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Traumatic brain injury (TBI) is common and costly. Although neuroimaging modalities such as resting-state functional MRI (rsfMRI) promise to differentiate injured from healthy brains and prognosticate long-term outcomes, the field suffers from heterogeneous findings. To assess whether this heterogeneity stems from variability in the TBI populations studied or the imaging methods used, and to determine whether a consensus exists in this literature, we performed the first systematic review of studies comparing rsfMRI functional connectivity (FC) in patients with TBI to matched controls for seven canonical brain networks across injury severity, age, chronicity, population type, and various imaging methods. Searching PubMed, Web of Science, Google Scholar, and ScienceDirect, 1,105 manuscripts were identified, 50 fulfilling our criteria. Across these manuscripts, 179 comparisons were reported between a total of 1,397 patients with TBI and 1,179 matched controls. Collapsing across injury characteristics, imaging methods, and networks, there were roughly equal significant to null findings and increased to decreased connectivity differences reported. Whereas most factors did not explain these mixed findings, stratifying across severity and chronicity, separately, showed a trend of increased connectivity at higher severities and greater chronicities of TBI. Among methodological factors, studies were more likely to find connectivity differences when scans were longer than 360 s, custom image processing pipelines were used, and when patients kept their eyes open versus closed during scans. We offer guidelines to address this variability, focusing on aspects of study design and rsfMRI acquisition to move the field toward reproducible results with greater potential for clinical translation.

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a mature, peripheral T-cell neoplasm caused by HTLV-1 and its lifetime risk is estimated as 4-7% among HTLV-1 carriers. Acute and lymphoma subtypes are highly aggressive diseases, characterized by shorter survival rates and a high risk of central nervous system involvement (iCNS) compared to other peripheral T-cell lymphomas. Currently, the treatment of ATLL remains a challenging. Our recent study on PTCL epidemiology and outcomes in Latin America (Thais et al. 2023 ASH Meeting) highlighted ATLL (18%) as the second most frequent subtype of PTCL, likely influenced by our distinct viral epidemiology. Objective: It is to assess the prevalence, clinical features, risk factors, and outcomes of iCNS in ATLL in Latin America. Methodology: Patients (pts) aged ≥18 years with newly diagnosed ATLL from GELL (n = 208, 2000-2023, retrospective) and TCBP (n = 83, 2015-2022, ambispective). Overall survival (OS) and progression free survival (PFS) were our endpoints. REDcap Platform (by Vanderbilt) was used to collect and store data, whereas for statistical analysis IBM-SPSS v.24. This trial is registered at Clinical trials (NCT03207789). Results: It was enrolled 291 pts, the prevalence of iCNS in ATLL was 7.9% (23/291), considering only aggressive forms (acute 40% and 60% lymphomatous). Pts'characteristics were similar between those without and with iCNS. There was a high frequency of advanced stage (90% vs 82%); ECOG ≥ 2 (45% vs 43%); B symptoms (74% vs 56%); elevated LDH (84% vs 78%); and IPI ≥3 (82% vs 65%) in the iCNS group. Treatment was heterogeneous including: IFN+AZT (74%) for acute subtypes, and CHOP (52%), CHOEP (26%) and EPOCH (2%), for lymphoma subtypes. Less than 30% of both groups achieved complete response at end of first treatment. Two clinical features were identified as possibly associated to iCNS: median age at diagnosis (55 [20-95] vs 44 [23-65]; p < 0.0001) and extra nodal involvement ≥ 2 (32% vs 65%, p = 0.005). The entire cohort of ATLL had 60- month OS and PFS of 16% [95% CI: 12-20%] and 9% [95% CI: 5-13%]; with median time of OS and PFS of 7 months (6-9) and 5 months (4-6). iCNS did not have an impact on survival outcomes (60 months OS 14% iCNS (n = 23) vs 16% no iCNS (n = 254), p = 0.91; PFS 12% vs 9% no iCNS, p = 0.61;) despite being a devastating complication. Outcomes in pts with lymphoma subtypes were slightly better than acute (60 months OS 19% vs 10%, p < 0.0001; PFS 12% vs 5%, p < 0.0001, respectively). Conclusion: Unlike other lymphoma subtypes, iCNS in ATLL does not appear to significantly impact outcomes. This paradoxical finding underscores the complexity of ATLL and may reflect the limitations of existing treatment options and the absence of standardized therapeutic protocols for this aggressive malignancy. The lack of significant survival difference, despite the severity of iCNS, points to an urgent need for innovative therapies and more effective treatment strategies. Our analysis identified median age at diagnosis and extranodal involvement as potential risk factors for iCNS, suggesting avenues for future prospective studies to further elucidate their role in disease progression. Given the high prevalence of ATLL in Latin America, there is a unique opportunity to advance our understanding of this disease through region-specific research. Collaborative efforts in this region could pave the way for breakthroughs in the management of ATLL and potentially offer insights applicable on a global scale.

Introduction: PTCL accounts for 10-15% of all NHL. As previously demonstrated, Latin America has its own epidemiological distribution, with a high frequency of ATLL and ENKT, likely influenced by distinct genetic profiles and viral epidemiology. 3-year OS is about 40%. Treatment advances have also been limited, except for BV-CHP in some countries. The IPI, which includes extranodal (EN) site as a variable, has been validated for PTCL. However, the specific impact of EN involvement on nodal PTCL (such as PTCL-NOS, AIT, ALCL ALK+/ALK-) and its biological implications remain unclear. Simplification could improve the reproducibility and applicability of these models, especially in low-income countries. Objective: To evaluate number of EN sites in nodal PTCL lymphomas as a risk factors or surrogate for outcomes, as OS and PFS in Latin America cohort. Methodology: Patients (pts) aged ≥18 years with newly diagnosed nodal PTCL-NOS, AITL and ALCL ALK+/ALK-) from GELL (n = 339, 2000-2023, retrospective), TCBP (n = 427, 2015-2022, ambispective). Treatment outcome was determined by OS and PFS. REDcap Platform (by Vanderbilt) was used to collect and store data, whereas statistical analysis the IBM-SPSS v.24. This trial is registered at Clinical trials (NCT03207789). Results: 766 pts [427pts - TCBP and 339 - GELL] diagnosed with nodal PTCL were grouped according to the number of EN: no EN involvement (No EN - 383); one EN involvement (EN1 -168); and 32 (EN2 - 215). Considering all, 61% male; median age 56 y/o; 74% were staged III/IV; 69% IPI 32; 60% was PTCL-NOS, 19% ALCL ALK- and 12% AITL. 61% had B symptoms and 55% elevated LDH. CHOEP was used in 47% and 34% CHOP, and 47% achieved CR after first line; 16% used transplant as consolidation. No EN, EN1 and EN2 were similar regarding clinical characteristics, except, for stage III/IV (58% vs. 79% vs 96%; p < .0001); IPI 32 (58% vs. 59% vs. 99%; p < .0001); ECOG>1 (58% vs. 92% vs. 99%; p < .0001); BMO involvement (16% vs. 24% vs. 63%%; p

Introdução: Os linfomas cutâneos de células T (LCCT), como micose fungóide (MF) e síndrome de Sézary (SS), são subtipos raros de linfoma não-Hodgkin que afetam a qualidade de vida e têm resultados ruins, particularmente em estágios avançados, onde as taxas de sobrevida podem ser inferiores a 5 anos. O diagnóstico e manejo de LCCT é desafiador, visto que, requer uma abordagem multidisciplinar e os tratamentos são limitados. Os fatores prognósticos incluem idade avançada, estágio avançado e transformação de células grandes. Poucos tratamentos demonstraram melhorar a sobrevida livre de progressão (SLP) em casos avançado, e o papel do transplante alogênico (AloTMO) permanece incerto. O estudo CUTALLO, o único estudo prospectivo e randomizado neste campo, demonstrou um benefício na SLP e na qualidade de vida, mas não mostrou vantagens na sobrevida global (SG). Objetivo: Avaliar as características clínico-epidemiológicas e os resultados de pacientes com MF/SS em estágio avançado submetidos a AloTMO em um único centro no Brasil. Metodologia: Foram incluídos pacientes com idade ≥18 anos diagnosticados com MF/SS submetidos a AloTMO de nossa instituição. As informações clínicas incluíram paciente codificado, sexo, idade, data do diagnóstico, locais da doença, estágio TNM, número de linhas de terapia e sua resposta. As características e resultados do aloTMO também foram descritos. O resultado do tratamento foi determinado por SG e SLP. A plataforma REDcap (da Vanderbilt) foi utilizada para coletar e armazenar dados e para análise descritiva foi aplicado o IBM-SPSS versão 24. O método de Kaplan-Meier estimou o EO, enquanto o Log-Rank teste para comparar suas curvas. Resultados: Um total de 5 pacientes com MF/SS forma avançada foram submetidos ao AloTMO. A coorte foi composta por 3 mulheres e 2 homens, com idade média de 49 anos (variando de 26 a 55 anos). 80% dos pacientes (4/5) receberam duas ou mais linhas de terapia antes do AloTMO. Seus tratamentos incluíram terapias de baixa a intermediária intensidade, como interferon, metotrexato, brentuximabe ou radioterapia total skin. Apenas 2 pacientes foram tratados com poliquimioterapia, os quais também foram os que não receberam acompanhamento multidisciplinar. Apenas 1 dos 5 pacientes está vivo no momento desta análise, 4 anos após o transplante, e esse paciente não apresenta evidência de doença. A sobrevida global mediana nesta coorte foi de 16 meses (variando de 1 mês a 4 anos). Discussão: O AloTMO faz parte dos algoritmos de tratamento para MF/SS, particularmente para pacientes jovens com fatores prognósticos desfavoráveis. No entanto, dados e experiências do mundo real mostram que, apesar das melhorias na SLP a maioria dos pacientes ainda não atingem remissão prolongada ou mesmo cura. Nesta coorte foi demonstrado que apenas 20% dos pacientes (1/5) mantêm remissão completa em 4 anos de seguimento após o AloTMO. Apesar de uma coorte pequena, os resultados se assemelham a dados já publicados. A subclassificação de MF/SS com base no perfil molecular pode ajudar na seleção de melhores candidatos. Conclusão: Os resultados do estudo em consonância com a experiência mundial mantêm o questionamento do AloTMO na MF/SS: nunca indicar ou nunca é tarde demais? Há uma escassez de dados de vida real sobre a eficácia do tratamento com AloTMO em MF/SS.

Introdução: O Sarcoma Histiocítico Verdadeiro (SHV) é uma neoplasia rara derivada de histiócitos, caracterizada por apresentação agressiva e respostas insatisfatórias a quimioterápicos clássicos. De acordo com a Organização Mundial da Saúde, o SHV é definido como proliferação com características morfológicas e imunofenotípicas de histiócitos maduros. A mediana de idade no diagnóstico é de 63 anos, com uma distribuição semelhante entre homens e mulheres, com sobrevida média de 6 meses. O envolvimento nodal e extranodal, como tratos gastrointestinal, pulmonar e nasal, é comum. O diagnóstico é desafiador devido à semelhança com outras neoplasias, como linfomas, carcinomas indiferenciados, melanomas, sarcomas e tumores de células dendríticas. Dada a baixa representatividade de doenças raras e com desfechos desfavoráveis, este trabalho tem como objetivo relatar o caso de um paciente com SHV. Caso clínico: Paciente masculino de 24 anos apresentou dispneia, tosse e sudorese noturna em janeiro de 2024. Exames revelaram uma massa pulmonar de 16 × 12 × 17 cm, Hb 10,1 g/dL, leucócitos 12.560/mm3, plaquetas 643.000/mm3 e DHL 299 U/L. O estadiamento foi realizado com tomografias, PET-CT e biópsias. Após 10 dias de internação, apresentou desconforto respiratório, parada cardiorrespiratória e necessidade de intubação orotraqueal. Devido à deterioração clínica, foi iniciado dexametasona 40 mg e radioterapia (RDT) enquanto aguardava-se o resultado anatomopatológico. Após 15 dias, o diagnóstico de SHV foi confirmado. No 16° dia de internação, iniciou-se o tratamento com CHOP (Ciclofosfamida, Doxorrubicina, Vincristina e Prednisona), resultando em melhora clínica e hemodinâmica após o 1° ciclo, com extubação 12 dias após e significativa redução da massa pulmonar. Apesar da melhora inicial, evoluiu com neutropenia febril e nova intubação. O 2° ciclo de CHOP foi administrado após 28 dias, e apesar de haver a proposta do uso de Pembrolizumab, houve dificuldade no acesso. O paciente veio a óbito por piora respiratória e infecciosa após 48 dias de internação. Discussão: A evolução agressiva e desfavorável do paciente ressalta as dificuldades no diagnóstico e tratamento do SHV. A literatura é escassa, sem consenso sobre tratamento padrão e com acesso limitado a drogas alvo. Embora o paciente seja mais jovem que a mediana da literatura, há descrição em indivíduos jovens, e a sobrevida de 3 meses foi consistente com dados já existentes. A imunohistoquímica é crucial para o diagnóstico, com os marcadores principais CD163, CD68, lisozima e CD4, sendo o CD163 o mais sensível e restrito para o SHV. A pesquisa de mutações (PDL-1, BRAF, RAS/MAPK e MEK) podem orientar o uso de terapias alvo. O tratamento com CHOP, utilizado neste caso, é recomendado para doença multifocal, enquanto a ressecção cirúrgica e RDT são indicadas para doenças localizadas. Uma coorte de 330 pacientes com SHV mostrou que a cirurgia para doença localizada combinada à RDT melhora a sobrevida e a remissão. Estudos de terapias alvo, como inibidores de BRAF (Vemurafenib, Dabrafenib) e PD-L1 (Nivolumab, Pembrolizumab), surgem uma nova estratégia terapêutica. Conclusão: O SHV é uma doença rara, subnotificada, com altas taxas de mortalidade e poucos dados na literatura. Mais estudos são necessários para aumentar o conhecimento sobre essa doença, otimizar o diagnóstico precoce e definir o melhor tratamento.

Introdução: As doenças linfoproliferativas B (LPB) resultam de mutações durante a maturação dos linfócitos B. A coexistência de leucemia linfocítica crônica (LLC)/linfoma de pequenos linfócitos (LPL) com outras LPB é a associação mais comum dessas doenças. Este trabalho tem como objetivo relatar 2 casos de doenças biclonais, sendo Macroglobulinemia de Waldenstrom (MW)/Linfoma Linfoplasmocítico-IgM (LLP) e Linfoma de Células do Manto (LCM) concomitantes a LLC/LPL. Relato de caso: Paciente 1: 63 anos, masculino, apresentou em exame de rotina pico monoclonal (PM) de 3.7 g/dL em eletroforese de proteínas, IgM 5641 mg/dL e ao hemograma Hb 10.5 mg/dL e linfócitos 2930/mm3. A biópsia de medula óssea (BMO) revelou infiltração medular de 25% por LLP e 20% por LLC/LPL. Em tomografias evidenciadas linfonodomegalias, sendo feitas biópsias, com resultado de infiltração por LLC/LPL. Manteve-se sob observação clínica até março de 2024 quando apresentou sangramento conjuntival associado a IgM de 5850 mg/dL. Na análise genética apresentou IgH e MYD88 mutados, e del17p e mutação do TP53 negativos. Realizada plasmaférese com melhora do quadro agudo e indicado tratamento com Acalabrutinib, inibidor da tirosina quinase de Bruton (iBTK), pela ação nos dois clones. Com 2 meses de tratamento, houve melhora da anemia (Hb 13.7 mg/dL), redução de IgM em 31% (5725 > 3896 mg/dL) e do PM em 45% (3.71 g/dL > 2 g/dL) e redução de 64% dos linfonodos. Paciente 2: 62 anos, feminina, notou nódulo cervical em março de 2021, que foi biopsiado com resultado de LCM. Apresentava ao hemograma Hb 13.9 g/dL e linfócitos 2480/mm3 e a BMO com infiltração de 20% por LLC/LPL. Na análise genética apresentou IgH mutado e ausência de deleção do 17p. Ficou em seguimento até maio de 2024, quando evoluiu com disfagia e edema facial por compressão tumoral, sendo optado por Acalabrutinib e Obinutuzumab pela ação nos dois clones. Atualmente em uso do iBTK, em resposta, e aguardando autorização do convênio para Obinutuzumab. Discussão: Doenças biclonais concomitantes a LLC/LPL são raras, com poucos relatos na literatura. Sugere-se que a alteração do microambiente celular pela LLC/LPL seja o fator de risco para predisposição a outras LPB. Diante da suspeita de biclonalidade, é necessário individualizar o quadro clínico para melhor escolha terapêutica. Para o diagnóstico preciso recomenda-se análise laboratorial, histológica, imunofenotípica (IFT) e genética. A IFT é o melhor método para diferenciação, tanto na medula óssea quanto em sangue periférico. A pesquisa de mutação do MYD88 é útil para diferenciar a LLC de MW, visto que é rara em outras LPB, assim como as mutações do IgH são raras em MW e LCM e comuns na LLC. Já o LCM é caracterizado pela translocação (11;14) e SOX11 positivos, sendo bastante específicos no diagnóstico. Não há um tratamento padrão no cenário de duas doenças concomitantes. Relatos de casos disponíveis na literatura utilizaram iBTK devido ação para ambos os clones. Acredita-se que assim é possível evitar uma mudança no microambiente tumoral, seleção do clone mais agressivo e sua respectiva piora clínica. Conclusão: A identificação do clone preponderante versus o incidental é importante no contexto de doenças clonais concomitantes para se individualizar o tratamento visando controle do clone principal e otimizar desfechos clínicos.

Background: The hippocampal formation represents a key region in the pathophysiology of schizophrenia. Aerobic exercise poses a promising add-on treatment to potentially counteract structural impairments of the hippocampal formation and associated symptomatic burden. However, current evidence regarding exercise effects on the hippocampal formation in schizophrenia is largely heterogeneous. Therefore, we conducted a systematic review and meta-analysis to assess the impact of aerobic exercise on total hippocampal formation volume. Additionally, we used data from a recent multicenter randomized-controlled trial to examine the effects of aerobic exercise on hippocampal formation subfield volumes and their respective clinical implications., Methods: The meta-analysis comprised six studies that investigated the influence of aerobic exercise on total hippocampal formation volume compared to a control condition with a total of 186 people with schizophrenia (100 male, 86 female), while original data from 29 patients (20 male, 9 female) was considered to explore effects of six months of aerobic exercise on hippocampal formation subfield volumes., Results: Our meta-analysis did not demonstrate a significant effect of aerobic exercise on total hippocampal formation volume in people with schizophrenia ( g = 0.33 [-0.12 to 0.77]), p = 0.15), but our original data suggested significant volume increases in certain hippocampal subfields, namely the cornu ammonis and dentate gyrus., Conclusions: Driven by the necessity of better understanding the pathophysiology of schizophrenia, the present work underlines the importance to focus on hippocampal formation subfields and to characterize subgroups of patients that show neuroplastic responses to aerobic exercise accompanied by corresponding clinical improvements.

Context: Androgen excess (AE)-related symptoms can vary widely and may appear across the life course., Objective: We assessed the prevalence of signs of potential AE and heterogeneity by demographic/health characteristics., Methods: We used data of 24 435 participants who consented and enrolled during November 2019 to December 2022 in a US digital cohort to evaluate the prevalence and heterogeneity of self-reported signs of potential AE: possible hirsutism (having thick coarse hair on ≥4 of 8 body locations), hair level on the chin, hair loss on top of the head, and moderate to severe acne., Results: The prevalence of possible hirsutism, having several/a lot of hair on the chin, significantly reduced hair/visible scalp on top of the head, and moderate to severe acne were 6.9%, 12.6%, 1.7%, and 31.8%, respectively. While possible hirsutism and moderate to severe acne decreased with age (range: 18-86 years), hair on the chin and hair loss on the head increased with age. Participants who self-identified as Hispanic or South Asian reported a higher prevalence of possible hirsutism (11.2%, 16.9%, vs 6.3% among non-Hispanic White participants). Participants with higher body mass index had a higher prevalence of possible hirsutism. Moderate to severe acne was more common among those with polycystic ovary syndrome. Possible hirsutism and hair loss were less common among participants using hormones for contraception., Conclusion: In this large cohort, signs of potential AE varied by demographic and health factors. These results could provide a new understanding of how potential AE may appear differently in diverse groups, informing future work to develop more inclusive evaluation at a population level., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The red/green cyanobacteriochrome (CBCR) slr1393g3 exhibits a quantum yield of only 8 % for its forward photoconversion, significantly lower than other species from the same CBCR subfamily. The cause for this reduced photoconversion is not yet clear, although in the related NpR6012g4 dark-state structural heterogeneity of a paramount Trp residue has been proposed to cause the formation of nonproductive subpopulation. However, there is no such information on the equivalent residue in slr1393g3, W496. Here we use solid-state NMR to explore all possible sidechain rotamers of this Trp residue and their local interactions at the atomic level. The indole nitrogen (Nϵ1) is used as an NMR probe, achieved by site-specific 15 N-indole labeling of a quadruply Trp-deleted variant and trehalose vitrification technique. The data reveal a set of seven indole rotamers of W496 with four distinct environments for the Nϵ1-H group. Only a minority population of 20 % is found to retain the π-stacking and hydrogen-bonding interactions with the chromophore in the dark state that has been assigned to account for complete forward photoconversion. Our results demonstrate the direct role of W496 in modulating the forward quantum yield of slr1393g3 via rearrangement of its sidechain rotameric conformations., (© 2024 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Background: Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case-control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general., Methods: In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into "active" and "insufficiently active" to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination., Results: Compared to "insufficiently active" patients, "active" individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be "active" at baseline revealed significantly fewer AEs compared to "insufficiently" active patients. In detail, both severe and non-severe AEs occurred less frequently in the "active" patients group. In line with that, QoL and fatigue were better in physical "active" patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels., Conclusions: Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients' QoL and fatigue., Trial Registration: EUPAS9462. Registered 30th October 2012 "retrospectively registered.", (© 2024. The Author(s).)

Preliminary studies on a radioactive antibody against the neural cell adhesion molecule (NCAM) demonstrated a significant accumulation of [ 131 I]I-ERIC1 in neuroblastoma tumor cells in mice. This study aims to validate the therapeutic efficacy and potential adverse effects of these radioactive immunoconjugates (RICs) in neuroblastoma-bearing mice. To determine the highest tolerated dose, healthy SCID mice received 1 to 22 MBq of [ 131 I]I-ERIC1, with the survival time measured. Tumor response was evaluated by administering 0.8 to 22 MBq of [ 131 I]I-ERIC1 to neuroblastoma-bearing mice and assessing tumor size and systemic toxicity through body weight, blood counts, and survival. It was observed that doses up to approximately 3 MBq per animal (150 MBq/kg) were well tolerated, whereas higher doses resulted in systemic toxicity and death. The neuroblastomas exhibited a dose-dependent response, with optimal therapeutic efficacy achieved at 1.8-2.5 MBq per animal (90-125 MBq/kg), significantly extending survival by a factor of five. The antibody ERIC1 is a promising vehicle for the transport of beta emitters into NCAM-positive tumor tissue. An optimal dosage of the [ 131 I]I-ERIC1 antibody can be established with a balance of tumor-static effects and adverse effects, resulting in a marked extension of survival time.

This study evaluates the efficacy of [ 131 I]I-ERIC1 in targeting and inhibiting the growth of SCLC tumors in mice, focusing on tumor accumulation and regression and potential side effects. NCAM-positive NCI-H69 SCLC cells were implanted in CB 17 SCID mice, and [ 131 I]I-ERIC1 biokinetics were measured in organs and tissues at four post-injection time points (24, 72, 96, and 120 h). The experimental series compared tumor growth, survival, and changes in blood counts among three treatment groups (1, 2, or 3 MBq) and a control group, with treatments initiated either two or five days post implantation. [ 131 I]I-ERIC1 was synthesized with >95% radiochemical purity and a specific activity of 15 TBq/mmol. Tumor activity peaked at 31.5 ± 6.6% ID/g after four days, demonstrating significant antitumor efficacy, which resulted in sustained remission and extended survival. Hematological toxicity was observed, with the optimal dose identified as 2 MBq per animal administered two days post implantation. [ 131 I]I-ERIC1 shows promise as a theranostic agent for personalized cancer treatment by effectively targeting SCLC tumors with manageable side effects. However, further studies are required to optimize dosing strategies and minimize toxicity., Competing Interests: The authors declare no conflict of interest.

Context: The COVID-19 pandemic has highlighted how the European Union (EU) impacts national health systems and people's health. In November 2020, the European Commission launched the European Health Union (EHU) to better coordinate and maximize EU member states' abilities to deal with cross-border health threats. This article scrutinizes the early institutionalization of the EHU and its implications for EU health policy as a political determinant of health (PDoH)., Methods: The article explores how EU health policy may be appreciated from a PDoH perspective. It draws from EU documents and existing research to analyze the early-stage institutionalization of the EHU. The study complements this policy output-focused perspective with an outcome-based exploratory assessment of EU health policy as a PDoH focusing on three examples: joint vaccine procurement, health reforms and investments under the Recovery and Resilience Facility, and the development of a European Health Data Space., Findings: The article shows that the policy change triggered by the EHU and the potential impact on citizens' health are not necessarily congruent. Modest change can have a potentially strong impact on health outcomes and vice versa., Conclusions: The article argues that the PDoH perspective provides a useful approach that is complementary to policy output-based perspectives, allowing for a more comprehensive assessment of the EU's role in health., (Copyright © 2024 by Duke University Press.)

Fluorescence quenchers for application in DNA - like the BHQ family - tend to be large molecules which need to be attached, often post-synthetically, via long linkers. In this study, we present two new iminothioindoxyl- C -nucleosidic quenchers which are very compact, feature a native backbone and can be introduced into DNA via regular solid-phase synthesis. Especially with d T as juxtaposed nucleobase, they have a defined location and orientation in a DNA duplex with minimal perturbation of the structure and hence interaction capabilities. Depending on the nature of the fluorophore, they can be used for orientation-(un)specific FRET studies. Their Förster radius is smaller than the one of BHQ-2. This makes these quenchers ideal for sophisticated studies using conditional quenching in the range between 470 and 670 nm in DNA., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The Cajal body, a nuclear condensate, is crucial for ribonucleoprotein assembly, including small nuclear RNPs (snRNPs). While Coilin has been identified as an integral component of Cajal bodies, its exact function remains unclear. Moreover, no Coilin ortholog has been found in unicellular organisms to date. This study unveils Mug174 (Meiosis-upregulated gene 174) as the Coilin ortholog in the fission yeast Schizosaccharomyces pombe. Mug174 forms phase-separated condensates in vitro and is often associated with the nucleolus and the cleavage body in vivo. The generation of Mug174 foci relies on the trimethylguanosine (TMG) synthase Tgs1. Moreover, Mug174 interacts with Tgs1 and U snRNAs. Deletion of the mug174+ gene in S. pombe causes diverse pleiotropic phenotypes, encompassing defects in vegetative growth, meiosis, pre-mRNA splicing, TMG capping of U snRNAs, and chromosome segregation. In addition, we identified weak homology between Mug174 and human Coilin. Notably, human Coilin expressed in fission yeast colocalizes with Mug174. Critically, Mug174 is indispensable for the maintenance of and transition from cellular quiescence. These findings highlight the Coilin ortholog in fission yeast and suggest that the Cajal body is implicated in cellular quiescence, thereby preventing human diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Hexagonal boron nitride ( h BN), with its atomically flat structure, excellent chemical stability, and large band gap energy (∼6 eV), serves as an exemplary 2D insulator in electronics. Additionally, it offers exceptional attributes for the growth and encapsulation of semiconductor transition metal dichalcogenides (TMDCs). Current methodologies for producing h BN thin films primarily involve exfoliating multi-layer or bulk crystals and thin film growth via chemical vapor deposition (CVD), which entails the thermal decomposition and surface reaction of molecular precursors like ammonia boranes (NH 3 BH 3 ) and borazine (B 3 N 3 H 6 ). These molecular precursors contain pre-existing B-N bonds, thus promoting the nucleation of BN. However, the quality and phase purity of resulting BN films are greatly influenced by the film preparation and deposition process conditions that remain a substantial concern. This study aims to comprehensively investigate the impact of varied CVD systems, parameters, and precursor chemistry on the synthesis of high-quality, large scale h BN on both catalytic and non-catalytic substrates. The comparative analysis provided new insights into most effective approaches concerning both quality and scalability of vapor phase grown h BN films.

Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys. Using this model, we identify a dysregulated blood chemokine signature during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. Hyperglycemia also correlates with liver glycogen levels, but there is no evidence of substantial long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the African green monkey model exhibits important similarities to humans and can be utilized to assess therapeutic candidates to combat COVID-related metabolic defects., (© 2024. The Author(s).)

We isolated six Thermus thermophilus strains from Shirahama Hot Spring in Japan. Complete genome sequences, determined by combining Oxford Nanopore long-read and Illumina short-read sequence data, revealed that they showed >99.9% average nucleotide identities with each other and approximately 97% to the genome of the type strain HB8 T ., Competing Interests: The authors declare no conflict of interest

The ketogenic diet is used worldwide to treat various diseases, especially drug-resistant epilepsies. Medium-chain triglycerides or medium-chain fatty acids, primarily the major ketogenic compound caprylic acid (C8; C8:0), can significantly support ketogenesis. This review examines the effects of concurrent carbohydrate intake on C8-induced ketogenesis. A systematic literature search (PubMed and Web of Science) with subsequent data extraction was performed according to PRISMA guidelines and the Cochrane Handbook. Studies investigating the metabolic response to C8-containing MCT interventions with carbohydrate intake were included. The studies did not include a ketogenic diet. Three intervention groups were created. The quality of the studies was assessed using the RoB II tool, and the meta-analysis was performed using the Cochrane RevMan software. A total of 7 trials, including 4 RCTs, met the inclusion criteria. Ketone production was lower when C8 was combined with carbohydrates compared to MCT intake alone. The lower C8 dose group (11 g) did not show a significantly lower ketogenic effect than the higher dose group (19 g). Forest plot analysis showed heterogeneous data. The data suggest a non-linear relationship between C8, carbohydrate intake and ketone production. Further studies are needed to investigate the influence of different carbohydrates on C8-induced ketogenesis. Limitations include heterogeneous intervention conditions, such as different types of dispersions, caffeine intake, limited number of studies and variability in study design.

Objectives: The purpose of this meta-analysis was to determine the diagnostic performance of conventional MRI and MR arthrography for tendinosis, and partial and complete tears of the long head of the biceps tendon (LHBT) using arthroscopy as the reference standard., Materials and Methods: A systematic review was performed using predefined data fields in PubMed, and all articles published from January 2000 up to April 2022 were retrospectively pooled and reviewed. Six MRI studies on complete tear (n = 555) and ten studies on partial tear/tendinosis (n = 2487) were included in the analysis. Two of the included studies in each group investigated the use of MR arthrography. The data sets were analyzed using a univariate approach with the DerSimonian and Laird random effects model and the proportional hazards model., Results: MRI shows high specificities in diagnosing complete tears of the LHBT ranging from 93.0 to 99.0%. Diagnostic sensitivity was more heterogeneous ranging from 55.9 to 90.0%. The overall negative likelihood ratio was 0.29 (95% CI: 0.17-0.50) and the overall positive likelihood ratio was 37.3 (95% CI: 11.9-117.4). The mean sensitivity in diagnosing partial tear/tendinosis of the LHBT was 67.8% (95% CI: 54.3-78.9%) and the specificity was 75.9% (95% CI: 63.6-85.0%), resulting in a balanced accuracy of 71.9%. The overall negative likelihood ratio was 0.44 (95% CI: 0.32-0.59) and the overall positive likelihood ratio was 2.64 (95% CI: 1.91-3.65)., Conclusion: MRI is highly specific for the diagnosis of complete tears of the LHBT, whereas diagnostic sensitivity was more heterogeneous. The diagnosis of partial tears and/or tendinosis of the LHBT remains challenging on MRI, which may warrant complementary clinical examination or other imaging modalities to increase diagnostic confidence in equivocal cases., Clinical Relevance Statement: Conventional MRI and MR arthrography have high diagnostic performance for complete tendon tear when compared to arthroscopy. The diagnosis of tendinosis/partial tears remains challenging and may require comparison with clinical tests and other imaging modalities., Key Points: •There is no clear consensus regarding the primary imaging modality for the evaluation of LHBT disorders. •Conventional MRI and MR arthrography are highly specific in diagnosing complete tears of the LHBT. •Diagnosis of partial tears/tendinosis of the LHBT on conventional MRI and MR arthrography remains a diagnostic challenge., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

The anti-tumor capacity of natural killer (NK) cells heavily relies on their ability to migrate towards their target cells. This process is based on dynamic actinrearrangement, so-called actin treadmilling, andis tightly regulated by proteins such as cofilin-1. The aim of the present study was to identify the role of cofilin-1 (CFL-1) in the migratory behavior of NK cells and to investigate a possible impact of an obesity-associated micromilieu on these cells, as it is known that obesity correlates with various impaired NK cell functions. CFL-1 was knocked-down via transfection of NK-92 cells with respective siRNAs. Obesity associated micromilieu was mimicked by incubation of NK-92 cells with adipocyte-conditioned medium from human preadipocyte SGBS cells or leptin. Effects on CFL-1 levels, the degree of phosphorylation to the inactive pCFL-1 as well as NK-92 cell motility were analyzed. Surprisingly, siRNA-mediated CFL-1 knockdown led to a significant increase of migration, as determined by enhanced velocity and accumulated distance of migration. No effect on CFL-1 nor pCFL-1 expression levels, proportion of phosphorylation and cell migratory behavior could be demonstrated under the influence of an obesity-associated microenvironment. In conclusion, the results indicate a significant effect of a CFL-1 knockdown on NK cell motility.

BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients., (© 2024 UICC.)

Purpose: Ultrasound (US) is the primary imaging modality when a testicular tumor is suspected. Superb microvascular imaging (SMI) is a novel, highly sensitive Doppler technique that allows quantification of flow signals by determination of the Vascular Index (VI). The aim of the present study is to investigate the diagnostic significance of the SMI-derived VI in normal testicular tissue and testicular cancer., Methods: This retrospective analysis included patients who underwent testicular US in our department from 2018 to 2022. Inclusion criteria were: i) sufficient image quality of the stored images, ii) US with standardized SMI-default setting (colour gain of 44 ± 5), iii) patient age ≥ 18 years, and iv) normal testicular findings or testicular tumor with histopathological workup. US examinations were performed as part of clinical routine using a high-end ultrasound system (Aplio i800/i900, Canon Medical Systems Corporation, Tochigi, Japan). Statistical analysis included Chi-square test and Mann-Whitney U tests and receiver operating characteristic (ROC) curve analysis., Results: A total of 62 patients (31 each with normal findings and testicular tumors) were included. The VI differed statistically significantly (p < 0.001) between normal testis (median 2.5 %) and testicular tumors (median 17.4 %). Like vascular patterns (p < 0.001), the VI (p = 0.030) was shown to distinguish seminomas (median 14.8 %), non-seminomas (median 17.6 %) and lymphomas (median 34.5 %)., Conclusions: In conclusion, our study has shown the VI to be a quantitative tool that can add information for differentiating testicular tumor entities. While further confirmation in larger study populations is desirable, our results suggest that the VI may be a useful quantitative parameter., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Human epidermal growth factor receptor 2 (HER)-positive breast cancer (BC) is characterized by an aggressive clinical course. In the case of HER2 overexpression/amplification, patients benefit from HER2-targeting therapies. Standardized diagnostic HER2 assessment includes immunohistochemistry (IHC) and/or in situ hybridization (ISH). The aim of this study was to compare this "gold standard" with the Droplet Digital™ polymerase chain reaction (ddPCR), a method that allows sensitive and precise detection of copy number variations (CNV) in FFPE (formalin-fixed, paraffin-embedded) DNA samples. Partitioning of the PCR reaction into 20,000 droplets enables a precise quantitative "CN" discrimination also in heterogeneous samples. FFPE breast cancer samples (n = 170) with routinely assessed HER2 status by IHC/ISH were retrospectively analyzed using the ddPCR CNV ERBB2 assay. Comparison of HER2 status assessment by the two methods revealed concordant results in 92.9% (158/170) of the cases. Discrepant cases were verified and interpreted. For ddPCR, a cut off value of 3 HER2 copies was set to distinguish between HER2-negative and HER2-positive BC. Results obtained with the ddPCR CNV ERBB2 assay were consistent and reproducible, and serial dilutions demonstrated a high stability and sensitivity of the method. The ddPCR CNV ERBB2 assay may be a specific and convenient tool to quantify HER2 copy numbers in BC samples. In our study, this method showed high reproducibility in accuracy of HER2 assessment compared to IHC/ISH analysis., (© 2023. The Author(s).)

Background: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils., Methods: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1β. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied., Results: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals., Conclusions: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease., (© 2024. The Author(s).)

Mucocutaneous leishmaniasis is a severe infectious disease, predominantly endemic in Central and South America and is characterized by granulomatous, destructive mucosal lesions in the oral, nasal, and pharyngeal cavities. It is caused by protozoa of the genus Leishmania spp. transmitted to humans by sandflies. Mucocutaneous leishmaniasis occurs after untreated or inadequately treated cutaneous leishmaniasis and is more common in immunocompromised patients. The aim of this systematic review is to summarize all reported treatment options for mucocutaneous leishmaniasis. This review is based on all English, German, French, Spanish and Portuguese articles published in the databases "PubMed" and "Lilacs" from 1995 to 2020. Most of the medical literature is limited to case reports, small case series, retrospective studies, and a few randomized controlled trials. Various treatment options include pentavalent antimonates such as meglumine antimonate or sodium stibogluconate, amphotericin B (liposomal, deoxycholate, lipid complex, colloidal dispersion), miltefosine, and pentamidine. Other therapeutic options include itraconazole, fluconazole, ketoconazole, aminosidine sulfate, and azithromycin. The choice of drug depends primarily on its availability in the endemic area and the patient's comorbidities., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Ultrasound (US) is often the first method used to look for brain or cerebrospinal fluid (CSF) space pathologies. Knowledge of normal CSF width values is essential. Most of the available US normative values were established over 20 years ago, were obtained with older equipment, and cover only part of the age spectrum that can be examined by cranial US. This prospective study aimed to determine the normative values of the widths of the subarachnoid and internal CSF spaces (craniocortical, minimal and maximal interhemispheric, interventricular, and frontal horn) for high-resolution linear US probes in neurologically healthy infants and children aged 0-19 months and assess whether subdural fluid collections can be delineated., Methods: Two radiologists measured the width of the CSF spaces with a conventional linear probe and an ultralight hockey-stick probe in neurologically healthy children not referred for cranial or spinal US., Results: This study included 359 neurologically healthy children (n boys  = 178, 49.6%; n girls  = 181, 50.4%) with a median age of 46.0 days and a range of 1-599 days. We constructed prediction plots, including the 5th, 50th, and 95th percentiles, and an interactive spreadsheet to calculate normative values for individual patients. The measurements of the two probes and the left and right sides did not differ, eliminating the need for separate normative values. No subdural fluid collection was detected., Conclusion: Normative values for the widths of the subarachnoid space and the internal CSF spaces are useful for evaluating intracranial pathology, especially when determining whether an increase in the subarachnoid space width is abnormal., (© 2024. The Author(s).)

Introduction: This study aimed to determine whether implant surgery procedures can be implemented in the dental curriculum by designing novel courses for students. Additionally, this study assesses the perception of these courses and how they can be established in the future., Materials and Methods: Students from the third to fifth years participated in a programme consisting of 4 modules according to their academic year. The modules taught theoretical and practical content as well as clinical references. After participating, the students completed two questionnaires with research questions (RQ1 = evaluation of the relevance and effects; RQ2 = impact of modules 3 and 4) to evaluate the programme. The questionnaires consisted of 52 statements, each rated on a 6-point scale (1 'totally disagree' to 6 'totally agree'). Cronbach's alpha analysis was used, and median values, interquartile ranges and Pearson correlations (p-value) were statistically calculated., Results: In total, 94 students completed the questionnaires. Cronbach's alpha exceeded 0.7 for all constructs except for one (skills training). The highest evaluated median was 6, and the lowest was 4.75. Pearson correlations were significant (<0.05) for perceived importance/lectures, perceived importance/tutor performance, lectures/skills training, skills training/tutor performance and tutor performance/lectures. Seventeen analysed free comments expressed strong interest in implantology courses for the curriculum. 88% of the students wished for more practical exercises in dental implantology during the curriculum or suggested expanding the programme in the future., Conclusion: The programme was highly accepted among dental students. The students wished for more practice in the future to perform supervised procedures on patients., (© 2023 The Authors. European Journal of Dental Education published by John Wiley & Sons Ltd.)

Importance: Early menarche is associated with adverse health outcomes. Trends toward earlier menarche have been observed in the US, but data remain limited on differences by sociodemographic factors and body mass index (BMI). Time from menarche to cycle regularity is another understudied early-life characteristic with health implications., Objectives: To evaluate the temporal trends and disparities in menarche and time to regularity and explore early-life BMI as a mediator., Design, Setting, and Participants: This ongoing cohort study enrolled participants from an ongoing mobile application-based US cohort from November 14, 2019, to March 20, 2023., Exposures: Birth year (categorized as 1950-1969, 1970-1979, 1980-1989, 1990-1999, and 2000-2005)., Main Outcomes and Measures: Main outcomes were age at menarche and time to regularity, which were self-recalled at enrollment. In addition, early (aged <11 years), very early (aged <9 years), and late (aged ≥16 years) age at menarche was assessed., Results: Among the 71 341 female individuals who were analyzed (mean [SD] age at menarche, 12.2 [1.6] years; 2228 [3.1%] Asian, 3665 [5.1%] non-Hispanic Black, 4918 [6.9%] Hispanic, 49 518 [69.4%] non-Hispanic White, and 8461 [11.9%] other or multiple races or ethnicities), 5223 were born in 1950 to 1969, 12 226 in 1970 to 1979, 22 086 in 1980 to 1989, 23 894 in 1990 to 1999, and 7912 in 2000 to 2005. The mean (SD) age at menarche decreased from 12.5 (1.6) years in 1950 to 1969 to 11.9 (1.5) years in 2000 to 2005. The number of individuals experiencing early menarche increased from 449 (8.6%) to 1223 (15.5%), the number of individuals experiencing very early menarche increased from 31 (0.6%) to 110 (1.4%), and the number of individuals experiencing late menarche decreased from 286 (5.5%) to 137 (1.7%). For 61 932 participants with reported time to regularity, the number reaching regularity within 2 years decreased from 3463 (76.3%) to 4075 (56.0%), and the number not yet in regular cycles increased from 153 (3.4%) to 1375 (18.9%). The magnitude of the trend toward earlier menarche was greater among participants who self-identified as Asian, non-Hispanic Black, or other or multiple races (vs non-Hispanic White) (P = .003 for interaction) and among participants self-rated with low (vs high) socioeconomic status (P < .001 for interaction). Within a subset of 9865 participants with data on BMI at menarche, exploratory mediation analysis estimated that 46% (95% CI, 35%-61%) of the temporal trend in age at menarche was explained by BMI., Conclusions and Relevance: In this cohort study of 71 341 individuals in the US, as birth year increased, mean age at menarche decreased and time to regularity increased. The trends were stronger among racial and ethnic minority groups and individuals of low self-rated socioeconomic status. These trends may contribute to the increase in adverse health outcomes and disparities in the US.

Introduction and Objectives: Our aim was to assess the impact of prosthetic pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF) on changes in biventricular volumes and function and on adverse cardiac events., Methods: Adults with rTOF were identified from the SACHER-registry. Data from serial cardiac magnetic resonance imaging, echocardiography, exercise capacity and n-terminal pro b-type natriuretic peptide (NT-proBNP) were collected. The primary endpoint was right ventricular ejection fraction (RVEF) as measured by cardiac magnetic resonance. Secondary endpoints were biventricular volumes, left ventricular ejection fraction, exercise capacity and NT-proBNP levels, and time to adverse cardiac outcomes (atrial and ventricular arrhythmia, endocarditis). Associations between previous PVR and longitudinal changes in functional outcomes and time to adverse cardiac outcomes were analyzed using linear mixed-effects models and Cox proportional hazards models, respectively., Results: A total of 308 patients (153 with and 155 without PVR) with 887 study visits were analyzed. Previous PVR was not significantly associated with changes in RVEF (CE, -1.33; 95%CI, -5.87 to 3.21; P=.566). Previous PVR was associated with lower right ventricular end-diastolic volume but had no significant effect on left ventricular ejection fraction, exercise capacity, or NT-proBNP-levels. Previous PVR was associated with an increased hazard of atrial arrhythmias (HR, 2.09; 95%CI, 1.17-3.72; P=.012) and infective endocarditis (HR, 12.72; 95%CI, 4.69-34.49; P<.0001) but not with an increased hazard of sustained ventricular arrhythmias (HR, 0.64; 95%CI, 0.18-2.27; P=.490)., Conclusions: Previous PVR was not significantly associated with changes in RVEF but was associated with an increased risk of atrial arrhythmias and infective endocarditis., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Importance: Polycystic ovary syndrome (PCOS), characterized by irregular menstrual cycles and hyperandrogenism, is a common ovulatory disorder. Having an irregular cycle is a potential marker for cardiometabolic conditions, but data are limited on whether the associations differ by PCOS status or potential interventions., Objective: To evaluate the association of PCOS, time to regularity since menarche (adolescence), and irregular cycles (adulthood) with cardiometabolic conditions., Design, Setting, and Participants: This cross-sectional study used a large, US-based digital cohort of users of the Apple Research application on their iPhone. Eligibility criteria were having ever menstruated, living in the US, being at age of consent of at least 18 years (or 19 years in Alabama and Nebraska or 21 years in Puerto Rico), and being able to communicate in English. Participants were enrolled between November 14, 2019, and December 13, 2022, and completed relevant surveys., Exposures: Self-reported PCOS diagnosis, prolonged time to regularity (not spontaneously establishing regularity within 5 years of menarche), and irregular cycles., Main Outcomes and Measures: The primary outcome was self-reported cardiometabolic conditions, including obesity, prediabetes, type 1 and 2 diabetes, high cholesterol, hypertension, metabolic syndrome, arrhythmia, congestive heart failure, coronary artery disease, heart attack, heart valve disease, stroke, transient ischemic attack (TIA), deep vein thrombosis, and pulmonary embolism measured using descriptive statistics and logistic regression to estimate prevalence odds ratios (PORs) and 95% CIs. Effect modification by lifestyle factors was also estimated., Results: The study sample (N = 60 789) had a mean (SD) age of 34.5 (11.1) years, with 12.3% having PCOS and 26.3% having prolonged time to regularity. Among a subset of 25 399 participants who completed the hormonal symptoms survey, 25.6% reported irregular cycles. In covariate-adjusted logistic regression models, PCOS was associated with a higher prevalence of all metabolic and several cardiovascular conditions, eg, arrhythmia (POR, 1.37; 95% CI, 1.20-1.55), coronary artery disease (POR, 2.92; 95% CI, 1.95-4.29), heart attack (POR, 1.79; 95% CI, 1.23-2.54), and stroke (POR, 1.66; 95% CI, 1.21-2.24). Among participants without PCOS, prolonged time to regularity was associated with type 2 diabetes (POR, 1.24; 95% CI, 1.05-1.46), hypertension (POR, 1.09; 95% CI, 1.01-1.19), arrhythmia (POR, 1.20; 95% CI, 1.06-1.35), and TIA (POR, 1.33; 95% CI, 1.01-1.73), and having irregular cycles was associated with type 2 diabetes (POR, 1.36; 95% CI, 1.08-1.69), high cholesterol (POR, 1.17; 95% CI, 1.05-1.30), arrhythmia (POR, 1.21; 95% CI, 1.02-1.43), and TIA (POR, 1.56; 95% CI, 1.06-2.26). Some of these associations were modified by high vs low body mass index or low vs high physical activity., Conclusions and Relevance: These findings suggest that PCOS and irregular cycles may be independent markers for cardiometabolic conditions. Early screening and intervention among individuals with irregular menstrual cycles may be beneficial.

Background and Hypothesis: Reduced social cognition has been reported in individuals who have committed interpersonal violence. It is unclear if individuals with schizophrenia and a history of violence have larger impairments than violent individuals without psychosis and non-violent individuals with schizophrenia. We examined social cognition in two groups with violent offenses, comparing their performance to non-violent individuals with schizophrenia and healthy controls., Study Design: Two social cognitive domains were assessed in four groups: men with a schizophrenia spectrum disorder with (SSD-V, n = 27) or without (SSD-NV, n = 42) a history of violence, incarcerated men serving preventive detention sentences (V, n = 22), and healthy male controls (HC, n = 76). Theory of mind (ToM) was measured with the Movie for the Assessment of Social Cognition (MASC), body emotion perception with Emotion in Biological Motion (EmoBio) test., Study Results: Kruskal-Wallis H-tests revealed overall group differences for social cognition. SSD-V had a global and clinically significant social cognitive impairment. V had a specific impairment, for ToM. Binary logistic regressions predicting violence category membership from social cognition and psychosis (SSD status) were conducted. The model with best fit, explaining 18%-25% of the variance, had ToM as the only predictor., Conclusions: Social cognitive impairment was present in individuals with a history of violence, with larger and more widespread impairment seen in schizophrenia. ToM predicted violence category membership, psychosis did not. The results suggest a role for social cognition in understanding interpersonal violence., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

The DSL-6A/C1 murine pancreatic ductal adenocarcinoma (PDAC) tumor model was established in Lewis rats and characterized through a comprehensive multiparametric analysis to compare it to other preclinical tumor models and explore potential diagnostic and therapeutical targets. DSL-6A/C1 tumors were histologically analyzed to elucidate PDAC features. The tumor microenvironment was studied for immune cell prevalence. Multiparametric MRI and PET imaging were utilized to characterize tumors, and 68 Ga-FAPI-46-targeting cancer-associated fibroblasts (CAFs), were used to validate the histological findings. The histology confirmed typical PDAC characteristics, such as malformed pancreatic ductal malignant cells and CAFs. Distinct immune landscapes were identified, revealing an increased presence of CD8 + T cells and a decreased CD4 + T cell fraction within the tumor microenvironment. PET imaging with 68 Ga-FAPI tracers exhibited strong tracer uptake in tumor tissues. The MRI parameters indicated increasing intralesional necrosis over time and elevated contrast media uptake in vital tumor areas. We have demonstrated that the DSL-6A/C1 tumor model, particularly due to its high tumorigenicity, tumor size, and 68 Ga-FAPI-46 sensitivity, is a suitable alternative to established small animal models for many forms of preclinical analyses and therapeutic studies of PDAC.

Pathomechanisms of dementias involve increasing damage to neuronal energy metabolism, resulting in degeneration-related insulin resistance and glucose hypometabolism. In this case, ketone bodies can provide an alternative energy source. Supplementation with medium-chain triglycerides (MCTs), which can induce ketogenesis, may alleviate brain energy deficits and improve neuronal function. This review aims to determine the effectiveness of MCT as a symptomatic treatment approach. The systematic literature search was conducted in April 2023 following the Cochrane Handbook and PRISMA guidelines. A total of 21 studies were included, comprising eight uncontrolled trials and 13 RCTs investigating the effects of MCT on Alzheimer's disease (AD) and mild cognitive impairment (MCI). A substantial increase in plasma ketone levels and brain metabolic rates was observed. Cognitive assessments showed only occasional or domain-specific performance improvements. The effects on functional abilities or psychological outcomes have been inadequately studied. Besides gastrointestinal side effects, no harmful effects were observed. However, the evidence was severely weakened by heterogeneous and poorly designed study protocols, bias, and conflicts of interest. In conclusion, the ketogenic properties of MCTs may have beneficial effects on brain metabolism in AD and MCI but do not always result in measurable clinical improvement. Current evidence is insufficient to recommend MCT as a comparable symptomatic treatment option., Competing Interests: Only three trials (14%) had no apparent conflicts of interest with manufacturers of the intervention products (see Table 4). Very often, there was not only an involvement of paid staff and financial support but also the involvement of the companies in data collection and analysis of the results (high risk). In addition, some authors had various conflicts of interest due to company affiliations and financial benefits. In a few cases, information on patent rights was available at the time of publication, e.g., for the use of MCT oils in neurological diseases.The authors declare that they have no conflicts of interest., (Copyright © 2024 Nike Meer and Tobias Fischer.)

Background: Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC)., Methods: 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as "minor" (adaption of radiation field) or "major" (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue., Results: Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields ("minor change") in 5/32 patients (16%) and changed treatment regimen ("major change") in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p < 0.001)) with similar results for nuclear medical FTVs. IHC revealed heterogenous FAP-expression in all specimens (mean H-score: 36.3 (SD 24.6)) without correlation between FAP expression in IHC and FAPI tracer uptake in PET/CT., Conclusion: We report first data on the use of PET with FAPI-46 for patients with EC, who are scheduled to receive RT. Tumor uptake was high and not depending on FAP expression in TME. Further, FAPI-46/dual-tracer PET had relevant impact on management in this setting. Our data calls for prospective evaluation of FAPI-46/dual-tracer PET to improve clinical outcomes of EC., (© 2024. The Author(s).)

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches., Competing Interests: SL, VV, GM, VB, SG, GP, MI, FF, GM, JM, PC, GP, MH, DM, MB, TF, LP, FS No competing interests declared, (© 2023, Latini, Venafra et al.)

Syncope is a sudden loss of consciousness (transient loss of consciousness, TLOC) caused by a lack of cerebral perfusion that resolves spontaneously and completely after a short period of time 1. With a lifetime prevalence of 40% and constituting about 1% of all emergency department admissions, syncope is a common and medically relevant problem 2 3. The underlying causes of syncope are diverse and associated with significantly different prognoses. A structured approach is essential to identify high-risk patients and ensure appropriate treatment. This article aims at providing an overview of the current recommendations for the diagnosis and treatment of syncope., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen TF erhält aktuell Forschungsförderungen durch die Deutsche Forschungsgemeinschaft (DFG, FI2079/1-1) und die Deutsche Stiftung für Herzforschung (DSHF, F/62/21). TF: Referentenhonorare Deutsche Gesellschaft für Kardiologie (DGK), Biotronik und Boehringer Ingelheim, (Thieme. All rights reserved.)

Introduction: The diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) and, despite all the progress in this field, central nervous system infiltration (CNSi) still occurs at an incidence of 2-10%. The objective of the present study was to evaluate the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice regarding the reproducibility in a heterogeneous cohort apart from a clinical trial., Methods: Primary DLBCL patients were eligible for this study, between January 2007 and January 2017. All patients were treated with rituximab-based chemotherapy, mostly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The CNSi was diagnosed by liquor (positive cytology and/or immunophenotype), computerized tomography, magnetic resonance image and/or fluorodeoxy-glucose-positron emission tomography, requested only in symptomatic patients when the CNSi was clinically suspected. The CNS-IPI was assessed by graphical comparison and calibration., Results: After applying the inclusion/exclusion criteria, 322 patients were available for the analysis. The median follow-up was 60 months and the median age was 58 years. Seven patients experienced CNSi, characterizing an incidence of 2.17% (7/322). Comparing groups of patients with and without CNSi, we observed that the lactate dehydrogenase (LDH), number of extranodal sites, IPI, kidney/adrenal and absence of complete response were statistically different. The CNS-IPI model stratified patients in a three-risk group model as low-, intermediate- and high-risk. In our cohort, using the same stratification, we obtained an equivalent the 2-year rate of CNS relapse of 0.0%, 0.8% and 13.8%, respectively., Conclusion: Our study reinforces the reproducibility of the CNS-IPI, specifically apart from clinical trials, and suggests the CNS-IPI score as a tool to guide therapy., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Immunocompromised patients are at an increased risk of severe legionella infections. We present the results of an outbreak investigation initiated following a fatal case of hospital-acquired legionellosis linked to contaminated water from a toilet-flushing cistern. Additionally, we provide experimental data on the growth of Legionella spp. in flushing cisterns and propose a straightforward protocol for prevention., Methods: We monitored the growth of Legionella spp. in the building's hot- and cold-water systems using quantitative bacterial culture on selective agar. Molecular typing of Legionella pneumophila isolates from the infected patient and the water system was conducted through core-genome multi-locus sequence typing (cgMLST)., Results: Legionella contamination in the hospital building's cold-water system was significantly higher than in the hot-water system and significantly higher in toilet flushing cistern's water compared with cold water from bathroom sinks and showers. Isolates from the patient and from the flushing cistern of the patient's bathroom were identical by cgMLST. In an experimental setting, daily toilet flushing for a period of 21 days resulted in a 67% reduction in the growth of Legionella spp. in the water of toilet flushing cisterns. Moreover, a one-time disinfection of cisterns with peracetic acid, followed by daily flushing, decreased legionella growth to less than 1% over a period of at least seven weeks in these setting., Conclusions: One-time disinfection of highly contaminated cisterns with peracetic acid and daily toilet flushing as short-term measure can significantly reduce legionella contamination in flushing cisterns. These measures may aid in preventing legionella infection among immunocompromised patients., (Copyright © 2024 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Protophormia terraenovae is a colonizer of decomposing bodies and is known to cause pre-mortem myiasis as the female flies lay eggs in uncleaned wounds. In this study the effects of different concentrations of antibiotics levofloxacin and ceftriaxone on maggot development, weight, length, and mortality were examined. The maggot length and weight were significantly increased by therapeutical doses of levofloxacin and ceftriaxone. The maggot development time was significantly decreased in every levofloxacin treatment compared to the control. The time to start pupation was significantly increased in the control compared to the antibiotic treatments. Levofloxacin significantly increased the survivability of the maggots. Every levofloxacin treatment significantly improved the rearing conditions for the maggots. Reaching the third instar was delayed by 24 h in the control compared to the Levo 3.57 treatment. The Pupation in the control was delayed by an average of 48 h compared to the Levo 3.57 treatment. The significantly reduced development time of the maggots in the antibiotic treatments might lead to an overestimation of the post-mortem interval and therefore an incorrect time of death determination. The improved rearing conditions may be an indication of the potential of a combined application of antibiotics and maggot therapy., (© 2024. The Author(s).)