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Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal form of interstitial lung disease (ILD) characterized by the absence of a known cause and usual interstitial pneumonitis (UIP) pattern on chest CT imaging and/or histopathology. Distinguishing UIP/IPF from other ILD subtypes is essential given different treatments and prognosis. Lung biopsy is necessary when noninvasive data are insufficient to render a confident diagnosis.Research Question: Can we improve noninvasive diagnosis of UIP be improved by predicting ILD histopathology from CT scans by using deep learning?Study Design and Methods: This study retrospectively identified a cohort of 1,239 patients in a multicenter database with pathologically proven ILD who had chest CT imaging. Each case was assigned a label based on histopathologic diagnosis (UIP or non-UIP). A custom deep learning model was trained to predict class labels from CT images (training set, n = 894) and was evaluated on a 198-patient test set. Separately, two subspecialty-trained radiologists manually labeled each CT scan in the test set according to the 2018 American Thoracic Society IPF guidelines. The performance of the model in predicting histopathologic class was compared against radiologists' performance by using area under the receiver-operating characteristic curve as the primary metric. Deep learning model reproducibility was compared against intra-rater and inter-rater radiologist reproducibility.Results: For the entire cohort, mean patient age was 62 ± 12 years, and 605 patients were female (49%). Deep learning performance was superior to visual analysis in predicting histopathologic diagnosis (area under the receiver-operating characteristic curve, 0.87 vs 0.80, respectively; P < .05). Deep learning model reproducibility was significantly greater than radiologist inter-rater and intra-rater reproducibility (95% CI for difference in Krippendorff's alpha did not include zero).Interpretation: Deep learning may be superior to visual assessment in predicting UIP/IPF histopathology from CT imaging and may serve as an alternative to invasive lung biopsy. [ABSTRACT FROM AUTHOR]

Background: In India and other low- and middle-income countries, multiple family and community members are influential in caregivers' perceptions of vaccination. Existing literature indicates the primary caregiver, typically the mother, is instrumental in vaccine decision-making, but this may vary in contexts. We investigated the role of stakeholders in India who influence caregivers' vaccination perceptions, as this is essential to developing strategies to promote vaccine acceptance and improve uptake.Methods: This research was conducted in 2019 in Mewat District in Haryana, an area in India with extremely low vaccination coverage. We conducted six focus group discussions with 60 participants in the following categories: fathers of children under-5 years old, expectant mothers, mothers-in-law, community health workers, and community influencers such as locally elected officials and religious leaders.Results: Our results highlighted four themes that influence vaccine uptake. First, while caregivers associated vaccination with reductions in specific diseases, they also noted that vaccination services brought broad health gains, including improved nutrition, antenatal guidance, and social support. Second, community health workers critically influenced, positively or negatively, caregivers' vaccination perceptions. Third, community health workers faced gaps in their education such as limited training on vaccine side-effects, placing them at a disadvantage when dealing with families. Finally, we found that mothers-in-law, fathers, and religious leaders influence caregivers' perceptions of vaccination.Conclusions: Communication of broader benefits of vaccines and vaccination services by community health workers could be impactful in increasing vaccine acceptance. Vaccine uptake could potentially be improved by facilitating community health workers' ownership over vaccine acceptance and uptake by involving them in the design and implementation of interventions to target mothers and mothers-in-law. A 'bottom-up' approach, leveraging community health workers' knowledge to design interventions, and giving a voice to key members of the household and society beyond mothers alone, may sustain health improvement in low vaccine coverage areas. [ABSTRACT FROM AUTHOR]

Background: miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer.Methods: Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation.Results: A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen-nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094-0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24-0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08-0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033).Conclusion: A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy. [ABSTRACT FROM AUTHOR]

Background: The Government of Bihar (GoB) in India, the Bill and Melinda Gates Foundation and several non-governmental organisations launched the Ananya program aimed to support the GoB to improve reproductive, maternal, newborn and child health and nutrition (RMNCHN) statewide. Here we summarise changes in indicators attained during the initial two-year pilot phase (2012-2013) of implementation in eight focus districts of approximately 28 million population, aimed to inform subsequent scale-up.Methods: The quasi-experimental impact evaluation included statewide household surveys at two time points during the pilot phase: January-April 2012 ("baseline") including an initial cohort of beneficiaries and January-April 2014 ("midline") with a new cohort. The two arms were: 1) eight intervention districts, and 2) a comparison arm comprised of the remaining 30 districts in Bihar where Ananya interventions were not implemented. We analysed changes in indicators across the RMNCHN continuum of care from baseline to midline in intervention and comparison districts using a difference-in-difference analysis.Results: Indicators in the two arms were similar at baseline. Overall, 40% of indicators (20 of 51) changed significantly from baseline to midline in the comparison districts unrelated to Ananya; two-thirds (n = 13) of secular indicator changes were in a direction expected to promote health. Statistically significant impact attributable to the Ananya program was found for 10% (five of 51) of RMNCHN indicators. Positive impacts were most prominent for mother's behaviours in contraceptive utilisation.Conclusions: The Ananya program had limited impact in improving health-related outcomes during the first two-year period covered by this evaluation. The program's theories of change and action were not powered to observe statistically significant differences in RMNCHN indicators within two years, but rather aimed to help inform program improvements and scale-up. Evaluation of large-scale programs such as Ananya using theory-informed, equity-sensitive (including gender), mixed-methods approaches can help elucidate causality and better explain pathways through which supply- and demand-side interventions contribute to changes in behaviour among the actors involved in the production of population-level health outcomes. Evidence from Bihar indicates that deep structural constraints in health system organisation and delivery of interventions pose substantial limitations on behaviour change among health care providers and beneficiaries.Study Registration: ClinicalTrials.gov number NCT02726230. [ABSTRACT FROM AUTHOR]

Estrogen receptor 1 (ESR1, which encodes estrogen receptor-alpha) is a key driver gene for the initiation and progression of hormone receptor-positive breast cancer. Estrogen receptor-alpha (ER) is expressed in up to 70% of cases, and patients are routinely treated with endocrine therapies. However, the development of resistance over time is common and occurs in one-third of ER-positive breast tumors, leading to disease progression and death. X-box binding protein 1 (XBP1), a key component of the unfolded protein response (UPR) and ER signaling pathway, generates a positive feedback regulatory loop that leads to increased expression of XBP1 and ER in luminal breast cancer. In this review, we highlight new insights into the mechanisms of crosstalk between XBP1 and ER signaling and its clinical implications. Next, we describe the key signaling nodes that play an important role in XBP1-mediated endocrine resistance in breast cancer. Further, we discuss XBP1 gene mutations in breast cancer and the role of these mutations in the emergence of endocrine resistance and response to treatment. Finally, we discuss the current state and future directions for targeting XBP1 in combination with standard endocrine therapy to improve clinical outcomes in endocrine-resistant breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial.Methods: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression.Results: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis.Conclusions: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Lipid peroxidation is a major consequence of oxidative stress and can be evaluated via malondialdehyde (MDA) levels. The present study aims to assess MDA levels in the saliva of patients with chronic periodontitis (CP) and acute coronary syndrome (ACS) and establish their correlation with periodontal clinical parameters, serum high-sensitivity C-reactive protein (hsCRP), and plasma fibrinogen.Methods: The study enrolled 64 patients stratified into four age- and sex-matched groups: both ACS and CP, ACS only, CP only, and healthy controls. All patients were examined, periodontal clinical parameters were recorded, and saliva and blood samples were collected. Salivary MDA levels were measured using a spectrophotometric assay. A quantitative turbidimetric test was used for the measurement of serum hsCRP levels, and plasma fibrinogen levels were determined using an automated analyzer.Results: Salivary MDA levels were significantly higher in patients with both ACS and CP than in those with only ACS or only CP and healthy controls (P <0.05). There were significant positive correlations between salivary MDA levels and periodontal clinical parameters as well as biomarkers for cardiovascular events (P <0.001).Conclusions: To our knowledge, this study is the first to investigate salivary MDA levels in patients with ACS and their correlations with serum hsCRP and plasma fibrinogen levels. The results indicate that salivary MDA levels could be a biomarker for cardiovascular and/or periodontal disease. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the rate and level of microbial contamination of silver and non-silver (control) barrel contact lens storage cases in vivo.Methods: A prospective, single-centre, randomized, double blinded, crossover study was conducted to evaluate the efficacy of silver and control barrel cases used with an Oxipol™-based disinfecting solution over a two-month period. Lens cases were collected, and the frequency, type and level of microbial contamination evaluated using viable culture and standard identification methods. Questionnaires were used to assess the contact lens-related hygiene compliance of the participants.Results: Forty eight daily contact lens wearers completed the study. Overall, 27 % of silver and 35 % control lens cases (P > 0.05) were contaminated, predominantly with Gram-positive bacteria. Only, 12 % of participants had good compliance, with 46 % having average compliance and 43 % poor compliance. Compliance score was not associated with level of microbial contamination. However, the use of hydrogel lenses in combination with silver cases compared to non-silver barrel cases resulted significantly greater numbers of bacteria colonising cases.Conclusion: The present investigation demonstrated that the use of silver barrel cases does not reduce the overall rate and level of bacterial contamination, but that using hydrogel lenses in combination with silver cases resulted in higher numbers of bacteria isolated from cases. [ABSTRACT FROM AUTHOR]

Purpose: Whole pelvis radiation therapy (WPRT) may improve clinical outcomes over prostate-only radiation therapy (PORT) in high-risk prostate cancer patients by sterilization of micrometastatic nodal disease, provided there is optimal control of the primary site.Methods and Materials: A prospective multicenter cohort study of eligible patients (stage ≥T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) treated between 2009 and 2013 were enrolled in a United Kingdom national protocol delivering combined external beam radiation therapy and high-dose-rate brachytherapy. Centers elected to deliver WPRT, 46 Gy in 23 fractions or PORT 37.5 Gy in 15 fractions with 15 Gy single dose high-dose-rate brachytherapy. The primary endpoint was biochemical progression-free survival (bPFS). Secondary endpoints were overall survival, genitourinary, and gastrointestinal toxicity. This was not a randomized comparison and was subject to bias; the findings are therefore hypothesis generating, but not conclusive.Results: Eight hundred and twelve patients were entered; 401 received WPRT and 411 received PORT. With a median follow-up of 4.7 years, 5-year bPFS rates for WPRT versus PORT arms were 89% versus 81% (P = .007) for all patients and 84% versus 77% (P = .001) for high-risk patients. Differences in bPFS remained significant after accounting for Gleason score, presenting prostate-specific antigen, T stage, and androgen deprivation therapy duration as covariates. There was no difference in overall survival. The overall post treatment toxicities across both cohorts were low with no greater than 1.5% of ≥grade 3 toxicities at any follow-up time point. WPRT increased both prevalence and cumulative incidence of acute genitourinary toxicity (P = .004) and acute gastrointestinal toxicity (P = .003). No difference in late radiation toxicity was observed.Conclusions: A significant improvement in 5-year bPFS was seen in intermediate and high-risk prostate cancer treated with WPRT compared with PORT in a combined external beam radiation therapy and brachytherapy schedule with no increase in late radiation toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes.Methods and Materials: Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis.Results: We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08).Conclusions: Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification. [ABSTRACT FROM AUTHOR]

Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV ("MesoERV1-12") were identified and verified by qPCR in mouse tissues. "MesoERV1-12" expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. "MesoERV1-12" levels were significantly increased by demethylating agent 5-Aza-2'-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. "MesoERV7" promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson's disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) - not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances - not antagonizes - the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effectiveness of palliative pelvic radiation therapy (PRT) in patients with bladder cancer and identify factors associated with treatment outcome.Methods and Materials: Patients with bladder cancer receiving PRT were identified retrospectively from 2 cancer centers between 2014 and 2017. Patients were stratified by age, stage, performance status, comorbidities, previous chemotherapy, previous radiation therapy, and radiation therapy protocol. Patients were followed up at 6 weeks after radiation therapy (RT). Median overall survival (mOS) from the last fraction of RT was calculated. Death within 30 days of RT or noncompletion of treatment were considered as futile treatment.Results: Two hundred forty-one patients were identified as receiving PRT. A variety of RT protocols were used: 8 Gy in 1 fraction (11%), 21 Gy in 3 fractions (15%), 20 Gy in 5 fractions (18%), 36 Gy in 6 fractions (36%), and 27.5 to 30 Gy in 8 to 10 fractions (18%). Thirty-eight percent of patients were of poor performance status (Eastern Cooperative Oncology Group performance status ≥3), and 46.5% had significant comorbidities (Adult Comorbidity Evaluation-27 ≥2). The mOS from the last fraction of RT was 153 days (0-1289 days). The 30-day mortality after radiation therapy was 18% (n = 44), and the rate of incomplete planned radiation therapy treatment was 14% (n = 33). First follow-up information was available in 62% (n = 150) of patients. Median time to this follow-up was 49 days (14-238 days). At first follow-up at about 6 weeks after the last fraction of radiation therapy, symptoms were reported in 150 of 200 (75%) living patients; 80 of 150 (53%) patients reported improvement in symptoms after treatment. There were significant differences in mOS with stage, performance status, and comorbidities.Conclusions: One in 4 patients either did not complete the planned RT course or died within 30 days of treatment. These patients were unlikely to have received maximal benefit from treatment but may have experienced side effects, making treatment futile. Patients with good performance status and earlier stage disease survived longer. Patient selection and comprehensive assessment are crucial in selecting appropriate patients for treatment. [ABSTRACT FROM AUTHOR]

Purpose: Outcome data on radiation therapy for prostate cancer in an elderly population are sparse. The CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer) trial provides a large, prospectively collected, contemporary dataset in which to explore outcomes by age.Methods and Materials: CHHiP participants received 3 to 6 months of androgen deprivation therapy and were randomly assigned (1:1:1) to receive 74 Gy in 37 fractions (conventional fractionation), 60 Gy in 20 fractions, or 57 Gy in 19 fractions. Toxicity was assessed using clinician-reported outcome (CRO) and patient-reported outcome questionnaires. Participants were categorized as aged < 75 years or ≥ 75 years. Outcomes were compared by age group.Results: Of 3216 patients, 491 (15%) were aged ≥ 75 years. There was no difference in biochemical or clinical failure rates between the groups aged < 75 years and ≥ 75 years for any of the fractionation schedules. In the group aged ≥ 75 years, biochemical or clinical failure-free rates favored hypofractionation, and at 5 years, they were 84.7% for 74 Gy, 91% for 60 Gy, and 87.7% for 57 Gy. The incidence of CRO (grade 3) acute bowel toxicity was 2% in both age groups. The incidence of grade 3 acute bladder toxicity was 8% in patients aged < 75 years and 7% in those aged ≥ 75 years. The 5-year cumulative incidence of CRO grade ≥ 2 late bowel side effects was similar in both age groups. However, in the group aged ≥ 75 years, there was a suggestion of a higher cumulative incidence of bowel bother (small or greater) with 60 Gy compared with 74 Gy and 57 Gy. Patient-reported bladder bother was slightly higher in the group aged ≥ 75 years than the group aged < 75 years, and there was a suggestion of a lower cumulative incidence of bladder bother with 57 Gy compared with 74 Gy and 60 Gy in patients aged ≥ 75 years, which was not evident in those aged < 75 years.Conclusions: Hypofractionated radiation therapy appears to be well tolerated and effective in men aged ≥ 75 years. The 57-Gy schedule has potential advantages in that it may moderate long-term side effects without compromising treatment efficacy in this group. [ABSTRACT FROM AUTHOR]