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Fawaz Y Azizieh,1 Khulood O Alyahya,2 Kamaludin Dingle1 1Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, International Centre for Applied Mathematics and Computational Bioengineering, West Mishref, Kuwait; 2Science Department, College of Basic Education, Public Authority for Applied Education and Training, Kuwait City, Kuwait Background: Although a large number of studies have investigated possible relationships among serum levels of vitamin D or cytokines with disease progress and prognosis, similar studies on self-reported symptoms are still controversial. The overall objective of this study was to look into the association between serum levels of vitamin D or cytokines with self-reported symptoms related to musculoskeletal pain, sleep disorders, and premenstrual syndrome (PMS) in healthy adult women.Subjects and methods: Venous blood samples were collected from 117 healthy adult women, and serum levels of vitamin D, pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) were measured. Groups were tested for differences in single parameters, pro-:anti-inflammatory cytokine ratios, and differences in multivariate patterns.Results: There were no significant associations between serum levels of vitamin D and any of the self-reported symptoms studied. However, serum levels of certain pro-inflammatory cytokines were significantly higher in subjects with musculoskeletal pain (IL-8, P=0.008), sleep disorders (IFN-γ, P=0.02), and PMS (IL-8 and TNF-α, P=0.009 and 0.002, respectively) compared to subjects who reported no symptoms. The pro-:anti-inflammatory cytokine ratios showed pro-inflammatory cytokine dominance in subjects with self-reported symptoms, particularly in the groups with deficient levels of vitamin D. However, the multivariate cytokine-pattern analysis was significantly different between PMS groups only.Conclusion: These data point to a possible role of pro-inflammatory cytokines as a contributing factor in self-reported symptoms related to musculoskeletal pain, sleep disorders, and PMS. Keywords: vitamin D, cytokines, adult women, self-reported symptoms, inflammation

Thi-My-Uyen Nguyen,1 Esther TL Lau,1,3 Kathryn J Steadman,1 Julie AY Cichero,1 Kaeleen Dingle,2 Lisa M Nissen1,3 1School of Pharmacy, University of Queensland, Brisbane, QLD, Australia; 2School of Public Health, Queensland University of Technology, Brisbane, QLD, Australia; 3School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia Background: People often modify oral solid dosage forms when they experience difficulty swallowing them. Modifying dosage forms may cause adverse effects to the patient, and the person undertaking the modification. Pharmacists are often the first point of contact for people in the general community seeking advice regarding medications. Nurses are at the forefront of administering medications to patients and are likely to be most directly affected by a patient’s swallowing ability, while general practitioners (GPs) are expected to consider swallowing abilities when prescribing medications. Objective: To compare the perspectives and experiences of GPs, pharmacists, and nurses regarding medication dosage form modification and their knowledge of medication modification. Method: Questionnaires tailored to each profession were posted to 630 GPs, and links to an online version were distributed to 2,090 pharmacists and 505 nurses. Results: When compared to pharmacists and GPs, nurses perceived that a greater proportion of the general community modified solid dosage forms. Pharmacists and GPs were most likely to consider allergies and medical history when deciding whether to prescribe or dispense a medicine, while nurses’ priorities were allergies and swallowing problems when administering medications. While nurses were more likely to ask their patients about their ability to swallow medications, most health professionals reported that patients “rarely” or “never” volunteered information about swallowing difficulties. The majority of health professionals would advise a patient to crush or split noncoated non-sustained-release tablets, and would consult colleagues or reference sources for sustained-release or coated tablets. Health professionals appeared to rely heavily upon the suffix attached to medication names (which suggest modified release properties) to identify potential problems associated with modifying medications. Conclusion: The different professional roles and responsibilities of GPs, pharmacists, and nurses are associated with different perspectives of, and experiences with, people modifying medications in the general community and knowledge about consequences of medication modification. Keywords: crushing tablets, opening capsules, dosage form modification, health professional

Arguments inspired by algorithmic information theory predict an inverse relation between the probability and complexity of output patterns in a wide range of input-output maps. This phenomenon is known as simplicity bias. By viewing the parameters of dynamical systems as inputs, and the resulting (digitised) trajectories as outputs, we study simplicity bias in the logistic map, Gauss map, sine map, Bernoulli map, and tent map. We find that the logistic map, Gauss map, and sine map all exhibit simplicity bias upon sampling of map initial values and parameter values, but the Bernoulli map and tent map do not. The simplicity bias upper bound on the output pattern probability is used to make a priori predictions regarding the probability of output patterns. In some cases, the predictions are surprisingly accurate, given that almost no details of the underlying dynamical systems are assumed. More generally, we argue that studying probability-complexity relationships may be a useful tool when studying patterns in dynamical systems.

Respiratory viral infections are a major global clinical problem, and rapid, cheap, scalable and agnostic diagnostic tests that capture genome-level information on viral variation are urgently needed. Metagenomic approaches would be ideal, but remain currently limited in that much of the genetic content in respiratory samples is human, and amplifying and sequencing the viral/pathogen component in an unbiased manner is challenging. PCR-based tests, including those which detect multiple pathogens, are already widely used, but do not capture information on strain-level variation; tests with larger viral repertoires are also expensive on a per-test basis. One intermediate approach is the use of large panels of viral probes or 'baits', which target or 'capture' sequences representing complete genomes amongst several different common viral pathogens; these are then amplified, sequenced and analysed with a sequence analysis workflow. Here we evaluate one such commercial bait capture method (the Twist Bioscience Respiratory Virus Research Panel) and sequence analysis workflow (OneCodex), using control (simulated) and patient samples head-to-head with a validated multiplex PCR clinical diagnostic test (BioFire FilmArray). We highlight the limited sensitivity and specificity of the joint Twist Bioscience/OneCodex approach, which are further reduced by shortening workflow times and increasing sample throughput to reduce per-sample costs. These issues with performance may be driven by aspects of both the laboratory (e.g. capacity to enrich for viruses present in low numbers), bioinformatics methods used (e.g. a limited viral reference database) and thresholds adopted for calling a virus as present or absent. As a result, this workflow would require further optimization prior to any implementation for respiratory virus characterization in a routine diagnostic healthcare setting.

Phenotype robustness, defined as the average mutational robustness of all the genotypes that map to a given phenotype, plays a key role in facilitating neutral exploration of novel phenotypic variation by an evolving population. By applying results from coding theory, we prove that the maximum phenotype robustness occurs when genotypes are organized as bricklayer's graphs, so-called because they resemble the way in which a bricklayer would fill in a Hamming graph. The value of the maximal robustness is given by a fractal continuous everywhere but differentiable nowhere sums-of-digits function from number theory. Interestingly, genotype-phenotype maps for RNA secondary structure and the hydrophobic-polar (HP) model for protein folding can exhibit phenotype robustness that exactly attains this upper bound. By exploiting properties of the sums-of-digits function, we prove a lower bound on the deviation of the maximum robustness of phenotypes with multiple neutral components from the bricklayer's graph bound, and show that RNA secondary structure phenotypes obey this bound. Finally, we show how robustness changes when phenotypes are coarse-grained and derive a formula and associated bounds for the transition probabilities between such phenotypes.

Physical activity programs run by local government, public health and not-for-profit sectors are a key public health strategy for improving rates of physical activity within local communities. However, these programs are underutilized. This is especially the case among members of refugee-background communities whose participation could have far-ranging and multilevel benefits. To explore how greater engagement among refugee-background communities with these programs could be fostered in Brisbane, Queensland, Australia, a qualitative study was undertaken from the perspectives of both community-based physical activity program providers and agencies involved in delivering services to refugee-background communities. This study involved a series of semi-structured interviews with a purposive sample of personnel from agencies that work with individuals and families from refugee-background communities and organizations that provide low-cost or no-cost physical activity programs and initiatives. Reflexive thematic analysis was used to interpret meaning from these data. Three themes relating to how participation in community-based physical activity programs could be improved among refugee-background communities were identified: improving cultural safety through intersectoral collaboration; confronting constraints imposed by the broader public health policy environment; and building capacity and empowering the community to diversify the sector. The findings highlight the importance of localized, deep-level intersectoral collaborations in bridging the gap between the health and social care needs of refugee-background communities and existing physical activity programs. However, a range of systems-produced barriers to the creation of such collaborations must be addressed to enable local actors to help mitigate and address the systemic exclusion of marginalized populations from participation in broader society., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: Cytokines play important roles in pregnancy complications. Some hormones such as estrogen, progesterone, and dydrogesterone have been shown to alter cytokine profiles. Understanding how cytokine profiles are affected by these hormones is therefore an important step towards immunomodulatory therapies for pregnancy complications. We analyse previously published data on the effects of estrogen, progesterone, and dydrogesterone on cytokine balances in women having recurrent spontaneous miscarriages., Materials and Methods: Levels of eight cytokines (IFN-γ, IL-2, IL-6, IL-10, IL-13, IL-17, IL-23, TNF-α) from n = 22 women presenting unexplained recurrent spontaneous miscarriages were studied. Cytokine values were recorded after in vitro exposure of peripheral blood cells to estrogen, progesterone, and dydrogesterone. We expand on earlier analysis of the dataset by employing different statistical techniques including effect sizes for individual cytokine values, a more powerful statistical test, and adjusting p-values for multiple comparisons. We employ multivariate analysis methods, including to determine the relative magnitude of the effects of the hormone therapies on cytokines. A new statistical method is introduced based on pairwise distances able to accommodate complex relations in cytokine profiles., Results: We report several statistically significant differences in individual cytokine values between the control group and each hormone treated group, with estrogen affecting the fewest cytokines, and progesterone and dydrogesterone both affecting seven out of eight cytokines. Exposure to estrogen produces no large effects sizes however, while IFN-γ and IL-17 show large effect sizes for both progesterone and dydrogesterone, among other cytokines. Our new method for identifying which collections (i.e. subsets) of cytokines best distinguish contrasting groups identifies IFN-γ, IL-10 and IL-23 as especially noteworthy for both progesterone and dydrogesterone treatments., Conclusions: While some statistically significant differences in cytokine levels after exposure to estrogen are found, these have small effect sizes and are unlikely to be clinically relevant. Progesterone and dydrogesterone both induce statistically significant and large effect-size differences in cytokine levels, hence therapy with these two progestogens is more likely to be clinically relevant. Univariate and multivariate methods for identifying cytokine importances provide insight into which groups of cytokines are most affected and in what ways by therapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kamaludin Dingle reports financial support was provided by Kuwait Foundation for the Advancement of Sciences., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Universal access to drug susceptibility testing for newly diagnosed tuberculosis patients is recommended. Access to culture-based diagnostics remains limited, and targeted molecular assays are vulnerable to emerging resistance mutations. Improved protocols for direct-from-sputum Mycobacterium tuberculosis sequencing would accelerate access to comprehensive drug susceptibility testing and molecular typing. We assessed a thermo-protection buffer-based direct-from-sample M. tuberculosis whole-genome sequencing protocol. We prospectively analyzed 60 acid-fast bacilli smear-positive clinical sputum samples in India and Madagascar. A diversity of semiquantitative smear positivity-level samples were included. Sequencing was performed using Illumina and MinION (monoplex and multiplex) technologies. We measured the impact of bacterial inoculum and sequencing platforms on genomic read depth, drug susceptibility prediction performance, and typing accuracy. M. tuberculosis was identified by direct sputum sequencing in 45/51 samples using Illumina, 34/38 were identified using MinION-monoplex sequencing, and 20/24 were identified using MinION-multiplex sequencing. The fraction of M. tuberculosis reads from MinION sequencing was lower than from Illumina, but monoplexing grade 3+ samples on MinION produced higher read depth than Illumina ( P <  0.05) and MinION multiplexing ( P <  0.01). No significant differences in sensitivity and specificity of drug susceptibility predictions were seen across sequencing modalities or within each technology when stratified by smear grade. Illumina sequencing from sputum accurately identified 1/8 (rifampin) and 6/12 (isoniazid) resistant samples, compared to 2/3 (rifampin) and 3/6 (isoniazid) accurately identified with Nanopore monoplex. Lineage agreement levels between direct and culture-based sequencing were 85% (MinION-monoplex), 88% (Illumina), and 100% (MinION-multiplex). M. tuberculosis direct-from-sample whole-genome sequencing remains challenging. Improved and affordable sample treatment protocols are needed prior to clinical deployment.

Objectives: Sexual health knowledge among international students in Australia is lower than domestic students, however, little is known about what factors affect the uptake of STI testing, nor if there are differences for overseas-born domestic students., Methods: We included sexually active respondents from a survey of university students in Australia (N = 3,075). Multivariate regression and mediation analyses investigated associations of STI and HIV testing with STI and HIV knowledge respectively, sexual risk behaviour and demographics, including comparisons among: domestic Australian-born, domestic overseas-born, and international students., Results: STI and HIV knowledge was positively associated with STI and HIV testing respectively (STI OR = 1.13, 95% CI: 1.09, 1.16; HIV OR = 1.37, 95% CI: 1.27, 1.48). STI knowledge was significantly lower for international than domestic Australian-born students (10.8 vs. 12.2 out of 16), as was STI testing (32% vs. 38%); the difference in knowledge accounted for half the difference in STI testing rates between these two groups. International students from Southern Asia, and Eastern Asia reported the lowest STI testing rates. HIV testing was highest amongst international students from Africa and North America. Higher sexual risk behaviour, younger age, and identifying as gay or bisexual were positively associated with higher STI and HIV testing rates., Conclusions: Our study supports greater investment and commitment by universities for the provision of sexual health education that can promote access to testing to improve the health of their students., (© 2023. The Author(s).)

An important question in evolutionary biology is whether (and in what ways) genotype-phenotype (GP) map biases can influence evolutionary trajectories. Untangling the relative roles of natural selection and biases (and other factors) in shaping phenotypes can be difficult. Because the RNA secondary structure (SS) can be analyzed in detail mathematically and computationally, is biologically relevant, and a wealth of bioinformatic data are available, it offers a good model system for studying the role of bias. For quite short RNA (length L≤126), it has recently been shown that natural and random RNA types are structurally very similar, suggesting that bias strongly constrains evolutionary dynamics. Here, we extend these results with emphasis on much larger RNA with lengths up to 3000 nucleotides. By examining both abstract shapes and structural motif frequencies (i.e., the number of helices, bonds, bulges, junctions, and loops), we find that large natural and random structures are also very similar, especially when contrasted to typical structures sampled from the spaces of all possible RNA structures. Our motif frequency study yields another result, where the frequencies of different motifs can be used in machine learning algorithms to classify random and natural RNA with high accuracy, especially for longer RNA (e.g., ROC AUC 0.86 for L = 1000). The most important motifs for classification are the number of bulges, loops, and bonds. This finding may be useful in using SS to detect candidates for functional RNA within 'junk' DNA regions.

Unravelling the structure of genotype-phenotype (GP) maps is an important problem in biology. Recently, arguments inspired by algorithmic information theory (AIT) and Kolmogorov complexity have been invoked to uncover simplicity bias in GP maps, an exponentially decaying upper bound in phenotype probability with the increasing phenotype descriptional complexity. This means that phenotypes with many genotypes assigned via the GP map must be simple, while complex phenotypes must have few genotypes assigned. Here, we use similar arguments to bound the probability P ( x → y ) that phenotype x , upon random genetic mutation, transitions to phenotype y . The bound is [Formula: see text], where [Formula: see text] is the estimated conditional complexity of y given x , quantifying how much extra information is required to make y given access to x . This upper bound is related to the conditional form of algorithmic probability from AIT. We demonstrate the practical applicability of our derived bound by predicting phenotype transition probabilities (and other related quantities) in simulations of RNA and protein secondary structures. Our work contributes to a general mathematical understanding of GP maps and may facilitate the prediction of transition probabilities directly from examining phenotype themselves, without utilizing detailed knowledge of the GP map.