Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.

Pregnant patients requiring appendectomy: comparison between open and laparoscopic approaches in NY State.

INTRODUCTION: Even though acute appendicitis is the most common general surgical condition encountered during pregnancy, the preferred approach to appendectomy in pregnant patients remains controversial. Current guidelines support laparoscopic appendectomy as the treatment of choice for pregnant women with appendicitis, regardless of trimester. However, recent published data suggests that the laparoscopic approach contributes to higher rates of fetal demise. Our study aims to compare laparoscopic and open appendectomy in pregnancy at a statewide population level. METHODS: ICD-9 codes were used to extract 1006 pregnant patients undergoing appendectomy between 2005 and 2014 from the NY Statewide Planning and Research Cooperative System (SPARCS) database. Surgical outcomes (any complications, 30-day readmission rate, length of stay (LOS)) and obstetrical outcomes (antepartum hemorrhage, preterm delivery, cesarean section, sepsis, chorioamnionitis) were compared between open and laparoscopic appendectomy. Multivariable generalized linear regression models were used to compare different outcomes between two surgical approaches after adjusting for possible confounders. RESULTS: The laparoscopic cohort (n = 547, 54.4%) had significantly shorter LOS than the open group (median ± IQR: 2.00 ± 2.00 days versus 3.00 ± 2.00 days, p value < 0.0001, ratio = 0.789, 95% CI 0.727-0.856). Patients with complicated appendicitis had longer LOS than those with simple appendicitis (p value < 0.0001, ratio = 1.660, 95% CI 1.501-1.835). Obstetrical outcomes (p value = 0.097, OR 1.254, 95% CI 0.961-1.638), 30-day non-delivery readmission (p value = 0.762, OR 1.117, 95% CI 0.538-2.319), and any complications (p value = 0.753, OR 0.924, 95% CI 0.564-1.517) were not statistically significant between the laparoscopic versus open appendectomy groups. Three cases of fetal demise occurred, all within the laparoscopic appendectomy group. CONCLUSIONS: The laparoscopic approach resulted in a shorter LOS. Although fetal demise only occurred in the laparoscopic group, these results were not significant (p value = 0.255). Our large population-based study further supports current guidelines that laparoscopic appendectomy may offer benefits over open surgery for pregnant patients in any trimester due to reduced time in the hospital and fetal and maternal outcomes comparable to open appendectomy.

Altered Mental Status as a Novel Initial Clinical Presentation for COVID-19 Infection in the Elderly.

The coronavirus disease of 2019 or COVID-19 was first identified in Hubei Province in China in November of 2019 and quickly spread to become a global pandemic. The virus, SARS-Coronavirus-2, is particularly virulent in the elderly who can develop symptoms and become mortally ill within days of contracting the virus. The virus is easily transmitted by droplets (e.g., sneezing and coughing) and communal living settings such as personal care homes can be vulnerable to the spread of the virus. Identifying patients early in the disease process is important to providing appropriate medical interventions. To date, most of the medical literature, including Center for Disease Control guidelines, has relied on three necessary symptoms in making the diagnosis of COVID-19: fever, cough, and shortness of breath. We present four cases of elderly patients who developed altered mental status as their presenting symptom without associated fever or respiratory symptoms.

Decreased survival and increased recurrence in Merkel cell carcinoma significantly linked with immunosuppression.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. It is an immunogenic tumor as evident by its association with Polyomavirus, immunotherapy response, and increased prevalence in the immunosuppressed population. OBJECTIVE: We sought to evaluate the impact of known clinicopathological determinants and immunosuppression on the risk of recurrence and mortality of MCC patients. METHODS: A retrospective, observational cohort study of patients diagnosed and/or treated with MCC at two tertiary academic institutions. We compared clinicopathological determinants, treatment modalities, and immunosuppression status on clinical outcomes of recurrence, disease-specific survival, and overall survival. RESULTS: We evaluated 90 patients within our study and 34% had a cancer recurrence during follow-up. Patients with recurrence were significantly more likely to be immunosuppressed (32% vs 5%; P = .001). Estimated 5-year recurrence was 43%, and immunosuppressed patients were significantly more likely to recur (Hazard ratio [HR] 3.67 [1.80-7.51]; P < .0001). Immunosuppressed patients had significantly elevated cancer-specific mortality (HR 6.11[1.61-23.26]; P = .008). LIMITATIONS: Retrospective review with a prolonged observation period and changing treatment modalities. CONCLUSION: Immunocompromised patients had a threefold increased incidence of 5-year mortality and over twofold increased incidence of any recurrence as non-immunocompromised patients. Patients' immunosuppressive status should be considered when making decisions regarding treatment, surveillance, and prognostication.

Bronchial mucosal IFN-α/ß and pattern recognition receptor expression in patients with experimental rhinovirus-induced asthma exacerbations.

BACKGROUND: The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-ß, and the PRRs: Toll-like receptor 3, melanoma differentiation-associated gene 5, and retinoic acid-inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. RESULTS: We observed IFN-α/ß deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/ß expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/ß in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection-increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/ß expression and numbers of subepithelial IFN-α/ß-expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-α/ß expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity.

The Evolution and Impact of Hospital Price Transparency in North Carolina.

BACKGROUND Health care costs are on the rise and causing financial burden for many patients. Price transparency has been proposed as a tool to control health care costs. New federal legislation requires all hospitals to publish their chargemasters, or price lists, on their websites as of January 1, 2019.METHOD All general acute care hospitals in North Carolina were contacted in 2017 to request price information. After mandatory chargemaster publication was in effect in 2019, all hospitals previously contacted had their websites evaluated for chargemaster availability. Price information collected in 2019 was compared to information collected in 2017.RESULTS Zero percent of hospitals provided access to chargemasters in 2017, and 72% provided access in 2019. Average price per queried item decreased from 2017 to 2019. Price variability also decreased. However, there was no statistical significance when comparing price means.LIMITATIONS In 2017, price data was limited due to low hospital participation when queried for prices. In 2019, this study's definition of "access to chargemaster" inadvertently excluded some North Carolina hospitals from qualifying as providing price access.CONCLUSION After mandated chargemaster publication, consumer access to hospital price lists greatly increased in North Carolina. Price data, although limited, reveals decreased mean prices and decreased price variability for queried procedures after chargemaster publication was required.

A randomised, placebo-controlled trial of anti-interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease.

BACKGROUND: Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD). MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1ß. We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic, moderate-to-very severe COPD. METHODS: This was a phase II, randomised, double-blind, placebo-controlled, multicentre, parallel-group study. Subjects aged 45-75 years and receiving standard maintenance therapy with ≥2 exacerbations in the past year were randomised 1:1 to receive placebo or MEDI8968 300 mg (600 mg intravenous loading dose) subcutaneously every 4 weeks, for 52 weeks. The primary endpoint was the moderate/severe acute exacerbations of COPD (AECOPD) rate (week 56 post-randomisation). Secondary endpoints were severe AECOPD rate and St George's Respiratory Questionnaire-COPD (SGRQ-C) score (week 56 post-randomisation). RESULTS: Of subjects randomised to placebo (n = 164) and MEDI8968 (n = 160), 79.3% and 75.0%, respectively, completed the study. There were neither statistically significant differences between treatment groups in moderate/severe AECOPD rate ([90% confidence interval]: 0.78 [0.63, 0.96], placebo; 0.71 [0.57, 0.90], MEDI8968), nor in severe AECOPD rate or SGRQ-C scores. Post-hoc analysis of subject subgroups (by baseline neutrophil count or tertiles of circulating neutrophil counts) did not alter the study outcome. The incidence of treatment-emergent adverse events (TEAEs) with placebo and MEDI8968 treatment was similar. The most common TEAE was worsening of COPD. CONCLUSIONS: In this phase II study, MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function or quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01448850 , date of registration: 06 October 2011.

IL-18 associated with lung lymphoid aggregates drives IFNγ production in severe COPD.

BACKGROUND: Increased interferon gamma (IFNγ) release occurs in Chronic Obstructive Pulmonary Disease (COPD) lungs. IFNγ supports optimal viral clearance, but if dysregulated could increase lung tissue destruction. METHODS: The present study investigates which mediators most closely correlate with IFNγ in sputum in stable and exacerbating disease, and seeks to shed light on the spatial requirements for innate production of IFNγ, as reported in mouse lymph nodes, to observe whether such microenvironmental cellular organisation is relevant to IFNγ production in COPD lung. RESULTS: We show tertiary follicle formation in severe disease alters the dominant mechanistic drivers of IFNγ production, because cells producing interleukin-18, a key regulator of IFNγ, are highly associated with such structures. Interleukin-1 family cytokines correlated with IFNγ in COPD sputum. We observed that the primary source of IL-18 in COPD lungs was myeloid cells within lymphoid aggregates and IL-18 was increased in severe disease. IL-18 released from infected epithelium or from activated myeloid cells, was more dominant in driving IFNγ when IL-18-producing and responder cells were in close proximity. CONCLUSIONS: Unlike tight regulation to control infection spread in lymphoid organs, this local interface between IL-18-expressing and responder cell is increasingly supported in lung as disease progresses, increasing its potential to increase tissue damage via IFNγ.

A Sputum Proteomic Signature That Associates with Increased IL-1ß Levels and Bacterial Exacerbations of COPD.

PURPOSE: Activation of the interleukin-1ß (IL-1ß) signaling pathway has been implicated in COPD, but the proportion of COPD subjects whose disease is principally driven by activation of this pathway is poorly understood. In this study, we sought to differentiate an IL-1ß-associated sputum signature from other inflammation-associated COPD phenotypes. METHODS: Luminex-multiplex assays were used to study IL-1ß-mediated signature proteins within airway epithelium, smooth muscle, and vascular endothelial cell cultures. The IL-1ß-mediated signature was tested in a longitudinal study comprising of 35 paired stable-COPD and acute exacerbation (AECOPD) sputum samples. The presence of respiratory pathogens (H. influenzae, M. catarrhalis, S. pneumoniae, and P. aeruginosa) was evaluated by sputum cultures. RESULTS: Five proteins namely TNF-α, GCSF, IL-6, CD-40L, and MIP-1ß were found to be IL-1ß-regulated across all donors and cell types. All five of these IL-1ß-mediated proteins were significantly increased (p < 0.05) in sputum corresponding to AECOPD events showing at least a twofold increase in IL-1ß (IL-1ß(+) events, 18 of 35 total events), relative to preceding stable-COPD state. Sputum IL-1ß levels showed no significant association (p > 0.05, spearman) with known markers of other major COPD inflammation phenotypes. In addition, there was a significant association with bacterial presence in sputum culture with an odds ratio of 9 (95 % CI 1.56, 51.9) in IL-1ß(+) events versus IL-1ß(-) events. CONCLUSION: Our findings provide insights into potential markers of IL-1ß-associated AECOPD, and reaffirm association between IL-1ß pathway activation and airway bacterial infection in COPD. Taken together, our findings could help identify COPD patient subsets who may benefit from therapies targeting IL-1ß pathway.

High blood eosinophil count is associated with more frequent asthma attacks in asthma patients.

BACKGROUND: The clinical importance of eosinophils in asthma has been shown by the observation of frequent exacerbation in patients with high sputum eosinophil counts and a corresponding decrease in exacerbations when anti-inflammatory therapy was adjusted to maintain low sputum eosinophil percentages. However, less is known of the relation between blood eosinophilia and asthma exacerbation. OBJECTIVE: To examine whether patients with asthma and a higher blood eosinophil count have more asthma attacks than those with a lower count. METHODS: The authors analyzed data from the National Health and Nutrition Examination Survey, an annual cross-sectional survey of the US general population. Patients with asthma and asthma attacks were identified based on participants' self-report or parental report. A high blood eosinophil count was defined using 200, 300, or 400 cells/µL as cutoffs. The primary analysis used data from 2001 through 2010 after adjusting for demographic variables, obesity, smoking, neutrophil level, and past treatment for wheezing. A secondary analysis used data from 2007 through 2010 and included recent treatment for asthma and fraction of exhaled nitric oxide level as additional adjustment variables. RESULTS: In survey years 2001 through 2010, 3,162 patients with asthma had blood eosinophil data and approximately half (54% of children and 52% of adults) reported an asthma attack in the previous year. In the primary analysis, higher blood eosinophil counts were associated with more asthma attacks in children but not in adults. The secondary analysis suggested an association in both children and adults. CONCLUSION: Patients with asthma with higher blood eosinophil counts experienced more asthma attacks than those with lower eosinophil counts.

There is another way: empowering frontline staff caring for acutely unwell adults.

QUALITY PROBLEM OR ISSUE: It is estimated that only 17% of patients survive an in-hospital cardiac arrest. Medical evidence indicates that many patients show signs of deterioration during the 24 h period prior to their cardiac arrest. INITIAL ASSESSMENT: At Salford Royal NHS Foundation Trust (SRFT) 135 patients (outside critical care areas) suffered a cardiac arrest between March 2007 and April 2008. CHOICE OF SOLUTION: Quality improvement method-The breakthrough series (BTS) collaborative approach, change package-reliable manual vital signs, nurse-led response to the deteriorating patient, code red, structured ward round, ceilings of care, nurse-led do not attempt cardiopulmonary resuscitation (DNA-CPR) protocol and allocated roles. IMPLEMENTATION: The project was delivered over two phases with a total of 23 wards (12 wards in Phase One and 11 wards in Phase Two). Frontline teams worked to develop changes with the aim of reducing cardiac arrests by 50%. EVALUATION: The primary outcome measure was the number of cardiac arrests per 1000 admissions outside of critical care areas. Process and balancing measures were also used to evaluate the impact of the intervention. LESSONS LEARNED: The results showed a positive relationship between the change package and a reduction of 41% in cardiac arrests outside of critical care areas from the baseline period (April 2007-March 2008) to December 2012. The BTS model has the potential to reduce cardiac arrests without the need for initial large-scale financial investment.

Comparative effects of carbapenems on bacterial load and host immune response in a Klebsiella pneumoniae murine pneumonia model.

Doripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae. As the incidence of extended-spectrum ß-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine the in vivo comparative efficacy of doripenem, imipenem, and meropenem against a Klebsiella pneumoniae isolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced the Klebsiella lung burden by 2 log(10) CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log(10) CFU/g during this time period. Seven days postinfection, Klebsiella titers in the lungs of treated mice decreased an additional 2 log(10) CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasal K. pneumoniae inoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.

Novel antagonist antibody to TLR3 blocks poly(I:C)-induced inflammation in vivo and in vitro.

Toll-like receptor 3 (TLR3) binds and signals in response to dsRNA and poly(I:C), a synthetic double stranded RNA analog. Activation of TLR3 triggers innate responses that may play a protective or detrimental role in viral infections or in immune-mediated inflammatory diseases through amplification of inflammation. Two monoclonal antibodies, CNTO4685 (rat anti-mouse TLR3) and CNTO5429 (CDRs from CNTO4685 grafted onto a mouse IgG1 scaffold) were generated and characterized. These mAbs bind the extracellular domain of mouse TLR3, inhibit poly(I:C)-induced activation of HEK293T cells transfected with mTLR3, and reduce poly(I:C)-induced production of CCL2 and CXCL10 by primary mouse embryonic fibroblasts. CNTO5429 decreased serum IL-6 and TNFα levels post-intraperitoneal poly(I:C) administration, demonstrating in vivo activity. In summary, specific anti-mTLR3 mAbs have been generated to assess TLR3 antagonism in mouse models of inflammation.

Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project.

BACKGROUND: Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms. METHODS: Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits. RESULTS: Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers. CONCLUSIONS: Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

Vincristine overdose in a cat: clinical management, use of calcium folinate, and pathological lesions.

A 6-year-old female neutered Burmese cat received a 10 times overdose (5mg/m(2)) of vincristine, administered in error. Supportive therapy, including administration of calcium folinate, was instigated within 8h. Despite treatment, the patient exhibited deterioration in renal and respiratory function and died 72 h after overdose. Necropsy was performed within 24h of death. Gross examination revealed pulmonary oedema and a pale brown liver with a prominent lobular pattern. Histological examination revealed marked apoptosis and necrosis of the bone marrow myeloid series, and mild to moderate apoptosis and necrosis of the erythroid and megakaryocyte series. Multifocal necrosis of the renal tubules, hepatocytes, and small intestinal crypt epithelium was also observed. Use of calcium folinate as a rescue therapy following vincristine overdose in humans has been previously documented. If treatment is to be successful in cases of vincristine overdose in cats, then a more complete understanding of the pathogenesis of vincristine toxicity in companion animal species is required.

Impact of an integrated medicines management service on preventable medicines-related readmission to hospital: a descriptive study.

BACKGROUND: Medication contributes to 5-20% of hospital admissions, of which half are considered preventable. An integrated medicines management service (IMMS) was developed at a large general hospital in London to identify and manage patients at risk of a preventable medicines-related readmission (PMRR) to reduce the risk of PMRR. OBJECTIVE: To investigate the effect of the pharmacy IMMS on the rate of PMRR within 30 days of the first discharge. METHOD: 744 patients were identified between October 2008 and October 2014, using the PREVENT tool. Patients at risk were managed by the IMMS with medication reconciliation, review, consultation and follow-up, as required. RESULTS: Of 744 patients, 119 were readmitted within 30 days of discharge, with a PMRR for 2 patients (1.7%). The main reason for referral to the service was to assess the need to start a compliance aid. Most interventions involved communication: 84% included patient consultations with 50% involving discussion with the patient's community pharmacist and 32% with their general practitioner surgery. CONCLUSIONS: An IMMS may be an effective method of reducing the rate of PMRR. Further work is needed to establish the cost-effectiveness of the service.

Peer education as a strategy for reducing internalized stigma among depressed older adults.

OBJECTIVE: This article examines the mechanisms through which peer educator (PE) intervention targets and reduces internalized stigma. There is substantial evidence that internalized stigma negatively impacts the lives of those suffering with mental health concerns, and has been identified as 1 of the most significant barriers to seeking professional mental health services. There has been a push toward identifying interventions and programs that effectively reduce and mitigate the impact of internalized stigma. Research suggests that contact with other individuals who share a stigmatized condition may be a promising approach to targeting and reducing internalized stigma. However, there is a dearth of research that has identified the mechanism through which this contact impacts internalized stigma. METHODS: Study participants (n = 19) completed a 3-month PE intervention. Each participant was matched with an older adult with a history of depression currently in recovery who provided psychoeducation, social support, and motivational interviewing. Participants completed a demographic questionnaire, public stigma (PDD), and internalized stigma (Internalized Stigma of Mental Illness, ISMI) scales pre- and post-PE intervention. They further participated in a brief semistructured qualitative interview to attain in-depth information about their perceptions of stigma and of working with a PE. RESULTS: Overall, internalized stigma scores were significantly reduced after participating in the PE intervention. In addition, participants identified 4 mechanisms through which contact with their PE impacted their stigmatized beliefs: age related concerns, shared understanding, improved mental health literacy, and mutual support. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This study suggests that PE is a potentially valuable approach toward reducing internalized stigma among older adults with depression.

[15O]water pharmacokinetics: influence of age and gender in normal subjects.

PURPOSE: To compile a normal database for the characterization of global [15O]water pharmacokinetic behavior. PROCEDURES: The influences of age, gender, and body habitus on the pharmacokinetics of [15O]water were investigated in a series of normal subjects, N = 100 (50 males, 50 females, age = 19-79) who were participants in cognitive activation studies. Arterial blood was analyzed by autosampler and parametric images were constructed using a 40-second summed image and the autoradiographic model. RESULTS: Males and females were comparable with respect to age, number of injections administered, and dose (mCi) administered per injection but differed significantly with respect to height, weight, and normalized dose (mCi/kg). There were significant gender-based differences in the bolus arrival time, global cerebral blood flow (gCBF), area-under-the-curve (AUC), summed image concentration, and dose-normalized concentration but not dose-normalized AUC. Bolus arrival time, gCBF and dose-normalized AUC were significantly influenced by age. CONCLUSION: Age and gender are significant determinants of [15O]water pharmacokinetic behavior.

Contamination levels in blood samples drawn from the injection intravenous line.

PURPOSE: Securing two intravenous lines, one for injection and one for blood sampling, can be nearly impossible in compromised patients, therefore, a need exists to quantify the potential error when simplified techniques are employed. METHOD: Two venous catheters were placed. 2-deoxy-2-[18F]fluoro-glucose (FDG) was infused through one of the catheters. Venous blood samples were drawn from each line. Triplicate aliquots of plasma were analyzed in duplicate. RESULTS: Concentrations from the infusion line were 2.0% higher than the concentrations from the noninfusion line. The average error was 3.3%, 2.0%, and 0.7% higher for the first, second, and third samples, respectively. CONCLUSIONS: Blood sampling through the infusion catheter is a viable alternative to the placement of separate venous catheters. Sampling from the injection catheter, even with tubing flush and replacement, will potentially incur small (generally < 10%) over-estimations in concentration in initial samples. Subsequent sampling reduces the error to essentially zero by the third sample.

Effect of acute marijuana on cardiovascular function and central nervous system pharmacokinetics of [(15)O]water: effect in occasional and chronic users.

The objective of this study was to evaluate the effect of the acute administration of marijuana (MJ) on cardiovascular (CV) function and CNS pharmacokinetics (PK) of [(15)O]water in occasional (O) versus chronic (C) MJ users. Each subject received four injections of [(15)O]water (one prior and three postsmoking) on two occasions in which they received active or placebo MJ. For each injection, measures of CV function and CNS PK [(15)O]water were made. Postsmoking, MJ influenced all measured CV and [(15)O]water PK parameters. C users reported significantly lower "highness" and smaller heart rate (HR) changes, which resulted in reduced rate pressure product (RPP) changes compared to O users, even though Delta(9)-tetrahydrocannabinol levels were higher, whereas changes in blood pressure (BP), arrival time, and [(15)O]water concentration were not significantly different between the groups. Significant CV changes resulted in changes in the whole-body distribution of cardiac output rather than changes in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases induced by acute MJ smoking compared to changes observed in occasional users, without changing the effects on BP and [(15)O]water PK.