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We present new experimental measurements of resonance strengths in the astrophysical 23Al(p,γ)24Si reaction, constraining the pathway of nucleosynthesis beyond 22Mg in X-ray burster scenarios. Specifically, we have performed the first measurement of the (d,p) reaction using a radioactive beam of 23Ne to explore levels in 24Ne, the mirror analog of 24Si. Four strong single-particle states were observed and corresponding neutron spectroscopic factors were extracted with a precision of ∼20%. Using these spectroscopic factors, together with mirror state identifications, we have reduced uncertainties in the strength of the key ℓ = 0 resonance at Er = 157 keV, in the astrophysical 23Al(p,γ) reaction, by a factor of 4. Our results show that the 22Mg(p,γ)23Al(p,γ) pathway dominates over the competing 22Mg(α,p) reaction in all but the most energetic X-ray burster events (T>0.85 GK), significantly affecting energy production and the preservation of hydrogen fuel.

At the Weizmann Institute of Science, a new high-power-laser laboratory has been established that is dedicated to the fundamental aspects of laser–matter interaction in the relativistic regime and aimed at developing compact laser-plasma accelerators for delivering high-brightness beams of electrons, ions, and x rays. The HIGGINS laser system delivers two independent 100 TW beams and an additional probe beam, and this paper describes its commissioning and presents the very first results for particle and radiation beam delivery.

Abstract Introduction There is conflicting evidence whether high‐density lipoprotein cholesterol (HDL‐C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL‐C. We aimed to assess AD risk by genetically predicted HDL‐C. Methods Ten single nucleotide polymorphisms within the CETP locus predicting HDL‐C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR‐Egger. Results Based on 10 single nucleotide polymorphisms distinctly predicting HDL‐C in the CETP locus, we found that HDL‐C was not associated with risk of AD (P > .7). Discussion Our study does not support the role of HDL‐C on risk of AD through HDL‐C altered by CETP. This study does not rule out other mechanisms by which HDL‐C affects risk of AD.

Multiple sensors are used in a variety of geolocation systems. Many use Time Difference of Arrival (TDOA) or Received Signal Strength (RSS) measurements to estimate the most likely location of a signal. When an object does not emit an RF signal, Angle of Arrival (AOA) measurements using optical or infrared frequencies become more feasible than TDOA or RSS measurements. AOA measurements can be created from any sensor platform with any sort of optical sensor, location and attitude knowledge to track passive objects. Previous work has created a non-linear optimization (NLO) method for calculating the most likely estimate from AOA measurements. Two new modifications to the NLO algorithm are created and shown to correct AOA measurement errors by estimating the inherent bias and time-drift in the Inertial Measurement Unit (IMU) of the AOA sensing platform. One method corrects the sensor bias in post processing while treating the NLO method as a module. The other method directly corrects the sensor bias within the NLO algorithm by incorporating the bias parameters as a state vector in the estimation process. These two methods are analyzed using various Monte-Carlo simulations to check the general performance of the two modifications in comparison to the original NLO algorithm.

We measured circulating endothelial precursor cells (EPCs), activated circulating endothelial cells (aCECs), and mature circulating endothelial cells (mCECs) using four-color multiparametric flow cytometry in the peripheral blood of 84 chronic myeloid leukemia (CML) patients and 65 healthy controls; and vascular endothelial growth factor (VEGF) by quantitative real-time PCR in 50 CML patients and 32 healthy controls. Because of an increase in mCECs, the median percentage of CECs in CML blast crisis (0.0146%) was significantly higher than in healthy subjects (0.0059%, P0.05). In addition, VEGF gene expression was significantly higher in all phases of CML: 0.245 in blast crisis, 0.320 in the active phase, and 0.330 in chronic phase patients than it was in healthy subjects (0.145). In conclusion, CML in blast crisis had increased levels of CECs and VEGF gene expression, which may serve as markers of disease progression and may become targets for the management of CML.

Background: The public health relevance of daily Air Quality Index (AQI) activity guidelines for the general adult public in the United States to prevent atherosclerotic cardiovascular disease (ASCVD) events is questionable. Objectives: The purpose of the study was to explore the utility of a policy tailoring activity guidance to calculated ASCVD risk rather than uniform recommendations to the general adult public as currently provided. Methods: We calculated the number needed to treat (NNT) to prevent one ASCVD event per day by following activity recommendations across 10-year ASCVD risk scores (1% to 20%). Second, we modeled the benefits of tailoring recommendations to ASCVD risk. Results: The NNT decreased as ASCVD risk and/or AQI levels increased. At AQIs up to 151 (68% of days with AQIs above moderate in the United States), the NNTs remained untenably high (>2.7-55.3 million) across ASCVD risk. Under unhealthy conditions (AQIs 151-200), 28% of elevated AQIs, NNTs

Introduction: FL has heterogeneous biological behavior, variable clinical outcomes, and a natural history marked by histological transformation (HT). The management of FL and its outcomes are highly dependent on staging (CS) and tumor burden (TB). The identification of new molecular biomarkers is crucial, not only to understand FL's biology, but also, can guide better prognostic stratification, and determine new therapeutic targets. This study aims to outline the GEP in tissue samples from FL categorized by CS and TB using a large-scale gene microarray platform with subsequent expansion by RT-qPCR. Methods: This study involved 219 FL cases. FL patients were categorized into early-stage disease (I/II) (ES), advanced-stage (AS) (III/IV) with low tumor burden (LTB), and AS with high tumor burden (HTB) according to GELF criteria. The experimental phase involved 126 FFPE samples. Firstly, 42 samples (12 ES, 11 AS-LTV, 12 AS-HTV, 6 control lymph nodes and 1 control HELA) were submitted to the array using the Clariom D Array Human platform. The identification of differentially expressed genes (DEGs) between the 4 groups used the Transcriptome Analysis Console by the eBay ANOVA method. Bidimensional PCA sought to identify discriminatory DEGs clusters. A comparison between pairs was subsequently performed. The 7 most discriminatory DEGs were selected for a cohort expansion by RT-qPCR. Results: According to CS and TB, 14.6% of FL cases were categorized as ES, 17.8% as AS-LTB, and 67.6% as AS-HTB. With a median follow-up of 80.7 months, the median OS was 208.2, 130.5, and 126.3 months for ES, AS-LTB, and AS-HTB,p = 0.249. The median PFS was 113.3, 110.7, and 59.5 months, for the same groups, p = 0.018. The array identified 135,750 genes comparisons between the control, ES, AS-LTB, and AS-HTB. PCA analysis was not able to identify discriminatory DEGs clusters among the 4 groups. Pairwise comparative analysis identified 1913 DEGs among the 4 groups. Of these, 1759 (91.9%) were DEGs between FL and healthy controls, but only 218 (11.3%) were DEGs among the 3 different FL subgroups, evidencing a low molecular diversity in FL when categorized by CS and TB. In the cohort expansion by qRT-PCR, 7 pre-selected DEGs based on the microarray were tested, including the genes GNG7, ITGAM, AZN1, TIMD4, IL7R, PTGS2, and MTTL10. The comparison between the median expression of these genes among the 3 FL's groups showed that the expression of the ILR7 was downregulated with the progression of the disease, with marked hypoexpression in AS-HTB patients. These data may suggest downregulation of IL7R gene in the FLs natural history. We found that hypoexpression of the GNG7 (p = 0.024) and PTGS2 (p = 0.090) were associated with higher rates of disease progression/relapse, and hypoexpression of the GNG7 (p = 0.006) was associated with a higher probability of HT, highlighting the potential prognostic impact of these molecular biomarkers. Finally, we established phenotypic-genotypic associations, as hypoexpression of ITGAM was associated with higher rates of B-symptoms (p = 0.017) and bulky disease (p = 0.026), as well as hypoexpression of IL7R was correlated with a higher probability of bulky (p = 0.025) and extranodal involvement (p = 0.016). Conclusion: Although CS and TB are strong determinants of the prognostic heterogeneity of FL, this study did not find high molecular diversity by this categorization. We observed a relatively homogeneous GEP with low biological diversity in FL presenting different disease evolution phases. Moreover, new molecular biomarkers potentially implicated in FLs natural history, prognostication and specific clinical phenotypes were revealed.

Introduction: Circulating free DNA (cfDNA), particularly circulating tumor DNA (ctDNA), has emerged as a pivotal tool for diagnosis, response assessment, and monitoring of various malignancies. However, in most cancers, it has yet to be incorporated into clinical practice due to the lack of reproducible and widely accessible methodological standardization. In this context, numerous studies have been conducted to achieve such standardization. The purpose of this study was to evaluate the quantification of cfDNA and the identification of plasma ctDNA using the Z-scan technique in patients with diffuse large B-cell lymphoma (DLBCL). Methods: Peripheral blood samples were prospectively collected from DLBCL patients at diagnosis, after the fourth treatment cycle, and at the end of R-CHOP-like treatment. Simultaneously, samples from healthy individuals matched by sex and age were collected. After obtaining cfDNA, its concentration was assessed using Nanodrop, Qubit, Bioanalyzer, and Z-scan equipment. The results were compared and correlated with the clinical characteristics of the patients. Results: From January 2018 to December 2022, 54 DLBCL patients were recruited, with a median age of 58 years (ranging from 21 to 91 years), 33 (62.9%) of whom were female. The overall response rate of the cohort was 68.52%, with a median follow-up of 24.6 months, showing an overall survival of 32 months and event-free survival of six months. The concentrations of cfDNA varied significantly among the different reading methodologies used. The peak-to-valley distance (Theta values - Θ) of cfDNA from patients at diagnosis (mean of 0.438) obtained in the Z-scan was statistically distinct between the control group (background) and patients at different collection points. The peak-to-valley distance (Θ) of cfDNA samples collected at diagnosis was higher than that of the control group (background), p = 0.068, those collected after cycle 4 (mean 0.33), p = 0.016, and after treatment completion (mean 0.33), p = 0.0005. Several cut-off points for “Θ” were tested to identify the best discriminatory value between DLBCL and healthy control, with a sensitivity of 64.71% (95% CI: 50.99% to 76.37%) and specificity of 86.61% (95% CI: 62.86% to 93.02%) for Θ > 0.406. No correlations were found between “Θ” values and the clinical and demographic characteristics of the patients. Conclusion: The Z-Scan technique was able to distinguish DLBCL patients from healthy controls, as well as samples obtained during and after treatment from those collected before the start of anti-lymphoma therapy. We hypothesize that this discrimination was possible because the Z-scan technique may have been capable of distinguishing ctDNA from cfDNA.

ABCs and LRP transport proteins are involved in several metabolic processes, among which the transport of lipids and xenobiotics can be highlighted. Thus, the overexpression of some of these proteins, such as ABC-G2 and the LRP protein, are associated with the phenotype of resistance to multiple drugs, one of the main causes of relapses and relapses in patients with acute myeloid leukemia. Mesenchymal stem cells (MSC) are multipotent cells present in the bone marrow and are part of the hematopoietic niche. Phenotypic changes in MSCs are related to AML progression. The oxysterols, 7-KC and Triol, are derived from the auto-oxidation of the cholesterol molecule; and have functions in cell signaling, survival and death. Therefore, the objective of this work was to evaluate the action of oxysterols, in subtoxic concentrations, of 7-KC (30 μM, 50 μM and 70 μM) and Triol (20 μM, 30 μM and 40 μM) on the ABCs and LRP transport proteins of MSCs derived from bone marrow from patients with AML (MSC-D), being used as a comparator MSC of bone marrow from healthy individuals (MSC-S). Using the indirect immunofluorescence technique, it was observed that the amount of ABC-A1 protein was higher in MSC-S strains and that treatment with 30 μM of 7-KC increased ABC-A1 only in MSC-S strains. On the other hand, treatment with Triol decreased the concentration of ABC-A1 in MSC-S strains, and this decrease in ABC-A1 was associated with a decrease in the amount of the LXR-β receptor. Furthermore, treatment with 70 μM of 7-KC decreased LRP protein expression in MSC-S strains, while in MSC-D strains there was no difference. Treatment with Triol showed no significant effect on LRP protein expression in MSC-S, only in MSC-D strains, where there was an increase in the concentration of 20 μM, followed by a decrease in the concentrations of 30 μM and 40 μM of Triol. Both 7-KC and Triol treatment increased the concentration of SMO protein in the cytoplasm and its translocation to the nucleus in MSC-S cell lines. This effect was not observed in MSC-D strains. Treatment with Triol increased the concentration of ABC-D4 protein in the cytoplasm. Furthermore, the presence of ABC-D4 protein was observed in the nucleus of MSC-S and MSC-D strains. Our results demonstrated that in the MSCs lineages the effect of 7-KC and Triol is mainly metabolic, in which an increase in the oxidized glutathione content, alteration in the processes of mitochondrial dynamics with induction of genes related to the fission and fusion process in both 7-KC and Triol-treated MSC lines. Increased expression of the BCL2 gene and cytoplasmic survivin was also observed in MSCs treated with 7-KC. In conclusion, it is possible to observe differences in the expression of ABC transporters and LRP between CTM-S and CTM-D strains. Furthermore, at the same concentrations of 7-KC and Triol used, the observed effect was different between MSC-S and MSC-D, which demonstrates that there are different mechanisms between mesenchymal stem cell lines. In summary, our results are characteristic of the metabolic action of the oxysterols 7-KC and Triol on MSCs.

Abstract By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Abstract Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

Relations between central versus brachial blood pressure and major cardiovascular disease (CVD) events remain controversial. Central measures derived using radial tonometry and a generalized transfer function as implemented using the SphygmoCor device may better predict CVD risk compared to central pressures from carotid tonometry. We used proportional hazards models to examine relations of augmentation index, central systolic and pulse pressure, and central-to-peripheral pulse pressure amplification obtained using the Sphygmocor algorithm to first-onset major CVD events in 2183 participants (mean age 62 years, 58% women) in the Framingham Heart Study. During median follow-up of 7.8 (range 0.2 to 8.9) years, 149 participants (6.8%) had an incident event. Augmentation index (P = 0.6), central systolic pressure (P = 0.20), central pulse pressure (P = 0.24) and pulse pressure amplification (P = 0.15) were not related to outcomes in models that adjusted for age, sex, clinic systolic blood pressure, use of antihypertensive therapy, total and high density lipoprotein cholesterol concentrations, smoking, and presence of diabetes. When models were repeated using supine oscillometric systolic pressure recorded at the time of tonometry and excluding cases with tonometry pulse height variations >5%, pulse diastolic variation >5%, pulse shape variation >4% or an operator index

Abstract Objective Protocols to evaluate for myocardial infarction (MI) using high‐sensitivity cardiac troponin (hs‐cTn) have the potential to drive costs upward due to the added sensitivity. We performed an economic evaluation of an accelerated protocol (AP) to evaluate for MI using hs‐cTn to identify changes in costs of treatment and length of stay compared with conventional testing. Methods We performed a planned secondary economic analysis of a large, cluster randomized trial across nine emergency departments (EDs) from July 2020 to April 2021. Patients were included if they were 18 years or older with clinical suspicion for MI. In the AP, patients could be discharged without further testing at 0 h if they had a hs‐cTnI

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

Introduction: FL is the most common low-grade B-cell NHL. Although indolent, it has heterogeneous biological behavior and variable clinical outcomes. Histologic transformation (HT) to high-grade B-cell NHL is associated with dismal survival. The therapeutic management of FL and its prognosis are highly dependent on its staging and tumor burden. Here we aimed to describe clinical characteristics, assess outcomes, determine predictors of survival and HT, and compare responses between different therapies applied in a large cohort of FL patients. Methods: This retrospective study involved 223 patients with FL G1-3A, diagnosed at USP, Brazil, from 2006 to 2022. FL patients were categorized into early-stage (I/II) (ES), advanced-stage (AS) (III/IV) with low tumor burden (LTV), and AS with high tumor burden (HTV) according to the GELF criteria. Endpoints were OS, PFS, early-relapse (< 24 months) and HT rates. Survival curves were constructed using the KM method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate and multivariate analysis were performed. The results were presented in HR and 95% CI and p ≤ 0.05 was considered significant. Results: The median age at diagnosis was 60 years and 54.8% were female. 15% of cases had ES, 18.4% had AS-LTV, and 66.8% had AS-HTV. BM involvement, leukemic presentation, splenomegaly, and serous effusions occurred in 48.9%, 11.7%, 12.6%, and 21.1%, respectively. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and involvement of ≥ 4 nodal areas were observed in 44.4%, 51.6%, 15.2%, and 56%, respectively. 49% of patients were categorized as high-risk according to the FLIPI score. With a median follow-up of 79.5 months (95% CI 67.0-92.0) the OS medians were 18 years (95% CI 14.9-21.1), 11 years (95% CI 9.2-12.9), and 10.5 years (95% CI 9.3-11.8) for ES, AS-LTV, and AS-HTV, respectively, p = 0.138. Similarly, the PFS medians were 6.7 years (95% CI 3.6-9.8), 8.4 years (95% CI 2.0-14.8), and 3.5 years (95 CI 1.8-5.3) for ES, AS-LTV, and AS-HTV, respectively, p = 0.171. Early-relapses occurred in 36.3% of cases, being 18.2%, 31.7%, and 41.0% for ES, AS-LTV, and AS-HTV, respectively, p = 0.032. The overall mortality rate was 29.1% for the whole cohort. HT was documented in 16.7% of cases, being 3.0%, 14.6% and 20.1% for ES, AS-LTV, and AS-HTV, respectively, p = 0.053. Among patients with AS-HTV, the R-CHOP regimen did not promote increased OS compared to the R-CVP regimen (p = 0.415), however it was associated with a substantial increase in PFS (p = 0.005). Age ≥ 60 years (HR 1.06, p < 0.001), ≥ 2 comorbidities (HR 3.85, p = 0.014), B-symptoms (HR 2.35, p = 0.015), HT (HR 2.77, p = 0.002) and thrombocytopenia (HR 2.96, p = 0.028) were predictors of poor OS. Similarly, age ≥ 60 years (HR 1.08, p < 0.001), involvelment of ≥ 4 nodal areas (HR 1.27, p < 0.001), and high LDH (HR 1.65, p = 0.002) predicted decreased PFS. Serous effusions (HR 2.09, p = 0.05), albumin < 3.5 g/dL (HR 2.82, p = 0.05), B-symptoms (HR 2.00, p = 0.006), involvement of ≥ 4 nodal areas (HR 1.21, p = 0.014), and BM infiltration (HR 2.11, p = 0.05) were the main predictors for HT. Conclusion: Although it is characteristically an indolent disease, we demonstrated that a significant portion of FL patients have shortened survival. We confirmed this prognostic heterogeneity, particularly considering the clinical staging and tumor burden. Therefore, FL patients with AS-HTV had higher HT rates and early-relapses, both classic adverse prognostic markers, as well as a tendency to higher mortality. Additionally, we identified clinical and laboratory predictors for HT, which may in a near future direct adapted-risk therapeutic strategies.

Introduction: DLBCL is a malignancy with marked clinical, biological and prognostic heterogeneity. Its different outcomes may be predicted by the identification of molecular biomarkers. Therefore, quantification of circulating cell-free DNA (ccfDNA) and circulating tumor DNA (ctDNA) have emerged as minimally invasive methods able to predict its prognosis. However, such measurements are based on the use of costly technologies and with restricted access in clinical practice. Here, we aimed to quantify ccfDNA in DLBCL using capillary electrophoresis (CEF), a low-cost and widely available methodology, in order to establish prognostic associations between its serum concentrations, clinical characteristics and outcomes. Methods: This prospective study involved 54 DLBCL patients, diagnosed at USP, from 2019 to 2020, and 23 healthy-controls. All cases were treated with 6-8 cycles of R-CHOP. Plasma samples were collected from DLBCL at three moments: at diagnosis, after the 4th CT cycle and at the end of treatment. ccfDNA was extracted using the QIAamp MinElute ccfDNA kit and quantified by CEF (Agilent 2100 Bioanalyzer). Comparison between two groups was performed using the Mann-Whitney test, and between three groups using the Kruskall-Wallis test. The cut-off for [ccfDNA] (1147 ng/μl) was determined by ROC methodology. Survival curves were constructed using the KM method and Log-Rank test was used to assess the relationship between variables and outcomes, and p≤0.05 was considered significant. Results: The median age at diagnosis was 57 years and 61.1% were female. Advanced-stage was observed in 59.3%, 29.6% had ECOG ≥ 2, 52.6% had IPI ≥ 3, and 44.4% had bulky ≥ 10 cm. BM infiltration and involvement of ≥ 2 EN sites occurred in 5.6% and 16.8%, respectively. With a median follow-up of 32 months, the medians OS and EFS were 32 months (95% CI 28-35) and 31 months (95% CI 28-34), respectively. The ORR was 76% (95% CI 63.5-86). The overall mortality rate was 20.4% (95% CI 11.1-32.3). ccfDNA concentrations were significantly higher in DLBCL compared to controls (p < 0.001), however, it did not differ significantly between samples from DLBCL collected at the 3 different time points (p = 0.602). We observed positive associations between ccfDNA [ ] in diagnostic DLBCL samples and biomarkers of high tumor burden, including higher LDH levels (p = 0.003), bulky (p = 0.011), ECOG ≥ 2 (p < 0.001), and IPI ≥ 3 (p = 0.069). However, ccfDNA[ ] at diagnosis were not statistically associated with ORR (p = 0.264), nor with clinical outcomes, including OS (1-year OS: 92% for [ccfDNA] < 1147 ng/μl vs 76% for [ccfDNA] ≥ 1147 ng/μl, p = 0.217) and EFS (1-year EFS: 92% for [ccfDNA] < 1147 ng/μl vs 69% for [ccfDNA] ≥ 1147 ng/μl, p = 0.270). We believe that the short follow-up time and sample number restriction may have contributed to the lack of statistically significant association between ccfDNA [ ] and responses/outcomes observed. In this sense, cohort expansion and NGS techniques for ctDNA identification are ongoing to assess its potential impact as a prognostic biomarker in our cohort. Conclusion: We demonstrated that ccfDNA [ ] measured by CEF were able to accurately discriminate healthy individuals from DLBCL, highlighting its potential role as a minimally invasive diagnostic biomarker. Furthermore, ccfDNA [ ] at diagnosis in DLBCL patients were positively associated with markers of high tumor burden and adverse prognosis. Our results suggest that measurement of ccfDNA by CEF may be a highly cost-effective methodology to identify high-grade B-cell NHLs and recognize DLBCL subgroups with adverse clinical-prognostic characteristics.

Background: Mast cells are initiators and main effectors of allergic inflammation, together with eosinophils, with whom they can interact in a physical and soluble cross-talk with marked pro-inflammatory features, the Allergic Effector Unit. The pro-resolution role of mast cells, alone or in co-culture with eosinophils, has not been characterized yet. Objectives: We aimed to investigate select pro-resolution pathways in mast cells in vitro and in vivo in allergic inflammation. Methods: In vitro, we employed human and murine mast cells and analyzed release of resolvin D1 and expression of 15-lipoxygenase after IgE-mediated activation. We performed co-culture of IgE-activated mast cells with peripheral blood eosinophils and investigated 15-lipoxygenase expression and Resolvin D1 release. In vivo, we performed Ovalbumin/Alum and Ovalbumin/S. aureus enterotoxin B allergic peritonitis model in Wild Type mice following a MC “overshoot” protocol. Results: We found that IgE-activated mast cells release significant amounts of resolvin D1 30 min after activation, while 15-lipoxygenase expression remained unchanged. Resolvin D1 release was found to be decreased in IgE-activated mast cells co-cultured with peripheral blood eosinophils for 30 min In vivo, mast cell-overshoot mice exhibited a trend of reduced inflammation, together with increased peritoneal resolvin D1 release. Conclusions: Mast cells can actively contribute to resolution of allergic inflammation by releasing resolvin D1.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

Purpose: To investigate the association of the maximal severity of pneumonia on CT scans obtained within 6-week of diagnosis with the subsequent development of post-COVID-19 lung abnormalities (Co-LA). Methods: COVID-19 patients diagnosed at our hospital between March 2020 and September 2021 were studied retrospectively. The patients were included if they had (1) at least one chest CT scan available within 6-week of diagnosis; and (2) at least one follow-up chest CT scan available ≥ 6 months after diagnosis, which were evaluated by two independent radiologists. Pneumonia Severity Categories were assigned on CT at diagnosis according to the CT patterns of pneumonia and extent as: 1) no pneumonia (Estimated Extent, 0%); 2) non-extensive pneumonia (GGO and OP, 40%). Co-LA on follow-up CT scans, categorized using a 3-point Co-LA Score (0, No Co-LA; 1, Indeterminate Co-LA; and 2, Co-LA). Results: Out of 132 patients, 42 patients (32%) developed Co-LA on their follow-up CT scans 6–24 months post diagnosis. The severity of COVID-19 pneumonia was associated with Co-LA: In 47 patients with extensive pneumonia, 33 patients (70%) developed Co-LA, of whom 18 (55%) developed fibrotic Co-LA. In 52 with non-extensive pneumonia, 9 (17%) developed Co-LA: In 33 with no pneumonia, none (0%) developed Co-LA. Conclusions: Higher severity of pneumonia at diagnosis was associated with the increased risk of development of Co-LA after 6–24 months of SARS-CoV-2 infection.

La reparación primaria de los tendones flexores en la zona II ha sido un desafío desde el surgimiento de la cirugía de la mano como especialidad luego de la Segunda Guerra Mundial. Desde Bunnell hasta hoy, la forma de operar y rehabilitar estos tendones ha evolucionado y cambiado considerablemente gracias a estudios anatómicos, biológicos y, sobre todo, mecánicos. Actualmente la técnica quirúrgica se basa en realizar una sutura fuerte y prolija, que no sufra fricción dentro de la vaina y que tolere la carga necesaria para la movilidad activa del dígito sin resistencia. Se han descrito múltiples configuraciones de puntos con diferentes materiales. Operando con anestesia local, la prueba de flexo-extensión activa intraoperatoria revela la resistencia del tipo de sutura elegida y ha cobrado importancia para definir el protocolo de rehabilitación. El tratamiento de los flexores en la zona II es, hasta el momento, un conjunto inseparable de técnica quirúrgica y rehabilitación asociada. La manipulación farmacológica del proceso biológico reparador es el principal campo de investigación actual.

Abstract Angiotensin‐converting enzyme inhibitors (ACEi) are part of the indicated treatment in hypertensive African Americans. ACEi have blood pressure‐independent effects that may make them preferred for certain patients. We aimed to evaluate the impact of ACEi on anti‐fibrotic biomarkers in African American hypertensive patients with left ventricular hypertrophy (LVH). We conducted a post hoc analysis of a randomized controlled trial in which hypertensive African American patients with LVH and vitamin D deficiency were randomized to receive intensive antihypertensive therapy plus vitamin D supplementation or placebo. We selected patients who had detectable lisinopril (lisinopril group) in plasma using liquid‐chromatography/mass spectrometry analysis and compared them to subjects who did not (comparison group) at the one‐year follow‐up. The pro‐fibrotic marker type 1 procollagen C‐terminal propeptide (PICP) and the anti‐fibrotic markers matrix metalloproteinase‐1 (MMP‐1), tissue inhibitor of metalloproteinases 1 (TIMP‐1), telopeptide of collagen type I (CITP), and N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) peptide were measured. Sixty‐six patients were included, and the mean age was 46.2 ± 8 years. No difference was observed in the number and intensity of antihypertensive medications prescribed in each group. Patients with detectable lisinopril had lower blood pressure than those in the comparison group. The anti‐fibrotic markers Ac‐SDKP, MMP‐1, and MMP‐1/TIMP‐1 ratio were higher in patients with detectable ACEi (all p

Several groups have demonstrated that healthy individuals can present the t(14;18) translocation. In this report, the presence of the translocation was examined in healthy blood donors in Brazil, a country considered an ethnic melting pot. The translocation was detected by nested PCR in 227 peripheral blood samples from individuals with different ethnic backgrounds. The t(14;18) translocation was found in 45 of 85 White individuals (52.94%); in 57 of 72 Black individuals (79.17%); and in 68 of 70 individuals (97.14%) of Japanese-descent. In conclusion, the frequency of the t(14;18) translocation in the Brazilian population varies according to the ethnic background.