Use of a peracetic acid (PAA) disinfectant to reduce total viable bacteria count in hospital wastewater drains.

The periphery of the hospital water system interfaces at multiple points with patients and staff in clinical areas. This comprises mostly of sinks and showers and presents a significant infection control risk. Wastewater drains in particular act as a reservoir of pathogens that can be transmitted to patients. Numerous strategies have been investigated as potential methods to reduce biofilm and bacterial load including regular application of biocidal chemicals. Traditional methods of assessing the efficacy of such products relies on culture based microbiological techniques, usually targeting a limited range of key pathogens. We assessed the efficacy of a peracetic acid containing drain disinfectant product on seven clinical handwash basin drains, taking daily samples over six weeks (before, during and after use of the drain disinfectant product). We used a rapid, culture independent estimation of total bacterial viable count (TVC) to assess efficacy. We applied long read metagenomic sequencing to study the entire drain microbiome, which allowed taxonomic changes to be documented following use of the drain disinfectant product. All samples were found to be heavily contaminated, however the drain disinfectant product reduced the TVC from an estimated mean of 4228 cfu/mL to 2874 cfu/mL. This reduction was sustained in the two weeks following cessation of the product. Long-read metagenomic sequencing showed a microbiome dominated with Gram negative organisms, with some taxonomic shifts in samples before and after application of the drain disinfectant. The impact on hospital-acquired infections from reducing bioburden in hospital drains by approximately a third, along with any associated changes in bacterial composition, needs evaluation in future studies.

Respiratory infection- and asthma-prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways.

BACKGROUND: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunizations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripheral blood mononuclear cells from respiratory infection allergy/asthma-prone (IAP) infants and non-infection allergy/asthma prone (NIAP) were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fisher's exact p-value = 0.02). RESULTS: An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPL), a TLR agonist, partially reversed this signature at a subset of CpGs, suggesting the potential for epigenetic remodeling. CONCLUSIONS: This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for future investigation.

The drainome: longitudinal metagenomic characterisation of wastewater from hospital ward sinks to characterize the microbiome and resistome and assess the effects of decontamination interventions.

BACKGROUND: Hospital drains and water interfaces are implicated in nosocomial transmission of pathogens. Metagenomics can assess the microbial composition and presence of antimicrobial resistance genes in drains ('the drainome') but studies applying these methods longitudinally and to assess infection control interventions are lacking. AIM: Apply long-read metagenomics coupled with microbiological measurements to investigate the drainome and assess the effects of a peracetic acid-containing decontamination product. METHODS: 12-week study in three phases: a baseline phase, an intervention phase of enhanced decontamination with peracetic acid, and a post-intervention phase. Five hospital sink drains on an intensive care unit were sampled twice weekly. Each sample had 1) measurement of total viable count (TVC), 2) metagenomic analyses including i) taxonomic classification of bacteria and fungi ii) antibiotic resistance gene detection iii) plasmid identification, and 3) immunochromatographic detection of antimicrobial residues. FINDINGS: Overall TVCs remain unchanged in the intervention phase (+386 CFU/mL, SE 705, p=0.59). There was a small but significant increase in the microbial diversity in the intervention phase (-0.07 in Simpson's index, SE 0.03, p=0.007), which was not sustained post-intervention (-0.05, SE 0.03, p=0.08). The intervention was associated with increased relative abundance of the Pseudomonas genus (18.3% to 40.5% [+22.2%], SE 5.7%, p<0.001). Extended spectrum beta-lactamases were found in all samples, with NDM-carbapenemase found in 3 drains in 6 samples. Antimicrobial residues were detected in a large proportion of samples (31/115, 27%), suggesting use of sinks for non-handwashing activities. CONCLUSIONS: Metagenomics and other measurements can measure the composition of the drainome and assess the effectiveness of decontamination interventions.

Analytical and behavioral characterization of 1-hexanoyl-LSD (1H-LSD).

The development of lysergic acid diethylamide (LSD) derivatives and analogs continues to inform the design of novel receptor probes and potentially new medicines. On the other hand, a number of newly developed LSD derivatives have also emerged as recreational drugs, leading to reports of their detection in some countries. One position in the ergoline scaffold of LSD that is frequently targeted is the N1-position; numerous N1-alkylcarbonyl LSD derivatives have been reported where the acyl chain is attached to the indole nitrogen, for example, in the form of linear n-alkane substituents, which represent higher homologs of the prototypical 1-acetyl-N,N-diethyllysergamide (1A-LSD, ALD-52). In this study, 1-hexanoyl-LSD (1H-LSD, SYN-L-027), a novel N1-acyl LSD derivative, was characterized analytically using standard techniques, followed by evaluation of its in vivo behavioral effects using the mouse head-twitch response (HTR) assay in C57BL/6J mice. 1H-LSD induced the HTR, with a median effective dose (ED50) of 192.4 µg/kg (equivalent to 387 nmol/kg), making it roughly equipotent to ALD-52 when tested previously under similar conditions. Similar to other N1-acylated analogs, 1H-LSD is anticipated to by hydrolyzed to LSD in vivo and acts as a prodrug. It is currently unknown whether 1H-LSD has appeared as on the research chemical market or is being used recreationally.

Modified Dunn Procedure for Open Reduction of Chronic Slipped Capital Femoral Epiphysis.

Background: Abnormal femoral head anatomy following moderate-to-severe slipped capital femoral epiphysis (SCFE) can lead to femoroacetabular impingement and premature osteoarthritis4-10. Surgical correction at the deformity site through capital reorientation has the potential to fully ameliorate this but has traditionally been associated with high rates of osteonecrosis11-15. The modified Dunn procedure has the potential to restore anatomy in hips with SCFE while protecting the blood supply to the femoral head. Description: A surgical dislocation of the hip is performed according to the technique described by Ganz et al.16. The remaining posterosuperior portion of the greater trochanter is trimmed to the level of the femoral neck by subperiosteal bone removal performed in an inside-out manner. The periosteum of the femoral neck is gradually elevated. The resulting soft-tissue flap, consisting of the retinaculum and external rotators, holds the blood vessels supplying the epiphysis. The femoral epiphysis is pinned in situ (in unstable cases) with threaded Kirschner wires, the ligamentum teres is transected, and the femoral head is dislocated. With the femoral neck exposed, the epiphysis is gradually mobilized from the metaphysis, allowing exposure of the residual femoral neck and inspection of any posteroinferior callus. To avoid tension on the retinacular vessels during reduction of the epiphysis, the posterior neck callus is completely excised. The remaining physis is removed with use of a burr while holding the epiphysis stable. The epiphysis is gently reduced onto the femoral neck, avoiding tension on the retinacular vessels. If tension is noted, the femoral neck is rechecked for residual callus, which is excised. If no callus is found, the neck may be carefully shortened in order to minimize tension. Epiphyseal fixation is achieved with use of a 3-mm fully threaded wire inserted antegrade through the fovea to the lateral cortex below the greater trochanter. A second wire is inserted retrograde under fluoroscopy. After reducing the hip, the capsule is closed and the greater trochanter is reattached with use of 3.5-mm cortical screws. Alternatives: Alternatives include nonoperative treatment, in situ fixation (e.g., pinning or screw fixation), gentle closed reduction with pinning, and triplanar trochanteric osteotomy (e.g., Imhauser or Southwick osteotomies). Rationale: In situ pinning of mild-to-moderate, stable SCFE yields good long-term results with low rates of osteonecrosis9. Treatment of higher-grade SCFE without reduction aims to avoid osteonecrosis and assumes that the proximal femoral deformity will remodel; however, the head-neck offset will remain abnormal, risking impingement and early-onset osteoarthritis5,8. The procedure described in the present article allows anatomic reduction of the epiphysis with a low risk of osteonecrosis. Surgical dislocation of the hip16 with development of an extended retinacular soft-tissue flap17 provides extensive subperiosteal exposure of the circumferential femoral neck and preserves the vulnerable blood supply to the epiphysis18. The Dunn subcapital realignment procedure15 with callus removal and slip angle correction allows anatomic restoration of the proximal femur. Expected Outcomes: Reported results of various centers performing the procedure vary greatly with regard to the number of hips treated and the follow-up time. Most studies have been retrospective and have lacked a control group. The reported risk of osteonecrosis ranges from 0% to 25.9%19, with the wide range most likely because of the challenging nature of the technique, the low number of cases per surgeon, and the long learning curve associated with the procedure. In centers with extensive experience in pediatric hip-preserving surgery, the reported rate of osteonecrosis is low3. Studies with mid to long-term follow-up have shown no conversion to total hip arthroplasty3,20,21, but residual deformities can persist, and subsequent surgery is possible. Important Tips: Extensive experience in surgical hip dislocation and retinacular flap development is a prerequisite for successful outcomes and low rates of osteonecrosis.Sufficient callus and physeal remnant resections are needed to avoid tension on the retinacular vessels during epiphyseal reduction.The skin incision should be centered over the greater trochanterThe Gibson interval must be carefully prepared for adequate release and to avoid injury.Tension on the periosteal flap should be avoided to prevent stress on the retinacular vessels. Acronyms and Abbreviations: AP = anteroposteriorAVN = avascular necrosis (i.e., osteonecrosis)CI = confidence intervalCT = computed tomographyK-wire = Kirschner wireMRI = magnetic resonance imagingOA = osteoarthritisSHD = surgical hip dislocationTHA = total hip arthroplastyVTE = venous thromboembolism.

Accelerating Formulation Design via Machine Learning: Generating a High-throughput Shampoo Formulations Dataset.

Liquid formulations are ubiquitous yet have lengthy product development cycles owing to the complex physical interactions between ingredients making it difficult to tune formulations to customer-defined property targets. Interpolative ML models can accelerate liquid formulations design but are typically trained on limited sets of ingredients and without any structural information, which limits their out-of-training predictive capacity. To address this challenge, we selected eighteen formulation ingredients covering a diverse chemical space to prepare an open experimental dataset for training ML models for rinse-off formulations development. The resulting design space has an over 50-fold increase in dimensionality compared to our previous work. Here, we present a dataset of 812 formulations, including 294 stable samples, which cover the entire design space, with phase stability, turbidity, and high-fidelity rheology measurements generated on our semi-automated, ML-driven liquid formulations workflow. Our dataset has the unique attribute of sample-specific uncertainty measurements to train predictive surrogate models.

Bioisosteric analogs of MDMA: Improving the pharmacological profile?

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is re-emerging in clinical settings as a candidate for the treatment of specific neuropsychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile. In vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubations, metabolic stability studies, isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) but decreased agonist activity at 5-HT2A/2B/2C receptors. Regarding their hepatic metabolism, they differed from MDMA, with N-demethylation being the only metabolic route shared, and without forming phase II metabolites. In addition, TDMA showed an enhanced intrinsic clearance in comparison to its congeners. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane monoamine transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.

The role of accelerometer-derived sleep traits on glycated haemoglobin and glucose levels: a Mendelian randomization study.

Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active 5-h, mid-point most active 10-h, sleep fragmentation, and efficiency) on HbA1c/glucose in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 146,806). Cross-trait linkage disequilibrium score regression was applied to determine genetic correlations across accelerometer-derived, self-reported sleep traits, and HbA1c/glucose. We found no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Phenotypic and genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. These findings suggested accelerometer-derived sleep traits do not affect HbA1c. Accelerometer-derived measures of sleep duration and quality might not simply be 'objective' measures of self-reported sleep duration and insomnia, but rather captured different sleep characteristics.

The lung extracellular matrix protein landscape in severe early-onset and moderate chronic obstructive pulmonary disease.

Extracellular matrix (ECM) remodeling has been implicated in the irreversible obstruction of airways and destruction of alveolar tissue in chronic obstructive pulmonary disease (COPD). Studies investigating differences in the lung ECM in COPD have mainly focused on some collagens and elastin, leaving an array of ECM components unexplored. We investigated the differences in the ECM landscape comparing severe-early onset (SEO-) COPD and moderate COPD to control lung tissue for collagen type I α chain 1 (COL1A1), COL6A1, COL6A2, COL14A1, fibulin 2 and 5 (FBLN2, FBLN5), latent transforming growth factor-beta binding protein 4 (LTBP4), lumican (LUM), versican (VCAN), decorin (DCN), and elastin (ELN) using image analysis and statistical modelling. Percentage area and/or mean intensity of expression of LUM in the parenchyma, and COL1A1, FBLN2, LTBP4, DCN, and VCAN in the airway walls, was proportionally lower in COPD compared to controls. Lowered levels of most ECM proteins were associated with decreasing FEV1 measurements, indicating a relationship with disease severity. Furthermore, we identified six unique ECM signatures where LUM and COL6A1 in parenchyma and COL1A1, FBLN5, DCN, and VCAN in airway walls appear essential in reflecting the presence and severity of COPD. These signatures emphasize the need to examine groups of proteins to represent an overall difference in the ECM landscape in COPD, that are more likely to be related to functional effects, than individual proteins. Our study revealed differences in the lung ECM landscape between control and COPD and between SEO and moderate COPD signifying distinct pathological processes in the different subgroups.

Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

BACKGROUND: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. RESULTS: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

Distribution models of baleen whale species in the Irish Exclusive Economic Zone to inform management and conservation.

Irish waters are under increasing pressure from anthropogenic sources including the development of offshore renewable energy, vessel traffic and fishing activity. Spatial planning requires robust datasets on species distribution and the identification of important habitats to inform the planning process. Despite limited survey effort, long-term citizen science data on whale presence are available and provide an opportunity to fill information gaps. Using presence-only data as well as a variety of environmental variables, we constructed seasonal ensemble species distribution models based on five different algorithms for minke whales, fin whales, humpback whales, sei whales, and blue whales. The models predicted that the coastal waters off the south and west of Ireland are particularly suitable for minke, fin and humpback whales. Offshore waters in the Porcupine Seabight area were identified as a relevant habitat for fin whales, sei whales and blue whales. We combined model outputs with data on maritime traffic, fishing activity and offshore wind farms to measure the exposure of all the species to these pressures, identifying areas of concern. This study serves as a baseline for the species presence in Irish waters over the last two decades to help develop appropriate marine spatial plans in the future.

Molecular Pathways and Animal Models of d-Transposition of the Great Arteries.

During normal cardiovascular development, the outflow tract becomes septated and rotates so that the separate aorta and pulmonary trunk are correctly aligned with the left and right ventricles, respectively. However, when this process goes wrong, the aorta and pulmonary trunk are incorrectly positioned, resulting in oxygenated blood being directly returned to the lungs, with deoxygenated blood being delivered to the systemic circulation. This is termed transposition of the great arteries (TGA). The precise etiology of TGA is not known, but the use of animal models has elucidated that genes involved in determination of the left- embryonic body axis play key roles. Other factors such as retinoic acid levels are also crucial. This chapter reviews the animal models presenting with TGA that have been generated by genetic manipulation or with exogenous agents.

Insights into physical activity promotion among Australian chiropractors: a cross-sectional survey.

BACKGROUND: Despite the well-known benefits of physical activity, physical inactivity is presently a global health pandemic. Allied healthcare providers, such as chiropractors, knowingly recognise the importance of physical activity and are prepared to routinely discuss and/or counsel patients on this topic; however, little is known about Australian chiropractors in the physical activity setting. Our aim was to explore and identify factors associated with physical activity promotion among Australian chiropractors, including their knowledge of the physical activity and sedentary behaviour guidelines and their own levels of physical activity. METHODS: From February to May 2021, a convenience sample of Australian chiropractors completed an online survey. Items assessed by Likert scale included: physical activity promotion frequency, with the type, quantity, barriers, perceptions, and feasibility. We asked questions about their familiarity with, and knowledge of, Australian Physical Activity and Sedentary Behaviour Guidelines, chiropractors' own physical activity, and whether the chiropractors met activity guidelines. Survey responses were descriptively reported. Univariable logistic regression models explored factors explaining frequent physical activity promotion. RESULTS: Of 217 respondents, 64% reported that they frequently (≥ 70%) recommended a more physically active lifestyle. Only 15% often performed pre-exercise screening, 73% frequently prescribed resistance exercise, 19% reported time as the most frequent barrier, while 37% reported being not at all familiar with the guidelines. Univariable logistic regression models found male chiropractors were more likely to promote physical activity, [odds ratio (OR) = 2.33; 95% confidence interval (CI): 1.32-4.12)], while chiropractors who frequently treat children 0-3 years (OR = 0.5; 95% CI: 0.28-0.87), children 4-18 years (OR = 0.42; 95% CI: 0.21-0.86), and pregnant women (OR = 0.5; 95% CI: 0.26-0.94) were less likely. Chiropractors were more likely to promote physical activity if they were familiar with the activity guidelines (OR = 2.9; 95% CI: 1.32-6.41), were confident promoting (OR = 11.6; 95% CI: 1.37-98.71) and prescribing physical activity programs (OR = 4.5; 95% CI: 2.03-9.99). CONCLUSION: Most chiropractors confidently and regularly integrate physical activity into practice. Yet, despite acknowledging its importance, one third of chiropractors reported poor knowledge of the Physical Activity and Sedentary Behaviour Guidelines. Identifying barriers to the awareness, and implementation of physical activity guidelines should be further explored within chiropractic clinical settings.

Heterologous SARS-CoV-2 booster vaccine for individuals with hematological malignancies after a primary SARS-CoV-2 mRNA vaccine series.

Heterologous COVID-19 vaccine boosters have not been evaluated for patients with hematological malignancies. A Novavax booster was administered for 56 individuals with hematological malignancies who had received a primary COVID-19 series and prior boosters with mRNA vaccines only. Blood specimens were obtained at baseline (pre-vaccine), 28 days, and 168 days after vaccination with the Novavax booster. The median fold change of anti-Spike IgG was 1.02 (IQR 0.79, 1.3) between baseline and Day 28. Circulating Spike protein-specific B cells increased 1.4-fold at Day 28 (p < 0.05). Increases in antibody and T cell responses were modest without significance, with a waning of humoral and cellular responses at 168 days after vaccination.

Effectiveness and cost-effectiveness of an individualised, progressive walking and education intervention for the prevention of low back pain recurrence in Australia (WalkBack): a randomised controlled trial.

BACKGROUND: Recurrence of low back pain is common and a substantial contributor to the disease and economic burden of low back pain. Exercise is recommended to prevent recurrence, but the effectiveness and cost-effectiveness of an accessible and low-cost intervention, such as walking, is yet to be established. We aimed to investigate the clinical effectiveness and cost-effectiveness of an individualised, progressive walking and education intervention to prevent the recurrence of low back pain. METHODS: WalkBack was a two-armed, randomised controlled trial, which recruited adults (aged 18 years or older) from across Australia who had recently recovered from an episode of non-specific low back pain that was not attributed to a specific diagnosis, and which lasted for at least 24 h. Participants were randomly assigned to an individualised, progressive walking and education intervention facilitated by six sessions with a physiotherapist across 6 months or to a no treatment control group (1:1). The randomisation schedule comprised randomly permuted blocks of 4, 6, and 8 and was stratified by history of more than two previous episodes of low back pain and referral method. Physiotherapists and participants were not masked to allocation. Participants were followed for a minimum of 12 months and a maximum of 36 months, depending on the date of enrolment. The primary outcome was days to the first recurrence of an activity-limiting episode of low back pain, collected in the intention-to-treat population via monthly self-report. Cost-effectiveness was evaluated from the societal perspective and expressed as incremental cost per quality-adjusted life-year (QALY) gained. The trial was prospectively registered (ACTRN12619001134112). FINDINGS: Between Sept 23, 2019, and June 10, 2022, 3206 potential participants were screened for eligibility, 2505 (78%) were excluded, and 701 were randomly assigned (351 to the intervention group and 350 to the no treatment control group). Most participants were female (565 [81%] of 701) and the mean age of participants was 54 years (SD 12). The intervention was effective in preventing an episode of activity-limiting low back pain (hazard ratio 0·72 [95% CI 0·60-0·85], p=0·0002). The median days to a recurrence was 208 days (95% CI 149-295) in the intervention group and 112 days (89-140) in the control group. The incremental cost per QALY gained was AU$7802, giving a 94% probability that the intervention was cost-effective at a willingness-to-pay threshold of $28 000. Although the total number of participants experiencing at least one adverse event over 12 months was similar between the intervention and control groups (183 [52%] of 351 and 190 [54%] of 350, respectively, p=0·60), there was a greater number of adverse events related to the lower extremities in the intervention group than in the control group (100 in the intervention group and 54 in the control group). INTERPRETATION: An individualised, progressive walking and education intervention significantly reduced low back pain recurrence. This accessible, scalable, and safe intervention could affect how low back pain is managed. FUNDING: National Health and Medical Research Council, Australia.

Molecular Pathways and Animal Models of Truncus Arteriosus.

In normal cardiovascular development in birds and mammals, the outflow tract of the heart is divided into two distinct channels to separate the oxygenated systemic blood flow from the deoxygenated pulmonary circulation. When the process of outflow tract septation fails, a single common outflow vessel persists resulting in a serious clinical condition known as persistent truncus arteriosus or common arterial trunk. In this chapter, we will review molecular pathways and the cells that are known to play a role in the formation and development of the outflow tract and how genetic manipulation of these pathways in animal models can result in common arterial trunk.

Molecular Pathways and Animal Models of Semilunar Valve and Aortic Arch Anomalies.

The great arteries of the vertebrate carry blood from the heart to the systemic circulation and are derived from the pharyngeal arch arteries. In higher vertebrates, the pharyngeal arch arteries are a symmetrical series of blood vessels that rapidly remodel during development to become the asymmetric aortic arch arteries carrying oxygenated blood from the left ventricle via the outflow tract. At the base of the aorta, as well as the pulmonary trunk, are the semilunar valves. These valves each have three leaflets and prevent the backflow of blood into the heart. During development, the process of aortic arch and valve formation may go wrong, resulting in cardiovascular defects, and these may, at least in part, be caused by genetic mutations. In this chapter, we will review models harboring genetic mutations that result in cardiovascular defects affecting the great arteries and the semilunar valves.

Head Injury Evaluation and Ambulance Diagnosis (HOME) Study protocol: a feasibility study assessing the implementation of the Canadian CT Head Rule in the prehospital setting.

INTRODUCTION: Traumatic brain injury (TBI) is a common presentation in the prehospital environment. At present, paramedics do not routinely use tools to identify low-risk patients who could be left at scene or taken to a local hospital rather than a major trauma centre. The Canadian CT Head Rule (CCHR) was developed to guide the use of CT imaging in hospital. It has not been evaluated in the prehospital setting. We aim to address this gap by evaluating the feasibility and acceptability of implementing the CCHR to patients and paramedics, and the feasibility of conducting a full-scale clinical trial of its use. METHODS AND ANALYSIS: We will recruit adult patients who are being transported to an emergency department (ED) by ambulance after suffering a mild TBI. Paramedics will prospectively collect data for the CCHR. All patients will be transported to the ED, where deferred consent will be taken and the treating clinician will reassess the CCHR, blinded to paramedic interpretation. The primary clinical outcome will be neurosurgically significant TBI. Feasibility outcomes include recruitment and attrition rates. We will assess acceptability of the CCHR to paramedics using the Ottawa Acceptability of Decision Rules Instrument. Interobserver reliability of the CCHR will be assessed between paramedics and the treating clinician in the ED. Participating paramedics and patients will be invited to participate in semistructured interviews to explore the acceptability of trial processes and facilitators and barriers to the use of the CCHR in practice. Data will be analysed thematically. We anticipate recruiting approximately 100 patients over 6 months. ETHICS AND DISSEMINATION: This study was approved by the Health Research Authority and the Research Ethics Committee (REC reference: 22/NW/0358). The results will be published in a peer-reviewed journal, presented at conferences and will be incorporated into a doctoral thesis. TRIAL REGISTRATION NUMBER: ISRCTN92566288.