T4 Bacteriophage and E. coli Interaction in the Murine Intestine: A Prototypical Model for Studying Host-Bacteriophage Dynamics In Vivo.

Bacteriophages (phages) are viruses that infect bacteria with species- and strain-level specificity and are the most abundant biological entities across all known ecosystems. Within bacterial communities, such as those found in the gut microbiota, phages are implicated in regulating microbiota population dynamics and driving bacterial evolution. There has been renewed interest in phage research in the last decade, in part due to the host-specific killing capabilities of lytic phages, which offer a promising tool to counter the increasing threat of antimicrobial resistant bacteria. Furthermore, recent studies demonstrating that phages adhere to intestinal mucus suggest they may have a protective role in preventing bacterial invasion into the underlying epithelium. Importantly, like bacterial microbiomes, disrupted phageomes have been associated with worsened outcomes in diseases such as inflammatory bowel disease. Previous studies have demonstrated that phages can modulate the microbiome of animals and humans through fecal filtrate transplants, benefiting the host's health. With this recent wave of research comes the necessity to establish and standardize protocols for studying phages in the context of the gut microbiome. This protocol provides a set of procedures to study isolated T4 phages and their bacterial host, Escherichia coli, in the context of the murine gastrointestinal tract. The methods described here outline how to start from a phage lysate, administer it to mice and assess effects on bacterial host and phage levels. This protocol can be modified and applied to other phage-bacterial pairs and provides a starting point for studying host-phage dynamics in vivo.

Genomic attributes of airway commensal bacteria and mucosa.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

COPD in Never-Smokers: BOLD Australia Study.

Purpose: Tobacco smoking is the major risk factor for COPD, and it is common for other risk factors in never-smokers to be overlooked. We examined the prevalence of COPD among never-smokers in Australia and identified associated risk factors. Methods: We used data from the Australia Burden of Obstructive Lung Disease (BOLD) study, a cross-section of people aged ≥40 years from six sites. Participants completed interviews and post-bronchodilator spirometry. COPD was primarily defined as an FEV1/FVC ratio <0.70 and secondarily as the ratio less than the lower limit of normal (LLN). Results: The prevalence of COPD in the 1656 never-smokers who completed the study was 10.5% (95% CI: 9.1-12.1%) [ratio

Help-seeker satisfaction with diagnosis and treatment of tinnitus.

OBJECTIVE: To examine help-seeker satisfaction with the first communication of a tinnitus diagnosis by a healthcare provider, whether help-seekers undertook treatment and how they rated this treatment. DESIGN: A survey design assessed tinnitus characteristics and distress, health status, help-seeking, diagnosis communication, treatment and patient satisfaction. STUDY SAMPLE: A self-selected cohort and a population-based cohort. RESULTS: Satisfaction scores were examined against demographic, clinical factors, and type of healthcare provider. A total of 281 adults participated (median age 61.6, IQR = 10.8 years), 52.3% sought help for tinnitus and 22.4% received treatment. The most frequently seen healthcare providers were general practitioners (34.0%), audiologists (29.3%) and ear, nose and throat specialists (25.9%). About two-thirds (64.1%) of help-seekers were unsatisfied with the first communication of a tinnitus diagnosis they received, and 56.5% rated their first tinnitus treatment as poor. Help-seekers were significantly more satisfied with audiologists than other providers regarding the communication of the first tinnitus diagnosis. Higher tinnitus distress scores were significantly associated with lower patient satisfaction with communication of first tinnitus diagnosis. No other factors were associated with patient satisfaction. CONCLUSION: There are significant communication barriers along the tinnitus clinical pathway. Identifying and addressing these barriers could improve patient satisfaction.

The art of aging well: a study of the relationship between recreational arts engagement, general health and mental wellbeing in cohort of Australian older adults.

Introduction: Evidence of the benefits of arts engagement to community wellbeing has been mounting since the 1990s. However, large scale, quantitative, epidemiological studies of the "arts-healthy aging" relationship, or the types of arts older adults voluntarily choose to engage in as part of their everyday life, for enjoyment, entertainment or as a hobby (vs. therapy or interventions) are limited. The aims of this study were to describe older adult recreational arts engagement via the Busselton Healthy Ageing Study (BHAS) cohort, and to determine if there was an association between arts engagement, general health and mental wellbeing. Methods: Overall, 2,843 older adults (born 1946-1964) from the BHAS cohort (n = 5,107) who had completed a supplementary arts survey (n = 3,055, 60%) and had data on required variables were included in this study (93% of those eligible). The dependent variable was general health (SF12) and subjective mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale, WEMWBS). The independent variable was hours engaged in recreational arts in the last 12 months. A descriptive analysis followed by a linear regression analysis was conducted. Results: The prevalence of recreational arts engagement in the last 12 months was 85% (mean = 132 h/year). Older adults engaged in the arts in a number of ways including attending events (79%), actively participating/making art (40%), as an arts society/club/organization member (20%), by learning about the arts (13%) or by volunteering/working in the arts (non-professional, 11%). When general health was assessed via the SF12, the average physical component score (PCS) was 50.1 (SD 8.9) and the average mental component score (MCS) was 53.6 (SD 8.3). When mental wellbeing was assessed, the average WEMWBS score was 54.9 (SD = 8.6). After adjustment for 12 demographic and lifestyle covariates, it was found that older adults who engaged in any recreational arts in the last 12 months had significantly higher WEMWBS scores and higher SF12 physical component scores than those who did not engage in the arts (0 h/year). Discussion: Evidence of an arts-health relationship was found in this study. The suitability of the arts as a population based, healthy aging strategy to influence the mental wellbeing and general health of older adults should be investigated further.

Products of Variables in Structural Equation Models.

A general method is introduced in which variables that are products of other variables in the context of a structural equation model (SEM) can be decomposed into the sources of variance due to the multiplicands. The result is a new category of SEM which we call a Products of Variables Model (PoV). Some useful and practical features of PoV models include estimation of interactions between latent variables, latent variable moderators, manifest moderators with missing values, and manifest or latent squared terms. Expected means and covariances are analytically derived for a simple product of two variables and it is shown that the method reproduces previously published results for this special case. It is shown algebraically that using centered multiplicands results in an unidentified model, but if the multiplicands have non-zero means, the result is identified. The method has been implemented in OpenMx and Ωnyx and is applied in five extensive simulations.

Characterizing affect dynamics with a damped linear oscillator model: Theoretical considerations and recommendations for individual-level applications.

People show stable differences in the way their affect fluctuates over time. Within the general framework of dynamical systems, the damped linear oscillator (DLO) model has been proposed as a useful approach to study affect dynamics. The DLO model can be applied to repeated measures provided by a single individual, and the resulting parameters can capture relevant features of the person's affect dynamics. Focusing on negative affect, we provide an accessible interpretation of the DLO model parameters in terms of emotional lability, resilience, and vulnerability. We conducted a Monte Carlo study to test the DLO model performance under different empirically relevant conditions in terms of individual characteristics and sampling scheme. We used state-space models in continuous time. The results show that, under certain conditions, the DLO model is able to accurately and efficiently recover the parameters underlying the affective dynamics of a single individual. We discuss the results and the theoretical and practical implications of using this model, illustrate how to use it for studying psychological phenomena at the individual level, and provide specific recommendations on how to collect data for this purpose. We also provide a tutorial website and computer code in R to implement this approach. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

State Space Mixture Modeling: Finding People with Similar Patterns of Change.

Increasingly, behavioral scientists encounter data where several individuals were measured on multiple variables over numerous occasions. Many current methods combine these data, assuming all individuals are randomly equivalent. An extreme alternative assumes no one is randomly equivalent. We propose state space mixture modeling as one possible compromise. State space mixture modeling assumes that unknown groups of people exist who share the same parameters of a state space model, and simultaneously estimates both the state space parameters and group membership. The goal is to find people that are undergoing similar change processes over time. The present work demonstrates state space mixture modeling on a simulated data set, and summarizes the results from a large simulation study. The illustration shows how the analysis is conducted, whereas the simulation provides evidence of its general validity and applicability. In the simulation study, sample size had the greatest influence on parameter estimation and the dimension of the change process had the greatest impact on correctly grouping people together, likely due to the distinctiveness of their patterns of change. State space mixture modeling offers one of the best-performing methods for simultaneously drawing conclusions about individual change processes while also analyzing multiple people.

Estimation of nonlinear mixed-effects continuous-time models using the continuous-discrete extended Kalman filter.

Many intensive longitudinal measurements are collected at irregularly spaced time intervals, and involve complex, possibly nonlinear and heterogeneous patterns of change. Effective modelling of such change processes requires continuous-time differential equation models that may be nonlinear and include mixed effects in the parameters. One approach of fitting such models is to define random effect variables as additional latent variables in a stochastic differential equation (SDE) model of choice, and use estimation algorithms designed for fitting SDE models, such as the continuous-discrete extended Kalman filter (CDEKF) approach implemented in the dynr R package, to estimate the random effect variables as latent variables. However, this approach's efficacy and identification constraints in handling mixed-effects SDE models have not been investigated. In the current study, we analytically inspect the identification constraints of using the CDEKF approach to fit nonlinear mixed-effects SDE models; extend a published model of emotions to a nonlinear mixed-effects SDE model as an example, and fit it to a set of irregularly spaced ecological momentary assessment data; and evaluate the feasibility of the proposed approach to fit the model through a Monte Carlo simulation study. Results show that the proposed approach produces reasonable parameter and standard error estimates when some identification constraint is met. We address the effects of sample size, process noise variance, and data spacing conditions on estimation results.

Plasma lipoprotein subclass variation in middle-aged and older adults: Sex-stratified distributions and associations with health status and cardiometabolic risk factors.

BACKGROUND: Circulating lipids and lipoproteins mediate cardiovascular risk, however routine plasma lipid biochemistry provides limited information on pro-atherogenic remnant particles. OBJECTIVE: We analysed plasma lipoprotein subclasses including very low-density and intermediate-density lipoprotein (VLDL and IDL); and assessed their associations with health and cardiometabolic risk. METHODS: From 1,976 community-dwelling adults aged 45-67 years, 114/1071 women (10.6%) and 153/905 men (16.9%) were categorised as very healthy. Fasting plasma lipoprotein profiles comprising 112 parameters were measured using 1H nuclear magnetic resonance (NMR) spectroscopy, and associations with health status and cardiometabolic risk factors examined. RESULTS: HDL cholesterol was higher, and IDL and VLDL cholesterol and triglycerides lower, in very healthy women compared to other women, and women compared to men. IDL and VLDL cholesterol and triglyceride were lower in very healthy men compared to other men. HDL cholesterol and apolipoprotein (apo) A-I were inversely, and IDL and VLDL cholesterol, apoB-100, and apoB-100/apoA-I ratio directly associated with body mass index (BMI) in women and men. In women, LDL, IDL and VLDL cholesterol increased with age. Women with diabetes and cardiovascular disease had higher cholesterol, triglycerides, phospholipids and free cholesterol across IDL and VLDL fractions, with similar trends for men with diabetes. CONCLUSION: Lipoprotein subclasses and density fractions, and their lipid and apolipoprotein constituents, are differentially distributed by sex, health status and BMI. Very healthy women and men are distinguished by favorable lipoprotein profiles, particularly lower concentrations of VLDL and IDL, providing reference intervals for comparison with general populations and adults with cardiometabolic risk factors.

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration.

BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

Comparison of Four Dietary Pattern Indices in Australian Baby Boomers: Findings from the Busselton Healthy Ageing Study.

The assessment of dietary patterns comprehensively represents the totality of the diet, an important risk factor for many chronic diseases. This study aimed to characterise and compare four dietary pattern indices in middle-aged Australian adults. In 3458 participants (55% female) from the Busselton Healthy Ageing Study (Phase Two), a validated food frequency questionnaire was used to capture dietary data between 2016 and 2022. Four dietary patterns [Australian Dietary Guideline Index 2013 (DGI-2013); the Mediterranean Diet Index (MedDiet); the Literature-based Mediterranean Diet Index (Lit-MedDiet); and the EAT-Lancet Index], were calculated and compared by measuring total and sub-component scores, and concordance (𝜌c). Cross-sectional associations between the dietary indices and demographic, lifestyle, and medical conditions were modelled with linear regression and restricted cubic splines. Participants had the highest standardised scores for the DGI-2013 followed by the EAT-Lancet Index and the MedDiet, with the lowest standardised scores observed for the Lit-MedDiet. The DGI-2013 had the lowest agreement with the other scores (𝜌c ≤ 0.47). These findings indicate that the diets included in this Australian cohort align more closely with the Australian Dietary Guidelines than with the other international dietary patterns, likely due to the wide variation of individual food group weightings in the construction of these indices.

Simulated nonlinear genetic and environmental dynamics of complex traits.

Genetic studies of complex traits often show disparities in estimated heritability depending on the method used, whether by genomic associations or twin and family studies. We present a simulation of individual genomes with dynamic environmental conditions to consider how linear and nonlinear effects, gene-by-environment interactions, and gene-by-environment correlations may work together to govern the long-term development of complex traits and affect estimates of heritability from common methods. Our simulation studies demonstrate that the genetic effects estimated by genome wide association studies in unrelated individuals are inadequate to characterize gene-by-environment interaction, while including related individuals in genome-wide complex trait analysis (GCTA) allows gene-by-environment interactions to be recovered in the heritability. These theoretical findings provide an explanation for the "missing heritability" problem and bridge the conceptual gap between the most common findings of GCTA and twin studies. Future studies may use the simulation model to test hypotheses about phenotypic complexity either in an exploratory way or by replicating well-established observations of specific phenotypes.

Conversion Total Hip Arthroplasty in the Era of Bundled Care Payments: Impacts on Costs of Care.

BACKGROUND: Conversion hip arthroplasty is defined as a patient who has had prior open or arthroscopic hip surgery with or without retained hardware that is removed and replaced with arthroplasty components. Currently, it is classified under the same diagnosis-related group as primary total hip arthroplasty (THA); however, it frequently requires a higher cost of care. METHODS: A retrospective study of 228 conversion THA procedures in an orthopaedic specialty hospital was performed. Propensity score matching was used to compare the study group to a cohort of 510 primary THA patients by age, body mass index, sex, and American Society of Anesthesiologists score. These matched groups were compared based on total costs, implants used, operative times, length of stay (LOS), readmissions, and complications. RESULTS: Conversion THA incurred 25% more mean total costs compared to primary THA (P < .05), longer lengths of surgery (154 versus 122 minutes), and hospital LOS (2.1 versus 1.56 days). A subgroup analysis showed a 57% increased cost for cephalomedullary nail conversion, 34% increased cost for sliding hip screw, 33% for acetabular open reduction and internal fixation conversion, and 10% increased costs in closed reduction and percutaneous pinning conversions (all P < .05). There were 5 intraoperative complications in the conversion group versus none in the primary THA group (P < .01), with no statistically significant difference in readmissions. CONCLUSION: Conversion THA is significantly more costly than primary THA and has longer surgical times and greater LOS. Specifically, conversion THA with retained implants had the greatest impact on cost.

Longitudinal Stability of Vitamin D Status and Its Association With Bone Mineral Density in Middle-aged Australians.

Context: The skeletal effects of vitamin D remain controversial and it is uncertain whether variation in serum 25-hydroxyvitamin D (25OHD) levels over time influences bone mineral density (BMD). Objective: We evaluated longitudinal stability of serum 25OHD and associations with changes in BMD in participants aged 46-70 years at baseline. Methods: We studied 3698 Busselton Healthy Ageing Study participants (2040 female) with serum 25OHD and dual-energy x-ray absorptiometry (DXA) BMD assessments at baseline and at ∼6 years follow-up. Restricted cubic splines were used to evaluate associations between changes in 25OHD and BMD. Results: Mean season-corrected serum 25OHD was 81.3 ± 22.7 and 78.8 ± 23.1 nmol/L at baseline and 6 years, respectively, and showed moderate correlation (intraclass correlation coefficient: 0.724). Significant predictors of change in 25OHD concentration (Δ25OHD) included baseline 25OHD, change in body mass index and vitamin D supplementation at follow-up. Greater decline in serum 25OHD over time was associated with significantly greater reduction in BMD at total hip and femoral neck, but the magnitude of the differences was small (estimated differences 0.004 g/cm2 and 0.005-0.007 g/cm2, respectively, for lowest quartile of Δ25OHD compared with higher quartiles, adjusted for sex, baseline BMD, 25OHD, and demographics). No significant associations between Δ25OHD and lumbar spine BMD were observed. Increase in 25OHD levels was not associated with change in BMD. Conclusions: In this predominantly vitamin D-replete middle-aged cohort, serum 25OHD showed moderate longitudinal stability. Declining serum 25OHD over time was associated with greater reduction in BMD at the total hip and femoral neck.

Transcranial direct current stimulation modulates working memory and prefrontal-insula connectivity after mild-moderate traumatic brain injury.

Background: Persistent posttraumatic symptoms (PPS) may manifest after a mild-moderate traumatic brain injury (mmTBI) even when standard brain imaging appears normal. Transcranial direct current stimulation (tDCS) represents a promising treatment that may ameliorate pathophysiological processes contributing to PPS. Objective/Hypothesis: We hypothesized that in a mmTBI population, active tDCS combined with training would result in greater improvement in executive functions and post-TBI cognitive symptoms and increased resting state connectivity of the stimulated region, i.e., left dorsolateral prefrontal cortex (DLPFC) compared to control tDCS. Methods: Thirty-four subjects with mmTBI underwent baseline assessments of demographics, symptoms, and cognitive function as well as resting state functional magnetic resonance imaging (rsfMRI) in a subset of patients (n = 24). Primary outcome measures included NIH EXAMINER composite scores, and the Neurobehavioral Symptom Inventory (NSI). All participants received 10 daily sessions of 30 min of executive function training coupled with active or control tDCS (2 mA, anode F3, cathode right deltoid). Imaging and assessments were re-obtained after the final training session, and assessments were repeated after 1 month. Mixed-models linear regression and repeated measures analyses of variance were calculated for main effects and interactions. Results: Both active and control groups demonstrated improvements in executive function (EXAMINER composite: p < 0.001) and posttraumatic symptoms (NSI cognitive: p = 0.01) from baseline to 1 month. Active anodal tDCS was associated with greater improvements in working memory reaction time compared to control (p = 0.007). Reaction time improvement correlated significantly with the degree of connectivity change between the right DLPFC and the left anterior insula (p = 0.02). Conclusion: Anodal tDCS improved reaction time on an online working memory task in a mmTBI population, and decreased connectivity between executive network and salience network nodes. These findings generate important hypotheses for the mechanism of recovery from PPS after mild-moderate TBI.

Acute disseminated actinomycosis presenting as pneumonia with bilateral pulmonary nodules and pelvic osteomyelitis in an immunocompetent patient.

Actinomycosis is an indolent human infectious disease caused by gram-positive anaerobic filamentous bacteria Actinomyces. Despite its sluggish growth, clinical manifestations can be acute or chronic. Over the last five decades, a significant incidence decline in the western world is due to the discovery of effective antimicrobials and improved oral hygiene. Actinomycosis is now rarely encountered and often misdiagnosed as its manifestations mimic malignancy and other infectious diseases. Due to prior use of antimicrobials, laboratory diagnostic processes often fail to isolate the organism making it arduous to establish the diagnosis. Clinical classification is based on the geographical distribution of the disease as oro-cervicofacial, thoracic, abdominopelvic, neurologic, musculoskeletal, and disseminated. Disseminated and pulmonary actinomycosis in an immunocompetent individual is extremely rare. Here we present a 53-year-old healthy male presenting with acute disseminated actinomycosis with bilateral pulmonary nodules, right upper lobe pneumonia, and pelvic osteomyelitis from Actinomyces odontolyticus infection.

Tuberculosis Aortitis and Mycotic Pseudo-aneurysm of the Infra-renal Aorta after Intravesicular BCG Therapy.

We report a patient who presented with a rapidly expanding symptomatic tuberculous aortitis and mycotic pseudo-aneurysm of the infra-renal aorta, after intra-vesical BCG chemotherapy for bladder cancer, treated by required emergency open aneurysm repair. His case highlights this rare complication of intravesical BCG treatment, haematological seeding causing tuberculous aortitis and mycotic pseudo-aneurysm formation of the infra-renal aorta. It also illustrates successful treatment with emergency open surgery, local debridement of mycotic pseudoaneurysm, in-situ surgical reconstruction using a custom bovine-wrap interposition graft to create a neo-aorta and multi-agent anti-tuberculous chemotherapy.

Association between dietary niacin and retinal nerve fibre layer thickness in healthy eyes of different ages.

BACKGROUND: To investigate the relationship between dietary intake of niacin (water-soluble form of vitamin B3 ) and retinal nerve fibre layer (RNFL) thickness in healthy eyes. METHODS: This cross-sectional study examined the association between daily niacin intake and RNFL thickness in three large population-based cohorts with varied age differences. RNFL thickness was extracted from optical coherence tomography data; energy-adjusted niacin intake was estimated from food frequency questionnaires. Linear mixed-effects models were utilised to examine the association between RNFL thickness and energy-adjusted niacin intake. Three separate analyses were conducted, with niacin treated as a continuous, a categorical (quartiles) or a dichotomous (above/below Australian recommended daily intake) variable. RESULTS: In total, 4937 subjects were included in the study [Raine Study Gen2, n = 1204, median age 20; Busselton Healthy Ageing Study (BHAS), n = 1791, median age 64; TwinsUK, n = 1942, median age 64). When analysed as a continuous variable, there was no association between RNFL thickness and niacin intake in any of the three cohorts (95% CI ß: Raine Study Gen 2, -0.174 to 0.074; BHAS, -0.066 to 0.078; TwinsUK -0.435 to 0.350). Similar findings were observed with quartiles of niacin intake and for niacin intakes above or below Australian recommended daily intake levels in all three cohorts. CONCLUSIONS: Dietary intake of niacin from a standard diet does not appear to be associated with age-related RNFL thinning in healthy eyes. Supraphysiological doses of niacin may be required for therapeutic effect in the retina.