Clinical Outcomes of Rapid Respiratory Virus Testing in Emergency Departments: A Systematic Review and Meta-Analysis.

Importance: Rapid tests for respiratory viruses, including multiplex panels, are increasingly available in emergency departments (EDs). Their association with patient outcomes remains unclear. Objective: To determine if ED rapid respiratory virus testing in patients with suspected acute respiratory infection (ARI) was associated with decreased antibiotic use, ancillary tests, ED length of stay, and ED return visits and hospitalization and increased influenza antiviral treatment. Data Sources: Ovid MEDLINE, Embase (Ovid), Scopus, and Web of Science from 1985 to November 14, 2022. Study Selection: Randomized clinical trials of patients of any age with ARI in an ED. The primary intervention was rapid viral testing. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Two independent reviewers (T.S. and K.W.) extracted data and assessed risk of bias using the Cochrane Risk of Bias, version 2.0. Estimates were pooled using random-effects models. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Main Outcomes and Measures: Antibiotic use and secondary outcomes were pooled separately as risk ratios (RRs) and risk difference estimates with 95% CIs. Results: Of 7157 studies identified, 11 (0.2%; n = 6068 patients) were included in pooled analyses. Routine rapid viral testing was not associated with antibiotic use (RR, 0.99; 95% CI, 0.93-1.05; high certainty) but was associated with higher use of influenza antivirals (RR, 1.33; 95% CI, 1.02-1.75; moderate certainty) and lower use of chest radiography (RR, 0.88; 95% CI, 0.79-0.98; moderate certainty) and blood tests (RR, 0.81; 95% CI, 0.69-0.97; moderate certainty). There was no association with urine testing (RR, 0.95; 95% CI, 0.77-1.17; low certainty), ED length of stay (0 hours; 95% CI, -0.17 to 0.16; moderate certainty), return visits (RR, 0.93; 95%, CI 0.79-1.08; moderate certainty) or hospitalization (RR, 1.01; 95% CI, 0.95-1.08; high certainty). Adults represented 963 participants (16%). There was no association of viral testing with antibiotic use in any prespecified subgroup by age, test method, publication date, number of viral targets, risk of bias, or industry funding. Conclusions and Relevance: The results of this systematic review and meta-analysis suggest that there are limited benefits of routine viral testing in EDs for patients with ARI. Further studies in adults, especially those with high-risk conditions, are warranted.

Death from mantle cell lymphoma limits sequential therapy, particularly after first relapse: Patterns of care and outcomes in a series from Australia and the United Kingdom.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterised by a heterogeneous clinical course. Patients can often receive sequential treatments, yet these typically yield diminishing periods of disease control, raising questions about optimal therapy sequencing. Novel agents, such as chimeric antigen receptor T-cell therapies and bispecific antibodies, show promise in relapsed MCL, but are often reserved for later treatment lines, which may underserve patients with aggressive disease phenotypes who die early in the treatment journey. To assess the problem of patient attrition from lymphoma-related death limiting sequential treatment, we performed a multicentre retrospective cohort analysis of 389 patients treated at Australian and UK centres over a 10-year period. Deaths from MCL increased after each treatment line, with 7%, 23% and 26% of patients dying from uncontrolled MCL after first, second and third lines respectively. Patients with older age at diagnosis and early relapse after induction therapy were at particular risk of death after second-line treatment. This limitation of sequential treatment by lymphoma-related death provides support for the trial of novel therapies in earlier treatment lines, particularly in high-risk patient populations.

What's next?: Time is subjectively dilated not only for 'oddball' events, but also for events immediately after oddballs.

Our experience of time is strikingly plastic: Depending on contextual factors, the same objective duration can seem to fly by or drag on. Perhaps the most direct demonstration of such subjective time dilation is the oddball effect: when seeing identical objects appear one after another, followed by an "oddball" (e.g., a disc that suddenly grows in size, in a sequence of otherwise static discs), observers experience this oddball as having lasted longer than its nonoddball counterparts. Despite extensive work on this phenomenon, a surprisingly foundational question remains unasked: What actually gets dilated? Beyond the oddball, are the objects just before (or just after) the oddball also dilated? As in previous studies, observers viewed sequences of colored discs, one of which could be the oddball-and subsequently reproduced the oddball's duration. Unlike previous studies, however, there were also critical trials in which observers instead reproduced the duration of the disc immediately before or after the oddball. A clear pattern emerged: oddball-induced time dilation extended to the post-oddball disc, but not the pre-oddball disc. Whence this temporal asymmetry? We suggest that an oddball's sudden appearance may induce uncertainty about what will happen next, heightening attention until after the uncertainty is resolved.

COVID-19 Epidemiology during Delta Variant Dominance Period in 45 High-Income Countries, 2020-2021.

The SARS-CoV-2 Delta variant, first identified in October 2020, quickly became the dominant variant worldwide. We used publicly available data to explore the relationship between illness and death (peak case rates, death rates, case-fatality rates) and selected predictors (percentage vaccinated, percentage of the population >65 years, population density, testing volume, index of mitigation policies) in 45 high-income countries during the Delta wave using rank-order correlation and ordinal regression. During the Delta-dominant period, most countries reported higher peak case rates (57%) and lower peak case-fatality rates (98%). Higher vaccination coverage was protective against peak case rates (odds ratio 0.95, 95% CI 0.91-0.99) and against peak death rates (odds ratio 0.96, 95% CI 0.91-0.99). Vaccination coverage was vital to preventing infection and death from COVID-19 during the Delta wave. As new variants emerge, public health authorities should encourage the uptake of COVID-19 vaccination and boosters.

Full-length optic nerve regeneration in the absence of genetic manipulations.

The inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -nonautonomous factors. Although manipulations of cell-nonautonomous factors could have higher translational potential than genetic manipulations of RGCs, they have generally produced lower levels of optic nerve regeneration. Here, we report that preconditioning resulting from mild lens injury (conditioning LI, cLI) before optic nerve damage induced far greater regeneration than LI after nerve injury or the pro-inflammatory agent zymosan given either before or after nerve damage. Unlike zymosan-induced regeneration, cLI was unaltered by depleting mature neutrophils or T cells or blocking receptors for known inflammation-derived growth factors (oncomodulin, stromal cell-derived factor 1, CCL5) and was only partly diminished by suppressing CCR2+ monocyte recruitment. Repeated episodes of LI led to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor inhibitor PLX5622 enabled some axons to reinnervate the brain in just 6 weeks, comparable to the results obtained with the most effective genetic manipulations of RGCs. Thus, cell-nonautonomous interventions can induce high levels of optic nerve regeneration, paving the way to uncovering potent, translatable therapeutic targets for CNS repair.

Preclinical evaluation of triiodothyronine nanoparticles as a novel therapeutic intervention for resuscitation from cardiac arrest.

BACKGROUND: Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling. METHODS: Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis. RESULTS: Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np. CONCLUSIONS: T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.

Seeing Soft Materials Draped Over Objects: A Case Study of Intuitive Physics in Perception, Attention, and Memory.

We typically think of intuitive physics in terms of high-level cognition, but might aspects of physics also be extracted during lower-level visual processing? Might we not only think about physics, but also see it? We explored this using multiple tasks in online adult samples with objects covered by soft materials-as when you see a chair with a blanket draped over it-where you must account for the physical interactions between cloth, gravity, and object. In multiple change-detection experiments (n = 200), observers from an online testing marketplace were better at detecting image changes involving underlying object structure versus those involving only the superficial folds of cloths-even when the latter were more extreme along several dimensions. And in probe-comparison experiments (n = 100), performance was worse when both probes (vs. only one) appeared on image regions reflective of underlying object structure (equating visual properties). This work collectively shows how vision uses intuitive physics to recover the deeper underlying structure of scenes.

Centre-based comparison of double versus single prevention strategy on transfusion-transmitted cytomegalovirus in at-risk haemopoietic stem cell transplant patients and a state survey on cytomegalovirus-seronegative ordering practises.

BACKGROUND: Universal leucocyte depletion reduces the risk of transfusion-transmitted cytomegalovirus; however, many clinicians still prescribe cytomegalovirus seronegative units. AIM: Our retrospective study aims to confirm the low risk of transfusion-transmitted cytomegalovirus with leucocyte depletion alone and demonstrate the ongoing variability in cytomegalovirus seronegative transfusion prescribing. METHODS: Over a 9-year period (July 2009-July 2018), occurrences of transfusion transmitted cytomegalovirus in cytomegalovirus seronegative donor/recipient haemopoietic stem cell transplant pairs were compared at one allogeneic haemopoietic stem cell transplant centre providing cytomegalovirus seronegative blood products and leucocyte depletion (double prevention) versus another providing leucocyte depletion only (single prevention). Retrospective chart audit identified patient demographics, blood product exposure and cytomegalovirus infection by polymerase chain reaction. A separate audit examined cytomegalovirus seronegative blood product ordering in a broader range of hospital types. RESULTS: We identified 122 and 66 cytomegalovirus-negative donor/recipient haemopoietic stem cell transplant pairs using double and single transfusion prevention strategy respectively. Transfusion exposure to red cells and pooled platelets was similar, although more apheresis platelets were used in the double prevention group. The cytomegalovirus infection rate was 3 (2.4%) and zero in the double and single prevention groups respectively. Cytomegalovirus seronegative unit ordering was not limited to hospitals with obstetric or neonatal populations, suggesting ongoing reliance of cytomegalovirus seronegative units outside this population. CONCLUSIONS: The analysis suggests a double prevention strategy does not provide additional protection against transfusion-transmitted cytomegalovirus. There is ongoing variability in the acceptance of leucocyte depletion alone despite the low risk of cytomegalovirus infection.

Determining Gaps in Publicly Shared SARS-CoV-2 Genomic Surveillance Data by Analysis of Global Submissions.

Viral genomic surveillance has been a critical source of information during the COVID-19 pandemic, but publicly available data can be sparse, concentrated in wealthy countries, and often made public weeks or months after collection. We used publicly available viral genomic surveillance data submitted to GISAID and GenBank to examine sequencing coverage and lag time to submission during 2020-2021. We compared publicly submitted sequences by country with reported infection rates and population and also examined data based on country-level World Bank income status and World Health Organization region. We found that as global capacity for viral genomic surveillance increased, international disparities in sequencing capacity and timeliness persisted along economic lines. Our analysis suggests that increasing viral genomic surveillance coverage worldwide and decreasing turnaround times could improve timely availability of sequencing data to inform public health action.

Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors.

The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5-10 years.

CaFÉ: A Sensitive, Low-Cost Filtration Method for Detecting Polioviruses and Other Enteroviruses in Residual Waters.

Acute flaccid paralysis (AFP) surveillance has been used to identify polio cases and target vaccination campaigns since the inception of the Global Poliovirus Eradication Initiative (GPEI) in 1988. To date, only Afghanistan and Pakistan have failed to interrupt wild poliovirus transmission. Circulation of vaccine-derived polioviruses (VDPV) continues to be a problem in high-risk areas of the Eastern Mediterranean, African, and Southeast Asian regions. Environmental surveillance (ES) is an important adjunct to AFP surveillance, helping to identify circulating polioviruses in problematic areas. Stools from AFP cases and contacts (>200,000 specimens/year) and ES samples (>642 sites) are referred to 146 laboratories in the Global Polio Laboratory Network (GPLN) for testing. Although most World Health Organization supported laboratories use the two-phase separation method due to its simplicity and effectiveness, alternative simple, widely available, and cost-effective methods are needed. The CAFÉ (Concentration and Filtration Elution) method was developed from existing filtration methods to handle any type of sewage or residual waters. At $10-20 US per sample for consumable materials, CAFÉ is cost effective, and all equipment and reagents are readily available from markets and suppliers globally. The report describes the results from a parallel study of CAFÉ method with the standard two-phase separation method. The study was performed with samples collected from five countries (Guatemala, Haïti, Thailand, Papua New Guinea, and the Philippines), run in three laboratories-(United States, Thailand and in the Philippines) to account for regional and sample-to-sample variability. Samples from each site were divided into two 500 ml aliquots and processed by both methods, with no other additional concentration or manipulation. The results of 338 parallel-tested samples show that the CAFÉ method is more sensitive than the two-phase separation method for detection of non-polio enteroviruses (p-value < 0.0001) and performed as well as the two-phase separation method for polioviruses detection with no significant difference (p-value > 0.05). The CAFÉ method is a robust, sensitive, and cost-effective method for isolating enteroviruses from residual waters.

Use of guanidine thiocyanate-based nucleic acid extraction buffers to inactivate poliovirus in potentially infectious materials.

The efforts of the Global Poliovirus Eradication Initiative (GPEI) have brought about the near elimination of poliovirus worldwide. The World Health Organization has issued guidelines for the safe handling and containment of infectious materials (IM) and potentially infectious materials (PIM) following poliovirus eradication. Inactivation of poliovirus in IM and PIM is needed to prevent inadvertent re-introduction of polioviruses post-eradication. In this study, we investigated the use of guanidine thiocyanate-based nucleic acid extraction buffers from commercially available nucleic acid extraction kits to inactivate poliovirus in cell culture isolates and stool suspensions, two common types of poliovirus IM and PIM, respectively. Incubation with selected nucleic acid extraction buffers or extraction buffers supplemented with ethanol reduced the infectivity of high-titer wild poliovirus type 1 (WPV1), wild poliovirus type 3 (WPV3), Sabin 1 (SL1), and Sabin 3 (SL3) cell culture isolates below the limit of detection in CCID50 assays. Stool suspensions containing WPV1, WPV3, SL1, SL2, or SL3 were also inactivated by the extraction buffers tested. Blind passage of WPV1-spiked stool suspensions confirmed complete inactivation of WPV1 after incubation with extraction buffers. Moreover, treatment with a buffer consisting of 4 M guanidine thiocyanate with 30 % ethanol inactivated a high-titer WPV1 culture isolate and a WPV1-spiked stool suspension. Taken together, these results show that guanidine thiocyanate-based nucleic acid extraction buffers are an effective means of inactivating poliovirus IM and PIM, and thus will be instrumental in ensuring containment compliance and preventing potential re-emergence of contained polioviruses.

Environmental Surveillance for Risk Assessment in the Context of a Phase 2 Clinical Trial of Type 2 Novel Oral Polio Vaccine in Panama.

Environmental surveillance was recommended for risk mitigation in a novel oral polio vaccine-2 (nOPV2) clinical trial (M5-ABMG) to monitor excretion, potential circulation, and loss of attenuation of the two nOPV2 candidates. The nOPV2 candidates were developed to address the risk of poliovirus (PV) type 2 circulating vaccine-derived poliovirus (cVDPV) as part of the global eradication strategy. Between November 2018 and January 2020, an environmental surveillance study for the clinical trial was conducted in parallel to the M5-ABMG clinical trial at five locations in Panama. The collection sites were located upstream from local treatment plant inlets, to capture the excreta from trial participants and their community. Laboratory analyses of 49 environmental samples were conducted using the two-phase separation method. Novel OPV2 strains were not detected in sewage samples collected during the study period. However, six samples were positive for Sabin-like type 3 PV, two samples were positive for Sabin-like type 1 PV, and non-polio enteroviruses NPEVs were detected in 27 samples. One of the nOPV2 candidates has been granted Emergency Use Listing by the World Health Organization and initial use started in March 2021. This environmental surveillance study provided valuable risk mitigation information to support the Emergency Use Listing application.

Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve.

Axon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries, and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on RGC survival. Local injections of C1q function-blocking antibody revealed that complement acts primarily within the optic nerve, not retina, to support regeneration. Moreover, C1q opsonizes and CR3+ microglia/monocytes phagocytose growth-inhibitory myelin debris after ONI, a likely mechanism through which complement and myeloid cells support axon regeneration. Collectively, these results indicate that local optic nerve complement-myeloid phagocytic signaling is required for CNS axon regrowth, emphasizing the axonal compartment and highlighting a beneficial neuroimmune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENT Despite the importance of achieving axon regeneration after CNS injury and the inevitability of inflammation after such injury, the contributions of complement and microglia to CNS axon regeneration are largely unknown. Whereas inflammation is commonly thought to exacerbate the effects of CNS injury, we find that complement proteins C1q and C3 and microglia/monocyte phagocytic complement receptor CR3 are each required for retinal ganglion cell axon regeneration through the injured mouse optic nerve. Also, whereas studies of optic nerve regeneration generally focus on the retina, we show that the regeneration-relevant role of complement and microglia/monocytes likely involves myelin phagocytosis within the optic nerve. Thus, our results point to the importance of the innate immune response for CNS repair.

Environmental Surveillance for Polioviruses in Haïti (2017-2019): The Dynamic Process for the Establishment and Monitoring of Sampling Sites.

Haïti is at risk for wild poliovirus (WPV) importation and circulation, as well as vaccine-derived poliovirus (VDPV) emergence. Environmental surveillance (ES) for polioviruses was established in Port au Prince and Gonaïves in 2016. During 2017-2019, initial ES sites were re-evaluated, and ES was expanded into Cap Haïtien and Saint Marc. Wastewater samples and data on weather, hour of collection, and sample temperature and pH were collected every 4 weeks during March 2017-December 2019 (272 sampling events) from 21 sites in Cap Haïtien, Gonaïves, Port au Prince, and Saint Marc. Samples were processed for the detection of polio and non-polio enteroviruses using the two-phase and "Concentration and Filter Elution" methodologies. Polioviruses were serotyped and underwent intra-typic characterization. No WPV or VDPVs were isolated. Sabin-like polioviruses (oral vaccine strain) of serotypes 1 and 3 were sporadically detected. Five of six (83%), one of six (17%), five of six (83%), and two of three (67%) sites evaluated in Cap Haïtien, Gonaïves, Port au Prince, and Saint Marc, respectively, had enterovirus isolation from >50% of sampling events; these results and considerations, such as watershed population size and overlap, influence of sea water, and excessive particulates in samples, were factors in site retention or termination. The evaluation of 21 ES sampling sites in four Haïtian cities led to the termination of 11 sites. Every-four-weekly sampling continues at the remaining 10 sites across the four cities as a core Global Polio Eradication Initiative activity.

Identifying optimal program structure, motivations for and barriers to peer coaching participation for surgeons in practice: a qualitative synthesis.

BACKGROUND: Continuous advancement of surgical skills is of utmost importance to surgeons in practice, but traditional learning activities without personalized feedback often do not translate into practice changes in the operating room. Peer coaching has been shown to lead to very high rates of practice changes and utilization of new skills. The purpose of this study was to explore the opinions of practicing surgeons regarding the characteristics of peer coaching programs, in order to better inform future peer coaching program design. METHODS: Using a convenience sample, practicing general surgeons were invited to participate in focus group interviews. Allocation into groups was according to years in practice. The interviews were conducted using open-ended questions by trained facilitators. Audio recordings were transcribed and coded into themes by two independent reviewers using a grounded theory approach. RESULTS: Of 52 invitations, 27 surgeons participated: 74% male; years in practice: < 5 years: 33%; 5-15 years: 26%; > 15 years: 41%. Three main themes emerged during coding: ideal program structure, motivations for participation, and barriers to implementation. For the ideal structure of a peer coaching program all groups agreed coaching programs should be voluntary, involve bidirectional learning, and provide CME credits. Live, in situ coaching was preferred. Motivations for coaching participation included: desire to learn new techniques (48%), remaining up to date with the evolution of surgical practice (30%) and improvement of patient outcomes (18%). Barriers to program implementation were categorized as: surgical culture (42%), perceived lack of need (26%), logistical constraints (23%) and issues of coach-coachee dynamics (9%). CONCLUSION: Peer coaching to refine or acquire new skills addresses many shortcomings of traditional, didactic learning modalities. This study revealed key aspects of optimal program structure, motivations and barriers to coaching which can be used to inform the design of successful peer coaching programs in the future.

AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes.

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.

Optic nerve regeneration: A long view.

The optic nerve conveys information about the outside world from the retina to multiple subcortical relay centers. Until recently, the optic nerve was widely believed to be incapable of re-growing if injured, with dire consequences for victims of traumatic, ischemic, or neurodegenerative diseases of this pathway. Over the past 10-20 years, research from our lab and others has made considerable progress in defining factors that normally suppress axon regeneration and the ability of retinal ganglion cells, the projection neurons of the retina, to survive after nerve injury. Here we describe research from our lab on the role of inflammation-derived growth factors, suppression of inter-cellular signals among diverse retinal cell types, and combinatorial therapies, along with related studies from other labs, that enable animals with optic nerve injury to regenerate damaged retinal axons back to the brain. These studies raise the possibility that vision might one day be restored to people with optic nerve damage.

Lytic transglycosylases RlpA and MltC assist in Vibrio cholerae daughter cell separation.

The cell wall is a crucial structural feature in the vast majority of bacteria and comprises a covalently closed network of peptidoglycan (PG) strands. While PG synthesis is important for survival under many conditions, the cell wall is also a dynamic structure, undergoing degradation and remodeling by 'autolysins', enzymes that break down PG. Cell division, for example, requires extensive PG remodeling, especially during separation of daughter cells, which depends heavily upon the activity of amidases. However, in Vibrio cholerae, we demonstrate that amidase activity alone is insufficient for daughter cell separation and that lytic transglycosylases RlpA and MltC both contribute to this process. MltC and RlpA both localize to the septum and are functionally redundant under normal laboratory conditions; however, only RlpA can support normal cell separation in low-salt media. The division-specific activity of lytic transglycosylases has implications for the local structure of septal PG, suggesting that there may be glycan bridges between daughter cells that cannot be resolved by amidases. We propose that lytic transglycosylases at the septum cleave PG strands that are crosslinked beyond the reach of the highly regulated activity of the amidase and clear PG debris that may block the completion of outer membrane invagination.

Current Treatment Options for Primary Biliary Cholangitis.

Primary biliary cholangitis is a progressive, autoimmune disease of the interlobular bile ducts, leading to secondary damage of hepatocytes that may progress to cirrhosis and liver failure. Until recently, the only approved treatment was ursodeoxycholic acid. However, 40% of patients do not have an adequate response. Obeticholic acid was approved for treatment as add-on therapy in this group of patients. Off-label use of fibrates has also been reported to be effective. Several new therapies are in development and may further add to the treatment options available to patients with primary biliary cholangitis.