Systematic review and meta-analysis of residential radon and lung cancer in never-smokers

Background: Globally, radon is the leading risk factor for lung cancer in never-smokers (LCINS). In this study, we systematically reviewed and meta-analysed the evidence of the risk of LCINS associated with residential radon exposure. Methods: Medline and Embase databases were searched using predefined inclusion and exclusion criteria to identify relevant studies published from 1 January 1990 to 5 March 2020 focused on never-smokers. We identified four pooled collaborative studies (incorporating data from 24 case–control studies), one case–control study and one cohort study for systematic review. Meta-analysis was performed on the results of the four pooled studies due to different measures of effect and outcome reported in the cohort study and insufficient information reported for the case–control study. In a post hoc analysis, the corresponding risk for ever-smokers was also examined. Results: Risk estimates of lung cancer from residential radon exposure were pooled in the meta-analysis for 2341 never-smoker cases, 8967 never-smoker controls, 9937 ever-smoker cases and 12 463 ever-smoker controls. Adjusted excess relative risks (aERRs) per 100 Bq·m−3 of radon level were 0.15 (95% CI 0.06–0.25) for never-smokers and 0.09 (95% CI 0.03–0.16) for ever-smokers, and the difference between them was statistically insignificant (p=0.32). The aERR per 100 Bq·m−3was higher for men (0.46; 95% CI 0.15–0.76) than for women (0.09; 95% CI −0.02–0.20) among never-smokers (p=0.027). Conclusion: This study provided quantified risk estimates for lung cancer from residential radon exposure among both never-smokers and ever-smokers. Among never-smokers in radon-prone areas, men were at higher risk of lung cancer than womenS

Leveraging CD4 cell count at entry into care to monitor success of human immunodeficiency virus prevention, treatment, and public health programming in the greater St Louis area between 2017 and 2020

CD4 cell count at entry into human immunodeficiency virus (HIV) care is a useful indicator of success of multiple steps in HIV public health programming. We demonstrate that CD4 cell count at care initiation was stable in St Louis between 2017 and 2019 but declined in 2020. Missouri efforts in the Ending the HIV Epidemic plan should focus on rapidly identifying individuals with undiagnosed HIV infection

Predictors of the first cardiovascular event in patients with systemic lupus erythematosus - a prospective cohort study

Systemic Lupus Erythematosus (SLE) is an autoimmune, inflammatory disease that mainly affects women. The prognosis of SLE has improved dramatically, but mortality rates are still higher than in the general population. With the improved general prognosis, cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality among SLE patients. Previous studies have demonstrated that the development of atherosclerosis is accelerated in SLE, and have identified a set of traditional and nontraditional risk factors that characterize SLE patients with CVD. Nevertheless, many unsolved issues with respect to SLE related CVD remain. The general aim of this thesis was to investigate risk factors for manifest CVD and for cardiovascular mortality (CVM) in SLE, with special focus on traditional risk factors, lupus phenotype, inflammatory and endothelial biomarkers, autoantibodies and genetic predisposition. In the first paper, we prospectively studied traditional and non-traditional risk factors for the development of the first cardiovascular event (CVE) in 182 SLE patients with a follow-up time of 8 years. 24(13%) patients had a first event. We demonstrated that of the traditional risk factors, only age and smoking predicted the first CVE. Additionally, antiphospholipid antibodies (aPL), endothelial biomarkers, represented by soluble vascular cell adhesion molecule 1(sVCAM-1), and absence of thrombocytopenia were independent predictors of CVE. Thus, activation of the endothelium and the coagulation system are important features in SLE-related CVD and the importance to advocate smoking cessation among SLE patients is underscored In the second paper, we prospectively investigated causes of mortality and risk factors for overall mortality and CVM in a cohort of 208 SLE patients, with a follow-up time of 12 years. We also evaluated Systematic coronary risk evaluation (SCORE, tool for evaluating the 10 year risk for cardiovascular death in the age span 40-65 years, based on traditional risk factors) in this population. Cystatin C, a sensitive measure of renal function, in addition to traditional and non-traditional risk factors, were evaluated as risk factors. 42 patients died, 48 % of which were due to CVM. Age, previous arterial events and high cystatin C levels were the strongest predictors for overall mortality and for CVM. After adjusting for these three variables, smoking, sVCAM-1 and high sensitiviy C-reactive protein (hsCRP) predicted CVM. SCORE estimated 4 but we observed 9 cases of CVM, a non-significant difference. We conclude that except for smoking, traditional risk factors are less important than cystatin C, endothelial and inflammatory biomarkers as predictors of CVM in SLE patients. In the third paper, we investigated whether a risk allele for SLE in the signal transducer and activator of transcription factor 4 gene (STAT4) was associated with vascular events or presence of antiphospholipid antibodies (aPL). A total of 578 unrelated SLE patients (424 from mid-Sweden and 154 from southern-Sweden) were included in a cross-sectional design. Occurrence of previous cardiovascular events and aPL were tabulated. Matched controls (N=651) were genotyped as a comparison. The results demonstrate that the STAT4 risk allele was associated with ischemic cerebrovascular disease (ICVD), with a dose-dependent relationship between ICVD and number of risk alleles. The risk allele was furthermore associated with the presence of two or more aPLs, also in a dose-dependent manner. The association remained after adjustment for known traditional risk factors. We conclude that patients with the STAT4 risk allele have an increased risk of ICVD. Our results imply that genetic predisposition is an important risk factor for ICVD in SLE patients, and that aPL may be one underlying mechanism. In the fourth paper, we evaluated the potential association between smoking and aPL. 367 SLE patients were investigated in a cross-sectional study. Occurrence of aPL (anticardiolipin (aCL) IgG and IgM, anti-β2 glycoprotein-1 IgG (aβ2GP1 IgG), lupus anticoagulant (LAC)) and smoking habits (never, ever, former, current) were tabulated. Never smoking was used as reference in all calculations. In multivariable models, adjusted for age, sex and age at disease onset, aCL and aβ2GP1 of the IgG isotype and LAC were associated with ever smoking, this association seemed to be driven mainly by the former smoking group. Our results demonstrate that smoking is associated with pro-thrombotic aPL in SLE patients, though we can not from this study draw firm conclusions about the temporal relationship between exposure to smoking and occurrence of aPL. Further studies are warranted to investigate the mechanisms behind these observations. In prospective studies we have demonstrated that in particular smoking, systemic inflammation, endothelial activation and aPL are major risk factors for SLE related CVD and CVM. Furthermore, genetic predisposition, in our studies represented by a STAT4 SLE risk allele, contributes to the high risk of ICVD and to the occurrence of aPL, a possible underlying pathogenic mechanism. Finally we demonstrate that smoking, known to have unfavorable effects on the immune system and to significantly increase cardiovascular risk in SLE patients, is also associated with pro-thrombotic aPL in patients with SLE. Thus in SLE smoking stands out as the most important of the traditional risk factors with potential influence also on lupus related risk factors such as aPL

CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p \u3c 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p \u3c 0.0001), KMT2D (1% vs. 16%, p \u3c 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p \u3c 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment

Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Context.— Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy. Objective.— To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC. Design.— Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffin-embedded specimens and sequenced to high uniform coverage. Results.— The 20 patients with MPBC had a median age of 62 years (range, 42–86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1–11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing–based copy-number assessment. Conclusions.— Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC

Increased Ret signalling and impact of vandetanib in acquired tamoxifen resistant breast cancer

Deregulation of the tyrosine kinase Ret and its coreceptors (GFRα) has been implicated in neoplasia, and Ret is of interest as a therapeutic target in endocrine-treated breast cancer. This study evaluated in vitro impact of vandetanib, a tyrosine kinase inhibitor able to target Ret in addition to EGFR and VEGFR2, in ER+ breast cancer cells that have acquired resistance to tamoxifen treatment. Tamoxifen resistant TAMR and endocrine responsive MCF7 cells were grown in vitro for 7 days +/- vandetanib (0.5-5μM) +/- exogenous growth factors (10-50ng/ml), and also in continuous culture with vandetanib (1μM), to monitor growth impact and emergence of vandetanib resistance. For Western blotting or immunoprecipitation, log phase cells were transferred for 24hr to serum-free medium and pre-treated for 1hr +/- vandetanib followed by Ret ligands GDNF or artemin for 5mins. Immunohistochemistry for Ret activity was performed on an ER+ tamoxifen-treated clinical breast cancer TMA sample series using Y1062 Ret phospho-antibody with HScore staining assessment. Growth of TAMR cells was substantially inhibited by vandetanib (p<0.001, IC50 0.6μM) with complete cell loss by 17weeks, contrasting rapid emergence of resistance in endocrine responsive MCF7 cells. TAMR cells were more sensitive to vandetanib vs. gefitinib (p<0.001; 1μM each agent), indicating mitogenic signalling in addition to EGFR contributed to TAMR growth. TAMR cells had elevated basal Ret expression, activity and interaction with elevated GFRα3 coreceptor expression; mature VEGFR2 was not detected in TAMR cells. Exogenous GFRα3 ligands artemin or GDNF modestly stimulated TAMR cell growth and hyperactivated Ret, downstream kinases (including MAPK, AKT) and ER Ser167, confirming functional GFRα/Ret signalling and its cross-talk with ER. Increased phospho-Ret immunostaining was also associated with shortened DFI (p=0.036) and survival (p=0.011) in tamoxifen-treated clinical ER+ breast cancers. Vandetanib (0.5-1μM) depleted GFRα3/Ret activity and decreased phospho-EGFR in TAMR cells under basal and Ret ligand-stimulated conditions, inhibited MAPK, p70S6K and S6RP phosphorylation, and partially-reduced levels of phospho-AKT and phospho-ER. However, vandetanib failed to consistently impact on HER2, 3 or 4 activity; moreover, hyperactivation of all erbB receptors by exogenous heregulin B1 (10ng/ml) recovered AKT, MAPK, p70S6K and ER AF-1 phosphorylation in the presence of vandetanib and was able to overcome the basal growth-inhibitory impact of this agent in TAMR cells. These findings demonstrate a central importance for increased Ret signalling and its cross-talk with ER in tamoxifen resistant breast cancer that can be targeted in vitro by vandetanib. Further studies are required to determine optimal combination treatments with vandetanib to circumvent potential intrinsic resistance in clinical breast cancers that exhibit heregulin B1 enrichment

Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas

significantly enriched for genomic alterations (GAs) causing inactivation of DNA repair genes (45%); these GAs have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable GAs in the majority of PACCs, and provide a rationale for using personalized therapies in this disease. Statement of Significance PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two-thirds of these tumors

Using observational data to emulate a randomized trial of dynamic treatment switching strategies

BACKGROUND: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy).METHODS: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting.RESULTS: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death.CONCLUSIONS: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses

Constraints on dark matter to dark radiation conversion in the late universe with DES-Y1 and external data

84siWe study a class of decaying dark matter models as a possible resolution to the observed discrepancies between early- and late-time probes of the universe. This class of models, dubbed DDM, characterizes the evolution of comoving dark matter density with two extra parameters. We investigate how DDM affects key cosmological observables such as the CMB temperature and matter power spectra. Combining 3x2pt data from Year 1 of the Dark Energy Survey,Planck-2018 CMB temperature and polarization data, Supernova (SN) Type Ia data from Pantheon, and BAO data from BOSS DR12, MGS and 6dFGS, we place new constraints on the amount of dark matter that has decayed and the rate with which it converts to dark radiation. The fraction of the decayed dark matter in units of the current amount of dark matter, $zeta$, is constrained at 68% confidence level to be <0.32 for DES-Y1 3x2pt data, <0.030 for CMB+SN+BAO data, and <0.037 for the combined dataset. The probability that the DES and CMB+SN+BAO datasets are concordant increases from 4% for the $Lambda$CDM model to 8% (less tension) for DDM. Moreover, tension in $S_8=sigma_8sqrt{Omega_m/0.3}$ between DES-Y1 3x2pt and CMB+SN+BAO is reduced from 2.3$sigma$ to 1.9$sigma$. We find no reduction in the Hubble tension when the combined data is compared to distance-ladder measurements in the DDM model. The maximum-posterior goodness-of-fit statistics of DDM and $Lambda$CDM are comparable, indicating no preference for the DDM cosmology over $Lambda$CDM....partially_openopenChen, Angela; Huterer, Dragan; Lee, Sujeong; Ferté, Agnès; Weaverdyck, Noah; Alonso Alves, Otavio; Leonard, C. Danielle; MacCrann, Niall; Raveri, Marco; Porredon, Anna; Di Valentino, Eleonora; Muir, Jessica; Lemos, Pablo; Liddle, Andrew; Blazek, Jonathan; Campos, Andresa; Cawthon, Ross; Choi, Ami; Dodelson, Scott; Elvin-Poole, Jack; Gruen, Daniel; Ross, Ashley; Secco, Lucas F.; Sevilla, Ignacio; Sheldon, Erin; Troxel, Michael A.; Zuntz, Joe; Abbott, Tim; Aguena, Michel; Allam, Sahar; Annis, James; Avila, Santiago; Bertin, Emmanuel; Bhargava, Sunayana; Bridle, Sarah; Brooks, David; Carnero Rosell, Aurelio; Carrasco Kind, Matias; Carretero, Jorge; Costanzi, Matteo; Crocce, Martin; da Costa, Luiz; Elidaiana da Silva Pereira, Maria; Davis, Tamara; Doel, Peter; Eifler, Tim; Ferrero, Ismael; Fosalba, Pablo; Frieman, Josh; Garcia-Bellido, Juan; Gaztanaga, Enrique; Gerdes, David; Gruendl, Robert; Gschwend, Julia; Gutierrez, Gaston; Hinton, Samuel; Hollowood, Devon L.; Honscheid, Klaus; Hoyle, Ben; James, David; Jarvis, Mike; Kuehn, Kyler; Lahav, Ofer; Maia, Marcio; Marshall, Jennifer; Menanteau, Felipe; Miquel, Ramon; Morgan, Robert; Palmese, Antonella; Paz-Chinchon, Francisco; Plazas Malagón, Andrés; Roodman, Aaron; Sanchez, Eusebio; Scarpine, Vic; Schubnell, Michael; Serrano, Santiago; Smith, Mathew; Suchyta, Eric; Tarle, Gregory; Thomas, Daniel; To, Chun-Hao; Varga, Tamas Norbert; Weller, Jochen; Wilkinson, ReeseChen, Angela; Huterer, Dragan; Lee, Sujeong; Ferté, Agnès; Weaverdyck, Noah; Alonso Alves, Otavio; Leonard, C. Danielle; Maccrann, Niall; Raveri, Marco; Porredon, Anna; Di Valentino, Eleonora; Muir, Jessica; Lemos, Pablo; Liddle, Andrew; Blazek, Jonathan; Campos, Andresa; Cawthon, Ross; Choi, Ami; Dodelson, Scott; Elvin-Poole, Jack; Gruen, Daniel; Ross, Ashley; Secco, Lucas F.; Sevilla, Ignacio; Sheldon, Erin; Troxel, Michael A.; Zuntz, Joe; Abbott, Tim; Aguena, Michel; Allam, Sahar; Annis, James; Avila, Santiago; Bertin, Emmanuel; Bhargava, Sunayana; Bridle, Sarah; Brooks, David; Carnero Rosell, Aurelio; Carrasco Kind, Matias; Carretero, Jorge; Costanzi, Matteo; Crocce, Martin; da Costa, Luiz; Elidaiana da Silva Pereira, Maria; Davis, Tamara; Doel, Peter; Eifler, Tim; Ferrero, Ismael; Fosalba, Pablo; Frieman, Josh; Garcia-Bellido, Juan; Gaztanaga, Enrique; Gerdes, David; Gruendl, Robert; Gschwend, Julia; Gutierrez, Gaston; Hinton, Samuel; Hollowood, Devon L.; Honscheid, Klaus; Hoyle, Ben; James, David; Jarvis, Mike; Kuehn, Kyler; Lahav, Ofer; Maia, Marcio; Marshall, Jennifer; Menanteau, Felipe; Miquel, Ramon; Morgan, Robert; Palmese, Antonella; Paz-Chinchon, Francisco; Plazas Malagón, Andrés; Roodman, Aaron; Sanchez, Eusebio; Scarpine, Vic; Schubnell, Michael; Serrano, Santiago; Smith, Mathew; Suchyta, Eric; Tarle, Gregory; Thomas, Daniel; Chun-Hao, To; Varga, Tamas Norbert; Weller, Jochen; Wilkinson, Rees

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges