Developing and disseminating an electronic penicillin allergy de-labelling tool using the model for improvement framework.

Background: Many clinicians feel uncomfortable with de-labelling penicillin allergies despite ample safety data. Point of care tools effectively support providers with de-labelling. This study's objective was to increase the number of providers intending to pursue a penicillin oral challenge by 15% by February 2023.

C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.

Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR.

Molecular hallmarks of ageing in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor.

ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.

Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear.

Efficacy of beetroot juice on reducing blood pressure in hypertensive adults with autosomal dominant polycystic kidney disease (BEET-PKD): study protocol for a double-blind, randomised, placebo-controlled trial.

Background: In autosomal dominant polycystic kidney disease (ADPKD) impaired nitric oxide (NO) synthesis, in part, contributes to early-onset hypertension. Beetroot juice (BRJ) reduces blood pressure (BP) by increasing NO-mediated vasodilation. The aim of this double-blind, randomised, placebo-controlled study is to test the hypothesis that BRJ reduces systolic and diastolic clinic BP in hypertensive adults with ADPKD.

Culture of Three-Dimensional Madin-Darby Canine Kidney (MDCK) Cysts for In Vitro Drug Testing in Polycystic Kidney Disease.

The formation and growth of kidney cysts (fluid-filled structures lined by epithelial cells) is the primary pathological abnormality in polycystic kidney disease (PKD). Multiple molecular pathways are disrupted in kidney epithelial precursor cells, which lead to altered planar cell polarity, increased proliferation, and fluid secretion, which together with extracellular matrix remodelling culminates in the formation and growth of cysts. Three-dimensional (3D) in vitro cyst models serve as suitable preclinical models to screen candidate drugs for PKD.

Outcomes of extended total mesorectal excision in patients with locally advanced rectal cancer.

Aim: Extended total mesorectal excision (eTME) is a complex procedure involving en bloc resection of the structures surrounding the various quadrants of the rectum. This study, presenting the largest series so far of patients undergoing eTME, aimed to assess the surgical and survival outcomes of patients following treatment with eTME and to compare these outcomes with historical data on pelvic exenteration.

Method: The study is a retrospective review of all patients with locally advanced rectal cancer requiring an eTME (2014-2020).

Patterns of Utilization and Outcomes of Perioperative Chemotherapy in Patients With Locally Advanced-urothelial Bladder Cancer (LABC)-Real World Data From an Indian Tertiary Care Cancer Center.

Aim: Optimal utilization of perioperative systemic therapy in locally advanced bladder cancer (LABC) holds the key in improving the survival outcomes. We aim to analyze the oncological outcomes of clinically locally advanced urothelial bladder cancer patients treated with neoadjuvant (NACT) or adjuvant chemotherapy or without any systemic therapy in the perioperative period of radical cystectomy.

Methods & Material: We retrospectively analyzed the medical records of patients with cancer of the urinary bladder diagnosed between 2012 and 2020.

Penicillin de-labelling in vancouver, British Columbia, Canada: comparison of approaches, outcomes and future directions.

Background: Inaccurate penicillin allergy labels lead to inappropriate antibiotic prescriptions and harmful patient consequences. System-wide efforts are needed to remove incorrect penicillin allergy labels, but more health services research is required on how to best deliver these services.

Methods: Data was extracted from five hospitals in Vancouver, British Columbia, Canada from October 2018-May 2022.

Kidney Cyst Lining Epithelial Cells Are Resistant to Low-Dose Cisplatin-Induced DNA Damage in a Preclinical Model of Autosomal Dominant Polycystic Kidney Disease.

Increased DNA damage response (DDR) signaling in kidney cyst-lining epithelial cells (CECs) may provide an opportunity for cell-specific therapeutic targeting in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inhibiting ataxia telangiectasia mutated (ATM; a proximal DDR kinase) together with low-dose cisplatin overwhelms the DDR response and leads to selective apoptosis of cyst-lining epithelial cells (CECs). Pkd1RC/RC/Atm+/− mice were treated with either vehicle or a single low-dose cisplatin, and the acute effects on CECs (DNA damage and apoptosis) after 72 h and chronic effects on progression (cyst size, inflammation, fibrosis) after 3 weeks were investigated.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Arginine vasopressin promotes kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Increased water intake reduces arginine vasopressin and urine osmolality and may slow kidney cyst growth. METHODS: In this randomized controlled 3-year clinical trial, we randomly assigned adults with ADPKD who had a height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and an estimated glomerular filtration rate of 30 ml/min/1.

Clinical characteristics and outcomes of hyponatraemia associated with oral water intake in adults: a systematic review.

Introduction: Excessive water intake is rarely associated with life-threatening hyponatraemia. The aim of this study was to determine the clinical characteristics and outcomes of hyponatraemia associated with excess water intake.

Methods: This review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease.

Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.

Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease.

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner.

Possible role of the mitochondrial genome in the pathogenesis of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic renal disease in adults and is due to heterozygous germ line variants in either PKD1, PKD2 or rarely other genes. It is characterized by marked intra-familial disease variability suggesting that other genetic and/or environmental factors are involved in determining the lifetime course ADPKD. Recently, research indicates that polycystin-mediated mitochondrial dysfunction and metabolic re-programming contributes to the progression of ADPKD.

Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease.

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.

Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease.

The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD.

Up-Regulation of DNA Damage Response Signaling in Autosomal Dominant Polycystic Kidney Disease.

DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.

Assessment of Dietary Sodium Intake Using the Scored Salt Questionnaire in Autosomal Dominant Polycystic Kidney Disease.

The excess intake of dietary sodium is a key modifiable factor for reducing disease progression in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that the scored salt questionnaire (SSQ; a frequency questionnaire of nine sodium-rich food types) is a valid instrument to identify high dietary salt intake in ADPKD. The performance of the SSQ was evaluated in adults with ADPKD with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.

"We regret to inform you that you did not match": Reflections on how to improve the match experience.

There is increasing concern amongst stakeholders over the high numbers of unmatched Canadian Medical Graduates (CMGs), yet little is known from the perspective of those who go unmatched. We present an opinion-based narrative analysis examining the matching process by reflecting on the pre- and post-match period and provide suggestions related to the Canadian context from the unmatched perspective. The challenge in the pre-match period was a lack of transparency around elective availability, resident selection criteria, and what happens after going unmatched.

Regression of Peritubular Capillaries Coincides with Angiogenesis and Renal Cyst Growth in Experimental Polycystic Kidney Disease.

Background/aim: The natural history of the renal microvasculature changes in PKD is not known. The aim of this study was to test the hypothesis that angiogenesis is coupled with kidney cyst expansion, and the loss of peritubular capillary networks precedes the onset of interstitial fibrosis.

Methods: The renal microvasculature (RECA-1 and CD34) was evaluated in groups of Lewis polycystic kidney (LPK) rats and juvenile cystic kidney () mice during the early, mid and late stage of disease.

Role of cyclin-dependent kinase 2 in the progression of mouse juvenile cystic kidney disease.

A hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a pan-Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck) mice. Cdk2 is a key regulator of cell proliferation, but its specific role in PKD remains unknown.

The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1-2% of nephrons for reasons that are not clear.