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Introduction: Behavioural and psychological symptoms of dementia (BPSDs) are a group of highly prevalent symptoms in residents with a neurocognitive disorder (NCD), including agitation and depressive symptoms. Caregiving staff often mention knowledge and skills deficits regarding optimal BPSD management. While several staff trainings on BPSDs management exist internationally, their transferability to other clinical contexts is limited, owing to methodological challenges. Therefore, to address this implementation gap, there is a strong need for trainings based on high-quality research to strengthen existing evidence, ensure feasibility and reproducibility. Methods: This qualitative study, part of a larger research project, occurred in 2022 on a long-term care (LTC) center unit and an alternate level of care (ALT) hospital unit located in the Province of Quebec, Canada. This study aimed to: 1) evaluate the needs and perceptions of staff caregivers regarding BPSD management, 2) identify the training content and modalities to prioritize according to experts, 3) develop an intradisciplinary training on BPSD management, and 4) pretest the preliminarily version of the training. Objectives one and two were evaluated using focus groups and objective four using individual cognitive interviews. Qualitative interview data was audio-recorded with participants’ consent, transcribed verbatim, and thematically content analyzed using an established method. Results: Overall, thirteen caregivers participated in objective one (8 from the LTC unit, and 6 from the ALT unit). The main staff training need identified on each site was the management of resident’s aggressive behaviours. Staff verbalized a preference for a virtual training. Objective 2 involved a panel of eight experts. Experts recommended the use of an online training platform, and certain training models and indicators. Based on caregivers and experts’ input, five interactive online staff training capsules lasting from 20-25 minutes each and an algorithm guiding the evaluation and management of BPSDs were created. The training capsules and the algorithm were iteratively improved following cognitive interviews with 4 caregivers from the participating sites. Conclusion: An interactive virtual staff training on BPSD management was created based on staff and expert consultation. The next step in investigation will be to evaluate the feasibility and acceptability of the training.

Background: Reported advantages to robotic thoracic surgery include shorter length of stay (LOS), improved lymphadenectomy, and decreased complications. It is uncertain if these benefits occur when introducing robotics into a well-established video-assisted thoracoscopy (VATS) practice. We compared the two approaches to investigate these advantages. Materials and methods: IRB approval was obtained for this project. Patients who underwent segmentectomy or lobectomy from May 2016–December 2018 were propensity-matched 2: 1 (VATS: robotic) and compared using weighted logistic regression with age, gender, Charlson Comorbidity Index, surgery type, stage, Exparel, and epidural as covariates. Complication rates, operation times, number of sampled lymph nodes, pain level, disposition, and LOS were compared using Wilcoxon rank-sum and with Rao-Scott Chi-squared tests. Results: 213 patients (142 VATS and 71 robot) were matched. Duration of robotic cases was longer than VATS (median 186 min (IQR 78) vs. 164 min (IQR 78.75); p 0.05). Conclusions: The robotic approach facilitates better lymph node sampling, even in an established VATS practice.

Hypoparathyroidism is a potential outcome of anterior neck surgery. Commonly it is managed by calcium and vitamin D supplementation in large doses, with attendant side effects. A recombinant human parathyroid hormone (rhPTH) is now available in the USA, offering a potentially more effective treatment. No cost-effectiveness model investigating this new medication versus standard care has yet been published.We constructed a decision analytic model comparing usual care versus rhPTH treatment for postsurgical hypoparathyroidism. Threshold and sensitivity analyses on key parameters were conducted to assess robustness of the model. Costs and health outcomes were represented in US dollars and quality-adjusted life-years (QALYs).The rhPTH strategy was both more costly and more effective than the usual care (UC) strategy. In the base case, UC cost $37,196 and provided 7.54 QALYs. The rhPTH strategy cost $777,224 and provided 8.46 QALYs for an incremental cost-effectiveness ratio of $804,378/QALY. As this was above our willingness-to-pay of $100,000, treatment with rhPTH was not considered cost-effective. The model was robust to all other parameters.To our knowledge, this is the first formal cost-effectiveness analysis of rhPTH in comparison with UC. Our model suggests that although the new treatment is slightly more effective than UC, the modest gain in quality of life for patients who are reasonably well-managed by UC does not justify the cost. However, consideration must be given to rhPTH for patients who have failed UC, as the expenditure may be justified in that context.

To understand the potential and limitations of circulating tumor cell (CTC) sequencing for molecular diagnostics, we investigated the feasibility of identifying the ubiquitous KRAS mutation in single CTCs from pancreatic cancer (PC) patients. We used the NanoVelcro/laser capture microdissection CTC platform, combined with whole genome amplification and KRAS Sanger sequencing. We assessed both KRAS codon-12 coverage and the degree that allele dropout during whole genome amplification affected the detection of KRAS mutations from single CTCs. We isolated 385 single cells, 163 from PC cell lines and 222 from the blood of 12 PC patients, and obtained KRAS sequence coverage in 218 of 385 single cells (56.6%). For PC cell lines with known KRAS mutations, single mutations were detected in 67% of homozygous cells but only 37.4% of heterozygous single cells, demonstrating that both coverage and allele dropout are important causes of mutation detection failure from single cells. We could detect KRAS mutations in CTCs from 11 of 12 patients (92%) and 33 of 119 single CTCs sequenced, resulting in a KRAS mutation detection rate of 27.7%. Importantly, KRAS mutations were never found in the 103 white blood cells sequenced. Sequencing of groups of cells containing between 1 and 100 cells determined that at least 10 CTCs are likely required to reliably assess KRAS mutation status from CTCs.

BackgroundLong-term survival (LTS) is uncommon for patients with pancreatic ductal adenocarcinoma (PDAC). We sought to identify factors that predict 10-year, LTS after resection of PDAC.MethodsWe identified all patients with PDAC who underwent resection at UCLA after 1990 and included all patients eligible for observed LTS (1/1/1990-12/31/2004). An independent pathologist reconfirmed the diagnosis of PDAC in patients with LTS. Logistic regression was used to predict LTS on the basis of patient and tumor characteristics.ResultsOf 173 included patients, 53% were male, median age at diagnosis was 66 years, and median survival was 23 months. The rate of observed LTS was 12.1% (n = 21). Age, sex, number of lymph nodes evaluated, margin status, lymphovascular invasion, and adjuvant chemotherapy and radiation were not associated with LTS. The following were associated with LTS on bivariate analysis: low AJCC stage (Ia, Ib, IIa) (P = .034), negative lymph node status (P = .034), low grade (well-, moderately-differentiated) (P = .001), and absence of perineural invasion (P = .019). Only low grade (odds ratio 7.17, P = .012) and absent perineural invasion (odds ratio 3.28, P = .036) were independently associated with increased odds of LTS. Our multivariate model demonstrated good discriminatory power for LTS, as indicated by a c-statistic of 0.7856.ConclusionAbsence of perineural invasion and low tumor grade were associated with greater likelihood of LTS. Understanding the tumor biology of LTS may provide critical insight into a disease that is typically marked by aggressive behavior and limited survival.

Abstract Introduction Postoperative atrial fibrillation (POAF) is a frequent complication of cardiac surgery associated with important morbidity, mortality, and costs. To assess the effectiveness of preventive interventions, an important prerequisite is to have access to accurate measures of POAF incidence. The aim of this study was to develop and validate such a measure. Methods A validation study was conducted at two large Canadian university health centers. First, a random sample of 976 (10.4%) patients who had cardiac surgery at these sites between 2010 and 2016 was generated. Then, a reference standard assessment of their medical records was performed to determine their true POAF status on discharge (positive/negative). The accuracy of various algorithms combining diagnostic and procedure codes from: 1) the current hospitalization, and 2) hospitalizations up to 6 years before the current hospitalization was assessed in comparison with the reference standard. Overall and site-specific estimates of sensitivity, specificity, positive (PPV), and negative (NPV) predictive values were generated, along with their 95%CIs. Results Upon manual review, 324 (33.2%) patients were POAF-positive. Our best-performing algorithm combining data from both sites used a look-back window of 6 years to exclude patients previously known for AF. This algorithm achieved 70.4% sensitivity (95%CI: 65.1–75.3), 86.0% specificity (95%CI: 83.1–88.6), 71.5% PPV (95%CI: 66.2–76.4), and 85.4% NPV (95%CI: 82.5–88.0). However, significant site-specific differences in sensitivity and NPV were observed. Conclusion An algorithm based on administrative data can identify POAF patients with moderate accuracy. However, site-specific variations in coding practices have significant impact on accuracy.

PurposeProstate stem cell antigen (PSCA) is highly expressed in local prostate cancers and prostate cancer bone metastases and its expression correlates with androgen receptor activation and a poor prognosis. In this study, we investigate the potential clinical applications of immunoPET with the anti-PSCA A11 minibody, an antibody fragment optimized for use as an imaging agent. We compare A11 minibody immunoPET to (18)F-Fluoride PET bone scans for detecting prostate cancer bone tumors and evaluate the ability of the A11 minibody to image tumor response to androgen deprivation.Experimental designOsteoblastic, PSCA-expressing, LAPC-9 intratibial xenografts were imaged with serial (124)I-anti-PSCA A11 minibody immunoPET and (18)F-Fluoride bone scans. Mice bearing LAPC-9 subcutaneous xenografts were treated with either vehicle or MDV-3100 and imaged with A11 minibody immunoPET/CT scans pre- and posttreatment. Ex vivo flow cytometry measured the change in PSCA expression in response to androgen deprivation.ResultsA11 minibody demonstrated improved sensitivity and specificity over (18)F-Fluoride bone scans for detecting LAPC-9 intratibial xenografts at all time points. LAPC-9 subcutaneous xenografts showed downregulation of PSCA when treated with MDV-3100 which A11 minibody immunoPET was able to detect in vivo.ConclusionsA11 minibody immunoPET has the potential to improve the sensitivity and specificity of clinical prostate cancer metastasis detection over bone scans, which are the current clinical standard-of-care. A11 minibody immunoPET additionally has the potential to image the activity of the androgen signaling axis in vivo which may help evaluate the clinical response to androgen deprivation and the development of castration resistance.

PurposeIntact antibodies have a long serum persistence resulting in high background signal that inhibits their direct translation as imaging agents. Engineering of antibody fragments through the introduction of mutations in the fragment crystallizable (Fc) region can dramatically reduce serum persistence. We sought to develop a Fc-mutated, anti-CA19-9 antibody fragment (anti-CA 19-9 scFv-Fc H310A) to provide micro-positron emission tomography (microPET) imaging of pancreatic cancer xenografts.ProceduresThe anti-CA19-9 scFv-Fc H310A was successfully expressed and purified. Biochemical characterization included size exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and flow cytometry. The antibody fragment was labeled with iodine-124 ((124)I) and injected into mice containing human pancreatic cancer xenografts. MicroPET/CT images were then obtained. Blood, organ, and tumor radioactivity was measured and expressed as the percent of injected dose per gram of tissue (%ID/g).ResultsBiochemical characterization was consistent with the creation of a 105 kD dimer containing a human Fc region. Flow cytometry demonstrated antigen-specific binding, and cell-based ELISA further established a dissociation constant (K D) of 10.7 nM. (124)I-labeled scFv-Fc H310A localized to the antigen-positive tumor xenografts as detected by microPET. Objective confirmation of targeting was demonstrated by higher %ID/g in the antigen-positive tumor compared to the blood, antigen-negative tumor, and liver.ConclusionsWe successfully engineered and produced an anti-CA19-9 scFv-Fc H310A antibody fragment that retains similar affinity when compared to the parental intact murine antibody. Additionally, our engineered and mutated fragment exhibited antigen-specific microPET imaging of both subcutaneous and orthotopic pancreatic cancer xenografts at early time points secondary to decreased serum half-life.

Lack of a universal site-specific conjugation methodology for antibodies limits their potential to be developed as tumor-specific imaging agents or targeted therapeutics. A potential mechanism for site-specific conjugation involves utilization of the conserved N-glycosylation site in the CH2 domain. We sought to develop an antibody with an altered azido-sugar at this site whereby site-specific label could be added. The HB8059 hybridoma was cultured with peracetylated N-azidoacetlymannosamine (Ac4ManNAz). The resulting azido-sugar antibody was conjugated to phosphine-polyethylene glycol (PEG3)-biotin via a modified Staudinger reaction. Biochemical and functional characterization of the biotinylated antibody was performed. The azido-sugar antibody was also labeled with DyLight-650-Phosphine and injected into mice harboring pancreatic cancer xenografts. The tumors were dissected and imaged utilizing an IVIS fluorescent camera. The antibody was successfully produced in 100 μM Ac4ManNAz. The biotinylated antibody demonstrated a 50 kDa heavy and 25 kDa light chain on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but demonstrated a single band at 50 kDa on western blot. Treatment with a N-linked glycosidase extinguished the band. Flow cytometry demonstrated antigen-specific binding of CA19-9-positive cells and the antibody localized to the antigen-positive tumor in vivo. We successfully produced an antibody with an azido-sugar at the conserved CH2 glycosylation site. We were able to utilize this azide to label the antibody with biotin or fluorescent label and demonstrate that the label is added in a site-specific manner to the heavy chain, N-linked glycosylation site. Finally, we demonstrated functionality of our antibody for in vitro and in vivo targeting of pancreatic cancer cells.

BackgroundPancreatic ductal adenocarcinoma (PDAC) patients demonstrate highly variable survival within each stage of the American Joint Committee on Cancer (AJCC) staging system. We hypothesize that tumor grade is partly responsible for this variation. Recently our group developed a novel tumor, node, metastasis, grade (TNMG) classification system utilizing Surveillance Epidemiology and End Results (SEER) data in which the presence of high tumor grade results in advancement to the next higher AJCC stage. This study's objective was to validate this TNMG staging system utilizing single-institution data.MethodsAll patients with PDAC who underwent resection at UCLA between 1990 and 2009 were identified. Clinicopathologic data reviewed included age, sex, node status, tumor size, grade, and stage. Grade was redefined as a dichotomous variable. The impact of grade on survival was assessed by Cox regression analysis. Disease was restaged into the TNMG system and compared to the AJCC staging system.ResultsWe identified 256 patients who underwent resection for PDAC. Patients with low-grade tumors experienced a 13-month improvement in median survival compared to those with high-grade tumors. On multivariate analysis, tumor grade was the strongest predictor of survival with a hazard ratio of 2.02 (p = 0.0005). Restaging disease according to the novel TNMG staging system resulted in improved survival discrimination between stages compared to the current AJCC system.ConclusionsWe were able to demonstrate that grade is one of the strongest independent prognostic factors in PDAC. Restaging with our novel TNMG system demonstrated improved prognostication. This system offers an effective and convenient way of adding grade to the current AJCC staging system.

BackgroundAntibody-based therapeutics is a rapidly growing field. Small engineered antibody fragments demonstrate similar antigen affinity compared with the parental antibody but have a shorter serum half-life and possess the ability to be conjugated to nanoparticles. The goal of this study was to engineer an anti-carbohydrate antigen 19-9 (CA19-9) cys-diabody fragment in hopes of targeting nanoparticles to pancreatic cancer.MethodsThe anti-CA19-9 cys-diabody was created by engineering a C-terminal cysteine residue into the DNA single-chain Fv construct of the anti-CA19-9 diabody and expressed in NS0 cells. Maleimide chemistry was used to conjugate the cys-diabody to polymerized liposomal nanoparticles (PLNs) through the cysteine residues. Flow cytometry was used to evaluate targeting of cys-diabody and cys-diabody-PLN conjugate to human pancreatic cancer cell lines. The cys-diabody was radiolabeled with a positron emitter ((124)I) and evaluated in a mouse model of CA19-9-positive and CA19-9-negative xenografts with micro-positron emission tomography/micro-computed tomography at successive time intervals after injection. Percentage of injected dose per gram of radioactivity was measured in blood and tumor to provide objective confirmation of the micro-positron emission tomographic images.ResultsTumor xenograft imaging of the anti-CA19-9 cys-diabody demonstrated an average tumor-to-blood ratio of 3.0 and positive-to-negative tumor ratio of 7.4. Successful conjugation of the cys-diabody to PLNs was indicated by flow cytometry showing specific binding of cys-diabody-PLN conjugate to human pancreatic cancer cells in vitro.ConclusionsOur results show that the anti-CA19-9 cys-diabody targets pancreatic cancer providing specific molecular imaging in tumor xenograft models. Furthermore, the cys-diabody-PLN conjugate demonstrates target-specific binding of human pancreatic cancer cells with the potential to deliver targeted treatment.

Open in new tab Download slide OBJECTIVES To compare oncologic outcomes after segmentectomy with division of segmental bronchus, artery and vein (complete anatomic segmentectomy) versus segmentectomy with division of <3 segmental structures (incomplete anatomic segmentectomy). METHODS We conducted a single-centre, retrospective analysis of patients undergoing segmentectomy from March 2005 to May 2020. Operative reports were audited to classify procedures as complete or incomplete anatomic segmentectomy. Patients who underwent neoadjuvant therapy or pulmonary resection beyond indicated segments were excluded. Survival was estimated with Kaplan–Meier models and compared using log-rank tests. Cox proportional hazards models were used to estimate hazard ratios (HRs) for death. Cumulative incidence functions for loco-regional recurrence were compared with Gray's test, with death considered a competing event. Cox and Fine–Gray models were used to estimate cause-specific and subdistribution HRs, respectively, for loco-regional recurrence. RESULTS Of 390 cases, 266 (68.2%) were complete and 124 were incomplete anatomic segmentectomy. Demographics, pulmonary function, tumour size, stage and perioperative outcomes did not significantly differ between groups. Surgical margins were negative in all but 1 case. Complete anatomic segmentectomy was associated with improved lymph node dissection (5 vs 2 median nodes sampled; P  <   0.001). Multivariable analysis revealed reduced incidence of loco-regional recurrence (cause-specific HR = 0.42; 95% confidence interval 0.22–0.80; subdistribution HR = 0.43; 95% confidence interval 0.23–0.81), and non-significant improvement in overall survival (HR = 0.66; 95% confidence interval: 0.43–1.00) after complete versus incomplete anatomic segmentectomy. CONCLUSIONS This single-centre experience suggests complete anatomic segmentectomy provides superior loco-regional control and may improve survival relative to incomplete anatomic segmentectomy. We recommend surgeons perform complete anatomic segmentectomy and lymph node dissection whenever possible. [ABSTRACT FROM AUTHOR]

Background and Purpose: The purpose of this article is to document the development and validation process of an instrument adapted for French-speaking nurses and to measure the occurrence of omitted nursing care (ONC) in the intensive care unit (ICU). Methods: An electronic Delphi panel, involving ICU nursing experts from the province of Quebec (Canada), was used to develop the intensive care unit omitted nursing care (ICU-ONC) instrument. For the validation process, an electronic cross-sectional survey was conducted. Results: A total of 564 nurses participated in the validation study. Exploratory factor analysis performed on 478 complete observations supports the presence of a single-factor structure for the 22-item ICU-ONC instrument. Coefficient alpha for the scale was.93, 95% confidence interval (CI) was [0.92, 0.94], item–partial total correlations ranged from.49 and.68, and the mean/median interitem correlations were.38 and.37, respectively. Moderate negative correlations were found between the ICU-ONC instrument overall score and two related constructs: nurses' perception of the quality as well as the safety of care. Conclusions: Our current understanding of ONC in the ICU is based on the results drawn from the administration of generic instruments to ICU nurses. The novel 22-item ICU-ONC instrument can help better estimate the occurrence of the phenomena in the ICU. [ABSTRACT FROM AUTHOR]

Dispersal of whitebark pine (Pinus albicaulis Engelm.), a keystone species of many high-elevation ecosystems in western North America, depends on Clark's nutcracker (Nucifraga columbiana Wilson), a seed-caching bird with an affinity for whitebark seeds. To the extent that this dependence is mutual, declines in whitebark seed production could cause declines in nutcracker abundance. Whitebark pine is in decline across much of its range due to interacting stressors, including the non-native pathogen white pine blister rust (Cronartium ribicola J. C. Fisch.). We used avian point-count data and tree surveys from four national park units to investigate whether trends in whitebark pine can explain trends in Clark's nutcracker. Spatial trends were modeled using recent data from two parks, while temporal trends were modeled using longer time-series of nutcracker and whitebark data from two additional parks. To assess the potential dependence of nutcrackers on whitebark, we linked a model of nutcracker density (accounting for detection probability) with a model of whitebark trends, using a Bayesian framework to translate uncertainty in whitebark metrics to uncertainty in nutcracker density. In Mount Rainier National Park, temporal models showed dramatic declines in nutcracker density concurrent with significant increases in whitebark crown mortality and trees infected with white pine blister rust. However, nutcrackers did not trend with whitebark metrics in North Cascades National Park Service Complex. In spatial models of data from Yosemite National Park and Sequoia-Kings Canyon National Park, nutcracker density varied not only with local cover of whitebark but also with elevation and, in Sequoia-Kings Canyon, with cover of another species of white pine. Our results add support for the hypothesis that the mutualism between whitebark pine and Clark's nutcracker is vulnerable to disruption by blister rust, and our approach integrates data across monitoring programs to explore trends in species interactions.

INTRODUCTION:Postoperative cardiac events are frequent complications of surgery, and their occurrence could be associated with suboptimal nurse staffing practices, but the existing evidence remains scattered. We systematically reviewed studies linking nurse staffing practices to postoperative cardiac events and two related outcomes, all-cause mortality and failure-to-rescue. METHODS:A systematic search of the English/French literature was undertaken in the CINAHL, PsychInfo, and Medline databases. Studies were included if they: a) were published between 1996 and 2018; b) used a quantitative design; c) examined the association between at least one of seven staffing practices of interest (i.e., staffing levels, skill mix, work environment characteristics, levels of education and experience of the registered nurses, and overtime or temporary staff use) and postoperative cardiac events, mortality or failure-to-rescue; and d) were conducted among surgical patients. Data extraction, analysis, and synthesis, along with study methodological quality appraisal, were performed by two authors. High methodological heterogeneity precluded a formal meta-analysis. RESULTS:Among 3,375 retrieved articles, 44 studies were included (39 cross-sectional, 3 longitudinal, 1 case-control, 1 interrupted time series). Existing evidence shows that higher nurse staffing levels, a higher proportion of registered nurses with an education at the baccalaureate degree level, and more supportive work environments are related to lower rates of both 30-day mortality and failure-to-rescue. Other staffing practices were less often studied and showed inconsistent associations with mortality or failure-to-rescue. Similarly, few studies (n = 10) examined the associations between nurse staffing practices and postoperative cardiac events and showed inconsistent results. CONCLUSION:Higher nurse staffing levels, higher registered nurse education (baccalaureate degree level) and more supportive work environments were cross-sectionally associated with lower 30-day mortality and failure-to-rescue rates among surgical patients, but longitudinal studies are required to corroborate these associations. The existing evidence regarding postoperative cardiac events is limited, which warrants further investigation.