[Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units]. / Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

Influence of general anaesthesia on the intravenous acetaminophen pharmacokinetics in Beagle dogs.

OBJECTIVE: To determine if general anaesthesia influences the intravenous (IV) pharmacokinetics (PK) of acetaminophen in dogs. STUDY DESIGN: Prospective, crossover, randomized experimental study. ANIMALS: A group of nine healthy Beagle dogs. METHODS: Acetaminophen PK were determined in conscious and anaesthetized dogs on two separate occasions. Blood samples were collected before, and at 5, 10, 15, 30, 45, 60 and 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after 20 mg kg-1 IV acetaminophen administration. Haematocrit, total proteins, albumin, alanine aminotransferase, aspartate aminotransferase, urea and creatinine were determined at baseline and 24 hours after acetaminophen. The anaesthetized group underwent general anaesthesia (90 minutes) for dental cleaning. After the administration of dexmedetomidine (3 µg kg-1) intramuscularly, anaesthesia was induced with propofol (2-3 mg kg-1) IV, followed by acetaminophen administration. Anaesthesia was maintained with isoflurane in 50% oxygen (Fe'Iso 1.3-1.5%). Dogs were mechanically ventilated. Plasma concentrations were analysed with high-performance liquid chromatography. PK analysis was undertaken using compartmental modelling. A Wilcoxon test was used to compare PK data between groups, and clinical laboratory values between groups, and before versus 24 hours after acetaminophen administration. Data are presented as median and range (p < 0.05). RESULTS: A two-compartmental model best described time-concentration profiles of acetaminophen. No significant differences were found for volume of distribution values 1.41 (0.94-3.65) and 1.72 (0.89-2.60) L kg-1, clearance values 1.52 (0.71-2.30) and 1.60 (0.91-1.78) L kg-1 hour-1 or terminal elimination half-life values 2.45 (1.45-8.71) and 3.57 (1.96-6.35) hours between conscious and anaesthetized dogs, respectively. Clinical laboratory variables were within normal range. No adverse effects were recorded. CONCLUSIONS AND CLINICAL RELEVANCE: IV acetaminophen PK in healthy Beagle dogs were unaffected by general anaesthesia under the study conditions. Further studies are necessary to evaluate the PK in different clinical contexts.

KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia.

BACKGROUND AND PURPOSE: Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous myoclonus-dystonia in a UK kindred with affected individuals in three generations. METHODS: Known genetic causes of myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus-dystonia. RESULTS: The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. CONCLUSIONS: KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying myoclonus-dystonia.

Microarray and RASopathy-disorder testing in fetuses with increased nuchal translucency.

OBJECTIVES: To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RASopathy-disorder (RD) pathogenic variants in a cohort of pregnancies with nuchal translucency thickness (NT) ≥ 3.5 mm, and to propose a clinical protocol for surveillance of this group of patients. METHODS: This was a retrospective chart review of patients referred to The Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital between January 2013 and December 2015, due to NT ≥ 3.5 mm, who underwent chorionic villus sampling or amniocentesis. Patients underwent extensive genetic counseling prior to invasive procedures and testing. Quantitative fluorescence polymerase chain reaction (QF-PCR) was performed as the first-line test for aneuploidy. If the result was negative, patients underwent karyotyping and/or chromosomal microarray analysis (CMA), and if the findings were normal, they had testing for RD pathogenic variants, which included nine known genes. Patients also underwent detailed fetal ultrasound examinations and echocardiography, performed by expert operators. RESULTS: A total of 226 eligible patients were identified. In 116/226 (51.3%) patients, QF-PCR identified a chromosomal aneuploidy. The remaining 110/226 (48.7%) patients had further genetic testing. Karyotyping/CMA detected an abnormal/pathogenic cytogenetic result in 9/110 (8.2%) patients, as well as five variants of unknown significance (VOUS). RD testing yielded three pathogenic variants (3/103), giving a detection rate of 2.9%, and one VOUS. The optimal NT cut-off for RD screening was 7.9 mm in this population. In 92/110 (83.6%) patients, the genetic investigations were normal. Of these pregnancies, an early (14-16 weeks' gestation) detailed fetal ultrasound examination identified a structural abnormality in 24 (26.1%), 15 (16.3%) had an abnormal detailed ultrasound examination at 18-22 weeks' gestation and fetal echocardiography showed a cardiac abnormality in nine (9.8%). The birth outcome in the 83 pregnancies that had normal genetic investigations and known outcome included seven (8.4%) cases of termination of pregnancy, seven (8.4%) cases of intrauterine fetal death and 69 (83.1%) cases of live birth. Nine (9.8%) patients were lost to follow-up. CONCLUSIONS: Both CMA and molecular testing for RD are important investigations in pregnancies with NT ≥ 3.5 mm. The use of genetic testing combined with fetal ultrasound examination provides valuable information that can influence pregnancy outcome, and provide recurrence risks, in this patient population. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Novel biotechnological platform based on baculovirus occlusion bodies carrying Babesia bovis small antigenic peptides for the design of a diagnostic enzyme-linked immunosorbent assay (ELISA).

Baculoviruses are large DNA virus of insects principally employed in recombinant protein expression. Its ability to form occlusion bodies (OBs), which are composed mainly of polyhedrin protein (POLH), makes them biotechnologically attractive, as these crystals (polyhedra) can incorporate foreign peptides and can be easily isolated. On the other hand, peptide microarrays allow rapid and inexpensive high-throughput serological screening of new candidates to be incorporated to OBs. To integrate these 2 biotechnological approaches, we worked on Babesia bovis, one of the causative agents of bovine babesiosis. Current molecular diagnosis of infection with B. bovis includes enzyme-linked immunosorbent assay (ELISA) techniques, which use merozoite lysate obtained from infected bovine erythrocytes. However, it is important to produce recombinant antigens that replace the use of crude antigens. Here, we describe a new biotechnological platform for the design of indirect ELISAs based on 5 antigenic peptides of 15 amino acid residues of B. bovis (ApBb), selected from a peptide microarray and expressed as a fusion to POLH. An Sf9POLHE44G packaging cell line infected with recombinant baculoviruses carrying POLH-ApBb fusions yielded higher levels of chimeric polyhedra, highlighting the advantage of a trans-contribution of a mutant copy of polyhedrin. Finally, the use of dissolved recombinant polyhedra as antigens was successful in an ELISA assay, as B. bovis-positive sera recognized the fusion POLH-ApBb. Thus, the use of this platform resulted in a promising alternative for molecular diagnosis of relevant infectious diseases.

HIV-1 antiretroviral drug resistance patterns in patients failing NNRTI-based treatment: results from a national survey in South Africa.

BACKGROUND: Routine HIV-1 antiretroviral drug resistance testing for patients failing NNRTI-based regimens is not recommended in resource-limited settings. Therefore, surveys are required to monitor resistance profiles in patients failing ART. METHODS: A cross-sectional survey was conducted amongst patients failing NNRTI-based regimens in the public sector throughout South Africa. Virological failure was defined as two consecutive HIV-1 viral load results >1000 RNA copies/mL. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to Stanford HIVdb v7.0.1. RESULTS: A total of 788 sequences were available for analysis. Most patients failed a tenofovir-based NRTI backbone (74.4%) in combination with efavirenz (82.1%) after median treatment duration of 36 months. K103N (48.9%) and V106M (34.9%) were the most common NNRTI mutations. Only one-third of patients retained full susceptibility to second-generation NNRTIs such as etravirine (36.5%) and rilpivirine (27.3%). After M184V/I (82.7%), K65R was the most common NRTI mutation (45.8%). The prevalence of K65R increased to 57.5% in patients failing a tenofovir regimen without prior stavudine exposure. Cross-resistance to NRTIs was often observed, but did not seem to affect the predicted activity of zidovudine as 82.9% of patients remained fully susceptible to this drug. CONCLUSIONS: The introduction of tenofovir-based first-line regimens has dramatically increased the prevalence of K65R mutations in the HIV-1-infected South African population. However, most patients failing tenofovir-based regimens remained fully susceptible to zidovudine. Based on these data, there is currently no need to change either the recommended first- or second-line ART regimens in South Africa.

Prevalence of Antiretroviral Drug Resistance in Patients Who Are Not Responding to Protease Inhibitor-Based Treatment: Results From the First National Survey in South Africa.

Limited data exist on human immunodeficiency virus type 1 (HIV-1) resistance in patients who are not responding to protease inhibitor (PI)-based regimens in resource-limited settings. This study assessed resistance profiles in adults across South Africa who were not responding to PI-based regimens. pol sequencing was undertaken and submitted to the Stanford HIV Drug Resistance Database. At least 1 major PI mutation was detected in 16.4% of 350 participants. A total of 53.4% showed intermediate resistance to darunavir/ritonavir, whereas high-level resistance was not observed. Only 5.2% and 32.8% of participants showed high-level and intermediate resistance to etravirine, respectively. Although the prevalence of major PI mutations was within previously reported ranges, most patients will likely experience virological suppression during receipt of currently available South African third-line regimens.

Tigecycline therapy for infections due to carbapenemase-producing Klebsiella pneumoniae in critically ill patients.

BACKGROUND: The aim of this study was to assess the efficacy of tigecycline in the treatment of infections due to carbapenemase-producing Klebsiella pneumoniae (CPKP) in critically ill patients. METHODS: A retrospective observational study was conducted in critically ill patients receiving different tigecycline doses for severe CPKP infections. We evaluated demographic data, localization and severity of infection, response to therapy, and mortality. RESULTS: Fifteen patients received tigecycline for 16 episodes of CPKP infection. The main infections were pneumonia (31%), urinary tract infection (31%), peritonitis (20%), catheter-related bacteraemia (12%), and meningitis (6%). Most infections were complicated with severe sepsis (44%), septic shock (12%), and/or bacteraemia (19%). The daily maintenance dose of tigecycline was 200 mg in 10 episodes and 100 mg in 6 episodes. The overall 30-day mortality rate was 25%. Univariate analysis showed that mortality was significantly associated (p < 0.01) with mean APACHE II and SOFA scores and the presence of immunosuppression, but not with the tigecycline dose. CONCLUSIONS: Tigecycline appears to be an effective therapy for severe infections due to CPKP in critically ill patients. Mortality is related to the severity of the underlying disease. We observed no benefit from a higher maintenance dose of tigecycline, although the number of patients included in the study was too small to draw any general conclusions in this regard.

[Donation protocol following controlled cardiac death (Maastricht type III donation). First experience]. / Protocolo de donación tras la muerte cardiaca controlada (donante tipo iii de Maastricht). Experiencia inicial.

OBJECTIVE: To present our experience with the implementation of a donation protocol following controlled cardiac death (Maastricht type III donation). DESIGN: A retrospective descriptive and observational study was made. SETTING: Intensive Care Unit of a third-level university hospital. PATIENTS: Eight patients in an irreversible state, in which withdrawal of all life support had been agreed, were evaluated as potential donors. INTERVENTIONS: Application of the adopted protocol. VARIABLES OF INTEREST: Clinical data of donors, evaluation of a donation protocol following cardiac death, warm ischemia times, and short-term outcome of the recipients. RESULTS: Eight patients were evaluated. In one case donation was not possible because no cardiac arrest developed in the 120 minutes after extubation. The 7 remaining patients were effective kidney donors. Warm ischemia times were less than 23 minutes in all cases. Although 7 of the 14 recipients suffered delayed graft function, all of them achieved good renal function. CONCLUSION: Donation after cardiac death in patients in an overwhelming and irreversible state represents a potential source of donors not previously considered in this country. The prior development of a consensus-based protocol can help increase the number of organs in combination with those obtained after brain death. In our experience, the results of kidney transplants obtained from donors after cardiac death are good, and the success of these types of protocols could be extended to other organs such as the liver and lungs.

Cytogenomic characterization of small supernumerary marker chromosomes in patients with pigmentary mosaicism.

Introduction: The combination of gene content on the marker chromosome, chromosomal origin, level of mosaicism, origin mechanism (chromothripsis), and uniparental disomy can influence the final characterization of sSMCs. Several chromosomal aberrations, including sSMCs, have been observed in 30%-60% of patients with pigmentary mosaicism, and in more than 80%, chromosomal abnormalities are present in the mosaic state. In patients with pigmentary mosaicism the most representative chromosomes involved in sSMCs are 3, 5, 6, 9, 10, 13, 15, 18, 20, and X. In this study, we included the complete clinical, cytogenetic, and molecular characterization of seven patients with pigmentary mosaicism associated with the presence of SMCs of different chromosomal origins. Methods: The patients were diagnosed by the Genetics and Dermatology Department of three different hospitals. Cytogenetic and FISH analyses were performed on peripheral blood, light skin, and dark skin. FISH analysis was performed using different probes, depending on the marker chromosome description. Different array analysis was performed. Results: To date, of the seven cases studied, the chromosomal origins of six were successfully identified by FISH or array analysis. The chromosomes involved in SMCs were 6, 9, 15, and 18, X. The most frequently found was the centric minute structure. Discussion: To date, this group of seven patients constitutes the largest clinical and cytogenetically finely described study of cases with pigmentary mosaicism associated with sSMCs. Undoubtedly, analysis of the two skin types is a fundamental part of our study, as numerical differences may occur in the cell lines found in each skin type. The knowledge generated in this study will help delineate a very heterogeneous entity more accurately, and in the future, analyzing more patients with PM will likely establish a more definite association with the presence of this genetic alteration.

Individualised analgesia, sedation, delirium and comfort management strategies in the ICU: a narrative review.

This group is a product of the collaboration agreement signed by SOMIAMA (Sociedad de Medicina Intensiva de Madrid) and SAR MADRID (Sociedad de Anestesiología, Reanimación y Terapéutica del Dolor de Madrid) under which the organisations agreed to create joint working groups to improve critical patient care. Pain, discomfort, agitation, and delirium cause suffering, delay discharge, and can lead to serious complications in patients admitted to medical and surgical critical care units and post-anaesthesia care units. The main objectives in this type of unit include: Ensuring the comfort of patients suffering or recovering from a critical illness.Avoiding complications associated with the measures, particularly pharmacological, taken to ensure that comfort.

Neuropsychological rehabilitation for post-COVID-19 syndrome: results of a clinical programme and six-month follow up.

INTRODUCTION: Patients with post-COVID-19 syndrome may present cognitive and emotional symptomatology. This study aims to analyse the results of an outpatient neuropsychological intervention programme for post-COVID-19 syndrome. METHOD: In June 2020 Institut Guttmann started an outpatient post-COVID-19 neurorehabilitation programme, including respiratory therapy, physiotherapy, and neuropsychological rehabilitation. Before and after the programme, the cognitive-emotional state of all participants is assessed. Six months after treatment, a follow-up assessment is administered (which includes a collection of information on various aspects of daily life). RESULTS: The sample analysed consisted of 123 patients (mean age: 51 years, SD: 12.41). Seventy-four per cent (n = 91) had cognitive impairment and underwent cognitive treatment (experimental group); the remaining 26% (n = 32) constituted the control group. After the intervention, the experimental group improved in working memory, verbal memory (learning, recall and recognition), verbal fluency and anxious-depressive symptomatology. The control group showed changes in immediate memory, verbal memory (learning and recognition) and depressive symptomatology, although the effect size in the latter two was smaller than in the experimental group. Six months after treatment, 44.9% of the patients were unable to perform their pre-COVID-19 work activity, and 81.2% reported difficulties in their activities of daily living. CONCLUSIONS: Neuropsychological rehabilitation is an effective tool to treat the cognitive-emotional deficits present in post-COVID-19 syndrome. However, months after the end of treatment, not all patients recover their pre-COVID-19 functional level.

Determinants of mortality in cancer patients with unscheduled admission to the Intensive Care Unit: A prospective multicenter study.

OBJECTIVES: To analyze clinical features associated to mortality in oncological patients with unplanned admission to the Intensive Care Unit (ICU), and to determine whether such risk factors differ between patients with solid tumors and those with hematological malignancies. DESIGN: An observational study was carried out. SETTING: A total of 123 Intensive Care Units across Spain. PATIENTS: All cancer patients with unscheduled admission due to acute illness related to the background oncological disease. INTERVENTIONS: None. MAIN VARIABLES: Demographic parameters, severity scores and clinical condition were assessed, and mortality was analyzed. Multivariate binary logistic regression analysis was performed. RESULTS: A total of 482 patients were included: solid cancer (n=311) and hematological malignancy (n=171). Multivariate regression analysis showed the factors independently associated to ICU mortality to be the APACHE II score (OR 1.102; 95% CI 1.064-1.143), medical admission (OR 3.587; 95% CI 1.327-9.701), lung cancer (OR 2.98; 95% CI 1.48-5.99) and mechanical ventilation after the first 24h of ICU stay (OR 2.27; 95% CI 1.09-4.73), whereas no need for mechanical ventilation was identified as a protective factor (OR 0.15; 95% CI 0.09-0.28). In solid cancer patients, the APACHE II score, medical admission, antibiotics in the previous 48h and lung cancer were identified as independent mortality indicators, while no need for mechanical ventilation was identified as a protective factor. In the multivariate analysis, the APACHE II score and mechanical ventilation after 24h of ICU stay were independently associated to mortality in hematological cancer patients, while no need for mechanical ventilation was identified as a protective factor. Neutropenia was not identified as an independent mortality predictor in either the total cohort or in the two subgroups. CONCLUSIONS: The risk factors associated to mortality did not differ significantly between patients with solid cancers and those with hematological malignancies. Delayed intubation in patients requiring mechanical ventilation might be associated to ICU mortality.

Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

Gray matter volume deficits and correlation with insight and negative symptoms in first-psychotic-episode subjects.

OBJECTIVE: To determine brain areas reduced in first episode of psychotic subjects and its association with lack of insight and negative symptoms. METHOD: Twenty-one drug naive first-episode subjects and 20 controls underwent a structural MRI scan and were clinically assessed. Optimized voxel-based-morphometry analysis (VBM) was implemented to find between-group differences and correlations between GM volume and: (i) lack of insight and (ii) negative symptoms. RESULTS: Patients showed GM reduction in prefrontal and left temporal areas. A significant correlation was found between insight and GM volume in the cerebellum (corrected P = 0.01), inferior temporal gyrus (corrected P = 0.022), medial superior frontal gyrus (corrected P < 0.001), and inferior frontal gyrus (corrected P = 0.012), as the insight decreased, the volume decreased. Negative symptoms correlated with decreased GM volume at cerebellum (corrected P = 0.037) and frontal inferior regions (corrected P < 0.001), the more negative symptoms, the less volume. CONCLUSION: Our findings support an association between prefrontal, temporal, and cerebellar deficits and lack of insight in schizophrenia and confirm previous findings of GM deficits in patients since the first episode of psychosis.

Effect of thermal alkaline pretreatment on the anaerobic digestion of wasted activated sludge.

The effect of alkaline pretreatment of waste-activated sludge, using two models to study the sequential hydrolysis rates of suspended (Sanders' surface model) and dissolved (Goel's saturation model) solids, on the mesophilic and thermophilic anaerobic digestion rate is evaluated. The pretreatment, which reduces the size of the solids, increases the reaction rate by increasing the surface area and the specific surface hydrolysis constant (K(SBK)); at thermophilic conditions from 0.45 x 10(-3) kg m(-2) d(-1) for the fresh sludge to 0.74 x 10(-3) kg m(-2) d(-1) for the pretreated sludge and at mesophilic conditions these values are 0.28 x 10(-3) kg m(-2) d(-1) and 0.47 x 10(-3) kg m(-2) d(-1) confirming the usefulness of a pretreatment for solids reduction. But for soluble solids, the thermoalkaline pretreatment decreases the reaction rates by inducing a competitive inhibition on the thermophilic anaerobic digestion rate while in the mesophilic range, a non-competitive inhibition is observed. A mathematical simulation of the consecutive reactions, suspended solids to dissolved solids and to methane in staged anaerobic thermophilic-mesophilic digestion, shows that with 4% suspended solids concentration it is better not to use a thermoalkaline pretreatment because overall solids reduction and total methane production are not as good as without pretreatment.

Exertional chest pain is sometimes more than just coronary atherosclerosis.

CLINICAL CASE: A 64-year-old male, with cardiovascular risk factors and previous history of bilateral carpal tunnel syndrome, presented with exertional retrosternal pain. The resting echocardiogram was unremarkable. A stress echocardiogram with dobutamine revealed hypokinesis of the inferior wall, associated with angina, followed by ventricular tachycardia. The coronary angiography revealed slow flow, a dominant right coronary artery with non-obstructive atherosclerosis and a left anterior descending artery with intermediate lesions in mid and distal segments. The invasive functional evaluation, including fractional flow reserve, thermodilution coronary flow reserve and index of microvascular resistance, led to the diagnosis of microvascular angina, treated with calcium channel blockers and transdermal nitrate, giving symptom relief. EVOLUTION: Three years later he developed complete atrioventricular block and a dual chamber pacemaker was implanted. Shortly after, the patient developed progressive symmetrical tetraparesis, associated with marked muscle atrophy, hand numbness, orthostatic hypotension and dysphagia. The neurology workup led to the diagnosis of familial amyloidotic polyneuropathy, with the Val30Met mutation in the transthyretin gene. The following year he developed congestive heart failure. The echocardiogram showed moderate concentric left ventricular hypertrophy with preserved ejection fraction. A 99mTc-DPD Scintigraphy showed significant myocardial tracer uptake, leading to a diagnosis of TTR amyloid infiltration. DISCUSSION: Patients with exertional angina and microvascular disease should be kept under close surveillance, as they may have systemic disease with cardiac involvement. Carpal tunnel syndrome, in the context of undiagnosed cardiac disease, should trigger suspicion of cardiac amyloidosis.