Stakeholder preferences for attributes of digital health technologies to consider in health service funding

Objectives: Health service providers are currently making decisions on the public funding of digital health technologies (DHTs) for managing chronic diseases with limited understanding of stakeholder preferences for DHT attributes. This study aims to understand the community, patient/carer, and health professionals' preferences to help inform a prioritized list of evaluation criteria. Methods: An online best-worst scaling survey was conducted in Australia, New Zealand, Canada, and the United Kingdom to ascertain the relative importance of twenty-four DHT attributes among stakeholder groups using an efficient incomplete block design. The attributes were identified from a systematic review of DHT evaluation frameworks for consideration in a health technology assessment. Results were analyzed with multinomial models by stakeholder group and latent class. Results: A total of 1,251 participants completed the survey (576 general community members, 543 patients/carers, and 132 health professionals). Twelve attributes achieved a preference score above 50 percent in the stakeholder group model, predominantly related to safety but also covering technical features, effectiveness, ethics, and economics. Results from the latent class model supported this prioritization. Overall, connectedness with the patient's healthcare team seemed the most important; with Helps health professionals respond quickly when changes in patient care are needed as the most highly prioritized of all attributes. Conclusions: It is proposed that these prioritized twelve attributes be considered in all evaluations of DHTs that manage chronic disease, supplemented with a limited number of attributes that reflect the specific perspective of funders, such as equity of access, cost, and system-level implementation considerations

Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR

ST3Gal.I sialyltransferase relevance in bladder cancer tissues and cell lines

<p>Abstract</p> <p>Background</p> <p>The T antigen is a tumor-associated structure whose sialylated form (the sialyl-T antigen) involves the altered expression of sialyltransferases and has been related with worse prognosis. Since little or no information is available on this subject, we investigated the regulation of the sialyltransferases, able to sialylate the T antigen, in bladder cancer progression.</p> <p>Methods</p> <p>Matched samples of urothelium and tumor tissue, and four bladder cancer cell lines were screened for: <it>ST3Gal.I</it>, <it>ST3Gal.II </it>and <it>ST3Gal.IV </it>mRNA level by real-time PCR. Sialyl-T antigen was detected by dot blot and flow cytometry using peanut lectin. Sialyltransferase activity was measured against the T antigen in the cell lines.</p> <p>Results</p> <p>In nonmuscle-invasive bladder cancers, <it>ST3Gal.I </it>mRNA levels were significantly higher than corresponding urothelium (p < 0.001) and this increase was twice more pronounced in cancers with tendency for recurrence. In muscle-invasive cancers and matching urothelium, <it>ST3Gal.I </it>mRNA levels were as elevated as nonmuscle-invasive cancers. Both non-malignant bladder tumors and corresponding urothelium showed <it>ST3Gal.I </it>mRNA levels lower than all the other specimen groups. A good correlation was observed in bladder cancer cell lines between the <it>ST3Gal.I </it>mRNA level, the ST activity (r = 0.99; p = 0.001) and sialyl-T antigen expression, demonstrating that sialylation of T antigen is attributable to ST3Gal.I. The expression of sialyl-T antigens was found in patients' bladder tumors and urothelium, although without a marked relationship with mRNA level. The two <it>ST3Gal.I </it>transcript variants were also equally expressed, independently of cell phenotype or malignancy.</p> <p>Conclusion</p> <p>ST3Gal.I plays the major role in the sialylation of the T antigen in bladder cancer. The overexpression of <it>ST3Gal.I </it>seems to be part of the initial oncogenic transformation of bladder and can be considered when predicting cancer progression and recurrence.</p

Repeated BCG treatment of mouse bladder selectively stimulates small GTPases and HLA antigens and inhibits single-spanning uroplakins

<p>Abstract</p> <p>Background</p> <p>Despite being a mainstay for treating superficial bladder carcinoma and a promising agent for interstitial cystitis, the precise mechanism of Bacillus Calmette-Guerin (BCG) remains poorly understood. It is particularly unclear whether BCG is capable of altering gene expression beyond its well-recognized pro-inflammatory effects and how this relates to its therapeutic efficacy. The objective of this study was to determine differentially expressed genes in the mouse bladder following repeated intravesical BCG therapy.</p> <p>Methods</p> <p>Mice were transurethrally instilled with BCG or pyrogen-free on days 1, 7, 14, and 21. Seven days after the last instillation, urothelia along with the submucosa was removed and amplified ds-DNA was prepared from control- and BCG-treated bladder mucosa and used to generate suppression subtractive hybridization (SSH). Plasmids from control- and BCG-specific differentially expressed clones and confirmed by Virtual Northern were then purified and the inserts were sequenced and annotated. Finally, chromatin immune precipitation combined with real-time polymerase chain reaction assay (ChIP/Q-PCR) was used to validate SSH-selected transcripts.</p> <p>Results</p> <p>Repeated intravesical BCG treatment induced an up regulation of genes associated with antigen presentation (B2M, HLA-A, HLA-DQA1, HLA-DQB2, HLA-E, HLA-G, IGHG, and IGH) and representatives of two IFNγ-induced small GTPase families: the GBPs (GBP1, GBP2, and GBP5) and the p47GTPases (IIGTP1, IIGTP2, and TGTP). Genes expressed in saline-treated bladders but down-regulated by BCG included: the single-spanning uroplakins (UPK3a and UPK2), SPRR2G, GSTM5, and RSP 19.</p> <p>Conclusion</p> <p>Here we introduced a hypothesis-generator approach to determine key genes involved in the urothelium/sumbmucosa responses to BCG therapy. Urinary bladder responds to repeated BCG treatment by up-regulating not only antigen presentation-related genes, but also GBP and p47 small GTPases, both potentially serving to mount a resistance to the replication of the <it>Mycobacterium</it>. It will be of tremendous future interest to determine whether these immune response cascades play a role in the anti-cancer effects exerted by BCG.</p

Development and validation of a risk score to predict unplanned hospital readmissions in ICU survivors:A data linkage study

Background: Intensive Care Unit (ICU) follow-up clinics are growing in popularity internationally; however, there is limited evidence as to which patients would benefit most from a referral to this service. Objectives: The objective of this study was to develop and validate a model to predict which ICU survivors are most likely to experience an unplanned hospital readmission or death in the year after hospital discharge and derive a risk score capable of identifying high-risk patients who may benefit from referral to follow-up services. Methods: A multicentre, retrospective observational cohort study using linked administrative data from eight ICUs was conducted in the state of New South Wales, Australia. A logistic regression model was developed for the composite outcome of death or unplanned readmission in the 12 months after discharge from the index hospitalisation. Results: 12,862 ICU survivors were included in the study, of which 5940 (46.2%) patients experienced unplanned readmission or death. Strong predictors of readmission or death included the presence of a pre-existing mental health disorder (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.40–1.65), severity of critical illness (OR: 1.57, 95% CI: 1.39–1.76), and two or more physical comorbidities (OR: 2.39, 95% CI: 2.14–2.68). The prediction model demonstrated reasonable discrimination (area under the receiver operating characteristic curve: 0.68, 95% CI: 0.67–0.69) and overall performance (scaled Brier score: 0.10). The risk score was capable of stratifying patients into three distinct risk groups—high (64.05% readmitted or died), medium (45.77% readmitted or died), and low (29.30% readmitted or died). Conclusions: Unplanned readmission or death is common amongst survivors of critical illness. The risk score presented here allows patients to be stratified by risk level, enabling targeted referral to preventative follow-up services.</p

Diagnostic accuracy of handheld electrocardiogram devices in detecting atrial fibrillation in adults in community versus hospital settings : a systematic review and meta-analysis

With increasing use of handheld ECG devices for atrial fibrillation (AF) screening, it is important to understand their accuracy in community and hospital settings and how it differs among settings and other factors. A systematic review of eligible studies from community or hospital settings reporting the diagnostic accuracy of handheld ECG devices (ie, devices producing a rhythm strip) in detecting AF in adults, compared with a gold standard 12-lead ECG or Holter monitor, was performed. Bivariate hierarchical random-effects meta-analysis and meta-regression were performed using R V.3.6.0. The search identified 858 articles, of which 14 were included. Six studies recruited from community (n=6064 ECGs) and eight studies from hospital (n=2116 ECGs) settings. The pooled sensitivity was 89% (95% CI 81% to 94%) in the community and 92% (95% CI 83% to 97%) in the hospital. The pooled specificity was 99% (95% CI 98% to 99%) in the community and 95% (95% CI 90% to 98%) in the hospital. Accuracy of ECG devices varied: sensitivity ranged from 54.5% to 100% and specificity ranged from 61.9% to 100%. Meta-regression showed that setting (p=0.032) and ECG device type (p=0.022) significantly contributed to variations in sensitivity and specificity. The pooled sensitivity and specificity of single-lead handheld ECG devices were high. Setting and handheld ECG device type were significant factors of variation in sensitivity and specificity. These findings suggest that the setting including user training and handheld ECG device type should be carefully reviewed

Trends in modifiable risk factors amongst first presentation ST elevation myocardial infarction patients in a large longitudinal registry

Background: Recent studies suggest that the risk factor profile of patients presenting with ST elevation myocardial infarction (STEMI) is changing. Aim: The aim is to determine if there has been a shift of cardiovascular risk factors to cardiometabolic causes in the first presentation STEMI population. Method: We analysed data from a STEMI registry from a large tertiary referral percutaneous coronary intervention centre to determine the prevalence and trends of the modifiable risk factors of hypertension, diabetes, smoking and hypercholesterolaemia. Participants: Consecutive first presentation STEMI patients between January 2006 to December 2018. Results: Among the 2,366 patients included (mean age 59, SD 12.66, 80% male) the common risk factors were hypertension (47%), hypercholesterolaemia (47%) current smoking (42%) and diabetes (27%). Over the 13 years, patients with diabetes (20% to 26%, OR 1.09 per year, CI 1.06–1.11, p<0.001) and patients with no modifiable risk factors increased (9% to 17%, OR 1.08, CI 1.04–1.11, p<0.001). Concurrently there was a fall in prevalence of hypercholesterolaemia, (47% to 37%, OR 0.94 per year, CI 0.92–0.96, p<0.001) and smoking (44% to 41%, OR 0.94, CI 0.92–0.96, p<0.001) but no significant change in rates of hypertension (53% to 49%, OR 0.99, CI 0.97–1.01, p=0.25). Conclusion: The risk factor profile of first presentation STEMI has changed over time with a reduction in smoking and a concurrent rise in patients with no traditional risk factors. This suggests the mechanism of STEMI may be changing and further investigation of potential causal factors is warranted for the prevention and management of cardiovascular disease