Systemic in utero gene editing as a treatment for cystic fibrosis.

In utero gene editing has the potential to modify disease causing genes in multiple developing tissues before birth, possibly allowing for normal organ development, disease improvement, and conceivably, cure. In cystic fibrosis (CF), a disease that arises from mutations in the cystic fibrosis transmembrane conductance regulator ( ) gene, there are signs of multiorgan disease affecting the function of the respiratory, gastrointestinal, and reproductive systems already present at birth. Thus, treating CF patients early is crucial for preventing or delaying irreversible organ damage.

The impact of the California state lockdown during the COVID-19 pandemic on management of patients with pancreatic ductal adenocarcinoma.

Background And Objectives: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation.

DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid.

Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in -alkylation of the precursory serine side chain.

Current and Novel Biologic Therapies for Patients with Asthma and Nasal Polyps.

A substantial portion of asthma and nasal polyps (NPs) share a common pathogenesis, which includes type 2-mediated inflammation. Distinct endotypes and phenotypes characterizing asthma and chronic rhinosinusitis have been identified. With emerging evidence describing pathophysiology, novel targets for biologic monoclonal antibody treatments have been developed.

The majority of patients with resectable incidental lung cancers are ineligible for lung cancer screening.

Objective: The study objective was to determine what proportion of asymptomatic patients had resectable lung cancer detected through lung cancer screening versus incidentally.

Methods: We performed a retrospective study of patients who underwent resection for lung cancer between January 2015 and December 2020. We then assessed whether asymptomatic patients with incidentally found lung cancers were eligible for lung cancer screening using the National Comprehensive Cancer Network, United States Preventive Services Task Force, Centers for Medicare & Medicaid Services, American College of Chest Physicians, American Cancer Society, and American Society of Clinical Oncology guidelines.

Generation of liver metastases in a mouse model using ultrasound-guided intravenous injection.

Here, we present a protocol to generate a murine model of liver metastasis by directly injecting tumor cells into the portal vein under ultrasound guidance. We describe steps for animal and cell preparation and two techniques for injecting tumor cells. One technique is freehand, while the other technique is device-assisted using a 3D-printed prototype device.

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity.

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions.

Surface conjugation of antibodies improves nanoparticle uptake in bronchial epithelial cells.

Background: Advances in Molecular Therapy have made gene editing through systemic or topical administration of reagents a feasible strategy to treat genetic diseases in a rational manner. Encapsulation of therapeutic agents in nanoparticles can improve intracellular delivery of therapeutic agents, provided that the nanoparticles are efficiently taken up within the target cells. In prior work we had established proof-of-principle that nanoparticles carrying gene editing reagents can mediate site-specific gene editing in fetal and adult animals in vivo that results in functional disease improvement in rodent models of β-thalassemia and cystic fibrosis.

Long-acting and extended-release implant and nanoformulations with a synergistic antiretroviral two-drug combination controls HIV-1 infection in a humanized mouse model.

The HIV pandemic has affected over 38 million people worldwide with close to 26 million currently accessing antiretroviral therapy (ART). A major challenge in the long-term treatment of HIV-1 infection is nonadherence to ART. Long-acting antiretroviral (LA-ARV) formulations, that reduce dosing frequency to less than once a day, are an urgent need that could tackle the adherence issue.

Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance.

In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug.

Nanoparticles for delivery of agents to fetal lungs.

Fetal treatment of congenital lung disease, such as cystic fibrosis, surfactant protein syndromes, and congenital diaphragmatic hernia, has been made possible by improvements in prenatal diagnostic and interventional technology. Delivery of therapeutic agents to fetal lungs in nanoparticles improves cellular uptake. The efficacy and safety of nanoparticle-based fetal lung therapy depends on targeting of necessary cell populations.

The N-glycome regulates the endothelial-to-hematopoietic transition.

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from the transdifferentiation of hemogenic endothelial cells (hemECs). The mechanisms of this endothelial-to-hematopoietic transition (EHT) are poorly understood. We show that microRNA-223 (miR-223)-mediated regulation of N-glycan biosynthesis in endothelial cells (ECs) regulates EHT.

Optimizing biodegradable nanoparticle size for tissue-specific delivery.

Nanoparticles (NPs) are promising vehicles for drug delivery because of their potential to target specific tissues [1]. Although it is known that NP size plays a critical role in determining their biological activity, there are few quantitative studies of the role of NP size in determining biodistribution after systemic administration. Here, we engineered fluorescent, biodegradable poly(lactic-co-glycolic acid) (PLGA) NPs in a range of sizes (120-440nm) utilizing a microfluidic platform and used these NPs to determine the effect of diameter on bulk tissue and cellular distribution after systemic administration.

Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV.

Combination antiretroviral therapy (cART) has been proven effective in inhibiting human immunodeficiency virus type 1 (HIV-1) infection and has significantly improved the health outcomes in acquired immune deficiency syndrome (AIDS) patients. The therapeutic benefits of cART have been challenged because of the toxicity and emergence of drug-resistant HIV-1 strains along with lifelong patient compliance resulting in non-adherence. These issues also hinder the clinical benefits of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are one of the vital components of cART for the treatment of HIV-1 infection.

Healthcare-associated infection surveillance and bedside alerts.

Expectations and requirements concerning the identification and surveillance of healthcare-associated infections (HAIs) are increasing, calling for differentiated automated approaches. In an attempt to bridge the "definition swamp" of these infections and serve the needs of different users, we improved the monitoring of nosocomial infections (MONI) software to create better surveillance reports according to consented national and international definitions, as well as produce infection overviews on complex clinical matters including alerts for the clinician's ward and bedside work. MONI contains and processes surveillance definitions for intensive-care-unit-acquired infections from the European Centre for Disease Prevention and Control, Sweden, as well as the Centers for Disease Control and Prevention, USA.

Can we bridge the definition diversity in healthcare-associated infection surveillance? From IT-supported surveillance to IT-supported infection prevention and control.

Expectations and requirements of the surveillance of healthcare-associated infections (HAIs) trigger a growing differentiation of HAI surveillance approaches. In an attempt to bridge this diversity of definitions and to serve the needs of different user groups, we have enhanced MONI (identification, monitoring, and reporting of nosocomial infections) not only to create better reports, but also to output overviews on complex clinical matters, as well as to generate alerts and reminders for the clinicians' bedside work.

Concise healthcare-associated infection reporting and benchmarking with minimal staff resources.

We report on intelligent information technology tools that produce fully-automated surveillance reports of high precision for 12 intensive care units (ICUs) without relevant time expenditure of infection control or ICU staff. This is accomplished by MONI-ICU, a computerized system for automated identification and continuous monitoring of ICU-associated infections, which makes surveillance data readily accessible and presents them in easily perceptible reporting format.

Effectiveness of an automated surveillance system for intensive care unit-acquired infections.

This study assessed the effectiveness of a fully automated surveillance system for the detection of healthcare-associated infections (HCAIs) in intensive care units. Manual ward surveillance (MS) and electronic surveillance (ES) were performed for two intensive care units of the Vienna General Hospital. All patients admitted for a period longer than 48 h between 13 November 2006 and 7 February 2007 were evaluated according to HELICS-defined rules for HCAI.

Fully Automated Surveillance of Healthcare-Associated Infections with MONI-ICU: A Breakthrough in Clinical Infection Surveillance.

Objective: Expert surveillance of healthcare-associated infections (HCAIs) is a key parameter for good clinical practice, especially in intensive care medicine. Assessment of clinical entities such as HCAIs is a time-consuming task for highly trained experts. Such are neither available nor affordable in sufficient numbers for continuous surveillance services.

Personality, acculturation, and psychosocial adjustment of Chinese international students in Germany.

The effect of personality traits and acculturation variables on crosscultural adjustment were investigated in 139 Chinese students in Germany (52% girls; M age = 25.3 yr., SD = 2.

[Blended learning in continuing medical education. Evaluation of an innovative curriculum "bipolar and bipolar spectrum disorders"].

Background: In this article a blended learning concept in continuing medical education is evaluated over a broad range of ages, as there is little data on this topic so far. The aims of this study were to document the blended learning concept, to evaluate the subjective gain of knowledge, as well as didactic and virtual means. Finally the actual usage and accreditation are reported.

Processing gradual information with Fuzzy Arden syntax.

The programming language Arden Syntax is especially adapted to the needs of computer-based clinical decision support. Recently, an extension of Arden Syntax, named Fuzzy Arden Syntax, was proposed by the authors. Fuzzy Arden Syntax is a conservative extension of Arden Syntax and offers special functionality to process gradual information.

Electronic surveillance of healthcare-associated infections with MONI-ICU--a clinical breakthrough compared to conventional surveillance systems.

Surveillance of clinical entities such as healthcare-associated infections (HCAI) by conventional techniques is a time-consuming task for highly trained experts. Such are neither available nor affordable in sufficient numbers on a permanent basis. Nevertheless, expert surveillance is a key parameter for good clinical practice, especially in intensive care medicine.

Fuzzy Arden Syntax: A fuzzy programming language for medicine.

Objective: The programming language Arden Syntax has been optimised for use in clinical decision support systems. We describe an extension of this language named Fuzzy Arden Syntax, whose original version was introduced in S. Tiffe's dissertation on "Fuzzy Arden Syntax: Representation and Interpretation of Vague Medical Knowledge by Fuzzified Arden Syntax" (Vienna University of Technology, 2003).