B cell activity is impaired in human and mouse obesity and is responsive to an essential fatty acid upon murine influenza infection

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming theWestern diet had diminished Ab titers whereas theWestern diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism

MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis

Endometriosis is a common gynecologic disorder characterized by pain and infertility. In addition to estrogen dependence, progesterone resistance is an emerging feature of this disorder. Specifically, a delayed transition from the proliferative to secretory phase as evidenced by dysregulation of progesterone target genes and maintenance of a proliferative molecular fingerprint in the early secretory endometrium (ESE) has been reported. MicroRNAs (miRNAs) are small noncoding RNAs that collectively represent a novel class of regulators of gene expression. In an effort to investigate further the observed progesterone resistance in the ESE of women with endometriosis, we conducted array-based, global miRNA profiling. We report distinct miRNA expression profiles in the ESE of women with versus without endometriosis in a subset of samples previously used in global gene expression analysis. Specifically, the miR-9 and miR-34 miRNA families evidenced dysregulation. Integration of the miRNA and gene expression profiles provides unique insights into the molecular basis of this enigmatic disorder and, possibly, the regulation of the proliferative phenotype during the early secretory phase of the menstrual cycle in affected women

A Machine Learning Algorithm to Identify Patients at Risk of Unplanned Subsequent Surgery After Intramedullary Nailing for Tibial Shaft Fractures

Objectives: In the SPRINT trial, 18% of patients with a tibial shaft fracture (TSF) treated with intramedullary nailing (IMN) had one or more unplanned subsequent surgical procedures. It is clinically relevant for surgeon and patient to anticipate unplanned secondary procedures, other than operations that can be readily expected such as reconstructive procedures for soft tissue defects. Therefore, the objective of this study was to develop a machine learning (ML) prediction model using the SPRINT data that can give individual patients and their care team an estimate of their particular probability of an unplanned second surgery. Methods: Patients from the SPRINT trial with unilateral TSFs were randomly divided into a training set (80%) and test set (20%). Five ML algorithms were trained in recognizing patterns associated with subsequent surgery in the training set based on a subset of variables identified by random forest algorithms. Performance of each ML algorithm was evaluated and compared based on (1) area under the ROC curve, (2) calibration slope and intercept, and (3) the Brier score. Results: Total data set comprised 1198 patients, of whom 214 patients (18%) underwent subsequent surgery. Seven variables were used to train ML algorithms: (1) Gustilo-Anderson classification, (2) Tscherne classification, (3) fracture location, (4) fracture gap, (5) polytrauma, (6) injury mechanism, and (7) OTA/AO classification. The best-performing ML algorithm had an area under the ROC curve, calibration slope, calibration intercept, and the Brier score of 0.766, 0.954, -0.002, and 0.120 in the training set and 0.773, 0.922, 0, and 0.119 in the test set, respectively. Conclusions: An ML algorithm was developed to predict the probability of subsequent surgery after IMN for TSFs. This ML algorithm may assist surgeons to inform patients about the probability of subsequent surgery and might help to identify patients who need a different perioperative plan or a more intensive approach.Orthopaedics, Trauma Surgery and Rehabilitatio

A highly virulent variant of HIV-1 circulating in the Netherlands.

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log <sub>10</sub> increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence