (LDH), serum ferritin, C-reactive protein (CRP). Data were analyzed using SPSS version 23 (IBM Corp., Armonk, NY, USA). Quantitative variables such as age were presented as mean ± SD. Qualitative variables such as hypertension, diabetes, and levels of inflammatory markers were presented as frequency and percentages. Results In this study, 90 patients were included, with 51 (57%) females and 39 (43%) males, all of whom were either hypertensive, diabetic, or both. In total, 70 (78%) patients were admitted to ICUs and 20 (22%) to COVID-19 medical isolation wards. Among 70 ICU patients, 39 (43.3%) were on continuous positive airway pressure/bilevel positive airway pressure, seven (7.8%) were on ventilators, and 44 (48.8%) were on normal oxygen masks/non-rebreather masks with high-flow oxygen. Overall, 100% of the patients included in the study had raised levels of inflammatory markers, low lymphocyte count, and increased neutrophil count. In total, 84 (93%) patients had severely high and six (7%) patients had moderately high CRP levels. Moreover, 33 (36.7%) patients had severely high and 57 (63.3%) patients had moderately high D-dimer levels. Further, 25 (28%) patients had severely high, 26 (29%) patients had moderately high, and 39 (43.3%) patients had significantly raised levels of serum ferritin. In total, 21 (23%) patients had severely high, 37 (41%) had moderately high, and 32 (36%) had significantly raised levels of serum LDH. Among the 90 patients, 65 (73%) expired and 25 (27%) survived. Of the expired patients, 62 (95%) were admitted to ICUs, and three (5%) were admitted to wards. Conclusions Diabetes and hypertension are strong predictors of COVID-19 severity in terms of morbidity and mortality due to respiratory deterioration.

Risk Factors for Early Cytomegalovirus Reactivation and Impact of Early Cytomegalovirus Reactivation on Clinical Outcomes after T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patient outcomes have been extensively investigated after matched related or unrelated donor transplantation, but little is known in the setting of haploidentical stem cell transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), in which recipients are considered more severely immunocompromised. We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. Early CMV reactivation (occurring within the first 120 days post-transplantation) occurred in 242 patients, for an estimated cumulative incidence of 44%. Among those patients, 74 (30%) had recurrent CMV and 20 (8%) had CMV disease. On multivariable analysis, positive recipient CMV serostatus (hazard ratio [HR] >2.5; P < .001), disease histology (lymphoid versus myeloid: HR, 0.66; P = .003) and increasing recipient age (HR, 1.01; P = .015) were independent predictors of CMV reactivation. At a 4-month landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of nonrelapse mortality (NRM) relative to patients without reactivation: 13% versus 5% and 22% versus 9%, respectively (P < .001). On multivariable analysis, CMV reactivation was an independent negative predictor of NRM (HR, 2.69; P < .001) and was close to statistically significant for overall survival (HR, 1.38; P = .062). Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation. 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Establishing the Competency Development and Talent Cultivation Strategies for Physician-Patient Shared Decision-Making Competency Based on the IAA-NRM Approach.

Shared decision making (SDM) is a collaborative process involving patients and their healthcare workers negotiating to reach a shared decision about medical care. However, various physician stakeholders (attending physicians, medical residents, and doctors in post-graduate years) may have different viewpoints on SDM processes. The purpose of this study is to explore the core competence of physicians in performing SDM tasks and to investigate the significant competency development aspects/criteria by applying the literature research and expert interviews. We adopt the IAA (importance awareness analysis) technique for different stakeholders to evaluate the status of competency development aspects/criteria and to determine the NRM (network relation map) based on the DEMATEL (decision-making trial and evaluation laboratory) technique. The study combines the IAA and NRM methods and suggests using the IAA-NRM approach to evaluate the adoption strategies and common suitable paths for different levels of physicians. Our findings reveal that SDM perception and practice is the primary influencer of SDM competence development for all stakeholders. The current model can help hospital administrators and directors of medical education understand the diverse stakeholders' perspectives on the core competence of SDM tasks and determine common development plans. It provides strategic directions for SDM competency development and talent cultivation programs.

Determining the Development Strategy and Suited Adoption Paths for the Core Competence of Shared Decision-Making Tasks through the SAA-NRM Approach.

Shared decision making (SDM) is an interactive process that involves patients and their healthcare professionals reaching joint decisions about medical care through negotiation. As the initiators of medical decision-making in daily routine, physicians should be aware of and concerned about the SDM process. Thus, professional competency development for SDM has become increasingly critical for physicians' training. Therefore, this study investigates the professional competency and the important competency development aspects/criteria of SDM tasks through expert interviews and literature research. The study adopts the SAA (satisfaction-attention analysis) method to assess the status of competency development aspects/criteria and determine the NRM (network relation map) based on the DEMATEL (decision-making trial and evaluation laboratory) technique. The results demonstrate that the CE (concept and evaluation) aspect is the dominant aspect, and the CR (communication and relationship) aspect is the aspect being dominated. The CE aspect influences the aspects of SP (skill and practice), JM (joint information and decision making) and CR, and the SP aspect affects the aspects of JM and CR. Then, the JM aspect affects the CR aspect. The study also suggests suitable adoption paths of competency development for SDM tasks using the NRM approach. It provides recommendations and strategic directions for SDM competency development and sustainable training programs.

Increased Late Noncardiac Nonrelapse Mortality in Patients with Atrial Fibrillation Diagnosed During Their Hospital Stay for Allogeneic Stem Cell Transplantation.

Atrial fibrillation (AF) is the most common arrhythmia in adults but its impact on allogeneic stem cell transplantation (SCT) is not well characterized. We studied AF manifestation during the hospital stay for allogeneic SCT, referred to as AF in hospital (AFiH), and analyzed the incidence of, risk factors for, and clinical impact of AFiH on intensive care unit (ICU)-/hospital-/ and overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS). This retrospective matched cohort study comprised 553 consecutive SCT recipients at Hannover Medical School between January 2013 and October 2019. Patients with AFiH were compared with a non-AFiH control cohort matched for Hematopoietic Stem Cell-Specific Comorbidity Index (HCT-CI), European Group for Blood and Marrow Transplantation (EBMT) risk score, disease, conditioning regimen and availability of molecular genetic data for patients with myeloid diseases. AFiH occurred in 46 patients (8%) at a median of 2 days (interquartile range, 0 to 8 days) after SCT. Patient history of AF and elevated NT-proBNP and high-sensitivity troponin T levels, but not conventional echocardiographic parameters, were predictive for AFiH. AFiH occurred more often in patients with mutations in DNMT3A, TET2, and ASXL1 genes related to clonal hematopoiesis compared with patients with wild-type alleles, with the greatest impact from DMT3A mutations. ICU admission was significantly higher in the AFiH cohort (46% versus 7%), without significant differences in ICU or post-ICU hospital survival (62% versus 40% and 52% versus 40%, respectively). The main cause of death was sepsis. In terms of long-term outcomes, the incidences of relapse and grade II-IV acute GVHD did not differ significantly between the AFiH and the non-AFiH groups; however, OS was significantly shorter in the AFiH group (1 year OS, 39% versus 65%), owing to late noncardiac NRM (1 year NRM, 49% versus 27%). Although the underlying cellular and molecular mechanisms remain to be characterized in further detail, these data clearly demonstrate the impact of inpatient AF manifestation/AFiH on long-term outcomes of SCT recipients.

Bioengineering of Novel Non-Replicating mRNA (NRM) and Self-Amplifying mRNA (SAM) Vaccine Candidates Against SARS-CoV-2 Using Immunoinformatics Approach.

Presently, the world needs safe and effective vaccines to overcome the COVID-19 pandemic. Our work has focused on formulating two types of mRNA vaccines that differ in capacity to copy themselves inside the cell. These are non-amplifying mRNA (NRM) and self-amplifying mRNA (SAM) vaccines. Both the vaccine candidates encode an engineered viral replicon which can provoke an immune response. Hence we predicted and screened twelve epitopes from the spike glycoprotein of SARS-CoV-2. We used five CTL, four HTL, and three B-cell-activating epitopes to formulate each mRNA vaccine. Molecular docking revealed that these epitopes could combine with HLA molecules that are important for boosting immunogenicity. The B-cell epitopes were adjoined with GPGPG linkers, while CTL and HTL epitopes were linked with KK linkers. The entire protein chain was reverse translated to develop a specific NRM-based vaccine. We incorporate gene encoding replicase in the upstream region of CDS encoding antigen to design the SAM vaccine. Subsequently, signal sequences were added to human mRNA to formulate vaccines. Both vaccine formulations translated to produce the epitopes in host cells, initiate a protective immune cascade, and generate immunogenic memory, which can counter future SARS-CoV-2 viral exposures before the onset of infection.

Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge.

The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.