Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts

BACKGROUND: The magnitude of the association between Helicobacter pylori and incidence of gastric cancer is unclear. H pylori infection and the circulating antibody response can be lost with development of cancer; thus retrospective studies are subject to bias resulting from classifi- cation of cases as H pylori negative when they were infected in the past. AIMS: To combine data from all case control studies nested within prospective cohorts to assess more reliably the relative risk of gastric cancer associated with H pylori infection.To investigate variation in relative risk by age, sex, cancer type and subsite, and interval between blood sampling and cancer diagnosis. METHODS: Studies were eligible if blood samples for H pylori serology were collected before diagnosis of gastric cancer in cases. Identified published studies and two unpublished studies were included. Individual subject data were obtained for each. Matched odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the association between H pylori and gastric cancer. RESULTS: Twelve studies with 1228 gastric cancer cases were considered. The association with H pylori was restricted to noncardia cancers (OR 3.0; 95% CI 2.3–3.8) and was stronger when blood samples for H pylori serology were collected 10+ years before cancer diagnosis (5.9; 3.4–10.3). H pylori infection was not associated with an altered overall risk of cardia cancer (1.0; 0.7–1.4). CONCLUSIONS: These results suggest that 5.9 is the best estimate of the relative risk of non-cardia cancer associated with H pylori infection and that H pylori does not increase the risk of cardia cancer. They also support the idea that when H pylori status is assessed close to cancer diagnosis, the magnitude of the non-cardia association may be underestimated

Hope in action—facing cardiac death: A qualitative study of patients with life-threatening disease

Coping with existential challenges is important when struck by serious disease, but apart from cancer and palliative care little is known about how patients deal with such issues and maintain hope. To explore how patients with life-threatening heart disease experience hope when coping with mortality and other existential challenges, we conducted a qualitative study with semi-structured interviews. We made a purposive sample of 11 participants (26–88 years) who had experienced life-threatening disease: eight participants with serious heart disease, two with cancer, and one with severe chronic obstructive pulmonary disease. Analysis was by systematic text condensation. The findings showed that hope could enhance coping and diminish existential distress when patients were confronted with mortality and other existential challenges. Hope was observed as three types of dynamic work: to shift perception of mortality from overwhelming horror toward suppression or peaceful acceptance, to foster reconciliation instead of uncertainty when adapting to the new phase of life, and to establish go-ahead spirit instead of resignation as their identity. Meaning of life could, hence, be sustained in spite of serious threats to the persons' future, everyday life, and self-conception. The work of hoping could be supported or disturbed by relationships with family, friends, and health care professionals. Hope can be regarded as an active, dynamic state of existential coping among patients with life-threatening disease. Physicians may support this coping and thereby provide personal growth and alleviation of existential distress by skillfully identifying, acknowledging, and participating in the work of hoping performed by the patient

Prenatal phthalates, maternal thyroid function, and risk of attention-deficit hyperactivity disorder in the Norwegian mother and child cohort

BACKGROUND: There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning defects suggestive of an attentiondeficit hyperactivity disorder (ADHD) phenotype. OBJECTIVES: We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case - control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008. METHODS: Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (n = 297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (n = 553) from the MoBa population was obtained. RESULTS: In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (Σ DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of Σ DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR = 2: 99 (95% CI: 1.47, 5.49)]. When Σ DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR = 1: 47 (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery. CONCLUSIONS: In this population-based case - control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD

Pregnancy exposure to common-detect organophosphate esters and phthalates and maternal thyroid function

Background: Contemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered thyroid function, however, inconsistencies exist across thyroid function biomarkers. Research on OPEs is sparse, particularly during pregnancy, when maintaining normal thyroid function is critical to maternal and fetal health. In this paper, we aimed to characterize relationships between OPEs and phthalates exposure and maternal thyroid function during pregnancy, using a cross-sectional investigation of pregnant women nested within the Norwegian Mother, Father, and Child Cohort (MoBa). Methods: We included 473 pregnant women, who were euthyroid and provided bio-samples at 17 weeks' gestation (2004–2008). Four OPE and six phthalate metabolites were measured from urine; six thyroid function biomarkers were estimated from blood. Relationships between thyroid function biomarkers and log-transformed concentrations of OPE and phthalate metabolites were characterized using two approaches that both accounted for confounding by co-exposures: co-pollutant adjusted general linear model (GLM) and Bayesian Kernal Machine Regression (BKMR). Results: We restricted our analysis to common-detect OPE and phthalate metabolites (>94%): diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), and all phthalate metabolites. In GLM, pregnant women with summed di-isononyl phthalate metabolites (∑DiNP) concentrations in the 75th percentile had a 0.37 ng/μg lower total triiodothyronine (TT3): total thyroxine (TT4) ratio (95% credible interval: [−0.59, −0.15]) as compared to those in the 25th percentile, possibly due to small but diverging influences on TT3 (−1.99 ng/dL [−4.52, 0.53]) and TT4 (0.13 μg/dL [−0.01, 0.26]). Similar trends were observed for DNBP and inverse associations were observed for DPHP, monoethyl phthalate, mono-isobutyl phthalate, and mono-n-butyl phthalate. Most associations observed in co-pollutants adjusted GLMs were attenuated towards the null in BKMR, except for the case of ∑DiNP and TT3:TT4 ratio (−0.48 [−0.96, 0.003]). Conclusions: Maternal thyroid function varied modestly with ∑DiNP, whereas results for DPHP varied by the type of statistical models

Prenatal phthalate exposures and executive function in preschool children

Background: Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF. Methods: Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks’ gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding. Results: Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: −0.63 [−2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: −0.15 [−1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT. Conclusion and relevance: Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures

The Impact of HIV Infection and CD4 Cell Count on the Performance of an Interferon Gamma Release Assay in Patients with Pulmonary Tuberculosis

BACKGROUND:The performance of the tuberculosis specific Interferon Gamma Release Assays (IGRAs) has not been sufficiently documented in tuberculosis- and HIV-endemic settings. This study evaluated the sensitivity of the QuantiFERON TB-Gold In-Tube (QFT-IT) in patients with culture confirmed pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance. METHODOLOGY/PRINCIPAL FINDINGS:161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT-IT was positive in 74% (119/161; 95% CI: 67-81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion decreased with increasing CD4 cell count in HIV-positive patients (test for trend p = 0.03). Low CD4 cell count (<300 cells/microl) did not account for all QFT-IT indeterminate nor all negative results. Sensitivity when excluding indeterminate results was 86% (95% CI: 81-92%) and did not differ between HIV-negative and HIV-positive patients (88 vs. 83%, p = 0.39). CONCLUSIONS/SIGNIFICANCE:Sensitivity of the QFT-IT for diagnosing active PTB infection was reasonable when excluding indeterminate results and in HIV-negative patients. However, since the test missed more than 10% of patients, its potential as a rule-out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV-infection is prevalent

Falciparum malaria and HIV-1 in hospitalized adults in Maputo, Mozambique: does HIV-infection obscure the malaria diagnosis?

<p>Abstract</p> <p>Background</p> <p>The potential impact of HIV-1 on falciparum malaria has been difficult to determine because of diagnostic problems and insufficient epidemiological data.</p> <p>Methods</p> <p>In a prospective, cross-sectional study, clinical and laboratory data was registered consecutively for all adults admitted to a medical ward in the Central Hospital of Maputo, Mozambique, during two months from 28^thOctober 2006. Risk factors for fatal outcome were analysed. The impact of HIV on the accuracy of malaria diagnosis was assessed, comparing "Presumptive malaria", a diagnosis assigned by the ward clinicians based on fever and symptoms suggestive of malaria in the absence of signs of other infections, and "Verified malaria", a malaria diagnosis that was not rejected during retrospective review of all available data.</p> <p>Results</p> <p>Among 333 included patients, fifteen percent (51/333) had "presumptive malaria", ten percent (28 of 285 tested persons) had positive malaria blood slides, while 69.1% (188/272) were HIV positive. Seven percent (n = 23) had "verified malaria", after the diagnosis was rejected in patients with neck stiffness or symptom duration longer than 2 weeks (n = 5) and persons with negative (n = 19) or unknown malaria blood slide (n = 4). Clinical stage of HIV infection (CDC), hypotension and hypoglycaemia was associated with fatal outcome. The "presumptive malaria" diagnosis was rejected more frequently in HIV positive (20/31) than in HIV negative patients (2/10, p = 0.023).</p> <p>Conclusion</p> <p>The study suggests that the fraction of febrile illness attributable to malaria is lower in HIV positive adults. HIV testing should be considered early in evaluation of patients with suspected malaria.</p

PDGF-Rα gene expression predicts proliferation, but PDGF-A suppresses transdifferentiation of neonatal mouse lung myofibroblasts

<p>Abstract</p> <p>Background</p> <p>Platelet-derived growth factor A (PDGF-A) signals solely through PDGF-Rα, and is required for fibroblast proliferation and transdifferentiation (fibroblast to myofibroblast conversion) during alveolar development, because <it>pdgfa</it>-null mice lack both myofibroblasts and alveoli. However, these PDGF-A-mediated mechanisms remain incompletely defined. At postnatal days 4 and 12 (P4 and P12), using mouse lung fibroblasts, we examined (a) how PDGF-Rα correlates with ki67 (proliferation marker) or alpha-smooth muscle actin (αSMA, myofibroblast marker) expression, and (b) whether PDGF-A directly affects αSMA or modifies stimulation by transforming growth factor beta (TGFβ).</p> <p>Methods</p> <p>Using flow cytometry we examined PDGF-Rα, αSMA and Ki67 in mice which express green fluorescent protein (GFP) as a marker for PDGF-Rα expression. Using real-time RT-PCR we quantified αSMA mRNA in cultured Mlg neonatal mouse lung fibroblasts after treatment with PDGF-A, and/or TGFβ.</p> <p>Results</p> <p>The intensity of GFP-fluorescence enabled us to distinguish three groups of fibroblasts which exhibited absent, lower, or higher levels of PDGF-Rα. At P4, more of the higher than lower PDGF-Rα + fibroblasts contained Ki67 (Ki67+), and Ki67+ fibroblasts predominated in the αSMA + but not the αSMA- population. By P12, Ki67+ fibroblasts comprised a minority in both the PDGF-Rα + and αSMA+ populations. At P4, most Ki67+ fibroblasts were PDGF-Rα + and αSMA- whereas at P12, most Ki67+ fibroblasts were PDGF-Rα- and αSMA-. More of the PDGF-Rα + than - fibroblasts contained αSMA at both P4 and P12. In the lung, proximate αSMA was more abundant around nuclei in cells expressing high than low levels of PDGF-Rα at both P4 and P12. Nuclear SMAD 2/3 declined from P4 to P12 in PDGF-Rα-, but not in PDGF-Rα + cells. In Mlg fibroblasts, αSMA mRNA increased after exposure to TGFβ, but declined after treatment with PDGF-A.</p> <p>Conclusion</p> <p>During both septal eruption (P4) and elongation (P12), alveolar PDGF-Rα may enhance the propensity of fibroblasts to transdifferentiate rather than directly stimulate αSMA, which preferentially localizes to non-proliferating fibroblasts. In accordance, PDGF-Rα more dominantly influences fibroblast proliferation at P4 than at P12. In the lung, TGFβ may overshadow the antagonistic effects of PDGF-A/PDGF-Rα signaling, enhancing αSMA-abundance in PDGF-Rα-expressing fibroblasts.</p

Position paper on screening for breast cancer by the European Society of Breast Imaging (EUSOBI) and 30 national breast radiology bodies from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Israel, Lithuania, Moldova, The Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Sweden, Switzerland and Turkey.

UNLABELLED: EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50-69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1-10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40-49 years and 70-74 years, although with "limited evidence". Thus, we firstly recommend biennial screening mammography for average-risk women aged 50-69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40-45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become "routine mammography" in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged. KEY POINTS: • EUSOBI and 30 national breast radiology bodies support screening mammography. • A first priority is double-reading biennial mammography for women aged 50-69 years. • Extension to 73-75 and from 40-45 to 49 years is also encouraged. • Digital mammography (not film-screen or computer radiography) should be used. • DBT is set to become "routine mammography" in the screening setting in the next future