Valproic acid decreases resuscitation requirements after hemorrhage in a prolonged damage-control resuscitation model.

Background: Hemorrhage is the leading cause of preventable death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. There is a need to demonstrate that p-DCR is feasible and to optimize its logistics.

3-Dimensional objective aesthetic evaluation to replace panel assessment after breast-conserving treatment.

Background: Two-thirds of patients with early breast cancer undergo breast-conserving treatment (BCT). Aesthetic outcome is important and has long term implications for psychosocial wellbeing. The aesthetic goal of BCT is symmetry for which there is no gold-standard measure.

Microsized inflammaging protects stem cells.

In this issue of , Grants et al have identified connections between reduced expression of microRNA-146a (miR-146a), increased inflammation, impaired hematopoietic stem cell (HSC) quiescence, and a poor prognosis for acute myeloid leukemia (AML). miR-146a was originally identified as an anti-inflammatory microRNA that targets signaling proteins, which mediate inflammatory responses. Deletion of miR-146a in mice phenocopies many aspects of age-dependent inflammation, termed “inflammaging.

Protein-based, but not viral vector alone, HIV vaccine boosting drives an IgG1-biased polyfunctional humoral immune response.

The RV144 HIV-1 vaccine trial results showed moderate reduction in viral infections among vaccinees as well as induction of antibody-dependent cellular cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable loop regions 1 and 2 of the HIV envelope protein. However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. One of the changes included in the HVTN 702 study was the addition of a late boost, aimed at augmenting peak immunity and durability.

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth.

The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed to identify miRNAs that control BL cell growth.

Microglia influence host defense, disease, and repair following murine coronavirus infection of the central nervous system.

The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes microglia, prior to infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality compared with control mice that correlated with impaired control of viral replication. Single cell RNA sequencing (scRNASeq) of CD45+ cells isolated from the CNS revealed that PLX5622 treatment resulted in muted CD4+ T cell activation profile that was associated with decreased expression of transcripts encoding MHC class II and CD86 in macrophages but not dendritic cells.

CIPR: a web-based R/shiny app and R package to annotate cell clusters in single cell RNA sequencing experiments.

Background: Single cell RNA sequencing (scRNAseq) has provided invaluable insights into cellular heterogeneity and functional states in health and disease. During the analysis of scRNAseq data, annotating the biological identity of cell clusters is an important step before downstream analyses and it remains technically challenging. The current solutions for annotating single cell clusters generally lack a graphical user interface, can be computationally intensive or have a limited scope.

Evidence accumulation during perceptual decisions in humans varies as a function of dorsal frontoparietal organization.

Animal neurophysiological studies have identified neural signals within dorsal frontoparietal areas that trace a perceptual decision by accumulating sensory evidence over time and trigger action upon reaching a threshold. Although analogous accumulation-to-bound signals are identifiable on extracranial human electroencephalography, their cortical origins remain unknown. Here neural metrics of human evidence accumulation, predictive of the speed of perceptual reports, were isolated using electroencephalography and related to dorsal frontoparietal network (dFPN) connectivity using diffusion and resting-state functional magnetic resonance imaging.

Uric acid predicts long-term cardiovascular risk in type 2 diabetes but does not mediate the benefits of fenofibrate: The FIELD study.

Aim: To explore the relationship between baseline uric acid (UA) levels and long-term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA-lowering effects.

Methods: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6-week, active fenofibrate run-in phase in all participants.

Handheld Osteotomes Facilitate Arthroscopic Treatment of Elbow Valgus Extension Overload.

Arthroscopic elbow surgery can be difficult due to the highly congruent nature of the joint and the surrounding neurovascular and ligamentous structures at risk. In a patient with valgus extension overload, posterior medial olecranon osteophytes must be removed safely to restore range of motion and alleviate pain. Arthroscopic burrs and shavers create significant debris, therefore limiting visualization, and their use has inherent risks to the surrounding structures that need to be preserved.

An Unusual Impaction Fracture of the Tibial Tubercle and Its Surgical Repair: A Case Report.

Case: A 55-year-old man sustained a Schatzker type I lateral tibial plateau fracture, an ipsilateral tibial tubercle (TT) impaction fracture, and an avulsion fracture of the inferior patellar pole. He underwent disimpaction and bone grafting of the tubercle, followed by open reduction internal fixation of the tibial plateau and tubercle, with ligamentum patellae tendon augmentation. At 1-year postoperatively, the patient returned to full activity.

Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

Background: Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects.

T Cell-Expressed microRNA-155 Reduces Lifespan in a Mouse Model of Age-Related Chronic Inflammation.

Aging-related chronic inflammation is a risk factor for many human disorders through incompletely understood mechanisms. Aged mice deficient in microRNA (miRNA/miR)-146a succumb to life-shortening chronic inflammation. In this study, we report that miR-155 in T cells contributes to shortened lifespan of miR-146a mice.

Evaluating the neurophysiological evidence for predictive processing as a model of perception.

For many years, the dominant theoretical framework guiding research into the neural origins of perceptual experience has been provided by hierarchical feedforward models, in which sensory inputs are passed through a series of increasingly complex feature detectors. However, the long-standing orthodoxy of these accounts has recently been challenged by a radically different set of theories that contend that perception arises from a purely inferential process supported by two distinct classes of neurons: those that transmit predictions about sensory states and those that signal sensory information that deviates from those predictions. Although these predictive processing (PP) models have become increasingly influential in cognitive neuroscience, they are also criticized for lacking the empirical support to justify their status.

Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection.

The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined.

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity-Induced Adiposity and Insulin Resistance.

Objective: Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88 ) would prevent, whereas miR146a (MyD88 inhibitor) would exacerbate, inactivity-induced metabolic disturbances.

Methods: Cre-control, MusMyD88 , and miR146a mice were given running wheels for 5 weeks to model an active phenotype.

A multicenter study of thromboembolic events among patients diagnosed with ROS1-rearranged non-small cell lung cancer.

Objectives: This study aimed to describe the longitudinal thromboembolism (TE) risk relative to the natural history of disease and clinical course of ROS1 rearranged non-small cell lung cancer (NSCLC).

Materials And Methods: Cases of ROS1-rearranged NSCLC from six Australian hospitals were pooled and evaluated for incidence, timing, predictors and outcomes of venous or arterial TE, as well as objective response rate (ORR) to active therapy and overall survival (OS).

Results: Of 42 patients recruited, 20 (48%) experienced TE; one (2%) arterial, 13 (31%) a pulmonary emboli (PE), and 12 (29%) a deep vein thrombosis.

Inhibition of SHP-1 Expands the Repertoire of Antitumor T Cells Available to Respond to Immune Checkpoint Blockade.

The presence and activity of CD8 T cells within the tumor microenvironment are essential for the control of tumor growth. Utilizing B16-F10 melanoma tumors that express altered peptide ligands of chicken ovalbumin, OVA, we measured high- and low-affinity OVA-specific responses following adoptive transfer of OT-I CD8 T cell into mice subsequently challenged with tumors. T-cell receptor (TCR) affinity positively correlated with the frequency of OT-I tumor-infiltrating lymphocytes (TIL).

Therapeutic mammaplasty is a safe and effective alternative to mastectomy with or without immediate breast reconstruction.

Background: Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR.

Methods: The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study.

Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial.

Background: The RV144 phase 3 vaccine trial in Thailand demonstrated that ALVAC-HIV (vCP1521) and AIDSVAX B/E administration over 6 months resulted in a 31% efficacy in preventing HIV acquisition. In this trial, we assessed the immunological effect of an additional vaccine boost to the RV144 regimen at varying intervals between the priming vaccine series and the boost.

Methods: RV306 is a double-blind, placebo-controlled, randomised clinical trial done at three clinical sites in Thailand.

Evaluation of Fluorodeoxyglucose Positron Emission Tomography Scanning in the Neoadjuvant Therapy Paradigm in Pancreatic Ductal Adenocarcinoma.

Objectives: Little data exist on the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in operable pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant (NA) therapy.

Methods: Consecutively treated patients with potentially operable PDAC were recruited from a quaternary referral center between 2015 and 2018. Data were collated on demographic, clinical, radiological, treatment, and disease-free and overall survival (OS) outcome measures, correlated with FDG-PET findings.

Inhibition of jasmonate-mediated plant defences by the fungal metabolite higginsianin B.

Infection of Arabidopsis thaliana by the ascomycete fungus Colletotrichum higginsianum is characterized by an early symptomless biotrophic phase followed by a destructive necrotrophic phase. The fungal genome contains 77 secondary metabolism-related biosynthetic gene clusters, whose expression during the infection process is tightly regulated. Deleting CclA, a chromatin regulator involved in the repression of some biosynthetic gene clusters through H3K4 trimethylation, allowed overproduction of three families of terpenoids and isolation of 12 different molecules.

HIV vaccine delayed boosting increases Env variable region 2-specific antibody effector functions.

In the RV144 HIV-1 phase III trial, vaccine efficacy directly correlated with the magnitude of the variable region 2-specific (V2-specific) IgG antibody response, and in the presence of low plasma IgA levels, with the magnitude of plasma antibody-dependent cellular cytotoxicity. Reenrollment of RV144 vaccinees in the RV305 trial offered the opportunity to define the function, maturation, and persistence of vaccine-induced V2-specific and other mAb responses after boosting. We show that the RV144 vaccine regimen induced persistent V2 and other HIV-1 envelope-specific memory B cell clonal lineages that could be identified throughout the approximately 11-year vaccination period.