Metabolic energetics underlying attractors in neural models.

Neural population modeling, including the role of neural attractors, is a promising tool for understanding many aspects of brain function. We propose a modeling framework to connect the abstract variables used in modeling to recent cellular-level estimates of the bioenergetic costs of different aspects of neural activity, measured in ATP consumed per second per neuron. Based on recent work, an empirical reference for brain ATP use for the awake resting brain was estimated as ∼2 × 109 ATP/s-neuron across several mammalian species. The energetics framework was applied to the Wilson-Cowan (WC) model of two interacting populations of neurons, one excitatory (E) and one inhibitory (I). Attractors were considered to exhibit steady-state behavior and limit cycle behavior, both of which end when the excitatory stimulus ends, and sustained activity that persists after the stimulus ends. The energy cost of limit cycles, with oscillations much faster than the average neuronal firing rate of the population, is tracked more closely with the firing rate than the limit cycle frequency. Self-sustained firing driven by recurrent excitation, though, involves higher firing rates and a higher energy cost. As an example of a simple network in which each node is a WC model, a combination of three nodes can serve as a flexible circuit element that turns on with an oscillating output when input passes a threshold and then persists after the input ends (an "on-switch"), with moderate overall ATP use. The proposed framework can serve as a guide for anchoring neural population models to plausible bioenergetics requirements.NEW & NOTEWORTHY This work bridges two approaches for understanding brain function: cellular-level studies of the metabolic energy costs of different aspects of neural activity and neural population modeling, including the role of neural attractors. The proposed modeling framework connects energetic costs, in ATP consumed per second per neuron, to the more abstract variables used in neural population modeling. In particular, this work anchors potential neural attractors to physiologically plausible bioenergetics requirements.

A mathematical model for velocity-selective arterial spin labeling.

PURPOSE: To present a theoretical framework that rigorously defines and analyzes key concepts and quantities for velocity selective arterial spin labeling (VSASL). THEORY AND METHODS: An expression for the VSASL arterial delivery function is derived based on (1) labeling and saturation profiles as a function of velocity and (2) physiologically plausible approximations of changes in acceleration and velocity across the vascular system. The dependence of labeling efficiency on the amplitude and effective bolus width of the arterial delivery function is defined. Factors that affect the effective bolus width are examined, and timing requirements to minimize quantitation errors are derived. RESULTS: The model predicts that a flow-dependent negative bias in the effective bolus width can occur when velocity selective inversion (VSI) is used for the labeling module and velocity selective saturation (VSS) is used for the vascular crushing module. The bias can be minimized by choosing a nominal labeling cutoff velocity that is lower than the nominal cutoff velocity of the vascular crushing module. CONCLUSION: The elements of the model are specified in a general fashion such that future advances can be readily integrated. The model can facilitate further efforts to understand and characterize the performance of VSASL and provide critical theoretical insights that can be used to design future experiments and develop novel VSASL approaches.

The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.

Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection.

Toll-like receptor 9 (TLR9), its adaptor MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7), and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c(+) cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMos) to the draining lymph node (dLN). In the dLN, the major producers of IFN-I were infected iMos, which used the DNA sensor-adaptor STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFN-α and IFN-ß, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.

Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

CRISPR-guided DNA polymerases enable diversification of all nucleotides in a tunable window.

The capacity to diversify genetic codes advances our ability to understand and engineer biological systems1,2. A method for continuously diversifying user-defined regions of a genome would enable forward genetic approaches in systems that are not amenable to efficient homology-directed oligonucleotide integration. It would also facilitate the rapid evolution of biotechnologically useful phenotypes through accelerated and parallelized rounds of mutagenesis and selection, as well as cell-lineage tracking through barcode mutagenesis. Here we present EvolvR, a system that can continuously diversify all nucleotides within a tunable window length at user-defined loci. This is achieved by directly generating mutations using engineered DNA polymerases targeted to loci via CRISPR-guided nickases. We identified nickase and polymerase variants that offer a range of targeted mutation rates that are up to 7,770,000-fold greater than rates seen in wild-type cells, and editing windows with lengths of up to 350 nucleotides. We used EvolvR to identify novel ribosomal mutations that confer resistance to the antibiotic spectinomycin. Our results demonstrate that CRISPR-guided DNA polymerases enable multiplexed and continuous diversification of user-defined genomic loci, which will be useful for a broad range of basic and biotechnological applications.

Admission avoidance hospital at home.

BACKGROUND: Admission avoidance hospital at home provides active treatment by healthcare professionals in the patient's home for a condition that would otherwise require acute hospital inpatient care, and always for a limited time period. This is the fourth update of this review. OBJECTIVES: To determine the effectiveness and cost of managing patients with admission avoidance hospital at home compared with inpatient hospital care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL on 24 February 2022, and checked the reference lists of eligible articles. We sought ongoing and unpublished studies by searching ClinicalTrials.gov and WHO ICTRP, and by contacting providers and researchers involved in the field. SELECTION CRITERIA: Randomised controlled trials recruiting participants aged 18 years and over. Studies comparing admission avoidance hospital at home with acute hospital inpatient care. DATA COLLECTION AND ANALYSIS: We followed the standard methodological procedures expected by Cochrane and the Effective Practice and Organisation of Care (EPOC) Group. We performed meta-analysis for trials that compared similar interventions, reported comparable outcomes with sufficient data, and used individual patient data when available. We used the GRADE approach to assess the certainty of the body of evidence for the most important outcomes. MAIN RESULTS: We included 20 randomised controlled trials with a total of 3100 participants; four trials recruited participants with chronic obstructive pulmonary disease; two trials recruited participants recovering from a stroke; seven trials recruited participants with an acute medical condition who were mainly older; and the remaining trials recruited participants with a mix of conditions. We assessed the majority of the included studies as at low risk of selection, detection, and attrition bias, and unclear for selective reporting and performance bias. For an older population, admission avoidance hospital at home probably makes little or no difference on mortality at six months' follow-up (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.68 to 1.13; P = 0.30; I2 = 0%; 5 trials, 1502 participants; moderate-certainty evidence); little or no difference on the likelihood of being readmitted to hospital after discharge from hospital at home or inpatient care within 3 to 12 months' follow-up (RR 1.14, 95% CI 0.97 to 1.34; P = 0.11; I2 = 41%; 8 trials, 1757 participants; moderate-certainty evidence); and probably reduces the likelihood of living in residential care at six months' follow-up (RR 0.53, 95% CI 0.41 to 0.69; P < 0.001; I2 = 67%; 4 trials, 1271 participants; moderate-certainty evidence). Hospital at home probably results in little to no difference in patient's self-reported health status (2006 patients; moderate-certainty evidence). Satisfaction with health care received may be improved with admission avoidance hospital at home (1812 participants; low-certainty evidence); few studies reported the effect on caregivers. Hospital at home reduced the initial average hospital length of stay (2036 participants; low-certainty evidence), which ranged from 4.1 to 18.5 days in the hospital group and 1.2 to 5.1 days in the hospital at home group. Hospital at home length of stay ranged from an average of 3 to 20.7 days (hospital at home group only). Admission avoidance hospital at home probably reduces costs to the health service compared with hospital admission (2148 participants; moderate-certainty evidence), though by a range of different amounts and using different methods to cost resource use, and there is some evidence that it decreases overall societal costs to six months' follow-up. AUTHORS' CONCLUSIONS: Admission avoidance hospital at home, with the option of transfer to hospital, may provide an effective alternative to inpatient care for a select group of older people who have been referred for hospital admission. The intervention probably makes little or no difference to patient health outcomes; may improve satisfaction; probably reduces the likelihood of relocating to residential care; and probably decreases costs.

"Family doctors are also people": a qualitative analysis of how family physicians managed competing personal and professional responsibilities during the COVID-19 pandemic.

BACKGROUND: Family physicians (FPs) fill an essential role in public health emergencies yet have frequently been neglected in pandemic response plans. This exclusion harms FPs in their clinical roles and has unintended consequences in the management of concurrent personal responsibilities, many of which were amplified by the pandemic. The objective of our study was to explore the experiences of FPs during the first year of the COVID-19 pandemic to better understand how they managed their competing professional and personal priorities. METHODS: We conducted semi-structured interviews with FPs from four Canadian regions between October 2020 and June 2021. Employing a maximum variation sampling approach, we recruited participants until we achieved saturation. Interviews explored FPs' personal and professional roles and responsibilities during the pandemic, the facilitators and barriers that they encountered, and any gender-related experiences. Transcribed interviews were thematically analysed. RESULTS: We interviewed 68 FPs during the pandemic and identified four overarching themes in participants' discussion of their personal experiences: personal caregiving responsibilities, COVID-19 risk navigation to protect family members, personal health concerns, and available and desired personal supports for FPs to manage their competing responsibilities. While FPs expressed a variety of ways in which their personal experiences made their professional responsibilities more complicated, rarely did that affect the extent to which they participated in the pandemic response. CONCLUSIONS: For FPs to contribute fully to a pandemic response, they must be factored into pandemic plans. Failure to appreciate their unique role and circumstances often leaves FPs feeling unsupported in both their professional and personal lives. Comprehensive planning in anticipation of future pandemics must consider FPs' varied responsibilities, health concerns, and necessary precautions. Having adequate personal and practice supports in place will facilitate the essential role of FPs in responding to a pandemic crisis while continuing to support their patients' primary care needs.

Delay-driven phase transitions in an epidemic model on time-varying networks.

A complex networked system typically has a time-varying nature in interactions among its components, which is intrinsically complicated and therefore technically challenging for analysis and control. This paper investigates an epidemic process on a time-varying network with a time delay. First, an averaging theorem is established to approximate the delayed time-varying system using autonomous differential equations for the analysis of system evolution. On this basis, the critical time delay is determined, across which the endemic equilibrium becomes unstable and a phase transition to oscillation in time via Hopf bifurcation will appear. Then, numerical examples are examined, including a periodically time-varying network, a blinking network, and a quasi-periodically time-varying network, which are simulated to verify the theoretical results. Further, it is demonstrated that the existence of time delay can extend the network frequency range to generate Turing patterns, showing a facilitating effect on phase transitions.

Adverse Fetal Outcomes and Maternal Mortality Following Nonobstetric Abdominopelvic Surgery in Pregnancy: A Systematic Review and Meta-analysis.

OBJECTIVE: To quantify the absolute risks of adverse fetal outcomes and maternal mortality following nonobstetric abdominopelvic surgery in pregnancy. SUMMARY BACKGROUND DATA: Surgery is often necessary in pregnancy, but absolute measures of risk required to guide perioperative management are lacking. METHODS: We systematically searched MEDLINE, EMBASE, and EvidenceBased Medicine Reviews from January 1, 2000, to December 9, 2020, for observational studies and randomized trials of pregnant patients undergoing nonobstetric abdominopelvic surgery. We determined the pooled proportions of fetal loss, preterm birth, and maternal mortality using a generalized linear random/mixed effects model with a logit link. RESULTS: We identified 114 observational studies (52 [46%] appendectomy, 34 [30%] adnexal, 8 [7%] cholecystectomy, 20 [17%] mixed types) reporting on 67,111 pregnant patients. Overall pooled proportions of fetal loss, preterm birth, and maternal mortality were 2.8% (95% CI 2.2-3.6), 9.7% (95% CI 8.3-11.4), and 0.04% (95% CI 0.02-0.09; 4/10,000), respectively. Rates of fetal loss and preterm birth were higher for pelvic inflammatory conditions (eg, appendectomy, adnexal torsion) than for abdominal or nonurgent conditions (eg, cholecystectomy, adnexal mass). Surgery in the second and third trimesters was associated with lower rates of fetal loss (0.1%) and higher rates of preterm birth (13.5%) than surgery in the first and second trimesters (fetal loss 2.9%, preterm birth 5.6%). CONCLUSIONS: Absolute risks of adverse fetal outcomes after nonobstetric abdom- inopelvic surgery vary with gestational age, indication, and acuity. Pooled estimates derived here identify high-risk clinical scenarios, and can inform implementation of mitigation strategies and improve preoperative counselling.

Resistance to lethal ectromelia virus infection requires Type I interferon receptor in natural killer cells and monocytes but not in adaptive immune or parenchymal cells.

Type I interferons (IFN-I) are antiviral cytokines that signal through the ubiquitous IFN-I receptor (IFNAR). Following footpad infection with ectromelia virus (ECTV), a mouse-specific pathogen, C57BL/6 (B6) mice survive without disease, while B6 mice broadly deficient in IFNAR succumb rapidly. We now show that for survival to ECTV, only hematopoietic cells require IFNAR expression. Survival to ECTV specifically requires IFNAR in both natural killer (NK) cells and monocytes. However, intrinsic IFNAR signaling is not essential for adaptive immune cell responses or to directly protect non-hematopoietic cells such as hepatocytes, which are principal ECTV targets. Mechanistically, IFNAR-deficient NK cells have reduced cytolytic function, while lack of IFNAR in monocytes dampens IFN-I production and hastens virus dissemination. Thus, during a pathogenic viral infection, IFN-I coordinates innate immunity by stimulating monocytes in a positive feedback loop and by inducing NK cell cytolytic function.

LNK/SH2B3 as a novel driver in juvenile myelomonocytic leukemia.

Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss of function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

Lewy body disease as a potential negative outcome modifier of glioblastoma treatment: a case report.

BACKGROUND: Elderly patients with glioblastoma are particularly susceptible to the adverse effects of ionizing radiation to the brain. This population also has an increasing prevalence of dementia in the successive seventh, eighth and nineth decade of life, and dementia with Lewy bodies is characterized by pathologic α-synucleins, proteins that take part in neuronal DNA damage repair. CASE PRESENTATION: We report a 77-year-old man, with a history of coronary artery disease and mild cognitive impairment, who experienced subacute behavioral changes over 3 months with wording-finding difficulty, memory loss, confusion, perseveration, and irritable mood. Neuroimaging studies disclosed a 2.5 × 2.4 × 2.7 cm cystic enhancing mass with central necrosis in the left temporal lobe of the brain. Gross total resection of the tumor revealed IDH-1 wild-type glioblastoma. After treatment with radiation and temozolomide chemotherapy, his cognitive status deteriorated rapidly, and he died from unexpected sudden death 2 months after radiation. Autopsy of his brain revealed (i) tumor cells with atypical nuclei and small lymphocytes, (ii) neuronal cytoplasmic inclusions and Lewy bodies that were positive for α-synuclein in the midbrain, pons, amygdala, putamen and globus pallidus, and (iii) no amyloid plaques and only rare neurofibrillary tangles near the hippocampi. CONCLUSIONS: This patient most likely had pre-clinical limbic subtype of dementia with Lewy bodies prior to his diagnosis of glioblastoma. The radiation and temozolomide that was used to treat his tumor may have accelerated neuronal damage due to induction of DNA breakage when his brain was already compromised by pathologic α-synucleins. α-Synucleinopathy could be a negative outcome modifier in glioblastoma patients.

Validation of ICD-10 hospital discharge diagnosis codes to identify incident and recurrent ischemic stroke from a US integrated healthcare system.

PURPOSE: This study validated incident and recurrent ischemic stroke identified by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) hospital discharge diagnosis codes. METHODS: Using electronic health records (EHR) of adults (≥18 years) receiving care from Kaiser Permanente Southern California with ICD-10 hospital discharge diagnosis codes of ischemic stroke (I63.x, G46.3, and G46.4) between October 2015 and September 2020, we identified 75 patients with both incident and recurrent stroke events (total 150 cases). Two neurologists independently evaluated validity of ICD-10 codes through chart reviews. RESULTS: The positive predictive value (PPV, 95% CI) for incident stroke was 93% (95% CI: 88%, 99%) and the PPV for recurrent stroke was 72% (95% CI: 62%, 82%). The PPV for recurrent stroke improved after applying a gap of 20 days (PPV of 75%; 95% CI: 63%, 87%) or removing hospital admissions related to stroke-related procedures (PPV of 78%; 95% CI: 68%, 88%). CONCLUSION: The ICD-10 hospital discharge diagnosis codes for ischemic stroke showed a high PPV for incident cases, while the PPV for recurrent cases were less optimal. Algorithms to improve the accuracy of ICD-10 codes for recurrent ischemic stroke may be necessary.

Are older adults considered in asthma and chronic obstructive pulmonary disease mobile health research? A scoping review.

BACKGROUND: The use of mobile health (mHealth) for asthma and chronic obstructive pulmonary disease (COPD) is rapidly growing and may help address the complex respiratory care needs of our ageing population. However, little is currently known about how airways mHealth is developed and used among older adults (≥65 years). OBJECTIVE: To identify if and how older adults with asthma and COPD have been incorporated across the mHealth research cycle. METHODS: We searched Ovid MEDLINE, EMBASE, CINAHL and the Cochrane Central Registry of Controlled Trials for studies pertaining to the development or evaluation of asthma and COPD mHealth for adults published after 2010. Study, participant and mHealth details, including any considerations of older age, were extracted, synthesised and charted. RESULTS: A total of 334 studies of 191 mHealth tools were identified. Adults ≥65 years old were included in 33.3% of asthma mHealth studies and 85.3% of COPD studies. Discussions of older age focused on barriers to technology use. Methodologic and/or analytic considerations of older age were mostly absent throughout the research cycle. Among the 28 instances quantitative age-related analyses were detailed, 12 described positive mHealth use and satisfaction outcomes in older adults versus negative or equivocal outcomes. CONCLUSION: We identified an overall lack of consideration for older age throughout the airways mHealth research cycle, even among COPD mHealth studies that predominantly included older adults. We also found a contrast between the perceptions of how older age might negatively influence mHealth use and available quantitative evaluations. Future airways mHealth research must better integrate the needs and concerns of older adults.

Cholinesterase inhibitors and falls, syncope and injuries in patients with cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits. OBJECTIVE: To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders. METHODS: Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19 years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis. RESULTS: Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures. CONCLUSION: In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.

Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells.

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton's tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.

Outcome of an elective readmission policy in patients receiving acute myeloid leukaemia consolidation therapy and implications for an outpatient management programme.

Safe outpatient management of acute leukaemia consolidation cycles may enable substantial savings in admission costs. Safety involves the prompt administration of antibiotics in patients with neutropenic fever. Our unit in a metropolitan tertiary referral hospital analysed a cohort of patients spanning a 10-year period, with two key observations: (i) a high proportion of patients living a substantial distance from hospital and (ii) the high incidence and generally prompt onset of fever after severe neutropenia, suggesting this broad applicability of this approach is unfeasible without addressing travel issues and potentially reducing and/or delaying neutropenic fever with prophylactic antibiotics.

Outcomes of critically ill older adults with COVID-19: a multicentre retrospective cohort study.

PURPOSE: Older adults with COVID-19 have a high prevalence of complications and mortality during hospitalization. Given the large proportion of older adults requiring admission to an intensive care unit (ICU), we aimed to describe the management and outcomes of older adults with COVID-19 requiring ICU care and identify predictors of hospital mortality. METHODS: We included consecutive patients ≥ 65 yr of age who were admitted between 11 March 2020 and 30 June 2021 to one of five Toronto (ON, Canada) ICUs with a primary diagnosis of SARS-CoV-2 infection in a retrospective cohort study. Patient characteristics, ICU treatment, and outcomes were recorded. We used multivariable logistic regression to identify predictors of in-hospital mortality. RESULTS: Of the 273 patients, the median [interquartile range] age was 74 [69-80] yr, 104 (38.1%) were female, and 164 (60.1%) required invasive mechanical ventilation. One hundred and forty-two patients (52.0%) survived their hospital stay. Compared with survivors, nonsurvivors were older (74 [70-82] yr vs 73 [68-78] yr; P = 0.03), and a smaller proportion was female (39/131, 29.8% vs 65/142, 45.8%; P = 0.01). Patients had long hospital (19 [11-35] days) and ICU (9 [5-22] days) stays, with no significant differences in ICU length of stay or duration of invasive mechanical ventilation between the two groups. Higher APACHE II score, increasing age, and the need for organ support were independently associated with higher in-hospital mortality while female sex was associated with lower mortality. CONCLUSIONS: Older critically ill COVID-19 patients had long ICU and hospital stays, and approximately half died in hospital. Further research is needed to identify individuals who will benefit most from an ICU admission and to evaluate posthospitalization outcomes.

RéSUMé: OBJECTIF: Les personnes âgées atteintes de la COVID-19 ont une prévalence élevée de complications et de mortalité pendant l'hospitalisation. Compte tenu de la forte proportion de personnes âgées nécessitant une admission dans une unité de soins intensifs (USI), nous avons cherché à décrire la prise en charge et les devenirs des personnes âgées atteintes de COVID-19 nécessitant des soins intensifs et à identifier les prédicteurs de mortalité hospitalière. MéTHODE: Nous avons inclus des patient·es consécutif·ves âgé·es de ≥ 65 ans admis·es entre le 11 mars 2020 et le 30 juin 2021 dans l'une des cinq unités de soins intensifs de Toronto (ON, Canada) avec un diagnostic primaire d'infection par le SRAS-CoV-2 dans une étude de cohorte rétrospective. Les caractéristiques des patient·es, le traitement en USI et les devenirs ont été enregistrés. Nous avons utilisé une régression logistique multivariable pour identifier les prédicteurs de mortalité hospitalière. RéSULTATS: Parmi les 273 patient·es, l'âge médian [écart interquartile] était de 74 [69-80] ans, 104 (38,1 %) étaient des femmes et 164 (60,1 %) ont nécessité une ventilation mécanique invasive. Cent quarante-deux personnes (52,0 %) ont survécu à leur séjour à l'hôpital. Comparativement aux personnes survivantes, les personnes qui n'ont pas survécu étaient plus âgées (74 [70-82] ans vs 73 [68­78] ans; P = 0,03), et une plus faible proportion était de sexe féminin (39/131, 29,8 % vs 65/142, 45,8 %; P = 0,01). Les séjours des patient·es à l'hôpital (19 [11-35] jours) et à l'USI (9 [5-22] jours) étaient longs, sans différence significative dans la durée du séjour en USI ou la durée de la ventilation mécanique invasive entre les deux groupes. Un score APACHE II plus élevé, un âge plus avancé et le besoin de mesures de soutien d'organes étaient indépendamment associés à une mortalité plus élevée à l'hôpital, tandis que le sexe féminin était associé à une mortalité plus faible. CONCLUSION : Les personnes plus âgées gravement malades atteintes de la COVID-19 ont eu de longs séjours en soins intensifs et à l'hôpital, et environ la moitié sont décédées à l'hôpital. D'autres recherches sont nécessaires pour identifier les personnes qui bénéficieraient le plus d'une admission à l'USI et pour évaluer les devenirs post-hospitalisation.

"There's nothing like a good crisis for innovation": a qualitative study of family physicians' experiences with virtual care during the COVID-19 pandemic.

BACKGROUND: Prior to the pandemic, Canada lagged behind other Organisation for Economic Cooperation and Development countries in the uptake of virtual care. The onset of COVID-19, however, resulted in a near-universal shift to virtual primary care to minimise exposure risks. As jurisdictions enter a pandemic recovery phase, the balance between virtual and in-person visits is reverting, though it is unlikely to return to pre-pandemic levels. Our objective was to explore Canadian family physicians' perspectives on the rapid move to virtual care during the COVID-19 pandemic, to inform both future pandemic planning for primary care and the optimal integration of virtual care into the broader primary care context beyond the pandemic. METHODS: We conducted semi-structured interviews with 68 family physicians from four regions in Canada between October 2020 and June 2021. We used a purposeful, maximum variation sampling approach, continuing recruitment in each region until we reached saturation. Interviews with family physicians explored their roles and experiences during the pandemic, and the facilitators and barriers they encountered in continuing to support their patients through the pandemic. Interviews were audio-recorded, transcribed, and thematically analysed for recurrent themes. RESULTS: We identified three prominent themes throughout participants' reflections on implementing virtual care: implementation and evolution of virtual modalities during the pandemic; facilitators and barriers to implementing virtual care; and virtual care in the future. While some family physicians had prior experience conducting remote assessments, most had to implement and adapt to virtual care abruptly as provinces limited in-person visits to essential and urgent care. As the pandemic progressed, initial forays into video-based consultations were frequently replaced by phone-based visits, while physicians also rebalanced the ratio of virtual to in-person visits. Medical record systems with integrated capacity for virtual visits, billing codes, supportive clinic teams, and longitudinal relationships with patients were facilitators in this rapid transition for family physicians, while the absence of these factors often posed barriers. CONCLUSION: Despite varied experiences and preferences related to virtual primary care, physicians felt that virtual visits should continue to be available beyond the pandemic but require clearer regulation and guidelines for its appropriate future use.