Inverse kinematic total knee arthroplasty using conventional instrumentation restores constitutional coronal alignment.

PURPOSE: Restricted inverse kinematic alignment (iKA) is a contemporary alignment strategy for total knee arthroplasty (TKA), commonly performed with robotic assistance. While superior clinical results are reported for kinematic-type alignment strategies, registry data indicate no survivorship benefit for navigation or robotic assistance. This study aimed to determine the efficacy of an instrumented, restricted iKA technique for achieving patient-specific alignment. METHODS: Seventy-nine patients undergoing 84 TKAs (five bilateral procedures) using an iKA technique were included for preoperative and postoperative lower limb alignment analysis. The mean age was 66.5 (range: 43-82) with 33 male and 51 female patients. Artificial intelligence was employed for radiographic measurements. Alignment profiles were classified using the Coronal Plane Alignment of the Knee (CPAK) system. Preoperative and postoperative alignment profiles were compared with subanalyses for preoperative valgus, neutral and varus profiles. RESULTS: The mean joint-line convergence angle (JLCA) reduced from 2.5° to -0.1° postoperatively. The mean lateral distal femoral angle (LDFA) remained unchanged postoperatively, while the mean medial proximal tibial angle (MPTA) increased by 2.5° (p = 0.001). By preservation of the LDFA and restoration of the MPTA, the mean hip knee ankle angle (HKA) moved through 3.5° varus to 1.2° valgus. The CPAK system was used to visually depict changes in alignment profiles for preoperative valgus, neutral and varus knees; with 63% of patients observing an interval change in classification. CONCLUSION: Encouraged by the latest evidence supporting both conventional instrumentation and kinematic-type TKA strategies, this study describes how a restricted, conventionally instrumented iKA technique may be utilised to restore constitutional lower limb alignment. LEVEL OF EVIDENCE: Level III.

Conventionally instrumented inverse kinematic alignment for total knee arthroplasty: How is it done?

Purpose: For primary total knee arthroplasty (TKA), there is an increasing trend towards patient-specific alignment strategies such as kinematic alignment (KA) and inverse kinematic alignment (iKA), which by restoring native joint mechanics may yield higher patient satisfaction rates. Second, the most recent Australian joint registry report describes favourable revision rates for conventionally instrumented TKA compared to technology-assisted techniques such as those using navigation, robotics or custom-cutting blocks. The aim of this technique article is to describe in detail a surgical technique for TKA that: (1) utilises the principles of iKA and (2) uses conventionally instrumented guided resections thereby avoiding the use of navigation, robotics or custom blocks. Methods: A TKA technique is described, whereby inverse kinematic principles are utilised and patient-specific alignment is achieved. Additionally, the patellofemoral compartment of the knee is restored to the native patellofemoral joint line. The sequenced technical note provided may be utilised for cemented or cementless components; cruciate retaining or sacrificing designs and for fixed or rotating platforms. Results: An uncomplicated, robust and reproducible technique for TKA is described. Discussion: Knee arthroplasty surgeons may wish to harness the emerging benefits of both a conventionally instrumented technique and a patient-specific alignment strategy. Level of Evidence: Level V.

The Irish National Orthopaedic Register Under Cyberattack: What Happened, and What Were the Consequences?

BACKGROUND: On May 14, 2021, a criminal cyberattack was launched against the Irish public healthcare system, the Health Service Executive, resulting in a complete shutdown of all national healthcare computer systems, including the Irish National Orthopaedic Register (INOR). Cyberattacks of this kind occur sporadically, and postevent analyses can inform future preparedness efforts, but few such analyses have been published. QUESTION/PURPOSE: What was the impact of the cyberattack in terms of (1) registry downtime, (2) harms to patients, and (3) costs to the INOR for data contingency and reconciliation? METHODS: All nine hospitals using the INOR were included for data collection. Since establishment in 2014, the INOR has been rolled out to all eight public elective hospitals, capturing all hip and knee arthroplasty procedures. One private hospital was also captured, with plans to expand the private sector coverage. Individual institutional records and central INOR records were queried with respect to downtime, potential harms to patients (including intraoperative complications because of a lack of data on existing implanted components and complications directly attributed to delayed or canceled procedures), and costs related to additional person-hours addressing data reconciliation. Objective data directly related to the uncontrolled INOR downtime were collected, including duration of downtime, contingency methods employed, quality of contingency data collected, adverse patient events, methods of data salvage and reconciliation, and the cost of data contingency and reconciliation measures. Costs were estimated by the additional person-hours of work completed, multiplied by the hourly rate of that employee. Employees at each of the nine hospitals were asked to provide their additional person-hours of work performed because of the attack. These hours were corroborated by observing the time taken at each unit to reconcile data for single cases multiplied by the number of cases at that unit. Employees included nurses, clinical nurse specialists, and doctors of various grades. Person-hour rates were calculated using the Health Service Executive's published salary scales. RESULTS: The INOR suffered a median downtime of 134 days (range 119 to 272 days) across nine sites. No serious adverse patient events were identified. The immediate implementation of a paperwork fallback method for the INOR successfully resulted in 100% case capture during the downtime. However, 2850 additional person-hours were required for data reconciliation at an estimated cost of USD 181,000 to USD 216,000. More subjectively, as reported by interviews with INOR leads at each hospital, the cyberattack negatively impacted operating room efficiency with delays between procedures because of additional paperwork data collection, disrupted patient flow for paperwork data collection on the ward level and in the outpatient clinics, and disrupted resource allocations and staff capabilities because of additional paperwork requirements during the contingency period. CONCLUSION: Disruptions to data collection and data accessibility after this cyberattack were successfully countered by a contingency plan; however, substantial financial costs and additional resources were required for data conservation and reconciliation. CLINICAL RELEVANCE: In addition to robust preventative security measures, national registers and other healthcare systems should have secondary data backup facilities and reliable fallback procedures prepared for such events.

A simple method to rapidly assess the tibial tuberosity-trochlear groove distance using computed tomography.

BACKGROUND: The tibial tuberosity-trochlear groove (TTTG) distance is used to assess patellofemoral instability (PFI) and the likelihood of the development of patellofemoral disorders. The current gold standard in the assessment of the TTTG is computed tomography (CT) or magnetic resonance imaging (MRI). The current image software used for viewing these CT images does not allow for easy assessment of the TTTG. AIMS: This study presents a simple method to measure the TTTG on any image software, utilizing easily available and affordable stationary. METHODS: Four consecutive patients with no known knee pathologies were selected from recent studies at our institution. Their TTTGs were measured using this study's method and validated using the standard, freely available image analysis software Fiji. Pre-defined anatomical landmarks were located and marked using adhesive pieces of paper. The TTTG was defined as the distance between parallel lines through the apex of the tibial tuberosity and trough of the trochlear groove, where each of these lines is perpendicular to the Dorsal Condylar Line. RESULTS: The TTTG measured using this study's method was found to be in agreement with the measurements made using Fiji software. CONCLUSIONS: This study demonstrates that the TTTG can be simply and quickly assessed using readily available and affordable stationery, without the need for expensive or complex secondary analysis software. This could allow for the assessment of PFI in the outpatient clinic whilst the patient is present, offering valuable assistance to the orthopaedic surgeon in clinical decision making.

Can Bar Code Scanning Improve Data Capture in a National Register? Findings from the Irish National Orthopaedic Register.

BACKGROUND: The Irish National Orthopaedic Register (INOR) provides a national mechanism for managing data on THA and TKA in Ireland, including a detailed implant record populated by intraoperative implant bar code scanning. It is critically important that implant details are recorded accurately for longitudinal outcome studies, implant recalls, and revision surgery planning. Before INOR's 2014 launch, Irish hospitals maintained separate, local institutional arthroplasty databases. These individual databases typically took the form of hardcopy operating room (OR) logbooks with handwritten patient details alongside the descriptive stickers from the implant packaging and/or individual institution electronic records using manual electronic implant data input. With the introduction of the INOR, a single, unifying national database was established with the ability to instead collect implant data using bar code scanning at time of implant unpackaging in the OR. We observed that bar code data entry represented a novel and potentially substantial change to implant recording methods at our institution and so sought to examine the potential effect on implant data quality. QUESTIONS/PURPOSES: We compared the new bar code scanning method of implant data collection used by the INOR to the previously employed recording methods at our institution (in our case, the previous methods included both an electronic operation note database [Bluespier software] and a duplicate hardcopy OR logbook) and asked (1) Does bar code scanning improve the completeness of implant records? (2) Does bar code scanning improve the accuracy of implant records? METHODS: Although the INOR was launched in 2014, our institution went live with it in 2019. To avoid any potential recording issues that may have occurred during the 2019 introduction of the novel system, a clear period before the introduction of INOR was selected at our institution to represent an era of manual data input to Bluespier software: July 2018. Although we initially aimed for 2 months of data from July 1, 2018, to August 31, 2018 (n = 247), we decided to proceed to 250 consecutive, primary THAs or TKAs for clarity of results. No procedure meeting these criteria was excluded. A second recent period, January 2021, was identified to represent an era of bar code data input; 250 consecutive, primary THAs or TKAs were also included from this date (to February 15, 2021). No case meeting these criteria was excluded. A total of 4244 implant parameters from these 500 primary THAs or TKAs were manually cross-referenced for missing or incorrect data. Eleven THA and six TKA parameters were chosen for comparison, including implant names and component sizes. For each case, either the 2018 Bluespier electronic record or the 2021 INOR electronic record was manually interrogated, and implant details were recorded by two authors before they were compared against the duplicate record for every case (the reference-standard OR logbook containing the corresponding implant product stickers) for both completeness and accuracy. Completeness was defined binarily as the implant parameter being either present or absent; we did likewise for accuracy, either that parameter was correct or incorrect. The OR logbooks were chosen as the reference standard because we felt the risk of product stickers containing errors (inaccuracies) was negligible, and in our collective experience, missing stickers (incompleteness) has not been encountered. Logbook case completeness was also confirmed by comparison to our inpatient management system. RESULTS: With the introduction of the automated bar code data entry in the INOR, the proportion of missing data declined from 7% (135 of 2051) to 0% (0 of 2193), and the proportion of incorrectly recorded implant parameters declined from 2% (45 of 2051) to 0% (0 of 2193). The proportion of procedures with entirely accurate implant records rose from 53% (133 of 250) to 100% (250 of 250). CONCLUSION: The completeness and accuracy of implant data capture was improved after the introduction of a contemporary electronic national arthroplasty registry that utilizes bar code data entry. CLINICAL RELEVANCE: Based on the results of this study, other local and national registers may consider bar code data entry in the OR to achieve excellent implant data quality. Future studies may examine implant data quality at a national level to validate the bar code-populated data of the INOR.

CT versus MRI planning for reverse geometry total shoulder arthroplasty.

INTRODUCTION: Preoperative planning for Reverse Total Shoulder Arthroplasty (RTSA) using CT or MRI is well described.1, 2, 3, 4, 5, 6, 7 We aimed to compare pre-operative CT versus MRI measurement accuracy for predicting intra-operative glenoid implant sizing. METHODS: All patients with a preoperative CT or MRI undergoing RTSA at our tertiary referral center from October 2017 to February 2020 were included. Data was collected from theatre and implant registers. Glenosphere Width (GW) and Baseplate Central Screw Length (BCSL) were independently predicted from pre-operative CT or MRI imaging by 2 blinded senior authors. A sub-group analysis was also performed between trauma and non-trauma CT cases. SPSS v26 was used for statistical comparison between predicted and actual implants. RESULTS: 71 data sets from 69 patients were included for analysis: 31 CT predictions and 40 MRI predictions. 61.3% of CT measured GW predictions were accurate compared to 82.5% of MRI predictions (p = 0.045). BCSL predictions were 77.4% and 70% accurate for CT and MRI respectively, without significant difference. There was no significant difference in sub-group analysis for trauma vs elective CT accuracy of BCSL or GW measurements. CONCLUSION: MRI imaging may be superior to CT for predicting GW and no less accurate than CT for predicting BCSL in the elective setting. No difference in CT measurement accuracy was seen between trauma and elective settings. While simultaneously clearly defining shoulder soft tissue anatomy, MRI may also be the preferred modality for bony measurements during pre-operative planning for elective RTSA.

SIGIRR Negatively Regulates IL-36-Driven Psoriasiform Inflammation and Neutrophil Infiltration in the Skin.

SIGIRR has been described as a negative regulator of several IL-1R/TLR family members and has been implicated in several inflammatory disease conditions. However, it is unknown whether it can suppress IL-36 family cytokines, which are members of the broader IL-1 superfamily that have emerged as critical orchestrators of psoriatic inflammation in both humans and mice. In this study, we demonstrate that SIGIRR is downregulated in psoriatic lesions in humans and mice, and this correlates with increased expression of IL-36 family cytokines. Using Sigirr -/- mice, we identify, for the first time (to our knowledge), SIGIRR as a negative regulator of IL-36 responses in the skin. Mechanistically, we identify dendritic cells and keratinocytes as the primary cell subsets in which IL-36 proinflammatory responses are regulated by SIGIRR. Both cell types displayed elevated IL-36 responsiveness in absence of SIGIRR activity, characterized by enhanced expression of neutrophil chemoattractants, leading to increased neutrophil infiltration to the inflamed skin. Blockade of IL-36R signaling ameliorated exacerbated psoriasiform inflammation in Sigirr -/- mice and inhibited neutrophil infiltration. These data identify SIGIRR activity as an important regulatory node in suppressing IL-36-dependent psoriatic inflammation in humans and mice.

Trabecular Metal Augments for Severe Acetabular Defects in Revision Hip Arthroplasty: A Long-Term Follow-Up.

BACKGROUND: Paprosky type IIIa and IIIb acetabular defects remain technically challenging during revision hip arthroplasty. Numerous surgical options exist to counter extensive acetabular bone loss with high postoperative complication and revision rates reported. Our aim was to report comprehensive long-term outcomes of our experience with Trabecular Metal (TM) augments for these difficult cases. METHODS: 38 patients underwent revision total hip arthroplasty at our institution from 2009 to 2014 where a TM augment was used for acetabular deficiency. Prospective radiographic and Patient-Reported Outcome Measures were recorded and analyzed to a mean of 7.3 years (range: 5.4 to 10.8). RESULTS: No patient was excluded or lost to follow-up. Complications included 3 intraoperative fractures, 1 early infection requiring washout with implant retention, 1 early revision due to allograft resorption, and 6 patients who required late repeat revision surgery: 3 for late infection, 2 for aseptic loosening with augment fracture or dislocation, and 1 for recurrent dislocation. The estimated mean implant survivorship was 8.99 years. 93.5% of augments remaining were well osseointegrated while 97% of the acetabular shells were osseointegrated. Hip center of rotation was restored by a mean of 14 mm inferiorly without significant medialization. Short Form-12 (SF-12) and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were significantly reduced postoperatively to a level comparable to the average individual. CONCLUSION: This long-term study details our experience of TM augments for the most severe acetabular defects. For such cases, no excellent surgical solution exists; in comparison to alternative methods, we advocate that this technique is reasonably safe and effective.

Pediatric Trauma and the COVID-19 Pandemic: A 12-Year Comparison in a Level-1 Trauma Center.

BACKGROUND: The effect of COVID-19 on pediatric trauma rates is still largely under investigation. With the potential need to reallocate human and financial resources at this challenging time, it will be useful to have detailed descriptions of the rates of pediatric trauma and understanding of how the pandemic affects these rates. QUESTIONS/PURPOSES: We sought to describe the effect of the COVID-19 pandemic on the number of acute pediatric trauma admissions and procedures performed in a level-I trauma center in Cork University Hospital, Ireland. METHODS: We compared the number of acute traumatic pediatric admissions and procedures that occurred during the first 4 weeks of a nationwide lockdown due to COVID-19 with that of the same 4-week period in each of the preceding 11 years. Seasonal variables were measured and controlled for using multivariate regression analysis. RESULTS: A total of 545 pediatric patients (under 16 years of age) were included. Over 12 years, the lowest number of acute traumatic pediatric admissions and procedures was recorded during the 2020 pandemic. There was a significant correlation between the number of school days and the number of acute traumatic admissions, as well as the procedures performed. The relationship between the number of school days and the number of trauma procedures was evident even when controlling for confounder variables of seasonal variation. CONCLUSION: The COVID-19 pandemic significantly reduced the number of acute traumatic pediatric admissions and procedures performed in our level-I trauma center, likely because of a reduction in school days. With the reopening of schools, playgrounds, and sporting events, an increase in pediatric trauma admissions is anticipated. The results of this study can help prepare institutions and regulatory bodies to plan appropriately for this new phase.

Optimized simultaneous pressurized fluid extraction and in-cell clean-up, and analysis of polycyclic aromatic hydrocarbons (PAHs), and nitro-, carbonyl-, hydroxy -PAHs in solid particles.

The development, modification and optimization of analytical methods capable of simultaneous extraction and in-cell clean-up of extracts for subsequent determination of parent PAHs and their associated transformed nitro-PAHs (NPAH), carbonyl-PAHs (CPAH) and hydroxy-PAHs (HO-PAH) products (TPPs) is essential for reducing the time and cost of analysis. The aim of this study was to modify and optimize the pressurized fluid extraction (PFE) technique capable of simultaneous extraction and in-cell clean-up of PAHs and TPPs in urban dust standard reference material and road dust for GC-MS analyses. In this study, multivariate data analysis such as factor analysis (FA), and preference ranking organisation method for enrichment evaluation (PROMETHEE) and geometrical analysis for interactive aid (GAIA) were used to assess the performance of the methods. As the key outcome of the study, an optimized selective reaction monitoring (SRM) Triple Quadrupole (TQ) electron ionization (EI)-GC/MS for measuring PAHs and TPPs without derivatization of polar HO-PAHs was developed. The limits of detection (LOD) for parent PAHs, CPAHs, NPAHs and HO-PAHs using Shimadzu TQ were 1.0-5.0 pg, 1.0-5.0 pg, 1.0-50.0 pg, and 1.0-25.0 pg, respectively. The PROMETHEE-GAIA analysis of the results showed that a combination of 3% deactivated silica gel and activated alumina (2:1) as in-cell clean-up material, and sequential PFE extraction (200 °C ASE temperature, 9 min preheat time and 3 times extraction cycle) using 100% hexane followed by hexane/DCM (1:1) is the best condition for analytes extraction from road dust. An optimized, fast and reliable GC/MS method operated solely in electron ionization (EI) mode was developed for measuring all analytes. The outcomes of this study will contribute significantly to future research on PAHs and TPPs, thereby promoting a safe and sustainable environment.

Cause of irreducible dislocation of a re-revision THR.

Instability or recurrent dislocations are a common reason for revision of total hip replacements (THRs). Dual-mobility constructs can help improve stability by increasing the femoral head jump distance. These constructs are used to decrease the risk of re-revision in the setting of recurrent dislocation. This case describes an unusual case of irreducible dislocation of a re-revision THR due to intraprosthetic dislocation. The patient required open reduction and revision of this construct to a tripolar implant. This is important to appreciate from an emergency medicine point of view as repeated attempts at reduction will be fruitless and may result in a femur fracture. This particular type of dislocation is very rare. Perioperative considerations should include early referral to the orthopaedic team for reduction in theatre, and having a low threshold for open reduction. Revision options should be available when bringing a case like this to the operating theatre.

Modulating Wettability of Layered Materials by Controlling Ligand Polar Headgroup Dynamics.

Integrating functionalized 2D materials into multilayer device architectures increasingly requires understanding the behavior of noncovalently adsorbed ligands during solution processing. Here, we demonstrate that the headgroup dynamics of polymerized monolayers of functional alkanes can be controlled to modify surface wetting and environmental interactions. We find that headgroup dynamics are sensitive to the position of the polymerizable diyne group; thus, the polymerization process, typically used to stabilize the noncovalent monolayer, can also be used to selectively destabilize chain-chain interactions near the headgroups, making the headgroups more solvent-accessible and increasing surface hydrophilicity. Conversely, interactions with divalent ions can be used to tether headgroups in-plane, decreasing surface hydrophilicity. Together, these results suggest a strategy for the rational design of 2D chemical interfaces in which the polymerization step reconfigures the monolayer to promote the desired environmental interactions.

Sitting Phase Monolayers of Polymerizable Phospholipids Create Dimensional, Molecular-Scale Wetting Control for Scalable Solution-Based Patterning of Layered Materials.

The use of dimensionally ordered ligands on layered materials to direct local electronic structure and interactions with the environment promises to streamline integration into nanostructured electronic, optoelectronic, sensing, and nanofluidic interfaces. Substantial progress has been made in using ligands to control substrate electronic structure. Conversely, using the exposed face of the ligand layer to structure wetting and binding interactions, particularly with scalable solution- or spray-processed materials, remains a significant challenge. However, nature routinely utilizes wetting control at scales from nanometer to micrometer to build interfaces of striking geometric precision and functional complexity, suggesting the possibility of leveraging similar control in synthetic materials. Here, we assemble striped "sitting" phases of polymerizable phospholipids on highly oriented pyrolytic graphite, producing a surface consisting of 1 nm wide hydrophilic stripes alternating with 5 nm wide hydrophobic stripes. Protruding, strongly wetting headgroup chemistries in these monolayers enable formation of rodlike wetted patterns with widths as little as ∼6 nm and lengths up to 100 nm from high-surface-tension liquids (aqueous solutions of glycerol) commonly utilized to assess interfacial wetting properties at larger length scales. In contrast, commonly used lying-down phases of diynoic acids with in-plane headgroups do not promote droplet sticking or directional spreading. These results point to a broadly applicable strategy for achieving high-resolution solution-based patterning on layered materials, utilizing nanometer-wide patterns of protruding, charged functional groups in a noncovalent monolayer to define pattern edges.

Sitting Phases of Polymerizable Amphiphiles for Controlled Functionalization of Layered Materials.

Precisely tailoring surface chemistry of layered materials is a growing need for fields ranging from electronics to biology. For many applications, the need for noncovalently adsorbed ligands to simultaneously control interactions with a nonpolar substrate and a polar solvent is a particular challenge. However, biology routinely addresses a similar challenge in the context of the lipid bilayer. While conventional standing phases of phospholipids (such as those found in a bilayer) would not provide spatially ordered interactions with the substrate, here we demonstrate formation of a sitting phase of polymerizable phospholipids, in which the two alkyl chains extend along the surface and the two ionizable functionalities (a phosphate and an amine) sit adjacent to the substrate and project into the solvent, respectively. Interfacial ordering and polymerization are assessed by high-resolution scanning probe measurements. Water contact angle titrations demonstrate interfacial pKa shifts for the lipid phosphate but not for the amine, supporting localization of the phosphate near the nonpolar graphite surface.

Peptide interfaces with graphene: an emerging intersection of analytical chemistry, theory, and materials.

Because noncovalent interface functionalization is frequently required in graphene-based devices, biomolecular self-assembly has begun to emerge as a route for controlling substrate electronic structure or binding specificity for soluble analytes. The remarkable diversity of structures that arise in biological self-assembly hints at the possibility of equally diverse and well-controlled surface chemistry at graphene interfaces. However, predicting and analyzing adsorbed monolayer structures at such interfaces raises substantial experimental and theoretical challenges. In contrast with the relatively well-developed monolayer chemistry and characterization methods applied at coinage metal surfaces, monolayers on graphene are both less robust and more structurally complex, levying more stringent requirements on characterization techniques. Theory presents opportunities to understand early binding events that lay the groundwork for full monolayer structure. However, predicting interactions between complex biomolecules, solvent, and substrate is necessitating a suite of new force fields and algorithms to assess likely binding configurations, solvent effects, and modulations to substrate electronic properties. This article briefly discusses emerging analytical and theoretical methods used to develop a rigorous chemical understanding of the self-assembly of peptide-graphene interfaces and prospects for future advances in the field.

Using Community Advisory Boards to Build Partnerships and Develop Peer-Led Services for Rural Student Veterans.

BACKGROUND: The Department of Veterans' Affairs (VA)/Student Partnership for Rural Veterans (VSP) built partnerships between institutional (health services researchers, VA chaplains) and community groups to develop veteran-to-veteran services on college campuses. OBJECTIVES: Describe challenges and lessons learned in year 1 of the VSP project at six campuses in rural Arkansas. METHODS: Researchers leveraged established community advisory boards (CABs) to develop veteran-to-veteran services. Ethnographic and qualitative methods were used to assess partnership building and evaluate peer-led services. RESULTS: Local established CABs and buy-in from student services and veteran organizations was instrumental to building partnerships and developing services. Challenges included developing rapport with campus leaders and creating sustainable role/expectations for student veteran leaders. CONCLUSIONS: Peer-led services are an ideal way to connect student veterans and link them to resources and health care services. Partnerships can facilitate grassroots efforts to develop local services that meet the needs of diverse student veteran populations.

Activated protein C ß-glycoform promotes enhanced noncanonical PAR1 proteolysis and superior resistance to ischemic injury.

Activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. In this study, a recombinant APC variant (APC(N329Q)) mimicking the naturally occurring APC-ß plasma glycoform was found to exhibit superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling. APC(N329Q) also enhanced integrin αMß2-dependent PAR1 proteolysis to exert significantly improved antiinflammatory activity on macrophages compared with wild-type APC. Recent therapeutic applications of recombinant APC in ischemic stroke models have used APC variants with limited anticoagulant activity to negate potential bleeding side effects. Using a mouse model of ischemic stroke and late t-PA intervention, the neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPC(PS)) was compared with an identical APC variant except for the absence of glycosylation at the APC-ß sequon (mAPC(PS/N329Q)). Remarkably, mAPC(PS/N329Q) limited cerebral ischemic injury and reduced brain lesion volume significantly more effectively than mAPC(PS). Collectively, this study reveals the importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC and demonstrates the potential of novel APC variants with superior cytoprotective signaling function as enhanced therapeutic agents for the treatment of ischemic stroke.

Building partnerships with rural Arkansas faith communities to promote veterans' mental health: lessons learned.

BACKGROUND: The Mental Health-Clergy Partnership Program established partnerships between institutional (Department of Veterans' Affairs [VA] chaplains, mental health providers) and community (local clergy, parishioners) groups to develop programs to assist rural veterans with mental health needs. OBJECTIVES: Describe the development, challenges, and lessons learned from the Mental Health-Clergy Partnership Program in three Arkansas towns between 2009 and 2012. METHODS: Researchers identified three rural Arkansas sites, established local advisory boards, and obtained quantitative ratings of the extent to which partnerships were participatory. RESULTS: Partnerships seemed to become more participatory over time. Each site developed distinctive programs with variation in fidelity to original program goals. Challenges included developing trust and maintaining racial diversity in local program leadership. CONCLUSIONS: Academics can partner with local faith communities to create unique programs that benefit the mental health of returning veterans. Research is needed to determine the effectiveness of community based programs, especially relative to typical "top-down" outreach approaches.