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Summary: Background: Clinical trials and registry studies are essential for advancing research and developing novel treatments. However, these studies rely on manual entry of thousands of variables for each patient. Repurposing real-world data can significantly simplify the data collection, reduce transcription errors, and make the data entry process more efficient, consistent, and cost-effective. Methods: We developed an open-source computational pipeline to collect laboratory and medication information from the electronic health record (EHR) data and populate case report forms. The pipeline was developed and validated with data from two independent pediatric hospitals in the US as part of the Long-terM OUtcomes after Multisystem Inflammatory Syndrome In Children (MUSIC) study. Our pipeline allowed the completion of two of the most time-consuming forms. We compared automatically extracted results with manually entered values in one hospital and applied the pipeline to a second hospital, where the output served as the primary data source for case report forms. Findings: We extracted and populated 51,845 laboratory and 4913 medication values for 159 patients in two hospitals participating in a prospective pediatric study. We evaluated pipeline performance against data for 104 patients manually entered by clinicians in one of the hospitals. The highest concordance was found during patient hospitalization, with 91.59% of the automatically extracted laboratory and medication values corresponding with the manually entered values. In addition to the successfully populated values, we identified an additional 13,396 laboratory and 567 medication values of interest for the study. Interpretation: The automatic data entry of laboratory and medication values during admission is feasible and has a high concordance with the manually entered data. By implementing this proof of concept, we demonstrate the quality of automatic data extraction and highlight the potential of secondary use of EHR data to advance medical science by improving data entry efficiency and expediting clinical research. Funding: NIH Grant 1OT3HL147154-01, U24HL135691, UG1HL135685.

All climate models use parameterizations and tuning in order to be accurate. The different parameterizations and tuning processes are the primary source of difference between models. Because models are tuned with present observations of Earth, they may not accurately simulate climates of other planets or palaeoclimate. A model with no adjustable parameter that happens to fit today's observations is probably more universal and should be more appropriate to model palaeoclimate. However, to our knowledge, such a model does not exist or is yet to be developed. This paper aims to improve a parameter-free radiative–convective model that computes a realistic temperature vertical profile to compute the water cycle, giving a value on average tropical precipitation. Although it is known that the radiative transfer constrains the order of magnitude of precipitation, no parameter-free model has yet been able to compute precipitation. Our model finds a precipitation value closer to observations than similar radiative–convective models or some general circulation models (GCMs).

Summary: Cohesin is key to eukaryotic genome organization and acts throughout the cell cycle in an ATP-dependent manner. The mechanisms underlying cohesin ATPase activity are poorly understood. Here, we characterize distinct steps of the human cohesin ATPase cycle and show that the SMC1A and SMC3 ATPase domains undergo specific but concerted structural rearrangements along this cycle. Specifically, whereas the proximal coiled coil of the SMC1A ATPase domain remains conformationally stable, that of the SMC3 displays an intrinsic flexibility. The ATP-dependent formation of the heterodimeric SMC1A/SMC3 ATPase module (engaged state) favors this flexibility, which is counteracted by NIPBL and DNA binding (clamped state). Opening of the SMC3/RAD21 interface (open-engaged state) stiffens the SMC3 proximal coiled coil, thus constricting together with that of SMC1A the ATPase module DNA-binding chamber. The plasticity of the ATP-dependent interface between the SMC1A and SMC3 ATPase domains enables these structural rearrangements while keeping the ATP gate shut. Video abstract: Video abstract

Summary: Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene – encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flnaflox/flox mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations.

Combining multiple drugs broadens the window of therapeutic opportunities and is crucial for diseases that are currently lacking fully curative treatments. A powerful emerging tool for selecting effective drugs and combinations is the high-throughput drug screening (HTP). The histone deacetylase inhibitor (HDACi) givinostat (ITF2357) has been shown to act effectively against CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), a subtype characterized by poor outcome and enriched in children with Down Syndrome, very fragile patients with a high susceptibility to treatment-related toxicity. The aim of this study is to investigate possible synergies with givinostat for these difficult-to-treat patients by performing HTP screening with a library of 174 drugs, either approved or in preclinical studies. By applying this approach to the CRLF2-r MHH-CALL-4 cell line, we identified 19 compounds with higher sensitivity in combination with givinostat compared to the single treatments. Next, the synergy between givinostat and the promising candidates was further validated in CRLF2r cell lines with a broad matrix of concentrations. The combinations with trametinib (MEKi) or venetoclax (BCL2i) were found to be the most effective and with the greatest synergy across three metrics (ZIP, HAS, Bliss). Their efficacy was confirmed in primary blasts treated ex vivo at concentration ranges with a safe profile on healthy cells. Finally, we described givinostat-induced modifications in gene expression of MAPK and BCL-2 family members, supporting the observed synergistic interactions. Overall, our study represents a model of drug repurposing strategy using HTP screening for identifying synergistic, efficient, and safe drug combinations.

Objectives: The burden of histoplasmosis is as great as that of tuberculosis in Latin America and the attributable mortality is even higher. A better assessment of severity could help reduce mortality. Methods: From the French Guiana HIV-histoplasmosis database, we attempted to identify factors associated with 30-day death after antifungal drug initiation and constructed a prognostic score. We evaluated its discrimination performance using several resampling methods. Results: Of the 415 patients included, 56 (13.5%) died within 30 days of treatment. The fatality-associated factors were performance status ≥3, altered mental status, dyspnea, C-reactive protein ≥75 mg/l, hemoglobin

Working memory (WM) training has been proposed as a promising intervention to enhance cognitive abilities, but convincing evidence for transfer to untrained abilities is lacking. Prevalent limitations of WM training studies include the narrow assessment of both WM and cognitive abilities, the analysis of manifest variables subject to measurement error, and training dosages too low to likely cause changes in the cognitive system. To address these limitations, we conducted a 2-year longitudinal study to investigate the effects of working memory training on latent factors of working memory capacity, fluid intelligence and crystallized intelligence. One hundred twelve students initially attending 9th grade practiced a heterogenous set of validated WM tasks on a biweekly basis. A control group of 113 students initially attending 9th grade participated in the pretest and posttest. Broad and prototypical measures of fluid and crystallized intelligence served as measures of nearer and farer transfer. We found substantial and reliable training effects on the practiced WM tasks, as well as on a latent WM factor constituted by them. However, no transfer of training effects to fluid or crystallized intelligence were observed. These results add to the literature questioning the utility and validity of WM training as means of improving cognitive abilities.

(1) Background: Only a few studies on histoplasmosis in immunocompetent patients have been reported in French Guiana. Therefore, we conducted a detailed clinical description of hospitalized patients suffering with histoplasmosis among non-HIV patients. (2) Methods: This is a single-center, retrospective study conducted at Cayenne Hospital Center between 2008 and 2022. (3) Results: Our cohort was composed of 31 (91%) adults (>18 years of age) and 3 (9%) children, with a sex ratio, M:F, of 1:2. The median age was higher among the women than among the men (70 versus 54 years). The collection of respiratory samples constituted the majority of the performed examinations (38%). Fever (>37 °C) was found in 56% of patients. Surprisingly, the histoplasmosis was disseminated in 82% of patients with an overall case fatality rate of 14.7%. However, immunosuppressive conditions were found in 52% (16/31) of the adult patients, including lymphoid hemopathies, diabetes and immunosuppressive drugs. Conclusions: This disease, though rare and usually considered a mostly benign disease in non-HIV patients, presented a relatively high mortality rate in our cohort. Thus, histoplasmosis should be suspected, screened and investigated as a first line of defense in highly endemic areas, even in immunocompetent and non-HIV patients, especially those with fever or chronic respiratory symptoms.

Single germline or somatic activating mutations of mammalian target of rapamycin (mTOR) pathway genes are emerging as a major cause of type II focal cortical dysplasia (FCD), hemimegalencephaly (HME) and tuberous sclerosis complex (TSC). A double-hit mechanism, based on a primary germline mutation in one allele and a secondary somatic hit affecting the other allele of the same gene in a small number of cells, has been documented in some patients with TSC or FCD. In a patient with HME, severe intellectual disability, intractable seizures and hypochromic skin patches, we identified the ribosomal protein S6 (RPS6) p.R232H variant, present as somatic mosaicism at ~15.1% in dysplastic brain tissue and ~11% in blood, and the MTOR p.S2215F variant, detected as ~8.8% mosaicism in brain tissue, but not in blood. Overexpressing the two variants independently in animal models, we demonstrated that MTOR p.S2215F caused neuronal migration delay and cytomegaly, while RPS6 p.R232H prompted increased cell proliferation. Double mutants exhibited a more severe phenotype, with increased proliferation and migration defects at embryonic stage and, at postnatal stage, cytomegalic cells exhibiting eccentric nuclei and binucleation, which are typical features of balloon cells. These findings suggest a synergistic effect of the two variants. This study indicates that, in addition to single activating mutations and double-hit inactivating mutations in mTOR pathway genes, severe forms of cortical dysplasia can also result from activating mutations affecting different genes in this pathway. RPS6 is a potential novel disease-related gene.

Mental health problems in early childhood are common, but there is a lack of psychiatric research on this age group. DC:0-5 is a multiaxial classification system for mental disorders in early childhood, providing a framework for standardizing clinical practice and research. However, research on the validity of DC:0-5 is scarce. The Developmental Psychiatry Diagnostic Challenges Study (DePsy) is a multi-site, prospective clinical study including six German early childhood mental health (ECMH) clinics. The main objective of the study is to contribute to the validation of Axis I and Axis II of DC:0-5. A second aim of the study is to describe the population of the participating clinics regarding diagnoses, family context, and treatment outcomes. Additionally, the impact of environmental risk factors, including parental Adverse Childhood Experiences (ACEs) and media use, on child psychopathology and caregiver–child relationships will be examined. Over two years, patients aged 0.0–5.9 years old will be enrolled in the study. Assessments include ICD-10 and DC:0-5 diagnoses, developmental tests, video-based observations of caregiver—child interactions, and questionnaires on child psychopathology, media use, parental stress, and treatment satisfaction. Study results will promote the standardization of assessment and treatment in ECMH clinics aiming to improve the development of patients and their families.

Tax haven leaks have attracted negative public attention in recent years, prompting scrutiny of corporate behavior in leaked jurisdictions. We investigate whether U.S. companies with subsidiaries in implicated tax havens change their disclosure behavior after a leak. The Offshore Leaks, Panama Papers, Bahamas Leaks, and Paradise Papers are included in this study. We analyze the leaks as separate exogenous shocks to the affected firms' behavior using a difference-in-differences approach. First, we focus on the readability of tax footnotes in annual reports. Our results suggest that tax footnotes are less readable after a firm's tax haven is implicated in a leak. This finding suggests that implicated firms try to obfuscate information and hide unethical conduct. Second, we investigate firms' disclosures of tax expenses using GAAP effective tax rates and find that companies report higher tax expenses after a leak. These changes in behavior could indicate that firms are concerned about the increasingly critical public attitude toward doing business in leaked low-tax jurisdictions and that they are taking measures to counteract possible negative reputational consequences. JEL Classification: F23, G14, H26, M41 [ABSTRACT FROM AUTHOR]

Preschool mental disorders are often associated with significant interpersonal problems, related to impaired affect recognition, theory of mind (ToM), and empathy. To date, these skills have not been studied together in preschoolers with externalizing behavior problems (EBPs). The aim of the present study was to investigate whether and to what extent preschool children with EBPs show impairments in affect recognition, ToM, and empathy. Preschoolers with EBPs, defined by current psychiatric treatment and T-scores ≥ 60 on the externalizing problem scale of the Child Behavior Checklist (CBCL/1½-5 or 6-18R) were compared to non-clinical controls (HCs), defined by no past and no current psychiatric treatment and T-scores < 60 on all CBCL broad-band scales. Groups were compared on affect recognition (NEuroPSYchological Assessment-II), affective ToM (Test of Emotion Comprehension), cognitive ToM (Extended Theory-of-Mind Scale), parent-reported emotional contagion, attention to others’ feelings, and prosocial action (Empathy Questionnaire), IQ and language (Wechsler Preschool and Primary Scale of Intelligence-III Matrices, Active and Passive Vocabulary test), controlling for age, sex, and language abilities. Compared to 28 HCs, 22 preschoolers with EBPs (total sample meanage = 5.5 years +/− 0.8 years, range= 4.2–6.9 years, males 66%) had significantly greater impairments in cognitive ToM (p = 0.0012, η2 = 0.266), attention to others’ feelings (p = 0.0049, η2 = 0.222), and prosocial action (p = 0.0070, η2 = 0.210), each representing strong effect sizes. EBPs were significantly related to cognitive domains, like prosocial action (r = −0.501), cognitive ToM (r = −0.425), and attention to others’ feelings (r = −0.332), but not to affective domains of social cognition. Social cognitive development may be impaired as early as preschool age and should be promoted before the child starts school.