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Background Home blood pressure measurements have equal or even greater predictive value than clinic blood pressure measurements regarding cardiovascular outcomes. With advances in home blood pressure monitors, we face an imminent flood of home measurements, but current electronic health record systems lack the functionality to allow us to use this data to its fullest. We designed a data visualization display for blood pressure measurements to be used for shared decision making around hypertension. Methods We used an iterative, rapid-prototyping, user-centred design approach to determine the most appropriate designs for this data display. We relied on visual cognition and human factors principles when designing our display. Feedback was provided by expert members of our multidisciplinary research team and through a series of end-user focus groups, comprised of either hypertensive patients or their healthcare providers required from eight academic, community-based practices in the Midwest of the United States. Results A total of 40 participants were recruited to participate in patient (N = 16) and provider (N = 24) focus groups. We describe the conceptualization and development of data display for shared decision making around hypertension. We designed and received feedback from both patients and healthcare providers on a number of design elements that were reported to be helpful in understanding blood pressure measurements. Conclusions We developed a data display for substantial amounts of blood pressure measurements that is both simple to understand for patients, but powerful enough to inform clinical decision making. The display used a line graph format for ease of understanding, a LOWESS function for smoothing data to reduce the weight users placed on outlier measurements, colored goal range bands to allow users to quickly determine if measurements were in range, a medication timeline to help link recorded blood pressure measurements with the medications a patient was taking. A data display such as this, specifically designed to encourage shared decision making between hypertensive patients and their healthcare providers, could help us overcome the clinical inertia that often results in a lack of treatment intensification, leading to better care for the 35 million Americans with uncontrolled hypertension.

Shigella ssp cause bacillary dysentery (shigellosis) which has high global morbidity in young children and the elderly. The virulence of Shigella relies upon a type III secretion system (T3SS) which injects host altering effector proteins into targeted intestinal cells. The Shigella T3SS contains two components, invasion plasmid antigen D (IpaD) and invasion plasmid antigen B (IpaB), that were previously identified as broadly protective antigens. When IpaD and IpaB were co-expressed to give the DB fusion (DBF) protein, vaccine efficacy was further improved. Biophysical characterization under various pH conditions showed that DBF is most stable at pH 7 and 8 and loses its conformational integrity at 48 and 50 °C respectively. Forced degradation studies revealed significant effects on the secondary structure, tertiary structure and conformational stability of DBF. In the presence of phosphate buffers as well as other anionic excipients, DBF demonstrated a concentration dependent conformational stabilization. Molecular docking revealed potential polyanion binding sites in DBF that may interact with phytic acid. These sites can be exploited to stabilize the DBF protein. This work highlights potential destabilizing and stabilizing factors, which not only improves our understanding of the DBF protein but helps in future development of a stable Shigella vaccine.

The serotype-specific early detection of dengue fever is very effective in predicting the pervasiveness of fatal infections such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This fever results from reinfection (secondary) with a serotype of the dengue virus, which is different from the serotype involved in primary infection. Hence, the present work was aimed to develop a multiplexed electrochemical paper-based analytical device (ePAD) consisting of graphene oxide-silicon dioxide (GO-SiO

Cabazitaxel, a novel tubulin inhibitor with poor affinity for P-glycoprotein, is a second-generation taxane holding great promise for the treatment of metastatic castration-resistant prostate cancer. However, its poor solubility and lack of target-ability limit its therapeutic applications. Herein, we develop a biodegradable, enzyme-responsive, and targeted polymeric micelle for cabazitaxel. The micelle is formed from two amphiphilic block copolymers. The first block copolymer consists of PEG, an enzyme-responsive peptide, and cholesterol; whereas the second block copolymer consists of a targeting ligand, PEG and cholesterol. The enzyme-responsive peptide is cleavable in the presence of matrixmetaloproteinase-2 (MMP-2), which is overexpressed in the tumor microenvironment of prostate cancer. The micelle showed a very low critical micelle concentration (CMC), high drug loading, and high entrapment efficiency. Release of cabazitaxel from the micelle is dependent on the cleavage of the enzyme-responsive peptide. Moreover, the micelle showed dramatically higher cellular uptake in prostate cancer cells compared to free cabazitaxel. Importantly, the ligand-coupled polymeric micelle demonstrated better inhibition of tumor growth in mice bearing prostate cancer xenografts compared to unmodified micelle and free cabazitaxel. Taken together, these findings suggest that the enzyme-responsive cabazitaxel micelle is a potent and promising drug delivery system for advanced prostate cancer therapy. STATEMENT OF SIGNIFICANCE: Herein, we develop a biodegradable, enzyme-responsive, and actively targeted polymer micelle for cabazitaxel, which is a novel tubulin inhibitor with poor affinity for P-glycoprotein. Despite cabazitaxel's great promise for metastatic castration-resistant prostate cancer, its poor solubility, lack of target-ability, and high systemic toxicity limit its therapeutic applications, and therefore a targeted delivery system is highly needed for cabazitaxel. Our results demonstrate the importance of active targeting in targeted prostate cancer therapy. Encapsulating cabazitaxel in the micelle increases its activity and is expected to reduce its systemic toxicity, which is a major hurdle in its clinical applications. Moreover, the polymeric micelle may servers as a promising nanoscale platform for the targeted delivery of other chemotherapeutic agents to prostate cancer.

Immunotherapy using monoclonal antibodies targeting the PD-1/PD-L1 interaction has shown enormous success for various cancers. Despite their encouraging results in clinics, antibody-based checkpoint inhibitors have several limitations, such as poor tumor penetration. To address these limitations of monoclonal antibodies, there is a growing interest in developing low-molecular-weight checkpoint inhibitors, such as antibody fragments. Several antibody fragments targeting PD-1/PD-L1 were recently discovered using phage libraries from camel or alpaca. However, animal-derived antibody fragments may elicit unwanted immune responses, which limit their therapeutic applications. For the first time, we used a human domain antibody phage library and discovered anti-human PD-L1 human single-domain antibodies (dAbs) that block the PD-1/PD-L1 interaction. Among them, the CLV3 dAb shows the highest affinity to PD-L1. The CLV3 dAb also exhibits the highest blocking efficacy of the PD-1/PD-L1 interaction. Moreover, the CLV3 dAb significantly inhibits tumor growth in mice implanted with CT26 colon carcinoma cells. These results suggest that CLV3 dAb can be potentially used as an anti-PD-L1 inhibitor for cancer immunotherapy.

Explanations for police misconduct often center on a narrow notion of “problem officers,” the proverbial “bad apples.” Such an individualistic approach not only ignores the larger systemic problems of policing but also takes for granted the group-based nature of police work. Nearly all of police work is group-based and officers’ formal and informal networks can impact behavior, including misconduct. In extreme cases, groups of officers (what we refer to as, “crews”) have even been observed to coordinate their abusive and even criminal behaviors. This study adopts a social network and machine learning approach to empirically investigate the presence and impact of officer crews engaging in alleged misconduct in a major U.S. city: Chicago, IL. Using data on Chicago police officers between 1971 and 2018, we identify potential crews and analyze their impact on alleged misconduct and violence. Results detected approximately 160 possible crews, comprised of less than 4% of all Chicago police officers. Officers in these crews were involved in an outsized amount of alleged and actual misconduct, accounting for approximately 25% of all use of force complaints, city payouts for civil and criminal litigations, and police-involved shootings. The detected crews also contributed to racial disparities in arrests and civilian complaints, generating nearly 18% of all complaints filed by Black Chicagoans and 14% of complaints filed by Hispanic Chicagoans.

Desmoplasia plays a pivotal role in promoting pancreatic cancer progression and is associated with poor clinical outcome. Targeting the desmoplastic tumor microenvironment in combination with chemotherapy is therefore a promising strategy for pancreatic cancer therapy. Here, we report a novel biodegradable copolymer to codeliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the tumor microenvironment. Hydrophobic CPI-613 is conjugated to the hydrophilic copolymer via a newly designed MMP-2-responsive linker to form a trigger-responsive nanopolyplex. LY2109761 is hydrophobic and encapsulated into the hydrophobic core of the nanopolyplex. The resulting nanopolyplex is modified with a plectin-1-targeting peptide to enhance the accumulation of the nanopolyplex in pancreatic tumors. The nanopolyplex aims to normalize the stroma by blocking the interaction between tumor cells and pancreatic stellate cells to inhibit the activation of pancreatic stellate cells and subsequently reduce the dense extracellular matrix. Normalized stroma increases the penetration of the nanopolyplex into the tumor. The nanopolyplex shows enhanced accumulation in xenograft pancreatic tumors in a biodistribution study. Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy.

Liver fibrosis is caused by excessive accumulation of extracellular matrix during chronic liver injuries. Although clinical evidence suggests that liver fibrosis can be reversed, there is no standard therapy for liver fibrosis. Moreover, there is a lack of diagnostic tools to detect early-stage liver fibrosis. Activation of hepatic stellate cells (HSCs) is the key step during liver fibrogenesis, and its mechanism has been extensively studied by various cell culture and animal models. Targeted delivery of therapeutic agents to activated HSCs is therefore critical for the successful treatment of liver fibrosis. A number of protein markers have been found to be overexpressed in activated HSCs, and their ligands have been used to specifically deliver various antifibrotic agents. In this review, we summarize these HSC-specific protein markers and their ligands for targeted delivery of antifibrotic agents.

Objective. Uncontrolled hypertension is driven by clinical uncertainty around blood pressure data. This research sought to determine whether decision support—in the form of enhanced data visualization—could improve judgments about hypertension control. Methods. Participants (Internet sample of patients with hypertension) in 3 studies ( N = 209) viewed graphs depicting blood pressure data for fictitious patients. For each graph, participants rated hypertension control, need for medication change, and perceived risk of heart attack and stroke. In study 3, participants also recalled the percentage of blood pressure measurements outside of the goal range. The graphs varied by systolic blood pressure mean and standard deviation, change in blood pressure values over time, and data visualization type. Results. In all 3 studies, data visualization type significantly affected judgments of hypertension control. In studies 1 and 2, perceived hypertension control was lower while perceived need for medication change and subjective perceptions of stroke and heart attack risk were higher for raw data displays compared with enhanced visualization that employed a smoothing function generated by the locally weighted smoothing algorithm. In general, perceptions of hypertension control were more closely aligned with clinical guidelines when data visualization included a smoothing function. However, conclusions were mixed when comparing tabular presentations of data to graphical presentations of data in study 3. Hypertension was perceived to be less well controlled when data were presented in a graph rather than a table, but recall was more accurate. Conclusion. Enhancing data visualization with the use of a smoothing function to minimize the variability present in raw blood pressure data significantly improved judgments about hypertension control. More research is needed to determine the contexts in which graphs are superior to data tables.

Co-delivery of IKBKE siRNA and cabazitaxel inhibits invasiveness and growth of triple-negative breast cancer., IKBKE is an oncogene in triple-negative breast cancer (TNBC), and we demonstrate that IKBKE small interfering RNA (siRNA) inhibits the proliferation, migration, and invasion of TNBC cells. Despite the recent success of siRNA therapeutics targeting to the liver, there still remains a great challenge to deliver siRNAs to solid tumors. Here, we report a hybrid nanocomplex to co-deliver the IKBKE siRNA and cabazitaxel to TNBC to achieve an optimal antitumor effect. The nanocomplex is modified with hyaluronic acid to target CD44 on TNBC cells. The nanocomplex shows higher cellular uptake and better tumor penetration of the encapsulated cargos. The nanocomplex also exhibits high tumor accumulation and antitumor activity in an orthotopic TNBC mouse model. Encapsulation of cabazitaxel in the nanocomplex enhances the activity of the IKBKE siRNA. The hybrid nanocomplex provides a novel and versatile platform for combination therapies using siRNAs and chemotherapy.

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are an established treatment for patients with type 2 diabetes (T2D). Differences between GLP‐1RAs in pharmacokinetics, dosing regimens and clinical effects, including cardiovascular (CV) outcomes, mean there may be benefits to switching from one to another. However, clinical guidance on switching is lacking and data from clinical trials are limited. This article provides a clinical perspective and consensus on the benefits of switching between GLP‐1RAs, the triggers for switching and how best to manage this in clinical practice. Once weekly (OW) semaglutide is used as an example to illustrate how the authors might switch to a different GLP‐1RA in clinical practice. Methods Literature was searched and perspectives from 10 healthcare professionals with experience in switching patients with T2D to OW semaglutide from another GLP‐1RA were collated. Results Medical triggers for switching to another GLP‐1RA included HbA1c targets not being met, a desire for additional weight loss, poor adherence, patients moving to increased CV risk status and adverse effects with the current GLP‐1RA. Non‐medical triggers for switching included patient preference, cost, formulary changes and insurance mandates. Once the decision to switch is made, an individualised approach is recommended, based on considerations that include reimbursement requirements, treatment duration with (and dose of) previous GLP‐1RA, the patient's experience initiating the prior GLP‐1RA, any concomitant treatment and clinical characteristics. When switching, it is important to emphasise that treatment burden will not increase and that if gastrointestinal adverse effects occur, they are typically transient. Any transient gastrointestinal adverse effects that may occur (or recur) when switching to another GLP‐1RA can be reduced by slow up‐titration and advising patients to reduce food portion sizes and fat intake. Conclusion Switching from one GLP‐1RA to another, such as OW semaglutide, can provide clinical benefits and may delay the need for treatment intensification.

Background Nearly half of US adults with diagnosed hypertension have uncontrolled blood pressure. Clinical inertia may contribute, including patient-physician uncertainty about how variability in blood pressures impacts overall control. Better information display may support clinician-patient hypertension decision making through reduced cognitive load and improved situational awareness. Methods A multidisciplinary team employed iterative user-centered design to create a blood pressure visualization EHR prototype that included patient-generated blood pressure data. An attitude and behavior survey and 10 focus groups with patients (N = 16) and physicians (N = 24) guided iterative design and confirmation phases. Thematic analysis of qualitative data yielded insights into patient and physician needs for hypertension management. Results Most patients indicated measuring home blood pressure, only half share data with physicians. When receiving home blood pressure data, 88% of physicians indicated entering gestalt averages as text into clinical notes. Qualitative findings suggest that including a data visualization that included home blood pressures brought this valued data into physician workflow and decision-making processes. Data visualization helps both patients and physicians to have a fuller understanding of the blood pressure ‘story’ and ultimately promotes the activated engaged patient and prepared proactive physician central to the Chronic Care Model. Both patients and physicians expressed concerns about workflow for entering and using home blood pressure data for clinical care. Conclusions Our user-centered design process with physicians and patients produced a well-received blood pressure visualization prototype that includes home blood pressures and addresses patient-physician information needs. Next steps include evaluating a recent EHR visualization implementation, designing annotation functions aligned with users’ needs, and addressing additional stakeholders’ needs (nurses, care managers, caregivers). This significant innovation has potential to improve quality of care for hypertension through better patient-physician understanding of control and goals. It also has the potential to enable remote monitoring of patient blood pressure, a newly reimbursed activity, and is a strong addition to telehealth efforts.

Purpose To quantify the torsional load to fracture for subpectoral biceps tenodesis with interference screw fixation. Methods We randomized 28 specimens from 14 matched-pair full-length humeri (mean age, 55.3 years) into 3 groups: (1) empty ream group (ERG), (2) screw-only group (SOG), and (3) screw–plus–biceps tendon group (SBG). In each group, 1 humerus of each matched pair was prepared according to group allocation and the contralateral humerus remained intact as a control. In the ERG, an 8-mm unicortical hole was reamed 1 cm proximal to the inferior border of the pectoralis major tendon insertion; in the SOG, the humerus was filled with an 8-mm × 12-mm PEEK (polyether ether ketone) screw; and in the SBG, the humerus was filled with a PEEK screw and the cadaveric long head of the biceps tendon. Humeri were tested under torsional displacement at a rate of 1°/s until fracture. Maximum torque, energy to maximum torque, and linear stiffness were used to assess humerus strength. Results Compared with contralateral intact specimens, the maximum torque to fracture was reduced by 28% in the ERG ( P = .005), 30% in the SOG ( P = .014), and 20% in the SBG ( P = .046). Energy to maximum torque was similarly reduced in the ERG ( P = .007), SOG ( P = .023), and SBG ( P = .049). Stiffness was increased by 4% in the ERG ( P = .498), 9% in the SOG ( P = .030), and 4% in the SBG ( P = .439). Conclusions Drilling an 8-mm unicortical hole in zone 3 of the bicipital tunnel for open subpectoral biceps tenodesis reduces the torsional load to humeral fracture up to 28% at time 0. The addition of a PEEK tenodesis screw alone reduced the maximum torque by 30%, and the addition of a screw with the long head of the biceps tendon reduced the maximum torque by 20%. The total load to fracture was reduced in all settings. Stiffness was not significantly different for the ERG and SBG, but stiffness was significantly higher for the SOG compared with the intact matched humeri at time 0. Clinical Relevance When performing a biceps tenodesis, humeral fracture susceptibility is increased with an applied torsional load at time 0. Thus providers must be aware of this reduced integrity when a subpectoral biceps tenodesis is used.

Insulin-like growth factor 2 receptor (IGF2R) is overexpressed in activated Hepatic stellate cells (HSCs) and therefore can be utilized for HSC-specific drug delivery. We recently discovered an IGF2R-specific peptide using a novel biopanning. Here, we adopted biotin-conjugated IGF2R-specific peptide, cholesterol, and vitamin A as the targeting ligands for the neutravidin-based siRNA nanocomplex to deliver PCBP2 siRNA, a potentially antifibrotic agent, to HSCs. Compared to Vitamin A and cholesterol, the IGF2R-specific peptide exhibited the highest targeting effect to human LX-2 HSC, rat HSC-T6 cell line, and activated primary rat HSCs. Accordingly, the IGF2R-specific peptide coupled nanocomplex demonstrated higher silencing activity of PCBP2 and better inhibition on the migration of activated HSCs. Compared to free siRNA and the nanocomplexes coupled with Vitamin A and cholesterol, the IGF2R-specific peptide coupled nanocomplex showed the highest uptake in the liver and lowest uptake in the lung and kidney of the rats with CCl4-induced liver fibrosis.

This paper reports an electrochemical paper analytical device (EPAD) for detection of recreational drug; methylenedioxymethamphetamine (MDMA). MDMA is used as an addictive narcotic by youth and there is an urgent need to detect this drug as it is a potential neurotoxic agent. The proposed EPAD represents many advantageous features of being simple, low-cost, consistent and disposable. The working electrode of the EPAD features zinc oxide nanorods (ZnONRs). The morphological, optical, elemental composition and phase analysis of the synthesized ZnONRs has been characterized by field emission scanning electron microscopy (FESEM), UV-Vis spectroscopy, energy dispersive X-ray spectroscopy (EDAX), photo-luminescence (PL) and X-ray diffraction (XRD). The developed sensor showed optimum response at 7.0 pH and wide linear range of 1 µM-1 mM with a low detection limit of 0.1 µM for MDMA. Evaluation of the sensor also revealed best results in terms of analytical recovery (95%) and accuracy (95%). The designed EPAD could prove to be very effective in case of forensic diagnostic applications. This work provides a reliable diagnostic method for remote areas with limited resources, and will also help people who cannot afford expensive medical tests and have limited access to power and trained personnel.

Purpose To compare the initial fixation stability, failure strength, and mode of failure of 5 different screw types and fixation methods commonly used for the classic Latarjet procedure. Methods Thirty-five fresh-frozen cadaveric shoulder specimens were allocated into 5 groups. A 25% anteroinferior glenoid defect was created, and a classic Latarjet coracoid transfer procedure was performed. All grafts were fixed with 2 screws, differing by screw type and/or fixation method. The groups included partially threaded solid 4.0-mm cancellous screws with bicortical fixation, partially threaded solid 4.0-mm cancellous screws with unicortical fixation, fully threaded solid 3.5-mm cortical screws with bicortical fixation, partially threaded cannulated 4.0-mm cancellous screws with bicortical fixation, and partially threaded cannulated 4.0-mm captured screws with bicortical fixation. All screws were stainless steel. Outcomes included cyclic creep and secant stiffness during cyclic loading, as well as load and work to failure during the failure test. Intergroup comparisons were made by a 1-way analysis of variance. Results There were no significant differences among different screw types or fixation methods in cyclic creep or secant stiffness after cyclic loading or in load to failure or work to failure during the failure test. Post-failure radiographs showed evidence of screw bending in only 1 specimen that underwent the Latarjet procedure with partially threaded solid cancellous screws with bicortical fixation. The mode of failure for all specimens analyzed was screw cutout. Conclusions In this biomechanical study, screw type and fixation method did not significantly influence biomechanical performance in a classic Latarjet procedure. When performing this procedure, surgeons may continue to select the screw type and method of fixation (unicortical or bicortical) based on preference; however, further studies are required to determine the optimal method of treatment. Clinical Relevance Surgeons may choose the screw type and fixation method based on preference when performing the Latarjet procedure.

Avidin-biotin interaction is one of the strongest non-covalent interactions in the nature. Avidin and its analogues have therefore been extensively utilized as probes and affinity matrices for a wide variety of applications in biochemical assays, diagnosis, affinity purification, and drug delivery. Recently, there has been a growing interest in exploring this non-covalent interaction in nanoscale drug delivery systems for pharmaceutical agents, including small molecules, proteins, vaccines, monoclonal antibodies, and nucleic acids. Particularly, the ease of fabrication without losing the chemical and biological properties of the coupled moieties makes the avidin-biotin system a versatile platform for nanotechnology. In addition, avidin-based nanoparticles have been investigated as diagnostic systems for various tumors and surface antigens. In this review, we will highlight the various fabrication principles and biomedical applications of avidin-based nanoparticles in drug delivery and diagnosis. The structures and biochemical properties of avidin, biotin and their respective analogues will also be discussed.

Insulin like growth factor II receptor (IGFIIR) is a transmembrane protein overexpressed in activated hepatic stellate cells (HSCs), which are the major target for the treatment of liver fibrosis. In this study, we aim to discover an IGFIIR-specific aptamer that can be potentially used as a targeting ligand for the treatment and diagnosis of liver fibrosis. Systematic evolution of ligands by exponential enrichment (SELEX) was conducted on recombinant human IGFIIR to identify IGFIIR-specific aptamers. The binding affinity and specificity of the discovered aptamers to IGFIIR and hepatic stellate cells were studied using flow cytometry and Surface Plasmon Resonance (SPR). Aptamer-20 showed the highest affinity to recombinant human IGFIIR protein with a Kd of 35.5 nM, as determined by SPR. Aptamer-20 also has a high affinity (apparent Kd 45.12 nM) to LX-2 human hepatic stellate cells. Binding of aptamer-20 to hepatic stellate cells could be inhibited by knockdown of IGFIIR using siRNA, indicating a high specificity of the aptamer. The aptamer formed a chimera with an anti-fibrotic PCBP2 siRNA and delivered the siRNA to HSC-T6 cells to trigger silencing activity. In Vivo biodistribution study of the siRNA-aptamer chimera also demonstrated a high and specific uptake in the liver of the rats with CCl4-induced liver fibrosis. These data suggest that aptamer-20 is a high-affinity ligand for antifibrotic and diagnostic agents for liver fibrosis.

Background Immunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors. Methods We developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Anti-tumor activity of the peptides was evaluated in mice bearing CT26 tumor cells. Results We discover several anti-PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice. Conclusions This study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy. Electronic supplementary material The online version of this article (10.1186/s40425-019-0705-y) contains supplementary material, which is available to authorized users.

Digital, Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p, Ciencias Médicas y de la Salud

Digital, Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p, Ciencias Médicas y de la Salud

Introduction With the increase in the population of older adults around the world, a significant amount of work has been done on in-home sensor technology to aid the elderly age independently. However, due to the large amounts of data generated by the sensors, it takes a lot of effort and time for the clinicians to makes sense of this data. In this work, we develop a system to help make this data more useful by presenting it in the form of natural language. Methods We start by identifying important attributes in the sensor data that are relevant to the health of the elderly. We then develop algorithms to extract these important health related features from the sensor parameters and summarize them in natural language. We focus on making the natural language summaries to be informative, accurate and concise. Results We designed multiple surveys using real and synthetic data to validate the summaries produced by our algorithms. We show that the algorithms produce meaningful results comparable to human subjects. We also implemented our linguistic summarization system to produce summaries of data leading to health alerts derived from the sensor data. The system is running live in 110 apartments currently. By the means of retrospective case studies, we illustrate that the linguistic summaries are able to make the connection between changes in the sensor data and the health of the elderly. Conclusions We present a system that extracts important clinically relevant features from in-home sensor data generated in the apartments of the elderly and summarize those features in natural language. The preliminary testing of our summarization system shows that it has the potential to help the clinicians utilize this data effectively.

Triple negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat. TNBC patients have significantly higher expression of vascular endothelial growth factor (VEGF) in tumors compared to non-TNBC patients. VEGF not only exerts its pro-angiogenic effects on endothelial cells but also acts as a survival and autocrine growth factor for VEGF receptor (VEGFR) expressing cancer cells. Silencing the expression of VEGF is therefore a potential therapy for TNBC. Methods: A novel biocompatible linear copolymer poly[bis(e-Lys-PEI)Glut-PEG] (PLEGP) was developed to deliver VEGF siRNA for TNBC therapy. The copolymer is composed of lysine and glutaric acid, a natural metabolite of amino acids in the body. Low-molecular weight polyethyleneimine (PEI) was grafted to the copolymer to efficiently condense siRNA into nanocomplex without inducing cytotoxicity. Various in vitro studies were performed to evaluate the stability, cellular uptake, tumor penetration, and biological activities of the VEGF siRNA nanocomplex. The anti-tumor activities of the nanocomplex was also evaluated in an orthotopic TNBC mouse model. Results: PEIs with different molecular weights were evaluated, and the copolymer PLEGP1800 was able to easily form a stable nanocomplex with siRNAs and protect them from serum degradation. The siRNA/PLEGP1800 nanocomplex exhibited negligible cytotoxicity but showed high cellular uptake, high transfection efficiency, and high tumor penetration. In vitro activity studies showed that the siRNA nanocomplex significantly inhibited migration and invasion of TNBC cells. Moreover, the VEGF siRNA nanocomplex efficiently inhibited tumor growth in an orthotopic TNBC mouse model and down-regulated VEGF expression in the tumor. Conclusion: PLEGP1800 is a safe and efficient copolymer to deliver siRNAs for TNBC therapy. It could potentially be applied to other cancers by changing the cargo and incorporating tumor-specific ligands.

An enzyme-responsive peptide drug conjugate was developed for TGX-D1, a promising PI3K inhibitor for prostate cancer therapy. LNCaP-specific KYL peptide was used as the targeting ligand and the prostate specific antigen (PSA) cleavable peptide (SSKYQSL) was used as the enzyme-responsive linker. SSKYQSL is cleaved by recombinant human PSA at 10–250 μg/mL. By contrast, the linker is stable in the serum of prostate cancer patients with high PSA levels (>500 ng/mL), indicating that this linker can survive the systemic circulation in prostate cancer patients but be cleaved in the tumor microenvironment. Cellular uptake of the peptide drug conjugate in prostate cancer cells is improved by about nine times. Biodistribution study reveals significant tumor accumulation of the peptide drug conjugate in nude mice bearing C4–2 tumor xenografts. Meanwhile, distribution of the conjugate in other major tissues is the same as the parent drug, indicating a high specificity of the conjugate to prostate cancers in vivo.

Despite the importance of siRNA delivery systems, understanding of their intracellular fate remains elusive. We recently developed a multi-component siRNA nanocomplex to deliver siRNA to hepatic stellate cells (HSCs). The objective of this study is to study post internalization trafficking of this siRNA nanocomplex and its multiple components like siRNA, protamine, and streptavidin, in HSCs. After internalization, the nanocomplex entrapped in early endosomes undergoes three possible routes including endosomal escape, exocytosis, and entrapment in lysosomes. Significant amount of siRNA dissociates form the nanocomplex to exert silencing activity. After escaping from endosomes, protamine dissociates from the nanocomplex and stays inside the cytoplasm. Golgi complex plays an important role in exocytosis of the nanocomplex. We also demonstrate that exocytosis is one of the major reasons accounting for the transient silencing activity of nonviral siRNA delivery. Incorporation of exocytosis inhibitors in nonviral siRNA delivery systems may extend the silencing activity of siRNA.

Purpose To determine the trends in SLAP repairs over time, including patient age, and percentage of SLAP repairs versus other common shoulder arthroscopic procedures. Methods The records of 4 sports or shoulder/elbow fellowship trained orthopaedic surgeons were used to identify the total number of common shoulder arthroscopic cases performed between 2004 and 2014 using current procedural terminology codes (CPT): 29822, 29823, 29826, 29827, 29806, 29807, 29825, and 29828. The number of SLAP repairs (CPT code 29807) as a combined or isolated procedure were recorded, and the classification of SLAP type was undertaken using operative reports. Patient age was recorded. Linear regression was used to determine statistical significance. Results There were 9,765 patients who underwent arthroscopic shoulder procedures using the defined CPT codes between 2004 and 2014 by our 4 orthopaedic surgeons. Of these, 619 underwent a SLAP repair (6.3%); average age 31.2 ± 11.9. The age of patients undergoing SLAP repair significantly decreased over time ( P R 2 = 0.794). Most SLAP repairs were performed on type II SLAP tears ( P = .015, R 2 = 0.503). The percentage of SLAP repairs compared with the total number of shoulder arthroscopic surgeries and total number of patients who underwent SLAP repair significantly decreased over time ( P R 2 = 0.832 and P = .002, R 2 = 0.674, respectively). Conversely, the number and percentage of biceps tenodeses are increasing over time ( P = .0024 and P = .0099, respectively). Conclusions Over the past 10 years, the total number of biceps tenodeses has increased, whereas the number and relative percentage of SLAP repairs within our practice have decreased. The average age of patients undergoing SLAP repair is decreasing, and most SLAP repairs are performed for type II SLAP tears. Level of Evidence Level IV, therapeutic case series.

Purpose The aims of the study were as follows: (1) to perform a systematic review of meta-analyses evaluating platelet-rich plasma (PRP) use at the time of arthroscopic rotator cuff repair surgery and to determine its effect on retear rates and clinical outcomes; (2) to provide a framework for the analysis and interpretation of the best currently available evidence; and (3) to identify gaps within the literature where suggestions for continued investigational efforts would be valid. Methods Literature searches were performed to identify meta-analyses examining arthroscopic rotator cuff repairs augmented with PRP versus control (no PRP). Clinical data were extracted and meta-analysis quality was assessed using the Quality of Reporting of Meta-analyses and Oxman-Guyatt scales. Results Seven meta-analyses met inclusion and exclusion criteria. All were considered as being of similar quality with Quality of Reporting of Meta-analyses scores >15 and Oxman scores of 7. A total of 3,193 overlapping patients treated were included with mean follow-up from 12 to 31 months. When compared with control patients, use of PRP at the time of rotator cuff repair did not result in significantly lower overall retear rates or improved clinical outcome scores. The following postoperative functional scores comparing PRP versus control were reported: Constant (no significant difference demonstrated with PRP use in 5 of 6 reporting meta-analyses), University of California – Los Angeles (no difference, 6 of 6), American Shoulder and Elbow Society (no difference, 4 of 4), and Simple Shoulder Test (no difference, 3 of 5). Subgroup analysis performed by 3 meta-analyses showed evidence of improved outcomes with solid PRP matrix versus liquid, small- and/or medium-sized versus large and/or massive tears, PRP application at the tendon-bone interface versus over tendon, and in the setting of double-row versus single-row rotator cuff. Conclusions The current highest level of evidence suggests that PRP use at the time of arthroscopic rotator cuff repair does not universally improve retear rates or affect clinical outcome scores. However, the effects of PRP use on retear rates trend toward beneficial outcomes if evaluated in the context of the following specific variables: use of a solid PRP matrix; application of PRP at the tendon-bone interface; in double-row repairs; and with small- and/or medium-sized rotator cuff tears. Level of Evidence Level III, systematic review of Level II and III studies.

The disease burden of chronic-relapsing and therapy-refractory superficial dermatophytosis dramatically increased in India within the past 5-6 years. In order to evaluate the prevalence of this trend, 201 skin scrapings were collected from patients from all parts of India and were tested for dermatophytes using both fungal culture and a PCR-ELISA directly performed with native skin scrapings. Fungal culture material was identified by genomic Sanger sequencing of the internal transcribed spacer (ITS) region and the translation elongation factor (TEF)-1α gene. In total, 149 (74.13%) out of the 201 samples showed a dermatophyte-positive culture result. Out of this, 138 (92.62%) samples were identified as Trichophyton (T.) mentagrophytes and 11 (7.38%) as Trichophyton rubrum. The PCR-ELISA revealed similar results: 162 out of 201 (80.56%) samples were dermatophyte-positive showing 151 (93.21%) T mentagrophytes- and 11 (6.79%) T rubrum-positive samples. In this study, we show for the first time a dramatic Indian-wide switch from T rubrum to T mentagrophytes. Additionally, sequencing revealed a solely occurring T mentagrophytes "Indian ITS genotype" that might be disseminated Indian-wide due to the widespread abuse of topical clobetasol and other steroid molecules mixed with antifungal and antibacterial agents.

The purpose of the study is to assess the stability of a dehydrated cartilage allograft combined with platelet-rich plasma sealed with fibrin glue within trochlear and medial femoral condyle (MFC) chondral defects in a cadaver knee model.Defects were made in the trochlea (20, 25, and 30 mm) and MFC (15, 20, and 25 mm) of 6 cadaver specimens. Allograft was applied utilizing 2 different techniques: (1) proud in which the fibrin level extends beyond surrounding cartilage and (2) recessed in which the fibrin level is even with or below the surrounding cartilage. The knees were cycled by using a continuous passive motion machine through a range of motion. Defects were assessed for superficial delamination and displacement of the allograft. This was quantified as the percentage of surface delamination and/or exposed bone. Comparisons were made with regard to defect size, location, and fill.In both the MFC and trochlea, proud application resulted in an increased rate of fibrin delamination. In the trochlea, an average of 38% delamination was detected in the recessed 20-mm defect compared with 70% in the proud 30-mm defect (P.05). This effect was increased with increasing defect size. In the MFC, mean delamination of 43% and 28% exposed bone was noticed in the proud 15-mm defect compared with 95% delamination and 71% exposed bone at 25 mm. In 82% of specimens, displacement and/or delamination occurred within the first 15 minutes of testing.Increased defect size in both the trochlea and femoral condyle, as well as a proud construct application, were associated with significant delamination and displacement of the allograft/fibrin construct.Proud application of allograft increases the likelihood of fibrin delamination and graft displacement in both trochlear and MFC defects. This effect is increased with increasing defect size. These data may support limiting range of motion immediately after an allograft procedure.

Retrospective review of prospectively collected data.To determine the incidence and risk factors for the development of a urinary tract infection (UTI) after a posterior lumbar fusion procedure.UTI after surgery is common and has important clinical consequences for both patients and the health care system. Few studies have examined UTI after spinal fusion procedures.Patients undergoing posterior lumbar fusion procedures during 2011 to 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Statistical comparisons were made using multivariate regression with adjustment for demographic, comorbidity, and operative characteristics.A total of 10,825 patients met inclusion criteria. The incidence of a UTI was 1.77% (95% confidence interval = 1.52%-2.02%). Independent risk factors for a UTI were greater age (for 50-59 yr, relative risk [RR] = 1.0; 60-69 yr, RR = 2.1; ≥70 yr, RR = 3.5; P 0.001), female sex (RR = 2.2, P 0.001), dependent functional status (RR = 2.1, P = 0.010), malnutrition (RR = 2.3, P = 0.004), diabetic status (for non-insulin-dependent diabetes, RR = 1.5; for insulin-dependent diabetes, RR = 1.9; P = 0.011), and increased operative duration (for 120-179 min, RR = 1.4; 180-239 min, RR = 2.3; and for ≥240 min, RR = 2.7; P 0.001).Patients who developed a UTI had a greater risk for systemic sepsis than other patients (11.5% vs. 0.63%; adjusted RR = 14.4, P 0.001). Patients who developed a UTI had a greater risk for readmission than other patients (36.7% vs. 5.0%; adjusted RR = 6.1, P 0.001).UTIs occur in nearly 1 in 50 patients undergoing posterior lumbar fusion procedures. Patients who are older, female, dependent, malnourished, or diabetic are at greater risk and should be counseled and monitored accordingly. In addition, morbidity associated with a UTI in this population is substantial, as demonstrated by a 14-fold increase in the risk for systemic sepsis and a 6-fold increase in the risk for readmission. As such, increased preventative measures should be targeted to the patients identified here to be at greatest risk.3.

The long head of the biceps (LHB) tendon is a potential generator of pain within the shoulder. Tenodesis of the LHB is a treatment option for several pathologic shoulder conditions. We conducted a study to determine trends in LHB tenodesis at a subspecialty-focused shoulder orthopedic practice. We hypothesized that the rate of LHB tenodesis would increase significantly over time and that there would be no significant change in the age of patients who underwent LHB tenodesis. Records of 4 fellowship-trained sports or shoulder/elbow orthopedic surgeons were used to identify total number of common arthroscopic shoulder surgeries performed between 2004 and 2014. Number of LHB tenodesis cases, combined or isolated, was recorded. Linear regression was used for analysis with significance set at P.05. Of the 7640 patients who underwent arthroscopic shoulder procedures between 2004 and 2014, 2125 had LHB tenodesis. Mean (SD) age of the subgroup was 49.33 (13.2) years, and mean (SD) number of LHB tenodesis cases per year was 193.2 (130.5). Over time, mean number of LHB tenodesis cases increased significantly (P = .0024), mean age of patients who had these procedures did not change significantly (P = .934), and percentage of LHB tenodesis cases increased significantly relative to percentage of all arthroscopic shoulder procedures (P = .0099). The number of LHB tenodesis cases is increasing without a significant change in patient age.

Extracting information from the sensors installed in the homes of elderly pose a unique set of challenges. Add to it the short amount of time the clinicians and nurses have to analyze this data, and the problem becomes more complicated. A system already in place at an "Aging in Place" facility monitors the activities of residents through multiple non-intrusive sensors and sends alerts on detecting an unusual event. We present an approach to generate textual summaries of events leading to the alerts. We analyze our system using four case studies and also list the comments provided by collaborators in healthcare domain. The system was then iterated to take some of those suggestions into account to give a glimpse of what an ideal system should look like.

Background For surgical treatment of lumbar and lumbosacral tuberculosis, the anterior approach has been the most popular approach because it allows direct access to the infected tissue, thereby providing good decompression. However, anterior fixation is not strong, and graft failure and loss of correction are frequent complications. The posterior approach allows circumferential decompression of neural elements along with three-column fixation attained via pedicle screws by the same approach. The purpose of this study was to evaluate the outcome (functional, neurological, and radiological) in patients with lumbar and lumbosacral tuberculosis operated through the posterior approach. Methods Twenty-eight patients were diagnosed with tuberculosis of the lumbar and lumbosacral region from August 2012 to August 2013. Of these, 13 patients had progressive neurological deterioration or increasing back pain despite conservative measures and underwent posterior decompression and pedicle screw fixation with posterolateral fusion. Antitubercular therapy was given till signs of radiological healing were evident (9 to 16 months). Functional outcome (visual analogue scale [VAS] score for back pain), neurological recovery (Frankel grading), and radiological improvement were evaluated preoperatively, immediately postoperatively and 3 months, 6 months, and 1 year postoperatively. Results The mean VAS score for back pain improved from 7.89 (range, 9 to 7) preoperatively to 2.2 (range, 3 to 1) at 1-year follow-up. Frankel grading was grade B in 3, grade C in 7, and grade D in 3 patients preoperatively, which improved to grade D in 7 and grade E in 6 patients at the last follow-up. Radiological healing was evident in the form of reappearance of trabeculae formation, resolution of pus, fatty marrow replacement, and bony fusion in all patients. The mean correction of segmental kyphosis was 9.85° postoperatively. The mean loss of correction at final follow-up was 3.15°. Conclusions Posterior decompression with instrumented fusion is a safe and effective approach for management of patients with lumbar and lumbosacral tuberculosis.

Insulin pen devices have revolutionized the self-management of diabetes. Prefilled insulin pens are preferred by healthcare providers and patients because of ease-of-use, dosage flexibility, disposability, and widespread availability. However, like any mechanical device, these pens have the potential for mechanical malfunction. We are present a case in which glycemic control deteriorated because of a malfunction of an insulin pen. The possibility of insulin pen malfunction needs to be considered in addition to other factors in patients who present with acute deterioration of glycemic control.