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Introduction Penicillin allergy labels (PALs) are reported in 1 in 10 hospitalised patients globally and associated with inferior patient, hospital and microbiological outcomes; however, the majority are incorrect and should be removed. Direct oral penicillin challenge has been demonstrated to be a safe and effective method for the removal of PALs. However, the question of whether a single dose is sufficient to ascertain true allergy status remains unanswered, with some studies suggesting that extended challenges of 3 or more days are superior for the exclusion of delayed immune reactions. The aim of the PROSPECTOR studies was to determine the feasibility (PROSPECTOR-1) of a definitive trial (PROSPECTOR-2) to evaluate the safety and effectiveness of prolonged oral challenge (ie, 5 days) versus single-dose oral challenge in patients with a delayed or unknown penicillin allergy phenotype (PROSPECTOR-2).Methods and analysis A pair of double-blind two-arm parallel placebo-controlled trials will be undertaken—PROlonged versus Single dose in PEnicillin oral Challenge Testing double-blind parallel group randomised placebo-cOntrolled tRial (PROSPECTOR Studies). Patients with a reported delayed or unknown timing penicillin allergy who have passed a supervised single-dose oral amoxicillin challenge (with or without prior skin testing/single or split dose) will be recruited. Informed patient consent will be granted for sites to recruit patients and collect routine clinical data. PROSPECTOR-1 will assess the safety and feasibility of a placebo-controlled trial for single-dose amoxicillin challenge versus 5-day prolonged oral challenge. PROSPECTOR-2 will assess the superiority of the 5-day prolonged oral challenge compared with single-dose amoxicillin challenge in excluding a delayed immune reaction. PROSPECTOR-2 will commence immediately post completion of PROSPECTOR-1 in a vanguard design, with adjustments to the projected sample size for superiority made following completion of PROSPECTOR-1. PROSPECTOR-2 will commence recruitment immediately following closure of PROSPECTOR-1; however, data from each trial will be analysed separately.Ethics and dissemination These studies were reviewed and approved by the Austin Health Human Research Ethics Committee (PROSPECTOR-1: HREC/99740/Austin-2023 and PROSPECTOR-2: HREC/109785/Austin-2024). The results will be published in peer-reviewed journals and presented at relevant conferences.Trial registration number PROSPECTOR-1: ACTRN12623001242617 and PROSPECTOR-2: ACTRN12624001107516.

IntroductionMitochondrial dysfunction promotes vascular aging and disease through diverse mechanisms beyond metabolic supply, including calcium and radical signaling and inflammation. Mitochondrial DNA (mtDNA) replication by the POLG-encoded mitochondrial DNA polymerase (POLG) is critical for mitochondrial health. Loss-of-function POLG variants are associated with a predisposition to hypertension. We hypothesized that impaired POLG, through reduced mtDNA copy number or other mechanisms, would promote smooth muscle hypertrophy or hyperplasia that drives vascular remodeling associated with hypertension.MethodsWe characterized the effect of over-expressing POLG variants that were previously observed in a cohort of hypertensive patients (p.Tyr955Cys, p.Arg964Cys, p.Asn1098Ile, and p.Arg1138Cys) in A7r5 cells.ResultsAlphaFold modeling of the POLG holoenzyme complexed with DNA predicted changes in the catalytic site in the p.Tyr955Cys and p.Asn1098Ile variants, while p.Arg964Cys and p.Arg1138Cys showed minimal effects. The POLG variants reduced mtDNA copy number, assessed by immunofluorescence and droplet digital PCR, by up to 27% in the order p.Tyr955Cys > p.Arg964Cys > p.Asn1098Ile > p.Arg1138Cys relative to wild-type-transfected cultures. Loss of mtDNA was reduced in cultures grown in low serum and glucose media, but the cell density was increased in the same rank order in both 10% serum and 1% serum. POLG constructs contained a Myc epitope, the counterstaining for which showed that the mtDNA copy number was reduced in both transfected cells and untransfected neighbors. Live-cell imaging of mitochondrial membrane potential with TMRM and radical oxygen species production with MitoSOX showed little effect of the POLG variants. POLG variants had little effect on oxygen consumption, assessed by Seahorse assay. Live-cell imaging growth analyses again showed increased growth in A7r5 cells transfected with p.Tyr955Cys but a decreased growth with p.Arg1138Cys, while p.Tyr955Cys increased growth of HeLa cells. Conditioned media from HeLa cells transfected with POLG variants reduced doubling times in naïve cultures. Pharmacologically, wedelolactone and MitoTEMPOL, but not indomethacin or PD98059, suppressed the mitogenic effects of p.Tyr955Cys and p.Arg964Cys in A7r5 cells.DiscussionWe conclude that POLG dysfunction induces secretion of a mitogenic signal from A7r5 and HeLa cells even when changes in mtDNA copy number are below the limit of detection. Such mitogenic stimulation could stimulate hypertrophic remodeling that could contribute to drug-resistant hypertension in patient populations with loss-of-function POLG variants.

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR. Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites. Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%). Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality. Trial registration: ANZCTR ACTRN12619000241134. Registered 19 February 2019.

Females were regarded as incompetent as a leader before the current modern era. But, female in managerial positions has been increasing since 2015. As part of corporate governance, there is only a few research regarding gender diversity’s relationship with financial distress with different results on different context. This research investigates the role of board gender diversity on firms’ financial distress. Multiple linear regression is used as the method of study. In general, board gender diversity does not have any relationship with financial distress in the infrastructure firms. When dissected into 4 sub-sectors, 1 out of 3 sub-sectors with 1 other sub-sector excluded, shown a negative relationship between board gender diversity and financial distress while the other 3 sub-sectors do not show any significant relationship. Keywords: Corporate Governance; Financial Distress; Gender Diversity.

Histone deacetylase 3 (HDAC3) is a regulator of lipid homeostasis in several tissues, however, its role in intestinal lipid metabolism was not yet known. Here the authors study intestine specific HDAC3 knock out mice and report that these animals have increased fatty acid oxidation and undergo remodeling of the intestinal epithelial cell lipidome.

Hypoxia-inducible factor 1α (HIF1α) is a transcription factor that regulates the adaptation of cells to hypoxic microenvironments, for example inside solid tumours. Stabilisation of HIF1α can also occur in normoxic conditions in inflamed tissue or as a result of inactivating mutations in negative regulators of HIF1α. Aberrant overexpression of HIF1α in many different cancers has led to intensive efforts to develop HIF1α-targeted therapies. However, the role of HIF1α is still poorly understood in chronic inflammation that predisposes the colon to carcinogenesis. We have previously reported that the transcription of HIF1α is upregulated and that the protein is stabilised in inflammatory lesions that are caused by the non-steroidal anti-inflammatory drug (NSAID) sulindac in the mouse proximal colon. Here, we exploited this side effect of long-term sulindac administration to analyse the role of HIF1α in colon inflammation using mice with a Villin-Cre-induced deletion of Hif1α exon 2 in the intestinal epithelium (Hif1αΔIEC). We also analysed the effect of sulindac sulfide on the aryl hydrocarbon receptor (AHR) pathway in vitro in colon cancer cells. Most sulindac-treated mice developed visible lesions, resembling the appearance of flat adenomas in the human colon, surrounded by macroscopically normal mucosa. Hif1αΔIEC mice still developed lesions but they were smaller than in the Hif1α-floxed siblings (Hif1αF/F). Microscopically, Hif1αΔIEC mice had significantly less severe colon inflammation than Hif1αF/F mice. Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1αΔIEC mice. However, immunohistochemistry analysis revealed a defect of E-cadherin protein expression in sulindac-treated Hif1αΔIEC mice. Sulindac sulfide treatment in vitro upregulated Hif1α, c-JUN and IL8 expression through the AHR pathway. Taken together, HIF1α expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.