Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys.

Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. ZIKV-specific neutralizing antibodies correlated with rapid clearance of virus in peripheral blood but remained undetectable in CSF for the duration of the study. Viral persistence in both CSF and LN correlated with upregulation of mechanistic target of rapamycin (mTOR), proinflammatory, and anti-apoptotic signaling pathways, as well as downregulation of extracellular matrix signaling pathways. These data raise the possibility that persistent or occult neurologic and lymphoid disease may occur following clearance of peripheral virus in ZIKV-infected individuals.

Directed information exchange between cortical layers in macaque V1 and V4 and its modulation by selective attention.

Achieving behavioral goals requires integration of sensory and cognitive information across cortical laminae and cortical regions. How this computation is performed remains unknown. Using local field potential recordings and spectrally resolved conditional Granger causality (cGC) analysis, we mapped visual information flow, and its attentional modulation, between cortical layers within and between macaque brain areas V1 and V4. Stimulus-induced interlaminar information flow within V1 dominated upwardly, channeling information toward supragranular corticocortical output layers. Within V4, information flow dominated from granular to supragranular layers, but interactions between supragranular and infragranular layers dominated downwardly. Low-frequency across-area communication was stronger from V4 to V1, with little layer specificity. Gamma-band communication was stronger in the feedforward V1-to-V4 direction. Attention to the receptive field of V1 decreased communication between all V1 layers, except for granular-to-supragranular layer interactions. Communication within V4, and from V1 to V4, increased with attention across all frequencies. While communication from V4 to V1 was stronger in lower-frequency bands (4 to 25 Hz), attention modulated cGCs from V4 to V1 across all investigated frequencies. Our data show that top-down cognitive processes result in reduced communication within cortical areas, increased feedforward communication across all frequency bands, and increased gamma-band feedback communication.

Factors contributing to a longer length of stay in adults admitted to a quaternary spinal care center.

BACKGROUND: Longer hospital length of stay (LOS) has been associated with worse outcomes and increased resource utilization. However, diagnostic and patient-level factors associated with LOS have not been well studied on a large scale. The goal was to identify patient, surgical and organizational factors associated with longer patient LOS for adult patients at a high-volume quaternary spinal care center. METHODS: We performed a retrospective analysis of 13,493 admissions from January 2006 to December 2019. Factors analyzed included age, sex, admission status (emergent vs scheduled), ASIA grade, operative vs non-operative management, mean blood loss, operative time, and adverse events. Specific adverse events included surgical site infection (SSI), other infection (systemic or UTI), neuropathic pain, delirium, dural tear, pneumonia, and dysphagia. Diagnostic categories included trauma, oncology, deformity, degenerative, and "other". A multivariable linear regression model was fit to log-transformed LOS to determine independent factors associated with patient LOS, with effects expressed as multipliers on mean LOS. RESULTS: Mean LOS for the population (SD) was 15.8 (34.0) days. Factors significantly (p < 0.05) associated with longer LOS were advanced patient age [multiplier on mean LOS 1.011/year (95% CI: 1.007-1.015)], emergency admission [multiplier on mean LOS 1.615 (95% CI: 1.337-1.951)], ASIA grade [multiplier on mean LOS 1.125/grade (95% CI: 1.051-1.205)], operative management [multiplier on mean LOS 1.211 (95% CI: 1.006-1.459)], and the occurrence of one or more AEs [multiplier on mean LOS 2.613 (95% CI: 2.188-3.121)]. Significant AEs included postoperative SSI [multiplier on mean LOS 1.749 (95% CI: 1.250-2.449)], other infections (systemic infections and UTI combined) [multiplier on mean LOS 1.650 (95% CI: 1.359-2.004)], delirium [multiplier on mean LOS 1.404 (95% CI: 1.103-1.787)], and pneumonia [multiplier on mean LOS 1.883 (95% CI: 1.447-2.451)]. Among the diagnostic categories explored, degenerative patients experienced significantly shorter LOS [multiplier on mean LOS 0.672 (95%CI: 0.535-0.844), p < 0.001] compared to non-degenerative categories. CONCLUSION: This large-scale study taking into account diagnostic categories identified several factors associated with patient LOS. Future interventions should target modifiable factors to minimize LOS and guide hospital resource allocation thereby improving patient outcomes and quality of care and decreasing healthcare-associated costs.

Degenerative spinal conditions requiring emergency surgery: an evolving crisis in a publicly funded health care system.

BACKGROUND: Surgery for degenerative spine pathologies is typically performed on a scheduled basis; however, worsening symptoms may warrant emergency surgery. An increasing number of patients requiring emergency surgery has been observed (22.6% in 2006 to 34.8% in 2019). We sought to compare the outcomes of patients who received scheduled surgery and those who required emergency surgery. METHODS: All patients treated between Jan. 1, 2006, and Dec. 31, 2019, were included. Retrospective comparisons were made between patients who were scheduled (elective) for surgery and those requiring emergency surgery, patients who were scheduled for surgery and those who decompensated while on the surgical waitlist and patients who presented as de novo emergencies and those who decompensated while on the surgical waitlist. RESULTS: Among the 6217 patients with degenerative pathologies, 4654 (74.9%) patients were scheduled (elective) for surgery and 1563 (25.1%) were patients requiring emergency surgery. Compared with patients who were scheduled, patients requiring emergency surgery had a longer length of stay (LOS) in hospital (5.1 d, interquartile range [IQR] 2.7-11.2 v. 3.6 d, IQR 1.3-6.4, p < 0.001) and lower rate of home discharge (78.6% v. 94.2%, p < 0.001). Patients requiring emergency surgery were 1.34 times more likely to have any adverse events (95% confidence interval [CI] 1.06-1.68, p = 0.01). When compared with patients who were scheduled for surgery, those who decompensated while on the surgical waitlist had longer LOS (7.0 d, IQR 3.3-15.0 v. 3.6 d, IQR 1.3-6.4, p < 0.001), less home discharge (77.6% v. 94.2%, p < 0.001) and were 2.5 times more likely to have any adverse events (95% CI 1.5-4.1, p < 0.001). Patients who decompensated had a 2.1 times higher risk of having any adverse events than patients who presented as de novo emergencies (95% CI 1.2-3.6, p < 0.001). CONCLUSION: We observed worse perioperative outcomes for patients requiring emergency surgery for degenerative spinal conditions than for patients who were scheduled for surgery. Patients who decompensated while on the surgical waitlist had the worst outcomes.

Vaccine protection against Zika virus from Brazil.

Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. The rapid development of a safe and effective ZIKV vaccine is a global health priority, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization with a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a strain of ZIKV involved in the outbreak in northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice. We produced DNA vaccines expressing ZIKV pre-membrane and envelope (prM-Env), as well as a series of deletion mutants. The prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV, as measured by absence of detectable viraemia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and depletion of CD4 and CD8 T lymphocytes in vaccinated mice did not abrogate this protection. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans is likely to be achievable.

Patient controlled analgesia for the management of acute pain in the emergency department: A systematic review.

BACKGROUND: The most common presenting complaint to the emergency department (ED) is pain. Several studies have shown that a large proportion of ED patients either receive no or sub-optimal analgesia. Patient-controlled analgesia (PCA) pumps used in the post-operative setting has shown to decrease total opioid consumption and has increased patient and nurse satisfaction. OBJECTIVE: The purpose of this systematic review was to evaluate clinical trials that have used PCAs in the ED setting, to evaluate safety and efficacy as well as patient and healthcare provider experience. METHODS: A search of PubMed, MEDLINE, and the Cochrane Database was conducted using the MESH search terms emergency department, patient-controlled analgesia, and acute pain up to September 2021. These terms were searched in all fields of publication and were limited to the English-language articles, clinical "human" studies, and studies that included the use of patient-controlled analgesia in the setting of the emergency department. RESULTS: The search initially identified 227 potentially relevant articles and a total of 10 studies met criteria for inclusion. ED use of PCA therapy was associated with increased patient satisfaction, decreased pain scores, and an overall increase in opioid consumption. CONCLUSION: The quality, the differences in study methods and outcome measures used, and heterogeneity of the studies performed to date do not provide adequate evidence to support its widespread use in the ED. Well-designed studies conducted in the ED are still needed to evaluate the ideal patient population to whom these PCAs may provide the most benefit as well as a robust cost-analysis to ensure feasibility of use in the future.

Patient perspective: diagnosis and prognosis of acute spinal cord injuries.

STUDY DESIGN: Qualitative study. OBJECTIVES: The purpose of this study is to understand the patient perspective after diagnosis of an acute traumatic spinal cord injury (tSCI). Discussing the diagnosis and prognosis of a tSCI with a patient can be a challenging experience for both the patient and the physician. As such, this paper attempts to better understand the patient experience to improve communication when discussing this life-altering injury. SETTING: Vancouver General Hospital, Vancouver, British Columbia, Canada. METHODS: This study is a qualitative study utilizing grounded theory and semi-structured interviews. The interview transcripts were manually coded using manifest and latent content analysis. Major and minor codes were identified and discussed. RESULTS: In total, 17 interviews were conducted, fifteen individuals with tSCI who received acute care at Vancouver General Hospital (VGH) and eleven family members were interviewed. Patient participants were interviewed individually or in a paired interview with a participating family member. Patient participants had varying spinal cord injuries from AIS A-D. Two major themes were identified from the interviews. The first major theme was physician demeanor (general approach and attitude towards patients) and the second major theme was delivery of information (content, timing, and source). CONCLUSIONS: This study summarizes the preferences of patients who sustained a tSCI discussions regarding their diagnosis and prognosis in the acute care setting. The goal of this study is to help guide physician interactions at this difficult and vulnerable time for patients with hopes to improve patient care through effective communication.

Visible-Light-Mediated N-Desulfonylation of N-Heterocycles Using a Heteroleptic Copper(I) Complex as a Photocatalyst.

A photoredox protocol that uses a heteroleptic Cu (I) complex, [Cu(dq)(BINAP)]BF4, has been developed for the photodeprotection of benzenesulfonyl-protected N-heterocycles. A range of substrates was examined, including indazoles, indoles, pyrazoles, and benzimidazole, featuring both electron-rich and electron-deficient substituents, giving good yields of the N-heterocycle products with broad functional group tolerance. This transformation was also found to be amenable to flow reaction conditions.

Application of a Dual Catalytic Nickel/Iridium-Based Photoredox Reaction to Synthesize 2-Alkyl-N-Arylindoles in a Continuous Flow.

A versatile one-pot procedure for the preparation of 2-alkyl-substituted N-arylindoles is described. The method combines a visible light-mediated Ni/Ir-photoredox dual catalytic N-arylation of alkynyl anilines under continuous flow conditions with a subsequent base-mediated cyclization to afford the desired substituted indoles. The initial Ni/Ir photoredox-promoted N-arylation of alkynylanilines proceeds efficiently in a continuous flow to afford the desired products in moderate to excellent yields with a short residence time (20 min) and mild conditions at ambient temperature and without the exclusion of air. The methodology was amenable for a multi-gram scale-up to deliver 2-alkyl-N-arylindoles in high yields followed with only a single purification step.

Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials.

BACKGROUND: A safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings. METHODS: We did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 µg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233. FINDINGS: We enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies. INTERPRETATION: The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults. FUNDING: Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases.

Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice.

Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies. However, administration of purified bNAbs poses challenges in resource-poor settings, where the HIV-1 disease burden is greatest. In vivo vector-based production of bNAbs represents an alternative strategy. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121 in wild-type and immunocompromised C57BL/6 mice as well as in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice. Ad5.PGT121 and AAV1.PGT121 produced functional antibody in vivo Ad5.PGT121 produced PGT121 rapidly within 6 h, whereas AAV1.PGT121 produced detectable PGT121 in serum by 72 h. Serum PGT121 levels were rapidly reduced by the generation of anti-PGT121 antibodies in immunocompetent mice but were durably maintained in immunocompromised mice. In HIV-1-infected BLT humanized mice, Ad5.PGT121 resulted in a greater reduction of viral loads than did AAV1.PGT121. Ad5.PGT121 also led to more-sustained virologic control than purified PGT121 IgG. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice. Further evaluation of vector delivery of HIV-1 bNAbs is warranted, although approaches to prevent the generation of antiantibody responses may also be required.IMPORTANCE Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies, but delivery of purified antibodies may prove challenging. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice.

Rapid Cloning of Novel Rhesus Adenoviral Vaccine Vectors.

Human and chimpanzee adenovirus vectors are being developed to circumvent preexisting antibodies against common adenovirus vectors such as Ad5. However, baseline immunity to these vectors still exists in human populations. Traditional cloning of new adenovirus vaccine vectors is a long and cumbersome process that takes 2 months or more and that requires rare unique restriction enzyme sites. Here we describe a novel, restriction enzyme-independent method for rapid cloning of new adenovirus vaccine vectors that reduces the total cloning procedure to 1 week. We developed 14 novel adenovirus vectors from rhesus monkeys that can be grown to high titers and that are immunogenic in mice. All vectors grouped with the unusual adenovirus species G and show extremely low seroprevalence in humans. Rapid cloning of novel adenovirus vectors is a promising approach for the development of new vector platforms. Rhesus adenovirus vectors may prove useful for clinical development.IMPORTANCE To overcome baseline immunity to human and chimpanzee adenovirus vectors, we developed 14 novel adenovirus vectors from rhesus monkeys. These vectors are immunogenic in mice and show extremely low seroprevalence in humans. Rhesus adenovirus vectors may prove useful for clinical development.

Impact of prior flavivirus immunity on Zika virus infection in rhesus macaques.

Studies have demonstrated cross-reactivity of anti-dengue virus (DENV) antibodies in human sera against Zika virus (ZIKV), promoting increased ZIKV infection in vitro. However, the correlation between in vitro and in vivo findings is not well characterized. Thus, we evaluated the impact of heterotypic flavivirus immunity on ZIKV titers in biofluids of rhesus macaques. Animals previously infected (≥420 days) with DENV2, DENV4, or yellow fever virus were compared to flavivirus-naïve animals following infection with a Brazilian ZIKV strain. Sera from DENV-immune macaques demonstrated cross-reactivity with ZIKV by antibody-binding and neutralization assays prior to ZIKV infection, and promoted increased ZIKV infection in cell culture assays. Despite these findings, no significant differences between flavivirus-naïve and immune animals were observed in viral titers, neutralizing antibody levels, or immune cell kinetics following ZIKV infection. These results indicate that prior infection with heterologous flaviviruses neither conferred protection nor increased observed ZIKV titers in this non-human primate ZIKV infection model.

Studies of radiation health effects inform EPA actions.

In 1970, the US Environmental Protection Agency (EPA) was given the responsibility to provide guidance to other federal agencies in the formulation of radiation protection standards. To carry out its federal guidance responsibilities and protect human health, the EPA must estimate risk at low doses to limit the risk of radiogenic cancers from environmental exposures. These risk estimates are based on models which conform to the linear no threshold (LNT) hypothesis. A cancer risk model conforms to the LNT hypothesis if the excess risk of cancer at low doses increases approximately proportional to dose, with no threshold. Risk models with a linear-quadratic dose response can satisfy the LNT hypothesis. Based on careful review of evidence from epidemiological and radiobiological studies, authoritative scientific bodies have repeatedly endorsed the use of LNT models for estimating and regulating risk and concluded that despite uncertainties at low dose and dose rates, the LNT model remains the most practical and implementable model for radiation protection. This article describes the rationale underlying the use of LNT models for calculating risk for low dose and dose rate exposures and discusses some of the epidemiological evidence which inform on its continued use.

Production of Mucosally Transmissible SHIV Challenge Stocks from HIV-1 Circulating Recombinant Form 01_AE env Sequences.

Simian-human immunodeficiency virus (SHIV) challenge stocks are critical for preclinical testing of vaccines, antibodies, and other interventions aimed to prevent HIV-1. A major unmet need for the field has been the lack of a SHIV challenge stock expressing circulating recombinant form 01_AE (CRF01_AE) env sequences. We therefore sought to develop mucosally transmissible SHIV challenge stocks containing HIV-1 CRF01_AE env derived from acutely HIV-1 infected individuals from Thailand. SHIV-AE6, SHIV-AE6RM, and SHIV-AE16 contained env sequences that were >99% identical to the original HIV-1 isolate and did not require in vivo passaging. These viruses exhibited CCR5 tropism and displayed a tier 2 neutralization phenotype. These challenge stocks efficiently infected rhesus monkeys by the intrarectal route, replicated to high levels during acute infection, and established chronic viremia in a subset of animals. SHIV-AE16 was titrated for use in single, high dose as well as repetitive, low dose intrarectal challenge studies. These SHIV challenge stocks should facilitate the preclinical evaluation of vaccines, monoclonal antibodies, and other interventions targeted at preventing HIV-1 CRF01_AE infection.

C-H Functionalization of Heteroarenes Using Unactivated Alkyl Halides through Visible-Light Photoredox Catalysis under Basic Conditions.

C-H functionalization of electron-deficient heteroarenes using commercial unactivated alkyl halides through reductive quenching photoredox catalysis was developed. Mainstream approaches rely on the use of an excess of strong acids that result in regioselectivities dictated by the innate effect of the protonated heteroarene, leaving the functionalization of other carbons unexplored. We report a mild method under basic conditions that allows access to previously underexplored regioselectivities by relying on a combination of conjugate and halogen  ortho-directing effects. Overall, this methodology gives quick access to a variety of alkylated heteroarenes that will be of interest to medicinal chemistry programs.

Generation of Diversity Sets with High sp3 Fraction Using the Photoredox Coupling of Organotrifluoroborates and Organosilicates with Heteroaryl/Aryl Bromides in Continuous Flow.

The photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3-Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluoroborates. We have developed a generally useful, continuous flow Csp3-Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborates and silicate reagents. This universal protocol provides diversity sets from both primary and secondary coupling partners. This easily scalable procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high sp3 fraction.

The HAS-Choice study: Utilizing the HEART score, an ADP, and shared decision-making to decrease admissions in chest pain patients.

OBJECTIVE: The HAS-Choice pathway utilizes the HEART Score, an accelerated diagnostic protocol (ADP), and shared decision-making using a visual aid in the evaluation of chest pain patients. We seek to determine if our intervention can improve resource utilization in a community emergency department (ED) setting while maintaining safe patient care. METHODS: This was a single-center prospective cohort study with historical that included ED patients ≥21years old presenting with a primary complaint of chest pain in two time periods. The primary outcome was patient disposition. Secondary outcomes focused on 30-day ED bounce back and major adverse cardiac events (MACE). We used multivariate logistic regression to estimate the odds ratio (OR) and its 95% confidence interval (CI). RESULTS: In the pre-implementation period, the unadjusted disposition to inpatient, observation and discharge was 6.5%, 49.1% and 44.4%, respectively, whereas in the post period, the disposition was 4.8%, 41.5% and 53.7%, respectively (chi-square p<0.001). The adjusted odds of a patient being discharged was 40% higher (OR=1.40; 95% CI, 1.30, 1.51; p<0.001) in the post-implementation period. The adjusted odds of patient admission was 30% lower (OR=0.70; 95% CI, 0.60, 0.82; p<0.001) in the post-implementation period. The odds of 30-day ED bounce back did not statistically differ between the two periods. MACE rates were <1% in both periods, with a significant decrease in mortality in the post-implementation period. CONCLUSION: Our study suggests that implementation of a shared decision-making tool that integrates an ADP and the HEART score can safely decrease hospital admissions without an increase in MACE.

The use of vacuum-assisted closure in spinal wound infections with or without exposed dura.

INTRODUCTION: The treatment of postoperative deep spinal wound infection involves debridement and intravenous antibiotics. Authors have previously reported success in a small series of patients treated with vacuum-assisted closure (VAC) therapy, but its use over exposed dura is controversial and the outcome has not been reported in large series. PURPOSE: To review the outcomes following the treatment of postoperative spinal infections with VAC therapy, particularly those with exposed dura. METHODS: This is a review of prospectively collected data in 42 patients, all of whom had deep postoperative spinal infections. 30 of these patients had exposed dura. All patients had an initial debridement followed by application of VAC Whitefoam (with exposed dura) or grey Granufoam (where no dura was exposed). Pressure was set at 50 mmHg with exposed dura or 125 mmHg where no dura was exposed. All patients underwent a minimum 6 week course of antibiotics. We report on the number of visits to theatre required for dressing changes and debridement and the eventual outcomes. RESULTS: Five patients required a flap reconstruction. Two patients died before definitive final closure due to other complications (pneumonia and stroke). In all the other patients, their wounds healed fully. A mean of 2.3 infection surgeries were required to eradicate infection and achieve wound closure. CONCLUSIONS: This is one of the largest studies which confirms the safety and efficacy of VAC dressings in patients with spinal wound infections, even when the dura is exposed. These slides can be retrieved under Electronic Supplementary Material.

Initiation and outcomes with Class Ic antiarrhythmic drug therapy.

BACKGROUND: Expert opinion recommends performing exercise testing with initiation of Class Ic antiarrhythmic medication. OBJECTIVE: To evaluate the rate and reason for discontinuation of Ic agent within the first year of follow up, with particular attention to rate of proarrhythmia and the value of routine treadmill testing. METHODS: This is a single center retrospective cohort study including consecutive patients with atrial arrhythmias who were initiated on a Class Ic agent from 2011 to 2016. Data was collated from chart review and pharmacy database. RESULTS: The study population included 300 patients (55% male, mean age 61; mean ejection fraction, 56%) started on flecainide (n = 153; 51%) and propafenone (n = 147; 49%). Drug initiation was completed while hospitalized on telemetry and the staff electrophysiologists directed dosing. There was one proarrhythmic event during initiation (0.3%). The primary reason for not being discharged on Ic agent was due to detection of proarrhythmia (n = 15) or ischemia (n = 1) with treadmill testing (5.3%). Exercise testing was the single significant variable to affect the decision to discontinue Ic drug, p < 0.0001 (95% CI: 1.89-6.08%). During follow up, the primary reason for discontinuation of Ic agent was lack of efficacy, 32%. CONCLUSIONS: With proper screening, initiation of Class Ic agent is associated with very low rate of proarrhythmia. Treadmill testing is of incremental value and should be completed in all patients after loading Class Ic antiarrhythmic.