Workforce strategies during the first wave of the COVID-19 pandemic: a retrospective online survey at intensive care units in Germany.

BACKGROUND: As the COVID-19 pandemic swept across the globe at the beginning of 2020, healthcare systems were forced to rapidly adapt and expand to meet the sudden surge in demand for intensive care services. This study is the first systematic analysis of the strategies employed by German hospitals to recruit personnel and expand bed capacities during the first wave of the pandemic, and to evaluate the effectiveness of those recruitment measures. METHODS: 152 German hospitals with intensive care capacities were selected and invited to participate in an online-based retrospective survey. Factors like the geographic distribution, individual COVID burden and level of care were considered for inclusion in the sample. The data were analyzed descriptively. RESULTS: A total of 41 hospitals participated in the survey. The additional demand for intensive care beds was met primarily by activating intensive care beds that were previously considered as non-operational in existing intensive care units (81% of respondents) and by upgrading recovery rooms (73%). The physician staffing requirements were met at approximately 75%, while the nursing staffing requirements were only met by about 45%. Staffing needs were met through reallocations/transfers (85%), staff recruitment from parental leave or retirement (49%), increased hours worked by internal staff (49%), new staff hiring (44%) and increased use of temporary staff (32%). Staff reallocations/transfers to critical care within a hospital were rated as the most effective measure. In this context, specialized personnel mostly from anesthesiology departments were appointed to intensive care medicine. CONCLUSIONS: Despite multiple recruitment efforts, the pandemic has exacerbated the nursing staff shortage. The reallocation of existing staff within hospitals was a key element in covering the staffing needs. However, additional measures and efforts are required in order to ensure that critically ill patients can be cared for without compromise. The results of this study may have important implications for healthcare providers and policymakers, offering an evidence-based foundation for responding to future public health emergencies with agility, efficiency, and success.

Chronic dietary supplementation with nicotinamide riboside reduces sleep need in the laboratory mouse.

Non-rapid eye movement sleep (NREMS) is accompanied by a reduction in cerebral glucose utilization. Enabling this metabolic change may be a central function of sleep. Since the reduction in glucose metabolism is inevitably accompanied by deceleration of downstream oxidation/reduction reactions involving nicotinamide adenine dinucleotide (NAD), we hypothesized a role for NAD in regulating the homeostatic dynamics of sleep at the biochemical level. We applied dietary nicotinamide riboside (NR), a NAD precursor, in a protocol known to improve neurological outcome measures in mice. Long-term (6-10 weeks) dietary supplementation with NR reduced the time that mice spent in NREMS by 17 percent and accelerated the rate of discharge of sleep need according to a mathematical model of sleep homeostasis (Process S). These findings suggest that increasing redox capacity by increasing nicotinamide availability reduces sleep need and increases the cortical capacity for energetically demanding high-frequency oscillations. In turn, this work demonstrates the impact of redox substrates on cortical circuit properties related to fatigue and sleep drive, implicating redox reactions in the homeostatic dynamics of cortical network events across sleep-wake cycles.

Reflective practice improves Basic Life Support training outcomes: A randomized controlled study.

INTRODUCTION: Practical skills training is an essential part of medical education. An important example is the training of Basic Life Support (BLS) skills, which are key to improve patient outcomes in life-threatening situations. However, despite practical training, BLS performance is often sub-optimal even among healthcare professionals and medical students. Finding more effective training methods is therefore of high importance. A promising method to enhance learning outcomes is reflective practice. The goal of the present study was to evaluate whether a short reflective practice intervention following standard BLS training (Peyton's 4-step approach) improves BLS training outcomes, reflected in higher BLS performance and higher self-confidence to perform BLS. METHOD: 287 first-year medical students were randomly assigned to one of two BLS training conditions: 1) standard BLS training (ST), 2) ST followed by a 15-minute reflective practice exercise. Outcome parameters included objective BLS performance data assessed by a resuscitation manikin, and students' self-reported confidence in their BLS skills. Outcomes were assessed directly after the training (T0) and re-assessed one week later (T1). A two-way mixed model analysis of variance (ANOVA) was conducted to examine the effect of the intervention on BLS performance and self-reported confidence. Significance was determined by two-sided 95% confidence intervals. RESULTS: The intervention group performed significantly more effective compressions at T1 and began significantly faster with performing their first chest compression at T0 and T1, in comparison to the control group. No significant differences between study groups regarding their self-reported confidence to perform BLS were observed. CONCLUSION: This research shows that standard BLS training accompanied with a simple, cost-effective reflective practice exercise can improve learners' BLS skill acquisition and retention. This shows that reflective practice has the potential to enhance practical skills training in medicine; yet, more empirical studies are needed to examine its broader applicability.

Effect of N-Acetylcysteine on Sleep: Impacts of Sex and Time of Day.

Non-rapid eye movement sleep (NREMS) is accompanied by a decrease in cerebral metabolism, which reduces the consumption of glucose as a fuel source and decreases the overall accumulation of oxidative stress in neural and peripheral tissues. Enabling this metabolic shift towards a reductive redox environment may be a central function of sleep. Therefore, biochemical manipulations that potentiate cellular antioxidant pathways may facilitate this function of sleep. N-acetylcysteine increases cellular antioxidant capacity by serving as a precursor to glutathione. In mice, we observed that intraperitoneal administration of N-acetylcysteine at a time of day when sleep drive is naturally high accelerated the onset of sleep and reduced NREMS delta power. Additionally, N-acetylcysteine administration suppressed slow and beta electroencephalographic (EEG) activities during quiet wake, further demonstrating the fatigue-inducing properties of antioxidants and the impact of redox balance on cortical circuit properties related to sleep drive. These results implicate redox reactions in the homeostatic dynamics of cortical network events across sleep/wake cycles, illustrating the value of timing antioxidant administration relative to sleep/wake cycles. A systematic review of the relevant literature, summarized herein, indicates that this "chronotherapeutic hypothesis" is unaddressed within the clinical literature on antioxidant therapy for brain disorders such as schizophrenia. We, therefore, advocate for studies that systematically address the relationship between the time of day at which an antioxidant therapy is administered relative to sleep/wake cycles and the therapeutic benefit of that antioxidant treatment in brain disorders.

Corrigendum: Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

[This corrects the article DOI: 10.3389/fnsys.2022.1052441.].

Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

Introduction: Insufficient sleep is pervasive worldwide, and its toll on health and safety is recapitulated in many settings. It is thus important to understand how poor sleep affects the brain and decision making. A robust literature documents the adverse effects of sleep deprivation on cognitive processes including cognitive flexibility, which is the capacity to appraise new feedback and make behavioral adjustments to respond appropriately. Animal models are often used to unravel the molecules, genes and neural circuits that are altered by sleep loss. Herein we take a translational approach to model the effects of sleep deprivation on cognitive rigidity, i.e., impaired cognitive flexibility in rats. Methods: There are several approaches to assess cognitive rigidity; in the present study, we employ a pairwise discrimination reversal task. To our knowledge this is the first time this paradigm has been used to investigate sleep deprivation. In this touchscreen operant platform, we trained rats to select one of two images to claim a sucrose pellet reward. If the non-rewarded image was selected the rats proceeded to a correction trial where both images were presented in the same position as before. This image presentation continued until the rat selected the correct image. Once rats reached performance criteria, the reward contingencies were reversed. In one group of rats the initial reversal session was preceded by 10 h of sleep deprivation. We compared those rats to controls with undisturbed sleep on the number of sessions to reach performance criteria, number of trials per session, response latencies, correct responses, errors, perseverative errors and perseveration bouts in the initial training and reversal phases. Results: We report that on reversal session one, sleep deprived rats completed a fraction of the trials completed by controls. On subsequent reversal sessions, the sleep deprived rats struggled to adapt to the reversed contingencies despite completing a similar number of trials, suggesting an effect of cognitive rigidity separate from fatigue. Discussion: We discuss the delayed performance dynamics incurred by sleep loss in the context of fatigue and the implications of using pairwise discrimination reversal as a model to further examine the effects of sleep loss on adaptive decision making.

Safety management in times of crisis: Lessons learned from a nationwide status-analysis on German intensive care units during the COVID-19 pandemic.

Background: The status of Safety Management is highly relevant to evaluate an organization's ability to deal with unexpected events or errors, especially in times of crisis. However, it remains unclear to what extent Safety Management was developed and sufficiently implemented within the healthcare system during the COVID-19 pandemic. Providing insights of potential for improvement is expected to be directional for ongoing Safety Management efforts, in times of crisis and beyond. Method: A nationwide survey study was conducted among healthcare professionals and auxiliary staff on German Intensive Care Units (ICUs) evaluating their experiences during the first wave of the COVID-19 pandemic. Error Management and Patient Safety Culture (PSC) measures served to operationalize Safety Management. Data were analyzed descriptively and by using quantitative content analysis (QCA). Results: Results for n = 588 participants from 53 hospitals show that there is a gap between errors occurred, reported, documented, and addressed. QCA revealed that low quality of safety culture (27.8%) was the most mentioned reason for errors not being addressed. Overall, ratings of PSC ranged from 26.7 to 57.9% positive response with Staffing being the worst and Teamwork Within Units being the best rated dimension. While assessments showed a similar pattern, medical staff rated PSC on ICUs more positively in comparison to nursing staff. Conclusion: The status-analysis of Safety Management in times of crisis revealed relevant potential for improvement. Human Factor plays a crucial role in the occurrence and the way errors are dealt with on ICUs, but systemic factors should not be underestimated. Further intensified efforts specifically in the fields of staffing and error reporting, documentation and communication are needed to improve Safety Management on ICUs. These findings might also be applicable across nations and sectors beyond the medical field.

Telemedicine in medical education: An example of a digital preparatory course for the clinical traineeship - a pre-post comparison.

Introduction: Telemedicine is a significant component of healthcare in most disciplines, giving great importance to the education of young physicians in this field. However, the topic of telemedicine has not yet been implemented in medical schools' curricula. This paper makes an important contribution to closing this gap by designing, implementing and evaluating a course with telemedical components. Using the example of a clinical traineeship preparation course, we investigated the extent to which integrated telemedical modules can contribute to the subjective confidence of students with regard to knowledge and confidence in performing practical telemedical skills, such as doctor-patient communication, taking medical histories, and applying handover techniques. Project description: The course evaluation was descriptive. Subjective confidence in clinical telemedicine skills was assessed before and after completion of the course using an online questionnaire and calculated in a pre-post design using Wilcoxon's signed-rank test. Results: The course was rated "very good" (31%) and "good" (54.2%) by the vast majority of students. The results of the Wilcoxon test show significant increases in students' feelings of confidence in performing practical telemedicine skills for all items. Discussion: This study shows that telemedicine modules integrated in a digital preparatory course contribute positively to students' subjective confidence in terms of knowledge and confidence in performing practical telemedicine skills. Specifically, this paper illustrates that professional digital doctor-patient communication, digital documentation of a medical history, and handoff techniques can be learned through telemedicine course content. Conclusion: Telemedicine modules increase students' subjective confidence in performing practical telemedicine skills. Practical telemedicine course content can thus reduce uncertainty in the use of telemedicine and prepare future physicians for its use.

The rat Lux Actuating Search Task (LAST) and effects of sleep deprivation on task reversal performance.

Sleep deprivation (SD) causes significant deficits in multiple aspects of cognition, including sustained attention and working memory. Investigating the neural processes underpinning these cognitive losses has proven challenging due to the confounds of current animal tasks; many employ appetitive or aversive stimuli to motivate behavior, while others lack task complexity that translates to human studies of executive function. We established the Lux Actuating Search Task (LAST) to circumvent these issues. The LAST is performed in a circular, open-field arena that requires rats to find an unmarked, quasi-randomly positioned target. Constant low-level floor vibrations motivate ambulation, while light intensity (determined by the rodent's proximity to the target destination) provides continuous visual feedback. The task has two paradigms that differ based on the relationship between the light intensity and target proximity: the Low Lux Target (LLT) paradigm and the High Lux Target paradigm (HLT). In this study, on days 1-6, the rats completed nine trials per day on one of the two paradigms. On day 7, the rats were either sleep deprived by gentle handling or were left undisturbed before undertaking the opposite (reversal) paradigm on days 7-9. Our results showed that SD significantly impeded the ability of Long Evans rats to learn the reversal paradigm, as indicated by increased times to target and increased failure percentages compared to rats whose sleep was undisturbed. Rats also showed reduced learning with the HLT paradigm, as the initial task or as the reversal task, likely due to the rodents' photophobia limiting their motivation to navigate toward a bright light, which is required to succeed.

From Stable PH-Ylides to α-Carbanionic Phosphines as Ligands for Zwitterionic Catalysts.

Although ylides are commonly used reagents in organic synthesis, the parent methylphosphine MePH2 only exists in its phosphine form in the condensed phase. Its ylide tautomer H3 P+ -CH2 - is considerably higher in energy. Here, we report on the formation of bis(sulfonyl)methyl-substituted phosphines of the type (RO2 S)2 C(H)-PR2, which form stable PH ylides under ambient conditions, amongst the first examples of an acyclic phosphine which only exists in its PH ylide form. Depending on the exact substitution pattern the phosphines form an equilibrium between the PH ylide and the phosphine form or exist as one of both extremes. These phosphines were found to be ideal starting systems for the facile formation of α-carbanionic phosphines. The carbanion-functionalization leads to a switch from electron-poor to highly electron-rich phosphines with strong donor abilities and high basicities. Thus, the phosphines readily react with different electrophiles exclusively at the phosphorus atom and not at the carbanionic center. Furthermore, the anionic nature of the phosphines allows the formation of zwitterionic complexes as demonstrated by the isolation of a gold(I) complex with a cationic metal center. The cationic gold center allows for catalytic activity in the hydroamination of alkyne without requiring a further activation step.

Innovative Tele-Instruction Approach Impacts Basic Life Support Performance: A Non-inferiority Trial.

Background: Sustaining Basic Life Support (BLS) training during the COVID-19 pandemic bears substantial challenges. The limited availability of highly qualified instructors and tight economic conditions complicates the delivery of these life-saving trainings. Consequently, innovative and resource-efficient approaches are needed to minimize or eliminate contagion while maintaining high training standards and managing learner anxiety related to infection risk. Methods: In a non-inferiority trial 346 first-year medical, dentistry, and physiotherapy students underwent BLS training at AIXTRA-Competence Center for Training and Patient Safety at the University Hospital RWTH Aachen. Our objectives were (1) to examine whether peer feedback BLS training supported by tele-instructors matches the learning performance of standard instructor-guided BLS training for laypersons; and (2) to minimize infection risk during BLS training. Therefore, in a parallel group design, we compared arm (1) Standard Instructor Feedback (SIF) BLS training (Historical control group of 2019) with arm (2) a Tele-Instructor Supported Peer-Feedback (TPF) BLS training (Intervention group of 2020). Both study arms were based on Peyton's 4-step approach. Before and after each training session, objective data for BLS performance (compression depth and rate) were recorded using a resuscitation manikin. We also assessed overall BLS performance via standardized instructor evaluation and student self-reports of confidence via questionnaire. Non-inferiority margins for the outcome parameters and sample size calculation were based on previous studies with SIF. Two-sided 95% confidence intervals were employed to determine significance of non-inferiority. Results: The results confirmed non-inferiority of TPF to SIF for all tested outcome parameters. A follow-up after 2 weeks found no confirmed COVID-19 infections among the participants. Conclusion: Tele-instructor supported peer feedback is a powerful alternative to in-person instructor feedback on BLS skills during a pandemic, where infection risk needs to be minimized while maximizing the quality of BLS skill learning. Trial registration: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00025199, Trial ID: DRKS00025199.

Development of Entrustable Professional Activities for Specialist Hospice and Palliative Care Pharmacists.

CONTEXT: Entrustable professional activities (EPAs) translate competencies into explicit, practical terms that clearly state the expected roles and responsibilities of clinicians who have achieved proficiency and expertise in a field. EPAs are defined for Hospice and Palliative Medicine physicians but not for other members of Hospice and Palliative Care (HAPC) interprofessional teams, including pharmacists. OBJECTIVES: The objective of this study was to develop EPAs for HAPC pharmacists. METHODS: An 11-member workgroup of HAPC pharmacists was convened to develop candidate EPAs using nominal group and modified-Delphi methods. Content validity index was used as a measure of consensus, defined a priori at ≥ 60%. Vetting occurred via intra- and interprofessional stakeholder reactor groups and a national survey of HAPC pharmacists. RESULTS: Following an iterative process of workgroup and stakeholder consensus-building, 15 HAPC pharmacist EPAs were developed. Among the workgroup, all 15 EPAs reached ≥ 70% consensus, indicating appropriate internal validity. In a national survey of 185 HAPC pharmacists with a 20% response rate, 13 EPAs were rated by most respondents as "essential" and 2 were rated by most respondents as "important but not essential." Respondents indicated the 15 EPA set represented the core professional activities of HAPC pharmacists well (median rating of 5 on a Likert-like scale, IQR 1). CONCLUSION: Fifteen consensus EPAs describe essential activities of HAPC pharmacists in direct patient care, leadership, education, and scholarship. These EPAs will further guide pharmacist training programs, HAPC services seeking to incorporate a specialized pharmacist on the team, and currently practicing HAPC pharmacists.

Multicomponent drug Neurexan mitigates acute stress-induced insomnia in rats.

The aim of this study was to determine whether the multicomponent drug Neurexan could mitigate acute insomnia after exposure to a psychosocial stressor. We administered Neurexan orally to rats and examined stress-induced insomnia using the male rat dirty cage exchange method. The neurocircuitry and electrophysiological correlates of the model are characterised, and it represents various human insomnia conditions. Male rats were randomly assigned in a crossover design to six treatment groups and electroencephalography (EEG) electrodes attached. Three groups were exposed to a cage inhabited by another male rat for a week and the other three groups received a clean cage. Prior to cage change, rats were given either no drug, vehicle control or Neurexan. Non-rapid eye movement (NREM) sleep, REM sleep, and waking were assessed manually via EEG recordings. Group means were compared for sleep latency and for the 2 h after cage change for: time in each state, state-specific episode duration/frequency, in addition to NREM delta, gamma and REM theta EEG spectral power. Rats administered Neurexan fell asleep faster than vehicle-treated rats and spent less time awake with shorter, albeit more waking episodes and increased NREM episodes after dirty cage exposure. Neurexan-treated rats given dirty cages were not statistically different on any outcomes from Neurexan-treated rats given clean cages, thereby mitigating the stressor. In the EEG power spectra analysed, changes between treatment groups were not detected. This research confirms that Neurexan treatment has somnogenic effects and ameliorates psychological stressor-induced acute insomnia.

[Medical students as helpers in the pandemic : Innovative concept for recruitment, training and assignment planning of medical students as medical personnel during the COVID-19 pandemic]. / Medizinstudierende als Helfende in der Pandemie : Innovatives Konzept zu Rekrutierung, Schulung und Einsatzplanung von Medizinstudierenden als medizinisches Personal während der COVID-19-Pandemie.

BACKGROUND: The COVID-19 pandemic posed enormous challenges to the German healthcare system and highlighted the need for strategies to recruit, train, and deploy medical personnel. Until now, no holistic concept existed to use medical students as support for professionals in intensive care units (ICU) to avoid staff shortages in medical care. METHOD: In a large-scale pilot project 265 medical students were trained for an ICU assignment. The innovative training module was accompanied by a pre-post questionnaire for self-assessment of the skills learned. 22 weeks after the training module and still during the pandemic deployment, another questionnaire was used to evaluate experiences in deployment and the efficiency of the training module with respect to preparation for ICU deployment. RESULTS: The analysis revealed significant mean differences for all COVID-19-specific variables (safety dimension) in favor of the training module (n = 168). The deployment evaluation showed that the training concept was inconsistently assessed as preparation for the work deployment for 69 of the 89 deployed students in total (53% agreement/47% disagreement). CONCLUSION: The results show a good feasibility of an innovative training concept for medical students with respect to a pandemic deployment as assistants in intensive care units. The concept is suitable for providing additional helpers in intensive care units during a pandemic; however, the inconsistent evaluation indicates that the concept can be expanded and needs to be adapted.

Floor vibrations for motivation and feedback in the rat vibration actuating search task.

Motivating rodents to perform cognitive tasks often relies on the application of aversive stimuli. The Vibration Actuating Search Task (VAST) is a novel open-field task in which gradient floor vibration provides motivation for the rodent to navigate in the direction of diminishing vibration to an unmarked target destination. Using floor vibration as a motivational stimulus may overcome several of the potential confounds associated with stimuli used in other tasks. In a series of three experiments, we determined whether (1) rats exhibit place preference for floor vibration over other aversive stimuli (i.e., water, foot shock, and bright light), (2) exposure to floor vibration is associated with a lower corticosterone response than exposure to these other stimuli, (3) rats successfully acquire the VAST, and (4) VAST performance is sensitive to 6 h of sleep deprivation (SD). Our results showed that rats exhibited place preference for vibration over water, foot shock, and bright light environments, and that corticosterone levels were lower in rats exposed to vibration than those exposed to water. VAST performance also significantly improved over two days of testing for some metrics, and SD impaired VAST performance. Overall, we conclude that (1) rats exhibit place preference for vibration over other stimuli commonly used to motivate task performance, (2) the vibrations employed by the VAST produce lower concentrations of circulating corticosterone than forced swimming, (3) rats can learn to use gradient floor vibration as a mode of performance feedback within two days of testing, and (4) VAST performance is substantially impaired by SD. Thus, the VAST is an effective and practical testbed for studying the mechanisms by which SD causes deficits in feedback-dependent decision making.

Do Digital Handover Checklists Influence the Clinical Outcome Parameters of Intensive Care Unit Patients? A Randomized Controlled Pilot Study.

Background: Clinical handovers have been identified as high-risk situations for medical treatment errors. It has been shown that handover checklists lead to a reduced rate of medical errors and mortality. However, the influence of handover checklists on essential patient outcomes such as prevalence of sepsis, mortality, and length of hospitalization has not yet been investigated in a randomized controlled trial (RCT). Objectives: The aim of the present pilot study was to estimate the effect of two different handover checklists on the 48 h sepsis-related organ failure assessment (SOFA) score and the feasibility of a respective clinical RCT. Methods: Outcome parameters and feasibility were investigated implementing and comparing an intervention with a control checklist. Design: Single center two-armed cluster randomized prospective crossover pilot study. Setting: The study took place over three 1-month periods in an intensive care unit (ICU) setting at the University Hospital Aachen. Patients/Participants: Data from 1,882 patients on seven ICU wards were assessed, of which 1,038 were included in the analysis. Intervention: A digital standardized handover checklist (ISBAR3) was compared to a control checklist (VICUR). Main Outcome Measures: Primary outcome was the 2nd 24 h time window sepsis-related organ failure assessment (SOFA) score. Secondary outcomes were SOFA scores on the 3rd and 5th 24 h time window, mortality, reuptake, and length of stay; handover duration, degree of satisfaction, and compliance as feasibility-related outcomes. Results: Different sepsis scores were observed only for the 1st 24 h time window after admission to the ICU, with higher values for ISBAR3. With respect to the patient-centered outcomes, both checklists achieved similar results. Average handover duration was shorter for VICUR, whereas satisfaction and compliance were higher for ISBAR3. However, overall compliance was low (25.4% for ISBAR3 and 15.8% for VICUR). Conclusions: Based on the results, a stratified randomization procedure is recommended for following RCTs, in which medical treatment errors should also be investigated as an additional variable. The use of control checklists is discouraged due to lower acceptance and compliance among healthcare practitioners. Measures should be undertaken to increase compliance with the use of checklists. Clinical outcome parameters should be carefully selected. Trial Registration: ClinicalTrials.gov, Identifier [NCT03117088]. Registered April 14, 2017.

Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma.

Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant.See related commentary by Larkin and Byrd, p. 1324.This article is highlighted in the In This Issue feature, p. 1307.

Solvation Effects on the Structure and Stability of Alkali Metal Carbenoids.

s-Block metal carbenoids are carbene synthons and applied in a myriad of organic transformations. They exhibit a strong structure-activity relationship, but this is only poorly understood due to the challenging high reactivity and sensitivity of these reagents. Here, we report on systematic VT and DOSY NMR studies, XRD analyses as well as DFT calculations on a sulfoximinoyl-substituted model system to explain the pronounced solvent dependency of the carbenoid stability. While the sodium and potassium chloride carbenoids showed high stabilities independent of the solvent, the lithium carbenoid was stable at room temperature in THF but decomposed at -10 °C in toluene. These divergent stabilities could be explained by the different structures formed in solution. In contrast to simple organolithium reagents, the monomeric THF-solvate was found to be more stable than the dimer in toluene, since the latter more readily forms direct Li/Cl interactions which facilitate decomposition via α-elimination.

Cellular and molecular outcomes of glutamine supplementation in the brain of succinic semialdehyde dehydrogenase-deficient mice.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with low levels of glutamine in the brain, suggesting that central glutamine deficiency contributes to pathogenesis. Recently, we attempted to rescue the disease phenotype of aldh5a1 -/- mice, a murine model of SSADHD with dietary glutamine supplementation. No clinical rescue and no central glutamine improvement were observed. Here, we report the results of follow-up studies of the cellular and molecular basis of the resistance of the brain to glutamine supplementation. We first determined if the expression of genes involved in glutamine metabolism was impacted by glutamine feeding. We then searched for changes of brain histology in response to glutamine supplementation, with a focus on astrocytes, known regulators of glutamine synthesis in the brain. Glutamine supplementation significantly modified the expression of glutaminase (gls) (0.6-fold down), glutamine synthetase (glul) (1.5-fold up), and glutamine transporters (solute carrier family 7, member 5 [slc7a5], 2.5-fold up; slc38a2, 0.6-fold down). The number of GLUL-labeled cells was greater in the glutamine-supplemented group than in controls (P < .05). Reactive astrogliosis, a hallmark of brain inflammation in SSADHD, was confirmed. We observed a 2-fold stronger astrocyte staining in mutants than in wild-type controls (optical density/cell were 1.8 ± 0.08 in aldh5a1 -/- and 0.99 ± 0.06 in aldh5a1 +/+ ; P < .0001), and a 3-fold higher expression of gfap and vimentin. However, glutamine supplementation did not improve the histological and molecular signature of astrogliosis. Thus, glutamine supplementation impacts genes implicated in central glutamine homeostasis without improving reactive astrogliosis. The mechanisms underlying glutamine deficiency and its contribution to SSADHD pathogenesis remain unknown and should be the focus of future investigations.

DRD2 C957T genotype modulates the time-on-task effect during total sleep deprivation.

Total sleep deprivation (TSD) and time-on-task (TOT), especially in combination, increase cognitive instability and cause performance impairment. There are large inter-individual differences in TSD and TOT effects which, in part, have a genetic basis. Here, we show that the dopamine receptor D2 C957T genetic polymorphism predicts the magnitude of the TOT effect on a psychomotor vigilance test (PVT) during 38 h of TSD. This finding indicates that dopamine availability in the striatum, where the dopamine receptor D2 is most prevalent, influences the TOT effect, suggesting a role for dopaminergic pathways in sustained attention deficits during sleep loss.