Molecular triage on HPV-positive samples in a cervical screening setting

by Gabriella Lillsunde Larsson, Jessica Carlsson, Gisela Helenius, Lovisa Bergengren

Objective

To improve human papilloma virus (HPV) screening, more effective triage methods for HPV-positive samples need development and validation. Cytology, the most common triage method today, is subjective and can only be applied to professionally collected samples. Methylation status has been shown to be informative, as genes are highly methylated in HPV-induced cervical dysplasia and cancer. This study aimed to assess whether triaging HPV-positive samples using molecular methods, such as methylation and genotyping for high-risk HPV types, could be as effective as cytology in cervical screening.

Methods

A retrospective biobank study was conducted on HPV-positive samples collected in 2017–2018, analyzing FAM19A4/MiR-124-2 hypermethylation and HPV genotyping for types 16, 18, 31, 33, 45, 52, and/or 59, comparing these results to cytology triage for detecting histologically confirmed high-grade squamous intraepithelial lesions (HSIL) and cancer.

Results

Results from 1915 positive screening samples were analyzed, including 1052 follow-up biopsies with 402 HSIL or cancer cases. Genotyping showed slightly higher sensitivity than cytology but lower specificity, while methylation had higher specificity but much lower sensitivity. Cytology’s positive predictive value (PPV) was 36%, with lower PPVs for the molecular methods. Combining molecular methods increased the PPV but significantly reduced sensitivity.

Conclusions

Based on these findings with molecular methods reducing sensitivity, we do not recommend adopting the molecular triage methods evaluated in this study in the Swedish setting. The trade-off between sensitivity and specificity does not support a change from the current cytology-based triage approach.

Reassigning sources of misophonic trigger sounds to change their unpleasantness: Testing alternative mechanisms with a new set of movies, paintings, and words

by Laurie M. Heller, Urszula Oszczapinska, Jessica M. Smith, Megan M. Julien

We conducted nine experiments to determine why a sound’s pleasantness can be altered by movies, abstract paintings, and words. In Expt. 1, unpleasant sounds, such as the sound of a person sniffing, were paired either with their original video track or with video tracks depicting neutral events that could plausibly have produced the sound, such as pulling tissues out of a tissue box. While the unpleasant sounds were mildly unpleasant to an unscreened population, these sounds were expected to be more unpleasant for people who have misophonia, a condition in which certain everyday sounds are unbearable. Consistent with past literature, neutral video tracks increased the sounds’ pleasantness for the non-misophonic and misophonic populations, by 0.98 and 1.59 points, respectively (on an 11-point scale). Movies rated as having better audio-visual matches produced greater changes in pleasantness, consistent with the hypothesis that source reassignment caused the changes. Expt. 2 found a consistent result when the video tracks were replaced with written event descriptions, although the effect size was reduced. Expt. 3 inverted Expt. 1 and found that unpleasant video tracks decreased the pleasantness of neutral sounds by 2.12 points, but better-matching movies did not produce greater changes in pleasantness. In Expts. 4–6, we sought an alternative to the source reassignment explanation by obtaining ratings of audio-visual synchrony, cross-modal agreement in symbolism, source plausibility, and sound identifiability. No complete explanation was found for the effect of unpleasant videos. Furthermore, pleasant abstract paintings increased the pleasantness of unpleasant sounds by 0.37 points, correlating with cross-modal agreement but not with audio-visual match. Taken together, different types and patterns of match ratings can help discern the causal mechanisms by which visual stimuli affect sound pleasantness (e.g., source reassignment, cross-modal agreement).

Fat-tail allele-specific expression genes may affect fat deposition in tail of sheep

by Hossein Mansourizadeh, Mohammad Reza Bakhtiarizadeh, Luciana Correia de Almeida Regitano, Jennifer Jessica Bruscadin

Different sheep breeds show distinct phenotypic plasticity in fat deposition in the tails. The genetic background underlying fat deposition in the tail of sheep is complex, multifactorial, and may involve allele-specific expression (ASE) mechanism to modulate allelic expression. ASE is a common phenomenon in mammals and refers to allelic imbalanced expression modified by cis-regulatory genetic variants that can be observed at heterozygous loci. Therefore, regulatory processes behind the fat-tail formation in sheep may be to some extent explained by cis- regulatory variants, through ASE mechanism, which was investigated in the present study. An RNA-Seq-based variant calling was applied to perform genome-wide survey of ASE genes using 45 samples from seven independent studies comparing the transcriptome of fat-tail tissue between fat- and thin-tailed sheep breeds. Using a rigorous computational pipeline, 115 differential ASE genes were identified, which were narrowed down to four genes (LPL, SOD3, TCP1 and LRPAP1) for being detected in at least two studies. Functional analysis revealed that the ASE genes were mainly involved in fat metabolism. Of these, LPL was of greater importance, as 1) observed in five studies, 2) reported as ASE gene in the previous studies and 3) with a known role in fat deposition. Our findings implied that complex physiological traits, like fat-tail formation, can be better explained by considering various genetic mechanisms, which can be more finely mapped through ASE analyses. The insights gained in this study indicate that biallelic expression may not be a common mechanism in sheep fat-tail development. Hence, allelic imbalance of the fat deposition-related genes can be considered a novel layer of information for future research on genetic improvement and increased efficiency in sheep breeding programs.

Questionnaires of self-perception poorly correlate with instability elicited by walking balance perturbations

by Andrew D. Shelton, Jessica L. Allen, Vicki S. Mercer, Jeremy R. Crenshaw, Jason R. Franz

Rehabilitation to prevent falls should not only directly address intrinsic and extrinsic factors, but also the neuropsychology of falls to promote safe and independent mobility in our aging population. The purpose of this study was to determine the relation between falls self-efficacy and objective responses to a series of walking balance perturbations. 29 healthy younger adults and 28 older adults completed four experimental trials, including unperturbed walking and walking while responding to three perturbations: mediolateral optical flow, treadmill-induced slips, and lateral waist-pulls; and three self-reported questionnaires: Activity-specific Balance Confidence, Falls Efficacy Scale, and the Fear of Falling Questionnaire-Revised. We quantified stabilizing responses as a change in margin of stability from unperturbed walking. Older adults generally exhibited larger instability than younger adults in response to walking balance perturbations. Only the Fear of Falls Questionnaire-Revised showed an increase in perceived falls risk for older adults. We found no significant correlations for older adults between any balance perturbation response and questionnaires of self-perception. Given the disconnect between self-perceived falls risk and responses to walking balance perturbations, rehabilitation to prevent falls while maintaining mobility and independence will likely require personalized techniques that combine neuromuscular training with approaches for neurophysiological reeducation.