Procedural justice training reduces police use of force and complaints against officers.

Existing research shows that distrust of the police is widespread and consequential for public safety. However, there is a shortage of interventions that demonstrably reduce negative police interactions with the communities they serve. A training program in Chicago attempted to encourage 8,480 officers to adopt procedural justice policing strategies. These strategies emphasize respect, neutrality, and transparency in the exercise of authority, while providing opportunities for civilians to explain their side of events. We find that training reduced complaints against the police by 10.0% and reduced the use of force against civilians by 6.4% over 2 y. These findings affirm the feasibility of changing the command and control style of policing which has been associated with popular distrust and the use of force, through a broad training program built around the concept of procedurally just policing.

Oophorectomy in NMDA receptor encephalitis and negative pelvic imaging.

Ovarian teratomas are found in one-third of females presenting with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. When a teratoma is detected on imaging, its removal is first-line therapy. Even with multiple imaging modalities, occasionally, the teratoma is found only on subsequent imaging, long after initial presentation. Very rarely, patients have undergone oophorectomy despite negative imaging, with pathology demonstrating teratoma, and resulting clinical improvement. We present a patient in whom removal of a teratoma, not visible on conventional imaging, resulted in marked clinical improvement. Such cases present a major clinical challenge, needing to consider the risks of oophorectomy, including sterilisation and early menopause, versus the possibility of death in the absence of response to first-line (eg, corticosteroids, plasma exchange, intravenous immunoglobulin), second-line (eg, rituximab) and third-line (eg, bortezomib) immunosuppression. This decision is made more difficult as patients are usually females of childbearing age who at the time lack capacity to make medical decisions. This case also highlights the lack of consensus and guidelines for imaging modalities used to detect teratoma and when to pursue oophorectomy.

Nebulization of Cyclic Arginine-Glycine-(D)-Aspartic Acid-Peptide Grafted and Drug Encapsulated Liposomes for Inhibition of Acute Lung Injury.

PURPOSE: Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1ß) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo. METHODS: In vivo ALI model was simulated through intra-tracheal instillation of IL-1ß solution (100 µg/mL in PBS, pH 7.2, 200 µL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (LcRGD) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-LcRGD). Formulations were nebulized in vivo in rats using micro-pump nebulizer. RESULTS: Liposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-LcRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels. CONCLUSION: From the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.

Non-Invasive Detection of Lung Inflammation by Near-Infrared Fluorescence Imaging Using Bimodal Liposomes.

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome results in respiratory obstruction and severe lung inflammation. Critical characteristics of ALI are alveolar edema, infiltration of leukocytes (neutrophils and monocytes), release of pro-inflammatory cytokines and chemokines into broncho-alveolar lavage fluid, and activation of integrin receptors. The purpose of the study was to demonstrate non-invasive detection of lung inflammation using integrin receptor targeted fluorescence liposomes. An inflammation similar to that observed in ALI was elicited in rodents by intra-tracheal instillation of interleukin-1beta (IL-1beta). Cyclic arginine glycine-(D)-aspartic acid-peptide (cRGD-peptide) grafted fluorescence liposomes were administered to ALI induced male Sprague-Dawley rats for targeting lung integrin receptors. Near-infrared fluorescence imaging (NIRFI) was applied for visualization and quantitation of lung inflammation. NIRFI signals were correlated with inflammatory cellular and biochemical markers of lungs. A positive correlation was observed between NIRF signals and lung inflammation markers. Compared to control group, an intense NIRF signal was observed in ALI induced rats in the window 6-24 h post-IL-1beta instillation. Interaction of integrin receptors with targeted liposomes was assumed to contribute to intense NIRF signal. RT-PCR studies showed an elevated lung expression of alphavbeta5 integrin receptors, 12 h post-IL-1beta instillation. In vitro studies demonstrated integrin receptor specificity of targeted liposomes. These targeted liposomes showed binding to alphavbeta5 integrin receptors expressed on alveolar cells. Non-invasive detection of lung inflammation was demonstrated using a combination of integrin receptor targeting and NIRFI.

Effect of sucrose as a lyoprotectant on the integrity of paclitaxel-loaded liposomes during lyophilization.

CONTEXT: The stability of liposomes in the form of dispersion is a major concern due to drug leakage and fusion or aggregation. The stability can be improved by lyophilization, but the stress induced by the lyophilization process can affect the integrity of liposomes. OBJECTIVE: The objective of this study was to evaluate the lyoprotective effect of sucrose on drug leakage and vesicle size of paclitaxel-loaded liposomes during the lyophilization process. MATERIALS AND METHODS: Paclitaxel-loaded liposomal dispersions were prepared with sucrose at several lipid-sugar ratios, and internal-external sugar ratios, and then lyophilized. The entrapped paclitaxel content and vesicle size were monitored before and after lyophilization. The stability of the formulation was evaluated at 5 and 25 °C. RESULTS: A significant increase in free paclitaxel and vesicle size was observed with the liposomes lyophilized without sucrose. Inclusion of sucrose in the formulation significantly reduced the free paclitaxel concentration and minimized the changes in vesicle size. The extent of protection improved further when sucrose was also present in the internal portion of the bilayer. The lyophilized formulation was stable at 5 °C for 3 months. DISCUSSION: A significant (p < 0.05) correlation was observed between free paclitaxel content and the average diameter of the liposomes with respect to sucrose concentrations in the formulation. Sucrose protected the liposomes from drug leakage and aggregation/fusion induced by the lyophilization process in a concentration dependent manner. CONCLUSION: The integrity of paclitaxel-loaded liposomes was preserved during lyophilization by optimal levels of lyoprotectant sucrose in the formulation.

Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes.

The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage.

Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform.

The focus of nanoparticle design over the years has evolved toward more complex nanoscopic core-shell architecture using a single delivery system to combine multiple functionalities within nanoparticles. Core-shell-type lipid-polymer hybrid nanoparticles (CSLPHNs), which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes, have emerged as a robust and promising delivery platform. In CSLPHNs, a biodegradable polymeric core is surrounded by a shell composed of layer(s) of phospholipids. The hybrid architecture can provide advantages such as controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on CSLPHNs including classification, advantages, methods of preparation, physicochemical characteristics, surface modifications, and immunocompatibility. Additionally, the review deals with applications for cancer chemotherapy, vaccines, and gene therapeutics. FROM THE CLINICAL EDITOR: This comprehensive review covers the current applications of core-shell-type lipid-polymer hybrid nanoparticles, which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes to enable an efficient drug delivery system.

"We know what's going on in our community": A qualitative analysis identifying community assets that deter gun violence.

Communities of color are disproportionately impacted by gun violence. Unlocking potential community-led solutions could be the key to quelling the gun violence epidemic and its impact on these communities. In this qualitative study, we explored community perspectives on local assets that may prevent and mitigate gun violence. We conducted semi-structured, in-depth interviews (n = 45) among individuals not directly involved in gun violence (i.e., shooting victim or perpetrator) despite having a high probability of being involved in gun violence in New Haven, CT. Participants were asked to describe social structures that may deter local gun violence. Here, we report emergent themes to preventing gun violence across multiple levels, including role models (interpersonal), social cohesion and home ownership (neighborhood), and community-based organizations (organizational). Our findings suggest that investments in stable housing, efforts to build social cohesion, access to community-based mental health services, and youth activities are needed to curb the drivers of community gun violence.

Development and validation of a spectrofluorimetric method for the determination of erlotinib in spiked human plasma.

A rapid and sensitive spectrofluorimetric method was developed and validated for the determination of erlotinib (ETB), a potent anticancer drug, in spiked human plasma without any derivatization. The described method was validated and the analytical parameters of linearity, accuracy, precision (intra- and inter-day), limit of detection (LOD), and limit of quantification (LOQ) were evaluated. The relation between the fluorescence intensity and concentration was found to be linear (r(2) 0.9998) over the range 125 to 1000 ng/mL with the detection limit of 15 ng/mL. A simple liquid-liquid extraction method was followed in order to extract the drug from spiked plasma. The mean absolute recoveries of ETB were 85.59 % (±0.57), 86.91 % (±1.77) and 89.31 % (±3.01) at spiked plasma ETB concentration of 5000, 3750 and 2500 ng/mL, respectively. The spectrofluorimetric method presented here is a rapid, simple, specific, and reproducible method and can be used to characterize the plasma pharmacokinetics of ETB.

1H, 15N and 13C resonance assignments of the HR1c domain of PRK1, a protein kinase C-related kinase.

PRK1 is a member of the protein kinase C-related kinase (PRK) family of serine/threonine kinases and a downstream effector of Rho GTPases. PRK1 has three N-terminal Homology Region 1 (HR1) domains (HR1a, HR1b and HR1c), which form antiparallel coiled coils that interact with Rho family GTPases. PRK1 also has a C2-like domain that targets it to the plasma membrane and a kinase domain, which is a member of the protein kinase C superfamily. PRK1 is involved in cytoskeletal regulation, cell adhesion, cell cycle progression and the immune response, and is implicated in cancer. There is currently no structural information for the HR1c domain. The 1H, 15N and 13C NMR backbone and sidechain resonance assignment of the HR1c domain presented here forms the basis for this domain's structural characterisation. This work will also enable studies of interactions between the three HR1 domains in an effort to obtain structural insight into the regulation of PRK1 activity.

Building community resilience to prevent and mitigate community impact of gun violence: conceptual framework and intervention design.

INTRODUCTION: The USA has the highest rate of community gun violence of any developed democracy. There is an urgent need to develop feasible, scalable and community-led interventions that mitigate incident gun violence and its associated health impacts. Our community-academic research team received National Institutes of Health funding to design a community-led intervention that mitigates the health impacts of living in communities with high rates of gun violence. METHODS AND ANALYSIS: We adapted 'Building Resilience to Disasters', a conceptual framework for natural disaster preparedness, to guide actions of multiple sectors and the broader community to respond to the man-made disaster of gun violence. Using this framework, we will identify existing community assets to be building blocks of future community-led interventions. To identify existing community assets, we will conduct social network and spatial analyses of the gun violence episodes in our community and use these analyses to identify people and neighbourhood blocks that have been successful in avoiding gun violence. We will conduct qualitative interviews among a sample of individuals in the network that have avoided violence (n=45) and those living or working on blocks that have not been a location of victimisation (n=45) to identify existing assets. Lastly, we will use community-based system dynamics modelling processes to create a computer simulation of the community-level contributors and mitigators of the effects of gun violence that incorporates local population-based based data for calibration. We will engage a multistakeholder group and use themes from the qualitative interviews and the computer simulation to identify feasible community-led interventions. ETHICS AND DISSEMINATION: The Human Investigation Committee at Yale University School of Medicine (#2000022360) granted study approval. We will disseminate study findings through peer-reviewed publications and academic and community presentations. The qualitative interview guides, system dynamics model and group model building scripts will be shared broadly.

Lyophilized Iron Oxide Nanoparticles Encapsulated in Amphotericin B: A Novel Targeted Nano Drug Delivery System for the Treatment of Systemic Fungal Infections.

We formulated and tested a targeted nanodrug delivery system to help treat life-threatening invasive fungal infections, such as cryptococcal meningitis. Various designs of iron oxide nanoparticles (IONP) (34-40 nm) coated with bovine serum albumin and coated and targeted with amphotericin B (AMB-IONP), were formulated by applying a layer-by-layer approach. The nanoparticles were monodispersed and spherical in shape, and the lead formulation was found to be in an optimum range for nanomedicine with size (≤36 nm), zeta potential (-20 mV), and poly dispersity index (≤0.2), and the drug loading was 13.6 ± 6.9 µg of AMB/mg of IONP. The drug release profile indicated a burst release of up to 3 h, followed by a sustained drug release of up to 72 h. The lead showed a time-dependent cellular uptake in C. albicans and C. glabrata clinical isolates, and exhibited an improved efficacy (16-25-fold) over a marketed conventional AMB-deoxycholate product in susceptibility testing. Intracellular trafficking of AMB-IONP by TEM and confocal laser scanning microscopy confirmed the successful delivery of the AMB payload at and/or inside the fungal cells leading to potential therapeutic advantages over the AMB-deoxycholate product. A short-term stability study at 5 °C and 25 °C for up to two months showed that the lyophilized form was stable.

Reducing gunshot victimization in high-risk social networks through direct and spillover effects.

More than 60,000 people are victimized by gun violence each year in the United States. A large share of victims cluster in bounded and identifiable social networks. Despite a growing number of violence reduction programmes that leverage networks to broaden programmatic effects, there is little evidence that reductions in victimization are achieved through spillover effects on the peers of participants. This study estimates the direct and spillover effects of a gun violence field intervention in Chicago. Using a quasi-experimental design, we test whether a desistance-based programme reduced gunshot victimization among 2,349 participants. The study uses co-arrest network data to further test spillover effects on 6,132 non-participants. Direct effects were associated with a 3.2-percentage point reduction in victimization among seeds over two years, while potential spillover was associated with a 1.5-percentage point reduction among peers. Findings suggest that peer influence and the structure of networks might be leveraged to amplify gun violence reduction efforts.

Comparing docosahexaenoic acid (DHA) concomitant with neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in the treatment of breast cancer (DHA WIN): protocol of a double-blind, phase II, randomised controlled trial.

INTRODUCTION: Neoadjuvant chemotherapy for breast cancer treatment is prescribed to facilitate surgery and provide confirmation of drug-sensitive disease, and the achievement of pathological complete response (pCR) predicts improved long-term outcomes. Docosahexaenoic acid (DHA) has been shown to reduce tumour growth in preclinical models when combined with chemotherapy and is known to beneficially modulate systemic immune function. The purpose of this trial is to investigate the benefit of DHA supplementation in combination with neoadjuvant chemotherapy in patients with breast cancer. METHODS AND ANALYSIS: This is a double-blind, phase II, randomised controlled trial of 52 women prescribed neoadjuvant chemotherapy to test if DHA supplementation enhances chemotherapy efficacy. The DHA supplementation group will take 4.4 g/day DHA orally, and the placebo group will take an equal fat supplement of vegetable oil. The primary outcome will be change in Ki67 labelling index from prechemotherapy core needle biopsy to definitive surgical specimen. The secondary endpoints include assessment of (1) DHA plasma phospholipid content; (2) systemic immune cell types, plasma cytokines and inflammatory markers; (3) tumour markers for apoptosis and tumour infiltrating lymphocytes; (4) rate of pCR in breast and in axillary nodes; (5) frequency of grade 3 and 4 chemotherapy-associated toxicities; and (6) patient-perceived quality of life. The trial has 81% power to detect a significant between-group difference in Ki67 index with a two-sided t-test of less than 0.0497, and accounts for 10% dropout rate. ETHICS AND DISSEMINATION: This study has full approval from the Health Research Ethics Board of Alberta - Cancer Committee (Protocol #: HREBA.CC-18-0381). We expect to present the findings of this study to the scientific community in peer-reviewed journals and at conferences. The results of this study will provide evidence for supplementing with DHA during neoadjuvant chemotherapy treatment for breast cancer. TRIAL REGISTRATION NUMBER: NCT03831178.

The electronic medical office: optimizing solutions.

Optimizing the care for patients in the orthopaedic clinical setting involves a wide range of issues. Surgical techniques, preoperative and postoperative care, long-term outcomes follow-up, continuing education, and patient communication are a few of the important areas that surgeons deal with on a regular basis. Successful management of this information has an impact on clinical outcomes, direct patient care, financial decisions, and management of the surgeon's time. The development of a comprehensive electronic medical office is a powerful and probably necessary tool to successfully manage such information and achieve the goals of an effective and safe orthopaedic practice.

Formulation, Development, and In Vitro Evaluation of a CD22 Targeted Liposomal System Containing a Non-Cardiotoxic Anthracycline for B Cell Malignancies.

Doxorubicin cardiotoxicity has led to the development of superior chemotherapeutic agents such as AD 198. However, depletion of healthy neutrophils and thrombocytes from AD 198 therapy must be limited. This can be done by the development of a targeted drug delivery system that delivers AD 198 to the malignant cells. The current research highlights the development and in vitro analysis of targeted liposomes containing AD 198. The best lipids were identified and optimized for physicochemical effects on the liposomal system. Physiochemical characteristics such as size, ζ-potential, and dissolution were also studied. Active targeting to CD22 positive cells was achieved by conjugating anti-CD22 Fab’ to the liposomal surface. Size and ζ-potential of the liposomes was between 115 and 145 nm, and −8 to−15 mV. 30% drug was released over 72 h. Higher cytotoxicity was observed in CD22+ve Daudi cells compared to CD22−ve Jurkat cells. The route of uptake was a clathrin- and caveolin-independent pathway. Intracellular localization of the liposomes was in the endolysosomes. Upon drug release, apoptotic pathways were activated partly by the regulation of apoptotic and oncoproteins such as caspase-3 and c-myc. It was observed that the CD22 targeted drug delivery system was more potent and specific compared to other untargeted formulations.

Emergent pelvic fixation in patients with exsanguinating pelvic fractures.

BACKGROUND: An alternative to embolization or external pelvic fixation (EPF) in patients with multiple pelvic fractures and hemorrhage is a pelvic orthotic device (POD), which may easily be placed in the resuscitation area. Little published information is available about its effectiveness. This study evaluated the efficacy of the POD compared with EPF in patients with life-threatening pelvic fractures. STUDY DESIGN: We evaluated patients with blunt pelvic fractures over a 10-year period. Inclusion required multiple pelvic fractures with vascular disruption and severe retroperitoneal hematoma, open book fracture with symphysis diastasis, or sacroiliac disruption with vertical shear. Patients with EPF were compared with those in whom a POD was used. Outcomes included transfusions, hospital stay, and mortality. RESULTS: There were 3,359 patients with pelvic fractures who were admitted: 186 (6%) met entry criteria; 93 had EPF and 93 had POD. There were no differences in age or shock severity. Both 24-hour (4.9 versus 17.1 U, p < 0.0001) and 48-hour transfusions (6.0 versus 18.6 U, p < 0.0001) were reduced with POD. Twenty-three percent of each group underwent pelvic angiography, and 24-hour transfusion amounts for those patients were also reduced with POD (9.9 versus 21.5 U, p < 0.007). Hospital length of stay (16.5 versus 24.4 days, p < 0.03) was less with POD. Although there was decreased mortality with POD (26%) versus EPF (37%), it was not statistically significant (p=0.11). CONCLUSIONS: The therapeutic shift to POD has substantially reduced transfusion requirements and length of hospital stay, and has reduced mortality in patients with unstable pelvic fractures. POD has made a major contribution to the care of critically injured patients with the most severe pelvic fractures.

New Robust and Reproducible Stereological IHC Ki67 Breast Cancer Proliferative Assessment to Replace Traditional Biased Labeling Index.

There is a pressing need for an objective decision tool to guide therapy for breast cancer patients that are estrogen receptor positive and HER2/neu negative. This subset of patients contains a mixture of luminal A and B tumors with good and bad outcomes, respectively. The 2 main current tools are on the basis of immunohistochemistry (IHC) or gene expression, both of which rely on the expression of distinct molecular groups that reflect hormone receptors, HER2/neu status, and most importantly, proliferation. Despite the success of a proprietary molecular test, definitive superiority of any method has not yet been demonstrated. Ki67 IHC scoring assessments have been shown to be poorly reproducible, whereas molecular testing is costly with a longer turnaround time. This work proposes an objective Ki67 index using image analysis that addresses the existing methodological issues of Ki67 quantitation using IHC on paraffin-embedded tissue. Intrinsic bias related to numerical assessment performed on IHC is discussed as well as the sampling issue related to the "peel effect" of tiny objects within a thin section. A new nonbiased stereological parameter (VV) based on the Cavalieri method is suggested for use on a double-stained Ki67/cytokeratin IHC slide. The assessment is performed with open-source ImageJ software with interobserver concordance between 3 pathologists being high at 93.5%. Furthermore, VV was found to be a superior method to predict an outcome in a small subset of breast cancer patients when compared with other image analysis methods being used to determine the Ki67 labeling index. Calibration methodology is also discussed to further this IHC approach.

A tumor vasculature targeted liposome delivery system for combretastatin A4: design, characterization, and in vitro evaluation.

The objective of this study was to develop an efficient tumor vasculature targeted liposome delivery system for combretastatin A4, a novel antivascular agent. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, distearoyl phosphoethanolamine-polyethylene-glycol-2000 conjugate (DSPE-PEG), and DSPE-PEG-maleimide were prepared by the lipid film hydration and extrusion process. Cyclic RGD (Arg-Gly-Asp) peptides with affinity for alphavbeta3-integrins expressed on tumor vascular endothelial cells were coupled to the distal end of PEG on the liposomes sterically stabilized with PEG (long circulating liposomes, LCL). The liposome delivery system was characterized in terms of size, lamellarity, ligand density, drug loading, and leakage properties. Targeting nature of the delivery system was evaluated in vitro using cultured human umbilical vein endothelial cells (HUVEC). Electron microscopic observations of the formulations revealed presence of small unilamellar liposomes of approximately 120 nm in diameter. High performance liquid chromatography determination of ligand coupling to the liposome surface indicated that more than 99% of the RGD peptides were reacted with maleimide groups on the liposome surface. Up to 3 mg/mL of stable liposomal combretastatin A4 loading was achieved with approximately 80% of this being entrapped within the liposomes. In the in vitro cell culture studies, targeted liposomes showed significantly higher binding to their target cells than nontargeted liposomes, presumably through specific interaction of the RGD with its receptors on the cell surface. It was concluded that the targeting properties of the prepared delivery system would potentially improve the therapeutic benefits of combretastatin A4 compared with nontargeted liposomes or solution dosage forms.