Invited commentary: Immunization and Bell's palsy in children.

Based on case reports, it has been speculated that certain vaccines may increase the risk of Bell's palsy. In a study using a novel approach (case-centered analysis) among children aged 18 years or less, results of which appear in this issue of the Journal, Rowhani-Rahbar et al. (Am J Epidemiol. 2012;175(9):878-885) found no association between immunization with trivalent influenza vaccine (TIV), hepatitis B virus (HBV) vaccine, or any vaccine (all vaccines combined) and Bell's palsy (definite and probable cases combined). In this commentary, the author evaluates the validity of the case-centered approach. In the study by Rowhani-Rahbar et al., the study population was not representative of the population of children at risk. The analytical approach resulted in the loss of information for 72% of the cases. There were insufficient data to assess TIV and HBV. Only the risk for all vaccines could be assessed, and only if it was assumed that the findings could be generalized. Possible effect modification by antecedent vaccination could not be assessed. The author concludes that a nested case-control study would have been more statistically robust and more informative.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Part 4: the Million Women Study.

BACKGROUND: Based principally on findings in three studies, the collaborative reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1-3). OBJECTIVE: To evaluate the evidence for causality in the MWS. METHODS: Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET. RESULTS: Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50-55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported. CONCLUSION: HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 3. The Women's Health Initiative: unopposed estrogen.

BACKGROUND: Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed. OBJECTIVE: To evaluate the evidence for unopposed estrogen. METHODS: In a related article (Part 2) the authors apply generally accepted causal criteria to the findings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the findings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study. RESULTS: In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an 'intention-to-treat' analysis (95% CI 0.59-1.01) and 0.67 (95% CI 0.47-0.97) in an 'as treated' analysis; after 10.7 years the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the 'as treated' analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed. In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed. CONCLUSIONS: The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women's Health Initiative: estrogen plus progestogen.

BACKGROUND: Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy (HRT) with estrogen plus progestogen is now an established cause of breast cancer. For unopposed estrogen therapy the evidence in the three studies is conflicting: the CR and MWS have reported increased risks in estrogen users, while the WHI has not. The authors have previously reviewed the findings in the CR (Part 1). OBJECTIVE: To evaluate the evidence for causality in the WHI studies. METHODS: Using generally accepted causal criteria, in this paper (Part 2) the authors evaluate the findings in the WHI for estrogen plus progestogen; in a related paper (Part 3) the authors evaluate the findings for unopposed estrogen. An evaluation of the MWS (Part 4), and of trends in breast cancer incidence following publication of the WHI findings in 2002 (Part 5) will follow. RESULTS: For estrogen plus progestogen the findings did not adequately satisfy the criteria of bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION: HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Part 1. The Collaborative Reanalysis.

BACKGROUND Concern that hormone replacement therapy (HRT) may cause breast cancer has existed since the time it was introduced, and based on evidence in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that causality is now established. OBJECTIVE To evaluate the evidence for causality in the three studies. Methods Using generally accepted causal criteria, in this paper the authors begin with an evaluation of the CR. Analogous evaluations of the WHI and MWS will follow. RESULTS The findings in the CR did not adequately satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, dose/duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION HRT may or may not increase the risk of breast cancer, but the CR did not establish that it does.

Determination by Relaxation Tests of the Mechanical Properties of Soft Polyacrylamide Gels Made for Mechanobiology Studies.

Following the general aim of recapitulating the native mechanical properties of tissues and organs in vitro, the field of materials science and engineering has benefited from recent progress in developing compliant substrates with physical and chemical properties similar to those of biological materials. In particular, in the field of mechanobiology, soft hydrogels can now reproduce the precise range of stiffnesses of healthy and pathological tissues to study the mechanisms behind cell responses to mechanics. However, it was shown that biological tissues are not only elastic but also relax at different timescales. Cells can, indeed, perceive this dissipation and actually need it because it is a critical signal integrated with other signals to define adhesion, spreading and even more complicated functions. The mechanical characterization of hydrogels used in mechanobiology is, however, commonly limited to the elastic stiffness (Young's modulus) and this value is known to depend greatly on the measurement conditions that are rarely reported in great detail. Here, we report that a simple relaxation test performed under well-defined conditions can provide all the necessary information for characterizing soft materials mechanically, by fitting the dissipation behavior with a generalized Maxwell model (GMM). The simple method was validated using soft polyacrylamide hydrogels and proved to be very useful to readily unveil precise mechanical properties of gels that cells can sense and offer a set of characteristic values that can be compared with what is typically reported from microindentation tests.

Development of a Diagnostic Biosensor Method of Hypersensitivity Pneumonitis towards a Point-of-Care Biosensor.

In spite of a current increasing trend in the development of miniaturized, standalone point-of-care (PoC) biosensing platforms in the literature, the actual implementation of such systems in the field is far from being a reality although deeply needed. In the particular case of the population screenings for local or regional diseases related to specific pathogens, the diagnosis of the presence of specific antibodies could drastically modify therapies and even the organization of public policies. The aim of this work was to develop a fast, cost-effective detection method based on the manipulation of functionalized magnetic beads for an efficient diagnosis of hypersensitivity pneumonitis (HP), looking for the presence of anti-pigeon antigen antibodies (APAA) in a patient's serum. We presented a Diagnostic Biosensor Method (DBM) in detail, with validation by comparison with a traditional high-throughput platform (ELISA assay). We also demonstrated that it was compatible with a microfluidic chip that could be eventually incorporated into a PoC for easy and broad deployment using portable optical detectors. After standardization of the different reaction steps, we constructed and validated a plastic chip that could easily be scaled to high-volume manufacturing in the future. The solution proved comparable to conventional ELISA assays traditionally performed by the clinicians in their laboratory and should be compatible with other antibody detection directly from patient samples.

Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies.

BACKGROUND: Two recent studies, a cohort study from Denmark, and a case-control study from The Netherlands, have reported increased risks of venous thromboembolism (VTE) among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to the use of levonorgestrel. CRITIQUE: In the Danish study the comparisons were not valid. (1) VTE risk is highest soon after commencement of OC use, and duration of use was underestimated for levonorgestrel users, but not for drospirenone users; for the remaining compounds duration was only slightly underestimated. The underestimation for levonorgestrel resulted in systematic overestimation of the relative risks for the compared OCs. (2) Duration was also incorrectly estimated: only the duration of current use, not duration of all episodes of use was relevant to VTE risk. (3) Confounding was not adequately controlled. In The Netherlands study the comparisons were not valid. (1) The relative risk for drospirenone versus levonorgestrel was not statistically significant. (2) Extensive publicity had been given to the risk of VTE among users of desogestrel, gestodene, drospirenone and cyproterone: information bias and detection bias were therefore likely. (3) Inadequate allowance was made for duration of use. (4) The combination of two different control groups, both of them likely to have been biased, into a single category was not valid. CONCLUSION: The best evidence continues to suggest that the increased risk of VTE in OC users is a class effect, dependent on the estrogen dose and duration of use, and independent of the progestogen used.

Cervical human papillomavirus (HPV) infection in South African women: implications for HPV screening and vaccine strategies.

The prevalence of cervical human papillomavirus (HPV) in South African women (n = 1,073) increased from 20.4% (173/848) in women with normal cytology to 41.7% (48/115) in women with atypical squamous cells of undetermined significance, 70.2% (40/57) in women with low-grade squamous intraepithelial lesions, and 83% (44/53) in women with high-grade squamous intraepithelial lesions (HSILs). HPV types 16 and 35 were the dominant types in women with HSILs but not in women in the other categories.

Cervical human papillomavirus (HPV) infection and HPV type 16 antibodies in South African women.

There is a high incidence of cervical cancer in South African women. No large studies to assess human papillomavirus virus (HPV) infection or HPV type 16 (HPV-16) exposure have occurred in the region, a requirement for policy making with regards to HPV screening and the introduction of vaccines. Control women (n = 1,003) enrolled in a case control study of hormonal contraceptives and cervical cancer were tested for 27 cervical HPV types by reverse line blot analysis. The seroprevalence of HPV-16 immunoglobulin G (IgG) and IgA antibodies was assessed by a virus-like particle-based enzyme-linked immunoassay of 908 and 904 control women, respectively, and of 474 women with cervical cancer. The cervical HPV prevalence was 26.1%. The HPV-16 IgG seroprevalence was 44.4% and the HPV-16 IgA seroprevalence was 28.7% in control women, and these levels were significantly higher (61.8% and 52.7%, respectively) for women with cervical cancer (odds ratio [OR], 2.1 and 2.8, respectively). The cervical HPV prevalence showed an association with cervical disease, and the HPV-16 IgG prevalence decreased while the HPV-16 IgA prevalence increased with increasing age (P < 0.05). The prevalence of oncogenic HPV types (including HPV-16) decreased with age, whereas nononcogenic HPV types showed limited association with age. Multivariate analysis revealed cervical HPV infection to be associated with herpes simplex virus type 2 infection (OR, 1.7) and increasing years of education (OR, 1.9). HPV-16 IgG antibodies were inversely associated with current smoking status (OR, 0.6), and the presence of HPV-16 IgA antibodies was inversely associated with the use of alcohol (OR, 2.1) and inversely associated with the use of oral contraceptives (OR, 0.6). High levels of exposure to HPV, and particularly HPV-16, were evident in this population. The apparent increase of serum HPV-16 IgA with increasing age requires further investigation.

Determinants of sexual activity and its relation to cervical cancer risk among South African women.

BACKGROUND: Invasive cervical cancer is the commonest cause of cancer morbidity and mortality in South African women. This study provides information on adult women's sexual activity and cervical cancer risk in South Africa. METHODS: The data were derived from a case-control study of hormonal contraceptives and cervical cancer risk. Information on age of sexual debut and number of lifetime sexual partners was collected from 524 incident cases and 1541 hospital controls. Prevalence ratios and adjusted prevalence ratios were utilised to estimate risk in exposures considered common. Crude and adjusted relative risks were estimated where the outcome was uncommon, using multiple logistic regression analysis. RESULTS: The median age of sexual debut and number of sexual partners was 17 years and 2 respectively. Early sexual debut was associated with lower education, increased number of life time partners and alcohol use. Having a greater number of sexual partners was associated with younger sexual debut, being black, single, higher educational levels and alcohol use. The adjusted odds ratio for sexual debut < 16 years and >/= 4 life-time sexual partners and cervical cancer risk were 1.6 (95% CI 1.2 - 2.2) and 1.7 (95% CI 1.2 - 2.2), respectively. CONCLUSION: Lower socio-economic status, alcohol intake, and being single or black, appear to be determinants of increased sexual activity in South African women. Education had an ambiguous effect. As expected, cervical cancer risk is associated with increased sexual activity. Initiatives to encourage later commencement of sex, and limiting the number of sexual partners would have a favourable impact on risk of cancer of the cervix and other sexually transmitted infections.

HIV and pre-neoplastic and neoplastic lesions of the cervix in South Africa: a case-control study.

BACKGROUND: Cervical cancer and infection with human immunodeficiency virus (HIV) are both major public health problems in South Africa. The aim of this study was to determine the risk of cervical pre-cancer and cancer among HIV positive women in South Africa. METHODS: Data were derived from a case-control study that examined the association between hormonal contraceptives and invasive cervical cancer. The study was conducted in the Western Cape (South Africa), from January 1998 to December 2001. There were 486 women with invasive cervical cancer, 103 control women with atypical squamous cells of undetermined significance (ASCUS), 53 with low-grade squamous intraepithelial lesions (LSIL), 50 with high-grade squamous intraepithelial lesions (HSIL) and 1159 with normal cytology. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multiple logistic regression. RESULTS: The adjusted odds ratios associated with HIV infection were: 4.4 [95% CI (2.3 - 8.4) for ASCUS, 7.4 (3.5 - 15.7) for LSIL, 5.8 (2.4 - 13.6) for HSIL and 1.17 (0.75 - 1.85) for invasive cervical cancer. HIV positive women were nearly 5 times more likely to have high-risk human papillomavirus infection (HR-HPV) present compared to HIV negative women [OR 4.6 (95 % CI 2.8 - 7.5)]. Women infected with both HIV and high-risk HPV had a more than 40 fold higher risk of SIL than women infected with neither of these viruses. CONCLUSION: HIV positive women were at an increased risk of cervical pre-cancer, but did not demonstrate an excess risk of invasive cervical cancer. An interaction between HIV and HR-HPV infection was demonstrated. Our findings underscore the importance of developing locally relevant screening and management guidelines for HIV positive women in South Africa.

Graphic Depictions: Portrayals of Mental Illness in Video Games.

Although studies have examined portrayals of mental illness in the mass media, little attention has been paid to such portrayals in video games. In this descriptive study, the fifty highest-selling video games in each year from 2011 to 2013 were surveyed through application of search terms to the Wikia search engine, with subsequent review of relevant footage on YouTube. Depiction categories were then assigned based on the extent of portrayal and qualitative characteristics compared against mental illness stereotypes in cinema. Twenty-three of the 96 surveyed games depicted at least one character with mental illness. Forty-two characters were identified as portraying mental illness, with most characters classified under a "homicidal maniac" stereotype, although many characters did not clearly reflect cinema stereotypes and were subcategorized based on the shared traits. Video games contain frequent and varied portrayals of mental illness, with depictions most commonly linking mental illness to dangerous and violent behaviors.