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Machine learning potentials (MLPs) have revolutionized the field of atomistic simulations by describing atomic interactions with the accuracy of electronic structure methods at a small fraction of the cost. Most current MLPs construct the energy of a system as a sum of atomic energies, which depend on information about the atomic environments provided in the form of predefined or learnable feature vectors. If, in addition, nonlocal phenomena like long-range charge transfer are important, fourth-generation MLPs need to be used, which include a charge equilibration (Qeq) step to take the global structure of the system into account. This Qeq can significantly increase the computational cost and thus can become a computational bottleneck for large systems. In this Article, we present a highly efficient formulation of Qeq that does not require the explicit computation of the Coulomb matrix elements, resulting in a quasi-linear scaling method. Moreover, our approach also allows for the efficient calculation of energy derivatives, which explicitly consider the global structure-dependence of the atomic charges as obtained from Qeq. Due to its generality, the method is not restricted to MLPs and can also be applied within a variety of other force fields.
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This case report describes a 67-year-old woman who had received adoptive immunotherapy with chimeric antigen receptor T cells for multiple myeloma and was experiencing parkinsonism-like symptoms.
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There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants.
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BACKGROUND: The role that preoperative Satisfaction with Breast plays in a patient's postoperative course after postmastectomy breast reconstruction (PMBR) is not understood. The aim of this study is to understand the impact of the preoperative score on postoperative outcome as an independent variable. METHODS: We examined patients who underwent PMBR between 2017 and 2021 and who completed the BREAST-Q Satisfaction with Breasts at 1 year postoperatively. Two multiple linear regression models (Model 1 with the preoperative Satisfaction with Breasts score and Model 2 without the preoperative score), likelihood ratio tests, simple t-statistics, and sample patient dataset to predict the 1 year score were performed. Multiple imputation was used to account for missing preoperative scores. RESULTS: Overall, 2324 patients were included. Model 1 showed that the preoperative score is significantly associated with the postoperative score (ß = 0.09, 95% confidence interval 0.04-0.14; p < 0.001). Comparing Model 1 and Model 2 demonstrated that including preoperative Satisfaction with Breasts in a regression significantly improves model fit (test statistic = 10.04; p = 0.0021). Using the absolute value of the t-statistics as a measure of variable importance in linear regression, the importance of the preoperative score was quantified as 3.39-more important than neoadjuvant radiation, mastectomy weight, body mass index, bilateral prophylactic mastectomy, and race, but less than adjuvant radiation, reconstruction type, and psychiatric diagnoses. CONCLUSION: Preoperative Satisfaction with Breasts scores are an important independent predictor of postoperative satisfaction after PMBR. Just as vital sign and work-up are carefully documented before surgery, preoperative scores should be collected to pre-emptively gauge patients' satisfaction and optimize postoperative outcomes.
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Background: Rates of direct-to-implant (DTI) breast reconstruction, in which breast implants are placed at the time of mastectomy, have been consistently rising. Advances in surgical adjuncts and technology, such as acellular dermal matrices (ADM), have made DTI reconstruction safer and more reliable. However, few studies have characterized early (30-day) postoperative complications following DTI. The aim of this study was to obtain a current understanding of early postoperative outcomes following DTI breast reconstruction. Methods: Using data from the American College of Surgeons-National Surgical Quality Improvement Program, we analyzed complications for female patients who underwent DTI reconstruction from 2017 to 2019, as well as trends in DTI reconstruction from data on mastectomy and DTI reconstruction from 2010 to 2019. We grouped complications into major surgical (including return to the operating room) or medical complications. Statistical analysis was performed using Fischer's exact test for categorical variables, Student's t-test for continuous variables, and logistic regression. Results: DTI breast reconstruction rates have increased since 2010. Among our 2017-2019 cohort of 4204 patients, the early major surgical complication rate was approximately 10% (422 patients) and the major medical complication rate was 0.83% (35 patients). Regression modeling identified body mass index, smoking status, hypertension, bleeding disorders, and intraoperative blood transfusion as having a relationship with surgical complications (P < .001). Conclusions: Despite increased use of ADM and indocyanine green angiography, compared to prior studies, early postoperative complications have remained stable. Further studies are needed to assess long-term complications and patient-reported outcomes in DTI breast reconstruction.
Historique: Le taux de reconstructions mammaires immédiates, c'est-à-dire que les implants mammaires sont installés au moment de la mastectomie, augmentent régulièrement. Grâce aux progrès des adjuvants chirurgicaux et de la technologie, tels que les matrices dermiques acellulaires (MDA), la reconstruction mammaire immédiate est désormais plus sécuritaire et plus fiable. Cependant, peu d'études ont caractérisé les complications précoces suivant une telle intervention (dans les 30 jours). La présente étude visait à comprendre les résultats postopératoires précoces actuels après une reconstruction mammaire immédiate. Méthodologie: À l'aide des données de l'American College of Surgeons-National Surgical Quality Improvement Program, les chercheurs ont analysé les complications qu'ont subies les femmes après une reconstruction mammaire immédiate entre 2017 et 2019, de même que les tendances de ce type de reconstruction à partir des données sur la mastectomie et la reconstruction mammaire immédiate entre 2010 et 2019. Ils ont divisé les complications entre les complications chirurgicales majeures (y compris le retour en salle opératoire) et les complications médicales. Ils ont effectué les analyses statistiques à l'aide de la méthode exacte de Fischer pour les variables nominales, du test de Student pour les variables continues et de la régression logistique. Résultats: Le taux de reconstructions mammaires directes a augmenté depuis 2010. Dans la cohorte de 4 204 patients de 2017 à 2019, le taux de complications chirurgicales majeures précoces s'élevait à environ 10% (422 patients) et le taux de complications médicales majeures, à 0,83% (35 patients). Selon la modélisation de régression, l'indice de masse corporelle, le tabagisme, l'hypertension, les troubles hémorragiques et la transfusion sanguine intraopératoire sont liés aux complications chirurgicales (P < 0001). Conclusions: Malgré le recours accru aux MDA et l'angiographie au vert d'indocyanine, par rapport aux études antérieures, les complications postopératoires précoces sont demeurées stables. D'autres études devront être réalisées pour évaluer les complications à long terme et les résultats cliniques déclarés par les patientes après une reconstruction mammaire immédiate.
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BACKGROUND: Up to 85% of breast cancer patients report sexual health concerns, but their concerns are not adequately addressed by providers. Sexual dysfunction among breast cancer patients remains understudied. We aimed to investigate the impact of breast-conserving therapy (BCT) and postmastectomy breast reconstruction (PMBR) on the sexual health of breast cancer patients and frequency of sexual medicine consultation in postoperative care. METHODS: We conducted a retrospective analysis of patients who underwent BCT or PMBR and completed the Sexual Well-being of the BREAST-Q BCT and Reconstruction modules from January 2010 to October 2022. We compared Sexual Well-being scores between BCT and PMBR patients overtime up to 5-years postoperatively, delineated associated demographic and clinical factors with Sexual Well-being, and evaluated the frequency of sexual medicine consultations. RESULTS: Of 15,857 patients, 8,510 (53.7%) underwent BCT and 7,347 (46.3%) underwent PMBR. PMBR patients had significantly lower Sexual Well-being scores than BCT patients from preoperative to 5-year postoperative. Regression analyses showed that PMBR patients scored 7.6 points lower at 1-year than BCT patients. Separated marital status, higher body mass index, cardiovascular disease, hyperlipidemia, psychiatric diagnosis, and neoadjuvant chemotherapy were associated with significantly lower Sexual Well-being. 299 (3.5%) of BCT and 400 (5.4%) of PMBR patients received sexual medicine consultations. CONCLUSION: Sexual health concerns must be considered in breast cancer care, particularly among patients who undergo PMBR. Although many patients experience sexual dysfunction, most do not receive a sexual medicine consultation, suggesting an opportunity for providers to improve breast cancer patients' sexual health.
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It is estimated that only 0.02% of disseminated tumour cells are able to seed overt metastases1. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unclear. Here, combining transposon technology2 and fluorescence niche labelling3, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. We identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal and pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism through which plexin B2 interacts with class IV semaphorins on tumour cells, leading to KLF4 upregulation and thereby promoting the acquisition of epithelial traits. Our results highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumour cells before the establishment of a growth-promoting niche. Our findings further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the plexin-B2-semaphorin axis abolishes metastatic colonization of the liver and therefore represents a therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumour-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.
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Sistemas CRISPR-Cas , Hepatocitos , Neoplasias Hepáticas , Hígado , Metástasis de la Neoplasia , Proteínas del Tejido Nervioso , Animales , Femenino , Humanos , Masculino , Ratones , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Sistemas CRISPR-Cas/genética , Modelos Animales de Enfermedad , Elementos Transponibles de ADN , Fluorescencia , Hepatocitos/metabolismo , Hepatocitos/citología , Hepatocitos/patología , Factor 4 Similar a Kruppel/metabolismo , Hígado/citología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/secundario , Melanoma/metabolismo , Melanoma/patología , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Semaforinas/antagonistas & inhibidores , Semaforinas/metabolismoRESUMEN
The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1-3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial-mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.
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Sistemas CRISPR-Cas , Carcinoma de Células Escamosas , Transformación Celular Neoplásica , Evolución Clonal , Células Clonales , Análisis de la Célula Individual , Factores de Necrosis Tumoral , Animales , Femenino , Humanos , Masculino , Ratones , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Evolución Clonal/genética , Células Clonales/citología , Células Clonales/metabolismo , Células Clonales/patología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Sistemas CRISPR-Cas/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Macrófagos/metabolismo , Mutación , Invasividad Neoplásica/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal/genética , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Factores de Necrosis Tumoral/genética , Factores de Necrosis Tumoral/metabolismo , Comunicación Autocrina , Análisis de SupervivenciaRESUMEN
Water and ice are routinely studied with X-rays to reveal their diverse structures and anomalous properties. We employ a hybrid collisional-radiative/molecular-dynamics method to explore how femtosecond X-ray pulses interact with hexagonal ice. We find that ice makes a phase transition into a crystalline plasma where its initial structure is maintained up to tens of femtoseconds. The ultrafast melting process occurs anisotropically, where different geometric configurations of the structure melt on different time scales. The transient state and anisotropic melting of crystals can be captured by X-ray diffraction, which impacts any study of crystalline structures probed by femtosecond X-ray lasers.
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BACKGROUND: Although studies have compared patient-reported outcomes (PROs) after breast conserving-therapy (BCT) and postmastectomy breast reconstruction (PMBR), they often have been confounded by treatment or other factors that complicate a direct comparison. This study aimed to compare PROs after BCT and PMBR by using propensity score-matching analysis. METHODS: Patients who underwent BCT or PMBR between 2010 and 2022 and completed the BREAST-Q were identified. Each BCT patient was matched to a PMBR patient using nearest-neighbor 1:1 matching with replacement for each BREAST-Q time point. Outcomes included all prospectively collected BREAST-Q domains preoperatively, at 6 months, and at 1, 2, and 3 years postoperatively. A 4-point difference was considered clinically meaningful. RESULTS: For this study, 6215 patients (2501 BCT [40.2%] and 3714 PMBR [59.8%] patients) were eligible, and 2616 unique patients were matched. Preoperatively, 463 BCT and 463 PMBR patients were matched for analysis (6 months [443 matched pairs], 1 year [639 matched pairs], 2 years [421 matched pairs], 3 years [254 matched pairs]). At 6 months postoperatively, the BCT patients scored higher on all BREAST-Q domains than the PMBR patients (p < 0.05; differences > 4 points). At 1, 2, and 3 years, the patients who underwent BCT consistently had superior Satisfaction With Breasts, Psychosocial Well-Being, and Sexual Well-Being (p < 0.05), and the differences were clinically meaningful. CONCLUSION: In this statistically powered study, the BCT patients reported higher quality of life than the PMBR patients in early assessment and also through 3 years of follow-up evaluation. Given the equivalency in survival and recurrence outcomes between BCT and PMBR, patients eligible for either surgery should be counseled regarding the superiority of BCT in terms of PROs.
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BACKGROUND: First-line treatment in patients with acute myeloid leukemia (AML) unfit for intensive therapy is the combination of a hypomethylating agent (HMA) with venetoclax (VEN). However, retrospective data confirming the benefits of this regimen outside of clinical trials have shown conflicting results. METHODS: We performed a multicenter retrospective analysis of outcomes with first-line HMA-VEN versus HMA in AML patients unfit for intensive chemotherapy. RESULTS: A total of 213 patients were included from three German hospitals (125 HMA-VEN, 88 HMA). Median overall survival in the HMA-VEN cohort was 7.9 months (95% confidence interval [CI], 5.1-14.7) versus 4.9 months (3.1-7.1) with HMA. After 1 year, 42% (95% CI, 33-54) and 19% (12-30) of patients were alive, respectively (hazard ratio [HR] for death, 0.64; 95% CI, 0.46-0.88). After adjusting for clinical and molecular baseline characteristics, treatment with HMA-VEN remained significantly associated with both prolonged survival (HR, 0.48; 95% CI, 0.29-0.77) and time to next treatment (HR, 0.63; 95% CI, 0.47-0.85). Patients who achieved recovery of peripheral blood counts had a favorable prognosis (HR for death, 0.52; 95% CI, 0.33-0.84). DISCUSSION: These data align with findings from the pivotal VIALE-A trial and support the use of HMA-VEN in patients unfit for intensive therapy.
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INTRODUCTION: Maxillary reconstruction is a complex undertaking characterized by a 3-dimensional surgical site with deficiencies in multiple tissue types. Prior to virtual surgical planning(VSP), bony reconstruction was inaccurate and inefficient, thus reconstructions defaulted to soft tissue flaps or obturators. The current study describes an efficient and accurate approach to bony maxillary reconstruction with immediate dental implant placement(IDIP). METHODS: A reconstructive workflow was developed for osseous reconstruction to improve functional and aesthetic outcomes. Critical aspects include VSP, 3-D printed plates and IDIP. Review of a prospectively maintained database identified patients who underwent osseous maxillary reconstruction with a fibula flap and immediate dental implants from 2017-2022, with a focus on oncologic characteristics and reconstructive outcomes. RESULTS: During the study, 20 patients underwent maxillary reconstruction with VSP and IDIP. One dental implant out of 55 failed to osseointegrate and no flaps were lost. Three patients suffered partial loss of the fibula skin island; one required palatal closure with a radial forearm flap, and two were managed with outpatient debridement. Fifteen patients achieved either an interim or final retained dental prosthesis. All prostheses achieved acceptable aesthetic results without the instability associated with non-bone borne devices(e.g.dentures/obturators). No patients experienced delays in oncologic treatment. CONCLUSIONS: VSP technology has enabled surgeons to replace like with like to achieve better outcomes with acceptable morbidity for maxillary defects. IDIP provides all patients an opportunity for a fixed prosthesis even though not all complete the process. This maxillary reconstruction workflow can be safely accomplished in oncologic patients with promising and effective early results.
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The underlying pathogenesis of neurological sequelae in post-COVID-19 patients remains unclear. Here, we used multidimensional spatial immune phenotyping and machine learning methods on brains from initial COVID-19 survivors to identify the biological correlate associated with previous SARS-CoV-2 challenge. Compared to healthy controls, individuals with post-COVID-19 revealed a high percentage of TMEM119+P2RY12+CD68+Iba1+HLA-DR+CD11c+SCAMP2+ microglia assembled in prototypical cellular nodules. In contrast to acute SARS-CoV-2 cases, the frequency of CD8+ parenchymal T cells was reduced, suggesting an immune shift toward innate immune activation that may contribute to neurological alterations in post-COVID-19 patients.
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Encéfalo , COVID-19 , Inmunidad Innata , Humanos , COVID-19/inmunología , Inmunidad Innata/inmunología , Encéfalo/inmunología , Encéfalo/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Microglía/inmunología , Microglía/patología , Adulto , Linfocitos T CD8-positivos/inmunología , SARS-CoV-2/inmunología , Cicatriz/inmunología , Cicatriz/patología , Aprendizaje AutomáticoRESUMEN
PURPOSE: CT perfusion (CTP) is a valuable tool in suspected acute ischemic stroke. A substantial variability of the delay between contrast injection and bolus arrival in the brain is conceivable. We investigated the distribution of the peak positions of the concentration time curves measured in an artery (arterial input function, AIF) and - in cases with ischemia - also measured in the penumbra. METHODS: We report on 2624 perfusion scans (52 % female, mean age 72.2 ± 14.4 years) with stroke present in 1636 cases. From the attenuation time curves of the AIF and the penumbra, we calculated the respective bolus peak positions and investigated the distribution of the peak positions. Further, we analyzed the bolus peak positions for associations with age. RESULTS: The bolus peaked significantly later in older patients, both in the AIF and in the penumbra (all p < 0.001). In the whole cohort, we found a significant association of age with the bolus peak position of the AIF (ρ = 0.334; p < 0.001). In patients with stroke, age was also associated to the peak position of the AIF (ρ = 0.305; p < 0.001), and the penumbra (ρ = 0.246, p < 0.001). However, a substantial range of peak positions of the AIF and penumbra was noted across all age ranges. CONCLUSIONS: This study revealed a strong age-dependency of the contrast bolus arrival in both healthy and ischemic tissue. This variability makes non-uniform sampling schemes, which have been suggested to reduce radiation dose, problematic, as they might not always optimally capture the bolus in all cases.