Fragment-based development of small molecule inhibitors targeting cholesterol metabolism.

() is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi- (MDR) and extensively- (XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.

Expression and purification of Mycobacterium tuberculosis F-dependent glucose-6-phosphate dehydrogenase enzyme using Escherichia coli.

Since their discovery in Mycobacterium tuberculosis (Mtb), F-dependent enzymes have been identified as both important drug targets and potential industrial biocatalysts, including for bioremediation of otherwise recalcitrant substrates. Mtb-FGD1, utilizes glucose 6-phosphate (G6P) as an electron donor for the reduction of F. Current expression systems for Mtb-FGD1 use Mycobacterium smegmatis as host, because of the tendency for it to form inclusion bodies in E.

Will they come back? Evaluation of health student placements in remote and very remote regions of Australia.

Background: Despite the benefits of rural placements in attracting healthcare professionals to rural areas, there remains a gap in understanding the specific impact of placements in remote and very remote areas of Australia, particularly within the unique context of the Kimberley region. There is a need to elucidate differences across geographical areas and contribute to the knowledge about the specifics of where and how student placement programs work. This research explored the impact of a remote placement program at Majarlin Kimberley Centre for Remote Health ('Majarlin') on educational outcomes and workforce intentions of participating students.

Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression.

A stepped wedge randomised controlled trial assessing the efficacy and patient acceptability of virtual clinical pharmacy in rural and remote Australian hospitals.

Background: Despite medication being the most common healthcare intervention and medication-related incidents being common in hospitals, many rural and remote hospitals in Australia lack onsite pharmacy services due to resource constraints. A Virtual Clinical Pharmacy Service (VCPS) staffed by two senior, rural generalist hospital pharmacists assigned to four hospitals each was implemented in rural and remote facilities to determine whether the VCPS increased adherence to National Safety and Quality Health Service Standards (NSQHS).

Methods: A stepped-wedge randomised controlled trial was employed to sequentially implement a telehealth pharmacy service at one-month intervals in eight hospitals.

Cycles of susceptibility: Immunity debt explains altered infectious disease dynamics post -pandemic.

The concept of immunity debt is a phenomenon resulting from the suppression of endemic pathogens during the COVID-19 pandemic due to non-pharmaceutical interventions (NPIs). The reduced circulation of various pathogens during the pandemic, particularly respiratory syncytial virus (RSV), altered typical infectious disease dynamics by reducing levels of population immunity usually acquired through exposure to infection. This concept is demonstrated through post-pandemic resurgence of diseases such as RSV and Group A Streptococcus, and highlights the interplay between reduced pathogen exposure and increased susceptibility in populations.

Lived experiences of transgender and nonbinary people in the perioperative context: a qualitative study.

Background: Transgender and nonbinary (TNB) people experience obstacles that create barriers to accessing health care, including stigmatization and health inequities. Our intention was to describe the lived experiences of TNB patients and identify potential gaps in the education of health care professionals.

Methods: We conducted a qualitative descriptive study influenced by phenomenology by interviewing with TNB adults who underwent surgery in Canada within the previous 5 years.

An Innovative Approach to Determine Programmed Intermittent Epidural Bolus Pump Settings for Labor Analgesia: A Randomized Controlled Trial.

Background: Three settings are required on a programmed intermittent epidural bolus (PIEB) pump for labor analgesia: the PIEB next bolus (PIEBnb), PIEB interval (PIEBi), and PIEB volume (PIEBv). The ideal settings for these parameters are still unknown. We hypothesized a mathematical modeling tool, response surface methodology (RSM), could estimate 3 PIEB pump parameters while balancing 3 clinically important patient outcomes simultaneously.

Assessment of body composition in breast cancer patients: concordance between transverse computed tomography analysis at the fourth thoracic and third lumbar vertebrae.

Introduction: Specific body composition markers derived from L3 axial computed tomography (CT) images predict clinical cancer outcomes, including chemotherapy toxicity and survival. However, this method is only applicable to those undergoing lumbar (L3) CT scanning, which is not universally conducted in early breast cancer cases. This study aimed to evaluate CT analysis at T4 as a feasible alternative marker of body composition in breast cancer.

Vaccination against COVID-19 - risks and benefits in children.

Countries in Europe and around the world have taken varying approaches to their policies on COVID-19 vaccination for children. The low risk of severe illness from COVID-19 means that even small risks from vaccination warrant careful consideration. Vaccination appears to result in a decreased risk of severe illness including the paediatric multi-system inflammatory syndrome known to be associated with COVID-19.

A cautionary note on the use of N-acetylcysteine as a reactive oxygen species antagonist to assess copper mediated cell death.

A new form of cell death has recently been proposed involving copper-induced cell death, termed cuproptosis. This new form of cell death has been widely studied in relation to a novel class of copper ionophores, including elesclomol and disulfiram. However, the exact mechanism leading to cell death remains contentious.

Testing feasibility of relevant outcome measures in an inpatient setting to demonstrate the value of occupational therapy.

Introduction: Measures of participation restrictions in daily life occupations are not typically used and may aid discharge planning and demonstrate the impact of occupational therapy services in inpatient settings. The overall aim of this mixed-methods study was to test the feasibility of relevant outcome measures by (1) investigating which of the three identified measures-the Home Support Needs Assessment, the Personal Care Participation Assessment and Resource Tool, and the Functional Autonomy Measurement System-best identifies meaningful changes in participation restrictions in daily life occupations required for community life; and (2) investigating the acceptability, usefulness, and feasibility of each measure to support inpatient practice.

Methods: Occupational therapists (n = 3) completed the three measures with patient participants (n = 12) at admission and discharge.

Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking.

Reliability and Measurement Error of the Qualitative Analysis of Single Leg Loading (QASLS) Tool For Unilateral Tasks.

Background: Movement quality assessment is popular within clinical and sporting practice, due to the contribution diminished or suboptimal movement quality is believed to have on musculoskeletal (MSK) injury risk. Various movement quality assessments exist, many are limited to bilateral or jumping movements evaluation. Qualitative analysis of single leg loading (QASLS) is a new clinical assessment tool for unilateral tasks that utilizes a dichotomous scoring system of ten questions relating to the segmental body regions of the trunk, lower and upper limb.

The association between labour epidural analgesia and postpartum depression in primiparous patients: a historical cohort study.

Purpose: Peripartum pain has been associated with postpartum depression (PPD), and labour epidural analgesia (LEA) may be able to modify this risk. The objective of this historical cohort study was to examine the association between LEA and PPD among primiparous patients.

Methods: With institutional research ethics board approval, a provincial perinatal database was searched for primiparous patients who delivered a liveborn singleton infant between 2004 and 2018.

Exploring the responses of smallscale poultry keepers to avian influenza regulations and guidance in the United Kingdom, with recommendations for improved biosecurity messaging.

Understanding how smallscale ('backyard') poultry keepers interpret and respond to governmental directives designed to reduce the transmission of highly pathogenic avian influenza (HPAI) is of paramount importance in preparing for future HPAI outbreaks. Qualitative insights from open questions in an online survey conducted during the 2021-22 HPAI season (1,559 responses) shed light on smallscale poultry keepers' understanding of, and responses to, governmental directives to control HPAI exposure and onwards transmission. A follow-up participatory workshop (21 participants) explored the HPAI-related information sources used by smallscale poultry keepers, their trust in these sources, perceptions of HPAI-related risk, and interpretation of, opinions on and adherence to government regulations and communications regarding biosecurity and housing measures.

The disease burden of respiratory syncytial virus in Infants.

Purpose Of Review: To describe the current global burden of respiratory syncytial virus (RSV) in infants and its implications for morbidity, health resources and economic costs.

Recent Findings: New prophylactic therapies are on the horizon for RSV in the form of long-acting monoclonal antibodies suitable for healthy infants and maternal immunizations.

Summary: Despite being responsible for significant global infant morbidity and mortality, until recently there have been no effective therapeutics available for healthy infants to protect them from RSV.

Policies on children and schools during the SARS-CoV-2 pandemic in Western Europe.

During the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mitigation policies for children have been a topic of considerable uncertainty and debate. Although some children have co-morbidities which increase their risk for severe coronavirus disease (COVID-19), and complications such as multisystem inflammatory syndrome and long COVID, most children only get mild COVID-19. On the other hand, consistent evidence shows that mass mitigation measures had enormous adverse impacts on children.

Aotearoa New Zealand emergency ambulance services and the provision of end-of-life care: a short survey.

Aim: To characterise emergency ambulance service (EAS) clinical roles and experiences (including cultural competency and pastoral care) in the delivery of end-of-life (EOL) and palliative care in Aotearoa New Zealand.

Method: A nine question online survey was distributed to St John and Wellington Free Ambulance clinicians. Four questions enabled voluntary free-text comments to be submitted for thematic analysis.

Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization.