Identification of an exosite at the neutrophil elastase/alpha-1-antitrypsin interface.

Neutrophil elastase (NE) is released by activated neutrophils during an inflammatory response and exerts proteolytic activity on elastin and other extracellular matrix components. This protease is rapidly inhibited by the plasma serine protease inhibitor alpha-1-antitrypsin (AAT), and the importance of this protective activity on lung tissue is highlighted by the development of early onset emphysema in individuals with AAT deficiency. As a serpin, AAT presents a surface-exposed reactive centre loop (RCL) whose sequence mirrors the target protease specificity.

Prostate Cancer Risk Prediction Model Using Clinical and Magnetic Resonance Imaging-Related Findings: Impact of Combining Lesions' Locations and Apparent Diffusion Coefficient Values.

Objectives: The aims of the study are to develop a prostate cancer risk prediction model that combines clinical and magnetic resonance imaging (MRI)-related findings and to assess the impact of adding Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions-level findings on its diagnostic performance.

Methods: This 3-center retrospective study included prostate MRI examinations performed with clinical suspicion of clinically significant prostate cancer (csPCa) between 2018 and 2022. Pathological diagnosis within 1 year after the MRI was used to diagnose csPCa.

In-field prostate cancer recurrence following radical prostatectomy and salvage radiation.

Objective: To define the natural history, patterns of recurrence and treatment modalities for local prostate cancer (PCa) recurrence following radical prostatectomy (RP) and radiation therapy (RT), and to investigate factors that could predict metastasis-free survival (MFS) in this unique patient population.

Methods: We queried a prospectively maintained PCa registry to identify men developing in-field recurrence (IFR) following RP and RT from 2008 to 2021 at a single institution. IFR was defined as biopsy-proven recurrent PCa or the presence of persistent positron emission tomography-avid lesions in the prior radiation field without evidence of metastasis.

Estimated diagnostic performance of prostate MRI performed with clinical suspicion of prostate cancer.

Purpose: To assess the diagnostic performance of prostate MRI by estimating the proportion of clinically significant prostate cancer (csPCa) in patients without prostate pathology.

Materials And Methods: This three-center retrospective study included prostate MRI examinations performed for clinical suspicion of csPCa (Grade group ≥ 2) between 2018 and 2022. Examinations were divided into two groups: pathological diagnosis within 1 year after the MRI (post-MRI pathology) is present and absent.

Biomarkers Associated With Future Severe Liver Disease in Children With Alpha-1-Antitrypsin Deficiency.

Background And Aims: Children with alpha-1-antitrypsin deficiency (AATD) exhibit a wide range of liver disease outcomes from portal hypertension and transplant to asymptomatic without fibrosis. Individual outcomes cannot be predicted. Liver injury in AATD is caused by the accumulation in hepatocytes of the mutant Z alpha-1-antitrypsin (AAT) protein, especially the toxic, intracellular polymerized conformation.

Fibrosis, biomarkers and liver biopsy in AAT deficiency and relation to liver Z protein polymer accumulation.

Background And Aims: The course of adults with ZZ alpha-1-antitrypsin deficiency (AATD) liver disease is unpredictable. The utility of markers, including liver biopsy, is undefined.

Methods: A prospective cohort, including protocol liver biopsies, was enrolled to address these questions.

The Impact of Double Pelvic Osteotomy on Dorsolateral Subluxation in 24 Dogs.

Objective:  The aim of this study was to determine the effect of double pelvic osteotomy (DPO) on dorsolateral subluxation (DLS) of the femoral head in a weight-bearing position.

Study Design:  Retrospective observational study with treatment effect analysis. Twenty-four client-owned dogs that underwent DPO due to hip dysplasia.

Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors.

Background: Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 "Z" genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease.

Methods: We conducted a high-throughput image-based small molecule screen using patient-derived induced pluripotent stem cell-hepatocytes (iPSC-hepatocytes).

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion.

Magnetic Resonance Imaging-Guided Cryoablation of Prostate Cancer Lymph Node Metastasis.

Purpose: To evaluate the safety and effectiveness of magnetic resonance (MR) imaging-guided cryoablation of prostate cancer metastatic lymph nodes (LNs).

Materials And Methods: Fifty-two patients with prostate cancer who underwent MR imaging-guided LN ablation from September 2013 to June 2022 were retrospectively reviewed. Of these, 6 patients were excluded because adequate ablation margins (3-5 mm) could not be achieved secondary to adjacent structures.

Automated surgical step recognition in transurethral bladder tumor resection using artificial intelligence: transfer learning across surgical modalities.

Objective: Automated surgical step recognition (SSR) using AI has been a catalyst in the "digitization" of surgery. However, progress has been limited to laparoscopy, with relatively few SSR tools in endoscopic surgery. This study aimed to create a SSR model for transurethral resection of bladder tumors (TURBT), leveraging a novel application of transfer learning to reduce video dataset requirements.

A novel pathological mutant reveals the role of torsional flexibility in the serpin breach in adoption of an aggregation-prone intermediate.

Mutants of alpha-1-antitrypsin cause the protein to self-associate and form ordered aggregates ('polymers') that are retained within hepatocytes, resulting in a predisposition to the development of liver disease. The associated reduction in secretion, and for some mutants, impairment of function, leads to a failure to protect lung tissue against proteases released during the inflammatory response and an increased risk of emphysema. We report here a novel deficiency mutation (Gly192Cys), that we name the Sydney variant, identified in a patient in heterozygosity with the Z allele (Glu342Lys).

Developing the Healthy Actions and Lifestyles to Avoid Dementia or program.

Introduction: With Alzheimer's disease and related dementias (ADRD) representing an enormous public health challenge, there is a need to support individuals in learning about and addressing their modifiable risk factors (e.g., diet, sleep, and physical activity) to prevent or delay dementia onset.

Native and Ion Mobility Mass Spectrometry Characterization of Alpha 1 Antitrypsin Variants and Oligomers.

In this chapter, we describe a method for analyzing both recombinant and plasma-derived alpha 1 antitrypsin and its oligomers by means of native ion mobility mass spectrometry. Our experimental workflow can be applied to other variants of alpha 1 antitrypsin and its oligomers as well as being used to probe their interactions with small molecules in the gas phase.

Decreased prostate MRI cancer detection rate due to moderate to severe susceptibility artifacts from hip prosthesis.

Objectives: To evaluate the impact of susceptibility artifacts from hip prosthesis on cancer detection rate (CDR) in prostate MRI.

Materials And Methods: This three-center retrospective study included prostate MRI studies for patients without known prostate cancer between 2017 and 2021. Exams with hip prosthesis were searched on MRI reports.

Cancer Detection Rate and Abnormal Interpretation Rate of Prostate MRI in Patients With Low-Grade Cancer.

Purpose: The aim of this study was to evaluate the utility of cancer detection rate (CDR) and abnormal interpretation rate (AIR) in prostate MRI for patients with low-grade prostate cancer (PCa).

Methods: This three-center retrospective study included patients who underwent prostate MRI from 2017 to 2021 with known low-grade PCa (Gleason score 6) without prior treatment. Patient-level highest Prostate Imaging Reporting & Data System (PI-RADS®) score and pathologic diagnosis within 1 year after MRI were used to evaluate the diagnostic performance of prostate MRI in detecting clinically significant PCa (csPCa; Gleason score ≥ 7).

Cancer Detection Rate and Abnormal Interpretation Rate of Prostate MRI Performed for Clinical Suspicion of Prostate Cancer.

Purpose: To report cancer detection rate (CDR) and abnormal interpretation rate (AIR) in prostate MRI performed for clinical suspicion of prostate cancer (PCa).

Materials And Methods: This retrospective single-institution, three-center study included patients who underwent MRI for clinical suspicion of PCa between 2017 and 2021. Patients with known PCa were excluded.

Primary Whole-gland Ablation for the Treatment of Clinically Localized Prostate Cancer: A Focal Therapy Society Best Practice Statement.

Context: Whole-gland ablation is a feasible and effective minimally invasive treatment for localized prostate cancer (PCa). Previous systematic reviews supported evidence for favorable functional outcomes, but oncological outcomes were inconclusive owing to limited follow-up.

Objective: To evaluate the real-world data on the mid- to long-term oncological and functional outcomes of whole-gland cryoablation and high-intensity focused ultrasound (HIFU) in patients with clinically localized PCa, and to provide expert recommendations and commentary on these findings.

The under-appreciated world of the serpin family of serine proteinase inhibitors.

In the practice of medicine, many fundamental biological pathways that require tight on/off control, such as inflammation and circulatory homeostasis, are regulated by serine proteinases, but we rarely consider the unique protease inhibitors that, in turn, regulate these proteases. The serpins are a family of proteins with a shared tertiary structure, whose members largely act as serine protease inhibitors, found in all forms of life, ranging from viruses, bacteria, and archaea to plants and animals. These proteins represent up to 2-10% of proteins in the human blood and are the third most common protein family.

X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study.

Background: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations.

Methods: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case-control status, lung function, and quantitative emphysema.

A framework for designing AI systems that support community wellbeing.

Introduction: Designing artificial intelligence (AI) to support health and wellbeing is an important and broad challenge for technologists, designers, and policymakers. Drawing upon theories of AI and cybernetics, this article offers a design framework for designing intelligent systems to optimize human wellbeing. We focus on the production of wellbeing information feedback loops in complex community settings, and discuss the case study of My Wellness Check, an intelligent system designed to support the mental health and wellbeing needs of university students and staff during the COVID-19 pandemic.