Background: Breast cancer (BC) treatment is rapidly evolving with new and costly therapeutics. Existing costing models have a limited ability to capture current treatment costs. We used an ...Activity-Based Costing (ABC) method to determine a per-case cost for BC treatment by stage and molecular subtype. Methods: ABC was used to proportionally integrate multidisciplinary evidence-based patient and provider treatment options for BC, yielding a per-case cost for the total duration of treatment by stage and molecular subtype. Diagnostic imaging, pathology, surgery, radiation therapy, systemic therapy, inpatient, emergency, home care and palliative care costs were included. Results: BC treatment costs were higher than noted in previous studies and varied widely by molecular subtype. Cost increased exponentially with the stage of disease. The per-case cost for treatment (2023C$) for DCIS was C$ 14,505, and the mean costs for all subtypes were C$ 39,263, C$ 76,446, C$ 97,668 and C$ 370,398 for stage I, II, III and IV BC, respectively. Stage IV costs were as high as C$ 516,415 per case. When weighted by the proportion of molecular subtype in the population, case costs were C$ 31,749, C$ 66,758, C$ 111,368 and C$ 289,598 for stage I, II, III and IV BC, respectively. The magnitude of cost differential was up to 10.9 times for stage IV compared to stage I, 4.4 times for stage III compared to stage I and 35.6 times for stage IV compared to DCIS. Conclusion: The cost of BC treatment is rapidly escalating with novel therapies and increasing survival, resulting in an exponential increase in treatment costs for later-stage disease. We provide real-time, case-based costing for BC treatment which will allow for the assessment of health system economic impacts and an accurate understanding of the cost-effectiveness of screening.
Southwestern British Columbia (BC) is exposed to the highest seismic hazard in Canada. Ocean Networks Canada (ONC) has developed an Earthquake Early Warning (EEW) system for the region. The system ...successfully utilizes offshore cabled seismic instruments in addition to land-based seismic sensors and integrates displacement data from Global Navigation Satellite Systems (GNSS). The seismic and geodetic data are processed in real-time onsite at 40 different stations along the coast of BC. The processing utilizes P-wave and S-wave detection algorithms for epicentre calculations as well as incorporation of geodetic and seismic displacement data into a Kalman filter to provide magnitude estimates. The system is currently in its commissioning phase and has successfully detected over 60 earthquakes since being deployed in October 2018. To increase the coverage of the EEW system, we are in the process of incorporating detection parameters from neighbouring networks (e.g., the Pacific Northwest Seismic Network (PNSN)) to provide additional information for future event notifications.
Objectives
Early presentation and workup for acute infectious (IE) and autoimmune encephalitis (AE) are similar. This study aims to identify routine laboratory markers at presentation that are ...associated with IE or AE.
Methods
This was a multi‐center retrospective study at three tertiary care hospitals in New York City analyzing demographic and clinical data from patients diagnosed with definitive encephalitis based on a confirmed pathogen and/or autoantibody and established criteria for clinical syndromes.
Results
Three hundred and thirty‐three individuals with confirmed acute meningoencephalitis were included. An infectious‐nonbacterial (NB) pathogen was identified in 151/333 (45.40%), bacterial pathogen in 95/333 (28.50%), and autoantibody in 87/333 (26.10%). NB encephalitis was differentiated from AE by the presence of fever (NB 62.25%, AE 24.10%; p < 0.001), higher CSF white blood cell (WBC) (median 78 cells/μL, 8.00 cells/μL; p < 0.001), higher CSF protein (76.50 mg/dL, 40.90 mg/dL; p < 0.001), lower CSF glucose (58.00 mg/dL, 69.00 mg/dL; p < 0.001), lower serum WBC (7.80 cells/μL, 9.72 cells/μL; p < 0.050), higher erythrocyte sedimentation rate (19.50 mm/HR, 13.00 mm/HR; p < 0.05), higher C‐reactive protein (6.40 mg/L, 1.25 mg/L; p = 0.005), and lack of antinuclear antibody titers (>1:40; NB 11.54%, AE 32.73%; p < 0.001). CSF‐to‐serum WBC ratio was significantly higher in NB compared to AE (NB 11.3, AE 0.99; p < 0.001). From these findings, the association of presenting with fever, CSF WBC ≥50 cells/μL, and CSF protein ≥75 mg/dL was explored in ruling‐out AE. When all three criteria are present, an AE was found to be highly unlikely (sensitivity 92%, specificity 75%, negative predictive value 95%, and positive predictive value 64%).
Interpretations
Specific paraclinical data at initial presentation may risk stratify which patients have an IE versus AE.
Excess proteolytic activity of matrix metalloproteinases (MMPs) contributes to the development of arthritis, cardiovascular diseases and cancer progression, implicating these enzymes as therapeutic ...targets. While many small molecule inhibitors of MMPs have been developed, clinical uses have been limited, in part by toxicity and off-target effects. Development of the endogenous tissue inhibitors of metalloproteinases (TIMPs) as recombinant biopharmaceuticals represents an alternative therapeutic approach; however, the short plasma half-life of recombinant TIMPs has restricted their potential in this arena. To overcome this limitation, we have modified recombinant human TIMP-1 (rhTIMP-1) by PEGylation on lysine residues. We analyzed a mixture of mono- and di-PEGylated rhTIMP-1 species modified by attachment of 20 kDa mPEG chains (PEG(20K)-TIMP-1), as confirmed by SELDI-TOF mass spectrometry. This preparation retained complete inhibitory activity toward the MMP-3 catalytic domain and partial inhibitory activity toward full length MMP-9. Pharmacokinetic evaluation showed that PEGylation extended the plasma half-life of rhTIMP-1 in mice from 1.1 h to 28 h. In biological assays, PEG(20K)-TIMP-1 inhibited both MMP-dependent cancer cell invasion and tumor cell associated gelatinase activity. Overall these results suggest that PEGylated TIMP-1 exhibits improved potential for development as an anti-cancer recombinant protein therapeutic, and additionally may offer potential for clinical applications in the treatment of other diseases.
The amyloid precursor protein (APP) is a ubiquitously expressed transmembrane adhesion protein and the progenitor of amyloid-β peptides. The major splice isoforms of APP expressed by most tissues ...contain a Kunitz protease inhibitor domain; secreted APP containing this domain is also known as protease nexin 2 and potently inhibits serine proteases, including trypsin and coagulation factors. The atypical human trypsin isoform mesotrypsin is resistant to inhibition by most protein protease inhibitors and cleaves some inhibitors at a substantially accelerated rate. Here, in a proteomic screen to identify potential physiological substrates of mesotrypsin, we find that APP/protease nexin 2 is selectively cleaved by mesotrypsin within the Kunitz protease inhibitor domain. In studies employing the recombinant Kunitz domain of APP (APPI), we show that mesotrypsin cleaves selectively at the Arg15-Ala16 reactive site bond, with kinetic constants approaching those of other proteases toward highly specific protein substrates. Finally, we show that cleavage of APPI compromises its inhibition of other serine proteases, including cationic trypsin and factor XIa, by 2 orders of magnitude. Because APP/protease nexin 2 and mesotrypsin are coexpressed in a number of tissues, we suggest that processing by mesotrypsin may ablate the protease inhibitory function of APP/protease nexin 2 in vivo and may also modulate other activities of APP/protease nexin 2 that involve the Kunitz domain.
High GATA2 expression has been associated with an increased risk of poor clinical outcomes after radical prostatectomy; however, this has not been studied in relation to risk of biochemical ...recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer after radical prostatectomy. Our aim was to evaluate the association between protein expression levels of GATA2 in primary prostate cancer tumour samples and the risk of BCR after SRT.
109 males who were treated with SRT were included. The percentage of cells with nuclear staining and GATA2 staining intensity were both measured. These two measures were multiplied together to obtain a GATA2 H-score (range 0-12) which was our primary GATA2 staining measure.
In unadjusted analysis, the risk of BCR was higher for patients with a GATA2 H-score >4 (hazard ratio = 2.04, p = 0.033). In multivariable analysis adjusting for SRT dose, pre-SRT PSA, pathological tumour stage and Gleason score, this association weakened substantially (hazard ratio = 1.45, p = 0.31). This lack of an independent association with BCR appears to be the result of correlations between GATA2 H-score >4 and higher pre-SRT PSA (p = 0.021), higher Gleason score (p = 0.044) and more severe pathological tumour stage (p = 0.068).
Higher levels of GATA2 expression appear to be a marker of prostate cancer severity; however, these do not provide independent prognostic information regarding BCR beyond that of validated clinicopathological risk factors. Advances in knowledge: A higher GATA2 expression level appears to be correlated with known measures of prostate cancer severity and therefore is likely not an independent marker of outcome after SRT.
Community pharmacies are an ideal setting to manage high-risk medications and screen older adults at risk for falls. Appropriate training and resources are needed to successfully implement services ...in this setting. The purpose of this paper is to identify the key training, tools, and resources to support implementation of fall prevention services. The service was implemented in a network of community pharmacies located in North Carolina. Pharmacies were provided with onboard and longitudinal training, and a project coach. A toolkit contained resources to collect medication information, identify high-risk medications, develop and share recommendations with prescribers, market the service, and educate patients. Project champions at each pharmacy received a nine-question, web-based survey (Qualtrics) to identify usefulness of the training and resources. The quantitative data were analyzed using descriptive statistics. Thirty-one community pharmacies implemented the service. Twenty-three project champions (74%) completed the post-intervention survey. Comprehensive onboard training was rated as more useful than longitudinal training. Resources to identify high-risk medications, develop recommendations, and share recommendations with prescribers were considered most useful. By providing appropriate training and resources to support fall prevention services, community pharmacists can improve patient care as part of their routine workflow.
Throughout American history, scholars called Christian higher education by other names. They used terms such as "denominational," "sectarian," "church-related," "church-sponsored," "church-based," ...and "church-affiliated" higher education to describe Christian higher education. What these terms failed to include, however, were the increasing number of nondenominational institutions that began to emerge in the nineteenth century.
In The Dying of the Light, James Burtchaell (
1998
) did include these institutions in his argument. He suggested that nondenominational colleges and universities had the same weakness as denominational institutions that abandoned their church connections. In fact, compared to institutions that kept their church ties, in Burtchaell's eyes, they appeared to be weaker institutions since they lacked direct denominational support.
Apart from Burtchaell's one historical case study, very little empirical literature exists that supports this argument. This study explores this claim empirically, and compares faculty attitudes, theological beliefs, and religious behaviors at denominational and nondenominational institutions that are part of the Council for Christian Colleges & Universities (CCCU). Respondents included 1,999 full-time faculty from 49 CCCU institutions. Contrary to what certain scholars claim, results demonstrated that faculty at nondenominational institutions did not significantly differ in their theological beliefs from their denominational counterparts. Further empirical research is needed to understand the reasons for this outcome, although we offer some possible hypotheses.
Background: Certain medications place older adults at higher risk for experiencing falls. This is a modifiable risk factor that may be managed by community pharmacists, but requires prescriber ...acceptance of recommendations. Previous studies indicate that prescriber acceptance of pharmacist recommendations may be impacted by patient-reported concerns. Objective: To examine the relationship between patient-reported fear of falling and prescriber acceptance of pharmacist recommendations. Methods: A prospective, observational study design was used. Eligible patients were age 65 and older and received care at one of 31 participating pharmacies. Patients were screened for falls risk using three evidence-based questions; patients screening positive were eligible for a comprehensive medication review. Data were collected via a prescriber response form. The primary outcome was the prescriber acceptance of pharmacist recommendations. Results: Pharmacists communicated 562 recommendations to prescribers, with 338 (60%) for patients who worried about falling. There was no significant difference in prescriber acceptance rate between those who worried about falling and those who did not (36.1% vs. 41.1%, X
2
= 0.23, p = 0.43). However, patient pharmacy was a significant predictor of recommendation acceptance (p = 0.047). Conclusion: Prescribers were not more likely to consider a pharmacist's recommendations regarding medications that contribute to falls risk for patients who worried about falling.
Objective
Preliminary evidence suggests that chronic pain patients complete pain intensity measures using idiosyncratic methods. Our objective was to understand these methods and how they might ...impact the psychometric properties of the instruments.
Design
A qualitative focus‐group based study.
Setting
An academic center in New York City.
Subjects
Outpatients (n = 36) with chronic low back pain, or neuropathic pain due to diabetes or HIV.
Methods
Participants were divided into three focus groups based on their pain condition, and asked to discuss pain intensity measures (visual analog and numeric rating scales for average pain over 24 hours; Brief Pain Inventory; and McGill Pain Questionnaire). Audio‐recordings were transcribed and analyzed using an inductive thematic method.
Results
We discovered four main themes, and five sub‐themes: 1) doubt that pain can be accurately measured (subthemes: pain measurement is influenced by things other than pain, the numbers used to rate pain do not have an absolute meaning, and preference for pain intensity ratings “in the middle” of the scale); 2) confusion regarding the definition of pain; 3) what experiences to use as referents (subthemes: appropriate comparator experiences and the interpretation of the anchors of the scale); and 4) difficulty averaging pain.
Conclusions
The themes discovered suggest that patients include sensations and experiences other than pain intensity in their ratings, experience the rating of pain as a comparative task, and do not use the scale in a linear manner. These themes are relevant to understanding the validity and scale properties of commonly used pain intensity measures.
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