Health economic evaluation of lung cancer screening using a 2 diagnostic blood test : the Early detection of Cancer of the Lung 3 Scotland (ECLS)

Funding: Funding for the ECLS study was received from Oncimmune Ltd and the Scottish Government Health & Social Care Directorate of the Chief Scientist Office (CSO).Background: Diagnostic blood tests have the potential to identify lung cancer in people at high risk. We assessed the cost-effectiveness of a lung cancer screening intervention, using the EarlyCDT®-Lung Test (ECLS) with subsequent X-ray and low-dose chest CT scans (LDCT) for patients with a positive test result, compared to both usual care and LDCT screening for the target population. Methods: We conducted a model-based lifetime analysis from a UK NHS and personal social services perspective. We estimated incremental net monetary benefit (NMB) for the ECLS intervention compared to no screening and to LDCT screening. Results: The incremental NMB of ECLS intervention compared to no screening was GBP 33,179 (95% CI: −GBP 81,396, GBP 147,180) and GBP 140,609 (95% CI: -GBP 36,255, GBP 316,612), respectively, for a cost-effectiveness threshold of GBP 20,000 and GBP 30,000 per quality-adjusted life year. The same figures compared with LDCT screening were GBP 162,095 (95% CI: GBP 52,698, GBP 271,735) and GBP 52,185 (95% CI: −GBP 113,152, GBP 220,711). Conclusions: The ECLS intervention is the most cost-effective screening alternative, with the highest probability of being cost-effective, when compared to no screening or LDCT screening. This result may change with modifications of the parameters, suggesting that the three alternatives considered in the main analysis are potentially cost-effective.Peer reviewe

Effects of climate variability and accelerated forest thinning on watershed-scale runoff in southwestern USA ponderosa pine forests

The recent mortality of up to 20% of forests and woodlands in the southwestern United States, along with declining stream flows and projected future water shortages, heightens the need to understand how management practices can enhance forest resilience and functioning under unprecedented scales of drought and wildfire. To address this challenge, a combination of mechanical thinning and fire treatments are planned for 238,000 hectares (588,000 acres) of ponderosa pine (Pinus ponderosa) forests across central Arizona, USA. Mechanical thinning can increase runoff at fine scales, as well as reduce fire risk and tree water stress during drought, but the effects of this practice have not been studied at scales commensurate with recent forest disturbances or under a highly variable climate. Modifying a historical runoff model, we constructed scenarios to estimate increases in runoff from thinning ponderosa pine at the landscape and watershed scales based on driving variables: pace, extent and intensity of forest treatments and variability in winter precipitation. We found that runoff on thinned forests was about 20% greater than unthinned forests, regardless of whether treatments occurred in a drought or pluvial period. The magnitude of this increase is similar to observed declines in snowpack for the region, suggesting that accelerated thinning may lessen runoff losses due to warming effects. Gains in runoff were temporary (six years after treatment) and modest when compared to mean annual runoff from the study watersheds (0–3%). Nonetheless gains observed during drought periods could play a role in augmenting river flows on a seasonal basis, improving conditions for water-dependent natural resources, as well as benefit water supplies for downstream communities. Results of this study and others suggest that accelerated forest thinning at large scales could improve the water balance and resilience of forests and sustain the ecosystem services they provide

Health economic evaluation of lung cancer screening using a diagnostic blood test: the Early detection of Cancer of the Lung Scotland (ECLS)

Background: Diagnostic blood tests have the potential to identify lung cancer in people at high risk. We assessed the cost-effectiveness of a lung cancer screening intervention, using the Early CDT®-Lung Test (ECLS) with subsequent X-ray and low-dose chest CT scans (LDCT) for patients with a positive test result, compared to both usual care and LDCT screening for the target population. Methods: We conducted a model-based lifetime analysis from a UK NHS and personal social services perspective. We estimated incremental net monetary benefit (NMB) for the ECLS intervention compared to no screening and to LDCT screening. Results: The incremental NMB of ECLS intervention compared to no screening was GBP 33,179 (95% CI: −GBP 81,396, GBP 147,180) and GBP 140,609 (95% CI: -GBP 36,255, GBP 316,612), respectively, for a cost-effectiveness threshold of GBP 20,000 and GBP 30,000 per quality-adjusted life year. The same figures compared with LDCT screening were GBP 162,095 (95% CI: GBP 52,698, GBP 271,735) and GBP 52,185 (95% CI: −GBP 113,152, GBP 220,711). Conclusions: The ECLS intervention is the most cost-effective screening alternative, with the highest probability of being cost-effective, when compared to no screening or LDCT screening. This result may change with modifications of the parameters, suggesting that the three alternatives considered in the main analysis are potentially cost-effective

Standardising Marine Renewable Energy Testing: Gap Analysis and Recommendations for Development of Standards

Marine renewable energy (MRE) is still an emerging technology. As such, there is still a lack of mature standards and guidance for the development and testing of these devices. The sector covers a wide range of disciplines, so there is a need for more comprehensive guidance to cover these. This paper builds on a study undertaken in the MaRINET2 project to summarise recommendations and guidance for testing MRE devices and components, by reviewing the recently published guidance. Perceived gaps in the guidance are then discussed, expanding on the previous study. Results from an industry survey are also used to help quantify and validate these gaps. The main themes identified can be summarised as: the development progression from concept to commercialisation, including more complex environmental conditions in testing, accurately modelling and quantifying the power generated, including grid integration, plus modelling and testing of novel moorings and foundation solutions. A pathway to a standardised approach to MRE testing is presented, building on recommendations learnt from the MaRINET2 round-robin testing, showing how these recommendations are being incorporated into the guidance and ultimately feeding into the development of international standards for the marine renewable energy sector

Possible roles of protein kinase A in cell motility and excystation of the early diverging eukaryote Giardia lamblia

Since little is known of how the primitive protozoan parasite, Giardia lamblia, senses and responds to its changing environment, we characterized a giardial protein kinase A (gPKA) catalytic subunit with unusual subcellular localization. Sequence analysis of the 1080-base pair open reading frame shows 48% amino acid identity with the cyclic AMP-dependent kinase from Euglena gracilis, Northern analysis indicated a 1.28-kilobase pair transcript at relatively constant concentrations during growth and encystation, gPKA is autophosphorylated, although amino acid residues corresponding to Thr-197 and Ser-338 of human protein kinase A (PKA) that are important for autophosphorylation are absent, Kinetic analysis of the recombinant PKA showed that ATP and magnesium are preferred over GTP and manganese, Kinase activity of the native PKA has also been detected in crude extracts using kemptide as a substrate. A myristoylated PKA inhibitor, amide 14-22, inhibited excystation with an IC50 of 3 muM, suggesting an important role of gPKA during differentiation from the dormant cyst form into the active trophozoite, gPKA localizes independently of cell density to the eight flagellar basal bodies between the two nuclei together with centrin, a basal body/centrosome-specific protein. However, localization of gPKA to marginal plates along the intracellular portions of the anterior and caudal pairs of flagella was evident only at low cell density and higher endogenous cAMP concentrations or after refeeding with fresh medium. These data suggest an important role of PKA in trophozoite motility during vegetative growth and the cellular activation of excystation

AKT activation seems to be associated with apoptotic signals and not with pro-survival signals in a pristane-induced lupus model.

Several studies have shown that in addition to its role as a survival factor and tumor promoting agent, AKT is also able to exhibit pro-apoptotic effects under diverse conditions, including oxidative stress, cytokine stimulation and exposure to cytotoxic chemicals like staurosporine, methotrexate, docetaxel and etoposide. Moreover, phosphorylation of second mitochondria-derived activator of caspases (SMAC) by AKT promotes caspase-3 activation during etoposide-induced apoptosis in HeLa cells. Our data show that injection of pristane into the peritoneum induces apoptosis-mediated cell death of peritoneal exudate cells (PECs), as evidenced by the increased number of annexin V+ peritoneal cells and their increased levels of cleaved/active caspase-3. Indeed, the higher levels of activated caspase-3 protein in WT PECs, particularly at 2-weeks post pristane treatment, are indicative of a higher rate of apoptosis compared to Cd38¿/¿ cells. In contrast, no differences were observed in the levels of MCL-1, an anti-apoptotic protein and member of the BCL2 family. Furthermore, kinases ERK1/2 and AKT showed distinct activation kinetics in pristane-elicited PECs. Interestingly, caspase-3 activation followed similar kinetics to AKT activation in both WT and Cd38¿/¿ PECs, while ERK activation correlated with increased levels of MCL-1. In summary our data strongly suggest that in the pristane-induced lupus model AKT activation is associated with apoptotic signals and not with survival signals. Further studies, however, are required to identify specific pro- and anti-apoptotic target proteins that are phosphorylated by ERK or AKT following pristane treatment, and that regulate the apoptotic process

Self-reported side effects after vaccination against COVID-19 in Honduras

Background: In December 2019, in the community of Wuhan, in Hubei, China, a series of atypical pneumonia cases with severe course was identified and the new disease was called COVID-19. By March 2020, the World Health Organization declared a pandemic. Understanding SARS-CoV2 genomic allowed the scientific community to develop vaccine candidates against COVID-19. Over 41 scientific groups conducted clinical trials to prove vaccines efficiency, efficacy, and safety.Method: A cross sectional retrospective study performed in Honduras since July 21st, 2021, to December 1st, 2021. This study included the population who received at least one dose of any COVID-19 vaccine. The data were collected using an online survey using Google Forms and a QR code to make it easier for the participants to access the survey and to avoid collecting any personal data from the participants. The symptoms were self-reported. A total of 2108 participants were included in the study through the online survey.Results: The average age of the participants was 34.61±11.129 years with higher frequency of people between 20-29 years old. In 60.7% of the cases, side effects were reported after the first dose of COVID-19 vaccine or in cases when only one dose was required. Only 1916 received a second dose of COVID-19 vaccine and 38.9% of them presented side effects after that second dose. The most common side effect is pain in the injection site (49.7% and 30.7%). The most common systemic side effects are fever (34.8% and 17.5%), headache (33.5% and 19.1%) and myalgia (32.8% and 17.6%). Conclusions: The side effects reported by the population after any vaccination against COVID-19 are mainly systemic effects like fever, myalgia and headache, while the most common local side effect is pain in the injection site. The rates of side effects are higher in females, and younger participants after both doses, the differences are statistically significant

Cervicovaginal Fungi and Bacteria Associated With Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Infections in a Hispanic Population

The human cervicovaginal microbiota resides at an interface between the host and the environment and may affect susceptibility to disease. Puerto Rican women have high human papillomavirus (HPV) infection and cervical cancer rates. We hypothesized that the population structure of the cervicovaginal bacterial and fungal biota changed with cervical squamous intraepithelial lesions and HPV infections. DNA was extracted from cervix, introitus, and anal sites of 62 patients attending high-risk San Juan clinics. The 16S rRNA V4 region and ITS-2 fungal regions were amplified and sequenced using Illumina technology. HPV genotyping was determined by reverse hybridization with the HPV SPF10-LiPA25 kit. HPV prevalence was 84% of which ∼44% subjects were infected with high-risk HPV, ∼35% were co-infected with as many as 9 HPV types and ∼5% were infected with exclusively low-risk HPV types. HPV diversity did not change with cervical dysplasia. Cervical bacteria were more diverse in patients with CIN3 pre-cancerous lesions. We found enrichment of Atopobium vaginae and Gardnerella vaginalis in patients with CIN3 lesions. We found no significant bacterial biomarkers associated with HPV infections. Fungal diversity was significantly higher in cervical samples with high-risk HPV and introitus samples of patients with Atypical Squamous Cells of Undetermined Significance (ASCUS). Fungal biomarker signatures for vagina and cervix include Sporidiobolaceae and Sacharomyces for ASCUS, and Malassezia for high-risk HPV infections. Our combined data suggests that specific cervicovaginal bacterial and fungal populations are related to the host epithelial microenvironment, and could play roles in cervical dysplasia

Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging

The EarlyCDT-Lung test is a high specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. Here we report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent CT scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/Unspecified lung cancer at diagnosis, compared with the standard clinical practice at the time the study began.ECLS was a randomised controlled trial of 12,208 participants at risk of developing lung cancer in Scotland. The intervention arm received the EarlyCDT-Lung test and, if test positive, low-dose CT scanning six-monthly for up to two years. EarlyCDT-Lung test negative and control arm participants received standard clinical care. Outcomes wereassessed at two years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities. At two years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33/56 (58.9%) lung cancers were diagnosed at stage III/IV compared to 52/71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% confidence interval 0.41, 0.99). There were non-significant differences in lung cancer and all-cause mortality after two years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation), and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage-shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of LDCT.Registration: ClinicalTrials.Gov registration number NCT01925625

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: An international case-cohort study

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (\u3baw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the Cindex. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (\u3baw=0.65, IQR 0.53-0.72, p20 years of experience (C-index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72-0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts