Reasons for not Using HIV Pre-Exposure Prophylaxis (PrEP) among Gay and Bisexual Men in Australia: Mixed-Methods Analyses from a National, Online, Observational Study

Although approximately 31,000 Australian gay and bisexual men (GBM) are eligible for HIV pre-exposure prophylaxis (PrEP), only 18,500 people currently use it, indicating a need to investigate why GBM do not use it. This article uses data from a national, online, observational study. It adopts a mixed-methods analysis to responses to survey questions asking about reasons Australian GBM were not using PrEP in 2018, according to their level of HIV risk as delineated by the Australian PrEP prescribing guidelines at the time. Participants responded to check-box questions and had the option to respond to a qualitative free-text question. Results showed that just over one-fifth of men were at higher risk of HIV acquisition. Compared to lower-risk men, higher-risk men were more likely to indicate PrEP was too expensive and more likely to cite embarrassment asking for it. Reasons for not using PrEP included a lack of personal relevance, poor accessibility or knowledge, concerns about PrEP’s inability to protect against STIs, potential side effects, and a preference for condoms. We conclude that health promotion more effectively targeting GBM who may benefit the most from PrEP may be valuable

Tracking the genomic evolution of breast cancer metastasis

Therapeutic choices for metastatic tumors are, in most cases, based upon the histological and molecular analysis of the corresponding primary tumor. Understanding whether and to what extent the genomic landscape of metastasis differs from the tumors from which they originated is critical yet largely unknown. A recent report tackled this key issue by comparing the genomic and transcriptional profile of a metastatic lobular breast tumor with that of the primary tumor surgically removed 9 years earlier. The extent of the differences suggests a high degree of mutational heterogeneity between primary and metastatic lesions and indicates that significant evolution occurs during breast cancer progression

Workplace interventions for increasing standing or walking for decreasing musculoskeletal symptoms in sedentary workers

BACKGROUND: The prevalence of musculoskeletal symptoms among sedentary workers is high. Interventions that promote occupational standing or walking have been found to reduce occupational sedentary time, but it is unclear whether these interventions ameliorate musculoskeletal symptoms in sedentary workers. OBJECTIVES: To investigate the effectiveness of workplace interventions to increase standing or walking for decreasing musculoskeletal symptoms in sedentary workers. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH UPDATE, PEDro, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal up to January 2019. We also screened reference lists of primary studies and contacted experts to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-randomised controlled trials (cluster-RCTs), quasi RCTs, and controlled before-and-after (CBA) studies of interventions to reduce or break up workplace sitting by encouraging standing or walking in the workplace among workers with musculoskeletal symptoms. The primary outcome was self-reported intensity or presence of musculoskeletal symptoms by body region and the impact of musculoskeletal symptoms such as pain-related disability. We considered work performance and productivity, sickness absenteeism, and adverse events such as venous disorders or perinatal complications as secondary outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts, and full-text articles for study eligibility. These review authors independently extracted data and assessed risk of bias. We contacted study authors to request additional data when required. We used GRADE considerations to assess the quality of evidence provided by studies that contributed to the meta-analyses. MAIN RESULTS: We found ten studies including three RCTs, five cluster RCTs, and two CBA studies with a total of 955 participants, all from high-income countries. Interventions targeted changes to the physical work environment such as provision of sit-stand or treadmill workstations (four studies), an activity tracker (two studies) for use in individual approaches, and multi-component interventions (five studies). We did not find any studies that specifically targeted only the organisational level components. Two studies assessed pain-related disability. Physical work environment There was no significant difference in the intensity of low back symptoms (standardised mean difference (SMD) -0.35, 95% confidence interval (CI) -0.80 to 0.10; 2 RCTs; low-quality evidence) nor in the intensity of upper back symptoms (SMD -0.48, 95% CI -.096 to 0.00; 2 RCTs; low-quality evidence) in the short term (less than six months) for interventions using sit-stand workstations compared to no intervention. No studies examined discomfort outcomes at medium (six to less than 12 months) or long term (12 months and more). No significant reduction in pain-related disability was noted when a sit-stand workstation was used compared to when no intervention was provided in the medium term (mean difference (MD) -0.4, 95% CI -2.70 to 1.90; 1 RCT; low-quality evidence). Individual approach There was no significant difference in the intensity or presence of low back symptoms (SMD -0.05, 95% CI -0.87 to 0.77; 2 RCTs; low-quality evidence), upper back symptoms (SMD -0.04, 95% CI -0.92 to 0.84; 2 RCTs; low-quality evidence), neck symptoms (SMD -0.05, 95% CI -0.68 to 0.78; 2 RCTs; low-quality evidence), shoulder symptoms (SMD -0.14, 95% CI -0.63 to 0.90; 2 RCTs; low-quality evidence), or elbow/wrist and hand symptoms (SMD -0.30, 95% CI -0.63 to 0.90; 2 RCTs; low-quality evidence) for interventions involving an activity tracker compared to an alternative intervention or no intervention in the short term. No studies provided outcomes at medium term, and only one study examined outcomes at long term. Organisational level No studies evaluated the effects of interventions solely targeted at the organisational level. Multi-component approach There was no significant difference in the proportion of participants reporting low back symptoms (risk ratio (RR) 0.93, 95% CI 0.69 to 1.27; 3 RCTs; low-quality evidence), neck symptoms (RR 1.00, 95% CI 0.76 to 1.32; 3 RCTs; low-quality evidence), shoulder symptoms (RR 0.83, 95% CI 0.12 to 5.80; 2 RCTs; very low-quality evidence), and upper back symptoms (RR 0.88, 95% CI 0.76 to 1.32; 3 RCTs; low-quality evidence) for interventions using a multi-component approach compared to no intervention in the short term. Only one RCT examined outcomes at medium term and found no significant difference in low back symptoms (MD -0.40, 95% CI -1.95 to 1.15; 1 RCT; low-quality evidence), upper back symptoms (MD -0.70, 95% CI -2.12 to 0.72; low-quality evidence), and leg symptoms (MD -0.80, 95% CI -2.49 to 0.89; low-quality evidence). There was no significant difference in the proportion of participants reporting low back symptoms (RR 0.89, 95% CI 0.57 to 1.40; 2 RCTs; low-quality evidence), neck symptoms (RR 0.67, 95% CI 0.41 to 1.08; two RCTs; low-quality evidence), and upper back symptoms (RR 0.52, 95% CI 0.08 to 3.29; 2 RCTs; low-quality evidence) for interventions using a multi-component approach compared to no intervention in the long term. There was a statistically significant reduction in pain-related disability following a multi-component intervention compared to no intervention in the medium term (MD -8.80, 95% CI -17.46 to -0.14; 1 RCT; low-quality evidence). AUTHORS' CONCLUSIONS: Currently available limited evidence does not show that interventions to increase standing or walking in the workplace reduced musculoskeletal symptoms among sedentary workers at short-, medium-, or long-term follow up. The quality of evidence is low or very low, largely due to study design and small sample sizes. Although the results of this review are not statistically significant, some interventions targeting the physical work environment are suggestive of an intervention effect. Therefore, in the future, larger cluster-RCTs recruiting participants with baseline musculoskeletal symptoms and long-term outcomes are needed to determine whether interventions to increase standing or walking can reduce musculoskeletal symptoms among sedentary workers and can be sustained over time

Do rare variant genotypes predict common variant genotypes?

The synthetic association hypothesis proposes that common genetic variants detectable in genome-wide association studies may reflect the net phenotypic effect of multiple rare polymorphisms distributed broadly within the focal gene rather than, as often assumed, the effect of common functional variants in high linkage disequilibrium with the focal marker. In a recent study, Dickson and colleagues demonstrated synthetic association in simulations and in two well-characterized, highly polymorphic human disease genes. The converse of this hypothesis is that rare variant genotypes must be correlated with common variant genotypes often enough to make the phenomenon of synthetic association possible. Here we used the exome genotype data provided for Genetic Analysis Workshop 17 to ask how often, how well, and under what conditions rare variant genotypes predict the genotypes of common variants within the same gene. We found nominal evidence of correlation between rare and common variants in 21-30% of cases examined for unrelated individuals; this rate increased to 38-44% for related individuals, underscoring the segregation that underlies synthetic association

An improved method for undertaking limiting dilution assays for in vitro cloning of Plasmodium falciparum parasites

Abstract. Background: Obtaining single parasite clones is required for many techniques in malaria research. Cloning by limiting dilution using microscopy-based assessment for parasite growth is an arduous and labor-intensive process. An alternative method for the detection of parasite growth in limiting dilution assays is using a commercial ELISA histidine-rich protein II (HRP2) detection kit. Methods. Detection of parasite growth was undertaken using HRP2 ELISA and compared to thick film microscopy. An HRP2 protein standard was used to determine the detection threshold of the HRP2 ELISA assay, and a HRP2 release model was used to extrapolate the amount of parasite growth required for a positive result. Results: The HRP2 ELISA was more sensitive than microscopy for detecting parasite growth. The minimum level of HRP2 protein detection of the ELISA was 0.11ng/ml. Modeling of HRP2 release determined that 2,116 parasites are required to complete a full erythrocytic cycle to produce sufficient HRP2 to be detected by the ELISA. Under standard culture conditions this number of parasites is likely to be reached between 8 to 14 days of culture. Conclusions: This method provides an accurate and simple way for the detection of parasite growth in limiting dilution assays, reducing time and resources required in traditional methods. Furthermore the method uses spent culture media instead of the parasite-infected red blood cells, enabling culture to continue

Invertebrate DNA metabarcoding reveals changes in communities across mine site restoration chronosequences

Invertebrate biomonitoring can reveal crucial information about the status of restoration projects; however, it is routinely underused because of the high level of taxonomic expertise and resources required. Invertebrate DNA metabarcoding has been used to characterize invertebrate biodiversity but its application in restoration remains untested. We use DNA metabarcoding, a new approach for restoration assessment, to explore the invertebrate composition from pitfall traps at two mine site restoration chronosequences in southwestern Australia. Invertebrates were profiled using two cytochrome oxidase subunit 1 assays to investigate invertebrate biodiversity. The data revealed differences between invertebrate communities at the two mines and between the different age plots of the chronosequences. Several characteristic taxa were identified for each age within the chronosequence, including springtails within the youngest sites (Order: Collembola) and millipedes within the oldest and reference sites (Order: Julida). This study facilitates development of a molecular “toolkit” for the monitoring of ecological restoration projects. We suggest that a metabarcoding approach shows promise in complementing current monitoring practices that rely on alpha taxonomy

Identity-by-descent filtering as a tool for the identification of disease alleles in exome sequence data from distant relatives

Large-scale, deep resequencing may be the next logical step in the genetic investigation of common complex diseases. Because each individual is likely to carry many thousands of variants, the identification of causal alleles requires an efficient strategy to reduce the number of candidate variants. Under many genetic models, causal alleles can be expected to reside within identity-by-descent (IBD) regions shared by affected relatives. In distant relatives, IBD regions constitute a small portion of the genome and can thus greatly reduce the search space for causal alleles. However, the effectiveness of this strategy is unknown. We test the simulated mini-exome data set in extended pedigrees provided by Genetic Analysis Workshop 17. At the fourth- and fifth-degree level of relatedness, case-case pairs shared between 1% and 9% of the genome identical by descent. As expected, no genes were shared identical by descent by all case subjects, but 43 genes were shared by many case subjects across at least 50 replicates. We filtered variants in these genes based on population frequency, function, informativeness, and evidence of association using the family-based association test. This analysis highlighted five genes previously implicated in triglyceride, lipid, and cholesterol metabolism. Comparison with the list of true risk alleles revealed that strict IBD filtering followed by association testing of the rarest alleles was the most sensitive strategy. IBD filtering may be a useful strategy for narrowing down the list of candidate variants in exome data, but the optimal degree of relatedness of affected pairs will depend on the genetic architecture of the disease under study

Next-generation sequencing

Next-generation sequencing (also known as massively parallel sequencing) technologies are revolutionising our ability to characterise cancers at the genomic, transcriptomic and epigenetic levels. Cataloguing all mutations, copy number aberrations and somatic rearrangements in an entire cancer genome at base pair resolution can now be performed in a matter of weeks. Furthermore, massively parallel sequencing can be used as a means for unbiased transcriptomic analysis of mRNAs, small RNAs and noncoding RNAs, genome-wide methylation assays and high-throughput chromatin immunoprecipitation assays. Here, I discuss the potential impact of this technology on breast cancer research and the challenges that come with this technological breakthrough