Diagnosis and treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States: Recommendations from a panel of experts.

Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.

Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis.

BACKGROUND: ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. OBJECTIVES: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Carotid baroreceptor dysfunction after carotid body tumour resections.

OBJECTIVE: Carotid body tumours (CBTs) and baroreceptor failure (BRF) are two distinct but interrelated conditions, affecting the carotid body and its regulatory mechanisms. We aim to describe and quantify BRF after unilateral and bilateral CBT resections. METHODS: Prospective cohort study. We included all patients with unilateral or bilateral CBT undergoing resection from April 2021 to January 2023. Demographics and CBTs characteristics were analysed; baroreceptor sensitivity assessment was conducted using the Composite Autonomic Severity Score (CASS). Statistical analyses were performed using R. Significance level was set at a 2-tailed α = 0.05. RESULTS: A total of 30 patients with CBT underwent surgical resection, twenty-three were included in the study (18 unilateral and 5 bilateral CBTs). All 23 (100 %) were females, median age of 60 years. Regarding patients with unilateral CBT; preoperatively, 13 had BRF, the most common dysfunction subtype was mixed. Postoperatively, the most common dysfunction subtype was sympathetic failure. With regards to bilateral CBTs; 2 patients did not have autonomic dysfunction preoperatively. After bilateral surgical resection one patient remained without autonomic dysfunction; however, all other patients persisted with BRF. CONCLUSION: BRF was present in 13 patients with unilateral CBT and 3 patients with bilateral tumours preoperatively; most will remain with BRF and will only change the characteristics postoperatively. No associations were found between type, severity of BRF and Shamblin classification or laterality. It is paramount that research in this area continues as many features are yet unknown regarding CBT pathogenesis, hence, BRF may be present yet not affect significantly quality of life.

Bioethics in medical care rationing during the coronavirus disease-19 pandemic

ABSTRACT Background: Coronavirus (CoV) disease (COVID)-19 poses difficult situations in which the ethical course of action is not clear, or choices are made between equally unacceptable responses. Methods: A web search was performed using the terms “bioethics; COVID-19; ethics; severe acute respiratory syndrome CoV-2; emergent care; pandemic; and public health emergencies.” Results: Protection from COVID-19 has resulted in the cancellation of necessary medical interventions, lengthened suffering, and potential non-COVID-19 deaths. Prolonged lockdown reduced well-being, triggering or aggravating mental illnesses and violence, and escalated medical risks. Collateral damage includes restrictions on visitations to hospitals, alienation from the deceased relative, or lack of warm caring of patients. Finally, in a public health crisis, public health interest overrides individual rights if it results in severe harm to the community. Conclusion: Balancing ethical dilemmas are one more challenge in the COVID-19 pandemic. (REV INVEST CLIN. 2021;73(1):1-5)

Bioethics in the COVID-19 Pandemic Research: Challenges and Strategies

As all other aspects in times of the coronavirus disease (COVID)-19 pandemic, carrying-out quality clinical research has been challenging. Many well-established paradigms have shifted as a consequence of the rapid demand for new knowledge. New treatments are fast-moving, informed consent forms are difficult to obtain, a competitive invitation from researchers to participate in different studies is common, and non-COVID-19 research protocols are suffering continuity. However, these challenges should not imply taking shortcuts or accepting deficiencies in bioethical standards, but rather enhance the alertness for rigorous ethical approaches despite these less than ideal circumstances. In this manuscript, we point out some interrogates in COVID-19 research and outline possible strategies to overcome the difficult task to continue with high-quality research without violating the ethical principles. (REV INVEST CLIN. 2020;72(5):265-70)

II. The research ethics involving vulnerable groups

Abstract Vulnerability in research occurs when the participant is incapable of protecting his or her interests and therefore, has an increased probability of being intentionally or unintentionally harmed. This manuscript aims to discuss the conditions that make a group vulnerable and the tools and requirements that can be used to reduce the ethical breaches when including them in research protocols. The vulnerability can be due either to an inability to understand and give informed consent or to unequal power relationships that hinder basic rights. Excluding subjects from research for the only reason of belonging to a vulnerable group is unethical and will bias the results of the investigation. To consider a subject or group as vulnerable depends on the context, and the investigator should evaluate each case individually.

III. The role of the Research Ethics Committees in the regulation of Pharma-Sponsored studies

Participants of Pharma-sponsored research are exposed to risks, benefits, and uncertainties that do not occur in other forms of clinical studies. Ethics committees represent the subjects’ first line of protection. This responsibility begins with the study review and ends after all study subjects finish the intervention. The objective of this paper is to review the most common controversial issues found in Pharma-sponsored studies. Potential solutions are proposed to prevent or resolve the polemical aspects. However, different challenges will be faced in the near future (e.g., when new therapies reach their late stage of development). All parties involved in research should work together to guarantee the protection of participants, the paramount principle on which clinical investigation is based. Pharma-sponsored research is a crucial driver to develop and implement innovative approaches to improve the informed consent process and the execution of the studies.

Left atrial function and volume by magnetic resonance in patients with hereditary amyloidosis

ABSTRACT Background Left atrial (LA) enlargement is a reliable predictor of adverse cardiovascular events, and reduced atrial function is an independent risk factor for mortality in patients with amyloidosis. The objective of this study was to characterize the LA function in Mexican patients with a confirmed diagnosis of hereditary transthyretin amyloidosis (amyloid transthyretin [ATTR]) Methods All consecutive patients with diagnosis of hereditary ATTR who underwent a cardiac magnetic resonance study in the period from March 2016 to June 2017 were included in the study; the volumes and function of the left atrium were evaluated Results Patients were divided into two groups, one with and one without cardiac amyloidosis. Statistically significant differences were observed between both groups in terms of indexed maximal LA volume, 26 mL versus 35.9mL, p = 0.03; indexed minimal LA volume, 10.7 mL versus 13.6mL, p = 0.03; and indexed LA pre-contraction volume, 17 mL versus 22.4mL, p = 0.03. No statistically significant differences were observed between both groups when comparing neither different ejection volumes nor the different ejection fractions Conclusions Patients with hereditary ATTR with cardiac involvement have remodeling of the left atrium, with increased atrial volumes, without diminishing its function.

I. The role of research ethics committees in observational studies: epidemiological registries, case reports, interviews, and retrospective studies

Abstract It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Antiagregantes plaquetarios en la prevención de la enfermedad vascular cerebral / Antiplatelates cerebral infartion prevention

Los mecanismos productores de isquemia cerebral son múltiples; sin embargo, el tromboembolismo explica una gran proporción de los casos de isquemia cerebral. El papel de los antiagregantes plaquetarios en la prevención secundaria del infarto cerebral esta bien definido. La presente revisión analiza los mecanismos de acción y la eficacia de las tres únicas drogas antiagregantes plaquetarias con efectividad demostrada en la prevención del infarto cerebral. Se analizan las relaciones riesgo-beneficio en cada uno de los agentes farmacológicos, así como también se discuten aspectos en cuanto a la dosis "ideal" de aspirina para esta indicación