Combined BCL-2 and PI3K/AKT Pathway Inhibition in KMT2A-Rearranged Acute B-Lymphoblastic Leukemia Cells.

Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.

Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia.

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.

New Deoxyribozymes for the Native Ligation of RNA.

Deoxyribozymes (DNAzymes) are small, synthetic, single-stranded DNAs capable of catalyzing chemical reactions, including RNA ligation. Herein, we report a novel class of RNA ligase deoxyribozymes that utilize 5'-adenylated RNA (5'-AppRNA) as the donor substrate, mimicking the activated intermediates of protein-catalyzed RNA ligation. Four new DNAzymes were identified by in vitro selection from an N40 random DNA library and were shown to catalyze the intermolecular linear RNA-RNA ligation via the formation of a native 3'-5'-phosphodiester linkage. The catalytic activity is distinct from previously described RNA-ligating deoxyribozymes. Kinetic analyses revealed the optimal incubation conditions for high ligation yields and demonstrated a broad RNA substrate scope. Together with the smooth synthetic accessibility of 5'-adenylated RNAs, the new DNA enzymes are promising tools for the protein-free synthesis of long RNAs, for example containing precious modified nucleotides or fluorescent labels for biochemical and biophysical investigations.

Engraftment Efficiency after Intra-Bone Marrow versus Intravenous Transplantation of Bone Marrow Cells in a Canine Nonmyeloablative Dog Leukocyte Antigen-Identical Transplantation Model.

An intra-bone marrow (IBM) hematopoietic stem cell transplantation (HSCT) is assumed to optimize the homing process and therefore to improve engraftment as well as hematopoietic recovery compared with conventional i.v. HSCT. This study investigated the feasibility and efficacy of IBM HSCT after nonmyeloablative conditioning in an allogeneic canine HSCT model. Two study cohorts received IBM HSCT of either density gradient (IBM-I, n = 7) or buffy coat (IBM-II, n = 6) enriched bone marrow cells. An historical i.v. HSCT cohort served as control. Before allogeneic HSCT experiments were performed, we investigated the feasibility of IBM HSCT by using technetium-99m marked autologous grafts. Scintigraphic analyses confirmed that most IBM-injected autologous cells remained at the injection sites, independent of the applied volume. In addition, cell migration to other bones occurred. The enrichment process led to different allogeneic graft volumes (IBM-I, 2 × 5 mL; IBM-II, 2 × 25 mL) and significantly lower counts of total nucleated cells in IBM-I grafts compared with IBM-II grafts (1.6 × 108/kg versus 3.8 × 108/kg). After allogeneic HSCT, dogs of the IBM-I group showed a delayed engraftment with lower levels of donor chimerism when compared with IBM-II or to i.v. HSCT. Dogs of the IBM-II group tended to reveal slightly faster early leukocyte engraftment kinetics than intravenously transplanted animals. However, thrombocytopenia was significantly prolonged in both IBM groups when compared with i.v. HSCT. In conclusion, IBM HSCT is feasible in a nonmyeloablative HSCT setting but failed to significantly improve engraftment kinetics and hematopoietic recovery in comparison with conventional i.v. HSCT.

Small-Molecule Inhibitors of the Tumor Suppressor Fhit.

The tumor suppressor Fhit and its substrate diadenosine triphosphate (Ap3 A) are important factors in cancer development and progression. Fhit has Ap3 A hydrolase activity and cleaves Ap3 A into adenosine monophosphate (AMP) and adenosine diphosphate (ADP); this is believed to terminate Fhit-mediated signaling. How the catalytic activity of Fhit is regulated and how the Fhit⋅Ap3 A complex might exert its growth-suppressive function remain to be discovered. Small-molecule inhibitors of the enzymatic activity of Fhit would provide valuable tools for the elucidation of its tumor-suppressive functions. Here we describe the development of a high-throughput screen for the identification of such small-molecule inhibitors of Fhit. Two clusters of inhibitors that decreased the activity of Fhit by at least 90 % were identified. Several derivatives were synthesized and exhibited in vitro IC50 values in the nanomolar range.

Low Radiation Dose and Low Cell Dose Increase the Risk of Graft Rejection in a Canine Hematopoietic Stem Cell Transplantation Model.

The canine hematopoietic stem cell transplantation (HSCT) model has become accepted in recent decades as a good preclinical model for the development of new transplantation strategies. Information on factors associated with outcome after allogeneic HSCT are a prerequisite for designing new risk-adapted transplantation protocols. Here we report a retrospective analysis aimed at identifying risk factors for allograft rejection in the canine HSCT model. A total of 75 dog leukocyte antigen-identical sibling HSCTs were performed since 2003 on 10 different protocols. Conditioning consisted of total body irradiation at 1.0 Gy (n = 20), 2.0 Gy (n = 40), or 4.5 Gy (n = 15). Bone marrow was infused either intravenously (n = 54) or intraosseously (n = 21). Cyclosporin A alone or different combinations of cyclosporine A, mycophenolate mofetil, and everolimus were used for immunosuppression. A median cell dose of 3.5 (range, 1.0 to 11.8) total nucleated cells (TNCs)/kg was infused. Cox analyses were used to assess the influence of age, weight, radiation dose, donor/recipient sex, type of immunosuppression, and cell dose (TNCs, CD34(+) cells) on allograft rejection. Initial engraftment occurred in all dogs. Forty-two dogs (56%) experienced graft rejection at median of 11 weeks (range, 6 to 56 weeks) after HSCT. Univariate analyses revealed radiation dose, type of immunosuppression, TNC dose, recipient weight, and recipient age as factors influencing long-term engraftment. In multivariate analysis, low radiation dose (P < .001) and low TNC cell count (P = .044) were identified as significant independent risk factors for graft rejection. Peripheral blood mononuclear cell chimerism ≥30% (P = .008) and granulocyte chimerism ≥70% (P = .023) at 4 weeks after HSCT were independent predictors of stable engraftment. In summary, these data indicate that even in low-dose total body irradiation-based regimens, the irradiation dose is important for engraftment. The level of blood chimerism at 4 weeks post-HSCT was predictive of long-term engraftment in the canine HSCT model.

Diagnosis of prosthetic joint infections using UMD-Universal Kit and the automated multiplex-PCR Unyvero i60 ITI(®) cartridge system: a pilot study.

BACKGROUND: Prosthetic joint infections (PJI) are associated with high morbidity and costs. Various efforts have been made to improve the diagnosis of PJI over the past years, but only few studies have assessed the diagnostic utility of nucleic acid amplification test (NAAT) techniques in this context. Here, we report our experience with a commercial 16S rRNA gene PCR and an automated multiplex-PCR cartridge system in identifying pathogens causing PJI. MATERIALS AND METHODS: A prospective single-centre study was performed including 54 patients with either septic or aseptic prosthetic joint replacement or surgical revision between February 2012 and April 2013. Conventional cultures of periprosthetic tissue samples were compared with the results of broad-range 16S rRNA gene real-time PCR (UMD-Universal Pathogen DNA Extraction and PCR Analysis, Molzym GmbH, Germany) and the multiplex-PCR Unyvero ITI(®) cartridge system (U-ITI; Curetis AG, Germany). Conventional culture and broad-range 16S rRNA gene real-time PCR were performed on all samples. U-ITI was used in a subgroup of 28 cases including all culture-positive cases. The agreement of the results from the methods was assessed. RESULTS: Of 54 cases, seven were culture-positive. Broad-range 16S rRNA gene real-time PCR gave 6, U-ITI 3 concordant positive results. Of the 47 culture-negative samples, 46 were also negative by broad-range 16S rRNA gene real-time PCR resulting in a 96 % (52/54) agreement between 16S rRNA gene PCR and culture. Of the 21 culture-negative samples analysed with U-ITI, 20 gave negative results, including the single 16S rRNA gene PCR-positive/culture-negative specimen. The rate of agreement between U-ITI and culture results was 82 % (23/28). CONCLUSION: This pilot study gave no indication of superiority of the used NAATs over conventional culture methods for the microbiological diagnosis of PJI. Drawbacks are susceptibility to contamination in the case of 16S rRNA gene real-time PCR, labour-intensive DNA extraction and limited pathogen panel in the case of the multiplex cartridge PCR system. More prospective trials are needed to evaluate the diagnostic performance of NAATs and their impact on the clinical management of PJI.

Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates.

The mammalian target of rapamycin inhibitor everolimus (RAD001) is a successfully used immunosuppressant in solid-organ transplantation. Several studies have already used RAD001 in combination with calcineurin inhibitors after hematopoietic stem cell transplantation (HSCT). We investigated calcineurin inhibitor-free pre- and post-transplantation immunosuppression of RAD001 combined with mycophenolate mofetil (MMF) in a nonmyeloablative HSCT setting. After nonmyeloablative conditioning with 2 Gy total body irradiation, 8 dogs received HSCT from dog leukocyte antigen-identical siblings. Immunosuppressives were given at doses of 1.5 mg RAD001 twice daily from day -1 to +49, then tapered until day +56, and 20 mg/kg MMF from day 0 to +28, then tapered until day +42. An historical cyclosporin A (CsA)/MMF regimen was used in the control group. All dogs engrafted. Median platelet nadir amounted in all dogs to 0 × 10(9)/L (median, day +10; duration <50 × 10(9)/L, 22 days) and median leukocyte nadir was 1.0 × 10(9)/L (range, .1 to 2.5 × 10(9)/L; median, day +13). Eventually, 5 of 8 (63%) animals rejected their grafts. Two dogs died of infections on day +19 and +25. Pharmacokinetics of RAD001 and MMF showed median trough levels of 19.1 (range, 10.5 to 43.2) µg/L and .3 (.1 to 1.3) mg/L, respectively. The median area under the curve was 325 (range, 178 to 593) µg/L × hour for RAD001 and 29.6 (range, 7.9 to 40.5) ng/L × hour for MMF. All dogs developed clinically mucosal viral infections during the clinical course. Compared with the control group, the level of toxicities for RAD001/MMF increased in all qualities. Combined immunosuppression of RAD001 and MMF after nonmyeloablative HSCT is associated with significant toxicities, including a prolonged platelet recovery time as well as increased infections compared to the CsA/MMF regimen.

Doctor's Orders-Why Radiologists Should Consider Adjusting Commercial Machine Learning Applications in Chest Radiography to Fit Their Specific Needs.

This retrospective study evaluated a commercial deep learning (DL) software for chest radiographs and explored its performance in different scenarios. A total of 477 patients (284 male, 193 female, mean age 61.4 (44.7-78.1) years) were included. For the reference standard, two radiologists performed independent readings on seven diseases, thus reporting 226 findings in 167 patients. An autonomous DL reading was performed separately and evaluated against the gold standard regarding accuracy, sensitivity and specificity using ROC analysis. The overall average AUC was 0.84 (95%-CI 0.76-0.92) with an optimized DL sensitivity of 85% and specificity of 75.4%. The best results were seen in pleural effusion with an AUC of 0.92 (0.885-0.955) and sensitivity and specificity of each 86.4%. The data also showed a significant influence of sex, age, and comorbidity on the level of agreement between gold standard and DL reading. About 40% of cases could be ruled out correctly when screening for only one specific disease with a sensitivity above 95% in the exploratory analysis. For the combined reading of all abnormalities at once, only marginal workload reduction could be achieved due to insufficient specificity. DL applications like this one bear the prospect of autonomous comprehensive reporting on chest radiographs but for now require human supervision. Radiologists need to consider possible bias in certain patient groups, e.g., elderly and women. By adjusting their threshold values, commercial DL applications could already be deployed for a variety of tasks, e.g., ruling out certain conditions in screening scenarios and offering high potential for workload reduction.

Analgesic Use in Patients during Cardio-Pulmonary Resuscitation.

INTRODUCTION: Cardiopulmonary resuscitation-induced consciousness is a newly recognized phenomenon with an increasing incidence. A return of consciousness during cardiopulmonary resuscitation affects up to 0.9% of cases. Patients may also experience physical pain associated with chest compressions, as most victims of cardiac arrest who are subjected to resuscitative efforts sustain ribs or sternum fractures. METHODS: A rapid review was carried out from August 2021 to December 2022. RESULTS: Thirty-two articles were included in the rapid review. Of these, eleven studies focused on the return of consciousness during CPR, and twenty-one on CPR-induced chest injuries. CONCLUSION: A small number of studies that have dealt with the return of consciousness associated with cardiopulmonary resuscitation made it hard to clearly determine how often this occurs. There were more studies that dealt with chest trauma during resuscitation, but no study considered the use of analgesics. Of note, there was no standardized therapeutic approach as far as the use of analgesics and/or sedatives was considered. This is probably due to the lack of guidelines for analgesic management during cardiopulmonary resuscitation and peri-resuscitative period.

Look at the future -perceptions of fertility counseling and decision-making among adolescents and their parents in the context of hematopoietic stem cell transplantation-experience of one major center for pediatric stem cell transplantation.

Introduction: Increasing survival rates after hematopoietic stem cell transplantation (HSCT) in childhood should put focus on improving the quality of life as adults. An essential aspect is fertility and its preservation. In order to take advantage of the possibility of fertility preservation, fertility counseling should be provided to patients and their parents prior to gonadotoxic therapies. Methods: The aim of this survey was to analyze the impact of fertility counseling in pediatric stem cell transplantation in patients and their parents using questionnaires designed for the study questions. Fifty-one parents and 7 adolescent patients were interviewed between February 2019 and October 2021 about the counseling, their perceptions of fertility issues, and the nature of decision- making concerning fertility preservation. The study included patients with malignant (e.g., leukemia, lymphoma, neuroblastoma) and nonmalignant diseases (e.g., thalassemia, sickle cell disease, immunodeficiency) who received counseling on fertility preservation before HSCT based on an in-house standard and analysed the impact for both groups. Results: Two-thirds of the study participants were concerned about having children and grandchildren respectively; for half of all respondents, the topic of fertility and fertility preservation proved to be hopeful. Forty percent of the study participants were burdened by the risk of possible fertility limitations after HSCT. Concerns about fertility was particularly significant for parents whose children were advised to undergo fertility preservation. Parents of children <12 years found deciding on appropriate measures more difficult. Parents with children >7 years involved their children in the decision. All study participants agreed that fertility counseling had not negatively affected the parent-child relationship. More than 90% of all study participants were in favor of addressing fertility, its potential limitations and fertility preservation measures before HSCT. There was no significant difference between the malignant and the non-malignant cohort in all study questions. Discussion: Overall, the standardized fertility counseling provided in our center of pediatric stem cell transplantation resulted in high satisfaction among patients and their parents. Multiple counseling on infertility risk, including the younger patients in the decision-making and further options after gonadotoxic therapy may increase the satisfaction of the counseled patients and their parents.

Nurses' knowledge, barriers and practice in the care of patients with delirium in the intensive care unit in Poland-A cross-sectional study.

Background: Delirium is a cognitive disorder that occurs with high frequency in patients in intensive care units and affects patient outcomes. Despite recommendations for monitoring and assessing delirium in the ICU, studies show that it is still not routinely assessed and often remains undiagnosed or misinterpreted as dementia or depression. Aim: The aim of this study was (1) to assess nurses' knowledge and clinical practices regarding delirium, (2) to identify the factors associated with nurses' knowledge, and (3) to define barriers to effective control of delirium. Methods: A cross-sectional study was conducted among 371 ICU nurses in Poland. Results: 53.1% of nurses had never been educated on delirium control resulting in a deficit in knowledge of delirium symptoms, risk factors and complications associated with delirium in ICU patients. Master's degree in nursing (vs. Registered nurses + Bachelor's), female gender, and working in university hospital (vs. other) were positively correlated with nurse's knowledge, while age had a negative impact on knowledge. Delirium is a marginalized state in ICU patients, only 16.4% of nurses assessed delirium routinely and 35.8% assessed delirium occasionally, rarely using validated scales. Barriers to effective delirium control were primarily the lack of a requirement to assess delirium, the difficulty of assessing delirium in intubated patients and nurses' lack of confidence in their ability to use delirium assessment tools. Conclusions: There is an urgent need to educate nurses about delirium and to make delirium assessment obligatory in clinical practice. The area of change should also include a hospital policy on delirium monitoring and management. The study was registered on ClinicalTrials.gov (NCT05384964).

Everolimus in combination with cyclosporin a as pre- and posttransplantation immunosuppressive therapy in nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Everolimus (RAD001) is an mTOR inhibitor that has been successfully used as an immunosuppressant in solid-organ transplantation. Data in allogeneic hematopoietic stem cell transplantation (HSCT) is limited. This study aimed to investigate pharmacokinetics, safety, and efficacy of RAD001 in a canine allogeneic HSCT model. First, pharmacokinetics of RAD001 were performed in healthy dogs in order to determine the appropriate dosing. Doses of 0.25 mg RAD001 twice daily in combination with 15 mg/kg cyclosporin A (CsA) twice daily were identified as appropriate starting doses to achieve the targeted range of RAD001 (3-8 µg/L) when orally administered. Subsequently, 10 dogs were transplanted using 2 Gy total body irradiation (TBI) for conditioning and 0.25 mg RAD001 twice daily plus 15 mg/kg CsA twice daily for pre- and posttransplantation immunosuppression. Seven of the 10 transplanted dogs were maintained at the starting RAD001 dose throughout the study. For the remaining 3 dogs, dose adjustments were necessary. RAD001 accumulation over time did not occur. All dogs initially engrafted. Five dogs eventually rejected the graft (weeks 10, 10, 13, 27, and 56). Two dogs died of pneumonia (weeks 8 and 72) but were chimeric until then. Total cholesterol rose from median 4.1 mmol/L (3.5-5.7 mmol/L) before HSCT to 6.0 mmol/l (5.0-8.5 mmol/l) at day 21 after HSCT, but remained always within normal range. Changes in creatinine and triglyceride values were not observed. Long-term engraftment rates were inferior to sirolimus/CsA and mycophenolate mofetil (MMF)/CsA regimen, respectively. RAD001/CsA caused a more pronounced reduction of platelet counts to median 2 × 10(9)/L (range: 0-21 × 10(9)/L) and longer time to platelet recovery of 21 days (range: 14-24 days) compared with MMF/CsA. CsA c(2h) levels were significantly enhanced in the RAD001/CsA regimen, but c(0h) and area under the curve from 0 to 12 hours (AUC(0-12h)) values did not differ compared with an MMF/CsA immunosuppression. In summary, immunosuppression consisting of RAD001 and CsA is well tolerated but not as efficient as with other established immunosuppressants in a canine nonmyeloablative HSCT regimen. Hence, our study does not support the application of RAD001/CsA as standard practice in this setting.

TNF-α induced secretion of HMGB1 from non-immune canine mammary epithelial cells (MTH53A).

BACKGROUND: Mammary neoplasias are one of the most frequent and spontaneously occurring malignancies in dogs and humans. Due to the similar anatomy of the mammary gland in both species, the dog has become an important animal model for this cancer entity. In human breast carcinomas, the overexpression of a protein named high-mobility group box 1 (HMGB1) was reported. Cells of the immune system were described to release HMGB1 actively exerting cytokine function. Thereby it is involved in the immune system activation, tissue repair, and cell migration. Passive release of HMGB1 by necrotic cells at sites of tissue damage or in necrotic hypoxic regions of tumors induces cellular responses e.g. release of proinflammatory cytokines leading to elevated inflammatory response and neo-vascularization of necrotic tumor areas. Herein we investigated if a time-dependent stimulation with the separately applied proinflammatory cytokines TNF-α and IFN-γ can cause secretion of HMGB1 in a non-immune related HMGB1-non-secreting epithelial canine mammary cell line (MTH53A) derived from non-neoplastic tissue. METHODS: The canine cell line was transfected with recombinant HMGB1 bicistronic expression vectors and stimulated after transfection with the respective cytokine independently for 6, 24 and 48 h. HMGB1 protein detection was performed by Western blot analysis and quantified a by enzyme-linked immunosorbent assay. Live cell laser scanning multiphoton microscopy of MTH53A cells expressing a HMGB1-GFP fusion protein was performed in order to examine, if secretion of HMGB1 under cytokine stimulating conditions is also visible by fluorescence imaging. RESULTS: The observed HMGB1 release kinetics showed a clearly time-dependent manner with a peak release 24h after TNF-α stimulation, while stimulation with IFN-γ had only small effects on the HMGB1 release. Multiphoton HMGB1 live cell microscopy showed diffuse cell membrane structure changes 29 h after cytokine-stimulation but no clear secretion of HMGB1-GFP after TNF-α stimulation was visible. CONCLUSION: Our results demonstrate that non-immune HMGB1-non-secreting cells of epithelial origin derived from mammary non-neoplastic tissue can be induced to release HMGB1 by single cytokine application. This indicates that tumor and surrounding tissue can be stimulated by tumor present inflammatory and necrotic cytokines to release HMGB1 acting as neo-vascularizing factor thus promoting tumor growth.

Non-Pharmacological Nursing Interventions to Prevent Delirium in ICU Patients-An Umbrella Review with Implications for Evidence-Based Practice.

Delirium in ICU patients is a complication associated with many adverse consequences. Given the high prevalence of this complication in critically ill patients, it is essential to develop and implement an effective management protocol to prevent delirium. Given that the cause of delirium is multifactorial, non-pharmacological multicomponent interventions are promising strategies for delirium prevention. (1) Background: To identify and evaluate published systematic review on non-pharmacological nursing interventions to prevent delirium in intensive care unit patients. (2) Methods: An umbrella review guided by the Joanna Briggs Institute was utilized. Data were obtained from PubMed, Scopus, EBSCO, Web of Science, Cochrane Library, and Google Scholar. The last search was conducted on 1 May 2022. (3) Results: Fourteen reviews met the inclusion criteria. Multicomponent interventions are the most promising methods in the fight against delirium. The patient's family is an important part of the process and should be included in the delirium prevention scheme. Light therapy can improve the patient's circadian rhythm and thus contribute to reducing the incidence of delirium. (4) Conclusions: Non-pharmacological nursing interventions may be effective in preventing and reducing the duration of delirium in ICU patients.

Conflict Sources and Management in the ICU Setting before and during COVID-19: A Scoping Review of the Literature.

INTRODUCTION: Conflicts are an inherent part of work within any organisation. They can arise between members of an interdisciplinary team (or between teams representing different departments), between patients and team members/family members, and patients' families and team members. Various conflict situations among employees may occur, therefore it is very important to identify their causes and take preventive or targeted corrective measures. The aim of this study was to review the available literature concerning conflicts arising in ICUs-their types, methods of expression as well as their management and mitigation. In addition, we reviewed the available literature on the impact of the pandemic on the ICU environment caring for COVID-19 patients. METHODS: The databases were searched. Single key words or their combinations using AND or OR operators were entered. Eventually, 15 articles were included in our review, which included two identical papers. RESULTS: Conflicts occurred occasionally or rarely; researchers describing ethical conflicts demonstrated a moderate level of exposure to conflicts. The pandemic created many challenges and ethical dilemmas that are a source of ethical conflict. CONCLUSIONS: As conflict by nature remains inevitable, adequate procedures in conflict management should be developed and the leadership of managing personnel should be reinforced, because team members frequently expect guidance from their supervisors. The importance of training in interpersonal communication and crisis situation management in healthcare should therefore be emphasised.

Patients' and Relatives' Experiences of Delirium in the Intensive Care Unit-A Qualitative Study.

(1) Introduction: Delirium is a cognitive disorder that affects up to 80% of ICU patients and has many negative consequences. The occurrence of delirium in an ICU patient also negatively affects the relatives caring for these patients. The aim of this study was to explore patients' and their families' experiences of delirium during their ICU stay. (2) Method: The study used a qualitative design based on phenomenology as a research method. A semi-structured interview method was used to achieve the aim. The responses of patients and their families were recorded and transcribed, and the data were coded and analyzed. (3) Results: Eight interviews were conducted with past ICU patients who developed delirium during hospitalization and their family members. The mean age of the participants was 71 years. Of the eight patients, 2 (25%) were female and 6 (75%) were male. The relationships of the 8 carers with the patients were wife (in 4 cases), daughter (in 2 cases), and son (in 2 cases). The average length of time a patient stayed in the ICU was 24 days. The following themes were extracted from the interviews: education, feelings before the delirium, pain, thirst, the day after, talking to the family/patient, and return home. (4) Conclusions: Post-delirium patients and their families feel that more emphasis should be placed on information about delirium. Most patients feel embarrassed and ashamed about events during a delirium episode. Patients fear the reaction of their families when delirium occurs. Patients' families are not concerned about their relatives returning home and believe that the home environment will allow them to forget the delirium events more quickly during hospitalization.

Delirium in ICU Patients after Cardiac Arrest: A Scoping Review.

INTRODUCTION: The incidence of delirium in the intensive care unit is high, although it may differ according to the specific characteristics of the unit. Despite the rapid development of research on delirium in recent years, the pathophysiological mechanisms leading to the clinical presentation of delirium are still subject to hypotheses. The aim of this review was to describe the incidence of delirium in cardiac arrest survivors and the clinical impact of delirium on patient outcomes. METHODS: A scoping review was conducted in the second quarter of 2022. The number of articles retrieved during each search test was limited to studies conducted between 2010 and 2020. Strict inclusion and exclusion criteria were applied. The last search was conducted in May 2022. RESULTS: A total of 537 records was initially obtained from the databases. After discarding duplicates, selecting titles and abstracts, and then analyzing full-text articles, 7 studies met the inclusion criteria. The incidence of delirium in the cardiac arrest survivor population ranged from 8% to as high as 100%. The length of stay in ICU and hospital was significantly longer in patients with delirium than those without. Ninety-eight percent of patients had cognitive or perceptual impairment and psychomotor impairment. Of the seven studies included in the analysis, the RASS, CAM, and NuDesc scales were used to diagnose delirium. Potential risk factors that may influence the duration of delirium include age and time since resuscitation; propofol use shortened the duration of delirium. CONCLUSION: the incidence of delirium in ICU patients who survived CA is high. Cardiac arrest is an additional predisposing factor for delirium. In cardiac arrest survivors, the occurrence of delirium prolongs the duration of ICU and hospital stay and adversely affects functional outcomes. The most common type of delirium among this population was hypoactive delirium. A large percentage of patients manifested symptoms such as cognitive or perception impairment, psychomotor impairment, and impaired concentration and attention.

Family experiences and attitudes toward care of ICU patients with delirium: A scoping review.

Introduction: The family has an important role in the care of the ICU patient. Research shows that the implementation of non-pharmacological interventions to prevent delirium, including interventions with the family, can reduce the incidence of delirium. The aim of this review was to search the available literature about the experiences and attitudes of family/carers of ICU patients diagnosed with delirium during hospitalization. Methods: A scoping review method was used to map terms relevant to the involvement of relatives in the care of critically ill patients with delirium. To identify studies, the following databases were searched: PubMed, Scopus, EBSCO, Web of Science, and Cochrane Library. The database search was ongoing from 15 July 2022, with a final search on 4 August 2022. Results: Thirteen articles reporting on the experiences and attitudes of family/carers of ICU patients who developed delirium during hospitalization were included in the scoping review. Of the included studies, eight were qualitative studies, three were quantitative studies and two were reviews (systematic review and integrative review). The studies were conducted in North America, Europe, South Africa, and Asia. Our findings show that carers experienced adverse effects associated with delirium in ICU patients such as stress, anxiety, embarrassment, uncertainty, anger, shock. Families/relatives need both emotional and informational support from medical staff. Conclusion: Relatives want to be involved in the care of the delirium patient, although this needs improvement in some aspects of care such as: lack of awareness, family/relatives knowledge of delirium, improved education, and communication with medical staff. Recognition of delirium by families is acceptable and feasible. Family involvement may induce an increased anxiety, but this aspect needs further research.

Effective tumor cell abrogation via Venetoclax-mediated BCL-2 inhibition in KMT2A-rearranged acute B-lymphoblastic leukemia.

Dysregulation of the intrinsic BCL-2 pathway-mediated apoptosis cascade is a common feature of hematological malignancies including acute B-lymphoblastic leukemia (B-ALL). The KMT2A-rearranged high-risk cytogenetic subtype is characterized by high expression of antiapoptotic protein BCL-2, likely due to the direct activating binding of KMT2A fusion proteins to the BCL2 gene. The BCL-2 inhibitor venetoclax (VEN) has proven great clinical value in other blood cancers, however, data on B-ALL is sparse and past studies have not so far described the effects of VEN on gene and protein expression profiles. Using cell lines and patient-derived in vivo xenograft models, we show BCL-2 pathway-mediated apoptosis induction and decelerated tumor cell counts in KMT2A-rearranged B-ALL but not in other cytogenetic subtypes. VEN treatment of cell line- and patient-derived xenografts reduced blast frequencies in blood, bone marrow, and spleen, and tumor cell doubling times were increased. Growth rates are further correlated with VEN concentrations in blood. In vitro incubation with VEN resulted in BCL-2 dephosphorylation and targeted panel RNA sequencing revealed reduced gene expression of antiapoptotic pathway members BCL2, MCL1, and BCL2L1 (BCL-XL). Reinforced translocation of BAX proteins towards mitochondria induced caspase activation and cell death commitment. Prolonged VEN application led to upregulation of antiapoptotic proteins BCL-2, MCL-1, and BCL-XL. Interestingly, the extrinsic apoptosis pathway was strongly modulated in SEM cells in response to VEN. Gene expression of members of the tumor necrosis factor signaling cascade was increased, resulting in canonical NF-kB signaling. This possibly suggests a previously undescribed mechanism of BCL-2-independent and NF-kB-mediated upregulation of MCL-1 and BCL-XL. In summary, we herein prove that VEN is a potent option to suppress tumor cells in KMT2A-rearranged B-ALL in vitro and in vivo. Possible evasion mechanisms, however, must be considered in subsequent studies.