Preoperative veterans RAND-12 mental composite score of < 35 is associated with increased length of stay and high rates of discharge to rehab after primary total joint arthroplasty.

PURPOSE: The association between preoperative mental health and immediate postoperative ambulation in primary Total Joint Arthroplasty (TJA) has sparsely been studied. Thus, this study's objective was to investigate the association between mental health (measured by the Mental Component Score (MCS) from the Veterans RAND 12 (VR-12)) and peri-operative metrics. METHODS: We conducted a retrospective study of patients who underwent primary TJA and completed a VR-12 questionnaire between January 2018 and June 2023 at a single academic hospital. Patients were stratified into terciles based on preoperative MCS. Patient demographics, ambulation within 4 h postop, LOS, and discharge location were compared. The effect of MCS on LOS while controlling discharge location was assessed using negative binomial regression. RESULTS: 1120 patients were included in this analysis (432 THA and 688 TKA). After stratification into terciles (Low: 34.7 ± 6.6, Middle: 49.3 ± 3.7, High:62.1 ± 4.4), comparison of demographics revealed significant differences in age (p = 0.005) and sex distribution (p = 0.04) but no difference in surgery type (p = 0.857). There was no significant difference in ambulation rate between MCS groups (p = 0.789) or in distance covered during first ambulation (p = 0.251). Low MCS patients had a longer LOS (p = 0.000, p = 0.002) and a lower rate of discharged home (p = 0.016). After controlling discharge location, no significant association was found between MCS and LOS (p = 0.288). CONCLUSION: Patient with low MCS tended to be younger, women, and had poorer preoperative HOOS/KOOS scores. Low MCS was associated with longer LOS and lower rates of discharge home. However, MCS was not associated with early ambulation rate and LOS after controlling discharge location.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Assessing Ability for ChatGPT to Answer Total Knee Arthroplasty-Related Questions.

BACKGROUND: Artificial intelligence in the field of orthopaedics has been a topic of increasing interest and opportunity in recent years. Its applications are widespread both for physicians and patients, including use in clinical decision-making, in the operating room, and in research. In this study, we aimed to assess the quality of ChatGPT answers when asked questions related to total knee arthroplasty. METHODS: ChatGPT prompts were created by turning 15 of the American Academy of Orthopaedic Surgeons Clinical Practice Guidelines into questions. An online survey was created, which included screenshots of each prompt and answers to the 15 questions. Surgeons were asked to grade ChatGPT answers from 1 to 5 based on their characteristics: (1) relevance, (2) accuracy, (3) clarity, (4) completeness, (5) evidence-based, and (6) consistency. There were 11 Adult Joint Reconstruction fellowship-trained surgeons who completed the survey. Questions were subclassified based on the subject of the prompt: (1) risk factors, (2) implant/intraoperative, and (3) pain/functional outcomes. The average and standard deviation for all answers, as well as for each subgroup, were calculated. Inter-rater reliability (IRR) was also calculated. RESULTS: All answer characteristics were graded as being above average (ie, a score > 3). Relevance demonstrated the highest scores (4.43 ± 0.77) by surgeons surveyed, and consistency demonstrated the lowest scores (3.54 ± 1.10). ChatGPT prompts in the Risk Factors group demonstrated the best responses, while those in the Pain/Functional Outcome group demonstrated the lowest. The overall IRR was found to be 0.33 (poor reliability), with the highest IRR for relevance (0.43) and the lowest for evidence-based (0.28). CONCLUSIONS: ChatGPT can answer questions regarding well-established clinical guidelines in total knee arthroplasty with above-average accuracy but demonstrates variable reliability. This investigation is the first step in understanding large language model artificial intelligence like ChatGPT and how well they perform in the field of arthroplasty.

Self-Immolative Carbamate Linkers for CD19-Budesonide Antibody-Drug Conjugates.

Antibody-drug conjugates consist of potent small-molecule payloads linked to a targeting antibody. Payloads must possess a viable functional group by which a linker for conjugation can be attached. Linker-attachment options remain limited for the connection to payloads via hydroxyl groups. A releasing group based on 2-aminopyridine was developed to enable stable attachment of para-aminobenzyl carbamate (PABC) linkers to the C21-hydroxyl group of budesonide, a glucocorticoid receptor agonist. Payload release involves a cascade of two self-immolative events that are initiated by the protease-mediated cleavage of the dipeptide-PABC bond. Budesonide release rates were determined for a series of payload-linker intermediates in buffered solution at pH 7.4 and 5.4, leading to the identification of 2-aminopyridine as the preferred releasing group. Addition of a poly(ethylene glycol) group improved linker hydrophilicity, thereby providing CD19-budesonide ADCs with suitable properties. ADC23 demonstrated targeted delivery of budesonide to CD19-expressing cells and inhibited B-cell activation in mice.

Radical treatment for blastomycosis following unsuccessful liposomal amphotericin.

Pulmonary blastomycosis is a respiratory disease that is caused by the fungus Blastomyces spp, which is acquired through inhalation of the fungal spores. Blastomycosis is relatively uncommon, with yearly incidence rate of 1-2 cases per 100 000 people. Blastomycosis is a disease that is endemic to the midwest and southern regions of the USA, most commonly affecting immunocompromised patients. About 50% of patients are asymptomatic, but for those who progress to acute respiratory distress syndrome (ARDS) mortality can be as high as 80%. Patients with severe blastomycosis are initially treated with intravenous amphotericin B, followed by long-term itraconazole maintenance therapy. In this Grand Round, we present the case of an immunocompetent 35-year-old man diagnosed with chronic pulmonary blastomycosis who had a poor response to 10 days of intravenous liposomal amphotericin B (L-AmB). He was endotracheally intubated and eventually cannulated for extracorporeal membrane oxygenation (ECMO), due to worsening respiratory function. L-AmB was replaced with a continuous infusion of intravenous amphotericin B deoxycholate (AmB-d). He improved significantly and was decannulated from ECMO on day 9 of AmBd continuous infusion and extubated on day 12 Although L-AmB is considered first-line treatment for blastomycosis, mortality remains high for patients with ARDS associated with blastomycosis. This case highlights the importance of considering AmB-d continuous infusions for patients with severe blastomycosis who might have poor clinical responses to L-AmB.

The HEART score to identify emergency department patients suspected of an acute coronary syndrome who can be removed from cardiac monitoring: A retrospective chart review.

OBJECTIVE: Continuous cardiac monitoring has been recommended for ED patients being evaluated for possible acute coronary syndrome (ACS) due to concern for arrhythmia, although evidence suggests this risk is low. Indiscriminate use of monitored beds restricts access for other critically unwell patients and contributes to overcrowding. The objective of the present study was to determine if a low/intermediate-risk HEART score identified patients at very low risk for a clinically important arrhythmia who could be removed from cardiac monitoring. METHODS: This was a single centre, retrospective, cohort study of consecutive ED patients in a tertiary referral hospital evaluated for possible ACS from July to August 2017. Patients with ST-elevation myocardial infarction or an arrhythmia at presentation which would mandate monitoring were excluded. Data was obtained by medical chart review. The primary outcome was the occurrence of an arrhythmia requiring treatment while in ED. RESULTS: Inter-rater reliability for data extraction demonstrated very strong agreement (kappa 0.87, 95% confidence interval 0.83-0.91). There were 653 participants included with 83 (12.7%) having a final diagnosis of ACS. Three (0.5%) clinically important arrhythmias occurred. There were no cases of ventricular tachycardia, ventricular fibrillation or cardiac arrest. Five hundred and forty (82.7%) participants were low/intermediate-risk HEART score and one (0.2%) clinically important arrhythmia occurred (this was supraventricular tachycardia treated by a valsalva manoeuvre). CONCLUSION: Among ED patients presenting with a possible ACS, a low/intermediate-risk HEART score identified those at very low risk for having a clinically important arrhythmia while in ED.

Zonal Fixation in Revision TKA: The Key Is Metaphyseal Fixation.

As the volume of primary total knee arthroplasties continues to rise, so will the volume of revision arthroplasties. Bone loss is commonly encountered in revision surgery and must be managed appropriately to optimize outcomes. The concept of zonal fixation highlights the importance of attaining secure fixation within each of the three major osseous zones: the epiphysis, the metaphysis, and the diaphysis. While each zone is important, the metaphysis carries particular significance. The development of new implants such as metaphyseal cones and sleeves has greatly expanded the orthopedic surgeon's armamentarium to allow for solid metaphyseal fixation in virtually every case.

Isolated Pauci-Immune Pulmonary Capillaritis Associated with Hydrocarbon Inhalation and Marijuana Smoking: An Unusual Case of Severe Hypoxemia.

We present a case report of a patient with Isolated pauci-immune pulmonary capillaritis (IPIPC). A 40-year-old male presented with acute onset severe hypoxemic respiratory failure. He had just returned home from work as a cabinetmaker, where he experienced inhalational exposure to hydrocarbons and solvents, and had smoked a marijuana cigarette. He was hypotensive, and his chest imaging showed bilateral dependent infiltrates. His hypoxemia made little improvement after conventional ventilator support and broad-spectrum antibacterial therapy and he was considered too unstable to tolerate diagnostic bronchoscopy with bronchoalveolar lavage. His laboratory evaluation initially showed microscopic hematuria which later cleared, but other tests including serologic autoimmune assessment were negative, and he did not have any traditional risk factors for vasculitis. A video-assisted thoracoscopic lung biopsy revealed diffuse alveolar hemorrhage with pulmonary capillaritis on histopathology. He was diagnosed with IPIPC and initiated on immunosuppressive therapy. He was soon liberated from mechanical ventilation and improved to hospital discharge. Diffuse alveolar hemorrhage from Goodpasture's Syndrome has manifested following inhalation of hydrocarbons and following smoking. This has not previously been reported with IPIPC. Given the lack of other findings and risk factors, his IPIPC was likely associated with occupational exposures to hydrocarbons as a cabinetmaker compounded by marijuana smoking.

Does Femoral Component Cementation Affect Costs or Clinical Outcomes After Hip Arthroplasty in Medicare Patients?

BACKGROUND: Bundled payment initiatives were introduced to reduce costs and improve quality of care. Cemented vs cementless femoral fixation is a modifiable variable that may influence the cost and quality of care. New bundled payment data from the Centers for Medicare and Medicaid Services allowed us to study the influence of femoral fixation strategy on (1) 90-day costs; (2) readmission rates; (3) reoperation rates; (4) length of stay (LOS); and (5) discharge disposition for Medicare patients undergoing total hip arthroplasty. METHODS: We retrospectively studied 1671 primary total hip arthroplasty Medicare cases, comparing 359 patients who received cemented femoral fixation to 1312 patients who received cementless fixation. Centers for Medicare and Medicaid Services cost data as well as clinical data were reviewed. Demographic differences were present between the 2 cohorts. Statistical analyses were performed, including multiple regression models to adjust for baseline differences. RESULTS: Controlling for cohort differences, cemented patients were significantly more likely to be discharged home compared to cementless patients. Cemented patients also demonstrated trends toward lower costs, lower readmission rates, and shorter LOS compared to cementless patients. All reoperations within the early postoperative period occurred in patients managed with cementless femoral fixation. CONCLUSION: Among Medicare patients, cemented femoral fixation outperformed cementless fixation with respect to discharge disposition and also trended toward superiority with regards to LOS, readmission, cost of care, and reoperation. Cemented femoral fixation remains relevant and useful despite the rising popularity of cementless fixation.

Anatomical Modifications during the Lateral Transpsoas Approach to the Lumbar Spine. The Impact of Vertebral Rotation.

BACKGROUND: We investigated impact of vertebral axial rotation on neurovascular anatomy in adult spinal deformity (ASD) patients and provided recommendations on the approach based on degree of axial rotation. In order to isolate vertebral rotation (VR) impact from the superimposed degenerative cascade observed in adulthood, adolescent idiopathic scoliosis (AIS) patients were analyzed. METHODS: Magnetic resonance imaging (MRI) scans (L1-S1) from 50 right-convex thoracic (left-convex lumbar) AIS patients were analyzed. At each intervertebral level, VR, lumbar plexus depth (LPD), and vascular structure depth (VSD) were evaluated. Paired t test analyses were used to describe anatomic differences between the concave and convex aspect of our patients' curves. Correlation analysis was used to investigate relationships with soft tissue modifications and VR. RESULTS: Fifty AIS patients (17M, 33F) with mean thoracic Cobb of 50.6° ± 17.0° and mean lumbar Cobb of 41.9° ± 13.0° were included. Mean VR at each level was L1-2 = -6.6°, L2-3 = -7.7°, L3-4 = -6.5°, L4-5 = -4.7°, L5-S1 = -2.6° (negative value denotes clockwise rotation). We found significant differences (P < .05) between concave-convex (right-left) LPD at each level (L1-2 = 3.7 mm, L2-3 = 5.1 mm, L3-4 = 4.2 mm, L4-5 = 2.2 mm, L5-S1 = 2.2 mm). Vascular structure depth was significantly different at L1-L2 (3.2 mm) and L5-S1 (3 mm). Significant correlation was found between increasing VR and concave-convex LPD difference (r = 0.68, P < .001). CONCLUSIONS: This study demonstrates that displacement of the lumbar plexus is tied to the magnitude of VR in patients with AIS. When approaching the lumbar spine, this displacement widens the safe surgical corridor on the convex side and narrows the corridor on the concave side. LEVEL OF EVIDENCE: IV. CLINICAL RELEVANCE: Preoperative review of MRI scans should occur to assess the patient's safe surgical corridor for lateral lumbar interbody fusion (LLIF). Adult spinal deformity surgeons who approach a degenerated spine in patients with progressive AIS in adulthood must carefully plan for patient positioning, neurovascular anatomy, and realignment objectives prior to the day of surgical intervention.

Cementless Total Knee Arthroplasty: A Comprehensive Review of the Literature.

This review evaluated (1) original and newer cementless implants; (2) outcomes of newer designs; (3) risks and benefits; and (4) newer cementless vs cemented total knee arthroplasties. A search for all reports on cementless total knee arthroplasties published from January 2010 to April 2017 was performed, and 31 studies were included for final analysis. Newer cementless total knee arthroplasty designs have shown excellent survivorship, functional outcomes, and satisfaction rates in both young and elderly populations. Compared with cement fixation, there may be potential benefits with the newer cementless implants. However, these findings need to be further substantiated with additional studies reporting longer-term results. [Orthopedics. 2018; 41(5):263-273.].

Novel Index to Quantify the Risk of Surgery in the Setting of Adult Spinal Deformity: A Study on 10,912 Patients From the Nationwide Inpatient Sample.

STUDY DESIGN: Retrospective review of the Nationwide Inpatient Sample from 2001 to 2010, a prospectively collected national database. OBJECTIVE: Structure an index to quantify adult spinal deformity (ASD) surgical risk based on risk factors for medical complications, surgical complications, revisions (R), mortality (M) rates, and length of hospital stay. SUMMARY OF BACKGROUND DATA: Evidence supporting ASD surgery cost-effectiveness and anticipating surgical risk is critical to evaluate the risk/benefit balance of such treatment for patients. MATERIALS AND METHODS: Discharges ages 25+, 4+ levels fused, diagnoses specific for scoliosis, and refusions. Five multivariate models determined independent risk factors that increased the risk of ≥1 for medical complications, surgical complications, R, M, and length of hospital stay. Models controlled for age, sex, race, revision status, surgical approach, levels fused, and osteotomy utilization. Odds ratios (ORs) were weighted using Nationwide Inpatient Sample weight files and based on their predictive category: 2 times for revision predictors and 4 times for mortality predictors. Predictors with OR≥1.5 were considered clinically relevant. Fifty points were distributed among the predictors based on their accumulative OR to establish a risk index. RESULTS: A total of 10,912 ASD discharges were identified (mean age: 62 y; 73% females; 14% revision cases). The structured risk index incorporated the following factors based on accumulative ORs: pulmonary circulation disorder (42.05), drug abuse (21.86), congestive heart failure (15.25), neurological disorder (17.31), alcohol abuse (13.24), renal failure (11.64), age>65 (12.28), coagulopathy (11.65), level +9 (6.7), revision (3.35), and osteotomy (3). These risk factors were scored: 14, 7, 5, 5, 4, 4, 4, 4, 2, 1, 1, respectively. Three risk thresholds were proposed: mild (0-10), moderate (10-20), severe >20/50 points. CONCLUSIONS: This study proposes an index to quantify the possible risk of morbidity before ASD surgery that will help patients, health insurance companies, and socioeconomic studies in assessing surgical risk/benefits. LEVEL OF EVIDENCE: Level III.

Diagnostic accuracy of flexion-extension radiography for the detection of ligamentous cervical spine injury following a normal cervical spine computed tomography.

BACKGROUND: Flexion-extension radiography (FER) has been utilised for the detection of ligamentous injury in patients who have been cleared of bony injury. Some studies call into question the diagnostic accuracy of FER, the high proportion of inadequate FER images and the adverse effects of prolonged cervical collar immobilisation although awaiting FER. METHODS: We conducted a two-part retrospective study of trauma patients presenting to a trauma centre between January 2007 and December 2014. A cross-sectional analytic study was used to determine diagnostic accuracy and a case-control design was used to compare characteristics and complications of those having FER with similar patients not having FER. Inclusion criteria were age ≥16, blunt trauma mechanism, a normal computed tomography (CT) of the cervical spine and FER to assess for ligamentous injury. The reference standard was magnetic resonance imaging evidence of ligamentous disruption or a therapeutic intervention to treat ligamentous instability. RESULTS: There were 176 participants meeting inclusion criteria. Studies were considered inadequate in 168 participants (95.5%). There were zero true positives, four false positives, 168 true negatives and four false negatives: sensitivity 0% (0.0-60.2%), specificity 97.7 (94.2-99.4%), positive predictive value 0% (0.0-60.2%) and negative predictive value 97.7 (94.2-99.4%). Participants having FER remained in cervical collars and in hospital longer than control patients. Complications of cervical collar use were uncommon. CONCLUSION: FER does not contribute additional diagnostic accuracy for the detection of ligamentous injury to the cervical spine following a normal CT of the cervical spine. We recommend FER be removed from cervical spine clearance protocols.

Utility of flexion-extension radiography for the detection of ligamentous cervical spine injury and its current role in the clearance of the cervical spine.

Detecting the presence of injuries to the cervical spine is an important component of the initial assessment of patients sustaining blunt trauma. A small proportion of cervical spine injuries consists of ligamentous disruption. Accurate detection of ligamentous injury is essential as it may result in sequelae including radiculopathy, quadriplegia and death. Flexion-extension (FE) radiography has traditionally been utilised for the detection of ligamentous injury in patients who have been cleared of bony injury. There are controversies surrounding the use of FE for alert patients with neck pain. There are studies that call into question the diagnostic accuracy of FE, the high proportion of inadequate FE images due to muscle spasm and the adverse effects of prolonged cervical collar immobilisation while awaiting FE. Other literature indicates that FE provides no additional diagnostic information following a multi-detector helical computed tomography. This review evaluates the literature on the utility of FE for the detection of ligamentous injury and explores alternate strategies for clearing the cervical spine of ligamentous injury.

Growth Conditions Control the Elastic and Electrical Properties of ZnO Nanowires.

Great efforts have been made to synthesize ZnO nanowires (NWs) as building blocks for a broad range of applications because of their unique mechanical and mechanoelectrical properties. However, little attention has been paid to the correlation between the NWs synthesis condition and these properties. Here we demonstrate that by slightly adjusting the NW growth conditions, the cross-sectional shape of the NWs can be tuned from hexagonal to circular. Room temperature photoluminescence spectra suggested that NWs with cylindrical geometry have a higher density of point defects. In situ transmission electron microscopy (TEM) uniaxial tensile-electrical coupling tests revealed that for similar diameter, the Young's modulus and electrical resistivity of hexagonal NWs is always larger than that of cylindrical NWs, whereas the piezoresistive coefficient of cylindrical NWs is generally higher. With decreasing diameter, the Young's modulus and the resistivity of NWs increase, whereas their piezoresistive coefficient decreases, regardless of the sample geometry. Our findings shed new light on understanding and advancing the performance of ZnO-NW-based devices through optimizing the synthesis conditions of the NWs.

TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination.

Systems biological analysis of immunity to the trivalent inactivated influenza vaccine (TIV) in humans revealed a correlation between early expression of TLR5 and the magnitude of the antibody response. Vaccination of Trl5(-/-) mice resulted in reduced antibody titers and lower frequencies of plasma cells, demonstrating a role for TLR5 in immunity to TIV. This was due to a failure to sense host microbiota. Thus, antibody responses in germ-free or antibiotic-treated mice were impaired, but restored by oral reconstitution with a flagellated, but not aflagellated, strain of E. coli. TLR5-mediated sensing of flagellin promoted plasma cell differentiation directly and by stimulating lymph node macrophages to produce plasma cell growth factors. Finally, TLR5-mediated sensing of the microbiota also impacted antibody responses to the inactivated polio vaccine, but not to adjuvanted vaccines or the live-attenuated yellow fever vaccine. These results reveal an unappreciated role for gut microbiota in promoting immunity to vaccination.

Immunity to viruses: learning from successful human vaccines.

For more than a century, immunologists and vaccinologists have existed in parallel universes. Immunologists have for long reveled in using 'model antigens', such as chicken egg ovalbumin or nitrophenyl haptens, to study immune responses in model organisms such as mice. Such studies have yielded many seminal insights about the mechanisms of immune regulation, but their relevance to humans has been questioned. In another universe, vaccinologists have relied on human clinical trials to assess vaccine efficacy, but have done little to take advantage of such trials for studying the nature of immune responses to vaccination. The human model provides a nexus between these two universes, and recent studies have begun to use this model to study the molecular profile of innate and adaptive responses to vaccination. Such 'systems vaccinology' studies are beginning to provide mechanistic insights about innate and adaptive immunity in humans. Here, we present an overview of such studies, with particular examples from studies with the yellow fever and the seasonal influenza vaccines. Vaccination with the yellow fever vaccine causes a systemic acute viral infection and thus provides an attractive model to study innate and adaptive responses to a primary viral challenge. Vaccination with the live attenuated influenza vaccine causes a localized acute viral infection in mucosal tissues and induces a recall response, since most vaccinees have had prior exposure to influenza, and thus provides a unique opportunity to study innate and antigen-specific memory responses in mucosal tissues and in the blood. Vaccination with the inactivated influenza vaccine offers a model to study immune responses to an inactivated immunogen. Studies with these and other vaccines are beginning to reunite the estranged fields of immunology and vaccinology, yielding unexpected insights about mechanisms of viral immunity. Vaccines that have been proven to be of immense benefit in saving lives offer us a new fringe benefit: lessons in viral immunology.

Systems biological approaches to measure and understand vaccine immunity in humans.

Recent studies have demonstrated the utility of using systems approaches to identify molecular signatures that can be used to predict vaccine immunity in humans. Such approaches are now being used extensively in vaccinology, and are beginning to yield novel insights about the molecular networks driving vaccine immunity. In this review, we present a broad review of the methodologies involved in these studies, and discuss the promise and challenges involved in this emerging field of "systems vaccinology."

Emergency diagnosis of subarachnoid hemorrhage: an evidence-based debate.

BACKGROUND: The diagnosis of subarachnoid hemorrhage is of paramount concern in patients presenting to the Emergency Department (ED) with acute headache. Computed tomography followed by lumbar puncture is a time-honored practice, but recent technologic advances in magnetic resonance imaging with magnetic resonance angiography and computed tomography with computed tomography angiography can present alternatives for clinicians and patients. OBJECTIVE: The aim of this article was to compare diagnostic strategies for ED patients in whom subarachnoid hemorrhage is suspected. METHODS: We analyze and discuss current protocols, in addition to summarizing the advantages and disadvantages of each method. RESULTS: Through our residency's journal club, we organized an evidence-based debate that pitted proponents of the three subarachnoid hemorrhage diagnostic strategies against one another. Proponents of each strategy described its advantages and disadvantages. Briefly, computed tomography/lumbar puncture is time honored and effective, but is limited by complications and indeterminate lumbar puncture results. Magnetic resonance imaging with magnetic resonance angiography might be more effective in late presentations and can visualize aneurysms, yet has limited availability. Computed tomography with computed tomography angiography offers rapid diagnosis and is considered the most sensitive for diagnosing aneurysms, but has the highest radiation exposure. CONCLUSIONS: Each of the three strategies used to diagnose subarachnoid hemorrhage has advantages and disadvantages with which clinicians should be familiar. Patient factors (e.g., age, body habitus, and risk factors), presentation factors (e.g., time from headache onset and severity of presentation), and institutional factors (availability of magnetic resonance imaging with magnetic resonance angiography) can influence the choice of protocol.

TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway.

Conjugation of TLR agonists to protein or peptide antigens has been demonstrated in many studies to be an effective vaccine formula in inducing cellular immunity. However, the molecular and cellular mediators involved in TLR-induced immune responses have not been carefully examined. In this study, we identify Type I IFN and IL-12 as critical mediators of cross-priming induced by a TLR7 agonist-antigen conjugate. We demonstrate that TLR7-driven cross-priming requires both Type I IFN and IL-12. Signaling through the IFN-αßR was required for the timely recruitment and accumulation of activated dendritic cells in the draining lymph nodes. Although IL-12 was indispensable during cross-priming, it did not regulate DC function. Therefore, the codependency for these 2 cytokines during TLR7-induced cross-priming is the result of their divergent effects on different cell-types. Furthermore, although dermal and CD8α(+) DCs were able to cross-prime CD8(+) T cells, Langerhans cells were unexpectedly found to potently cross-present antigen and support CD8(+) T-cell expansion, both in vitro and in vivo. Collectively, the data show that a TLR7 agonist-antigen conjugate elicits CD8(+) T-cell responses by the coordinated recruitment and activation of both tissue-derived and lymphoid organ-resident DC subsets through a Type I IFN and IL-12 codependent mechanism.