Attributable mortality of candidemia - Results from the ECMM Candida III multinational European Observational Cohort Study.

Introduction: Despite antifungal advancements, candidaemia still has a high mortality rate of up to 40%. The ECMM Candida III study in Europe investigated the changing epidemiology and outcomes of candidaemia for better understanding and management of these infections.

Methods: In this observational cohort study, participating hospitals enrolled the first ten consecutive adults with blood culture-proven candidemia.

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days.

Development and proof-of-concept demonstration of a clinical metagenomics method for the rapid detection of bloodstream infection.

Background: The timely and accurate diagnosis of bloodstream infection (BSI) is critical for patient management. With longstanding challenges for routine blood culture, metagenomics is a promising approach to rapidly provide sequence-based detection and characterisation of bloodborne bacteria. Long-read sequencing technologies have successfully supported the use of clinical metagenomics for syndromes such as respiratory illness, and modified approaches may address two requisite factors for metagenomics to be used as a BSI diagnostic: depletion of the high level of host DNA to then detect the low abundance of microbes in blood.

An Overview of Systematic Reviews of Polymerase Chain Reaction (PCR) for the Diagnosis of Invasive Aspergillosis in Immunocompromised People: A Report of the Fungal PCR Initiative (FPCRI)-An ISHAM Working Group.

This overview of reviews (i.e., an umbrella review) is designed to reappraise the validity of systematic reviews (SRs) and meta-analyses related to the performance of PCR tests for the diagnosis of invasive aspergillosis in immunocompromised patients.

Practical use of apomorphine infusion in Parkinson's disease: lessons from the TOLEDO study and clinical experience.

Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson's disease that can be considered when motor fluctuations become persistent and are no longer adequately controlled by oral/transdermal medication. Apomorphine infusion is less invasive than enteral levodopa, deep brain stimulation or focused ultrasound, and is often indicated even when neurosurgical approaches are contraindicated. This article aims to provide practical guidance for doctors and nurses initiating and treating patients with apomorphine infusion, and is based on both trial data and clinical experience from movement disorders specialists.

Guideline adherence and survival of patients with candidaemia in Europe: results from the ECMM Candida III multinational European observational cohort study.

Background: The European Confederation of Medical Mycology (ECMM) collected data on epidemiology, risk factors, treatment, and outcomes of patients with culture-proven candidaemia across Europe to assess how adherence to guideline recommendations is associated with outcomes.

Methods: In this observational cohort study, 64 participating hospitals located in 20 European countries, with the number of eligible hospitals per country determined by population size, included the first ten consecutive adults with culture-proven candidaemia after July 1, 2018, and entered data into the ECMM Candida Registry (FungiScope CandiReg). We assessed ECMM Quality of Clinical Candidaemia Management (EQUAL Candida) scores reflecting adherence to recommendations of the European Society of Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of America guidelines.

Reactions to using other nicotine and tobacco products instead of menthol cigarettes: A qualitative study of people who smoke menthol cigarettes in the United States.

The US Food and Drug Administration is considering banning menthol cigarettes, which could result in some people who smoke menthol cigarettes switching to other tobacco products (OTPs). This qualitative study explored reactions to using OTPs instead of menthol cigarettes. People who smoke menthol cigarettes (N=40) completed a behavioral economic assessment of the effects of menthol cigarette price increases on OTP purchasing.

A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation.

Background: A potential immunotherapeutic role for AZD1656 (a glucokinase activator) in the treatment of COVID-19 was hypothesized. The ARCADIA trial investigated the safety and efficacy of AZD1656 in diabetic patients admitted to hospital with COVID-19.

Methods: The ARCADIA trial was a Phase II randomised, double-blind, placebo-controlled clinical trial.

"I think it's a good idea for the people that's young, the kids, but for someone like me it's a bad idea." - Interviews about a U.S. menthol cigarette ban with people who smoke menthol cigarettes.

Objective: The US Food and Drug Administration recently announced its intention to pursue a federal ban on menthol cigarettes. This qualitative study assessed reactions to a potential menthol cigarette ban among people who smoke menthol cigarettes.

Methods: As part of a laboratory study examining menthol flavor regulations, we conducted follow-up interviews with participants who smoke menthol cigarettes (N = 35).

ARCADIA study protocol: a phase II, randomised, double-blind, placebo-controlled clinical trial to assess the safety and efficacy of AZD1656 in patients with diabetes hospitalised with suspected or confirmed COVID-19.

Introduction: COVID-19, caused by SARS-CoV-2, remains a global pandemic that has affected more than 100 million people worldwide with over 4.8 million deaths as of October 2021. Patients with diabetes have both an increased susceptibility to SARS-CoV-2 infection, enhanced disease severity and increased risk of mortality.

The citron homology domain as a scaffold for Rho1 signaling.

is a human opportunistic pathogen showing emerging resistance against a limited repertoire of antifungal agents available. The GTPase Rho1 has been identified as an important regulator of the cell wall integrity signaling pathway that regulates the composition of the cell wall, a structure that is unique to fungi and serves as a target for antifungal compounds. Rom2, the guanine nucleotide exchange factor to Rho1, contains a C-terminal citron homology (CNH) domain of unknown function that is found in many other eukaryotic genes.

Genetic and structural validation of phosphomannomutase as a cell wall target in Aspergillus fumigatus.

Aspergillus fumigatus is an opportunistic mold responsible for severe life-threatening fungal infections in immunocompromised patients. The cell wall, an essential structure composed of glucan, chitin, and galactomannan, is considered to be a target for the development of antifungal drugs. The nucleotide sugar donor GDP-mannose (GDP-Man) is required for the biosynthesis of galactomannan, glycosylphosphatidylinositol (GPI) anchors, glycolipid, and protein glycosylation.

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study.

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).

Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry.

The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.

Background: The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined.

Objectives: To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA).

Targeting a critical step in fungal hexosamine biosynthesis.

is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs.

Rapid Rule Out of Culture-Negative Bloodstream Infections by Use of a Novel Approach to Universal Detection of Bacteria and Fungi.

Background: Currently it can take up to 5 days to rule out bloodstream infection. With the low yield of blood cultures (approximately 10%), a significant number of patients are potentially exposed to inappropriate therapy that can lead to adverse events. More rapid rule out can accelerate deescalation or cessation of antimicrobial therapy, improving patient outcomes.

Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α.

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle.

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

Background: Fabry disease is an X-linked lysosomal storage disorder caused by mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant () forms of α-Gal to facilitate normal lysosomal trafficking.

Methods: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT.

The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity.

Methods: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat.

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

Background: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes.

Methods: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations.

The Impact of Obesity on the 30-day Morbidity and Mortality After Surgery for Ovarian Cancer.

Objectives: To examine the effect of body mass index (BMI) on postoperative 30-day morbidity and mortality after surgery for ovarian cancer (OC).

Methods: Patients with OC were identified from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2011. Women were divided into 3 groups: nonobese (BMI <30 kg/m), obese (30 to <40 kg/m), and morbidly obese (≥40 kg/m).

Impact of Age on 30-Day Mortality and Morbidity in Patients Undergoing Surgery for Ovarian Cancer.

Objective: To examine the effect of age on postoperative 30-day morbidity and mortality after surgery for ovarian cancer.

Methods: The American College of Surgeons National Surgical Quality Improvement Program files were used to identify patients with ovarian cancer who underwent surgery in 2005 to 2011. Women were divided into 4 age groups: <60, 60 to 69, 70 to 79, and ≥80 years.