Fish scale-derived hydroxyapatite for alveolar ridge preservation.

Alveolar ridge resorption following tooth extraction poses significant challenges for future dental restorations. This study investigated the efficacy of fish scale-derived hydroxyapatite (FSHA) as a socket preservation graft material to maintain alveolar bone volume and architecture. FSHA was extracted from *Labeo rohita* fish scales and characterized using Fourier transform infrared (FTIR) analysis. In vitro, biocompatibility and osteogenic potential were assessed using Saos-2 human osteosarcoma cells. Cell viability, migration, and proliferation were evaluated using MTT and scratch assays. In vivo performance was assessed in a rat model, and FSHA was compared to a commercial xenograft (Osseograft) and ungrafted controls. Histological analysis was performed at 8-week post-implantation to quantify new bone formation. FTIR confirmed the purity and homogeneity of FSHA. In vitro, FSHA enhanced Saos-2 viability, migration, and proliferation compared to controls. In vivo, FSHA demonstrated superior bone regeneration compared to Osseograft and ungrafted sites, with balanced graft resorption and new bone formation. Histological analysis revealed an active incorporation of FSHA into new bone, with minimal gaps and ongoing remodeling. Approximately 50%-60% of FSHA was resorbed by 8 weeks, closely matching the rate of new bone deposition. FSHA stimulated more bone formation in the apical socket region than in coronal areas. In conclusion, FSHA is a promising biomaterial for alveolar ridge preservation, exhibiting excellent biocompatibility, osteogenic potential, and balanced resorption. Its ability to promote robust bone regeneration highlights its potential as an effective alternative to currently used graft materials in socket preservation procedures.

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization.

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.

HIV-1 Nef hijacks both exocytic and endocytic pathways of host intracellular trafficking through differential regulation of Rab GTPases.

BACKGROUND: HIV-1 Nef regulates several cellular functions in an infected cell which results in viral persistence and AIDS pathogenesis. The currently understood molecular mechanism(s) underlying Nef-dependent cellular function(s) are unable to explain how events are coordinately regulated in the host cell. Intracellular membranous trafficking maintains cellular homeostasis and is regulated by Rab GTPases - a member of the Ras superfamily. RESULTS: In the current study, we tried to decipher the role of Nef on the Rab GTPases-dependent complex and vesicular trafficking. Expression profiling of Rabs in Nef-expressing cells showed that Nef differentially regulates the expression of individual Rabs in a cell-specific manner. Further analysis of Rabs in HIV-1NL4-3 or ΔNef infected cells demonstrated that the Nef protein is responsible for variation in Rabs expression. Using a panel of competitive peptide inhibitors against Nef, we identified the critical domain of HIV-1 Nef involved in modulation of Rabs expression. The molecular function of Nef-mediated upregulation of Rab5 and Rab7 and downregulation of Rab11 increased the transport of SERINC5 from the cell surface to the lysosomal compartment. Moreover, the Nef-dependent increase in Rab27 expression assists exosome release. Reversal of Rabs expression using competitive inhibitors against Nef and manipulation of Rabs expression reduced viral release and infectivity of progeny virions. CONCLUSION: This study demonstrates that Nef differentially regulates the expression of Rab proteins in HIV-1 infected cells to hijack the host intracellular trafficking, which augments viral replication and HIV-1 pathogenesis. SIGNIFICANCE: Our study emphasized the indispensable role of HIV-1 protein Nef on various aspects of the intracellular trafficking regulated by Rabs GTPases, which explained how HIV-1 Nef may hijack membrane trafficking pathways in infected cells.

Implementation of caregiver depression screening in an urban, community-based asthma clinic: a quality improvement project.

OBJECTIVE: Caregiver depressive symptoms are prevalent among children with asthma and associated with greater asthma morbidity. Identifying caregivers with depression and connecting them to appropriate treatment may reduce child asthma morbidity. The goal of this project was to implement a workflow for caregiver depression screening and treatment referral in an urban, community-based, asthma clinic serving under-resourced children. METHODS: The Model for Improvement with weekly Plan-Do-Study-Act cycles was utilized. A two-item depression screening tool (Patient Health Questionnaire-2; PHQ-2) and an acceptability question using a 5-point Likert scale were added to an existing social needs screening checklist administered to all caregivers during the child's clinic visit. Caregivers with a positive PHQ-2 score (≥3) received the PHQ-9. Positive screens on the PHQ-9 (≥5) received information and referrals by level of risk. PHQ-9 positive caregivers received a follow-up phone call two weeks post-visit to assess connection to support, improvement in depressive symptoms, and satisfaction with resources provided. RESULTS: The PHQ-2 was completed by 84.4% of caregivers (233/276). Caregivers had a mean age of 33.8 years (SD = 8.3; Range: 18-68) and were predominately female (86.4%), Black (80.4%), and non-Hispanic (78.4%). The majority (72.3%) found the screening acceptable (agree/strongly agree). Nearly one in six caregivers (37/233, 15.9%) reported depressive symptoms (PHQ-2 ≥ 3); 11.6% (27/233) had clinically significant symptoms (PHQ-9 score ≥ 10); and 2.1% (5/233) reported suicidal thoughts. Of those with depressive symptoms, 70.3% (26/37) participated in the follow-up phone call. While 50% (13/26) reported the resources given in clinic were "extremely helpful," no caregivers contacted or used them. CONCLUSIONS: Caregiver depression screening was successfully integrated into a pediatric asthma clinic serving under-resourced children. While caregivers found screening to be acceptable, it did not facilitate short-term connection to treatment among those with depressive symptoms.

StethAid: A Digital Auscultation Platform for Pediatrics.

(1) Background: Mastery of auscultation can be challenging for many healthcare providers. Artificial intelligence (AI)-powered digital support is emerging as an aid to assist with the interpretation of auscultated sounds. A few AI-augmented digital stethoscopes exist but none are dedicated to pediatrics. Our goal was to develop a digital auscultation platform for pediatric medicine. (2) Methods: We developed StethAid-a digital platform for artificial intelligence-assisted auscultation and telehealth in pediatrics-that consists of a wireless digital stethoscope, mobile applications, customized patient-provider portals, and deep learning algorithms. To validate the StethAid platform, we characterized our stethoscope and used the platform in two clinical applications: (1) Still's murmur identification and (2) wheeze detection. The platform has been deployed in four children's medical centers to build the first and largest pediatric cardiopulmonary datasets, to our knowledge. We have trained and tested deep-learning models using these datasets. (3) Results: The frequency response of the StethAid stethoscope was comparable to those of the commercially available Eko Core, Thinklabs One, and Littman 3200 stethoscopes. The labels provided by our expert physician offline were in concordance with the labels of providers at the bedside using their acoustic stethoscopes for 79.3% of lungs cases and 98.3% of heart cases. Our deep learning algorithms achieved high sensitivity and specificity for both Still's murmur identification (sensitivity of 91.9% and specificity of 92.6%) and wheeze detection (sensitivity of 83.7% and specificity of 84.4%). (4) Conclusions: Our team has created a technically and clinically validated pediatric digital AI-enabled auscultation platform. Use of our platform could improve efficacy and efficiency of clinical care for pediatric patients, reduce parental anxiety, and result in cost savings.

Chronic morphine administration differentially modulates viral reservoirs in SIVmac251 infected rhesus macaque model.

HIV persists in cellular reservoirs despite effective combined antiretroviral therapy (cART) and there is viremia flare up upon therapy interruption. Opioids modulate the immune system and suppress antiviral gene responses, which significantly impact people living with HIV (PLWH). However, the effect of opioids on viral reservoir dynamics remain elusive. Herein, we developed a morphine dependent SIVmac251 infected Rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. RMs on a morphine (or saline control) regimen were infected with SIVmac251. The cART was initiated in approximately half the animals five weeks post-infection, and morphine/saline administration continued until the end of the study. Among the untreated RM, we did not find any difference in plasma/CSF or in cell-associated DNA/RNA viral load in anatomical tissues. On the other hand, within the cART suppressed macaques, there was a reduction in cell-associated DNA load, intact proviral DNA levels, and in inducible SIV reservoir in lymph nodes (LNs) of morphine administered RMs. In distinction to LNs, in the CNS, the size of latent SIV reservoirs was higher in the CD11b+ microglia/macrophages in morphine dependent RMs. These results suggest that in the proposed model, morphine plays a differential role in SIV reservoirs by reducing the CD4+ T-cell reservoir in lymphoid tissues, while increasing the microglia/reservoir size in CNS tissue. The findings from this pre-clinical model will serve as a tool for screening therapeutic strategies to reduce/eliminate HIV reservoirs in opioid dependent PLWH.IMPORTANCE Identification and clearance of HIV reservoirs is a major challenge in achieving a cure for HIV. This is further complicated by co-morbidities that may alter the size of the reservoirs. There is an overlap between the risk factors for HIV and opioid abuse. Opiates have been recognized as prominent co-morbidities in HIV-infected populations. People infected with HIV also abusing opioids have immune modulatory effects and more severe neurological disease. However, the impact of opioid abuse on HIV reservoirs remains unclear. In this study, we used morphine dependent SIVmac251 infected rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. Our studies suggested that people with HIV who abuse opioids had higher reservoirs in CNS than the lymphoid system. Extrapolating the macaque findings in humans suggests that such differential modulation of HIV reservoirs among people living with HIV abusing opioids could be considered for future HIV cure research efforts.

Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection.

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ2) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.

Predictors of Elevated Social Risk in Pediatric Emergency Department Patients and Families.

OBJECTIVE: This study aimed to identify predictors of high unmet social needs among pediatric emergency department (ED) patients. We hypothesized that obesity, frequent nonurgent visits, reported food insecurity, or an at-risk chief complaint (CC) would predict elevated social risk. METHODS: We administered a tablet-based survey assessing unmet social needs in 13 domains to caregivers of patients aged 0 to 17 years presenting to an urban pediatric ED. Responses were used to tabulate a social risk score (SRS). We performed multivariable logistic regression to measure associations between a high SRS (≥3) and obesity, frequent nonurgent visits, food insecurity, or an at-risk CC (physical abuse, sexual abuse, assault, mammalian bites, reproductive/sexual health complaints, intoxication, ingestion/poisoning, psychiatric/behavioral complaints, or any complaint triaged as "least urgent"). RESULTS: Five hundred seventy caregivers completed the survey. Eighty-one percent reported at least one unmet social need, and 33% identified ≥3 social needs. Caregivers of patients with an at-risk CC had twice the odds of a high SRS (adjusted odds ratio [aOR], 1.8; 95% confidence interval [CI], 1.0-3.3). Caregivers of patients reporting food insecurity had 4 times the odds of a high SRS (aOR, 4.3; 95% CI, 2.5-7.3). Neither obesity (aOR, 1.5; 95% CI, 0.9-2.6) nor frequent nonurgent visits (aOR, 0.9; 95% CI, 0.4-1.9) were predictive of a high SRS. CONCLUSIONS: Unmet social needs are prevalent among caregivers of pediatric ED patients, supporting universal screening in this population. Patients with an at-risk CC or reported food insecurity might benefit from proactive intervention. Future studies should examine optimal methods for ED-based interventions that address social determinants of health.

Quality of life in at-risk school-aged children with asthma.

INTRODUCTION: Asthma is the most common chronic condition of childhood. Urban, minority children from families of lower socioeconomic status have disproportionately higher rates of asthma and worse outcomes. We investigated the association between the presence of asthma and asthma severity among American, urban, minority children and reported quality of life (QOL) of children and their families. METHODS: We performed a prospective, cross-sectional study comparing QOL of urban, minority elementary school-age children with and without asthma. A convenience sample of children was enrolled from the pediatric emergency department (ED) and a specialized asthma clinic, at a large urban children's hospital. We measured child and parent QOL using the Pediatric Quality of Life Inventory Version 4 (PEDSQL4), and evaluated associations with asthma, parental educational attainment, and frequency of ED visits. RESULTS: We enrolled 66 children, 76% were African American, and 61% were female. Overall child QOL was higher for those without asthma (p = 0.017, d = 0.59). Children with asthma also visited the ED almost twice as frequently (t [64] = -3.505, p < 0.001, d = 0.8), and parents of children with asthma reported a lower overall QOL (p = 0.04, d = 0.53) than those without asthma. Among children with asthma, a higher overall child QOL was associated with decreased asthma severity, more ED visits, and higher parental educational attainment. CONCLUSIONS: Urban, minority elementary school-age children with asthma report a lower QOL than those children without asthma, and decreased asthma severity was associated with higher QOL.

Regional Differences in Pediatric Firearm-Related Emergency Department Visits and the Association With Firearm Legislation.

OBJECTIVE: The objective of this study was to describe regional and temporal trends in pediatric firearm-related emergency department (ED) visits and investigate association with regional firearm legislation. METHODS: We conducted a cross-sectional analysis using the Nationwide Emergency Department Sample from 2009 to 2013 for children aged 21 years or younger. We calculated national estimates of firearm-related visits using annual census data and measured trends. We used state-level gun law scores to derive regional scores to measure strictness of firearm legislation. We used multivariable logistic and linear regression to measure regional differences in visits and their association with regional gun law scores, respectively. RESULTS: There were 111,839 (95% confidence interval, 101,248-122,431) ED visits for pediatric firearm-related injuries. Rates of visits varied by region, with the lowest rate in the Northeast and highest rate in the South (40.0 [34-45]; 70.8 [63.7-76.9] per 100,000 ED visits, respectively). Compared with the Northeast, odds of firearm-related ED visits were higher in the Midwest (adjusted odds ratio [aOR], 1.8; 1.4-2.3), West (aOR, 2.5; 2.0-3.2), and South (aOR, 1.9; 1.5-2.4). Firearm-related visits remained consistent over time. A higher (stricter) regional median Brady gun law score was associated with a lower rate of firearm-related visits (ß = -0.8; R2 = 0.9; P = 0.03). CONCLUSIONS: Rates of pediatric firearm-related ED visits vary by region. Stricter regional gun laws were associated with lower rates of ED visits for pediatric firearm-related injuries. Further study of the social and cultural regional differences in gun ownership and the role of legislation in the prevention of pediatric firearm-related morbidity and mortality is warranted.

A Leishmania donovani dominant-negative mutant for eIF2α kinase LdeK1 elicits host-protective immune response.

Dominant-negative mutation of LdeK1 gene, an eIF2α kinase from Leishmania donovani, revealed its role in translation regulation in response to nutrient starvation earlier. However, whether the kinase influences the infectivity of the parasites which naturally encounters nutrient deprivation during its life cycle was interesting to investigate. Both in vitro and in vivo experiments resulted in decrease of the parasite burden in peritoneal macrophages and in splenic/ hepatic load, respectively. An insight into the immune response of mice infected with mutant parasite showed enhanced pro-inflammatory cytokines and nitric oxide levels but reduced TH 2 and Treg population. The significantly reduced loss of infectivity of the parasites lacking a functional LdeK1 by modulating the immune response towards host protection makes it a potential vaccine candidate against Leishmaniasis.

Never Just a Shot in the Dark: Pediatric Firearm Advocacy.

Firearms remain a common cause of injury in children. Advocacy is a tool that can be useful in effecting systemic change. Yet for firearm injury prevention, traditional methods of effecting change face unique barriers not experienced in other areas of pediatric injury prevention. As pediatric emergency medicine physicians, we are on the front lines, and as part of the receiving end of the trauma inflicted on our communities by firearms, ours is a powerful voice well suited to overcome these barriers. Current firearm advocacy efforts include raising awareness via social media or editorials, organizing larger advocacy groups for support, challenging legislation, and implementing hospital-based violence intervention programs. Future advocacy directions should include collaborating with unique partners, teleadvocacy, direct action, and finding common ground with gun regulation opposition. Physician advocacy is essential to firearm injury prevention. Continuing to innovate around our advocacy efforts will be vital to the health and safety of our patients.

Safety and efficacy of tranexamic acid in children with cerebral palsy undergoing femoral varus derotational osteotomy: a double cohort study.

AIMS: The safety and efficacy of tranexamic acid (TXA) in reducing blood loss after total joint arthroplasty and spinal fusion surgery has been well documented. However, little data exist regarding the effectiveness of intraoperative TXA in children with cerebral palsy (CP). The aim of this double cohort study is to investigate the safety and efficacy of intraoperative TXA in reducing blood loss and transfusion requirements for children with CP undergoing a proximal unilateral or bilateral femoral varus derotational osteotomy (VDRO). PATIENTS AND METHODS: A retrospective review was performed of all paediatric theatre lists between May 2012 and January 2019 for all paediatric (< 16 years old) CP patients who underwent unilateral or bilateral VDRO combined with soft tissue release at our institution. Fifty-one patients were included in our study further subdivided into two individual groups, unilateral and bilateral VDRO. RESULTS: No statistically significant differences were found in demographics such as age, weight, ASA, GMFCS and antiepileptic medication between the groups. However, there were significant statistically differences in TBL and transfusion rates between the groups that received TXA and those that did not, both in unilateral [241 ml (TXA) vs. 369 ml (non-TXA)] and bilateral [287 ml (TXA) vs. 467 ml (non-TXA)] operations. CONCLUSION: TXA successfully reduced TBL (in both TXA subgroups) and the transfusion rates without associated complications. TXA's safety and efficacy should be explored further in adequately powered randomized controlled trials.

Local and Regional Spread of Primary Conjunctival Squamous Cell Carcinoma.

Two cases of biopsy-proven conjunctival squamous cell carcinoma (SCC) that developed local and regional spread are described. The cases involved a 65-year-old woman and a 79-year-old man who were initially treated at outside institutions for SCC of the conjunctiva. The patients did not have a history of immune compromise. The female patient presented with direct extension into the lacrimal gland but deferred recommended exenteration. Despite eventual exenteration, she developed metastasis to a neck node 6 months later, which was treated with radiotherapy. The male patient presented with local recurrence and a parotid node metastasis treated with exenteration, parotidectomy, selective neck dissection, and postoperative radiotherapy. Review of the outside pathology of both cases revealed positive tumor margins at the time of original resection. Local control of conjunctival SCC is of critical importance to reduce the risk of orbital extension and regional spread.

Changes in medical errors after implementation of a handoff program.

BACKGROUND: Miscommunications are a leading cause of serious medical errors. Data from multicenter studies assessing programs designed to improve handoff of information about patient care are lacking. METHODS: We conducted a prospective intervention study of a resident handoff-improvement program in nine hospitals, measuring rates of medical errors, preventable adverse events, and miscommunications, as well as resident workflow. The intervention included a mnemonic to standardize oral and written handoffs, handoff and communication training, a faculty development and observation program, and a sustainability campaign. Error rates were measured through active surveillance. Handoffs were assessed by means of evaluation of printed handoff documents and audio recordings. Workflow was assessed through time-motion observations. The primary outcome had two components: medical errors and preventable adverse events. RESULTS: In 10,740 patient admissions, the medical-error rate decreased by 23% from the preintervention period to the postintervention period (24.5 vs. 18.8 per 100 admissions, P<0.001), and the rate of preventable adverse events decreased by 30% (4.7 vs. 3.3 events per 100 admissions, P<0.001). The rate of nonpreventable adverse events did not change significantly (3.0 and 2.8 events per 100 admissions, P=0.79). Site-level analyses showed significant error reductions at six of nine sites. Across sites, significant increases were observed in the inclusion of all prespecified key elements in written documents and oral communication during handoff (nine written and five oral elements; P<0.001 for all 14 comparisons). There were no significant changes from the preintervention period to the postintervention period in the duration of oral handoffs (2.4 and 2.5 minutes per patient, respectively; P=0.55) or in resident workflow, including patient-family contact and computer time. CONCLUSIONS: Implementation of the handoff program was associated with reductions in medical errors and in preventable adverse events and with improvements in communication, without a negative effect on workflow. (Funded by the Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services, and others.).

Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage.

Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell-substrate impedance sensing and FITC-dextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1α. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2-related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1α/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1α and PDGF-BB. Pharmacological blocking of HIF-1α significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension.

Fellow Eye Comparisons for 7-Year Outcomes in Ranibizumab-Treated AMD Subjects from ANCHOR, MARINA, and HORIZON (SEVEN-UP Study).

PURPOSE: To compare study and fellow eyes in subjects with age-related macular degeneration (AMD) for 7-year outcomes arising from contrasting treatment histories and disease statuses. DESIGN: Multicenter cohort study, predetermined secondary analysis. PARTICIPANTS: A total of 65 participants from the ranibizumab-treatment arms of the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR), Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA), and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON) trials, recruited for an update evaluation from 14 study sites. METHODS: Seven-year visual outcomes and retinal imaging data were compared with the ANCHOR, MARINA, and HORIZON databases. Under the ANCHOR and MARINA protocols, study eyes had received monthly ranibizumab injections for the initial 2 years, during which fellow eyes were prohibited from anti-vascular endothelial growth factor (VEGF) treatments. MAIN OUTCOME MEASURES: Percentage of subjects with study eye vision better than fellow eye, vision change from baseline to year 7, and mean area of macular atrophy (MA) were predetermined secondary end points. RESULTS: Fellow eyes with exudative AMD had received a mean 7.3 total injections of anti-VEGF agents in the mean 3.4 years off-study. For the 35% of subjects with exudative AMD in both eyes at baseline, within-patient comparisons at year 7 showed better vision in the study eye in 82%, with better mean final vision in study eyes (54.7 vs. 27.3 letters in fellow eyes, P < 0.001). Also in this subgroup, study eyes, which had received 2 years of high-frequency ranibizumab, had less severe MA than the respective fellow eye at year 7 in 88% of patients (mean area ± standard deviation 2.8±2.2 mm(2) vs. 5.8±2.5 mm(2) in the fellow eyes, P = 0.0013). Final fellow eye vision outcome was significantly correlated with MA severity (coefficient -6.95, P < 0.001), and patients' inter-eye vision difference corresponded to the degree of MA asymmetry. CONCLUSIONS: Exudative fellow eyes remained at risk for further vision decline in later years under management with low-frequency anti-VEGF therapy. In patients with bilateral exudative AMD at baseline, final vision at year 7 was significantly better in study eyes than in fellow eyes, and MA was less severe. Macular atrophy area correlated with final visual outcomes, determined inter-eye vision differences, and was not attributable to high-frequency ranibizumab therapy.

HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution.

With the advent of the combination antiretroviral therapy era (cART), the development of AIDS has been largely limited in the USA. Unfortunately, despite the development of efficacious treatments, HIV-1-associated neurocognitive disorders (HAND) can still develop, and as many HIV-1 positive individuals age, the prevalence of HAND is likely to rise because HAND manifests in the brain with very low levels of virus. However, the mechanism producing this viral disorder is still debated. Interestingly, HIV-1 infection exposes neurons to proteins including Tat, Nef, and Vpr which can drastically alter mitochondrial properties. Mitochondrial dysfunction has been posited to be a cornerstone of the development of numerous neurodegenerative diseases. Therefore, we investigated mitochondria in an animal model of HAND. Using an HIV-1 transgenic rat model expressing seven of the nine HIV-1 viral proteins, mitochondrial functional and proteomic analysis were performed on a subset of mitochondria that are particularly sensitive to cellular changes, the neuronal synaptic mitochondria. Quantitative mass spectroscopic studies followed by statistical analysis revealed extensive proteome alteration in this model paralleling mitochondrial abnormalities identified in HIV-1 animal models and HIV-1-infected humans. Novel mitochondrial protein changes were discovered in the electron transport chain (ETC), the glycolytic pathways, mitochondrial trafficking proteins, and proteins involved in various energy pathways, and these findings correlated well with the function of the mitochondria as assessed by a mitochondrial coupling and flux assay. By targeting these proteins and proteins upstream in the same pathway, we may be able to limit the development of HAND.

Effectiveness of Non-Primary Care-Based Smoking Cessation Interventions for Adults with Diabetes: A Systematic Literature Review.

Diabetes is a chronic disease that affects over 25 million adults, many of whom are smokers. The negative health impact of diabetes and comorbid smoking is significant and requires comprehensive interdisciplinary management. The National Diabetes Education Program has identified specific providers, known as PPOD, who include pharmacists, podiatrists, optometrists, and dentists, as key individuals to improve diabetes-related clinical outcomes. These providers are encouraged to work together through interdisciplinary collaboration and to implement evidence-based strategies as outlined in the PPOD toolkit. The toolkit encourages healthcare providers to ask, advise, and assist patients in their efforts to engage in risk reduction and healthy behaviors, including smoking cessation as an important risk factor. While individual PPOD providers have demonstrated effective smoking cessation interventions in adults with other acute and chronic systemic diseases, they lack specific application and focus on adults with diabetes. This literature review examines the current role of PPOD providers in smoking cessation interventions delivered to adults with diabetes.

Engaging Pediatric Resident Physicians in Quality Improvement Through Resident-Led Morbidity and Mortality Conferences.

BACKGROUND: Increasingly, medical disciplines have used morbidity and mortality conferences (MMCs) to address quality improvement and patient safety (QI/PS), as well as teach systems-based improvement to graduate trainees. The goal of this educational intervention was to establish a pediatric resident physician­led MMC that not only focused on QI/PS principles but also engaged resident physicians in QI/ PS endeavors in their clinical learning environments. METHODS: Following a needs assessment, pediatric resident physicians at the Stanford University School of Medicine (Stanford, California) established a new MMC model in February 2010 as part of a required QI rotation. Cases were identified, explored, analyzed, and presented by resident physicians using the Johns Hopkins Learning from Defects tool. Discussions during the MMCs were resident physician­ directed and systems-based, and resulted in projects to address care delivery. Faculty advisors assessed resident physician comprehension of QI/PS. Conferences were evaluated through the end of the 2012­2013 academic year and outcomes tracked through the 2013­2014 academic year to determine trainee involvement in systems change resulting from the MMCs. RESULTS: The MMC was well received and the number of MMCs increased over time. By the end of the 2013­2014 academic year, resident physicians were involved in address ing 14 systems-based issues resulting from 25 MMCs. Examples of the resident physician­initiated improvement work included increasing use of the rapid response team, institution of a gastrostomy (g)-tube order set, and establishing a face-to-face provider handoff for pediatric ICU­to-acute-care-floor transfers. CONCLUSION: A resident physician­run MMC exposes resident physicians to QI/PS concepts and principles, enables direct faculty assessment of QI/PS knowledge, and can propel resident physicians into real-time engagement in the culture of safety in a complex hospital environment.