Bayesian networks in modeling leucocyte interplay following brain irradiation: A comprehensive framework.

BACKGROUND AND OBJECTIVE: Understanding the intricate interactions among leucocyte subpopulations following radiotherapy is crucial for advancing cancer research and immunology. Recently, interest in recent radiotherapy modalities, such as protons, has increased. Herein, we present a framework utilizing Bayesian networks to uncover these complex relationships via an illustrative example of brain irradiation in rodents. METHODS: We utilized data from 96 healthy C57BL/6 adult mice subjected to either X-ray or proton brain irradiation. Leucocyte subpopulations in the blood collected 12 h after the final irradiated fraction were quantified. We employed Bayesian networks to detect causal interplay between physiological parameters, radiation variables and circulating leucocytes. The causal structure was learned via the use of the Bayesian information criterion as a scored criterion. Parameter estimation was performed to quantify the strength of the identified causal relationships. Cross-validation was used to validate our Bayesian network model's performance. RESULTS: In the X-ray model, we discovered previously undisclosed interactions between NK-cells and neutrophils, and between monocytes and T-CD4+ cells. The proton model revealed an interplay involving T-CD4+ cells and neutrophils. Both X-rays and protons led to heightened interactions between T-CD8+ cells and B cells, indicating their significant role in orchestrating immune responses. Additionally, the proton model displayed strengthened interactions between T-CD4+ and T-CD8+ cells, emphasizing a dynamic and coordinated immune response post-irradiation. Cross-validation results demonstrated the robustness of the Bayesian network model in explaining data uncertainty. CONCLUSION: The use of Bayesian networks as tools for causal structure discovery has revealed novel insights into the dynamics of immune responses to radiation exposure.

Differential plasma cytokine variation following X-ray or proton brain irradiation using machine-learning approaches.

PURPOSE: X-ray and proton irradiation have been reported to induce distinct modifications in cytokine expression in vitro and in vivo, suggesting a dissimilar inflammatory response between X-rays and protons. We aimed to investigate the differences in cytokine profiles early following fractionated brain irradiation with X-rays or protons and their relationship with leukocyte subpopulations in rodents. MATERIALS AND METHODS: Our study utilized data from 80 tumor-free mice subjected to X-ray or proton brain irradiation in four fractions of 2.5Gy. Sixteen non-irradiated mice were used as the controls. Blood was collected 12h postirradiation to examine the profile of 13 cytokines. Correlation analysis, principal component analysis (PCA), and tree-based modeling were used to investigate the relationship between cytokine levels and leukocyte subpopulation variations following irradiation in the blood. RESULTS: Regardless of the irradiation type, brain irradiation resulted in a notable elevation in the plasma levels of IFN-γ and MCP-1. The use of either X-ray or proton beam had differential effect on plasma cytokine levels following brain irradiation. Specifically, X-ray irradiation was associated with significantly increased plasma levels of IFN-ß, IL-12p70, and IL-23, along with a decreased level of IL-1α, in comparison to proton irradiation. Correlation analysis revealed distinct cytokine regulatory patterns between X-ray and proton brain irradiation. PCA highlighted the association of MCP-1, IL-6, TNF-α, IL-17A, and IFN-γ with neutrophils, monocytes, and naïve T-cells following X-ray irradiation. TNF-α and IL-23 levels correlated with naïve CD4+-cells following proton irradiation. Tree-based models demonstrated that high TNF-α level resulted in an increase in naïve T-cells, neutrophils, and monocytes, whereas low IL-6 level was associated with decreases in these cell counts. CONCLUSION: Our findings revealed distinct inflammatory responses induced by X-ray irradiation in contrast to proton brain irradiation, as demonstrated by the differential regulation of cytokines in the bloodstream. Moreover, the study highlighted the association between specific cytokine levels and various leukocyte subpopulations. Further investigation is essential to accurately determine the impact of proton and X-ray brain irradiation on the inflammatory response and the efficacy of radiotherapy treatment.

Who is at-risk for severe anaphylaxis in France?

Background: The understanding of risk factors related to severe anaphylaxis is key to implementing prevention strategies. We present the first French population-based nine-year anaphylaxis hospitalization study evaluating specific trends and factors related to severe anaphylaxis (SA), to support identification of phenotypes at-risk. Methods: This study used descriptive data from the French hospitalization database for the years 2012-2021, and included all patients hospitalized with anaphylaxis using International Classification of Diseases (ICD)-10 codes listed as a primary diagnosis. SA were cases that either required a hospitalization in intensive care units or resulted in death. Potential risk factors were identified according to corresponding ICD codes, available as secondary data during the patient's hospitalization. Results: The average hospitalization rate of all cases of anaphylaxis (SA and non-SA) was 1.34/100,000/year, and rate of admissions for SA was 0.08/100,000/year. Among the 5463 SA, 37.7% had unspecified coding label, when trigger was not identified. For SA cases in which trigger was identified, most were related to drugs (45.6%), followed by food (9.3%) and insect sting (7.2%). Overall, admissions due to anaphylaxis (SA and non-SA) were more frequent in males (57%). However, when the trigger was drugs, the proportion was significantly higher in females. For children aged 5-9 years, the most common trigger for SA was food. Patients for which SA was triggered by insect stings were identified exclusively in the 10-14 years age group. Chronic spontaneous urticaria was associated with insect sting-induced anaphylaxis, regardless of the severity. Angioedema was associated with all causes of SA. Cases of anaphylaxis presenting with urticaria and angioedema included cases with identified and unidentified triggers. Asthma and a personal history of allergy were associated with drug- and food-induced anaphylaxis. Conclusion: This is the first study to provide data on severe phenotypes of anaphylaxis in France. Data presented is key to the implementation of public health actions and preventive strategies to improve quality care.

A human-serum-free medium can induce more infectious P. falciparum gametocytes than a conventional human-serum-containing medium.

Malaria remains a global health problem, and the standard membrane feeding assay (SMFA) is a key functional assay for development of new interventions to stop malaria transmission from human to mosquito. For SMFA, media with ~ 10% of human serum has been used for infectious gametocyte cultures, however, there are multiple challenges to obtain a suitable human serum. Here we show a human-serum-free culture medium (HSF), which was a mixture of two stem cell culture media and AlbuMAX, supported infectious gametocyte growth. Moreover, the HSF-induced gametocytes elicited significantly higher numbers of oocysts compared to gametocytes cultured with conventional human serum medium (Conv). While some caution is required when comparing percent transmission reducing activity data generated from HSF-SMFA and Conv-SMFA, the HSF method can facilitate the establishment of gametocyte cultures or SMFA by bypassing the need for human serum. Thus, this study will support future development of P. falciparum transmission-blocking interventions.

Cross-wavelength calibrating method for real-time imaging of tissue optical properties using frequency-domain diffuse optical spectroscopy.

Frequency-domain diffuse optical spectroscopy (FD-DOS) is a powerful non-invasive technique for assessing tissue optical properties, with applications ranging from basic research to clinical diagnosis. In this study, we introduce and validate a novel approach termed the cross-wavelength calibrating (CWC) method within the framework of TrackDOSI, a real-time FD-DOS imaging system for tissue characterization. The CWC method aims to mitigate the effects of changing optical coupling and motion artifacts encountered during probe scanning, thus enhancing the accuracy and reliability of optical property measurements. Notably, the CWC method also allows for a simpler geometry with fewer sources than traditional self-calibrating (SC) methods, reducing instrumental complexity and cost while maintaining robustness in estimating optical properties. We first validate the CWC method on solid silicone phantoms, demonstrating strong agreement with the gold standard SC method with an error of -10% and 1% for absorption and reduced scattering coefficients, respectively. Furthermore, experiments on phantom and human tissue reveal the CWC approach's ability to suppress motion artifacts and optical coupling variations, thereby improving measurement repeatability, signal fidelity, and artifact correction in dynamic imaging scenarios. Our findings underscore the potential of the CWC method to enhance the clinical utility of DOSI techniques by enabling real-time artifact correction and improving the accuracy of tissue optical property measurements.

BET Inhibition Rescues Acinar-Ductal-Metaplasia and Ciliogenesis and Ameliorates Chronic Pancreatitis-Driven Changes in Mice with Loss of the Polarity Protein Par3.

BACKGROUND & AIMS: The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas injury and regeneration are poorly understood. METHODS: Cerulein-induced pancreatitis was induced in mice with conditional deletion of the polarity protein Par3 in the pancreas. The impact of Par3 loss on pancreas injury and regeneration was assessed by histologic analyses and transcriptional profiling by RNA sequencing. Mice were pretreated with the bromodomain and extraterminal domain (BET) inhibitor JQ1 before cotreatment with cerulein to determine the effect of BET inhibition on pancreas injury and regeneration. RESULTS: Initially, we show that Par3 is increased in acinar-ductal metaplasia (ADM) lesions present in human and mouse chronic pancreatitis specimens. Although Par3 loss disrupts tight junctions, Par3 is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss exacerbates acute pancreatitis-induced injury and chronic pancreatitis-induced acinar cell loss, promotes pancreatic lipomatosis, and prevents regeneration. Par3 loss also results in suppression of chronic pancreatitis-induced ADM and primary ciliogenesis. Notably, targeting BET proteins attenuates chronic pancreatitis-induced loss of primary cilia and promotes ADM in mice lacking pancreatic Par3. Targeting BET proteins also attenuates cerulein-induced acinar cell loss and enhances recovery of acinar cell mass and body weight of mice lacking pancreatic Par3. CONCLUSIONS: Combined, this study demonstrates how Par3 restrains chronic pancreatitis-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate regeneration.

Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.

MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the pro-apoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also re-sensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in PDAC patients.

Cannula-Associated Deep Vein Thrombosis Following Extracorporeal Membrane Oxygenation Decannulation: Incidence and Risk Factors.

Thrombotic complications during and after extracorporeal membrane oxygenation (ECMO) are commonly observed clinically. The incidences of cannula-associated deep vein thrombosis (CaDVT) post-ECMO support have predominantly focused on Caucasian demographics. This study aims to determine the incidence and risk factors for CaDVT in Vietnamese patients following ECMO decannulation. The retrospective study from January 2019 to February 2020 observed ECMO weaning patients and screened for CaDVT using Doppler ultrasonography. Data were collected on patient demographics, ECMO parameters, and transfusion and coagulation profiles during ECMO support. Of the 82 patients successfully weaned ECMO, 89% were assessed for CaDVT. We observed a CaDVT incidence of 24.7%, and only one patient (5.6%) had a pulmonary embolism in the CaDVT group. Noteworthy is that the anticoagulation goals, transfusion during ECMO, and hospital mortality showed no significant difference between the CaDVT and non-CaDVT groups. The findings showed that the duration of ECMO support is a risk factor for CaDVT. The incidence of CaDVT following ECMO decannulation was 24.7%, and the diagnosis of CaDVT can be underestimated. Therefore, we suggest routine screening for CaDVT after cannula removal.

Trametinib potentiates anti-PD-1 efficacy in tumors established from chemotherapy-primed pancreatic cancer cells.

Despite advances in immune checkpoint inhibitors (ICIs), chemotherapy remains the standard therapy for patients with pancreatic ductal adenocarcinoma (PDAC). As the combinations of chemotherapy, including the FOLFIRINOX (5-fluorouracil (5FU), irinotecan, and oxaliplatin) regimen, and ICIs have failed to demonstrate clinical benefit in patients with metastatic PDAC tumors, there is increasing interest in identifying therapeutic approaches to potentiate ICI efficacy in PDAC patients. In this study, we report that neoadjuvant FOLFRINOX-treated human PDAC tumors exhibit increased MEK/ERK activation. We also show elevated MEK/ERK signaling in ex vivo PDAC slice cultures and cell lines treated with a combination of 5FU (F), irinotecan (I), and oxaliplatin (O) (FIO). In addition, we find that the KPC-FIO cells, established from repeated treatment of mouse PDAC cell lines with 6-8 cycles of FIO, display enhanced ERK phosphorylation and demonstrate increased sensitivity to MEK inhibition in vitro and in vivo. Significantly, the KPC-FIO cells develop tumors with a pro-inflammatory immune profile similar to human PDAC tumors following neoadjuvant FOLFIRINOX treatment. Furthermore, we found that the MEK inhibitor Trametinib enables additional infiltration of highly functional CD8+ T cells into the KPC-FIO tumors and potentiates the efficacy of anti-PD-1 antibody in syngeneic mouse models. Our findings provide a rationale for combining Trametinib and anti-PD-1 antibodies in PDAC patients following neoadjuvant or short-term FOLFIRINOX treatment to achieve effective anti-tumor responses.

Thoracic Endovascular Aortic Repair for an Aortoesophageal Fistula Caused by Esophageal Cancer: A Case Report and Literature Review.

Aortoesophageal fistula (AEF) is an uncommon complication of esophageal cancer and can be extremely fatal if left untreated. Compared to open repair, thoracic endovascular aortic repair (TEVAR), a less invasive technique, is the initial recommended treatment in cases of hemorrhagic shock secondary to AEF, as this procedure showed a favorable outcome in controlling the overt bleeding. Here, we present a case of a patient with a history of stage IV esophageal cancer being treated with chemotherapy and an esophageal stent due to a previous tracheoesophageal fistula who presented to the emergency room due to severe gastroesophageal bleeding and hemorrhagic shock. A CT angiography of the chest revealed an AEF. The patient was subsequently resuscitated and treated with TEVAR. After the procedure, the hemorrhage was managed, and the patient was discharged with palliative radiation therapy. However, after one month, the patient had a major gastrointestinal hemorrhage, which caused her death. This example indicates the necessity of early detection and surgical intervention in AEF patients with unstable hemodynamics who have underlying unresectable esophageal cancer and chemotherapy. TEVAR should be conducted as soon as possible before the open surgery to achieve the best outcome for patients.

Challenges in Diagnosing and Managing Severe Hypernatremia in Patients With Major Depressive Disorder: A Case Report.

Hypernatremia, characterized by a plasma sodium concentration above 145 mmol/L, is frequently observed in critically ill patients, often due to factors such as gastrointestinal losses, dehydration, and diabetes insipidus. Psychiatric patients, particularly those with major depressive disorder, are also at risk of developing hypernatremia due to abnormalities in thirst sensation, mineralocorticoid excess, or medication side effects. Severe hypernatremia in psychiatric patients is associated with a high mortality rate, presenting challenges in diagnosis and management. The treatment of chronic hypernatremia (>48 hours) typically involves administering isotonic saline to hypovolemic patients until normalization of vital signs, followed by dextrose 5% in water (D5W) based on water deficit and losses. The goal is to decrease plasma sodium by 8-10 mmol/day. Acute hypernatremia (<48 hours) is corrected with a plasma sodium reduction of 1 mmol/L/hour in the first six to eight hours. While there are no clear guidelines for sodium correction in severe hypernatremia, the literature suggests a safe correction rate of 8-10 mmol/day for chronic hypernatremia and 1 mmol/L/hour for acute cases. In a specific case, a 51-year-old female with severe depression and reduced oral intake was admitted. She exhibited signs of dehydration and was found to have severe hypernatremia (191 mmol/L) with acute kidney injury. Treatment involved D5W, followed by D5W/half-normal saline at 150 mL/hr. Within 24 hours, her plasma sodium decreased to 178 mmol/L and gradually normalized to 143 mmol/L without neurological complications. This case highlights the challenges and underscores the importance of early recognition and management of severe hypernatremia in psychiatric patients. The primary treatment approach addresses water deficits and losses and administers D5W. Recent findings suggest that rapid correction of the condition is acceptable.

A Case of Cameron Lesions: An Overlooked Cause of Anemia in Patients With Gastrointestinal Bleeding and Hiatal Hernia.

Cameron lesions are rare causes of upper gastrointestinal bleeding (UGIB). The lesions are linear erosions or ulcers that develop in the sac of a hiatal hernia, which often go unnoticed in the upper gastrointestinal system, and are a prevalent cause of anemia resulting from iron deficiency. Postponed treatment can result in severe consequences such as potentially fatal hemorrhaging. Here, we present a case of a young woman who presented to the emergency room with recurrent gastrointestinal bleeding and severe microcytic anemia. The chest X-ray revealed a partial intrathoracic stomach, and a large hiatal hernia was subsequently confirmed in the CT scan of the abdomen and pelvis. The esophagogastroduodenal endoscopy indicated Los Angeles Classification System grade A reflux esophagitis and an 8 cm hiatal hernia with multiple Cameron ulcers with pigmented material and chronic non-erosive gastritis. Biopsies of the gastric body and antrum showed Helicobacter pylori-associated chronic active gastritis and intestinal metaplasia. An esophagus biopsy showed squamous esophageal mucosa with mild chronic inflammation. The patient was treated with a transfusion of three units of red blood cells, iron replenishment, and pantoprazole infusion and underwent hiatal hernia repair with mesh and Toupet fundoplication without any complications. After that, the patient was discharged and scheduled for follow-up with general surgery at the outpatient clinic.

Dengue Hemorrhagic Fever in Quang Nam Province (Vietnam) from 2020 to 2022-A Study on Serotypes Distribution and Immunology Factors.

Background: Dengue hemorrhagic fever (DHF) is the most prevalent and fastest-growing vector-borne disease globally, with symptoms ranging from mild to severe and, in some cases, fatal. Quang Nam province in Vietnam can serve as a model for dengue epidemiological study, as it is an endemic region for DHF with a tropical climate, which significantly constrains the health system. However, there are very few epidemiological and microbiological reports on Dengue virus (DENV) serotypes in this region due to the limited availability of advanced surveillance infrastructure. Aims of the study: This study aims to (1) assess the PCR positivity rates among hospitalized patients with clinical Dengue presentation; (2) identify the circulating DENV serotypes; and (3) assess the impact of secondary DENV infections on outbreak severity by detecting the presence of DENV-specific IgG antibodies in the plasma of DENV-infected patients. Materials and methods: Blood samples from patients clinically diagnosed with DHF and admitted to Quang Nam General Hospital (2020-2022) were analyzed. RNA extraction was performed using the NKDNA/RNAprep MAGBEAD kit, followed by Multiplex Reverse Transcription real-time Polymerase Chain Reaction (MLP RT-rPCR) for DENV detection and serotype identification. Positive samples were further tested for DENV-specific IgG antibodies using an enzyme-linked immunosorbent assay (ELISA). Results: The PCR positivity rate among hospitalized patients was approximately 68% throughout the study period. A significant shift in DENV serotypes was observed, with DENV-2 initially dominant and later giving way to DENV-1. IgG was detected in nearly half of the MPL RT-rPCR-positive samples, indicating secondary DENV infections. Conclusions: Our study highlights persistent dengue prevalence and dynamic shifts in DENV serotypes in Quang Nam province, emphasizing the need for improved diagnostic strategies and timely sample collection. The significant serotype shifts and the presence of IgG in hospitalized patients suggest potential severe outcomes from recurrent DENV infections, possibly linked to antibody-dependent enhancement (ADE) effect, underscoring the importance of advanced surveillance, vector control, vaccination campaigns, and public education to predict and prevent future DHF epidemics.

Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types.

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (∼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.

Revealing the effect of X-ray or proton brain irradiation on systemic inflammation and leukocyte subpopulation interplay in rodents.

The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B-cells, NK-cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or Protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics were further examined using modeling. Leukocyte subpopulations interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK-cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B-cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.

Mitral valve repair with resection and non-resection techniques in Barlow's disease: A multi-center study.

BACKGROUND: Various mitral valve (MV) repair techniques are nowadays in use. Non-resection techniques, that rely exclusively on Gore-Tex® neochords and annuloplasty, have been popularized; however, their efficacy in Barlow's disease, characterized by large myxomatous leaflets, is yet unclear. METHODS: Consecutive patients undergoing MV repair for Barlow's disease between 2011 and 2019 were selected on the basis of being eligible for resection and non-resection techniques. Study endpoints included overall survival, freedom from MV reintervention and recurrent regurgitation. RESULTS: Of 209 patients meeting the inclusion criteria, 135 (65%) underwent MV repair with and 74 (35%) without resection. There was one early reoperation due to residual regurgitation (resection group). Mean clinical follow-up duration was 6.1 (IQR 3.9-8.5) years. At 6 years after surgery, there was no difference in overall survival or freedom from MV reintervention. Mean echocardiographic follow-up (95% complete) duration was 3.5 (IQR 2.3-5.8) years. At 6 years, there was no difference in freedom from recurrent regurgitation rate (86.1%, 95% CI 78.5-93.7% vs. 83.0%, 95% CI 71.6-94.4%, P = 0.20) between the groups. Inverse probability-of-treatment weighting adjusted analysis demonstrated no significant difference between groups (HR 0.535, 95% CI 0.212-1.349, P = 0.20). Uni- and multivariable Cox proportional regression analysis did not demonstrate an effect of valve repair technique on the occurrence of recurrent regurgitation. CONCLUSIONS: At mid-term, the clinical and echocardiographic results of valve repair for Barlow's disease were very good and MV reintervention was rarely needed. At this time point, the results of non-resection techniques were comparable to the "gold standard" resection techniques.

Lymphocyte radiosensitivity: An extension to the linear-quadratic model?

BACKGROUND AND PURPOSE: The linear-quadratic (LQ) model has been pivotal for evaluating the effects of radiation on cells, but it is primarily characterized by linear responses, which has exhibited limitations when applied to lymphocyte data. The present research aims to address these limitations and to explore an alternative model extended from the conventional LQ model. MATERIALS AND METHODS: Literature providing lymphocyte counts from assays investigating apoptosis and survival after in vitro irradiation was selected. To address the nonlinearity in lymphocyte responses to radiation, we developed a saturation model characterized by a negative exponential relationship between radiation dose and cellular response. We compared the performance of this saturation model against that of conventional models, including the LQ model and its variants (linear model LM and linear-quadratic-cubic model LQC), as well as the repair-misrepair (RMR) model. The models were evaluated based on prediction-residual plots, residual standard errors, and the Akaike information criterion (AIC). We applied the saturation model to two additional datasets: (1) a dataset from the existing literature that assessed stimulated and unstimulated human lymphocytes exposed to gamma irradiation in vitro and (2) a novel dataset involving T lymphocytes from rodent spleens after exposure to various radiation types (X-rays and protons). RESULTS: The literature (n = 15 out of 2342) showed that lymphocyte apoptosis varies with dose, time and experimental conditions. The saturation model had a lower AIC of 718 compared to the LM, LQ, LQC and RMR models (AIC of 728, 720, 720 and 734, respectively). The saturation model had a lower residual error and more consistent error distribution. Integrating time as a covariate, the saturation model also had a better AIC for demonstrating time-dependent variations in lymphocyte responses after irradiation. For datasets involving unstimulated lymphocytes before irradiation, the saturation model provided a more accurate fit than did the LM, LQ, and RMR models. In these cases, the fit of the saturation model was comparable to that of the LQC model but offered an advantage when extrapolating to higher doses, where the LQC model might underestimate survival. For stimulated lymphocytes, which are radioresistant, all the models approximated the LM. Both the LQ and saturation models indicated greater radiosensitivity to protons in vitro. CONCLUSION: The new "saturation model" performed better than the LQ model in quantifying lymphocyte apoptosis and survival, estimating time dependency and assessing the role of radiation modalities or lymphocyte stimulation. Further experiments are warranted to experimentally explore the validity of the saturation model as a promising alternative in the clinical setting.

Persistent T cell unresponsiveness associated with chronic visceral leishmaniasis in HIV-coinfected patients.

A large proportion of HIV-coinfected visceral leishmaniasis (VL-HIV) patients exhibit chronic disease with frequent VL recurrence. However, knowledge on immunological determinants underlying the disease course is scarce. We longitudinally profiled the circulatory cellular immunity of an Ethiopian HIV cohort that included VL developers. We show that chronic VL-HIV patients exhibit high and persistent levels of TIGIT and PD-1 on CD8+/CD8- T cells, in addition to a lower frequency of IFN-γ+ TIGIT- CD8+/CD8- T cells, suggestive of impaired T cell functionality. At single T cell transcriptome and clonal resolution, the patients show CD4+ T cell anergy, characterised by a lack of T cell activation and lymphoproliferative response. These findings suggest that PD-1 and TIGIT play a pivotal role in VL-HIV chronicity, and may be further explored for patient risk stratification. Our findings provide a strong rationale for adjunctive immunotherapy for the treatment of chronic VL-HIV patients to break the recurrent disease cycle.

Unmet needs in axial spondyloarthritis. Proceedings of the French spondyloarthritis taskforce workshop.

The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.

DeepARV: ensemble deep learning to predict drug-drug interaction of clinical relevance with antiretroviral therapy.

Drug-drug interaction (DDI) may result in clinical toxicity or treatment failure of antiretroviral therapy (ARV) or comedications. Despite the high number of possible drug combinations, only a limited number of clinical DDI studies are conducted. Computational prediction of DDIs could provide key evidence for the rational management of complex therapies. Our study aimed to assess the potential of deep learning approaches to predict DDIs of clinical relevance between ARVs and comedications. DDI severity grading between 30,142 drug pairs was extracted from the Liverpool HIV Drug Interaction database. Two feature construction techniques were employed: 1) drug similarity profiles by comparing Morgan fingerprints, and 2) embeddings from SMILES of each drug via ChemBERTa, a transformer-based model. We developed DeepARV-Sim and DeepARV-ChemBERTa to predict four categories of DDI: i) Red: drugs should not be co-administered, ii) Amber: interaction of potential clinical relevance manageable by monitoring/dose adjustment, iii) Yellow: interaction of weak relevance and iv) Green: no expected interaction. The imbalance in the distribution of DDI severity grades was addressed by undersampling and applying ensemble learning. DeepARV-Sim and DeepARV-ChemBERTa predicted clinically relevant DDI between ARVs and comedications with a weighted mean balanced accuracy of 0.729 ± 0.012 and 0.776 ± 0.011, respectively. DeepARV-Sim and DeepARV-ChemBERTa have the potential to leverage molecular structures associated with DDI risks and reduce DDI class imbalance, effectively increasing the predictive ability on clinically relevant DDIs. This approach could be developed for identifying high-risk pairing of drugs, enhancing the screening process, and targeting DDIs to study in clinical drug development.