Understanding Characteristics of Acute Brain Injury in Adult Extracorporeal Membrane Oxygenation: An Autopsy Study.

OBJECTIVES: Current studies lack information on characteristics of acute brain injury in patients with extracorporeal membrane oxygenation. We sought to characterize the types, timing, and risk factors of acute brain injury in extracorporeal membrane oxygenation. DESIGN: Retrospective analysis. SETTING: We reviewed the extracorporeal membrane oxygenation patients who had undergone brain autopsy with gross and microscopic examinations from January 2009 to December 2018 from a single tertiary center. PATIENTS: Twenty-five patients (median age 53 yr) had postmortem brain autopsy. INTERVENTIONS: Description and analysis of neuropathologic findings. MEASUREMENT AND MAIN RESULTS: Of 25, 22 had venoarterial extracorporeal membrane oxygenation (88%) (nine cardiac arrest; 13 cardiogenic shock) and three had venovenous extracorporeal membrane oxygenation cannulation (12%). The median extracorporeal membrane oxygenation support time was 96 hours (interquartile range, 26-181 hr). The most common acute brain injury was hypoxic-ischemic brain injury (44%), followed by intracranial hemorrhage (24%), and ischemic infarct (16%). Subarachnoid hemorrhage (20%) was the most common type of intracranial hemorrhage, followed by intracerebral hemorrhage (8%), and subdural hemorrhage (4%). Only eight patients (32%) were without acute brain injury after extracorporeal membrane oxygenation. The most common involved location for hypoxic-ischemic brain injury was cerebral cortices (82%) and cerebellum (55%). The pattern of ischemic infarct was territorial in cerebral cortices. The risk factors for acute brain injury included hypertension history (11 vs 1; p = 0.01), preextracorporeal membrane oxygenation antiplatelet use (7 vs 0; p = 0.03), and a higher day 1 lactate level (10.0 vs 5.1; p = 0.02). Patients with hypoxic-ischemic brain injury had more hypertension (8 vs 4; p = 0.047), a higher day 1 lactate level (12.6 vs 5.8; p = 0.02), and a lower pH level (7.09 vs 7.24; p = 0.027). Extracorporeal membrane oxygenation duration, cannulation methods, hemoglobin level, coma, renal impairment, and hepatic impairment were not associated with acute brain injury. CONCLUSIONS: In the population who underwent postmortem neuropathologic evaluation, 68% of extracorporeal membrane oxygenation nonsurvivors developed acute brain injury. Hypoxic-ischemic brain injury was the most common type of injury suggesting that patients sustained acute brain injury as a consequence of cardiogenic shock and cardiac arrest. Further research with a systematic neurologic monitoring is necessary to define the timing of acute brain injury in patients with extracorporeal membrane oxygenation.

Can Preoperative Patient-reported Outcome Measures Be Used to Predict Meaningful Improvement in Function After TKA?

BACKGROUND: Despite the overall effectiveness of total knee arthroplasty (TKA), a subset of patients do not experience expected improvements in pain, physical function, and quality of life as documented by patient-reported outcome measures (PROMs), which assess a patient's physical and emotional health and pain. It is therefore important to develop preoperative tools capable of identifying patients unlikely to improve by a clinically important margin after surgery. QUESTIONS/PURPOSES: The purpose of this study was to determine if an association exists between preoperative PROM scores and patients' likelihood of experiencing a clinically meaningful change in function 1 year after TKA. METHODS: A retrospective study design was used to evaluate preoperative and 1-year postoperative Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-12 version 2 (SF12v2) scores from 562 patients who underwent primary unilateral TKA. This cohort represented 75% of the 750 patients who underwent surgery during that time period; a total of 188 others (25%) either did not complete PROM scores at the designated times or were lost to follow-up. Minimum clinically important differences (MCIDs) were calculated for each PROM using a distribution-based method and were used to define meaningful clinical improvement. MCID values for KOOS and SF12v2 physical component summary (PCS) scores were calculated to be 10 and 5, respectively. A receiver operating characteristic analysis was used to determine threshold values for preoperative KOOS and SF12v2 PCS scores and their respective predictive abilities. Threshold values defined the point after which the likelihood of clinically meaningful improvement began to diminish. Multivariate regression was used to control for the effect of preoperative mental and emotional health, patient attributes quantified by SF12v2 mental component summary (MCS) scores, on patients' likelihood of experiencing meaningful improvement in function after surgery. RESULTS: Threshold values for preoperative KOOS and SF12v2 PCS scores were a maximum of 58 (area under the curve [AUC], 0.76; p < 0.001) and 34 (AUC, 0.65; p < 0.001), respectively. Patients scoring above these thresholds, indicating better preoperative function, were less likely to experience a clinically meaningful improvement in function after TKA. When accounting for mental and emotional health with a multivariate analysis, the predictive ability of both KOOS and SF12v2 PCS threshold values improved (AUCs increased to 0.80 and 0.71, respectively). Better preoperative mental and emotional health, as reflected by a higher MCS score, resulted in higher threshold values for KOOS and SF12v2 PCS. CONCLUSIONS: We identified preoperative PROM threshold values that are associated with clinically meaningful improvements in functional outcome after TKA. Patients with preoperative KOOS or SF12v2 PCS scores above the defined threshold values have a diminishing probability of experiencing clinically meaningful improvement after TKA. Patients with worse baseline mental and emotional health (as defined by SF12v2 MCS score) have a lower probability of experiencing clinically important levels of functional improvement after surgery. The results of this study are directly applicable to patient-centered informed decision-making tools and may be used to facilitate discussions with patients regarding the expected benefit after TKA. LEVEL OF EVIDENCE: Level III, prognostic study.

John Charnley Award: Preoperative Patient-reported Outcome Measures Predict Clinically Meaningful Improvement in Function After THA.

BACKGROUND: Despite the overall effectiveness of total hip arthroplasty (THA), a subset of patients remain dissatisfied with their results because of persistent pain or functional limitations. It is therefore important to develop predictive tools capable of identifying patients at risk for poor outcomes before surgery. QUESTIONS/PURPOSES: The purpose of this study was to use preoperative patient-reported outcome measure (PROM) scores to predict which patients undergoing THA are most likely to experience a clinically meaningful change in functional outcome 1 year after surgery. METHODS: A retrospective cohort study design was used to evaluate preoperative and 1-year postoperative SF-12 version 2 (SF12v2) and Hip Disability and Osteoarthritis Outcome Score (HOOS) scores from 537 selected patients who underwent primary unilateral THA. Minimum clinically important differences (MCIDs) were calculated using a distribution-based method. A receiver operating characteristic analysis was used to calculate threshold values, defined as the levels at which substantial changes occurred, and their predictive ability. MCID values for HOOS and SF12v2 physical component summary (PCS) scores were calculated to be 9.1 and 4.6, respectively. We analyzed the effect of SF12v2 mental component summary (MCS) scores, which measure mental and emotional health, on SF12v2 PCS and HOOS threshold values. RESULTS: Threshold values for preoperative HOOS and PCS scores were a maximum of 51.0 (area under the curve [AUC], 0.74; p < 0.001) and 32.5 (AUC, 0.62; p < 0.001), respectively. As preoperative mental and emotional health improved, which was reflected by a higher MCS score, HOOS and PCS threshold values also increased. When preoperative mental and emotional health were taken into account, both HOOS and PCS threshold values' predictive ability improved (AUCs increased to 0.77 and 0.69, respectively). CONCLUSIONS: We identified PROM threshold values that predict clinically meaningful improvements in functional outcome after THA. Patients with a higher level of preoperative function, as suggested by HOOS or PCS scores above the defined threshold values, are less likely to obtain meaningful improvement after THA. Lower preoperative mental and emotional health decreases the likelihood of achieving a clinically meaningful improvement in function after THA. The results of this study may be used to facilitate discussion between physicians and patients regarding the expected benefit after THA and to support the development of patient-based informed decision-making tools. For example, despite significant disease, patients with high preoperative function, as measured by PROM scores, may choose to delay surgery given the low likelihood of experiencing a meaningful improvement postoperatively. Similarly, patients with notably low MCS scores might best be counseled to address mental health issues before embarking on surgery. LEVEL OF EVIDENCE: Level III, prognostic study.

The Importance of Risk Adjustment in Reporting Total Joint Arthroplasty Outcomes.

BACKGROUND: This study describes and tests a risk adjustment model developed for the California Joint Replacement Registry to report predictors of complication rates. METHODS: Complication rates were analyzed for 9960 patients enrolled in the California Joint Replacement Registry at 22 medical centers. Multivariable logistic risk models were created to analyze risks of postoperative complications. RESULTS: Age and American Society of Anesthesiologists class were the strongest predictors of complication rates (P < .0001). Congestive heart failure and peripheral vascular disease were also statistically significant predictors of complications. Three hospitals were found to have statistically significantly worse than expected complication rates, and one was found to have a better than expected complication rate after case mix risk adjustment. CONCLUSION: Adequate risk adjustment is a key element in objective comparison of surgeons, hospitals, and devices using total joint arthroplasty registry data.

Higher Preoperative Patient Activation Associated With Better Patient-reported Outcomes After Total Joint Arthroplasty.

BACKGROUND: Despite widely reported success associated with hip and knee replacements, some patients remain dissatisfied with their outcomes. Patient activation, an individual's propensity to engage in adaptive health behaviors, has been measured as a potentially important factor contributing to health outcomes, cost, and patient experience of care. However, to our knowledge, it has not been studied in patients undergoing total joint arthroplasties (TJAs). QUESTIONS/PURPOSES: We wanted to determine whether patients with higher activation scores would experience (1) greater resolution of pain and improved activity, (2) greater improvements in postoperative physical and mental health, and (3) greater patient satisfaction after primary THA or TKA. METHODS: We approached 174 patients and enrolled 135 who were undergoing primary THA or TKA at one of two hospitals between January 2013 and May 2014. Patient Activation Measure (PAM) scores were obtained preoperatively and patient-reported outcomes were assessed and completed for 125 patients pre- and postoperatively at the 6- or 12-month visit. We assessed pain and activity with the Hip Disability and Osteoarthritis Outcome Score (HOOS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and University of California Los Angeles (UCLA) activity scores. We measured physical and mental health by calculating SF12v2® scores and measured patient satisfaction with the Hip and Knee Satisfaction Scale (HKSS). Linear regression models were used to test the association between baseline PAM and postoperative patient-reported outcomes. RESULTS: Overall, patients with a higher baseline PAM score experienced better pain relief using the HOOS/KOOS pain scores (R2=0.311, p=0.048) and symptoms using the HOOS/KOOS symptom scores (R2=0.272, p=0.021). In addition, higher PAM scores were associated with better postoperative mental health using the SF12v2® (R2=0.057, p<0.001), but were not associated with higher physical health (R2=0.176, p=0.173). Finally, higher PAM scores were associated with having greater postoperative satisfaction after surgery using the HKSS questionnaire (R2=0.048, p=0.023). CONCLUSIONS: Higher preoperative patient activation was associated with better pain relief, decreased symptoms, improved mental health, and greater satisfaction after TJA. Future efforts should be aimed at studying if improving patient activation before surgery results in better patient-reported outcomes after elective THA or TKA. LEVEL OF EVIDENCE: Level II, prognostic study.

Comparative Epidemiology of Revision Arthroplasty: Failed THA Poses Greater Clinical and Economic Burdens Than Failed TKA.

BACKGROUND: Revision THA and TKA are growing and important clinical and economic challenges. Healthcare systems tend to combine revision joint replacement procedures into a single service line, and differences between revision THA and revision TKA remain incompletely characterized. These differences carry implications for guiding care and resource allocation. We therefore evaluated epidemiologic trends associated with revision THAs and TKAs. QUESTIONS/PURPOSES: We sought to determine differences in (1) the number of patients undergoing revision TKA and THA and respective demographic trends; (2) differences in the indications for and types of revision TKA and THA; (3) differences in patient severity of illness scoring between THA and TKA; and (4) differences in resource utilization (including cost and length of stay [LOS]) between revision THA and TKA. METHODS: The Nationwide Inpatient Sample (NIS) was used to evaluate 235,857 revision THAs and 301,718 revision TKAs between October 1, 2005 and December 31, 2010. Patient characteristics, procedure information, and resource utilization were compared across revision THAs and TKAs. A revision burden (ratio of number of revisions to total number of revision and primary surgeries) was calculated for hip and knee procedures. Severity of illness scoring and cost calculations were derived from the NIS. As our study was principally descriptive, statistical analyses generally were not performed; however, owing to the large sample size available to us through this NIS analysis, even small observed differences presented are likely to be highly statistically significant. RESULTS: Revision TKAs increased by 39% (revision burden, 9.1%-9.6%) and THAs increased by 23% (revision burden, 15.4%-14.6%). Revision THAs were performed more often in older patients compared with revision TKAs. Periprosthetic joint infection (25%) and mechanical loosening (19%) were the most common reasons for revision TKA compared with dislocation (22%) and mechanical loosening (20%) for revision THA. Full (all-component) revision was more common in revision THAs (43%) than in TKAs (37%). Patients who underwent revision THA generally were sicker (> 50% major severity of illness score) than patients who underwent revision TKA (65% moderate severity of illness score). Mean LOS was longer for revision THAs than for TKAs. Mean hospitalization costs were slightly higher for revision THA (USD 24,697 +/- USD 40,489 [SD]) than revision TKA (USD 23,130 +/- USD 36,643 [SD]). Periprosthetic joint infection and periprosthetic fracture were associated with the greatest LOS and costs for revision THAs and TKAs. CONCLUSIONS: These data could prove important for healthcare systems to appropriately allocate resources to hip and knee procedures: the revision burden for THA is 52% greater than for TKA, but revision TKAs are increasing at a faster rate. Likewise, the treating clinician should understand that while both revision THAs and TKAs bear significant clinical and economic costs, patients undergoing revision THA tend to be older, sicker, and have greater costs of care.

Impact of socioeconomic factors on informed decision making and treatment choice in patients with hip and knee OA.

It is unclear how socioeconomic (SES) status influences the effectiveness of shared decision making (SDM) tools. The purpose of this study was to assess the impact of SES on the utility of SDM tools among patients with hip and knee osteoarthritis (OA). We performed a secondary analysis of data from a randomized controlled trial of 123 patients with hip or knee OA. Higher education and higher income were independently associated with higher knowledge survey scores. Patients with private insurance were 2.7 times more likely than patients with Medicare to arrive at a decision after the initial office visit. Higher education was associated with lower odds of choosing surgery, even after adjusting for knowledge. Patient knowledge of their medical condition and treatment options varies with SES.

Quantifying the Burden of Revision Total Joint Arthroplasty for Periprosthetic Infection.

Periprosthetic joint infection (PJI) represents substantial clinical and economic burdens. This study evaluated patient and procedure characteristics and resource utilization associated with revision arthroplasty for PJI. The Nationwide Inpatient Sample (Q4 2005-2010) was analyzed for 235,857 revision THA (RTHA) and 301,718 revision TKA (RTKA) procedures. PJI was the most common indication for RTKA, and the third most common reason for RTHA. PJI was most commonly associated with major severity of illness (SOI) in RTHA, and with moderate SOI in RTKA. RTHA and RTKA for PJI had the longest length of stay. Costs were higher for RTHA/RTKA for PJI than for any other diagnosis except periprosthetic fracture. Epidemiologic differences exist in the rank, severity and populations for RTHA and RTKA for PJI.

Patient, surgeon, and healthcare purchaser views on the use of decision and communication aids in orthopaedic surgery: a mixed methods study.

BACKGROUND: Despite evidence that decision and communication aids are effective for enhancing the quality of preference-sensitive decisions, their adoption in the field of orthopaedic surgery has been limited. The purpose of this mixed-methods study was to evaluate the perceived value of decision and communication aids among different healthcare stakeholders. METHODS: Patients with hip or knee arthritis, orthopaedic surgeons who perform hip and knee replacement procedures, and a group of large, self-insured employers (healthcare purchasers) were surveyed regarding their views on the value of decision and communication aids in orthopaedics. Patients with hip or knee arthritis who participated in a randomized controlled trial involving decision and communication aids were asked to complete an online survey about what was most and least beneficial about each of the tools they used, the ideal mode of administration of these tools and services, and their interest in receiving comparable materials and services in the future. A subset of these patients were invited to participate in a telephone interview, where there were asked to rank and attribute a monetary value to the interventions. These interviews were analyzed using a qualitative and mixed methods analysis software. Members of the American Hip and Knee Surgeons (AAHKS) were surveyed on their perceptions and usage of decision and communication aids in orthopaedic practice. Healthcare purchasers were interviewed about their perspectives on patient-oriented decision support. RESULTS: All stakeholders saw value in decision and communication aids, with the major barrier to implementation being cost. Both patients and surgeons would be willing to bear at least part of the cost of implementing these tools, while employers felt health plans should be responsible for shouldering the costs. CONCLUSIONS: Decision and communication aids can be effective tools for incorporating patients preferences and values into preference-sensitive decisions in orthopaedics. Future efforts should be aimed at assessing strategies for efficient implementation of these tools into widespread orthopaedic practice.

Risk factors for early revision after primary total hip arthroplasty in Medicare patients.

BACKGROUND: Patient, surgeon, health system, and device factors are all known to influence outcomes in THA. However, patient-related factors associated with an increased risk of early failure are poorly understood, particularly in elderly patients. QUESTIONS/PURPOSES: We identified specific demographic and clinical characteristics associated with increased risk of early revision in Medicare patients with THA. METHODS: The Medicare 5% national sample administrative database was used to calculate the relative risk of revision within 12 months following primary THA as a function of baseline medical comorbidities in 56,030 Medicare patients who underwent primary THA between 1998 and 2010. The impact of 29 comorbid conditions on risk of early revision was examined using Cox regression, controlling for age, sex, race, US Census region, socioeconomic status, and all other baseline comorbidities. RESULTS: Depression, rheumatologic disease, psychoses, renal disease, chronic urinary tract infection, and congestive heart failure were associated with revision THA within 12 months of the index arthroplasty (p ≤ 0.038 for all comparisons; risk factors listed in order of significance). CONCLUSIONS: This information is important when counseling elderly patients with THA regarding the risk of early failure and for risk stratifying publicly reported outcomes in Medicare patients with THA.

Risk factors for early revision after primary TKA in Medicare patients.

BACKGROUND: Patient, surgeon, health system, and device factors are all known to influence outcomes in total knee arthroplasty (TKA). However, patient-related factors associated with an increased risk of early failure are not well understood, particularly in elderly patients. QUESTIONS/PURPOSES: The purpose of this study was to identify specific comorbid conditions associated with increased risk of early revision in Medicare patients undergoing TKA. METHODS: A total of 117,903 Medicare patients who underwent primary TKA between 1998 and 2010 were identified from the Medicare 5% national sample administrative database and used to determine the relative risk of revision within 12 months after primary TKA as a function of baseline medical comorbidities. Cox regression was used to evaluate the impact of 29 comorbid conditions on risk of early failure controlling for age, sex, race, census region, socioeconomic status, and all other baseline comorbidities. RESULTS: The most significant independent risk factors for revision TKA within 12 months were chronic pulmonary disease, depression, alcohol abuse, drug abuse, renal disease, hemiplegia or paraplegia, and obesity. CONCLUSIONS: This information could be valuable to patients and their surgeons when making shared medical decisions regarding elective TKA and for risk-stratifying publicly reported outcomes in Medicare patients undergoing TKA.

Risk factors for periprosthetic joint infection following primary total hip arthroplasty: a case control study.

The purpose of this study was to identify the specific comorbidities and demographic factors that are independently associated with an increased risk of periprosthetic joint infection (PJI) in total hip arthroplasty (THA) patients. A case-control study design was used to compare 88 patients who underwent unilateral primary THA and developed PJI with 499 unilateral primary THA patients who did not develop PJI. The impact of 18 comorbid conditions and other demographic factors on PJI was examined. Depression, obesity, cardiac arrhythmia, and male gender were found to be independently associated with an increased risk of PJI in THA patients. This information is important to consider when counseling patients on the risks associated with elective THA, and for risk-adjusting publicly reported THA outcomes.

Collaborative Recall and the Construction of Collective Memory Organization: The Impact of Group Structure.

Collaborative recall synchronizes downstream individual retrieval processes, giving rise to collective organization. However, little is known about whether particular stimulus features (e.g., semantic relatedness) are necessary for constructing collective organization and how group dynamics (e.g., reconfiguration) moderates it. We leveraged novel quantitative measures and a rich dataset reported in recent articles to address, (a) whether collective organization emerges even for semantically unrelated material and (b) how group reconfiguration-changing partners from one recall to the next-influences collective organization. Participants studied unrelated words and completed three consecutive recalls in one of three conditions: Always recalling individually (III), collaborating with the same partners twice before recalling alone (CCI), or collaborating with different group members during two initial recalls, before recalling alone (CRI). Collective organization increased significantly following any collaboration (CCI or CRI), relative to "groups" who never collaborated (III). Interestingly, collaborating repeatedly with the same partners (CCI) did not increase collective organization compared to reconfigured groups, irrespective of the reference group structure (from Recall 1 or 2). Individuals, however, did tend to base their final individual retrieval on the most recent group recall. We discuss how the fundamental processes that underlie dynamic social interactions align the cognitive processes of many, laying the foundation for other collective phenomena, including shared biases, attitudes, and beliefs.

Resiquimod-loaded cationic liposomes cure mice with peritoneal carcinomatosis and induce specific anti-tumor immunity.

Peritoneal carcinomatosis (PC) is characterized by a high recurrence rate and mortality following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), primarily due to incomplete cancer elimination. To enhance the standard of care for PC, we developed two cationic liposomal formulations aimed at localizing a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity to activate the immune system locally to specifically eradicate residual tumor cells. These formulations effectively extended R848 retention in the peritoneum by >10-fold, resulting in up to a 2-fold increase in interferon α (IFN-α) induction in the peritoneal fluid, without increasing the plasma levels. In a CT26 colon cancer model with peritoneal metastases, these liposomal R848 formulations, when combined with oxaliplatin (OXA)-an agent used in HIPEC that induces immunogenic cell death-increased tumor infiltration of effector immune cells, including DCs, CD4, and CD8 T cells. This led to the complete elimination of PC in 60-70% of the mice, while the control mice reached humane endpoints by 30 days. The cured mice developed specific antitumor immunity, as re-challenging them with the same tumor cells did not result in tumor establishment. However, inoculation with a different tumor line led to tumor development. Additionally, exposing CT26 tumor antigens to the splenocytes isolated from the cured mice induced the expansion of CD4 and CD8 T cells and the release of IFN-γ, demonstrating long-term immune memory to the specific tumor. The anti-tumor efficacy of these liposomal R848 formulations was mediated via CD8 T cells with different levels of involvement of CD4 and B cells, and the combination with an anti-PD-1 antibody achieved a cure rate of 90%.

Deep learning-based cerebral aneurysm segmentation and morphological analysis with three-dimensional rotational angiography.

BACKGROUND: The morphological assessment of cerebral aneurysms based on cerebral angiography is an essential step when planning strategy and device selection in endovascular treatment, but manual evaluation by human raters only has moderate interrater/intrarater reliability. METHODS: We collected data for 889 cerebral angiograms from consecutive patients with suspected cerebral aneurysms at our institution from January 2017 to October 2021. The automatic morphological analysis model was developed on the derivation cohort dataset consisting of 388 scans with 437 aneurysms, and the performance of the model was tested on the validation cohort dataset consisting of 96 scans with 124 aneurysms. Five clinically important parameters were automatically calculated by the model: aneurysm volume, maximum aneurysm size, neck size, aneurysm height, and aspect ratio. RESULTS: On the validation cohort dataset the average aneurysm size was 7.9±4.6 mm. The proposed model displayed high segmentation accuracy with a mean Dice similarity index of 0.87 (median 0.93). All the morphological parameters were significantly correlated with the reference standard (all P<0.0001; Pearson correlation analysis). The difference in the maximum aneurysm size between the model prediction and reference standard was 0.5±0.7 mm (mean±SD). The difference in neck size between the model prediction and reference standard was 0.8±1.7 mm (mean±SD). CONCLUSION: The automatic aneurysm analysis model based on angiography data exhibited high accuracy for evaluating the morphological characteristics of cerebral aneurysms.

Systemic delivery of proteins using novel peptides via the sublingual route.

Therapeutic proteins often require needle-based injections, which compromise medication adherence especially for those with chronic diseases. Sublingual administration provides a simple and non-invasive alternative. Herein, two novel peptides (lipid-conjugated protamine and a protamine dimer) were synthesized to enable sublingual delivery of proteins through simple physical mixing with the payloads. It was found that the novel peptides promoted intracellular delivery of proteins via increased pore formation on the cell surface. Results from in vitro models of cell spheroids and human sublingual tissue substitute indicated that the novel peptides enhanced protein penetration through multiple cell layers compared to protamine. The novel peptides were mixed with insulin or semaglutide and sublingually delivered to mice for blood glucose (BG) control. The effects of these sublingual formulations were comparable to the subcutaneous preparations and superior to protamine. In addition to peptide drugs, the novel peptides were shown to enable sublingual absorption of larger proteins with molecular weights from 22 to 150 kDa in mice, including human recombinant growth hormone (rhGH), bovine serum albumin (BSA) and Immunoglobulin G (IgG). The novel peptides given sublingually did not induce any measurable toxicities in mice.

Intranasal delivery of low-dose anti-CD124 antibody enhances treatment of chronic rhinosinusitis with nasal polyps.

Frequent injections of anti-CD124 monoclonal antibody (αCD124) over long periods of time are used to treat chronic rhinosinusitis with nasal polyps (CRSwNP). Needle-free, intranasal administration (i.n.) of αCD124 is expected to provide advantages of localized delivery, improved efficacy, and enhanced medication adherence. However, delivery barriers such as the mucus and epithelium in the nasal tissue impede penetration of αCD124. Herein, two novel protamine nanoconstructs: allyl glycidyl ether conjugated protamine (Nano-P) and polyamidoamine-linked protamine (Dendri-P) were synthesized and showed enhanced αCD124 penetration through multiple epithelial layers compared to protamine in mice. αCD124 was mixed with Nano-P or Dendri-P and then intranasally delivered for the treatment of severe CRSwNP in mice. Micro-CT and pathological changes in nasal turbinates showed that these two nano-formulations achieved ∼50 % and ∼40 % reductions in nasal polypoid lesions and eosinophil count, respectively. Both nano-formulations provided enhanced efficacy in suppressing nasal and systemic Immunoglobulin E (IgE) and nasal type 2 inflammatory biomarkers, such as interleukin 13 (IL-13) and IL-25. These effects were superior to those in the protamine formulation group and subcutaneous (s.c.) αCD124 given at a 12.5-fold higher dose. Intranasal delivery of protamine, Nano-P, or Dendri-P did not induce any measurable toxicities in mice.

Factors that influence provider selection for elective total joint arthroplasty.

BACKGROUND: The growth of consumer-directed health plans has sparked increased demand for information regarding the cost and quality of healthcare services, including total joint arthroplasty (TJA). However, the factors that influence patients' choice of provider when pursuing elective orthopaedic care, such as TJA, are poorly understood. QUESTIONS/PURPOSES: We evaluated the factors patients consider when selecting an orthopaedic surgeon and hospital for TJA. METHODS: Two hundred fifty-one patients who sought treatment from either an academic or community-based orthopaedic practice for primary TJA completed a 37-item survey using a 5-point Likert scale rating ("unimportant" to "very important") regarding seven established clinical and nonclinical dimensions of care patients considered when selecting a provider and hospital. RESULT: Patients rated physician manner (average Likert, 4.7) and physician quality (eg, outcomes) (average Likert, 4.6) as most important in their selection of surgeon and hospital for TJA. Despite the expressed importance of surgeon and hospital quality, only 46% of patients were able to find useful information to compare outcomes among surgeons, and 47% for hospitals that perform TJA. CONCLUSIONS: Our findings suggest physician manner and surgical outcomes are the most important considerations for patients when choosing a provider for elective TJA. Cost sharing is the least important criterion patients considered. Patients expressed high motivation to seek out provider quality information but indicated accessible and actionable sources of information are lacking. Future efforts should be directed at developing clinically relevant, easily interpretable, objective, risk-adjusted measures of physician and hospital quality.

Trends in hip arthroscopy utilization in the United States.

INTRODUCTION: The purpose of this study was to evaluate the changing incidence of hip arthroscopy procedures among newly trained surgeons in the United States, the indications for hip arthroscopy, and the reported rate of post-operative complications. METHODS: The ABOS database was used to evaluate the annual incidence of hip arthroscopy procedures between 2006-2010. Procedures were categorized by indication and type of procedure. The rate of surgical complications was calculated and compared between the published literature and hip arthroscopy procedures performed for femoroacetabular impingement (FAI)/osteoarthritis (OA) and for labral tears among the newly trained surgeon cohort taking the ABOS Part II Board exam. RESULTS: The overall incidence of hip arthroscopy procedures performed by ABOS Part II examinees increased by over 600% during the 5-year period under study from approximately 83 in 2006 to 636 in 2010. The incidence of hip arthroscopy for FAI/OA increased steadily over the time period under study, while the incidence of hip arthroscopy for labral tears was variable over time. The rate of surgical complications was 5.9% for hip arthroscopy procedures for a diagnosis of FAI/OA vs. 4.4% for a diagnosis of labral tear (P=0.36). CONCLUSIONS: The incidence of hip arthroscopy has increased dramatically over the past 5 years, particularly for the indication of FAI/OA. Reported surgical complication rates are relatively low, but appear higher than those rates reported in previously published series. Appropriate indications for hip arthroscopy remain unclear.

Assessing the Immune Regulatory Role of Metabolites In Vitro.

One method of immune evasion that cancer cells employ is the secretion of immune regulatory metabolites into the tumor microenvironment (TME). These metabolites can promote immunosuppressive cell subsets, while inhibiting key tumor-killing subsets, such as T cells. Thus, the identification of these metabolites may help develop methods for improving cell-based therapy. However, after identifying a potential immune regulatory metabolite, it is crucial to assess the impacts of the metabolite on T cell immunobiology. In this chapter, we describe an in vitro method of testing and analyzing the influence of a specific metabolite on T cell proliferation and function.