Use of once-daily oral semaglutide and associated clinical outcomes among adults with type 2 diabetes in routine clinical practice in Canada: A multicentre, prospective real-world study (PIONEER REAL Canada).

AIM: PIONEER REAL Canada examined real-world clinical outcomes associated with the use of once-daily oral semaglutide in adults with type 2 diabetes. MATERIALS AND METHODS: This was a 34- to 44-week, multicentre, prospective, open-label, non-interventional study in adults who were treatment-naive to injectable glucose-lowering medication and initiated oral semaglutide in routine clinical practice. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to the end of the study (EoS). Secondary endpoints assessed at EoS were change from baseline in body weight (BW); the proportion of participants reaching HbA1c levels <7% and the composite endpoints, HbA1c reduction ≥1% point with BW reduction ≥3% and ≥5%; and treatment satisfaction measured using Diabetes Treatment Satisfaction Questionnaires (DTSQ) status and change. Primary analyses were based on the in-study observation period. RESULTS: In total, 182 participants initiated oral semaglutide (mean age, 58.6 years; HbA1c, 8.0%; BW, 93.7 kg). The estimated changes (95% confidence interval) from baseline to EoS in HbA1c and BW were -1.09% points (-1.24, -0.94; p < .0001) and -7.17% (-8.24, -6.11; p < .0001), respectively. At EoS, 53.7% of participants had HbA1c levels <7%; 39.3% and 31.6% reached HbA1c reduction ≥1% point plus BW reduction ≥3% and ≥5%, respectively. Treatment satisfaction significantly increased (DTSQ status, +4.47 points; DTSQ change, 11.83 points; both p < .0001). At EoS, 75.3% of participants remained on oral semaglutide (55.5% received oral semaglutide 14 mg). No new safety signals were identified for oral semaglutide. CONCLUSIONS: In PIONEER REAL Canada, participants treated with oral semaglutide in routine clinical practice experienced clinically relevant reductions in HbA1c and BW and increased treatment satisfaction.

Morbidity Associated With Distal Tibial Autograft Harvest.

Distal tibial autograft harvesting has been studied in the past, but morbidity at the level of the donor site is unclear. The purpose of this retrospective review is to assess morbidity in distal tibial autograft harvesting associated with foot and ankle arthrodesis procedures. A retrospective analysis was performed utilizing patients treated in the last 13 years at a large, multicenter, academic, tertiary referral, research institution. Included patients were between the ages of 18 and 80 years old. One-hundred and seven patients (39 male; 68 female) underwent ipsilateral distal tibial bone graft (n = 110) harvesting to augment the index procedure. Patients were followed for an average of 11.2 months after surgery (Range: 1-73 months). The incidence rate of distal tibial stress fractures was 4.5%, with an overall postoperative complication rate of 8.2%. Overall, low complication rates associated with distal tibial autograft harvesting were found, supporting the use of the distal tibia as an appropriate site for autograft harvesting in foot and ankle surgery.

Mucocele Arising from the Submandibular Gland Presenting as Neck Swelling: A Rare Case Report.

Mucoceles rarely involve major salivary glands. Very few cases involving the submandibular gland have been reported to date. A young male child presented with diffuse, soft, and painless swelling of the left submandibular region. Investigations suggested mucocele of the submandibular salivary gland. The mucocele was excised along with the left submandibular gland. Recovery was uneventful.

Switching between GLP-1 receptor agonists in clinical practice: Expert consensus and practical guidance.

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.

Home blood pressure data visualization for the management of hypertension: using human factors and design principles.

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.

Radiation Pattern Prediction for Metasurfaces: A Neural Network-Based Approach.

As the current standardization for the 5G networks nears completion, work towards understanding the potential technologies for the 6G wireless networks is already underway. One of these potential technologies for the 6G networks is reconfigurable intelligent surfaces. They offer unprecedented degrees of freedom towards engineering the wireless channel, i.e., the ability to modify the characteristics of the channel whenever and however required. Nevertheless, such properties demand that the response of the associated metasurface is well understood under all possible operational conditions. While an understanding of the radiation pattern characteristics can be obtained through either analytical models or full-wave simulations, they suffer from inaccuracy and extremely high computational complexity, respectively. Hence, in this paper, we propose a neural network-based approach that enables a fast and accurate characterization of the metasurface response. We analyze multiple scenarios and demonstrate the capabilities and utility of the proposed methodology. Concretely, we show that this method can learn and predict the parameters governing the reflected wave radiation pattern with an accuracy of a full-wave simulation (98.8-99.8%) and the time and computational complexity of an analytical model. The aforementioned result and methodology will be of specific importance for the design, fault tolerance, and maintenance of the thousands of reconfigurable intelligent surfaces that will be deployed in the 6G network environment.

The precious fluorine on the ring: fluorine NMR for biological systems.

The fluorine-19 nucleus was recognized early to harbor exceptional properties for NMR spectroscopy. With 100% natural abundance, a high gyromagnetic ratio (83% sensitivity compared to 1H), a chemical shift that is extremely sensitive to its surroundings and near total absence in biological systems, it was destined to become a favored NMR probe, decorating small and large molecules. However, after early excitement, where uptake of fluorinated aromatic amino acids was explored in a series of animal studies, 19F-NMR lost popularity, especially in large molecular weight systems, due to chemical shift anisotropy (CSA) induced line broadening at high magnetic fields. Recently, two orthogonal approaches, (i) CF3 labeling and (ii) aromatic 19F-13C labeling leveraging the TROSY (Transverse Relaxation Optimized Spectroscopy) effect have been successfully applied to study large biomolecular systems. In this perspective, we will discuss the fascinating early work with fluorinated aromatic amino acids, which reveals the enormous potential of these non-natural amino acids in biological NMR and the potential of 19F-NMR to characterize protein and nucleic acid structure, function and dynamics in the light of recent developments. Finally, we explore how fluorine NMR might be exploited to implement small molecule or fragment screens that resemble physiological conditions and discuss the opportunity to follow the fate of small molecules in living cells.

Home blood pressure data visualization for the management of hypertension: designing for patient and physician information needs.

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.

Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis.

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.

Linguistic summarization of in-home sensor data.

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.

The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes-A molecular study.

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.

Patient Judgments About Hypertension Control: The Role of Variability, Trends, and Outliers in Visualized Blood Pressure Data.

BACKGROUND: Uncontrolled hypertension is a significant health problem in the United States, even though multiple drugs exist to effectively treat this chronic disease. OBJECTIVE: As part of a larger project developing data visualizations to support shared decision making about hypertension treatment, we conducted a series of studies to understand how perceptions of hypertension control were impacted by data variations inherent in the visualization of blood pressure (BP) data. METHODS: In 3 Web studies, participants (internet sample of patients with hypertension) reviewed a series of vignettes depicting patients with hypertension; each vignette included a graph of a patient's BP. We examined how data visualizations that varied by BP mean and SD (Study 1), the pattern of change over time (Study 2), and the presence of extreme values (Study 3) affected patients' judgments about hypertension control and the need for a medication change. RESULTS: Participants' judgments about hypertension control were significantly influenced by BP mean and SD (Study 1), data trends (whether BP was increasing or decreasing over time-Study 2), and extreme values (ie, outliers-Study 3). CONCLUSIONS: Patients' judgment about hypertension control is influenced both by factors that are important predictors of hypertension related-health outcomes (eg, BP mean) and factors that are not (eg, variability and outliers). This study highlights the importance of developing data visualizations that direct attention toward clinically meaningful information.

In Vitro Analysis of Micronized Cartilage Stability in the Knee: Effect of Fibrin Level, Defect Size, and Defect Location.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL RELEVANCE: 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.

Development of a peptide-modified siRNA nanocomplex for hepatic stellate cells.

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.

Subpectoral Biceps Tenodesis With PEEK Interference Screw: A Biomechanical Analysis of Humeral Fracture Risk.

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.

Comparison of Avidin, Neutravidin, and Streptavidin as Nanocarriers for Efficient siRNA Delivery.

Protein-based drug delivery carrier has been one of the most employed modalities in biopharmaceuticals. In this study, we have compared avidin and its two analogues, neutravidin and streptavidin, as nanocarriers for the delivery of biotin-labeled siRNA with the help of biotinylated cholesterol (targeting ligand) and protamine (condensing agent). These proteins have similar binding affinity to biotin but substantial difference in their physical and chemical characteristics. Here, we have shown how these characteristics affect the size, cellular uptake, and activity of the avidin-based siRNA nanocomplex. In contrast to avidin and streptavidin nanocomplexes, neutravidin-based nanocomplex shows very low endosome entrapment and high cytoplasmic localization at extended times. High amount of the siRNA released in the cytoplasm by neutravidin-based nanocomplex at extended times (24 h) results in extensive and sustained PCBP2 gene silencing activity in HSC-T6 rat hepatic stellate cells. Neutravidin-based nanocomplex shows significantly low exocytosis in comparison to the streptavidin-based nanocomplex. Avidin-, neutravidin-, and streptavidin-based nanocomplexes are similar in size and had no significant cytotoxicity in transfected HSC-T6 cells or inflammatory cytokine induction in a whole blood assay. Compared to free siRNA, the neutravidin-based siRNA nanocomplex exhibits higher accumulation at 2 h in the liver of the rats with CCl4-induced liver fibrosis. Neutravidin has therefore been shown to be the most promising avidin analogue for the delivery of siRNA.

Biomechanical Analysis of Latarjet Screw Fixation: Comparison of Screw Types and Fixation Methods.

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.

Intracellular trafficking and exocytosis of a multi-component siRNA nanocomplex.

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 from 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.

An enzyme-responsive conjugate improves the delivery of a PI3K inhibitor to prostate cancer.

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.

SLAP Lesions: Trends in Treatment.

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 < .001, 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 < .001, 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.