Miracle-dz/UniFAR-FTUs huggingface dataset:
Trajectories of antipsychotic use before and during pregnancy and associated maternal and birth characteristics

Objective: To identify distinct trajectories of antipsychotic use prior to and during pregnancy and describe the associated maternal and birth characteristics. Methods: We conducted a population-based cohort study of births (2005–2012) using linked administrative data in New South Wales, Australia. We used group-based trajectory modelling to classify trajectories of antipsychotic use in the 450 days prior to pregnancy and during pregnancy. We characterised women with different trajectories according to maternal sociodemographic characteristics, mental health diagnoses and hospitalisations, use of psychotropic medicines and birth outcomes. Results: Of 137,993 women who gave birth, 2741 (2.0%) were exposed to antipsychotics prior to or during pregnancy. We identified six trajectories of antipsychotic use: two involved short-term use of low daily doses prior to pregnancy (51.1%), while three involved long-term use of low (20.9%), moderate (11.0%) and high (2.0%) daily doses throughout pregnancy. One trajectory (15.0%) involved increasing use during pregnancy. Women with long-term use were more likely to have a schizophrenia or bipolar disorder diagnosis, to have used multiple psychotropics and to have a mental health hospitalisation during pregnancy. Overall, women using antipsychotics had elevated rates of adverse birth outcomes compared to unexposed women. Women with the greatest antipsychotic exposure had the highest rates of gestational diabetes and gestational hypertension. Conclusion: Women using antipsychotics around pregnancy are heterogeneous, with varying patterns of use and associated birth outcomes, reflecting underlying differences in the indications for treatment and/or severity of illness. This diversity should be considered when developing clinical guidelines and designing safety studies.
Iron superoxide dismutase contributes to miltefosine resistance in Leishmania donovani

The emergence of drug‐resistant Leishmania is the major challenge to management of visceral leishmaniasis (VL) in areas in which this parasite is endemic. Miltefosine has been widely used against VL, but the emergence of resistant strains could impose a significant threat in the near future. The present study used high‐throughput proteomics to determine whether proteins are differentially expressed in miltefosine‐resistant (BHU875) and ‐sensitive (DD8) Leishmania donovani strains. Comparative proteomic analysis revealed up‐regulation of iron superoxide dismutase (FeSODA) in the resistant BHU875 strain compared to the drug‐sensitive DD8 strain. In accordance with the proteomic data, BHU875 showed higher FeSODA enzymatic activity relative to the sensitive strain. Molecular characterization of BHU875 parasites in which the gene encoding FeSODA was silenced demonstrated that drug sensitivity was restored and the intracellular survival of the parasite was lowered. This suggests that FeSODA activity plays a part in miltefosine resistance. Our study provides a drug target that could be used to overcome miltefosine resistance or help in rational redesigning of miltefosine‐based therapy to combat Leishmania infection.
Does three‐dimensional anatomy improve student understanding?

We aim to provide an overview of the various digital three‐dimensional visualizations used for learning anatomy and to assess whether these improve medical students' understanding of anatomy compared to traditional learning methods. Furthermore, we evaluate the attitudes of the users of three‐dimensional visualizations. We included articles that compared advanced newer three‐dimensional anatomy visualization methods (i.e., virtual reality, augmented reality, and computer‐based three‐dimensional visualizations) to traditional methods that have been used for a long time (i.e., cadaver and textbooks) with regard to users' understanding of anatomy. Of the 1,148 articles identified, 21 articles reported data on the effectiveness of using three‐dimensional visualization methods compared to two‐dimensional methods. Twelve articles found that three‐dimensional visualization is a significantly more effective learning method compared to traditional methods, whereas nine articles did not find that three‐dimensional visualization was a significantly more effective method. In general, based on these articles, medical students prefer to use three‐dimensional visualizations to learn anatomy. In most of the articles, using three‐dimensional visualization was shown to be a more effective method to gain anatomical knowledge compared to traditional methods. Besides that, students are motivated and interested in using these new visualization methods for learning anatomical structures. Clin. Anat. 32:25–33, 2019. © 2019 Wiley Periodicals, Inc.
Anticoagulation Therapy Using rh-Thrombomodulin and/or Antithrombin III Agent is Associated With Reduction in in-Hospital Mortality in Septic Disseminated Intravascular Coagulation: A Nationwide Registry Study

ABSTRACT We analyzed the Nationwide Registry database on sepsis to examine the effects of an anticoagulation therapy, especially with rh-thrombomodulin (rh-TM) and/or antithrombin (AT) III agent, in septic disseminated intravascular coagulation (DIC) patients. In 3,193 patients enrolled after the exclusion, we investigated the association with in-hospital mortality using Cox proportional hazards models. DIC was diagnosed using the Japanese Association of Acute Medicine (JAAM) and the International Society of Thrombosis and Hemostasis (ISTH) criteria. To analyze the separate treatment effects of rh-TM and/or AT III, we excluded the data of 345 patients treated with all available anticoagulation treatments (rh-TM and/or AT III plus “other anticoagulants”: protease inhibitors and heparin/heparinoids). The DIC criterion populations were as follows: JAAM DICs, n = 1,891 and ISTH DICs (overt DIC), n = 1,002. Septic DIC patients were divided into 3 groups: Group 1, no anticoagulation therapy for DIC; Group 2, received rh-TM and/or AT III; and Group 3, received only “other anticoagulants. ” In JAAM DIC patients, Group 2 did not show an independent association with a reduced risk of in-hospital mortality (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.73–1.01]) as compared with Group 1. However, in ISTH DIC patients, Group 2 showed an inverse association with the risk of in-hospital mortality (HR 0.74; 95% CI: 0.60–0.92) as compared with Group 1, but the same was not true for Group 3 (HR 0.73; 95% CI: 0.47–1.14). The present results support previous findings of the beneficial effects of anticoagulation therapies in septic DIC, also expands the importance of using rh-TM and/or AT agent for septic overt DIC.
Activation of PPARγ in Myeloid Cells Promotes Progression of Epithelial Lung Tumors through TGFβ1

Lung cancer is a heterogeneous disease in which patient-specific treatments are desirable and the development of targeted therapies has been effective. Although mutations in KRAS are frequent in lung adenocarcinoma, there are currently no targeted agents against KRAS. Using a mouse lung adenocarcinoma cell line with a Kras mutation (CMT167), we previously showed that PPARγ activation in lung cancer cells inhibits cell growth in vitro yet promotes tumor progression when activated in myeloid cells of the tumor microenvironment. Here, we report that PPARγ activation in myeloid cells promotes the production of TGFβ1, which, in turn, acts on CMT167 cancer cells to increase migration and induce an epithelial–mesenchymal transition (EMT). Targeting TGFβ1 signaling in CMT167 cells prevented their growth and metastasis in vivo. Similarly, another mouse lung adenocarcinoma cell line with a Kras mutation, LLC, induced TGFβ1 in myeloid cells through PPARγ activation. However, LLC cells are more mesenchymal and did not undergo EMT in response to TGFβ1, nor did LLC require TGFβ1 signaling for metastasis in vivo. Converting CMT167 cells to a mesenchymal phenotype through overexpression of ZEB1 made them unresponsive to TGFβ1 receptor inhibition. The ability of TGFβ1 to induce EMT in lung tumors may represent a critical process in cancer progression. We propose that TGFβ receptor inhibition could provide an additional treatment option for KRAS-mutant epithelial lung tumors. Implications: This study suggests that TGFβ receptor inhibitors may be an effective therapy in a subset of KRAS-mutant patients with non–small cell lung cancer, which show an epithelial phenotype.
Dissemination of a novel organ perfusion technique: ex vivo normothermic perfusion of deceased donor kidneys.

BACKGROUND Ex vivo normothermic perfusion (EVNP) technology is a promising means of organ preservation, assessment, and pre-conditioning prior to kidney transplantation, which has been pioneered by a single group. We describe the challenges of setting up clinical EVNP programmes in two new centres, as well as early patient outcomes. METHODS Governance, training and logistical pathways are described In order to demonstrate safety and proficiency in this new technique, early patient outcomes are also described. Patient outcomes included the incidence of primary non-function, delayed graft function, graft and patient survival at one year. Contralateral kidneys undergoing static cold storage alone were used as a comparator group. RESULTS Between March 2016 to July 2017, EVNP was performed on 14 kidneys from 12 donors (11 kidneys in centre 1, three kidneys in centre 2). Of the 14 kidneys that underwent EVNP, 12 organs were implanted into 10 recipients. Two pairs of kidneys were implanted as dual grafts and one kidney was implanted simultaneously with a pancreas. The remaining seven kidneys were transplanted as single allografts. Seven pairs of kidneys were available for paired analysis comparing EVNP versus static cold storage. Graft and patient outcomes were comparable between the two preservation techniques. CONCLUSION The introduction of a clinical EVNP service requires a careful multimodal approach, drawing on the expertise of specialists in transplantation, haematology and microbiology. Both new clinical EVNP programmes demonstrated proficiency and safety when a structured dissemination process was followed. This article is protected by copyright. All rights reserved.
Gender, Race, and Grant Reviews: Translating and Responding to Research Feedback

Grant-writing and grant-getting are key to success in many academic disciplines, but research points to gender gaps in both, especially as careers progress. Using a sample of National Institutes of Health (NIH) K-Awardees—Principal Investigators of Mentored Career Development Awards—we examined gender and race effects in response to imagined negative grant reviews that emphasized either promise or inadequacy. Women translated both forms of feedback into worse NIH priority scores than did men and showed reduced motivation to reapply for funding following the review highlighting inadequacy. Translation of feedback mediated the effects of gender on motivation, changing one’s research focus, and advice-seeking. Race effects were less consistent, and race did not moderate effects of gender. We suggest that gender bias in grant reviews (i.e., greater likelihood of highlighting inadequacy in reviews of women’s grants), along with gender differences in responsiveness to feedback, may contribute to women’s underrepresentation in academic medicine.
Clotrimazole-Loaded Mediterranean Essential Oils NLC: A Synergic Treatment of Candida Skin Infections

The increasing development of resistance of Candida species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (23 full factorial design) Mediterranean essential oil (Rosmarinus officinalis, Lavandula x intermedia “Sumian”, Origanum vulgare subsp. hirtum) lipid nanoparticles for clotrimazole delivery, exploring the potential synergistic effects against Candida spp. Small sized nanoparticles (<100 nm) with a very broad size distribution (PDI < 0.15) and long-term stability were successfully prepared. Results of the in vitro biosafety on HaCaT (normal cell line) and A431 (tumoral cell line), allowed us to select Lavandula and Rosmarinus as anti-proliferative agents with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases. Results of calorimetric studies on biomembrane models, confirmed the potential antimicrobial activity of the selected oils due to their interaction with membrane permeabilization. Nanoparticles provided a prolonged in vitro release of clotrimazole. In vitro studies against Candida albicans, Candida krusei and Candida parapsilosis, showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming nanostructured lipid carriers (NLC) containing Mediterranean essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis.
Pre-treatment Antiviral Resistance in Australians with Chronic Hepatitis C: Prevalence of NS3 and NS5A Resistance Data in the State of New South Wales

Background Direct-acting antivirals (DAAs) have revolutionized HCV treatment, but the impact of antiviral resistance at a population level is still not clear. The majority of patients who fail DAA therapy develop resistance-associated substitutions (RASs), which can impact re-treatment. There is potential for resistance prevalence to rise in the community with treatment scale up, due to transmission of resistant virus. Monitoring for increasing antiviral resistance requires a reliable baseline, yet there are few published data on the prevalence of HCV resistance in Australia. The aim of this study was to determine the prevalence of RASs among untreated Australians with HCV genotype-1a infection, to inform ongoing surveillance. Methods A cross-sectional study was performed at a single large university hospital pathology laboratory in Australia. Archived blood samples referred for HCV genotype testing were analysed. All patients were naive to DAAs. The prevalence of RASs in the HCV NS3 and NS5A regions was determined using Sanger based population sequencing. Results Of 379 samples tested, 34% contained DAA-resistant virus: 24% had resistance to NS3 protease inhibitors, 12% had NS5A inhibitor resistance and 4% of patients had resistance to both drug classes. Clinically relevant RASs conferring resistance against NS5A inhibitors ledipasvir, daclatasvir and elbasvir were detected in 5.8% of samples. Conclusions This is the largest study of HCV antiviral drug resistance in Australia, which differs from resistance prevalence in the USA. The results provide valuable data on the baseline prevalence of HCV resistance, which can be used in the future to monitor for increasing antiviral resistance.
Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome—Expanding the phenotype

Stickler syndrome (SS) is characterized by ophthalmic, articular, orofacial, and auditory manifestations. SS is usually autosomal dominantly inherited with variants in COL2A1 or COL11A1. Recessive forms are rare but have been described with homozygous variants in COL9A1, COL9A2, and COL9A3 and compound heterozygous COL11A1 variants. This article expands phenotypic descriptions in recessive SS due to variants in genes encoding Type IX collagen. Clinical features were assessed in four families. Genomic DNA samples derived from venous blood were collected from family members. Six affected patients were identified from four pedigrees with variants in COL9A1 (one family, one patient), COL9A2 (two families, three patients), and COL9A3 (one family, two patients). Three variants were novel. All patients were highly myopic with congenital megalophthalmos and abnormal, hypoplastic vitreous gel, and all had sensorineural hearing loss. One patient had severe arthropathy. Congenital megalophthalmos and myopia are common to dominant and recessive forms of SS. Sensorineural hearing loss is more common and severe in recessive SS. We suggest that COL9A1, COL9A2, and COL9A3 be added to genetic screening panels for patients with congenital hearing loss. Although recessive SS is rare, early diagnosis would have a high impact for children with potentially dual sensory impairment, as well as identifying risk to future children.
Interventions for cognitive problems in adults with brain cancer: A narrative review

Abstract Introduction Many patients with brain cancer experience cognitive problems. In this narrative review, we comprehensively evaluated empirical studies on various intervention approaches for cognitive problems in these patients. Methods Intervention studies that reported effects on cognitive functioning (either objectively tested or subjectively reported) in adult patients with primary and/or secondary brain tumours were identified through online searches in PubMed (MEDLINE) and Web of Science up to 13 March 2019. Results Of the 364 identified records, 10 pharmacological (including five randomised placebo‐controlled trials), 10 cognitive rehabilitation (including five [pilot] RCTs) and two multiple‐group exercise studies matched the inclusion criteria. Seventeen of 22 studies had final sample sizes smaller than 40. Several cognitive rehabilitation studies and some pharmacological approaches (donepezil and memantine) showed (at least partial) benefits for cognitive problems in adults with brain cancer. The effects of other pharmacological and exercise interventions were inconclusive and/or preliminary. Conclusion Overall, drawing firm conclusions is complicated due to various methodological shortcomings, including the absence of a (placebo) control group and small sample sizes. Promising effects have been reported for cognitive rehabilitation and some pharmacological approaches. Suggestions for more thorough research with respect to the various approaches are provided.
Melanoma-Derived Extracellular Vesicles: Focus on Their Proteome

Malignant melanoma is one of the most aggressive types of cancer, and its incidence is increasing rapidly each year. Despite the extensive research into improved diagnostic and treatment methods, early detection and disease constraint still present significant challenges. As successful isolation protocols have been developed, extracellular vesicles (EVs) have become the subject of extensive investigation in terms of their role in cancer progression and as a possible source of disease biomarkers. Besides functional studies, quantitative and qualitative proteomics have recently emerged as promising tools for the advancement of melanoma biomarkers. Nevertheless, the amount of data concerning the proteome of melanoma-derived EVs is still very limited. In this review we cover the current knowledge on protein content of melanoma-derived EVs, with a focus on their potential role in the development and progression of melanomas.
Low‐intensity pulsed ultrasound promotes the proliferation of human bone mesenchymal stem cells by activating PI3K/AKt signaling pathways

Low‐intensity pulsed ultrasound (LIPUS) is a promising therapy that is widely used in clinical applications and fundamental research. Previous research has shown that LIPUS exposure has a positive effect on stem cell proliferation. However, the impact of LIPUS exposure on human bone marrow mesenchymal stem cells (hBMSCs) remains unknown. In our study, the effect and mechanism of LIPUS exposure on the proliferation of hBMSCs were investigated, and the optimal parameters of LIPUS were determined. hBMSCs were obtained and identified by flow cytometry, and the proliferation of hBMSCs was measured using the Cell Counting Kit‐8 assay to determine cell cycle and cell count. Expression levels of the phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKt) pathway proteins and cyclin D1 were determined by western blot analysis. Next, hBMSCs were successfully cultured and identified as multipotent mesenchymal stem cells. We found that LIPUS could promote the proliferation of hBMSCs when the exposure time was 5 or 10 minutes per day. Furthermore, 50 or 60 mW/cm2 LIPUS had a more significant effect on cell proliferation, but if cells were irradiated by LIPUS for 20 minutes once a day, an intensity of at least 50 mW/cm2 could markedly inhibit cell growth. Cell cycle analysis demonstrated that LIPUS treatment drives cells to enter S and G2/M phases from the G0/G1 phase. LIPUS exposure increased phosphorylation of PI3K/AKt and significantly upregulated expression of cyclin D1. However, these effects were inhibited when cells were treated with PI3K inhibitor (LY294002), which in turn reduced LIPUS‐mediated proliferation of hBMSCs. These results suggest that LIPUS exposure may be involved in the proliferation of hBMSCs via activation of the PI3K/AKt signaling pathway and high expression of cyclin D1, and the intensity of 50 or 60 mW/cm2 and exposure time of 5 minutes were determined to be the optimal parameters for LIPUS exposure.
Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus: clinical characteristics in a case-control study.

Clinical characteristics associated with bacillary angiomatosis and bacillary peliosis (BAP) in patients with human immunodeficiency virus (HIV) infection were evaluated in a case-control study; 42 case-patients and 84 controls were matched by clinical care institution. Case-patients presented with fever (temperature, > 37.8 degrees C; 93%), a median CD4 lymphocyte count of 21/mm3, cutaneous or subcutaneous vascular lesions (55%), lymphadenopathy (21%), and/or abdominal symptoms (24%). Many case-patients experienced long delays between medical evaluation and diagnosis of BAP (median, 4 weeks; range, 1 day to 24 months). Case-patients were more likely than controls to have fever, lymphadenopathy, hepatomegaly, splenomegaly, a low CD4 lymphocyte count, anemia, or an elevated serum level of alkaline phosphatase (AP) (P < .001). In multivariate analysis, a CD4 lymphocyte count of < 200/mm3 (matched odds ratio [OR], 9.9; P < .09), anemia reflected by a hematocrit value of < 0.36 (OR, 19.7; P < .04), and an elevated AP level of > or = 2.6 mukat/L (OR, 23.9; P < .05) remained associated with disease after therapy with zidovudine was controlled for. BAP should be considered an AIDS-defining opportunistic infection and should be included in the differential diagnosis for febrile, HIV-infected patients with cutaneous or osteolytic lesions, lymphadenopathy, abdominal symptoms, anemia, or an elevated serum level of AP.