Single-Cell Transcriptomics and Fate Mapping of Ependymal Cells Reveals an Absence of Neural Stem Cell Function.

Ependymal cells are multi-ciliated cells that form the brain's ventricular epithelium and a niche for neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ). In addition, ependymal cells are suggested to be latent NSCs with a capacity to acquire neurogenic function. This remains highly controversial due to a lack of prospective in vivo labeling techniques that can effectively distinguish ependymal cells from neighboring V-SVZ NSCs. We describe a transgenic system that allows for targeted labeling of ependymal cells within the V-SVZ. Single-cell RNA-seq revealed that ependymal cells are enriched for cilia-related genes and share several stem-cell-associated genes with neural stem or progenitors. Under in vivo and in vitro neural-stem- or progenitor-stimulating environments, ependymal cells failed to demonstrate any suggestion of latent neural-stem-cell function. These findings suggest remarkable stability of ependymal cell function and provide fundamental insights into the molecular signature of the V-SVZ niche.

Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation.

Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells. Here, we examined the fate of microglia, BAMs, and recruited macrophages upon neuroinflammation and through resolution. Upon infection, Trypanosoma brucei parasites invaded the brain via its border regions, triggering brain barrier disruption and monocyte infiltration. Fate mapping combined with single-cell sequencing revealed microglia accumulation around the ventricles and expansion of epiplexus cells. Depletion experiments using genetic targeting revealed that resident macrophages promoted initial parasite defense and subsequently facilitated monocyte infiltration across brain barriers. These recruited monocyte-derived macrophages outnumbered resident macrophages and exhibited more transcriptional plasticity, adopting antimicrobial gene expression profiles. Recruited macrophages were rapidly removed upon disease resolution, leaving no engrafted monocyte-derived cells in the parenchyma, while resident macrophages progressively reverted toward a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Thus, brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and resolution.

The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages.

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.

Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity.

Most tumours have an aberrantly activated lipid metabolism1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells.

BACKGROUND AND AIMS: Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver instructs long-term alterations to the liver macrophage compartment. METHODS: We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single cell CITE-sequencing, single nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection. RESULTS: We show that T. b. brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection. CONCLUSION: Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term. IMPACT AND IMPLICATIONS: Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches.

A few good reasons to use nanobodies for cancer treatment.

mAbs have been instrumental for targeted cancer therapies. However, their relatively large size and physicochemical properties result in a heterogenous distribution in the tumor microenvironment, usually restricted to the first cell layers surrounding blood vessels, and a limited ability to penetrate the brain. Nanobodies are tenfold smaller, resulting in a deeper tumor penetration and the ability to reach cells in poorly perfused tumor areas. Nanobodies are rapidly cleared from the circulation, which generates a fast target-to-background contrast that is ideally suited for molecular imaging purposes but may be less optimal for therapy. To circumvent this problem, nanobodies have been formatted to noncovalently bind albumin, increasing their serum half-life without majorly increasing their size. Finally, nanobodies have shown superior qualities to infiltrate brain tumors as compared to mAbs. In this review, we discuss why these features make nanobodies prime candidates for targeted therapy of cancer.

Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Specific imaging of CD8 + T-Cell dynamics with a nanobody radiotracer against human CD8ß.

PURPOSE: While immunotherapy has revolutionized the oncology field, variations in therapy responsiveness limit the broad applicability of these therapies. Diagnostic imaging of immune cell, and specifically CD8+ T cell, dynamics could allow early patient stratification and result in improved therapy efficacy and safety. In this study, we report the development of a nanobody-based immunotracer for non-invasive SPECT and PET imaging of human CD8+ T-cell dynamics. METHODS: Nanobodies targeting human CD8ß were generated by llama immunizations and subsequent biopanning. The lead anti-human CD8ß nanobody was characterized on binding, specificity, stability and toxicity. The lead nanobody was labeled with technetium-99m, gallium-68 and copper-64 for non-invasive imaging of human T-cell lymphomas and CD8+ T cells in human CD8 transgenic mice and non-human primates by SPECT/CT or PET/CT. Repeated imaging of CD8+ T cells in MC38 tumor-bearing mice allowed visualization of CD8+ T-cell dynamics. RESULTS: The nanobody-based immunotracer showed high affinity and specific binding to human CD8 without unwanted immune activation. CD8+ T cells were non-invasively visualized by SPECT and PET imaging in naïve and tumor-bearing mice and in naïve non-human primates with high sensitivity. The nanobody-based immunotracer showed enhanced specificity for CD8+ T cells and/or faster in vivo pharmacokinetics compared to previous human CD8-targeting immunotracers, allowing us to follow human CD8+ T-cell dynamics already at early timepoints. CONCLUSION: This study describes the development of a more specific human CD8+ T-cell-targeting immunotracer, allowing follow-up of immunotherapy responses by non-invasive imaging of human CD8+ T-cell dynamics.

Improved mortality analysis in early-phase dose-ranging clinical trials for emergency medical diseases using Bayesian time-to-event models with active comparators.

Emergency medical diseases (EMDs) are the leading cause of death worldwide. A time-to-death analysis is needed to accurately identify the risks and describe the pattern of an EMD because the mortality rate can peak early and then decline. Dose-ranging Phase II clinical trials are essential for developing new therapies for EMDs. However, most dose-finding trials do not analyze mortality as a time-to-event endpoint. We propose three Bayesian dose-response time-to-event models for a secondary mortality analysis of a clinical trial: a two-group (active treatment vs control) model, a three-parameter sigmoid EMAX model, and a hierarchical EMAX model. The study also incorporates one specific active treatment as an active comparator in constructing three new models. We evaluated the performance of these six models and a very popular independent model using simulated data motivated by a randomized Phase II clinical trial focused on identifying the most effective hyperbaric oxygen dose to achieve favorable functional outcomes in patients with severe traumatic brain injury. The results show that the three-group, EMAX, and EMAX model with an active comparator produce the smallest averaged mean squared errors and smallest mean absolute biases. We provide a new approach for time-to-event analysis in early-phase dose-ranging clinical trials for EMDs. The EMAX model with an active comparator can provide valuable insights into the mortality analysis of new EMDs or other conditions that have changing risks over time. The restricted mean survival time, a function of the model's hazards, is recommended for displaying treatment effects for EMD research.

Assessing the incidence and severity of drug adverse events: a Bayesian hierarchical cumulative logit model.

Detection of safety signals based on multiple comparisons of adverse events (AEs) between two treatments in a clinical trial involves evaluations requiring multiplicity adjustment. A Bayesian hierarchical mixture model is a good solution to this problem as it borrows information across AEs within the same System Organ Class (SOC) and modulates extremes due merely to chance. However, the hierarchical model compares only the incidence rates of AEs, regardless of severity. In this article, we propose a three-level Bayesian hierarchical non-proportional odds cumulative logit model. Our model allows for testing the equality of incidence rate and severity for AEs between the control arm and the treatment arm while addressing multiplicities. We conduct simulation study to investigate the operating characteristics of the proposed hierarchical model. The simulation study demonstrates that the proposed method could be implemented as an extension of the Bayesian hierarchical mixture model in detecting AEs with elevated incidence rate and/or elevated severity. To illustrate, we apply our proposed method using the safety data from a phase III, two-arm randomized trial.

Very Few ACGME-accredited Orthopaedic Surgery Residency Programs Have Web-accessible Leave Policies Dedicated to Parental Leave for Residents, Despite ACGME Requirements.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires that all graduate medical education (GME) programs provide at least 6 paid weeks off for medical, parental, and caregiver leave to residents. However, it is unclear whether all orthopaedic residency programs have adapted to making specific parental leave policies web-accessible since the ACGME's mandate in 2022. This gap in policy knowledge leaves both prospective and current residents in the dark when it comes to choosing residency programs, and knowing what leave benefits they are entitled to when having children during training via birth, surrogacy, adoption, or legal guardianship. QUESTIONS/PURPOSES: (1) What percentage of ACGME-accredited orthopaedic surgery residency programs provide accessible parental leave policies on their program's website, their GME website, and through direct contact with their program's administration? (2) What percentage of programs offer specific parental leave policies, generic leave policies, or defer to the Family and Medical Leave Act (FMLA)? METHODS: As indicated in the American Medical Association's 2022 Freida Specialty Guide, 207 ACGME-accredited orthopaedic residency programs were listed. After further evaluation using previous literature's exclusion criteria, 37 programs were excluded based on osteopathic graduate rates. In all, 170 ACGME-accredited allopathic orthopaedic surgery residency programs were identified and included in this study. Three independent reviewers assessed each program website for the presence of an accessible parental leave policy. Each reviewer accessed the program's public webpage initially, and if no parental leave policy was available, they searched the institution's GME webpage. If no policy was found online, the program administrator was contacted directly via email and phone. Available leave policies were further classified into five categories by reviewers: parental leave, generic leave, deferred to FMLA, combination of parental and FMLA, and combination of parental and generic leave. RESULTS: Our results demonstrated that 6% (10 of 170) of orthopaedic residency programs had policy information available on their program's main orthopaedic web page. Fifty nine-percent (101 of 170) of orthopaedic residency programs had a clearly stated policy on their institution's GME website. The remaining 35% (59 of 170) had no information on their public website and required direct communication with program administration to obtain policy information. After directly contacting program administration, 12% (21 of 170) of programs responded to researchers request with a PDF explicitly outlining their policy. Twenty-two percent (38 of 170) of programs did not have an accessible policy available. Of the programs that had available policies, a total of 53% (70 of 132) of programs were categorized as offering explicit parental leave policies, 9% (12 of 132) were categorized as offering general leave policies, and 27% (36 of 132) deferred to FMLA. Seven percent (9 of 132) offered combined parental leave policies with FMLA, and 4% (5 of 132) offered combined general leave policies with FMLA. CONCLUSION: Although most ACGME-accredited allopathic orthopaedic surgery residency programs met the ACGME requirement of written parental leave policies in 2023, a small minority of programs have clear, accessible parental leave policies provided on their webpage. CLINICAL RELEVANCE: Parental leave policies should be easily accessible to prospective and current trainees and should clearly state compensation and length of leave. Ensuring orthopaedic surgery residency programs provide accessible and transparent parental leave policies is important for maintaining diversity in prospective applicants and supporting the work-life balance of current residents.

Correlations of pre- and post-operative symptoms with cytokines in different phenotypes and endotypes of chronic rhinosinusitis.

BACKGROUND: Recognising inflammatory endotypes in chronic rhinosinusitis (CRS) has become more important, especially with the advent of biological treatments. In this study, we investigated the correlations of pre- and post-operative symptoms with cytokine positivity in different endotypes and phenotypes of CRS. METHODOLOGY: In total, 102 patients undergoing routine functional endoscopic sinus surgery were enrolled. The endotype classification (type 1, 2, or 3 CRS) was defined based on positivity for interferon-γ, interleukin (IL)-5, or IL-17 respectively, in sinonasal tissue samples. Clinical symptom scores were evaluated pre- and post-operatively using the 22-item Sinonasal Outcome Test and its four symptom subdomains: sleep, nasal, otologic/facial symptoms, and emotional function. Symptoms were compared between endotypes and phenotypes, and exploratory factor analysis (EFA) based on principal component analysis (PCA) was performed. The correlations of cytokine levels with baseline symptoms and changes in symptoms after 1 year were analysed. RESULTS: Symptoms in the otologic/facial pain category were associated with non-type 2 endotypes in PCA and confirmatory analysis. Non-type 2 CRS patients exhibited significantly more improvement in facial symptoms 1 year after surgery. Neutrophil-associated cytokines, such as IL-17, matrix metalloproteinase 9, and myeloperoxidase, were significantly correlated with baseline otologic/facial pain symptoms and changes in those symptoms after surgery. CONCLUSIONS: Otologic/facial pain symptoms may be indicative of non-type 2 endotypes. Neutrophil-associated cytokines, such as IL-17, MMP-9, and MPO, were significantly correlated with these symptoms. The establishment of links between specific symptoms and certain cytokines may help use and develop biological therapies for CRS.

COVID-19 and the Impact on Delirium Care of Hospitalized Older Adults: A Qualitative Study.

BACKGROUND: Older adult patients with COVID-19 and delirium experience higher rates of adverse outcomes. Early recognition of at-risk patients and implementation of management strategies improve outcomes, though understanding barriers to acute care nurses implementing these strategies is limited. PURPOSE: This study's purpose was to understand the experiences of acute care nurses providing care to older adults with COVID-19 and delirium. Experiences explored included assessment, nursing management interventions, and barriers to care. METHODS: Purposive sampling to recruit nurses for semistructured focus groups was performed, and thematic analysis was generated by 4 members of the research team. RESULTS: Twenty-one nurses participated in focus groups. Thematic analysis revealed themes of increased patient social isolation, barriers to delirium assessment and prevention, increased staff demands, and stressful work environments. CONCLUSION: Rich findings reveal the profound impact of the pandemic on assessment for delirium and implementation of strategies for prevention and management in older adult patients.

Women Physicians and Promotion in Academic Medicine.

BACKGROUND: In 2000, a landmark study showed that women who graduated from U.S. medical schools from 1979 through 1997 were less likely than their male counterparts to be promoted to upper faculty ranks in academic medical centers. It is unclear whether these differences persist. METHODS: We merged data from the Association of American Medical Colleges on all medical school graduates from 1979 through 2013 with faculty data through 2018, and we compared the percentages of women who would be expected to be promoted on the basis of the proportion of women in the graduating class with the actual percentages of women who were promoted. We calculated Kaplan-Meier curves and used adjusted Cox proportional-hazards models to examine the differences between the early cohorts (1979-1997) and the late cohorts (1998-2013). RESULTS: The sample included 559,098 graduates from 134 U.S. medical schools. In most of the cohorts, fewer women than expected were promoted to the rank of associate or full professor or appointed to the post of department chair. Findings were similar across basic science and clinical departments. In analyses that included all the cohorts, after adjustment for graduation year, race or ethnic group, and department type, women assistant professors were less likely than their male counterparts to be promoted to associate professor (hazard ratio, 0.76; 95% confidence interval [CI], 0.74 to 0.78). Similar sex disparities existed in promotions to full professor (hazard ratio, 0.77; 95% CI, 0.74 to 0.81) and appointments to department chair (hazard ratio, 0.46; 95% CI, 0.39 to 0.54). These sex differences in promotions and appointments did not diminish over time and were not smaller in the later cohorts than in the earlier cohorts. The sex differences were even larger in the later cohorts with respect to promotion to full professor. CONCLUSIONS: Over a 35-year period, women physicians in academic medical centers were less likely than men to be promoted to the rank of associate or full professor or to be appointed to department chair, and there was no apparent narrowing in the gap over time. (Funded by the University of Kansas Medical Center Joy McCann Professorship for Women in Medicine and the American Association of University Women.).

Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.

Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.

Macrophage activation and polarization: nomenclature and experimental guidelines.

Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature.

No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, cross-over trial (ENERGIZE).

AIM: This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS: In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS: The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.

Risk Prediction of Pancreatic Cancer in Patients With Recent-onset Hyperglycemia: A Machine-learning Approach.

BACKGROUND: New-onset diabetes (NOD) has been suggested as an early indicator of pancreatic cancer. However, the definition of NOD by the American Diabetes Association requires 2 simultaneous or consecutive elevated glycemic measures. We aimed to apply a machine-learning approach using electronic health records to predict the risk in patients with recent-onset hyperglycemia. MATERIALS AND METHODS: In this retrospective cohort study, health plan enrollees 50 to 84 years of age who had an elevated (6.5%+) glycated hemoglobin (HbA1c) tested in January 2010 to September 2018 with recent-onset hyperglycemia were identified. A total of 102 potential predictors were extracted. Ten imputation datasets were generated to handle missing data. The random survival forests approach was used to develop and validate risk models. Performance was evaluated by c -index, calibration plot, sensitivity, specificity, and positive predictive value. RESULTS: The cohort consisted of 109,266 patients (mean age: 63.6 y). The 3-year incidence rate was 1.4 (95% confidence interval: 1.3-1.6)/1000 person-years of follow-up. The 3 models containing age, weight change in 1 year, HbA1c, and 1 of the 3 variables (HbA1c change in 1 y, HbA1c in the prior 6 mo, or HbA1c in the prior 18 mo) appeared most often out of the 50 training samples. The c -indexes were in the range of 0.81 to 0.82. The sensitivity, specificity, and positive predictive value in patients who had the top 20% of the predicted risks were 56% to 60%, 80%, and 2.5% to 2.6%, respectively. CONCLUSION: Targeting evaluation at the point of recent hyperglycemia based on elevated HbA1c could offer an opportunity to identify pancreatic cancer early and possibly impact survival in cancer patients.

Neuropsychological profile of executive functions in autism spectrum disorder and schizophrenia spectrum disorders: a comparative group study in adults.

As assessed by numerous neuropsychological tasks, individuals with autism spectrum disorder (ASD) and schizophrenia spectrum disorders (SSDs) have similar impairments related to executive functions (EFs). The neuropsychological profile of these two conditions was examined using the three-component EFs' framework of Miyake and Friedman (Cogn Psychol 41(1):49-100, 2000). This approach assesses Inhibition (suppression of unwanted and irrelevant information/responses), Updating (use and control of contents of working memory), and Shifting (disengagement between activities or mental tasks) using nine different tasks. In line with previous research, we expected greater performance deficits in ASD in all three components compared to SSD, as well as faster responses for the SSD group. A self-paced task format allowed us to examine whether unlimited time given for a task would lead to better performance. The sample was constituted by the control group (N = 25), ASD group (N = 24), and SSD group (N = 12). Groups did not differ on Inhibition performance. In Updating, individuals with SSD performed poorer than the other groups. As for Shifting, both groups demonstrated poorer performance compared to controls, with the SSD group presenting the greatest difficulties. In terms of reaction time (RT), SSD participants' RT were the slowest on Inhibition and Shifting tasks. There was a positive correlation between performance and time spent on Inhibition and Shifting only for the SSD group, which demonstrates that their performance improves when there are no time constraints. Our work provides a better understanding of spared and impaired EFs, which could be useful for designing strategies aimed at improving specific EFs in each group.