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This contribution investigates gains in technical economy in measuring language ability by considering one recurrent interest of JD Brown: cloze tests. In the various versions of the Test of Academic Literacy Levels (TALL), its Sesotho and Afrikaans (Toets van Akademiese Geletterdheidsvlakke -- TAG) counterparts, as well as related other tests used in South Africa, the test designers have used a modification of this procedure to very good effect. This paper reports on the steady evolution of its format over many years, how it is currently used, what its outstanding empirical properties are, and how the kind of technical economy it brings to the measurement of the ability to handle the demands of academic language at the level of tertiary education can be further applied. The modification involves the conventional, more or less systematic mutilation of a selected text, with two multiple choice questions about every gap in it: where the gap is, and which word has been omitted. We have not seen anywhere else analyses of this format, which in itself may be of interest to test designers. We proceed by defining technical economy, and then develop an argument on the basis of the empirical properties of TALL on how that idea can be applied, in particular to the design and task selection of such tests, before giving illustrations of how such choices may contribute to further and other productive and responsible designs and test formats.

In the context of policy-driven language testing for citizenship, a growing body of research examines the political justifications and ethical implications of language requirements and test use. However, virtually no studies have looked at the role that language testers play in the evolution of language requirements. Critical gaps remain in our understanding of language testers' first-hand experiences interacting with policymakers and how they perceive the use of tests in public policy. We examined these questions using an exploratory design and semi-structured interviews with 28 test executives representing 25 exam boards in 20 European countries. The interviews were transcribed and double coded in NVivo (weighted kappa = 0.83) using a priori and inductive coding. We used a horizontal analysis to evaluate responses by participant and a vertical analysis to identify between-case themes. Findings indicate that language testers may benefit from policy literacy to form part of policy webs wherein they can influence instrumental decisions concerning language in migration policy.

In recent years a number of discussions have sustained the debate on the def of applied linguistics, a debate which addresses both ends of the spectrum of applied linguistic work: the philosophical and the practical. This paper attempts to situate its response to such (re)considerations within an interpretative framework, considering the conception of the discipline as it has evolved over five generations. The argument of the paper is that the many and varied understandings of applied linguistic work during this period confirm the relativity of the discipline and prevent its practitioners from entertaining the illusion that, because they are involved in 'applied science', theit particular response to a language problem will provide a full and finite solution.

Abstract Purpose Our objective was to assess the association between state policies related to sexual orientation and gender identity (SOGI) and cancer prevalence and survivorship indicators in a sexual and gender minoritized (SGM) population in the United States. Methods Data from the 2017–2021 Behavioral Risk Factor Surveillance System were used to measure cancer diagnosis, physical and mental health, and substance use for SGM adult cancer survivors. A state policy Z‐score, ranging from most restrictive to most protective state policies related to SOGI, was computed from data available from the Movement Advancement Project. Survey‐weighted logistic regression was used to test the relationship between state policies and cancer‐related outcomes for SGM people. Results More protective state policies were associated with lower odds of a cancer diagnosis (adjusted odds ratio [AOR]: 0.92; 95% confidence interval [CI]: 0.87–0.97). Among SGM cancer survivors, increasing protective state policies were associated with lower odds of poor physical health (AOR: 0.83; 95% CI: 0.74–0.94), lower odds of difficulty walking or climbing stairs (AOR: 0.90; 95% CI: 0.80–1.00), and lower odds of difficulty concentrating or remembering (AOR: 0.87; 95% CI: 0.78–0.98). No significant associations were found between state policies and mental health, depression, substance use, diabetes, or cardiovascular disease among SGM cancer survivors. Conclusion SGM people diagnosed with cancer are more likely to live in restrictive policy states, and survivors in those states have worse physical health and cognitive disability. Additional research should investigate potential causal relationships between state policies and SGM cancer outcomes.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials: hazard ratio (HR) = 2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR = 1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR = 5.1 (95% CI: 1.6, 8.7); transported: HR = 5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

Abstract Background HCV self-testing (HCVST) may be an effective strategy to address low rates of HCV test uptake among men who have sex with men (MSM). We evaluated the effectiveness and cost of providing HCVST to increase HCV test uptake among MSM in China. Methods Two parallel, unmasked, individual-level randomized controlled trials were conducted. HIV-negative MSM and MSM living with HIV were enrolled from 22 cities in China. Men in both trials were randomly assigned (1:1) into standard-of-care (SOC) or HCVST arms. The primary outcome was the proportion of participants who tested for HCV during the trial period. Intervention effects were estimated using multiply imputed data in the main analysis. Costs were measured using a micro-costing approach. Results A total of 84 men who were HIV-negative (trial 1) and 84 men living with HIV were enrolled (trial 2). Overall, the proportion of individuals who underwent HCV testing during the trial period was higher in the HCVST arm compared to SOC in trial 1 (estimated risk difference (RD): 71.1%, 95% CI: 54.6 to 87.7%) and trial 2 (estimated RD: 62.9%, 95% CI: 45.7 to 80.1%). Over half (58.6%, 34/58) of HCV self-testers reported the self-test was their first HCV test. The cost per person tested in trial 1 was $654.52 for SOC and $49.83 for HCVST, and in trial 2 was $438.67 for SOC and $53.33 for HCVST. Conclusions Compared to the standard of care, providing HCVST significantly increased the proportion of MSM testing for HCV in China, and was cheaper per person tested. Trial registration Chinese Clinical Trial Registry. Registration number: ChiCTR2100048379.

This paper will deal, firstly, with the South African context, that cries out for attention to responsible language assessment. The renewed interest in language testing in South Africa is well illustrated in assessments of language ability for educational purposes generally, and more specifically in the assessment of academic literacy. Secondly, the paper presents a meaningful reminder that the assessment of academic literacy in South Africa brings: the benefits of paying diligent attention to the articulation of the construct. This is evident both in the descriptions of the major themes in language assessment in South Africa, and in some commentaries in the international literature about developments here. Finally, the paper describes the way that we are starting to deal with the validation of language tests from the vantage point of a theory of applied linguistics, rather than from the sometimes inconclusive debates on validity. In all three respects, there may be productive insights for those working in other contexts. The most important insight, perhaps, comes from relating the validation of these assessments to a theory of applied linguistics, indicating a way in which test designers may operationalize and satisfy a number of further conditions for their responsible design of language tests.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

Alzheimer’s disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.

HIV-associated Kaposi’s sarcoma (KS), which is caused by Kaposi’s sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally occurs in individuals with durable HIV viral suppression and CD4 T cell recovery under antiretroviral therapy (ART). The underlying mechanisms associated with this phenomenon are unclear. Suppression of viral infections can be mediated by CD8 T cells, which detect infected cells via their T cell receptor and the CD8 coreceptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 (“CD8dim T cells”) was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial alterations (PGC-1α, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS disease under ART. CD8 coreceptor down-modulation may be symptomatic of ongoing disease.

Test validation may more aptly be conceived of as the process of designing language tests responsibly. While a good test gains in reputation as it is administered over time, the early stages of its validation are perhaps the most critical. There is now general agreement that the validation process should be reported in the form of an argument that brings together multiple sets of evidence to justify the design and implementation of the measurement instrument, the language test. The format of such integration is, however, still contestable ground. Referring to an example of language test design and development, this paper seeks to demonstrate how a framework for responsible test design may be employed to achieve such an integrated argument, as well as how two of the methodological tools most frequently employed to muster empirical evidence for validating test design, namely classical test theory (CTT) and Rasch analyses, complement each other in designing tests responsibly. While most language tests designed in South Africa have used CTT, the employment of Rasch analyses has been more limited. A secondary aim of the paper is therefore to provide applied linguists who work in the subfield of language testing with an example of how the latter kind of analysis can complement the former. In all, however, these disparate approaches must be integrated into the theoretical justification for the development of language tests, in order to satisfy a number of conditions for their responsible design.

Background Recent data indicate that the three-month prevalence of severe headaches or migraines in the US general population is close to 25%. Participation of primary care providers will therefore be critical in providing care to affected individuals. Objective To determine the number of headache disorder consult requests to a neurology outpatient service in a tertiary medical center, the appropriateness of the consult requests, and the effectiveness of a lecture series on headache diagnosis and management in preventing inappropriate consult requests from non-neurology providers. Methods Clinical data on US Veterans is captured and documented in the Veterans Health Information Systems and Technology Architecture (VISTA). The Computerized Patient Record System (CPRS) electronic medical record (EMR) was used for data entry and retrieval. All consult requests for the study period within the VA North Texas Health Care System were identified in VISTA, and the clinical information reviewed in CPRS. Based on a defined algorithm, headache consult request were categorized as appropriate or inappropriate. A board-certified neurologist provided four in-person/virtual lectures to ambulatory care providers, primary care providers, internal medicine residents, and emergency room providers within the VA North Texas Health Care System on the diagnosis and management of headaches. Prior and post the lecture series, the total number of headache consults per day was assessed over 45-day periods. Results The number of daily headache consult requests in the 45-day period prior to the lecture series was 3.6 per day (standard deviation 2.7), and 6.0 per day after the lecture series (standard deviation 2.1). The difference was not statistically significant. There were as many inappropriate headache consult requests after the lecture series as appropriate ones (50% each). Conclusion We found that a short-term educational initiative that instructed primary care providers on the diagnosis and management of common headache disorders did not reduce the number of consultation requests and, surprisingly, it did not improve the appropriateness of the consults. Given the prevalence of headaches in the general population, better training of all primary care providers in headache management should be pursued.

Introduction: The pressure on universities worldwide has increased to transform themselves from isolated educational institutions to profit-generating businesses. The visibility of a Web page plays a role in attracting potential clients, as more and more young users are depending on the Web for their everyday information needs. One of the purposes of this study was to evaluate the visibility of homepages of top UK universities, and rank them. Secondly, the existence of a correlation between Website visibility ranking and academic ranking was investigated. The goal of this research was to provide a repeatable method of measuring university Website visibility, and for comparison with measurement of other institutes' Websites. Method: Website visibility elements were identified, and content investigation used to rank them according to an academic model. A scoring system was designed to cater for subjective measurements, producing a ranked list of university homepages. This was compared to an industry standard academic ranking for UK universities. Results and Analysis: Five sub-lists provided a wide span of resulting scores, combined into the final result list. In some cases it was clear that homepages were designed based on good practice (Universities of Liverpool and Cambridge), while in others little or no effort was expended to achieve a high degree of visibility. There was no correlation between the two types of ranking. Conclusions: Website visibility is a design feature often ignored in the design of university homepages in the UK, which could lead to missed opportunities. Guidelines are provided to improve this situation.

This article presents three cases of community-engaged, or "public," scholarship across diverse disciplines (social science, natural science, and health science) in which the rigid boundaries of what has been conceived as traditional service-learning have been blurred. The innovations represented within these cases explicitly address discipline-specific knowledge and civic skills acquisition. Moreover, they do so in ways that encourage the integration of scholarship, service, teaching, and learning. We argue that civic learning can be authentically realized through the synthesis of disciplinary content and civic sensibilities; integration of teaching, learning, research, and service; and by organizing our efforts around community problems (rather than organizing around specific pedagogical or research methods).

Background/Aims Safety for tumor necrosis factor inhibitors (TNFi) in cancer has been focused on risk of incident malignancies, but studies on prognostic effects have been scarce. We determined survival and recurrence rates at 1, 2, and 5 years after cancer diagnosis in patients with and without concurrent TNFi use. Methods Chart reviews were performed between 1996 and 2015 at the VA North Texas Healthcare System. Cases were patients with inflammatory disease, concomitant malignancy, and TNFi use while controls were patients with inflammatory disease, concomitant malignancy but no TNFi use. Cases and controls were matched for type of malignancy. Analysis was performed with log-rank tests on Kaplan-Meier curves. Results Thirty-six cases and 72 controls were identified. For cases, survival at 1, 2, and 5 years were 32 (89%), 31 (86%), and 29 (81%) compared to 63 (90%), 61 (87%), and 51 (73%) for the control group (P=0.985). For cases, recurrence rates at 1, 2, and 5 years were 3 (8%), 5 (14%), and 6 (17%) compared to 2 (3%), 5 (7%), and 7 (10%) for the control group (P=0.158). Conclusions Our findings suggest TNFi may be safely used in select inflammatory disease patients with concurrent cancer if therapy is needed for proper disease control. However, case-by-case consideration in conjunction with an oncologist is recommended while considering the apparent safety of TNFi for patients suffering from active inflammatory diseases despite having a concomitant malignancy.

The human immunodeficiency virus (HIV)-1 viral inhibition assay (VIA) measures CD8+ T cell-mediated inhibition of HIV replication in CD4+ T cells and is increasingly used for clinical testing of HIV vaccines and immunotherapies. Different VIAs that differ in length of CD8:CD4 T cell culture periods (6–13 days), purity of CD4 cultures [isolated CD4+ T cells or CD8+ depleted peripheral blood mononuclear cells (PBMCs)], HIV strains (laboratory strains, isolates, reporter viruses) and read-outs of virus inhibition (p24 ELISA, intracellular measurement of p24, luciferase reporter expression, and viral gag RNA) have been reported.Here, we describe multiple modifications to a 7-day VIA protocol, the most impactful being the introduction of independent replicate cultures for both HIV infected-CD4 (HIV-CD4) and HIV-CD4:CD8 T cell cultures. Virus inhibition was quantified using a ratio of weighted averages of p24+ cells in replicate cultures and the corresponding 95% confidence intervals. We identify methodological and analysis changes that could be incorporated into other protocols to improve assay reproducibility. We found that in people living with HIV (PLWH) on antiretroviral therapy (ART), CD8 T cell virus inhibition was largely stable over time, supporting the use of this assay and/or analysis methods to examine therapeutic interventions.Graphic abstract:

BackgroundLow syphilis testing uptake is a major public health issue among men who have sex with men (MSM) in many low- and middle-income countries. Syphilis self-testing (SST) may complement and extend facility-based testing. We aimed to evaluate the effectiveness and costs of providing SST on increasing syphilis testing uptake among MSM in China.Methods and findingsAn open-label, parallel 3-arm randomized controlled trial (RCT) was conducted between January 7, 2020 and July 17, 2020. Men who were at least 18 years of age, had condomless anal sex with men in the past year, reported not testing for syphilis in the last 6 months, and had a stable residence with mailing addresses were recruited from 124 cities in 26 Chinese provinces. Using block randomization with blocks of size 12, enrolled participants were randomly assigned (1:1:1) into 3 arms: standard of care arm, standard SST arm, and lottery incentivized SST arm (1 in 10 chance to win US$15 if they had a syphilis test). The primary outcome was the proportion of participants who tested for syphilis during the trial period and confirmed with photo verification and between arm comparisons were estimated with risk differences (RDs). Analyses were performed on a modified intention-to-treat basis: Participants were included in the complete case analysis if they had initiated at least 1 follow-up survey. The Syphilis/HIV Duo rapid test kit was used. A total of 451 men were enrolled. In total, 136 (90·7%, 136/150) in the standard of care arm, 142 (94·0%, 142/151) in the standard of SST arm, and 137 (91·3%, 137/150) in the lottery incentivized SST arm were included in the final analysis. The proportion of men who had at least 1 syphilis test during the trial period was 63.4% (95% confidence interval [CI]: 55.5% to 71.3%, p = 0.001) in the standard SST arm, 65.7% (95% CI: 57.7% to 73.6%, p = 0.0002) in the lottery incentivized SST arm, and 14.7% (95% CI: 8.8% to 20.7%, p < 0.001) in the standard of care arm. The estimated RD between the standard SST and standard of care arm was 48.7% (95% CI: 37.8% to 58.4%, p < 0.001). The majority (78.5%, 95% CI: 72.7% to 84.4%, p < 0.001) of syphilis self-testers reported never testing for syphilis. The cost per person tested was US$26.55 for standard SST, US$28.09 for the lottery incentivized SST, and US$66.19 for the standard of care. No study-related adverse events were reported during the study duration. Limitation was that the impact of the Coronavirus Disease 2019 (COVID-19) restrictions may have accentuated demand for decentralized testing.ConclusionsCompared to standard of care, providing SST significantly increased the proportion of MSM testing for syphilis in China and was cheaper (per person tested).Trial registrationChinese Clinical Trial Registry: ChiCTR1900022409.

Introduction: In this research project, an empirical pilot study on the relationship between JavaScript™ usage and Website visibility was carried out. The main purpose was to establish whether JavaScript™- based hyperlinks attract or repel crawlers, resulting in an increase or decrease in Website visibility. Method: A literature survey has established that there appears to be contradiction amongst claims by various authors as to whether or not crawlers can parse or interpret JavaScript™. The chosen methodology involved the creation of a Website that contains different kinds of links to other pages, where actual data files were stored. Search engine crawler visits to the page pointed to by the different kinds of links were monitored and recorded. Analysis: This experiment took into account the fact that JavaScript™ can be embedded within the HTML of a Web page or referenced as an external ".js" file. It also considered different ways of specifying links within JavaScript™. Results: The results obtained indicated that text links provide the highest level of opportunity for crawlers to discover and index non-homepages. In general, crawlers did not follow Javascript™-based links to Web pages blindly. Conclusions: Most crawlers evade Javascript™ links, implying that Web pages using forms of this technology, for example in pop-up/pull-down menus, could be jeopardising their chances of achieving high search engine rankings. Certain Javascript™ links were not followed at all, which has serious implications for designers of e-Commerce Websites.

No abstract available.

Abstract Background Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman’s familial BC risk. Methods Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm. Results We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85–1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92–1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07–1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80–1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (p interaction = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers. Conclusions Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA

Abstract Background The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers. Methods We analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically). Results From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33–1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57–0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15–0.97; combined HR = 0.29; 95% CI = 0.23–0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age. Conclusion Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk.

The management of language diversity and the mastery of language required by educational institutions affect those institutions from early education through to higher education. This paper will deal with three dimensions of how language is managed and developed in education. The first is the design of interventions for educational environments at policy level, as well as for instruction and for language development. The second dimension concerns defining the kind of competence needed to handle the language demands of an academic institution. The interventions can be productive if reference is made throughout to the conditions or design principles that language policies and language courses must meet. The third dimension concerns meeting an important requirement: the alignment of the interventions of language policy, language assessment and language development (and the language instruction that supports the latter). The paper will use a widely used definition of academic literacy to illustrate how this supports the design of language assessments and language courses. It is an additional critical condition for effective intervention design that assessments and language instruction (and development) work together in harmony. Misalignment among them is likely to affect the original intention of the designs negatively. Similarly, if those interventions are not supported by institutional policies, the plan will have little effect. The principle of alignment is an important, but not the only design condition. The paper will therefore conclude with an overview of a comprehensive framework of design principles for language artefacts that may serve to enhance their responsible design.

In an age of “Big Data” the study of the history and archaeology of religion faces an exponentially increasing quantity and range of data and scholarly interpretation. For the student and scholar alike, new tools that allow for efficient and accurate inquiry are a necessity. Here, the open-access and digital Database of Religious History (DRH) is presented as one such tool that addresses this need and is well suited for use in the classroom. In this article, we present the basic structure of the database along with a demonstration of its potential use. Following a thematic inquiry into questions concerning “high gods”, individual disciplinary-specific case studies examine applications to particular contexts across time and space. These case studies demonstrate the ways in which the DRH can test and disrupt ontologies through its ability to efficiently cross traditional disciplinary boundaries.

The HIV-1 viral inhibition assay (VIA) measures CD8 T cell-mediated inhibition of HIV replication in CD4 T cells and is increasingly used for clinical testing of HIV vaccines and immunotherapies. The VIA has multiple sources of variability arising from in vitro HIV infection and co-culture of two T cell populations. Here, we describe multiple modifications to a 7-day VIA protocol, the most impactful being the introduction of independent replicate cultures for both HIV infected-CD4 (HIV-CD4) and HIV-CD4:CD8 T cell cultures. Virus inhibition was quantified using a ratio of weighted averages of p24+ cells in replicate cultures and the corresponding 95% confidence interval. An Excel template is provided to facilitate calculations. Virus inhibition was higher in people living with HIV suppressed on antiretroviral therapy (n=14, mean: 40.0%, median: 43.8%, range: 8.2 to 73.3%; p < 0.0001, two-tailed, exact Mann-Whitney test) compared to HIV-seronegative donors (n = 21, mean: -13.7%, median: -14.4%, range: -49.9 to 20.9%) and was stable over time (n = 6, mean %COV 9.4%, range 0.9 to 17.3%). Cross-sectional data were used to define 8% inhibition as the threshold to confidently detect specific CD8 T cell activity and determine the minimum number of culture replicates and p24+ cells needed to have 90% statistical power to detect this threshold. Last, we note that, in HIV seronegative donors, the addition of CD8 T cells to HIV infected CD4 T cells consistently increased HIV replication, though the level of increase varied markedly between donors. This co-culture effect may contribute to the weak correlations observed between CD8 T cell VIA and other measures of HIV-specific CD8 T cell function.

From a practice point of view it seems as if there are certain factors that might contribute to the fact that emerging adults tend to negate therapeutic help and services. It also seems to be specifically true with regard to emerging adults at university. Help negation seems to occur albeit the fact that therapeutic intervention is seen as an effective tool in managing distress. The aim of the study therefore was to explore which factors contribute to help negation behaviour in emerging adults at a specific university in South Africa. A qualitative case study design was employed where participants who complied with the inclusion criteria set out for the study, were selected by means of non-probability target and snowball sampling. Fifteen students residing in campus residences respectively participated in one of three focus group discussions. Creswell's spiral of data analysis was used to analyse the transcribed data. The data crystallised into four themes, which contribute to help negation behaviour in emerging adults. Emerging adults have a fear of being judged, stigmatised, recognised, of not being treated confidentially and a fear of being vulnerable and hurt. They prefer to seek help and support from their family and peers and to put their trust in God and their religion; they have internalised beliefs about themselves and therapy and a need for independence; student interns work at the therapeutic centres on campus which specifically contributes to help negation for emerging adults at the university. It is crucial that the professionals revisit their strategies and approaches in order to overcome negation of formal help and create a more understandable, approachable and effective therapeutic service to emerging adults, especially at university therapeutic centres.

The aim of this study was to describe the type of risk-reducing gynaecologic surgery (RRGS) and the extent of pathological evaluation being undertaken for Australasian women at high familial risk of pelvic serous cancer. Surgical and pathology reports were reviewed for women with BRCA1/BRCA2 mutations, or a family history of breast and ovarian cancer, who underwent RRGS between 1998 and 2008. "Adequate" surgery was defined as complete removal of all ovarian and extra-uterine fallopian tube tissue. "Adequate" pathology was defined as paraffin embedding of all removed ovarian and tubal tissue. Predictors of adequacy were assessed using logistic regression. There were 201 women, including 173 mutation carriers, who underwent RRGS. Of these, 91% had adequate surgery and 23% had adequate pathology. Independent predictors of adequate surgery were surgeon type (OR = 20; 95% CI 2-167; P = 0.005 for gynaecologic oncologists versus general gynaecologists), more recent surgery (OR = 1.33/year; 95% CI 1.07-1.67; P = 0.012) and younger patient age (OR = 0.93/year of age; 95% CI 0.87-0.99; P = 0.028). Independent predictors of adequate pathology were more recent surgery (OR = 1.26/year; 95% CI 1.06-1.49; P = 0.008) and surgeon type (OR = 3.1; 95% CI 1.4-6.7; P = 0.004 for gynaecologic oncologists versus general gynaecologists). Four serous ovarian cancers and one endometrioid endometrial cancer were detected during surgery or pathological examination. In conclusion Australasian women attending a specialist gynaecologic oncologist for RRGS are most likely to have adequate surgery and pathological examination. Additional education of clinicians and consumers is needed to ensure optimal surgery and pathology in these women.

Most studies report the abundance of plastic items in the environment, but mass is an equally important currency for monitoring plastic pollution, particularly given attempts to balance the global plastic budget. We determined the size/mass composition of litter stranded on a remote, infrequently-cleaned sandy beach on the west coast of South Africa. Traditional surveys of superficial macro-litter were augmented by sieved transects for buried macro-litter (8-mm mesh), meso-litter (2-mm mesh) and sediment cores for micro-litter. Aggregating the data across all sampling scales, the total density was ∼1.9 × 105 anthropogenic particulate pollutants per linear meter of beach, 99.7% of which were microfibers (most of which are likely not ‘plastic’). Plastics comprised 99.6% of beach macro- and meso-litter by number and 89% by mass. Small items dominated samples numerically, but were trivial relative to larger items in terms of their mass. Buried litter accounted for 86% of macro-plastic items, but only 5% of the mass of macro-plastics, because smaller items are buried more easily than large items. The total density of plastic (∼1.2 kg⋅m–1), at least half of which was from fisheries and shipping, is much lower than predicted by global models of plastic leakage from land-based sources. Ongoing degradation of plastic items already in the environment, particularly on beaches, is likely to result in a marked increase in plastic fragments, even if we stop leaking additional plastic. The collection of large items from beaches is a useful stop-gap measure to limit the formation of micro-plastics while we formulate effective steps to prevent plastic leakage into the environment.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Background: Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer’s disease (AD). Materials and methods: Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates. Results: Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84–1.20, p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09–0.68, p