Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.

Editorial Commentary: Surgical Videos on YouTube Are Not Peer Reviewed and Have Low Educational Value.

The rise of online platforms like YouTube for health information has prompted scrutiny over the quality of medical/surgical-related video content. Recent research on YouTube videos regarding anterior cruciate ligament reconstruction (ACLR) with quadriceps tendon autograft shows low educational quality and reliability using established assessment tools. Physicians primarily published content, with longer videos, and physician-generated videos, generally correlating with higher quality. However, YouTube's inadequacy as a reliable source for ACLR information underscores the need for alternative educational resources. Orthopaedic health care professionals must play a pivotal role in guiding patients toward credible sources and take aim at improving online content quality. Understanding patient preferences for online resources is essential for enhancing patient education, the patient-provider relationship, and decision-making in orthopaedic care.

Ligamentum teres cardiopexy for post vertical sleeve gastrectomy gastroesophageal reflux.

PURPOSE: Vertical sleeve gastrectomy (VSG) evolved in the early 2000s into the standalone weight loss procedure we see today. While numerous studies highlight VSG's durability for weight loss, and improvements co-morbidities such as type 2 diabetes mellitus and cardiovascular disease, patients with gastroesophageal reflux disease (GERD) have been counseled against VSG due to the concern for worsening reflux symptoms. When considering anti-reflux procedures, VSG patients are unable to undergo traditional fundoplication due to lack of gastric cardia redundancy. Magnetic sphincter augmentation lacks long-term safety data and endoscopic approaches have undetermined longitudinal benefits. Until recently, the only option for patients with a history of VSG with medically refractory GERD has been conversion to roux en Y gastric bypass (RNYGB), however, this poses other risks including marginal ulcers, internal hernias, hypoglycemia, dumping syndrome, and nutritional deficiencies. Given the risks associated with conversion to RNYGB, we have adopted the ligamentum teres cardiopexy as an option for patients with intractable GERD following VSG. METHODS: A retrospective chart review was conducted of patients who had prior laparoscopic or robotic VSG and subsequently GERD symptoms refectory to pharmacological management who underwent ligamentum teres cardiopexy between 2017 and 2022. Pre-operative GERD disease burden, intraoperative cardiopexy characteristics, post-operative GERD symptomatology and changes in H2 blocker or PPI requirements were reviewed. RESULTS: Of the study's 60 patients the median age was 50 years old, and 86% were female. All patients had a diagnosis of GERD through pre-operative assessments and were taking antisecretory medication. Of the 36 patients who have completed their one year follow up, 81% of patients had either a decrease in dosage or cessation of the antisecretory medication at one year following ligamentum teres cardiopexy. CONCLUSION: Ligamentum teres cardiopexy is a viable alternative to RNYGB in patients with a prior vertical sleeve gastrectomy with medical refractory GERD.

Subacute groin complications related to ECMO cannulation are associated with longer hospitalizations.

Subacute groin complications associated with extracorporeal membrane oxygenation (ECMO) cannulation are well recognized, yet their effects on clinical outcomes remain unknown. This single-center, retrospective study reviewed all patients receiving venoarterial ECMO from 01/2017 to 02/2020. Cohorts analyzed included transplanted patients (TPs) and non-transplanted patients (N-TPs) who did or did not develop ECMO-related subacute groin complications. Standard descriptive statistics were used for comparisons. Logistic regressions identified associated risk factors. Overall, 82/367 (22.3%) ECMO patients developed subacute groin complications, including 25/82 (30.5%) seromas/lymphoceles, 32/82 (39.0%) hematomas, 18/82 (22.0%) infections, and 7/82 (8.5%) non-specified collections. Of these, 20/82 (24.4%) underwent surgical interventions, most of which were muscle flaps (14/20, 70.0%). TPs had a higher incidence of subacute groin complications than N-TPs (14/28, 50.0% vs. 68/339, 20.1%, P = 0.001). Seromas/lymphoceles more often developed in TPs than N-TPs (10/14, 71.4% vs. 15/68, 22.1%, P = 0.001). Most patients with subacute groin complications survived to discharge (60/68, 88.2%). N-TPs who developed subacute groin complications had longer post-ECMO lengths of stay than those who did not (34 days, IQR 16-53 days vs. 17 days, IQR 8-34 days, P < 0.001). Post-ECMO length of stay was also longer among patients who underwent related surgical interventions compared to those who did not (50 days, IQR 35-67 days vs. 29 days, IQR 16-49 days, P = 0.007). Transplantation was the strongest risk factor for developing subacute groin complications (OR 3.91, CI95% 1.52-10.04, P = 0.005). Subacute groin complications and related surgical interventions are common after ECMO cannulation and are associated with longer hospital stays. When surgical management is warranted, muscle flaps may reduce lengths of stay compared to other surgical interventions.

The impact of local vs general anesthesia in patients undergoing thoracic endovascular aortic surgery.

OBJECTIVE: General anesthesia (GA) is associated with inherent risks that can be avoided by the use of lesser invasive anesthetic strategies. We hypothesize that examine and compare the use of local or regional anesthesia (LRA) to that of GA in patients undergoing thoracic endovascular aortic repair (TEVAR). METHODS: Patients undergoing TEVAR between 2010 and 2020 in the Vascular Quality Initiative were analyzed. Exclusion criteria included receipt of branched or physician-modified endografts and devices extending distally beyond zone 5. Patients were categorized as receiving LRA or GA. Center volume was reported by quartile according to annualized TEVAR volume, and operative outcomes were compared using appropriate frequentists tests. Univariable and multivariable regression models for anesthesia type and operative outcomes were created to compare unadjusted and adjusted rates of each outcome. Long-term survival was estimated using a Kaplan-Meier survival estimator, whereas adjusted survival analysis was performed using a Cox proportional hazards model. RESULTS: Of the 17,099 patients who underwent TEVAR, 7299 met the inclusion and exclusion criteria. Of these, 3.8% received LRA. There were no significant differences in the annual proportion of patients who received LRA from 2011 to 2020 (P = .49, χ2 test for trend). Only 18.8% of patients who received LRA were treated at the highest quartile volume centers. Patients who received LRA were older and more comorbid compared with those who received GA. There were no differences in in-hospital mortality (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.42-1.38; P = .44) or composite of any complication (OR, 0.79; 95% CI, 0.54-1.14; P = .22) between patients who received LRA compared with those who received GA. This also applied to patients presenting with rupture. Receipt of LRA was associated with lower odds of postoperative congestive heart failure (OR, 0.19; 95% CI, 0.01-0.89; P = .01) as well as decreased length of intensive care unit (OR, 0.54; 95% CI, 0.40-0.72; P < .01) and hospital length of stay (OR, 0.64; 95% CI, 0.46-0.84; P < .01). LRA was not associated with decreased long-term survival compared with GA (hazard ratio, 0.95; 95% CI, 0.72-1.25; P = .72). CONCLUSIONS: Despite a greater number of baseline comorbidities, patients undergoing TEVAR with LRA experienced shorter intensive care unit and postoperative lengths of stay, with similar operative outcomes and long-term survival compared with patients who received GA. Similar findings were found among the rupture cohort. LRA should be considered more frequently in select patients undergoing TEVAR.

How Should ECMO Be Used Under Conditions of Severe Scarcity? A Population Study of Public Perception.

OBJECTIVE: To assess societal preferences regarding allocation of extracorporeal membrane oxygenation (ECMO) as a rescue option for select patients with coronavirus disease 2019 (COVID-19). DESIGN: Cross-sectional survey of a nationally representative sample. SETTING: Amazon Mechanical Turk platform. PARTICIPANTS: In total, responses from 1,041 members of Amazon Mechanical Turk crowd-sourcing platform were included. Participants were 37.9 ± 12.6 years old, generally white (65%), and college-educated (66.1%). Many reported working in a healthcare setting (22.5%) and having a friend or family member who was admitted to the hospital (43.8%) or died from COVID-19 (29.9%). MEASUREMENTS AND MAIN RESULTS: Although most reported an unwillingness to stay on ECMO for >one week without signs of recovery, participants were highly supportive of ECMO utilization as a life-preserving technique on a policy level. The majority (96.7%) advocated for continued use of ECMO to treat COVID patients during periods of resource scarcity but would prioritize those with highest likelihood of recovery (50%) followed by those who were sickest regardless of survival chances (31.7%). Patients >40 years old were more likely to prefer distributing ECMO on a first-come first-served basis (21.5% v 13.3%, p < 0.05). CONCLUSION: Even though participants expressed hesitation regarding ECMO in personal circumstances, they were uniformly in support of using ECMO to treat COVID patients at a policy level for others who might need it, even in the setting of severe scarcity.

Mitigation of a Coronavirus Disease 2019 Outbreak in a Nursing Home Through Serial Testing of Residents and Staff.

Nursing homes and long-term care facilities represent highly vulnerable environments for respiratory disease outbreaks, such as coronavirus disease 2019 (COVID-19). We describe a COVID-19 outbreak in a nursing home that was rapidly contained by using a universal testing strategy of all residents and nursing home staff.

The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss.

Mutations in the genes that encode the gap junction proteins connexin 26 (Cx26, encoded by GJB2) and Cx30 (GJB6) are the leading cause of hereditary hearing loss. That said, the Cx30 p.Ala88Val (A88V) mutant causes Clouston syndrome, but not hearing loss. Here, we report that the Cx30-A88V mutant, despite being toxic to inner ear-derived HEI-OC1 cells, conferred remarkable long-term protection against age-related high frequency hearing loss in Cx30A88V/A88V mice. During early development, there were no overt structural differences in the cochlea between genotypes, including a normal complement of hair cells; however, the supporting cell Cx30 gap junction plaques in mutant mice were reduced in size. In adulthood, Cx30A88V/A88V mutant mice had a reduction of cochlear Cx30 mRNA and protein, yet a full complement of hair cells. Conversely, the age-related high frequency hearing loss in Cx30+/+ and Cx30+/A88V mice was due to extensive loss of outer hair cells. Our data suggest that the Cx30-A88V mutant confers long-term hearing protection and prevention of hair cell death, possibly via a feedback mechanism that leads to the reduction of total Cx30 gap junction expression in the cochlea.

The learning curve of robotic coronary arterial bypass surgery: A report from the STS database.

BACKGROUND: There is limited data to inform minimum case requirements for training in robotically assisted coronary artery bypass grafting (RA-CABG). Current recommendations rely on nonclinical endpoints and expert opinion. OBJECTIVES: To determine the minimum number of RA-CABG procedures required to achieve stable clinical outcomes. METHODS: We included isolated RA-CABG in the Society of Thoracic Surgeons (STS) registry performed between 2014 and 2019 by surgeons without prior RA-CABG experience. Outcomes were approach conversion, reoperation, major morbidity or mortality, and procedural success. Case sequence number was used as a continuous variable in logistic regression with restricted cubic splines with fixed effects. Outcomes were compared between operations performed earlier versus later in case sequences using unadjusted and adjusted metrics. RESULTS: There were 1195 cases performed by 114 surgeons. A visual inflection point occurs by a surgeon's 10th procedure for approach conversion, major morbidity or mortality, and overall procedural success after which outcomes stabilize. There was a significant decrease in the rate of approach conversion (7.7% and 2.5%), reoperation (18.9% and 10.8%), and major morbidity or mortality (21.7% and 12.9%), as well as an increase in the rate of procedural success (72.9% and 85.3%) with increasing experience between groups. In a multivariable logistic regression model, case sequences of >10 were an independent predictor of decreased approach conversion (odds ratio [OR]: 0.27; 95% confidence interval [CI]: 0.09-0.84) and increased rate procedural success (OR: 1.96; 95% CI: 1.00-3.84). CONCLUSIONS: The learning curve for RA-CABG is initially steep, but stable clinical outcomes are achieved after the 10th procedure.

COVID-19 and cardiothoracic surgery: Effects on training and workforce utilization in a global pandemic.

BACKGROUND: The COVID-19 pandemic has disrupted all aspects of healthcare, including cardiothoracic surgery (CTS). We sought to determine the pandemic's impact on CTS trainees' educational experiences. METHODS: A survey was developed and distributed to members of the Thoracic Surgery Residents Association and other international CTS trainees. Trainees were asked to evaluate their cumulative experiences and share their overall perceptions of how CTS training had been impacted during the earliest months of the COVID-19 pandemic (i.e., since March 01, 2020). Surveys were distributed and responses were recorded June 25-August 05, 2020. In total, 748 surveys were distributed and 166 responses were received (overall response rate 22.2%). Of these, 126 of 166 responses (75.9%) met inclusion criteria for final analysis. RESULTS: Final responses analyzed included 45 of 126 (35.7%) United States (US) and 81 of 126 (64.3%) international trainees, including 101 of 126 (80.2%) senior and 25 of 126 (19.8%) junior trainees. Most respondents (76/126, 43.2%) lost over 1 week in the hospital due to the pandemic. Juniors (12/25, 48.0%) were more likely than seniors (20/101, 19.8%) to be reassigned to COVID-19-specific units (p < .01). Half of trainees (63/126) reported their case volumes were reduced by over 50%. US trainees (42/45, 93.3%) were more likely than international trainees (58/81, 71.6%) to report reduced operative case volumes (p < .01). Most trainees (104/126, 83%) believed their overall clinical acumen was not adversely impacted by the pandemic. CONCLUSIONS: CTS trainees in the United States and abroad have been significantly impacted by the COVID-19 pandemic, with time lost in the hospital, decreased operative experiences, less time on CTS services, and frequent reassignment to COVID-19-specific care settings.

Mice harbouring an oculodentodigital dysplasia-linked Cx43 G60S mutation have severe hearing loss.

Given the importance of connexin43 (Cx43, encoded by GJA1) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express GJA1 mutations resulting in mild or severe loss of Cx43 function. Although Cx43I130T/+ mutant mice, with ∼50% Cx43 channel function, did not have any hearing loss, Cx43G60S/+ mutant mice, with ∼20% Cx43 channel function, had severe hearing loss. There was no evidence of inner ear sensory hair cell loss, suggesting that the mechanism for Cx43-linked hearing loss lies downstream in the auditory pathway. Since evidence suggests that Cx26 function is essential for hearing and may be protective against noise-induced hearing loss, we challenged Cx43I130T/+ mice with a loud noise and found that they had a similar susceptibility to noise-induced hearing loss to that found in controls, suggesting that decreased Cx43 function does not sensitize the mice for environmentally induced hearing loss. Taken together, this study suggests that Cx43 plays an important role in baseline hearing and is essential for auditory processing.This article has an associated First Person interview with the first author of the paper.

Relationship Between Change in Heart Transplant Volume and Outcomes: A National Analysis.

INTRODUCTION: Although volume-outcome relationships in transplantation have been well-defined, the effects of large changes in center volume are less well understood. The purpose of the current study was to examine the impact of changes in center volume on outcomes after heart transplantation. METHODS: Retrospective analysis was performed of adult patients undergoing heart transplant between 2000 and 2017 identified in the United Network for Organ Sharing database. Exclusions included annual volume <10. Patients were grouped according to percentage change in center volume from the previous year. Multivariable Cox regression models were adjusted for the significant preoperative variance identified on univariate analyses. RESULTS: Of the 29,851 transplants during the study period, 64% were at centers with stable volume (±25% annual change), whereas 10% were performed at contracting (-25% change or more) and 26% were performed at growing (+25% change or more) centers. Average volume was lower with contracting centers compared with stable or growing programs (21 vs 36, P< .001). Thirty-day mortality was greater in decreasing centers (6% vs 4%, P < .001), with more acute rejection treatments at 1y (27% vs 24% P < .001). The adjusted risk of mortality among contracting centers was 1.25 ([1.07-1.46], P= .004), whereas growing centers had unaffected risk (0.90 [0.79-1.02], P= .103). Causes of death were similar between groups. CONCLUSIONS: Rapid growth of transplant center volume has occurred at select centers in the United States without decrement in programmatic outcomes. Decreasing center volume has been associated with poorer outcomes, although the causative nature of this relationship requires further investigation.

The Dubousset Functional Test is a Novel Assessment of Physical Function and Balance.

BACKGROUND: Currently, the functional status of patients undergoing spine surgery is assessed with quality-of-life questionnaires, and a more objective and quantifiable assessment method is lacking. Dr. Jean Dubousset conceptually proposed a four-component functional test, but to our knowledge, reference values derived from asymptomatic individuals have not yet been reported, and these are needed to assess the test's clinical utility in patients with spinal deformities. QUESTIONS/PURPOSES: (1) What are the reference values for the Dubousset Functional Test (DFT) in asymptomatic people? (2) Is there a correlation between demographic variables such as age and BMI and performance of the DFT among asymptomatic people? METHODS: This single-institution prospective study was performed from January 1, 2018 to May 31, 2018. Asymptomatic volunteers were recruited from our college of medicine and hospital staff to participate in the DFT. Included participants did not report any musculoskeletal problems or trauma within 5 years. Additionally, they did not report any history of lower limb fracture, THA, TKA, or patellofemoral arthroplasty. Patients were also excluded if they reported any active medical comorbidities. Demographic data collected included age, sex, BMI, and self-reported race. Sixty-five asymptomatic volunteers were included in this study. Their mean age was 42 ± 15 years; 27 of the 65 participants (42%) were women. Their mean BMI was 26 ± 5 kg/m. The racial distribution of the participants was 34% white (22 of 65 participants), 25% black (16 of 65 participants), 15% Asian (10 of 65 participants), 9% subcontinental Indian (six of 65 participants), 6% Latino (four of 65 participants), and 10% other (seven of 65 participants). In a controlled setting, participants completed the DFT after verbal instruction and demonstration of each test, and all participants were video recorded. The four test components included the Up and Walking Test (unassisted sit-to-stand from a chair, walk forward/backward 5 meters [no turn], then unassisted stand-to-sit), Steps Test (ascend three steps, turn, descend three steps), Down and Sitting Test (stand-to-ground, followed by ground-to-stand, with assistance as needed), and Dual-Tasking Test (walk 5 meters forwards and back while counting down from 50 by 2). Tests were timed, and data were collected from video recordings to ensure consistency. Reference values for the DFT were determined via a descriptive analysis, and we calculated the mean, SD, 95% CI, median, and range of time taken to complete each test component, with univariate comparisons between men and women for each component. Linear correlations between age and BMI and test components were studied, and the frequency of verbal and physical pausing and adverse events was noted. RESULTS: The Up and Walking Test was completed in a mean of 15 seconds (95% CI, 14-16), the Steps Test was completed in 6.3 seconds (95% CI, 6.0-6.6), the Down and Sitting Test was completed in 6.0 seconds (95% CI, 5.4-6.6), and the Dual-Tasking Test was performed in 13 seconds (95% CI, 12-14). The length of time it took to complete the Down and Sitting (r = 0.529; p = 0.001), Up and Walking (r = 0.429; p = 0.001), and Steps (r = 0.356; p = 0.014) components increased with as the volunteer's age increased. No correlation was found between age and the time taken to complete the Dual-Tasking Test (r = 0.134; p = 0.289). Similarly, the length of time it took to complete the Down and Sitting (r = 0.372; p = 0.005), Up and Walking (r = 0.289; p = 0.032), and Steps (r = 0.366; p = 0.013) components increased with increasing BMI; no correlation was found between the Dual-Tasking Test's time and BMI (r = 0.078; p = 0.539). CONCLUSIONS: We found that the DFT could be completed by asymptomatic volunteers in approximately 1 minute, although it took longer for older patients and patients with higher BMI. CLINICAL RELEVANCE: We believe, but did not show, that the DFT might be useful in assessing patients with spinal deformities. The normal values we calculated should be compared in future studies with those of patients before and after undergoing spine surgery to determine whether this test has practical clinical utility. The DFT provides objective metrics to assess function and balance that are easy to obtain, and the test requires no special equipment.

Induction of cell death and gain-of-function properties of connexin26 mutants predict severity of skin disorders and hearing loss.

Connexin26 (Cx26) is a gap junction protein that oligomerizes in the cell to form hexameric transmembrane channels called connexons. Cell surface connexons dock between adjacent cells to allow for gap junctional intercellular communication. Numerous autosomal dominant mutations in the Cx26-encoding GJB2 gene lead to many skin disorders and sensorineural hearing loss. Although some insights have been gained into the pathogenesis of these diseases, it is not fully understood how distinct GJB2 mutations result in hearing loss alone or in skin pathologies with comorbid hearing loss. Here we investigated five autosomal dominant Cx26 mutants (N14K, D50N, N54K, M163V, and S183F) linked to various syndromic or nonsyndromic diseases to uncover the molecular mechanisms underpinning these disease links. We demonstrated that when gap junction-deficient HeLa cells expressed the N14K and D50N mutants, they undergo cell death. The N54K mutant was retained primarily within intracellular compartments and displayed dominant or transdominant properties on wild-type Cx26 and coexpressed Cx30 and Cx43. The S183F mutant formed some gap junction plaques but was largely retained within the cell and exhibited only a mild transdominant reduction in gap junction communication when co-expressed with Cx30. The M163V mutant, which causes only hearing loss, exhibited impaired gap junction function and showed no transdominant interactions. These findings suggest that Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes will lead to skin diseases and hearing loss, whereas mutants having reduced channel function but exhibiting no aberrant effects on coexpressed connexins cause only hearing loss. Moreover, cell death-inducing GJB2 mutations lead to more severe syndromic disease.

Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis.

Glioblastoma is the most common and most malignant primary adult human brain tumour. Diagnosis of glioblastoma carries a dismal prognosis. Treatment resistance and tumour recurrence are the result of both cancer cell proliferation and their interaction with the tumour microenvironment. A large proportion of the tumour microenvironment consists of an inflammatory infiltrate predominated by microglia and macrophages, which are thought to be subverted by glioblastoma cells for tumour growth. Thus, glioblastoma-associated microglia and macrophages are logical therapeutic targets. Their emerging roles in glioblastoma progression are reflected in the burgeoning research into therapeutics directed at their modification or elimination. Here, we review the biology of glioblastoma-associated microglia and macrophages, and model systems used to study these cells in vitro and in vivo. We discuss translation of results using these model systems and review recent advances in immunotherapies targeting microglia and macrophages in glioblastoma. Significant challenges remain but medications that affect glioblastoma-associated microglia and macrophages hold considerable promise to improve the prognosis for patients with this disease.

Clinical pharmacy services in the emergency department.

The emergency department (ED) is a fast-paced, high-risk, and often overburdened work environment. Formal policy statements from several notable organizations, including the American College of Emergency Physicians (ACEP) and the American Society of Health-System Pharmacists (ASHP), have recognized the importance of clinical pharmacists in the emergency medicine (EM) setting. EM clinical pharmacists work alongside emergency physicians and nurses at the bedside to optimize pharmacotherapy, improve patient safety, increase efficiency and cost-effectiveness of care, facilitate antibiotic stewardship, educate patients and clinicians, and contribute to scholarly efforts. This paper examines the history of EM clinical pharmacists and associated training programs, the diverse responsibilities and roles of EM clinical pharmacists, their impact on clinical and financial outcomes, and proposes a conceptual model for EM clinical pharmacist integration into ED patient care. Finally, barriers to implementing EM clinical pharmacy programs and limitations are considered.

Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the number one cause of global mortality. Despite aggressive treatment, the prognosis is dismal. Patients with advanced NSCLC have a median survival of 4 months from the time of diagnosis. Fortunately, molecularly based approaches to drug discovery have yielded a tyrosine kinase inhibitor, crizotinib, which significantly prolongs median progression-free survival in a subset of patients. Although initial clinical trial results demonstrate crizotinib has a promising role to play in NSCLC treatment, development of resistance leaves much to be elucidated about how to effectively combat this deadly disease. In this review, we follow the discovery and development of crizotinib from bench to bedside and provide an example of successful bottom-up drug design. Then, we explore the clinical trial results that fast-tracked its eventual use as a frontline therapy for sensitive NSCLC patients and the development of resistance. Lastly, we discuss the potential for future uses of crizotinib both within and beyond NSCLC.

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions.

In the present study we investigated the life cycle, trafficking, assembly and cell surface dynamics of a poorly characterized connexin family member, connexin 30 (Cx30; also known as GJB6), which plays a critical role in skin health and hearing. Unexpectedly, Cx30 localization at the cell surface and gap junctional intercellular communication was not affected by prolonged treatments with the endoplasmic reticulum (ER)-Golgi transport inhibitor brefeldin A or the protein synthesis inhibitor cycloheximide, whereas Cx43 (also known as GJA1) was rapidly cleared. Fluorescent recovery after photobleaching revealed that Cx30 plaques were rebuilt from the outer edges in keeping with older channels residing in the inner core of the plaque. Expression of a dominant-negative form of Sar1 GTPase led to the accumulation of Cx30 within the ER, in contrast to a report that Cx30 traffics via a Golgi-independent pathway. Co-expression of Cx30 with Cx43 revealed that these connexins segregate into distinct domains within common gap junction plaques, suggesting that their assembly is governed by different mechanisms. In summary, Cx30 was found to be an unusually stable, long-lived connexin (half-life >12 h), which may underlie its specific role in the epidermis and cochlea.

Differential effects of pannexins on noise-induced hearing loss.

Hearing loss, including noise-induced hearing loss, is highly prevalent and severely hinders an individual's quality of life, yet many of the mechanisms that cause hearing loss are unknown. The pannexin (Panx) channel proteins, Panx1 and Panx3, are regionally expressed in many cell types along the auditory pathway, and mice lacking Panx1 in specific cells of the inner ear exhibit hearing loss, suggesting a vital role for Panxs in hearing. We proposed that Panx1 and/or Panx3 null mice would exhibit severe hearing loss and increased susceptibility to noise-induced hearing loss. Using the auditory brainstem response, we surprisingly found that Panx1-/- and Panx3-/- mice did not harbor hearing or cochlear nerve deficits. Furthermore, while Panx1-/- mice displayed no protection against loud noise-induced hearing loss, Panx3-/- mice exhibited enhanced 16- and 24-kHz hearing recovery 7 days after a loud noise exposure (NE; 12 kHz tone, 115 dB sound pressure level, 1 h). Interestingly, Cx26, Cx30, Cx43, and Panx2 were up-regulated in Panx3-/- mice compared with wild-type and/or Panx1-/- mice, and assessment of the auditory tract revealed morphological changes in the middle ear bones of Panx3-/- mice. It is unclear if these changes alone are sufficient to provide protection against loud noise-induced hearing loss. Contrary to what we expected, these data suggest that Panx1 and Panx3 are not essential for baseline hearing in mice tested, but the therapeutic targeting of Panx3 may prove protective against mid-high-frequency hearing loss caused by loud NE.

Have the Yearly Trends of Total Hip Arthroplasty in Ankylosing Spondylitis Patients Decreased?

INTRODUCTION: Ankylosing spondylitis (AS) is characterized by spinal inflammation and structural damage, primarily to the axial skeleton and sacroiliac joints. Between 25% and 70% of patients may experience progressive peripheral joint involvement, which, despite advancement in pharmacologic therapy, may necessitate surgical intervention. Total hip arthroplasty (THA) yields improved pain and functional outcomes for AS patients with hip involvement. It is unclear whether the annual rates of patients undergoing THA have changed due to newer pharmacologic management. Therefore, the purpose of this study was to evaluate the annual trends of AS patients who underwent THA. Specifically, we evaluated: 1) the annual trends of THAs due to AS in the United States population, and 2) the annual trends in the proportion of THAs due to AS in the United States. MATERIALS AND METHODS: This study used the Nationwide Inpatient Sample to identify all patients who underwent THA between 2002 and 2013 (n=3,135,904). Then, an additional query was performed to identify THA patients who had a diagnosis of AS, defined by the International Classification of Disease 9th revision diagnosis code 720. The incidence of THAs with a diagnosis of AS in the United States was calculated using the United States population as the denominator. Regression models were used to analyze the annual trends of AS in patients who underwent THA. RESULTS: Review of the database identified 5,562 patients with AS who underwent THA. The overall annual prevalence of THA in the AS population significantly decreased during the 12-year study period from 2.24 per 1,000 THAs in 2002 to 1.73 per 1,000 THAs in 2013 (R2=0.445; p=0.018). CONCLUSION: Annual THA trends in AS patients have significantly declined from 2002 to 2013. This decline may be attributed to improvements in medical management that delay the time from disease onset to requirement of a THA. Since THA is an option with advanced disease, the observed declining trends may indicate the efficacy of current medical management.