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This study uses experiments from the Energy Exascale Earth System Model (E3SM) to compare the influence on tropical cyclone (TC) activity of: (i) the atmospheric effect of aerosols under specified sea-surface temperatures (SSTs); and (ii) the net effect of greenhouse gases (GhGs) (including changes in SSTs). The experiments were performed using the CMIP6 Shared Socioeconomic Pathway SSP5-8.5 emissions scenario with GhG-induced SST warming specified and atmospheric aerosol effects simulated but without explicit ocean coupling. Insignificant changes in global TC frequency are found in response to the atmospheric effect of future aerosols and GhGs, as significant regional responses in TC frequency counteract each other. Future GhGs contribute to more frequent TCs in the North Atlantic, and reductions over the Northwestern Pacific and Southern Indian Ocean. The atmospheric effect of future aerosols drives more frequent TCs over the Northwestern Pacific and reductions over the Northeast Pacific and North Atlantic. Along with increases in TC intensity, global TC precipitation (TCP) is projected to increase by 52.8% (14.1%/K) due to the combined effect of future aerosols and GhGs. Although both forcings contribute to TCP increases (14.7–19.3% from reduced aerosols alone and 28.1–33.3% from increased GhGs alone), they lead to different responses in the spatial structure of TCP. TCP increases preferentially in the inner-core due to increased GhGs, whereas TCP decreases in the inner-core and increases in the outer-bands in response to the atmospheric effects of decreased aerosols. These changes are distinct from those caused by aerosol-induced SST changes, which have been considered in other studies.

Steroidal alkaloids are FDA-approved drugs (e.g., Zytiga) and promising drug candidates/leads (e.g., cyclopamine); yet many of the ≥697 known steroidal alkaloid natural products remain underutilized as drugs because it can be challenging to scale their biosynthesis in their producing organisms. Cyclopamine is a steroidal alkaloid produced by corn lily (Veratrum spp.) plants, and it is an inhibitor of the Hedgehog (Hh) signaling pathway. Therefore, cyclopamine is an important drug candidate/lead to treat human diseases that are associated with dysregulated Hh signaling, such as basal cell carcinoma and acute myeloid leukemia. Cyclopamine and its semi-synthetic derivatives have been studied in (pre)clinical trials as Hh inhibitor-based drugs. However, challenges in scaling the production of cyclopamine have slowed efforts to improve its efficacy and safety profile through (bio)synthetic derivatization, often limiting drug development to synthetic analogs of cyclopamine such as the FDA-approved drugs Odomzo, Daurismo, and Erivedge. If a platform for the scalable and sustainable production of cyclopamine were established, then its (bio)synthetic derivatization, clinical development, and, ultimately, widespread distribution could be accelerated. Ongoing efforts to achieve this goal include the biosynthesis of cyclopamine in Veratrum plant cell culture and the semi-/total chemical synthesis of cyclopamine. Herein, this work advances efforts towards a promising future approach: the biosynthesis of cyclopamine in engineered microorganisms. We completed the heterologous microbial production of verazine (biosynthetic precursor to cyclopamine) from simple sugars (i.e., glucose and galactose) in engineered Saccharomyces cerevisiae (S. cerevisiae) through the inducible upregulation of the native yeast mevalonate and lanosterol biosynthetic pathways, diversion of biosynthetic flux from ergosterol (i.e., native sterol in S. cerevisiae) to cholesterol (i.e., biosynthetic precursor to verazine), and expression of a refactored five-step verazine biosynthetic pathway. The engineered S. cerevisiae strain that produced verazine contains eight heterologous enzymes sourced from seven different species. Importantly, S. cerevisiae-produced verazine was indistinguishable via liquid chromatography-mass spectrometry from both a commercial standard (Veratrum spp. plant-produced) and Nicotiana benthamiana-produced verazine. To the best of our knowledge, this is the first report describing the heterologous production of a steroidal alkaloid in an engineered yeast. Verazine production was ultimately increased through design-build-test-learn cycles to a final titer of 83 ± 3 μg/L (4.1 ± 0.1 μg/g DCW). Together, this research lays the groundwork for future microbial biosynthesis of cyclopamine, (bio)synthetic derivatives of cyclopamine, and other steroidal alkaloid natural products.

We created a 2-week, dual-module summer course introducing high school students to environmental toxicology by teaching them quantitative polymerase chain reaction (qPCR) as a way to quantify gene expression of chemical defense proteins in response to exposure to environmental pollutants. During the course, students are guided through the various stages of a successful qPCR experiment: in silico primer design and quality control, total RNA extraction and isolation, cDNA conversion, primer test PCR, and evaluation of results via agarose gel electrophoresis or UV/Vis spectra. The course combines lectures, discussions, and demonstrations with dry and wet laboratory sections to give students a thorough understanding of the scope, utility, and chemical principles of qPCR. At the end of the course, the students are taught how to analyze qPCR data and are encouraged to discuss their findings with other classmates to evaluate their hypotheses and assess possible sources of error. This course was designed to be easily adaptable to multiple test species, chemical exposures, and genes of interest. To explore both terrestrial and aquatic toxicology, the students use honey bees (Apis mellifera) and mosquitofish (Gambusia affinis) as test organisms, as well as ABC-type efflux transporters, antioxidant enzymes, and cytochrome P450 enzymes as endpoints for assessing gene expression. We share this course setup and applied protocols to encourage others to design and offer similar courses that give high school students a hands-on introduction to a broad swath of environmental toxicology research and an opportunity to develop scientific skills necessary for university-level research.

This White Paper presents an overview of the current status and future perspective of QCD research, based on the community inputs and scientific conclusions from the 2022 Hot and Cold QCD Town Meeting. We present the progress made in the last decade toward a deep understanding of both the fundamental structure of the sub-atomic matter of nucleon and nucleus in cold QCD, and the hot QCD matter in heavy ion collisions. We identify key questions of QCD research and plausible paths to obtaining answers to those questions in the near future, hence defining priorities of our research over the coming decades.

QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans1,2. However, owing to the complex structure of QS-21, its availability is limited. Today, the supply depends on laborious extraction from the Chilean soapbark tree or on low-yielding total chemical synthesis3,4. Here we demonstrate the complete biosynthesis of QS-21 and its precursors, as well as structural derivatives, in engineered yeast strains. The successful biosynthesis in yeast requires fine-tuning of the host's native pathway fluxes, as well as the functional and balanced expression of 38 heterologous enzymes. The required biosynthetic pathway spans seven enzyme families-a terpene synthase, P450s, nucleotide sugar synthases, glycosyltransferases, a coenzyme A ligase, acyl transferases and polyketide synthases-from six organisms, and mimics in yeast the subcellular compartmentalization of plants from the endoplasmic reticulum membrane to the cytosol. Finally, by taking advantage of the promiscuity of certain pathway enzymes, we produced structural analogues of QS-21 using this biosynthetic platform. This microbial production scheme will allow for the future establishment of a structure-activity relationship, and will thus enable the rational design of potent vaccine adjuvants.

A hallmark of many unconventional superconductors is the presence of many-body interactions that give rise to broken-symmetry states intertwined with superconductivity. Recent resonant soft X-ray scattering experiments report commensurate 3a0 charge density wave order in infinite-layer nickelates, which has important implications regarding the universal interplay between charge order and superconductivity in both cuprates and nickelates. Here we present X-ray scattering and spectroscopy measurements on a series of NdNiO2+x samples, which reveal that the signatures of charge density wave order are absent in fully reduced, single-phase NdNiO2. The 3a0 superlattice peak instead originates from a partially reduced impurity phase where excess apical oxygens form ordered rows with three-unit-cell periodicity. The absence of any observable charge density wave order in NdNiO2 highlights a crucial difference between the phase diagrams of cuprate and nickelate superconductors.

Honey bees are unintentionally exposed to a wide range of chemicals through various routes in their natural environment, yet research on the cumulative effects of multi-chemical and sublethal exposures on important caste members, including the queen bee and brood, is still in its infancy. The hive's social structure and food-sharing (trophallaxis) practices are important aspects to consider when identifying primary and secondary exposure pathways for residential hive members and possible chemical reservoirs within the colony. Secondary exposures may also occur through chemical transfer (maternal offloading) to the brood and by contact through possible chemical diffusion from wax cells to all hive members. The lack of research on peer-to-peer exposures to contaminants and their metabolites may be in part due to the limitations in sensitive analytical techniques for monitoring chemical fate and dispersion. Combined application of automated honey bee monitoring and modern chemical trace analysis techniques could offer rapid progress in quantifying chemical transfer and accumulation within the hive environment and developing effective mitigation strategies for toxic chemical co-exposures. To enhance the understanding of chemical fate and toxicity within the entire colony, it is crucial to consider both the intricate interactions among hive members and the potential synergistic effects arising from combinations of chemical and their metabolites.

Issued in 2001, Presidential Executive Order 13221 directed federal agencies to purchase products with low standby power, with the goal of 1) reducing energy consumption in federal facilities, and 2) drawing attention to the problem of high standby power consumption, with guidance provided by the Federal Energy Management Program (FEMP). At that time, standby power was newly recognized as an increasing building energy load. Since then, procurement of products with low standby power have been set in place in acquisition processes, and the purchasing power of the federal government continues to influence manufacturers’ design decisions related to standby power. In recent years, FEMP has shifted effort from direct manufacturer outreach for data collection, to integrating low standby requirement into broader acquisition programs including Energy Star and Electronic Product Environmental Assessment Tool (EPEAT). Another milestone has been the labeling of low standby products on the GSA Advantage website to simplify and enhance compliance. Looking forward into the program’s future, this question arises “How do we design programs over time to reflect market and technology changes, by adjusting programmatic requirements while maintaining effectiveness?” This paper discusses that question for the case of standby power, which transitioned from covering a single to multiple environmental attributes, both in the context of the program’s past and future.

Jun-Xiang Wang,1,* Jia-Hui Zhang,1,* Mu Guo,1,* Wei-Rui Huang,1 Han-Lu Zheng,1 Yi-Qi Liao,1 Ying-Xue Yan,1 Zhao-Long Lin,1 Neng-Fu Qiu,1 Cui-Ting Dai,2 Xiang-Bin Yu,1 Yue Yu1 1School of Pharmacy & Fujian Center for New Drug Safety Evaluation, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2Department of Pathology, The People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, 350004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yue Yu; Xiang-Bin Yu, Email yyu@fjmu.edu.cn; yxb4666@fjmu.edu.cnIntroduction: Given the limitations and adverse effects of current rheumatoid arthritis (RA) treatments, there is an urgent need for safer and more effective therapeutic options. Levamisole (LVM) is a non-specific immunomodulator with potential for treating skin diseases, tumors, and autoimmune disorders. Recognizing LVM’s potential despite its controversial reputation, this study aimed to investigate its safety profile and therapeutic efficacy towards RA.Methods: To evaluate the potential toxicity of LVM, a 28-day oral administration was conducted in SD rats, assessing general toxicity and neurotoxicity using serum biochemical indicators, the Morris water maze test, transmission electron microscopy, and H&E staining. Subsequently, the therapeutic effects of LVM on RA were evaluated.Results: The results showed that 30 mg/kg LVM has promising therapeutic effects in the treatment of RA with negligible toxicity from 45 mg/kg to 180 mg/kg.Discussions: This study provides valuable preclinical data on the safety and efficacy of LVM, laying the groundwork for future clinical applications and potentially offering a safer and more effective treatment option for RA patients.Keywords: levamisole, general toxicity, neurotoxicity, rheumatoid arthritis

Chi-Han Lin,1,2,&ast; Yung-Chia Kuo,1– 3,&ast; Hsuan-Chih Kuo,1– 3,&ast; Ching-Ting Wang,4 Shi-Ming Lin,1,5 Alan Chao-Wei Lee,1,6 Ming-Chin Yu,1,6,7 Wei-Chen Lee,1,6 Cherry Chiao-Erh Chen,2,3 Jason Chia-Hsun Hsieh1– 3 1College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 4Registered Nurse, Case Manager of Nursing Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 6Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 7Department of Surgery, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jason Chia-Hsun Hsieh, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, No. 5, Fu-Hsin Street, Gueishan District, Taoyuan City, 333, Taiwan, Tel +886-3-3281200 Ext 8825, Email wisdom5000@gmail.comBackground: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.Keywords: hepatitis, immune checkpoint inhibitor, advanced hepatocellular carcinoma, liver enzymes, overall survival

Noni Novisari Soeroso,1 Muhammad Ichwan,2 Arlinda Sari Wahyuni,3 Causa Trisna Mariedina,4 Yabestin Alfrianus Pakpahan1 1Department of Pulmonology & Respiratory Medicine, Faculty of Medicine, Universitas Sumatera Utara, Prof. dr. Chairuddin P. Lubis Universitas Sumatera Utara Hospital, Medan, Indonesia; 2Department of Pharmacology & Therapeutic, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 3Department of Community Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 4Department of Anatomical Pathology, Faculty of Medicine, Universitas Sumatera Utara, Medan, IndonesiaCorrespondence: Noni Novisari Soeroso, Email noni@usu.ac.idIntroduction: Plant treatment has been used for thousands of years and has been proven to treat acute and chronic diseases. The function of the traditional plant Centella asiatica is as an antimicrobial agent, anticancer, antioxidant, and therapeutic gene in healing wounds and inflammation. Lung fibrosis caused by bleomycin can develop into chronic lung disease, which ends in tissue death if not treated immediately. The purpose of this study is to predict and explain the impact of Centella asiatica extract on model rats exposed to bleomycin in their lungs as a treatment or anti-fibrinolysis.Methods: This research is an analytical study with a randomized in-vivo experimental design divided into 3 groups of 5 male Wistar rats aged 10 weeks. Negative control group (K) with intratracheal induction of bleomycin alone. The positive group was given intratracheal bleomycin 4 mg/kg/BB on days 0 and 21 and added Centella asiatica induction at 400 mg (P1) on days 15 to 49. The other positive group was given intratracheal bleomycin 4 mg/kg/BB on days 0 and 21 and added Centella asiatica induction at 800 mg (P2) on days 15 to 49. Data were collected according to findings of lung histology analysis of rat samples.Results: In the interalveolar septum group, there was a difference in Masson’s Trichrome staining results in groups K and P1 with p< 0.05 (p=0.036). However, there was no difference in histopathological staining results in groups K and P2 (p> 0.05).Conclusion: The induction of bleomycin 4 mg/kg/BB was proven to cause fibrosis in the lungs of rats, and Centella asiatica extract was used as a treatment. Therefore, further research regarding antifibrotic drugs is hoped to reduce fibrotic areas significantly.Keywords: bleomycin, pulmonary fibrosis, Centella asiatica, treatment

Objetivos: Estimar a prevalência do traço falciforme (HbAS) na população de doadores de sangue de Belo Horizonte e analisar a recorrência das doações. Material e métodos: Entre janeiro de 2022 a dezembro de 2023 foram incluídos no estudo 48361 doadores de sangue saudáveis e aptos, submetidos a triagem clínica e laboratorial para a pesquisa de Hemoglobina S, empregando-se a técnica de solubilidade com tampão ditionito de sódio. Após a identificação destes doadores portadores de AS, foi realizada a análise da doação de repetição destes doadores no respectivo período. Resultados: Do total de 48361 doadores analisados, 53% homens e 47% mulheres, sendo que 48,5% destes doadores apresentaram idade entre 18 e 49 anos. Deste montante 23854 (49,3%) doadores foram considerados doadores de 1 vez, 13529 (27,9%) esporádicos e 10979 (22,7%) doadores de repetição. Identificamos 934 doadores HbAS que correspondem a 1,93% da população analisada. Dentre os doadores HbAS, apenas 134 indivíduos (14%) retornaram ao banco de sangue para nova doação no período analisado. Discussão: A identificação da Hemoglobina S é obrigatória e faz-se necessário a comunicação do resultado ao doador. No Brasil, estudos demonstram que esta prevalência pode variar de 0,43% a 9,80%, dependendo da região analisada, o que confere concordância com nossos achados. A porcentagem de doadores HbS de repetição é similar quando comparamos com a população de doadores global. Conclusão: A presença do traço falcêmico não é uma contraindicação para a doação de sangue e estes indivíduos devem receber as devidas orientações sobre sua condição para continuarem como doadores ativos. A compreensão da prevalência da HbS em doadores de sangue é importante para o delineamento e melhor direcionamento do hemocomponente coletado. Ações voltadas para os doadores portadores de HbS são necessárias visando maiores esclarecimentos acerca da doação de sangue para esta população.

Objetivos: Descrever os anticorpos identificados na aloimunização eritrocitária em pacientes que receberam transfusão de concentrado de hemácias (CH) em Belo Horizonte. Adicionalmente, busca-se analisar a relação entre a aloimunização e variáveis como sexo, idade e número de transfusões de CH recebidas. Material e métodos: : Foram avaliados os pacientes atendidos nos diversos hospitais de Belo Horizonte, pela Vita Hemoterapia, que receberam transfusões de CH e que desenvolveram aloimunização. Os dados foram coletados, a partir dos registros do sistema informatizado e NotiVisa, referentes a sexo e idade do paciente, número de transfusões recebidas antes da aloimunização e o tipo de anticorpo identificado, através da técnica de gel centrifugação. A análise estatística foi conduzida para avaliar a prevalência de aloimunização e sua associação com as variáveis estudadas. Resultados: : Entre o período de dezembro de 2022 a dezembro de 2023, foram identificados 73 pacientes que desenvolveram aloimunização após receberem transfusão de CH. Em relação a população analisada, foram identificados 31 (42,4%) pacientes do sexo masculino e 42 (57,5%) do sexo feminino, com média de idade de 63,5 anos. Ao analisarmos o número de CH transfundidos previamente à aloimunização, identificamos que 51 (69,9%) pacientes receberam entre 2 e 10 transfusões de CH e 12 (16,4%) foram aloimunizados após exposição de mais de 10 CH. Os demais foram aloimunizados após 1 transfusão de CH apenas. Dentre os anticorpos identificados, observamos que 61(49%) foram os pertencentes ao sistema RH e 16 (13%) pertencentes ao sistema Kell. Destes pacientes, 32 (44 %) desenvolveram múltiplos anticorpos, sendo a combinação mais frequente os anticorpos anti-Indeterminado e anti-E (34,3%), e 21,8% referente as combinações: anti- Indeterminado + anti-C, anti -E + anti-C e anti -K + anti- E na mesma proporção. Discussão: : Estimam-se as frequências em 1 a 2% em pacientes internados em hospitais gerais, 5% ou mais em pacientes politransfundidos e 20% ou mais em pacientes com doenças dependentes de transfusão. Os resultados obtidos nesse estudo estão de acordo com os resultados descritos na literatura. Em nosso estudo observamos uma maior prevalência na aquisição dos anticorpos entre os pacientes que receberam entre 2 e 10 CH. E sendo os anticorpos mais prevalentes do sistema RH e Kell. Não identificamos relação da presença dos anticorpos relacionados a idade ou sexo . Conclusão: Os resultados preliminares indicam que a prevalência de aloimunização eritrocitária em pacientes transfundidos nos hospitais de Belo Horizonte é significativa. A análise dos dados revela correlações importantes entre a aloimunização e fatores como o número de CH recebidas e o tipo de anticorpo identificado e fornece informações importantes a serem direcionadas para fenotipagem das bolsas mediante ao perfil dos pacientes atendidos. Esses achados ressaltam a importância de uma gestão rigorosa das transfusões sanguíneas e do monitoramento de anticorpos em pacientes cronicamente. Estudos adicionais são necessários para aprofundar a compreensão dos mecanismos subjacentes à aloimunização e desenvolver estratégias preventivas eficazes.

Evidence for a flavor asymmetry between the ū and d¯ quark distributions in the proton has been found in deep-inelastic scattering and Drell-Yan experiments. The pronounced dependence of this flavor asymmetry on x (fraction of nucleon momentum carried by partons) observed in the Fermilab E866 Drell-Yan experiment suggested a drop of the d¯(x)/ū(x) ratio in the x>0.15 region. We report results from the SeaQuest Fermilab E906 experiment with improved statistical precision for d¯(x)/ū(x) in the large x region up to x=0.45 using the 120 GeV proton beam. Two different methods for extracting the Drell-Yan cross section ratios, σpd/2σpp, from the SeaQuest data give consistent results. The d¯(x)/ū(x) ratios and the d¯(x)-ū(x) differences are deduced from these cross section ratios for 0.13

Environmental health science seeks to predict how environmental toxins, chemical toxicants, and prescription drugs accumulate and interact within the body. Xenobiotic transporters of the ATP-binding Cassette (ABC) and solute carrier (SLC) superfamilies are major determinants of the uptake and disposition of xenobiotics across the kingdoms of life. The goal of this study was to integrate drug and environmental chemical interactions (DECIs) of mammalian ABC and SLC proteins in a centralized, integrative database. We built upon an existing publicly accessible platform - the "TransPortal" - which was updated with novel data and searchable features on transporter-interfering chemicals (TICs) from manually curated literature data. The integrated resource TransPortal-TICBase (https://transportal.compbio.ucsf.edu) now contains information on 46 different mammalian xenobiotic transporters of the ABC- and SLC-type superfamilies, including 13 newly added rodent and two additional human drug transporters, 126 clinical drug-drug interactions (DDIs), and a more than quadrupled expansion of the initial in vitro chemical interaction data from 1402 to 6296 total interactions. Based on our updated database, environmental interference with major human and rodent drug transporters occurs across the ABC- and SLC-type superfamilies, with kinetics indicating that some chemicals, such as the ionic liquid 1-hexylpyridinium chloride and the antiseptic chlorhexidine, can act as strong inhibitors with potencies similar or even higher than pharmacological model inhibitors. The new integrated web portal serves as a central repository of current and emerging data for interactions of prescription drugs and environmental chemicals with human drug transporters. This archive has important implications for predicting adverse drug-drug and drug-environmental chemical interactions and can serve as a reference website for the broader scientific community of clinicians and researchers.

Yu-Chieh Ho,1,&ast; Chia-Ti Wang,1,&ast; Tzu-Chieh Weng,2 Chung-Han Ho,3,4 Kang-Ting Tsai,5,6 Chien-Chin Hsu,1,7 Hung-Jung Lin,1,7,8 Hsiu-Chin Chen,5,9 Chien-Cheng Huang1,7,10 1Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan; 2Division of Hospital Medicine, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 4Department of Information Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan; 5Department of Senior Welfare and Services, Southern Taiwan University of Science and Technology, Tainan, Taiwan; 6Division of Geriatrics and Gerontology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 7School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan; 8Department of Emergency Medicine, Taipei Medical University, Taipei, Taiwan; 9Department of Nursing, Chi Mei Medical Center, Tainan, Taiwan; 10Department of Emergency Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chien-Cheng Huang, Department of Emergency Medicine, Chi Mei Medical Center, 901 Zhonghua Road, Yongkang District, Tainan City, 710, Taiwan, Tel +886-6-281-2811, Fax +886-6-281-6161, Email jasonhuang0803@gmail.com Hsiu-Chin Chen, Department of Nursing, Chi Mei Medical Center, Tainan, Taiwan, 901 Zhonghua Road, Yongkang District, Tainan City, 710, Taiwan, Tel +886-6-281-2811, Fax +886-6-281-6161, Email 300006@mail.chimei.org.twPurpose: The home-based medical integrated program (HMIP) is a novel model for home healthcare (HHC) in Taiwan, initiated in 2016 to enhance care quality. However, the outcomes of this program on health outcomes and medical resource utilization in HHC patients remain unclear. Thus, we conducted this study to clarify it.Patients and Methods: The authors utilized the Taiwan National Health Insurance Research Database to identify HHC patients who received HMIP and those who did not between January 2015 and December 2017. A retrospective cohort study design was used. Convenience sampling was employed to select patients who met the inclusion criteria: being part of the HHC program and having complete data for analysis.Results: A total of 4982 HHC patients in the HMIP group and 10,447 patients in the non-HMIP group were identified for this study. The mean age in the HMIP group and non-HMIP group was 77.6 years and 76.1 years, respectively. Compared with the non-HMIP group, the HMIP group had lower total medical costs for HHC, fewer outpatient department visits and lower medical costs, lower medical costs for emergency department visits, fewer hospitalizations, and a lower mortality rate (34.6% vs 41.2%, p< 0.001).Conclusion: The HMIP is a promising model for improving care quality and reducing medical resource utilization in HHC patients. While this suggests that the non-HMIP model should be replaced, it’s important to note that both non-HMIP and HMIP models currently coexist. The HMIP may serve as an important reference for other nations seeking to improve care quality and reduce medical resource utilization in their own HHC systems.Keywords: home-based medical integrated plan, health outcomes, medical resource utilization, Taiwan

Yen-Hao Chen,1– 4 Wan-Ting Huang,5 Wen-Chin Lee,6 Ching-Mei Chen,5 Fu-Jen Cheng,7 Chia-Te Kung,7 Chin-Chou Wang,8 Liang-Jen Wang,9 Yu-Che Ou,10 Shau-Hsuan Li1 1Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 2School of Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; 4Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, 831, Taiwan; 5Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 6Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Department of Occupational Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 9Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 10Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, TaiwanCorrespondence: Shau-Hsuan Li, Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, 833, Taiwan, Email lee.a0928@msa.hinet.netBackground: The aim of this study was to investigate the role of phthalate in patients with esophageal squamous cell carcinoma (ESCC).Methods: A total of 116 ESCC patients and 58 controls without any known histories of malignancies were enrolled. All eight urine phthalate metabolites were measured to assess phthalate levels. Clinical and urine phthalate metabolite profiles were compared between subgroups to identify differences, and the effects of phthalates on clinical ESCC outcomes were also examined.Results: The concentrations of some urine phthalate metabolites were higher in the ESCC group than in the control group, including mono-(3-carboxypropyl) phthalate (MCPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). Higher concentrations of urine phthalate metabolites were associated with clinical T3–T4 status. Patients with higher concentration of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and MEOHP had lower 1-year and 2-year overall survival (OS) rates than those with lower concentrations of these metabolites in our univariate analysis. Multivariate analysis showed that urinary MEHP of ≥ 3 μg/L and clinical stage IVB were independent prognostic factors for worse OS.Conclusion: The results of our study showed that urine phthalate metabolites are elevated in ESCC patients and associated with advanced tumor stage, and that a high urinary concentration of MEHP is an independent prognostic factor of worse OS.Keywords: phthalate, esophageal cancer, squamous cell carcinoma, survival

Background: Malaria was once thought to be rare in the neonatal period, especially in neonates of semi-immune mothers in holoendemic areas. As a result, ill neonates admitted to newborn special care units are often presumed to have neonatal sepsis. Consequently, blood films for malaria parasites are not routinely included in the sepsis screening protocol for such neonates.. Objective: To highlight the manifestations of, and the significant morbidity associated with malaria in the newborn. Patients and Methods: In a prospective study, all consecutive term neonates admitted for presumed sepsis during a five-month rainy season period (April to August 2002) to the Ebonyi State University Teaching Hospital, Abakaliki period were investigated for septicaemia and malaria. Septicaemia was diagnosed by positive blood culture, while malaria parasitaemia was diagnosed on Gienisa stained blood smears. Results: Eighty four neonates were screened for sepsis and malaria parasitaemia during the study period. Out of this number, 28 (33.3 percent) had positive blood smears for malaria parasites alone, 10 (11.9 percent) had septicaemia alone, while four neonates (4.8 percent) had both malaria and septicaemia. Plasmodium falciparuim was found in all positive blood smears. Twenty-four (75.0 percent) of the 32 neonates with positive, malaria parasitaemia had congenital malaria, while the remaining eight (25 percent) most probably had acquired malaria. None of the neonates had transfusional malaria. Parasite densities were uniformly low. Infected neonates weighed 230g less than the non-infected (p< 0.005). Babies of primiparae were infected with malaria parasite in significantly greater proportion than those of the multiparae (p< 0.01). The presenting features in the 28 babies with neonatal malaria alone, included fever in 24 (85.7 percent), refusal of feeds in 23 (82.1 percent), respiratory distress in 19 (67.9 percent) and jaundice in 15 (53.6 percent). The features in the 10 babies with septicaemia alone, included refusal of feeds in 10 (100.0 percent), respiratory distress in 10 (100.0 percent), jaundice in 10 (100.0 percent) and fever in five (50.0 percent). Fever was significantly more prevalent in neonatal malaria than in septicaemia (p

Chun-Ta Chiu,1 Hsiao-Han Tsai,2 Jing-Yuan Chen,1,3 Che-Ming Jack Hu,2 Hui-Wen Chen1,3 1Department of Veterinary Medicine, National Taiwan University, Taipei, 10617, Taiwan; 2Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan; 3Animal Resource Center, National Taiwan University, Taipei, 10617, TaiwanCorrespondence: Hui-Wen Chen, Department of Veterinary Medicine, National Taiwan University, 1 Sec 4 Roosevelt Road, Taipei, 10617, Taiwan, Tel +886 2 33669450, Email winnichen@ntu.edu.twIntroduction: The clinical success of mRNA vaccine during the COVID-19 pandemic has inspired emerging approaches to elevate mRNA vaccine immunogenicity. Among them, antigen fusion protein designs for improved immune cell targeting have been shown to augment humoral immunity against small antigen targets.Methods: This research demonstrates that SARS-CoV-2 receptor binding domain (RBD) fusion with a minimalistic peptide segment of complement component 3b (C3b, residues 727– 767) ligand can improve mRNA vaccine immunogenicity through antigen targeting to complement receptor 1 (CR1). We affirm vaccines’ antigenicity and targeting ability towards specific receptors through Western blot and immunofluorescence assay. Furthermore, mice immunization studies help the investigation of the antibody responses.Results: Using SARS-CoV-2 Omicron RBD antigen, we compare mRNA vaccine formulations expressing RBD fusion protein with mouse C3b peptide (RBD-mC3), RBD fusion protein with mouse Fc (RBD-Fc), and wild-type RBD. Our results confirm the proper antigenicity and normal functionality of RBD-mC3. Upon validating comparable antigen expression by the different vaccine formulations, receptor-targeting capability of the fusion antigens is further confirmed. In mouse immunization studies, we show that while both RBD-mC3 and RBD-Fc elevate vaccine immunogenicity, RBD-mC3 leads to more sustained RBD-specific titers over the RBD-Fc design, presumably due to reduced antigenic diversion by the minimalistic targeting ligand.Conclusion: The study demonstrates a novel C3b-based antigen design strategy for immune cell targeting and mRNA vaccine enhancement. Keywords: vaccinology, nanotechnology, complement component 3b, follicular dendritic cells, complement receptor 1, immune cell targeting

Members of the polycystin family (PKD2 and PKD2L1) of transient receptor potential (TRP) channels conduct Ca2+ and depolarizing monovalent cations. Variants in PKD2 cause autosomal dominant polycystic kidney disease (ADPKD) in humans, whereas loss of PKD2L1 expression causes seizure susceptibility in mice. Understanding structural and functional regulation of these channels will provide the basis for interpreting their molecular dysregulation in disease states. However, the complete structures of polycystins are unresolved, as are the conformational changes regulating their conductive states. To provide a holistic understanding of the polycystin gating cycle, we use computational prediction tools to model missing PKD2L1 structural motifs and evaluate more than 150 mutations in an unbiased mutagenic functional screen of the entire pore module. Our results provide an energetic landscape of the polycystin pore, which enumerates gating sensitive sites and interactions required for opening, inactivation, and subsequent desensitization. These findings identify the external pore helices and specific cross-domain interactions as critical structural regulators controlling the polycystin ion channel conductive and nonconductive states.

Introdução: O linfoma difuso de grandes células B (LDGCB) é definido como uma neoplasia maligna que representa de 30 a 40% de todos os casos de Linfoma Não Hodgkin. O crescimento tumoral ocorre, majoritariamente, em linfonodos, mas também pode ocorrer em órgãos extra linfoides, como a mucosa do sistema digestório. O diagnóstico é confirmado através da imuno-histoquímica e identificação do marcador CD20. O LDGCB pode apresentar diversas manifestações clínicas e laboratoriais, incluindo picos monoclonais de imunoglobulinas em casos mais raros. Objetivo: Relatar o caso de uma paciente com Linfoma Não Hodgkin Difuso de Grandes Células B (LNHDGCB) com IgM elevada, discutindo a conduta adotada para o caso. Material e método: Estudo descritivo baseado no prontuário do paciente. Relato de caso: Feminino, 67 anos, encaminhada ao serviço em fevereiro/24 após diagnóstico de LNHDGCB por biópsia gástrica com BCL2+, BCL6+, CMYC + e Ki67 95%. Apresentava quadro de epigastralgia, vômitos e emagrecimento de 15 kg nos últimos 6 meses. Ao exame, apresentava esplenomegalia e linfonodomegalia em epigástrio. Durante a investigação, realizou eletroforese de proteínas com pico monoclonal em gamaglobulina de 2,73 g/dL e IgM 5.223 mg/dL. Diante do quadro foi optado por internação e realização de plasmaférese para prevenção de “flare” e após redução da IgM, tratamento com R-EPOCH. Durante seguimento, evoluiu com pancitopenia grave e, com isso, foi proposto 2°ciclo de imuno-quimioterapia com esquema R-CHOP. Discussão: A associação entre LDGCB e pico monoclonal de gamaglobulina por aumento de IgM não é bem discutida devido à sua incomum ocorrência. Considerando que a síntese de imunoglobulina é realizada pelos plasmócitos que, por sua vez, são originados pelos linfócitos B, é justificável que os distúrbios linfoproliferativos possam estar associados a picos monoclonais de imunoglobulinas. No contexto apresentado, o excesso de IgM pode levar a complicações relacionadas à hiperviscosidade sanguínea, semelhante ao quadro que pode ocorrer na macroglobulinemia de Waldenstrom. Ainda que com patogêneses distintas, devido a ausência de um protocolo bem estabelecido para a conduta referente a associação do caso, foi optado pela realização da plasmaférese, com objetivo de reduzir a concentração de IgM, em conjunto com a imunoquimioterapia, terapêutica já bem estabelecida e com bons resultados clínicos para LDGCB. Conclusão: Dessa forma, devido a raridade do caso, destaca-se a importância da investigação complementar durante o diagnóstico dos linfomas B, incluindo a Eletroforese de Proteínas e dosagem de imunoglobulinas. O presente relato acrescenta a ocorrência à literatura e mostra um manejo com bom resultado.

Introdução: A disqueratose congênita (DC) é uma doença rara, hereditária causada por mutações nos genes que codificam a biologia dos telômeros. A atividade da telomerase é reduzida formando telômeros mais curtos, resultando em morte celular prematura e cromossomos instáveis. São descritos 18 genes abrangendo herança autossômica dominante, recessiva ou ligada ao X. As manifestações são compostas por uma tríade clássica: distrofia ungueal, pigmentação anormal da pele e leucoplasia da cavidade oral, podendo evoluir com falência medular, Esses pacientes possuem risco aumentado para câncer, fibrose e malformações arteriovenosas pulmonares, imunodeficiências, estenose de uretra, esôfago ou ductos lacrimais, necrose avascular de quadril e/ou ombros, entre outros. O diagnóstico é feito por critérios clínicos e citometria de fluxo com hibridização fluorescente in situ (FISH) dos leucócitos, analisando o comprimento dos telômeros. O tratamento é direcionado conforme as manifestações clínicas de cada paciente. Objetivo: : Descrever um caso raro de DC, ressaltando os métodos utilizados para realizar diagnóstico e a abordagem terapêutica adotada. Materiais e métodos: Utilização de prontuário da paciente com levantamento de história clínica, exames e revisão bibliográfica. Relato de caso: FCL, 30 anos, branca, iniciou acompanhamento com equipe de hematologia do Centro Infantil Boldrini em 2001 com leucopenia e histórico de infecções de repetição como otite média aguda, vias aéreas superiores, pneumonia e erisipela. Em acompanhamento com a equipe de dermatologia, devido lesões ungueais, pigmentação anormal em pele e leucoplasia em região oral. Realizado diagnóstico de DC forma autossômica recessiva por meio de critérios clínicos e exames anatomopatológicos das lesões. Há 3 meses durante internação por pneumonia evoluiu com falência medular e foi diagnosticada com doença pulmonar restritiva. Foi encaminhada à Hematologia Clínica da UNICAMP para acompanhamento multidisciplinar e monitoramento de complicações clínicas e necessidade de transplante de medula óssea. Discussão: DC é uma doença que acomete a linhagem germinativa com encurtamento dos telômeros, promovendo heterogeneidade nos sintomas. Os pacientes podem ter dificuldades no diagnóstico pela variabilidade de apresentação clínica e o acesso restrito o FISH. A avaliação das múltiplas especialidades como hematologia, genética, dermatologia, pneumologia e otorrino podem ajudar neste cuidado. As neoplasias de pele, pulmão, trato gastrointestinal e cabeça e pescoço tem maior incidência nestes pacientes e o monitoramento ao longo da vida é mandatório. Conclusão: Este relato amplia o conhecimento de uma patologia rara com complexidade na obtenção do diagnóstico e contribuiu para que a equipe envolvida no cuidado sistematizasse os dados clínicos e se interessasse em novos estudos que poderão elucidar a relação genótipo-fenótipo da DC e buscar o melhor tratamento para os pacientes, impactando na qualidade de vida.

Objetivos: Estudar a frequência dos resultados positivos na triagem sorológica de HIV, Sífilis, Chagas, Hepatites B e C entre os doadores que realizaram doação no hemonúcleo. Material e métodos: Através de estudo retrospectivo, e dados obtidos pelo sistema informatizado, foi analisado o resultado sorológico das amostras obtidas de doações de sangue entre janeiro de 2021 e dezembro de 2023. Os resultados foram analisados quanto às variáveis: tipo de doador, gênero e idade e a positividade para cada teste. Resultados: Nestes três anos, foram contabilizados 72925 doadores aptos. Deste total, identificamos 34406 (48,15%) do sexo feminino e 38661 (51,85%) do sexo masculino, sendo que 82,18% destes doadores apresentaram idade entre 18 e 49 anos. Foi identificado o total de 780 sorologias positivas no período que correspondem a cerca de 1% dos doadores avaliados. Destes testes foram identificados 43 (0,06%) confirmados para HIV, 274 (0,38%) para Sífilis, 25 (0,03%) para Chagas, 423 (0,58%) para Hepatite B e 15 (0,02%) para Hepatite C. Considerando os anos avaliados, em 2021 foram contabilizados 24645 doadores, sendo 304 testes positivos, que perfazem 1,2% de positividade, sendo 20 para HIV, 107 para Sifilis, 5 casos para Chagas, 169 para Hepatite B e 3 casos positivos para Hepatite C. Em 2022, foram contabilizados 23926 doadores. Os testes positivos totais foram de 253, correspondendo a 1% das doações, sendo 07 para HIV, 92 para Sífilis, 09 para Chagas, 138 para Hepatite B e 07 para Hepatite C. No ano de 2023 foram 24.354 doadores avaliados. Os testes positivos totais foram de 223 que perfazem 1% de positividade, havendo 16 para HIV, 75 para Sífilis, 11 para Chagas, 116 para hepatite B e 05 para hepatite C. Os doadores receberam a comunicação para comparecimento ao hemonúcleo e os testes foram confirmados em segunda amostra. Discussão: Neste período, houve uma crescente de doadores menores de 18 anos, e maiores de 49 anos, entretanto, a maioria de 82,18% se manteve entre as idades de 18-49. Ademais, a porcentagem entre doadores masculinos e femininos se manteve constante durante o estudo, com o primeiro sempre se mantendo acima de 51%. Considerando os 3 anos analisados, identificamos uma redução dos testes positivos para Sífilis em 0,12%, e os de Hepatite B diminuíram 0,21%. De 2021 para 2023 as sorologias positivas para Chagas aumentaram em 0,03%. Não identificamos mudança significativa para as sorologias de HIV e Hepatite C. A taxa de soropositividade encontrada no hemonúcleo no período estudado condiz com os dados da literatura e aceitáveis pelos órgãos regulatórios vigentes. Conclusão: O estudo do perfil destes doadores é essencial para direcionar a triagem clínica e sorológica nos serviços de hemoterapia e as políticas de sangue que em última análise vão se refletir na segurança do sangue disponível para nossa comunidade.

Introdução: Os transplantes pediátricos de medula óssea são intervenções críticas para várias doenças hematológicas e oncológicas. O transplante de medula óssea, em pacientes pediátricos no Distrito Federal, representa o quarto tipo de transplante mais realizado no estado, conforme dados do Registro Brasileiro de Transplantes, disponibilizados pela Associação Brasileira de Transplantes de Órgãos. O Distrito Federal ocupa a 1ª posição no ranking de transplantes por milhão de população pediátrica (PMPP), em relação aos demais estados brasileiros. Comparando-se 2023 com o ano de 2022, observou-se diminuição de 1,23% nos transplantes ósseos em pacientes pediátricos, embora esse patamar ainda seja inferior aos índices registrados no período de pré-pandemia, de 2016 a 2021. Objetivos: Avaliar o panorama dos Transplantes Pediátricos de Medula Óssea no Distrito Federal, identificando os principais desafios e fatores que afetam a efetivação de doadores. Além disso, propor estratégias para otimizar o processo envolvido em todas as etapas, desde a catalogação de possíveis doadores até a fase pós-operatória, objetivando aumentar a taxa de efetivação dos transplantes e reduzir o número de pacientes na lista de espera. Metodologia: Foram analisadas informações do Dimensionamento dos Transplantes no Brasil, globalmente, e, em particular, o que se efetiva em cada unidade federativa, a partir de dados coletados pela Associação Brasileira de Transplante de Órgãos, no período de 2016 a 2023. Consideraram-se apenas dados referentes ao ano de 2023. Resultados: Em 2023, o Distrito Federal (DF) apresentou panorama desafiador nos transplantes pediátricos de medula óssea. Foram realizados 35 transplantes de medula óssea, dos quais 18 foram alogênicos e 17 autólogos, colocando o DF entre os estados com maior número de transplantes por milhão de população pediátrica. No entanto, a taxa de aproveitamento dos doadores efetivos ainda está abaixo do esperado, com apenas 53% dos doadores sendo aproveitados. Os principais desafios incluem a necessidade de capacitação de mais centros de transplantes e a facilitação do Tratamento Fora de Domicílio (TFD) para ampliar o acesso aos transplantes para todas as crianças que necessitam. Estratégias propostas incluem o aumento do número de doadores e a otimização do aproveitamento dos órgãos doados, além de esforços contínuos para melhorar a infraestrutura e a capacitação dos profissionais envolvidos no processo. A meta é elevar o número de doadores por milhão de população para 30, até 2028, visando a aumentar o número de transplantes e a reduzir a lista de espera. Conclusão: Conclui-se que, apesar dos avanços no número de transplantes pediátricos de medula óssea no Distrito Federal, desafios significativos ainda persistem, como subutilização dos doadores e necessidade de maior capacitação e infraestrutura. Estratégias para superar esses desafios incluem aumentar a taxa de aproveitamento dos doadores, expandir o número de centros capacitados e facilitar o acesso ao Tratamento Fora de Domicílio (TFD). Com esforços coordenados e contínuos, espera-se elevar o número de doadores por milhão de população para 30, até 2028, otimizar o processo de transplantes e reduzir a lista de espera, garantindo que mais crianças tenham acesso ao tratamento que necessitam.

Objetivos: A infecção por COVID-19 sabidamente gera um estado de hipercoagulabilidade que facilita eventos trombóticos. Até recentemente, havia poucas evidências sobre a melhor abordagem de anticoagulação - profilática ou terapêutica - para pacientes hospitalizados, tendo em vista mortalidade, eventos adversos, tempo de internação e custo-efetividade. Com esse objetivo, foi feita uma revisão da literatura sobre o tema. Material e método: Trata-se de uma revisão integrativa literária com abordagem qualitativa sob o tema proposto. Utilizou-se as bases de dados “Pubmed”, “Embase” e “The Cochrane Library” oriundo dos descritores “Anticoagulação”, “COVID-19”, “Hospitalização”e “Profilaxia”. Foram selecionados artigos publicados dos últimos 5 anos, resultando em 396 artigos em português e inglês, dos quais 17 foram escolhidos. Resultados e Discussão: A coagulopatia associada à COVID-19 está ligada a morbidade e mortalidade significativas. O SARS-CoV-2 afeta as células pulmonares através de enzimas conversoras de angiotensina (ECA), causando uma resposta inflamatória intensa e hipercoagulabilidade. As células imunológicas ativam o sistema complemento, comprometendo a coagulação e interrompendo a fibrinólise, o que favorece a formação de trombos. A doença pode cursar com disfunção orgânica, sendo que o estado de hipercoagulabilidade na sepse denominado coagulopatia induzida por sepse (SIC) antecede a coagulação intravascular disseminada (CIVD). Além disso, a doença progride com aumento gradativo dos níveis de D-dímero, elevando as taxas de mortalidade. O uso de anticoagulantes é fundamental na gestão da hipercoagulabilidade. Estudos sobre anticoagulação profilática em pacientes hospitalizados com COVID-19 indicam que a heparina profilática reduz a mortalidade significativamente; de acordo com um estudo coorte de destaque, a taxa corresponde a 27% nos primeiros 30 dias de internação sem amplificar o risco de sangramentos graves. Contudo, não há consenso quanto à dosagem. Metanálise e estudo coorte sugerem que a anticoagulação profilática é superior na eficácia e segurança em pacientes moderados a graves comparada à anticoagulação intermediária e terapêutica. No entanto, outros trabalhos apontam vantagem na abordagem terapêutica, nos desfechos de mortalidade e necessidade de internação, embora com maior risco de sangramentos. Segundo a Sociedade Internacional de Trombose e Hemostasia (ISTH), é sugerido que pacientes hospitalizados não gravemente enfermos selecionados recebam a dose terapêutica, enquanto pacientes mais graves recebam anticoagulação profilática. A discussão na literatura sobre a abordagem ideal é controversa, no quesito redução da mortalidade e eventos adversos, mas há consenso quanto à individualização do tratamento como base da tomada de decisão. Conclusão: O debate sobre o ideal esquema de anticoagulação continua, sendo necessária a individualização do tratamento conforme a gravidade e a história clínica do paciente, ponderando a opção mais prudente acerca do risco de sangramento e morbidade pelo uso de anticoagulante. Portanto, reafirma-se a atual recomendação da ISTH ao dar preferência a tromboprofilaxia em hospitalizados por Covid-19, reservando a dose terapêutica para casos individualizados, com fatores de risco adicionais.

Measures of physical growth, such as weight and height have long been the predominant outcomes for monitoring child health and evaluating interventional outcomes in public health studies, including those that may impact neurodevelopment. While physical growth generally reflects overall health and nutritional status, it lacks sensitivity and specificity to brain growth and developing cognitive skills and abilities. Psychometric tools, e.g., the Bayley Scales of Infant and Toddler Development, may afford more direct assessment of cognitive development but they require language translation, cultural adaptation, and population norming. Further, they are not always reliable predictors of future outcomes when assessed within the first 12–18 months of a child’s life. Neuroimaging may provide more objective, sensitive, and predictive measures of neurodevelopment but tools such as magnetic resonance (MR) imaging are not readily available in many low and middle-income countries (LMICs). MRI systems that operate at lower magnetic fields (< 100mT) may offer increased accessibility, but their use for global health studies remains nascent. The UNITY project is envisaged as a global partnership to advance neuroimaging in global health studies. Here we describe the UNITY project, its goals, methods, operating procedures, and expected outcomes in characterizing neurodevelopment in sub-Saharan Africa and South Asia.

In the originally published version of this manuscript em dashes were inadvertently added in place of short dashes and spaces, particularly in the canonical name of the database being described. In addition to this changes have also been made to the formatting of Table 1 to aid understanding. No changes have been made to the content. These errors, for which the publisher apologizes, have been corrected.

This White Paper presents the community inputs and scientific conclusionsfrom the Hot and Cold QCD Town Meeting that took place September 23-25, 2022 atMIT, as part of the Nuclear Science Advisory Committee (NSAC) 2023 Long RangePlanning process. A total of 424 physicists registered for the meeting. Themeeting highlighted progress in Quantum Chromodynamics (QCD) nuclear physicssince the 2015 LRP (LRP15) and identified key questions and plausible paths toobtaining answers to those questions, defining priorities for our research overthe coming decade. In defining the priority of outstanding physicsopportunities for the future, both prospects for the short (~ 5 years) andlonger term (5-10 years and beyond) are identified together with thefacilities, personnel and other resources needed to maximize the discoverypotential and maintain United States leadership in QCD physics worldwide. ThisWhite Paper is organized as follows: In the Executive Summary, we detail theRecommendations and Initiatives that were presented and discussed at the TownMeeting, and their supporting rationales. Section 2 highlights major progressand accomplishments of the past seven years. It is followed, in Section 3, byan overview of the physics opportunities for the immediate future, and inrelation with the next QCD frontier: the EIC. Section 4 provides an overview ofthe physics motivations and goals associated with the EIC. Section 5 is devotedto the workforce development and support of diversity, equity and inclusion.This is followed by a dedicated section on computing in Section 6. Section 7describes the national need for nuclear data science and the relevance to QCDresearch.

Oluwasolape Olawore,1 Lindsey E Turner,2,3 Michael D Evans,3 Steven G Johnson,4 Jared D Huling,2 Carolyn T Bramante,5 John B Buse,6 Til Stürmer1 On behalf of the N3C Consortium1Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Division of Biostatistics and Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN, USA; 3Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN, USA; 4Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA; 5Division of General Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; 6Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USACorrespondence: Oluwasolape Olawore, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, 135 Dauer Drive, Chapel Hill, NC, 27599, USA, Email oolawore@unc.eduBackground: Observed activity of metformin in reducing the risk of severe COVID-19 suggests a potential use of the anti-hyperglycemic in the prevention of post-acute sequelae of SARS-CoV-2 infection (PASC). We assessed the 3-month and 6-month risk of PASC among patients with type 2 diabetes mellitus (T2DM) comparing metformin users to sulfonylureas (SU) or dipeptidyl peptidase-4 inhibitors (DPP4i) users.Methods: We used de-identified patient level electronic health record data from the National Covid Cohort Collaborative (N3C) between October 2021 and April 2023. Participants were adults ≥ 18 years with T2DM who had at least one outpatient healthcare encounter in health institutions in the United States prior to COVID-19 diagnosis. The outcome of PASC was defined based on the presence of a diagnosis code for the illness or using a predicted probability based on a machine learning algorithm. We estimated the 3-month and 6-month risk of PASC and calculated crude and weighted risk ratios (RR), risk differences (RD), and differences in mean predicted probability.Results: We identified 5596 (mean age: 61.1 years; SD: 12.6) and 1451 (mean age: 64.9 years; SD 12.5) eligible prevalent users of metformin and SU/DPP4i respectively. We did not find a significant difference in risk of PASC at 3 months (RR = 0.86 [0.56; 1.32], RD = − 3.06 per 1000 [− 12.14; 6.01]), or at 6 months (RR = 0.81 [0.55; 1.20], RD = − 4.91 per 1000 [− 14.75, 4.93]) comparing prevalent users of metformin to prevalent users of SU/ DPP4i. Similar observations were made for the outcome definition using the ML algorithm.Conclusion: The observed estimates in our study are consistent with a reduced risk of PASC among prevalent users of metformin, however the uncertainty of our confidence intervals warrants cautious interpretations of the results. A standardized clinical definition of PASC is warranted for thorough evaluation of the effectiveness of therapies under assessment for the prevention of PASC.Plain Language Summary: Previous research suggests that metformin, due to its anti-viral, anti-inflammatory, and anti-thrombotic properties may reduce the risk of severe COVID-19. Given the shared etiology of COVID-19 and the post-acute sequelae of SARS-CoV-2 (PASC), and the proposed inflammatory processes of PASC, metformin may also be a beneficial preventive option. We investigated the benefit of metformin for PASC prevention in a population of type 2 diabetes mellitus patients with a COVID-19 diagnosis who were on metformin or two other anti-hyperglycemic medications prior to infection with SARS-CoV-2. Our results were consistent with a reduction in the risk of PASC with the use of metformin, however, the imprecise confidence intervals obtained warrants further investigation of this association of the potential beneficial effect of metformin for preventing PASC in patients with medication-managed diabetes.Keywords: COVID-19, Long COVID, Type 2 diabetes Mellitus, Metformin

Chuan T Foo,1,2 Graham M Donovan,3 Francis Thien,1,2 David Langton,2,4 Peter B Noble5 1Department of Respiratory Medicine, Eastern Health, Melbourne, VIC, Australia; 2Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia; 3Department of Mathematics, University of Auckland, Auckland, New Zealand; 4Department of Thoracic Medicine, Peninsula Health, Frankston, VIC, Australia; 5School of Human Sciences, The University of Western Australia, Crawley, WA, AustraliaCorrespondence: Chuan T Foo, Department of Respiratory Medicine, Eastern Health, Melbourne, Victoria, Australia, Tel +613 9095 2414, Email chuan.foo@monash.eduPurpose: Bronchial thermoplasty (BT) is a bronchoscopic intervention for the treatment of severe asthma. Despite demonstrated symptomatic benefit, the underlying mechanisms by which this is achieved remain uncertain. We hypothesize that the effects of BT are driven by improvements in ventilation heterogeneity as assessed using functional respiratory imaging (FRI).Patient and Methods: Eighteen consecutive patients with severe asthma who underwent clinically indicated BT were recruited. Patients were assessed at baseline, 4-week after treatment of the left lung, and 12-month after treatment of the right lung. Data collected included short-acting beta-agonist (SABA) and oral prednisolone (OCS) use, asthma control questionnaire (ACQ-5) and exacerbation history. Patients also underwent lung function tests and chest computed tomography. Ventilation parameters including interquartile distance (IQD; measure of ventilation heterogeneity) were derived using FRI.Results: 12 months after BT, significant improvements were seen in SABA and OCS use, ACQ-5, and number of OCS-requiring exacerbations. Apart from pre-bronchodilator FEV1, no other significant changes were observed in lung function. Ventilation heterogeneity significantly improved after treatment of the left lung (0.18 ± 0.04 vs 0.20 ± 0.04, p=0.045), with treatment effect persisting up to 12 months later (0.18 ± 0.05 vs 0.20 ± 0.04, p=0.028). Ventilation heterogeneity also improved after treatment of the right lung, although this did not reach statistical significance (0.18 ± 0.05 vs 0.19 ± 0.04, p=0.06).Conclusion: Clinical benefits after BT are accompanied by improvements in ventilation heterogeneity, advancing our understanding of its mechanism of action. Beyond BT, FRI has the potential to be expanded into other clinical applications.Keywords: asthma, computed tomography, computational fluid dynamics, imaging, mechanism of action, pathophysiology

Robert B Bot,1,2 Razvan Chirla,1 Calin Tudor Hozan,1,2 Simona Cavalu1 1Faculty of Medicine and Pharmacy, University of Oradea, Oradea, 410087, Romania; 2Department of Orthopedics, Emergency County Clinical Hospital Oradea, Oradea, 410169, RomaniaCorrespondence: Simona Cavalu, Email scavalu@uoradea.roPurpose: The purpose of this study was to quantify the modifications occurring in osteoporosis at the level of the human proximal femur throughout the trabecular structure, along with the identification of certain anatomic regions preferentially affected by osteoporosis. Another goal was to map the evolution of the radiodensity of the trabecular bone as osteoporosis progresses to an advanced stage.Methods: The study included CT scans (right femur) from 51 patients, out of which 40 had various degrees of osteoporosis, but no other local pathology. Ten regions of interest in two orthogonal slices have been identified and the differences in radiodensity as well as their evolution have been statistically analyzed in terms of relative and absolute changes.Results: A detailed spatial map showing the evolution of osteoporosis was obtained. As osteoporosis evolved, the relative decrease in radiodensity was inversely correlated to the radiodensity of the healthy bone. In particular, the region covering the Ward triangle decreased the most, by an average 61– 62% in osteopenia and 101– 106% in advanced osteoporosis, while the principal compressive group was affected the least, showing a decrease by an average 14– 15% in osteopenia and 29– 32% in advanced osteoporosis. The absolute decrease in radiodensity was not correlated to the radiodensity of the healthy bone and was shifted to the inferior-posterior edge of the femur. Inside the femoral head, the upper region was affected the most in absolute terms, while the greater trochanter was less affected than the femoral neck. The maximum metaphyseal cortical bone density was unaffected by the progression of osteoporosis.Conclusion: Significant differences were noticed in terms of the absolute and relative osteoporotic changes in radiodensity related to different anatomical regions of the human femoral bone. These differences become more pronounced as the disease progresses.Keywords: osteoporosis, radiodensity, CT, femur

BackgroundThe polygenic nature of Alzheimer's disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual's genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Because of the complexity of genomic data, current statistical analyses cannot comprehensively capture the polygenic risk of AD, resulting in unsatisfactory disease risk prediction. However, deep learning methods, which capture nonlinearity within high-dimensional genomic data, may enable more accurate disease risk prediction and improve our understanding of AD etiology. Accordingly, we developed deep learning neural network models for modeling AD polygenic risk.MethodsWe constructed neural network models to model AD polygenic risk and compared them with the widely used weighted polygenic risk score and lasso models. We conducted robust linear regression analysis to investigate the relationship between the AD polygenic risk derived from deep learning methods and AD endophenotypes (i.e., plasma biomarkers and individual cognitive performance). We stratified individuals by applying unsupervised clustering to the outputs from the hidden layers of the neural network model.ResultsThe deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms.ConclusionOur results suggest that deep learning methods are effective for modeling the genetic risks of AD and other diseases, classifying disease risks, and uncovering disease mechanisms.