Faculty Bibliography

INTRODUCTION/BACKGROUND:Hereditary (variant) transthyretin amyloidosis (ATTRv) with polyneuropathy (ATTR-PN) is a rare genetic disorder that causes progressive autonomic and sensorimotor neuropathy, severe disability, and death within 10 years of onset. Previous studies have primarily focused on how baseline cardiac characteristics affect mortality, but the impact of non-cardiac baseline characteristics is less defined. METHODS:We systematically searched PubMed/Medline (1990-2019) to identify studies that assessed the impact of baseline ATTR-PN characteristics on survival. Outcomes were first summarized descriptively. Extracted survival data were then disaggregated, and parametric mixture models were used to assess survival differences among patient groups defined by factors known to affect survival. RESULTS:The search yielded 1193 records, of which 35 were retained for analysis. Median survival ranged from 0.5 to > 25 years. The largest survival differences were between cohorts who underwent liver transplantation (LTx) versus those who did not. Among LTx cohorts, pre-LTx ATTR-PN disease duration ≥ 7 years, poor nutritional status, and late disease onset reduced median survival by 13, 12, and 10 years, respectively. Other prognostic survival factors included non-Val30Met genotype and baseline presence of urinary incontinence, erectile dysfunction, or muscle weakness. CONCLUSION/CONCLUSIONS:Survival in patients with ATTR-PN is highly variable and affected by non-cardiac baseline characteristics, such as autonomic dysfunction, large fiber involvement, late-onset disease, and non-Val30Met mutation. Careful interpretation of these findings is warranted given that this synthesis did not control for differences between studies. Survival in patients with ATTR-PN remains poor among those who are untreated or with delayed diagnosis.

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.

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.

Tuberculous Meningitis (TBM) is the most common form of central nervous system Tuberculosis (TB), accounting for 5-6% of extrapulmonary TB cases. Nowadays, TBM continues to be a major topic in public health because of its high prevalence worldwide. This retrospective study aimed to describe the clinical, laboratory, and imaging characteristics at admission; and in-hospital outcome of adult Mexican patients with TBM. We collected data from medical records of patients aged ≥18 years diagnosed with TBM according to the uniform case definition for clinical research who were treated at Tijuana General Hospital between January 2015 and March 2018 and compared them according to the subtype of diagnosis. We included 41 cases (26 males, median age 28 years, range 18-57 years), 13 (31.7%) patients were HIV positive, and 21 (51.2%) were illicit drug users. At admission, 7 (17.1%) patients were in stage I, 22 (53.6%) in stage II, and 12 (29.3%) in stage III. A definitive diagnosis was established in 23 (56.1%) patients, probable in 14 (34.1%), and possible in four (9.8%). Molecular testing was positive in 83% of the cases, yielding significantly higher positive results than other microbiological studies. There were eight (19.5%) deaths, without statistical difference between mortality and not having a definitive diagnosis (p = 0.109). We found that the baseline characteristics of our population were similar to those described by other authors worldwide. In this series, molecular testing showed to be very useful when used in the early stages, particularly in subjects with subacute onset of headache, fever, weight loss, and altered mental status.

The original version of this article unfortunately contained a mistake.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.