Structural and Biophysical Characterization of the Mycobacterium tuberculosis Protein Rv0577, a Protein Associated with Neutral Red Staining of Virulent Tuberculosis Strains and Homologue of the Streptomyces coelicolor Protein KbpA.

Mycobacterium tuberculosis protein Rv0577 is a prominent antigen in tuberculosis patients, the component responsible for neutral red staining of virulent strains of M. tuberculosis, a putative component in a methylglyoxal detoxification pathway, and an agonist of toll-like receptor 2. It also has an amino acid sequence that is 36% identical to that of Streptomyces coelicolor AfsK-binding protein A (KbpA), a component in the complex secondary metabolite pathways in the Streptomyces genus. To gain insight into the biological function of Rv0577 and the family of KpbA kinase regulators, the crystal structure for Rv0577 was determined to a resolution of 1.75 Å, binding properties with neutral red and deoxyadenosine were surveyed, backbone dynamics were measured, and thermal stability was assayed by circular dichroism spectroscopy. The protein is composed of four approximate repeats with a ßαßßß topology arranged radially in consecutive pairs to form two continuous eight-strand ß-sheets capped on both ends with an α-helix. The two ß-sheets intersect in the center at roughly a right angle and form two asymmetric deep "saddles" that may serve to bind ligands. Nuclear magnetic resonance chemical shift perturbation experiments show that neutral red and deoxyadenosine bind to Rv0577. Binding to deoxyadenosine is weaker with an estimated dissociation constants of 4.1 ± 0.3 mM for saddle 1. Heteronuclear steady-state {1H}-15N nuclear Overhauser effect, T1, and T2 values were generally uniform throughout the sequence with only a few modest pockets of differences. Circular dichroism spectroscopy characterization of the thermal stability of Rv0577 indicated irreversible unfolding upon heating with an estimated melting temperature of 56 °C.

Magnetic resonance imaging-ultrasound fusion biopsy for prediction of final prostate pathology.

PURPOSE: We explored the impact of magnetic resonance imaging-ultrasound fusion prostate biopsy on the prediction of final surgical pathology. MATERIALS AND METHODS: A total of 54 consecutive men undergoing radical prostatectomy at UCLA after fusion biopsy were included in this prospective, institutional review board approved pilot study. Using magnetic resonance imaging-ultrasound fusion, tissue was obtained from a 12-point systematic grid (mapping biopsy) and from regions of interest detected by multiparametric magnetic resonance imaging (targeted biopsy). A single radiologist read all magnetic resonance imaging, and a single pathologist independently rereviewed all biopsy and whole mount pathology, blinded to prior interpretation and matched specimen. Gleason score concordance between biopsy and prostatectomy was the primary end point. RESULTS: Mean patient age was 62 years and median prostate specific antigen was 6.2 ng/ml. Final Gleason score at prostatectomy was 6 (13%), 7 (70%) and 8-9 (17%). A tertiary pattern was detected in 17 (31%) men. Of 45 high suspicion (image grade 4-5) magnetic resonance imaging targets 32 (71%) contained prostate cancer. The per core cancer detection rate was 20% by systematic mapping biopsy and 42% by targeted biopsy. The highest Gleason pattern at prostatectomy was detected by systematic mapping biopsy in 54%, targeted biopsy in 54% and a combination in 81% of cases. Overall 17% of cases were upgraded from fusion biopsy to final pathology and 1 (2%) was downgraded. The combination of targeted biopsy and systematic mapping biopsy was needed to obtain the best predictive accuracy. CONCLUSIONS: In this pilot study magnetic resonance imaging-ultrasound fusion biopsy allowed for the prediction of final prostate pathology with greater accuracy than that reported previously using conventional methods (81% vs 40% to 65%). If confirmed, these results will have important clinical implications.

Emergent percutaneous closure of sub-annular aortic root pseudoaneurysm in the setting of composite graft dehiscence: a case report.

Background: Aortic conduit pseudoaneurysms are rare complications of surgical aortic root replacements. These complications are typically treated with a redo-sternotomy, but these surgeries carry high mortality rates, and patients may not always be good surgical candidates. There have been a few reported cases where aortic pseudoaneurysms have been successfully treated percutaneously with both short- and long-term success. We describe a case were a sub-annular aortic root pseudoaneurysm was closed using an Amplatzer Vascular Plug 2 device. Case summary: A 68-year-old man was admitted to the hospital 6 weeks after surgical aortic valve and aortic root replacement undergone for prosthetic valve endocarditis. On computed tomography, he was found to have a large fluid collection with extravasation into a false lumen located on the right side of the ascending aorta. Diagnostic catheterization confirmed flow into the pseudoaneurysm cavity from a sub-annular location. This defect was then closed using an Amplatzer Vascular Plug 2 device, with no residual flow or concern for re-opening at 8 months follow-up. Discussion: This case presents the first documented use of an Amplatzer Vascular Plug 2 to close an aortic root pseudoaneurysm in the sub-annular location. Heart team discussion is crucial in determining whether surgical or percutaneous treatment management should be performed. This case highlights a novel treatment method for sub-annular aortic root pseudoaneurysms which can be considered an alternative to surgery and potentially life-saving for high-risk patients.

Multiple decrements in switch task performance in female rats exposed to space radiation.

Astronauts on the Artemis missions to the Moon and Mars will be exposed to unavoidable Galactic Cosmic Radiation (GCR). Studies using male rats suggest that GCR exposure impairs several processes required for cognitive flexibility performance, including attention and task switching. Currently no comparable studies have been conducted with female rats. Given that both males and females will travel into deep space, this study determined whether simulated GCR (GCRsim) exposure impairs task switching performance in female rats. Female Wistar rats exposed to 10 cGy GCRsim (n = 12) and shams (n = 14) were trained to perform a touchscreen-based switch task that mimics a switch task used to evaluate pilots' response times. In comparison to sham rats, three-fold more GCRsim-exposed rats failed to complete the stimulus response stage of training, a high cognitive loading task. In the switch task, 50% of the GCRsim-exposed rats failed to consistently transition between the repeated and switch blocks of stimuli, which they completed during lower cognitive loading training stages. The GCRsim-exposed rats that completed the switch task only performed at 65% of the accuracy of shams. Female rats exposed to GCRsim thus exhibit multiple decrements in the switch task under high, but not low, cognitive loading conditions. While the operational significance of this performance decrement is unknown, if GCRSim exposure was to induce similar effects in astronauts, our data suggests there may be a reduced ability to execute task switching under high cognitive loading situations.

Radiation and CNS effects: summary of evidence from a recent symposium of the Radiation Research Society.

This article summarizes a Symposium on 'Radiation risks of the central nervous system' held virtually at the 67th Annual Meeting of the Radiation Research Society, 3-6 October 2021. Repeated low-dose radiation exposure over a certain period could lead to reduced neuronal proliferation, altered neurogenesis, neuroinflammation and various neurological complications, including psychological consequences, necessitating further research in these areas. Four speakers from radiation biology, genetics and epidemiology presented the latest data from their studies seeking insights into this important topic. This symposium highlighted new and important directions for further research on mental health disorders, neurodegenerative conditions and cognitive impairment. Future studies will examine risks of mental and behavioral disorders and neurodegenerative diseases following protracted radiation exposures to better understand risks of occupational exposures as well as provide insights into risks from exposures to galactic cosmic rays.

Simulated Space Radiation Exposure Effects on Switch Task Performance in Rats.

BACKGROUND: Astronauts on the mission to Mars will be subjected to galactic cosmic radiation (GCR) exposures. While ground-based studies suggest that simulated GCR (GCRsim) exposure impairs performance in multiple cognitive tasks, the impact of such exposures on task switching performance (an important skill for all aviators) has not yet been determined.METHODS: Male Wistar rats previously exposed to 10 cGy of 4He ions or GCRsim and their sham littermates were trained to perform a touchscreen-based switch task designed to mimic warning light response tests used to evaluate pilots' response times.RESULTS: Irradiated rats failed to complete a high cognitive task load training task threefold more frequently than shams. There were 18 (4 Sham, 7 He-, and 7 GCR-exposed) rats that successfully completed initial training and underwent switch task testing. Relative to the sham rats in the switch task, the GCRsim-exposed rats had significantly slower response times in switch but not repeat trials. The GCRsim-exposed rats had significantly (P < 0.01) higher switch response ratios (switch/repeat trial response time) and absolute switch costs (switch minus repeat trial response time) than either the sham or He-exposed rats.DISCUSSION: Rats exposed to GCRsim have significantly impaired performance in the switch task manifested as an absolute switch cost of ∼700 ms. The operational significance of such an increase requires further investigation, but a 1000-ms switch cost results in a twofold increase in cockpit error rates in pilots. If exposure to GCR in space results in similar effects in humans, the operational performance of astronauts on the Mars mission may be suboptimal.Stephenson S, Britten R. Simulated space radiation exposure effects on switch task performance in rats. Aerosp Med Hum Perform. 2022; 93(9):673-680.

A Comprehensive Summary of Systematic Reviews on Sports Injury Prevention Strategies.

BACKGROUND: A large volume of systematic reviews and meta-analyses has been published on the effectiveness of sports injury prevention programs. PURPOSE: To provide a qualitative summary of published systematic reviews and meta-analyses that have examined the effectiveness of sports injury prevention programs on reducing musculoskeletal injuries. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We searched the PubMed, CINAHL, EMBASE, and the Cochrane databases for systematic reviews and meta-analyses that evaluated the effectiveness of sports injury prevention programs. We excluded published abstracts, narrative reviews, articles not published in English, commentaries, studies that described sports injury prevention strategies but did not assess their effectiveness, studies that did not assess musculoskeletal injuries, and studies that did not assess sports-related injuries. The most relevant results were extracted and summarized. Levels of evidence were determined per the Oxford Centre for Evidence-Based Medicine, and methodological quality was assessed using the AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews, revised version). RESULTS: A total of 507 articles were retrieved, and 129 were included. Articles pertaining to all injuries were divided into 9 topics: sports and exercise in general (n = 20), soccer (n = 13), ice hockey (n = 1), dance (n = 1), volleyball (n = 1), basketball (n = 1), tackle collision sports (n = 1), climbing (n = 1), and youth athletes (n = 4). Articles on injuries by anatomic site were divided into 11 topics: general knee (n = 8), anterior cruciate ligament (n = 34), ankle (n = 14), hamstring (n = 11), lower extremity (n = 10), foot (n = 6), groin (n = 2), shoulder (n = 1), wrist (n = 2), and elbow (n = 1). Of the 129 studies, 45.7% were ranked as evidence level 1, and 55.0% were evidence level 2. Based on the AMSTAR-2, 58.9% of the reviews reported a priori review methods, 96.1% performed a comprehensive literature search, 47.3% thoroughly described excluded articles, 79.1% assessed risk of bias for individual studies, 48.8% reported a valid method for statistical combination of data (ie, meta-analysis), 45.0% examined the effect of risk of bias on pooled study results, and 19.4% examined the risk for publication bias. CONCLUSION: This comprehensive review provides sports medicine providers with a single source of the most up-to-date publications in the literature on sports injury prevention.

A Comparison in Outcomes of Preoperative Single-shot versus Continuous Catheter Fascia Iliaca Regional Anesthesia in Geriatric Hip Fracture Patients.

BACKGROUND: Fascia iliaca nerve blocks relieve pain in geriatric hip fracture patients and can be administered via a single-shot or continuous catheter. We compared perioperative opioid consumption and pain scores between these two blocks. METHODS: We performed a prospective, observational cohort study, including geriatric hip fracture patients who received a preoperative block. We compared morphine milligram equivalent (MME) consumption and visual analog scale (VAS) pain scores between single-shot and continuous fascia iliaca blocks at multiple time points: preoperative and on postoperative (POD) day 0, 1, and 2. We compared the change in preoperative total and hourly opioid consumption before and after block placement within and between groups. Secondary outcomes included opioid related adverse events, length of stay, and readmission rates. RESULTS: 107 patients were analyzed, 66 received a single-shot and 41 a continuous block. No significant differences were found between both blocks at any time point for median MME consumption or pain scores. MME [IQR]: preoperative 20.5 [6.0,48.8] vs. 24.0 [8.8,48.0], p=0.95; POD0 6.0 [0.0,18.6] vs. 10.0 [0.0,14.0], p=0.52; POD1 12.0 [0.0,30.0] vs. 18.0 [5.0,24.0], p=0.69; POD2 6.0 [0.0,21.2] vs. 12.0 [0.0,24.0], p=0.54. VAS [IQR]: preoperative 4.0 [2.2,5.3] vs. 4.6 [3.2,5.3], p=0.34; POD0 1.3 [0.0,3.7] vs. 2.5 [0.0,3.6], p=0.73; POD1 2.9 [1.7,4.4] vs. 3.7 [1.5,4.7], p=0.59; POD2 2.4 [1.0,4.4] vs. 3.3 [1.9,4.2], p=0.18. Preoperative MME/hr significantly decreased after the block for both groups: 1.05 [0.0,2.2] to 0.0 [0.0,0.0], p < 0.001; 1.4 [0.6,3.1] to 0.0 [0.0,0.1], p < 0.001. The reduction in MME/hr between groups was not significantly different: 0.9 [0.0,1.9] vs. 1.4 [0.6,3.1], p = 0.067. We found no significant differences in secondary outcomes between groups. CONCLUSIONS: We report no differences in opioid use and pain scores between single-shot and continuous catheter fascia iliaca nerve blocks. Both blocks similarly reduce preoperative opioid consumption.

Time to Block: Early Regional Anesthesia Improves Pain Control in Geriatric Hip Fractures.

BACKGROUND: Fascia iliaca nerve blocks (FIBs) anesthetize the thigh and provide opioid-sparing analgesia for geriatric patients with hip fracture awaiting a surgical procedure. FIBs are recommended for preoperative pain management; yet, block administration is often delayed for hours after admission, and delays in pain management lead to worse outcomes. Our objective was to determine whether opioid consumption and pain following a hip fracture are affected by the time to block (TTB). We also examined length of stay and opioid-related adverse events. METHODS: This prospective cohort study included patients who were ≥60 years of age, presented with a hip fracture, and received a preoperative FIB from March 2017 to December 2017. Individualized care timelines, including the date and time of admission, block placement, and surgical procedure, were created to evaluate the effect that TTB and time to surgery (TTS) had on outcomes. Patterns among TTB, TTS, and morphine milligram equivalents (MME) were investigated using the Spearman rho correlation. For descriptive purposes, we divided patients into 2 groups based on the median TTB. Multivariable regression for preoperative MME and length of stay was performed to assess the effect of TTB. RESULTS: There were 107 patients, with a mean age of 83.3 years, who received a preoperative FIB. The median TTB was 8.5 hours. Seventy-two percent of preoperative MME consumption occurred before block placement (pre-block MME). A longer TTB was most strongly correlated with pre-block MME (rho = 0.54; p < 0.001), and TTS was not correlated. Patients with a faster TTB consumed fewer opioids preoperatively (12.0 compared with 33.1 MME; p = 0.015), had lower visual analog scale scores for pain on postoperative day 1 (2.8 compared with 3.5 points; p = 0.046), and were discharged earlier (4.0 compared with 5.5 days; p = 0.039). There were no differences in preoperative pain scores, postoperative opioid consumption, delirium, or opioid-related adverse events. Multivariate regression showed that every hour of delay in TTB was associated with a 2.8% increase in preoperative MME and a 1.0% increase in the length of stay. CONCLUSIONS: Faster TTB in geriatric patients with hip fracture may reduce opioid use, pain, and length of stay. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Generation and Characterization of a Bivalent HIV-1 Subtype C gp120 Protein Boost for Proof-of-Concept HIV Vaccine Efficacy Trials in Southern Africa.

The viral envelope glycoprotein (Env) is the major target for antibody (Ab)-mediated vaccine development against the Human Immunodeficiency Virus type 1 (HIV-1). Although several recombinant Env antigens have been evaluated in clinical trials, only the surface glycoprotein, gp120, (from HIV-1 subtype B, MN, and subtype CRF_01AE, A244) used in the ALVAC prime-AIDSVAX gp120 boost RV144 Phase III HIV vaccine trial was shown to contribute to protective efficacy, although modest and short-lived. Hence, for clinical trials in southern Africa, a bivalent protein boost of HIV-1 subtype C gp120 antigens composed of two complementary gp120s, from the TV1.C (chronic) and 1086.C (transmitted founder) HIV-1 strains, was selected. Stable Chinese Hamster Cell (CHO) cell lines expressing these gp120s were generated, scalable purification methods were developed, and a detailed analytical analysis of the purified proteins was conducted that showed differences and complementarity in the antigenicity, glycan occupancy, and glycan content of the two gp120 molecules. Moreover, mass spectrometry revealed some disulfide heterogeneity in the expressed proteins, particularly in V1V2-C1 region and most prominently in the TV1 gp120 dimers. These dimers not only lacked binding to certain key CD4 binding site (CD4bs) and V1V2 epitope-directed ligands but also elicited reduced Ab responses directed to those epitopes, in contrast to monomeric gp120, following immunization of rabbits. Both monomeric and dimeric gp120s elicited similarly high titer Tier 1 neutralizing Abs as measured in standard virus neutralization assays. These results provide support for clinical evaluations of bivalent preparations of purified monomeric TV1.C and 1086.C gp120 proteins.

Screening and detection advances in magnetic resonance image-guided prostate biopsy.

Multiparametric magnetic resonance imaging (MRI) has provided a method for visualizing prostate cancer. MRI-ultrasonography fusion allows prostate biopsy to be performed quickly, on an outpatient basis, using the transrectal technique. Targeted biopsies are more sensitive for detection of prostate cancer than nontargeted, systematic biopsies and detect more significant prostate cancers and fewer insignificant cancers than conventional biopsies. A negative MRI scan should not defer biopsy. Two groups who will especially benefit from targeted prostate biopsy are men with low-risk lesions in active surveillance and men with increased prostate-specific antigen levels and previous negative conventional biopsies.