Polyneuropathies

Transthyretin amyloidosis (ATTR) is a disease where the normally occurring transthyretin (TTR) protein falls apart and forms amyloid, a sticky plaque-like substance that accumulates in different organs in the body and can cause damage to the organ. There are two ways that the TTR protein can fall apart. One way occurs as a person ages, where the normal TTR protein can fall apart and form amyloid that may no longer be sufficiently cleared by the body. This type of ATTR is known as wild-type ATTR (ATTRwt). The other way occurs when a person inherits a defective TTR gene that causes the TTR protein to spontaneously fall apart. This form of the disease is known as variant ATTR (ATTRv) and can be detected in adults by a genetic test of their TTR gene before they age. Amyloid build-up in the heart causes the heart wall to become thick and stiff and can result in heart failure and even death. Accumulation of TTR amyloid in the heart is known as transthyretin amyloid cardiomyopathy or ATTR-CM. Amyloid can also deposit in the nerve tissues leading to nerve problems. Accumulation of TTR in the nerves is known as transthyretin amyloid polyneuropathy or ATTR-PN. Acoramidis is an experimental drug designed to bind tightly to TTR in the blood and stabilize its structure, so it does not form the harmful amyloid plaques that can cause damage to organs. This study is intended to determine if treatment with acoramidis in participants with ATTRv who have not yet developed any symptoms of disease can prevent or delay the development of ATTR-CM or ATTR-PN disease. If adults with an inherited defective TTR gene are treated early before any of the symptoms of disease have developed, it may be possible to delay the onset or prevent the disease entirely.

This study will be conducted to evaluate the efficacy and safety of a single dose of nexiguran ziclumeran (NTLA-2001) compared to placebo in participants with ATTRv-PN.

\*\*Brief Summary\*\* Leprosy is a chronic granulomatous infectious disease caused by \*Mycobacterium leprae\* or \*Mycobacterium lepromatosis\*, characterized by peripheral nerve involvement that may lead to progressive neurological damage, disability, and deformities if not diagnosed and treated early. The diagnosis of leprosy is primarily clinical and epidemiological, supported by laboratory methods such as bacilloscopy and biopsy; however, these tests have limited sensitivity, particularly due to the bacillus' tropism for peripheral nerve structures. Ultrasonography has emerged as a non-invasive imaging method capable of detecting morphological changes in peripheral nerves, including nerve enlargement, fascicular abnormalities, and inflammatory hypervascularization. Despite its diagnostic value, ultrasonography alone cannot detect the presence of the bacillus. This prospective cohort study aims to evaluate the diagnostic and prognostic accuracy of combining clinical evaluation, peripheral nerve ultrasonography, and molecular detection techniques using subcutaneous perineural aspirate. Patients with suspected leprosy attending the Leprosy Outpatient Clinic at the University Hospital of Brasília will undergo clinical evaluation, ultrasound examination of the ulnar nerves, and ultrasound-guided subcutaneous perineural aspirate for molecular detection of \*Mycobacterium leprae\* DNA and RNA using real-time PCR and RT-PCR. Participants will be followed for one year, with assessments performed at diagnosis and after one year of treatment. The study will compare clinical, imaging, and molecular findings to determine whether perineural subcutaneous aspirate combined with ultrasonography improves early detection and diagnostic accuracy compared with conventional methods such as bacilloscopy and biopsy. The study aims to contribute to improved diagnostic strategies for leprosy, enabling earlier detection of neural involvement and potentially reducing disease transmission and long-term disability.

Approximately 30 minutes after needle EMG, patients who are taking direct oral anticoagulants (DOACs) will undergo an ultrasound examination to evaluate for the presence of possible intramuscular hematomas at the muscles where the EMG needle was inserted. These hematomas are considered a potential adverse effect of needle EMG. The aim of the study is to determine whether needle EMG can be considered a safe procedure in this group of patients, without posing a risk of intramuscular hematoma formation.

The AG10-504 study is an open-label extension study of acoramidis in participants with newly diagnosed transthyretin amyloid cardiomyopathy (ATTR-CM) or both ATTR-CM and transthyretin amyloid polyneuropathy (ATTR-PN).

Given the expansion of indications for genetic testing and our understanding of conditions for which the results change medical management, it is imperative to consider novel ways to deliver care beyond the traditional genetic counseling visit, which are both amenable to large-scale implementation and sustainable. The investigators propose an entirely new approach for the implementation of genomic medicine, supported by the leadership of Penn Medicine, investigating the use of non-geneticist clinician and patient nudges in the delivery of genomic medicine through a pragmatic randomized clinical trial, addressing NHGRI priorities. Our application is highly conceptually and technically innovative, building upon expertise and infrastructure already in place. Innovative qualities of our proposal include: 1) Cutting edge EHR infrastructure already built to support genomic medicine (e.g., partnering with multiple commercial genetic testing laboratories for direct test ordering and results reporting in the EHR); 2) Automated EHR-based direct ordering or referring by specialist clinicians (i.e., use of replicable modules that enable specialist clinicians to order genetic testing through Epic Smartsets, including all needed components, such as populated gene lists, smartphrases, genetic testing, informational websites and acknowledgement e-forms for patient signature); 3) EHR algorithms for accurate patient identification (i.e., electronic phenotype algorithms to identify eligible patients, none of which currently have phenotype algorithms present in PheKB; 4) Behavioral economics-informed implementation science methods: This trial will be the first to evaluate implementation strategies informed by behavioral economics, directed at clinicians and/or patients, for increasing the use of genetic testing; further it will be the first study in this area to test two forms of defaults as a potential local adaptation to facilitate implementation (ordering vs. referring); and 5) Dissemination: In addition to standard dissemination modalities,PheKB95, GitHub and Epic Community Library, the investigators propose to disseminate via AnVIL (NHGRI's Genomic Data Science Analysis, Visualization, and Informatics Lab-Space). Our results will represent an entirely new paradigm for the provision of genomic medicine for patients in whom the results of genetic testing change medical management.

The project aims to investigate the validity, and reliability of outcome measures of muscle strength, functioning (gait, balance, and fine motor skills), physical activity, and patient-reported outcome measures of functioning (gait, balance, and fine motor skills), and daily living among patients with polyneuropathy. Further, the project aims to compare physical activity and patient-reported outcome measures of functioning (gait, balance, and fine motor skills), and daily living among patients with polyneuropathy with physical activity and patient-reported outcome measures of functioning (gait, balance, and fine motor skills) and daily living in healthy adults.

The goal of this observational study is to investigate the applicability of 100 Hz tetanic stimulation with an electromyography device in the exclusion of postoperative residual neuromuscular block. The aim is to determine whether fatigue develops with 100 Hz tetanic stimulation in anaesthetized, non-relaxed patients with normal or abnormal baseline electroneurographic (ENG) findings.

The main goal of this trial is to establish recommendations for clinical practice that enhance the reliability, accessibility and convenience of sheer wave elastography as a routine diagnostic test for diverse peripheral neuropathies.

Biomarkers for prognosis of patients with polyneuropathy.

In the present study the investigators will search for new genetic variants relevant for the development of neuropathic pain.