Practice Advisory for Preoperative and Intraoperative Pain Management of Cardiac Surgical Patients: Part 2.

Pain after cardiac surgery is of moderate to severe intensity, which increases postoperative distress and health care costs, and affects functional recovery. Opioids have been central agents in treating pain after cardiac surgery for decades. The use of multimodal analgesic strategies can promote effective postoperative pain control and help mitigate opioid exposure. This Practice Advisory is part of a series developed by the Society of Cardiovascular Anesthesiologists (SCA) Quality, Safety, and Leadership (QSL) Committee's Opioid Working Group. It is a systematic review of existing literature for various interventions related to the preoperative and intraoperative pain management of cardiac surgical patients. This Practice Advisory provides recommendations for providers caring for patients undergoing cardiac surgery. This entails developing customized pain management strategies for patients, including preoperative patient evaluation, pain management, and opioid use-focused education as well as perioperative use of multimodal analgesics and regional techniques for various cardiac surgical procedures. The literature related to this field is emerging, and future studies will provide additional guidance on ways to improve clinically meaningful patient outcomes.

Practice Advisory for Preoperative and Intraoperative Pain Management of Thoracic Surgical Patients: Part 1.

Pain after thoracic surgery is of moderate-to-severe intensity and can cause increased postoperative distress and affect functional recovery. Opioids have been central agents in treating pain after thoracic surgery for decades. The use of multimodal analgesic strategies can promote effective postoperative pain control and help mitigate opioid exposure, thus preventing the risk of developing persistent postoperative pain. This practice advisory is part of a series developed by the Society of Cardiovascular Anesthesiologists (SCA) Quality, Safety, and Leadership (QSL) Committee's Opioid Working Group. It is a systematic review of existing literature for various interventions related to the preoperative and intraoperative pain management of thoracic surgical patients and provides recommendations for providers caring for patients undergoing thoracic surgery. This entails developing customized pain management strategies for patients, which include preoperative patient evaluation, pain management, and opioid use-focused education as well as perioperative use of multimodal analgesics and regional techniques for various thoracic surgical procedures. The literature related to this field is emerging and will hopefully provide more information on ways to improve clinically relevant patient outcomes and promote recovery in the future.

Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, Monotherapy in Patients with Advanced Non-Small Cell Lung Carcinoma.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate. Here, we present safety and efficacy data from a phase I/Ib study of Teliso-V monotherapy evaluated in once every 2 weeks/once every 3 weeks schedules in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: During dose escalation, patients received Teliso-V monotherapy intravenously once every 3 weeks (0.15-3.3 mg/kg) or once every 2 weeks (1.6-2.2 mg/kg). The dose-expansion phase enrolled patients with NSCLC and c-Met H-score ≥150 (c-Met+) or MET amplification/exon 14 skipping mutations. Safety, pharmacokinetics, and efficacy were assessed. Herein, the analysis of patients receiving ≥1.6 mg/kg once every 2 weeks or ≥2.4 mg/kg once every 3 weeks Teliso-V is reported. RESULTS: Fifty-two patients with NSCLC were enrolled and received ≥1.6 mg/kg Teliso-V once every 2 weeks (n = 28) or ≥2.4 mg/kg Teliso-V once every 3 weeks (n = 24). The most common adverse events were fatigue (54%), peripheral neuropathy (42%), and nausea (38%). No dose-limiting toxicities were observed for Teliso-V once every 2 weeks and once every 3 weeks up to 2.2 and 2.7 mg/kg, respectively. The recommended phase II dose was established at 1.9 mg/kg once every 2 weeks and 2.7 mg/kg once every 3 weeks on the basis of overall safety and pharmacokinetics. Forty of 52 patients were c-Met+ (33 nonsquamous, 6 squamous, 1 mixed histology) and were included in the efficacy-evaluable population. Of those, 9 (23%) had objective responses with median duration of response of 8.7 months; median progression-free survival was 5.2 months. CONCLUSIONS: Teliso-V monotherapy was tolerated and showed antitumor activity in c-Met+ NSCLC. On the basis of overall safety, pharmacokinetics, and efficacy outcomes, 1.9 mg/kg Teliso-V once every 2 weeks and 2.7 mg/kg once every 3 weeks schedules were selected for further clinical development.

Veliparib in Combination with Carboplatin and Etoposide in Patients with Treatment-Naïve Extensive-Stage Small Cell Lung Cancer: A Phase 2 Randomized Study.

PURPOSE: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. RESULTS: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50-0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. CONCLUSIONS: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

Modeling ligand docking to RNA in the design of RNA-based nanostructures.

RNA has grown in biological importance as the discovery of its many functional roles in the cellular machinery has revealed the potential for targeting it to disrupt cancer pathways. RNA structure underlies its functionality and suitability as a nanoparticle building material. Advances in modelling methods have been achieved by the recognition of common structural motifs in natural RNA molecules that can be employed in the prediction of new structures based on sequence information and in design of functional nanostructures. Ligand docking prediction programs and RNA dynamics adds an important and non-trivial aspect to the modeling and characterization of the RNA structures. This short review introduces the issues involved in RNA structure prediction and modeling, dynamics of RNA structures, the influence of ligands on the structure and the dynamics, and ways to incorporate this information in the design of RNA-based nanostructures.

Evaluation of a professional development experience designed to equip school support staff with skills to facilitate youth mental health promotion.

Background: Public policy across the world is increasingly focusing on the role of mental health promotion in whole of health strategies. There is a growing evidence-base that mental health promotion, delivered by trained facilitators, is effective in promoting self-awareness and self-care to prevent the damaging effects of ongoing stress in one's life and to promote early detection of any possible emerging mental health problems. Within Australia, however, few clinicians or school staff are confident or trained in mental health promotion.Aims: This paper reports the results of a two-day training designed for facilitators of a mental health program for secondary-school students. The goal was to develop facilitators' knowledge and understanding of best practice in youth mental health promotion and to increase their confidence in delivering the program.Design: A mixed methods evaluation assessed the impact that a solution-focused training program had on participating facilitators.Methods: A questionnaire was created and included eight quantitative items and one open ended, qualitative question. Twenty-seven nurses and guidance officers from central Queensland were recruited via convenience sampling and data were analysed using descriptive statistics and thematic analysis.Results: The evaluation revealed that participants' perception of their ability to facilitate a youth mental health program significantly improved after completing the training. Qualitative data indicated that participants found the professional development experience to be valuable, provide useful and transferable skills, and believed it to be necessary for mental health promotion work.Conclusion: By providing detailed description of the program's content and processes, other mental health professionals may be inspired to further develop effective learning experiences.

Impact of Emergent Circulating Tumor DNA RAS Mutation in Panitumumab-Treated Chemoresistant Metastatic Colorectal Cancer.

Purpose: The accumulation of emergent RAS mutations during anti-EGFR therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine RAS mutational status.Experimental Design: This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded RAS ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of RAS mutations by the PlasmaSelect-R 64-gene panel at 0.1% sensitivity.Results: Among panitumumab-treated patients with evaluable plasma samples at baseline (n = 238), 188 (79%) were wild-type (WT) RAS, and 50 (21%) were mutant RAS Of the 188 patients with baseline ctDNA WT RAS status, 164 had evaluable posttreatment results with a 32% rate of emergent RAS mutations. The median overall survival for WT and RAS mutant status by ctDNA at baseline was 13.7 (95% confidence interval, 11.5-15.4) and 7.9 months (6.4-9.6), respectively (P < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA RAS mutations.Conclusions: Although patients with baseline ctDNA RAS mutations had worse outcomes than patients who were WT RAS before initiating treatment, emergent ctDNA RAS mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA RAS mutations. Clin Cancer Res; 24(22); 5602-9. ©2018 AACR.

Building resilience in regional youth: Impacts of a universal mental health promotion programme.

Mental health is a leading health issue facing young people today, particularly those living in rural and regional areas. Although public policy supports schools-based health promotion, there is limited evidence of the efficacy of such programmes and the elements that enhance successful implementation in rural and regional areas. A study was designed to evaluate a mental health promotion programme, delivered collaboratively by nurses, guidance officers, and teachers, to 850 young people from 23 rural and regional high schools in Queensland, Australia. The study aims were to determine what effect the intervention had on young peoples' resilience, coping, and self-efficacy, and to understand the implications of delivering the programme in the regional Queensland school setting. Students completed self-report measures of self-efficacy, resilience, and coping strategies pre- and postprogramme, as well as at 8-week follow-up. We found that after programme completion there was a significant increase in self-efficacy and in the number of positive coping strategies used by the participating young people. Qualitative data indicated that participants benefited from the collaboration between health and education sectors; that is, nurses, guidance officers, and teachers delivered the programme together in ways that were perceived to be respectful of young people and effectively discussion-based, and engaging.

Merging contemporary learning theory with mental health promotion to produce an effective schools-based program.

Approximately three quarters of all major mental disorders begin in adolescence. Finding ways to buffer against stress, access social support and connection and flexibly draw upon a range of coping mechanisms are vital strategies that young people can use to promote mental health and wellbeing and to navigate this turbulent life transition successfully. Within Australia, like other parts of the world such as the UK and the USA, it is a sad reality that when young people do become distressed they are not self-caring or supporting others effectively, and not seeking or receiving appropriate help. In order to respond proactively to this issue, a nurse-initiated mental health promotion program was developed. It is termed, iCARE, which stands for Creating Awareness, Resilience and Enhanced Mental Health. The aim of this paper is to discuss the underpinning educational theory that assists in developing in young people a sense of belonging, empathy, self-care and resilience, and why the strategies chosen to engage young people are likely to be effective.

Mindfulness: A positive spirituality for ageing?

Research indicates that the religious faith of people in aged care contributes to their well-being. A more general spirituality, involving no established religion, is also likely to be of benefit, but will require new forms of expression that appeal to the next generation, many of whom reject established religions. The practice of mindfulness also has research support as a contributor to well-being and may be a suitable and easily accepted form of spirituality for non-religious people.

Regional variation and challenges in estimating the incidence of giant cell tumor of bone.

BACKGROUND: Estimating the incidence of giant cell tumor of bone is challenging because few population-based cancer registries record benign bone tumors. We compared two approaches, the indirect (relative index) estimation approach used in The Burden of Musculoskeletal Diseases in the United States (BMUS) and a direct incidence rate approach (from registries that record giant cell tumor), to estimate giant cell tumor incidence in France, Germany, Italy, Spain, the U.K., Sweden, Australia, Canada, Japan, and the U.S. METHODS: Giant cell tumor of bone incidence was calculated with use of the BMUS relative index of giant cell tumor to osteosarcoma in three scenarios (low, base case, and high) from case series. We compared the BMUS approach with the latest data from tumor registries in Australia (1972 to 1996), Japan (2006 to 2008), and Sweden (1993 to 2011) that record giant cell tumors. United Nations population estimates were used to project results to 2013. RESULTS: The low scenario in the BMUS approach reflects data from Unni and Inwards; the incidence of giant cell tumor of bone is 0.34 relative to osteosarcoma. As the incidence of osteosarcoma is 31.4% of the total incidence of bone and joint cancers, the incidence of giant cell tumor is 0.11 times that of all bone and joint cancers. The base scenario reflects the series by Mirra et al., with a giant cell tumor incidence of 0.47 relative to osteosarcoma (0.15 to all bone and joint cancers). The high scenario reflects the series by Ward, with an incidence of 0.84 relative to osteosarcoma (0.26 to all bone and joint cancers). Differences among the three series reflect referral to a national center of excellence compared with referral to a local oncology practice. Registry data indicated a giant cell tumor incidence rate per million per year of 1.33 in Australia, 1.03 in Japan, and 1.11 in Sweden in 2013. The estimated incidence rate per million in the ten countries in 2013 ranged from 1.03 (Japan) to 1.17 (Canada) with use of the registry-based approach and from 0.73 (Japan) for the low scenario) to 2.20 (Germany) for the base case with use of the BMUS approach. CONCLUSIONS: Giant cell tumor of bone affects approximately one person per million per year in the ten countries studied. Estimates derived with use of age-specific incidences from tumor registries were typically within the range of the low and base case BMUS scenarios. We recommend the registry-derived method for estimating the incidence of giant cell tumor.

An online sleep apnea detection method based on recurrence quantification analysis.

This paper introduces an online sleep apnea detection method based on heart rate complexity as measured by recurrence quantification analysis (RQA) statistics of heart rate variability (HRV) data. RQA statistics can capture nonlinear dynamics of a complex cardiorespiratory system during obstructive sleep apnea. In order to obtain a more robust measurement of the nonstationarity of the cardiorespiratory system, we use different fixed amount of neighbor thresholdings for recurrence plot calculation. We integrate a feature selection algorithm based on conditional mutual information to select the most informative RQA features for classification, and hence, to speed up the real-time classification process without degrading the performance of the system. Two types of binary classifiers, i.e., support vector machine and neural network, are used to differentiate apnea from normal sleep. A soft decision fusion rule is developed to combine the results of these classifiers in order to improve the classification performance of the whole system. Experimental results show that our proposed method achieves better classification results compared with the previous recurrence analysis-based approach. We also show that our method is flexible and a strong candidate for a real efficient sleep apnea detection system.

Lower than expected hepatitis B virus infection prevalence among first generation Koreans in the U.S.: results of HBV screening in the Southern California Inland Empire.

BACKGROUND: Hepatitis B virus (HBV) infection is prevalent in Asian immigrants in the USA. California's Inland Empire region has a population of approximately four million, including an estimated 19,000 first generation Koreans. Our aim was to screen these adult individuals to establish HBV serological diagnoses, educate, and establish linkage to care. METHODS: A community-based program was conducted in Korean churches from 11/2009 to 2/2010. Subjects were asked to complete a HBV background related questionnaire, provided with HBV education, and tested for serum HBsAg, HBsAb and HBcAb. HBsAg positive subjects were tested for HBV quantitative DNA, HBeAg and HBeAb, counseled and directed to healthcare providers. Subjects unexposed to HBV were invited to attend a HBV vaccination clinic. RESULTS: A total of 973 first generation Koreans were screened, aged 52.3y (18-93y), M/F: 384/589. Most (75%) had a higher than high school education and were from Seoul (62.2%). By questionnaire, 24.7% stated they had been vaccinated against HBV. The serological diagnoses were: HBV infected (3.0%), immune due to natural infection (35.7%), susceptible (20.1%), immune due to vaccination (40.3%), and other (0.9%). Men had a higher infection prevalence (4.9% vs. 1.7%, p = 0.004) and a lower vaccination rate (34.6% vs. 44.0%, p = 0.004) compared to women. Self-reports of immunization status were incorrect for 35.1% of subjects. CONCLUSIONS: This large screening study in first generation Koreans in Southern California demonstrates: 1) a lower than expected HBV prevalence (3%), 2) a continued need for vaccination, and 3) a need for screening despite a reported history of vaccination.

College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference on good laboratory practices in gynecologic cytology: background, rationale, and organization.

CONTEXT: Gynecologic cytopathology is a heavily regulated field, with Clinical Laboratory Improvement Amendments of 1988 mandating the collection of many quality metrics. There is a lack of consensus regarding methods to collect, monitor, and benchmark these data and how these data should be used in a quality assurance program. Furthermore, the introduction of human papilloma virus testing and proficiency testing has provided more data to monitor. OBJECTIVE: To determine good laboratory practices in quality assurance of gynecologic cytopathology. DATA SOURCES: Data were collected through a written survey consisting of 98 questions submitted to 1245 Clinical Laboratory Improvement Amendments-licensed or Department of Defense laboratories. There were 541 usable responses. Additional input was sought through a Web posting of results and questions on the College of American Pathologists Web site. Four senior authors who authored the survey and 28 cytopathologists and cytotechnologists were assigned to 5 working groups to analyze data and present statements on good laboratory practices in gynecologic cytopathology at the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference. Ninety-eight attendees at the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference discussed and voted on good laboratory practice statements to obtain consensus. CONCLUSIONS: This paper describes the rationale, background, process, and strengths and limitations of a series of papers that summarize good laboratory practice statements in quality assurance in gynecologic cytopathology.

Alcoholic hepatitis: a clinician's guide.

Alcoholic hepatitis is a frequent reason for admission and a common consultation request for hepatologists and gastroenterologists. Although it seems to occur acutely, it is usually subacute and often superimposed on underlying alcoholic cirrhosis. Typically patients have a background of drinking on a daily basis, but, in response to a life crisis, patients have started drinking massively.

Protein aggregation of SERCA2 mutants associated with Darier disease elicits ER stress and apoptosis in keratinocytes.

Mutations in sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) underlie Darier disease (DD), a dominantly inherited skin disorder characterized by loss of keratinocyte adhesion (acantholysis) and abnormal keratinization (dyskeratosis) resulting in characteristic mucocutaneous abnormalities. However, the molecular pathogenic mechanism by which these changes influence keratinocyte adhesion and viability remains unknown. We show here that SERCA2 protein is extremely sensitive to endoplasmic reticulum (ER) stress, which typically results in aggregation and insolubility of the protein. Depletion of ER calcium stores is not necessary for the aggregation but accelerates the progression. Systematic analysis of diverse mutants identical to those found in DD patients demonstrated that the ER stress initiator is the SERCA2 mutant protein itself. These SERCA2 proteins were found to be less soluble, to aggregate and to be more polyubiquitinylated. After transduction into primary human epidermal keratinocytes, mutant SERCA2 aggregates elicited ER stress, caused increased numbers of cells to round up and detach from the culture plate, and induced apoptosis. These mutant induced events were exaggerated by increased ER stress. Furthermore, knockdown SERCA2 in keratinocytes rendered the cells resistant to apoptosis induction. These features of SERCA2 and its mutants establish a mechanistic base to further elucidate the molecular pathogenesis underlying acantholysis and dyskeratosis in DD.

A Primer on Detecting Cirrhosis and Caring for These Patients without Causing Harm.

Many people who have cirrhosis are undiagnosed. The diagnosis may not become evident until they develop multiorgan failure after an invasive procedure. Patients with cirrhosis are unusually fragile and can be easily harmed and even set into a fatal down-spiral by seemingly innocuous treatments including medications and invasive procedures. There is much confusion regarding the care of these patients. For example, what medications can be used safely to treat pain, what sedatives are safe and effective, which medications are to be avoided, what diet should be prescribed, and which invasive procedures are safe. This paper provides the author's advice regarding clues to the presence of cirrhosis and the dos and do nots in the general care of these patients, based on his 30 years of experience in a liver-failure-focused academic practice.

Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.

An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overexpress mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In contrast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory proteins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial cells and to stimulate IFN-α synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role.