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Review Article| Volume 82, P7-15, December 2020
Transthyretin amyloid cardiomyopathy: An uncharted territory awaiting discovery
Aldostefano Porcari
Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), University of Trieste, Italy
Marco Merlo
Claudio Rapezzi
Cardiovascular Center, University of Ferrara, Italy
GVM Care & Research, Cotignola, Italy
Gianfranco Sinagra
Address for correspondence. Gianfranco Sinagra, MD, FESC, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), University of Trieste, Via P. Valdoni 7, 34100, Trieste, Italy
Published:October 05, 2020DOI:https://doi.org/10.1016/j.ejim.2020.09.025
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Transthyretin amyloid cardiomyopathy (ATTR-AC) is an under-diagnosed disease.
Many grey areas are emerging in clinical management and prognostic stratification.
Candidates' selection for novel drugs is crucial, but response criteria are lacking.
The impact of evidence-based therapies for HF in ATTR-AC should be investigated.
Multidisciplinary team is the way to deliver the best clinical management.
Transthyretin amyloid cardiomyopathy (ATTR-AC) is an under-recognized and underdiagnosed disease. Although traditionally considered a rare condition, the epidemiology of the disease is rapidly changing due to the possibility of non-invasive diagnosis through cardiac scintigraphy with bone tracers and novel disease-modifying treatments providing survival advantages. Nevertheless, many questions and grey areas have to be addressed, such as the natural history of ATTR-AC, the role and implications of genotype–phenotype interactions, the best clinical management, prognostic stratification and the most appropriate treatments, including those already recommended for patients with heart failure. Clinicians have to cope with old beliefs and evolving concepts in ATTR-AC. A wide horizon of possibilities for physicians of many specialties is unfolding and awaits discovery.
Cardiac amyloidosis
Transthyretin
Grey zones
Disease-modifying therapies
Prognostic stratification
Amyloidosis represents a largely unexplored field in medicine, with many grey areas remaining. The search for the mechanism triggering protein misfolding has been an important research topic for many decades. In recent years, cardiac involvement due to extracellular infiltration by transthyretin (TTR) amyloidosis, so-called 'TTR amyloid cardiomyopathy' (ATTR-AC), has proven to be a frequently unrecognized condition [
Maurer M.S.
Elliott P.
Comenzo R.
Semigran M.
Rapezzi C
Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis.
Circulation. 2017; 135: 1357-1377https://doi.org/10.1161/CIRCULATIONAHA.116.024438
]. TTR is a homotetrameric carrier protein produced mostly by the liver [
Emdin M.
Aimo A.
Rapezzi C.
Fontana M.
Perfetto F.
Seferović P.M.
Treatment of cardiac transthyretin amyloidosis: an update.
Eur Heart J. 2019; 40: 3699-3706https://doi.org/10.1093/eurheartj/ehz298
]. A higher tendency to dissociate in misfolded monomers and to fibrillate is thought to occur in the presence of favourable conditions, such as ageing with associated failure of homoeostatic mechanisms in wild-type TTR (TTRwt) [
Stakos D.A.
Stamatelopoulos K.
Bampatsias D.
Sachse M.
Zormpas E.
Vlachogiannis N.I.
The Alzheimer's Disease Amyloid-Beta Hypothesis in Cardiovascular Aging and Disease.
J Am Coll Cardiol. 2020; 75: 952-967https://doi.org/10.1016/j.jacc.2019.12.033
] or destabilizing mutations in variant TTR (TTRv) [
]. Progressive interstitial infiltration and direct 'toxic' effects exerted by circulating TTR oligomers lead to oxidative stress and mitochondrial damage, increased cardiac wall thickness and diastolic dysfunction [
Lorenzini M.
Longhi S.
Milandri A.
Gagliardi C.
Bartolomei I.
Cardiac amyloidosis: the great pretender.
Heart Fail Rev. 2015; 20: 117-124https://doi.org/10.1007/s10741-015-9480-0
Palladini G.
Merlini G.
Systemic amyloidoses: what an internist should know.
Eur J Intern Med. 2013; 24: 729-739https://doi.org/10.1016/j.ejim.2013.10.007
Although histological confirmation was traditionally required, the diagnosis of ATTR-AC can currently be made upon the presence of cardiac accumulation of bone tracers revealed by scintigraphy in patients with no evidence of monoclonal proteins [
Gillmore J.D.
Falk R.H.
Damy T.
Dispenzieri A.
Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
González-Calle V.
Mateos M.V.
Monoclonal gammopathies of unknown significance and smoldering myeloma: assessment and management of the elderly patients.
]. This non-invasive strategy represents a major step forward in meeting the urgent need for early diagnosis of AC, particularly as novel treatments able to modify the natural history of disease have been discovered [
]. A major reappraisal is underway concerning ATTR-AC in the modern era of precision medicine, and many questions about accurate diagnosis, the best clinical management, prognostic stratification and the most effective therapies have to be addressed.
2. Changing perspectives on ATTR-AC
2.1 The epidemiology: moving from 'zero' to 'two-digit' prevalence
Historically, ATTR-AC has been considered a rare condition predominantly affecting elderly subjects and has mostly been recorded as an incidental finding at post-mortem examination [
]. This perception derived from low awareness of the disease, fragmented knowledge and frequent misdiagnosis due to phenotypic heterogeneity and overlap with other conditions [
Despite an estimated raw prevalence of 〈 1 in 100,000 individuals [
Bokhari S.
Dorbala S.
Drachman B.M.
Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis.
Circ Hear Fail. 2019; : 12https://doi.org/10.1161/CIRCHEARTFAILURE.119.006075
], the real epidemiology of ATTR-AC is currently unknown. Major insights into disease epidemiology have been provided by cardiac scintigraphy with bone tracers, revealing ATTRv-AC in 13% of patients 〉 60 years with left ventricular (LV) wall thickness ≥ 12 mm hospitalized for heart failure (HF) with preserved ejection fraction (EF) [
González-López E.
Gallego-Delgado M.
Guzzo-Merello G.
De Haro-Del Moral F.J.
Cobo-Marcos M.
Robles C.
Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.
Eur Heart J. 2015; https://doi.org/10.1093/eurheartj/ehv338
], in 5% of patients with hypertrophic cardiomyopathy and in 16% of patients with 'paradoxical' low-flow low-gradient (LF-LG) aortic stenosis [
Ternacle J.
Krapf L.
Mohty D.
Magne J.
Nguyen A.
Galat A.
Aortic Stenosis and Cardiac Amyloidosis.
These findings suggest ATTR-AC prevalence to be substantially higher than traditionally thought, leading to a paradigm shift from monoclonal light chains to ATTR-AC as the most frequent form [
].The increasing rate of diagnosed cases calls into question whether ATTR-AC should continue to be considered a rare disease or should rather be considered a common condition not adequately diagnosed.
2.2 Beyond traditional clinical phenotypes: a broadening spectrum of disease
Early recognition of ATTR-AC is crucial to address proper management and treatment [
Hanna M.
Grogan M.
Witteles R.
Drachman B.
Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).
Hutchinson M.
Lachmann H.J.
Martinez-Naharro A.
A new staging system for cardiac transthyretin amyloidosis.
Eur Heart J. 2018; 39: 2799-2806https://doi.org/10.1093/eurheartj/ehx589
Scott C.G.
Kyle R.A.
Zeldenrust S.R.
Lin G.
Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System.
J Am Coll Cardiol. 2016; https://doi.org/10.1016/j.jacc.2016.06.033
]. The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry has reported cardiac involvement in half of patients [
]. Significant regional differences have emerged, with the vast majority of subjects from the United States being elderly men with ATTRwt-AC and a cardiac-predominant phenotype compared to subjects in Europe (Table 1).
Table 1Characteristics of patients with amyloid cardiomyopathy due to wild type TTR and the two most diffuse variant TTR forms.
Wild-Type
Val30Met
Val122Ile
Median age at diagnosis ≥ 75 years Early-onset ~ 30 years
Late-onset ≥ 50 years (variable) ~ 70 years
Mode of transmission – Autosomal dominant Autosomal dominant
Genetic abnormality – Single nucleotide mutation Single nucleotide mutation
Geographical distribution Worldwide Diffused worldwide, but with endemic areas including Portugal, Japan, Sweden and Cyprus United States, United Kingdom, Western Africa
Clinical phenotype [
Kristen A.V.
Suhr O.B.
Planté-Bordeneuve V.
Yu C.-.R.
Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS).
Eur Heart J. 2019; https://doi.org/10.1093/eurheartj/ehz173
] Cardiac 79%, NNNeurological 2.4% Mixed 18% Early-onset: Cardiac 3%, Neurological 80%, Mixed 17%
Late-onset: Cardiac 9%, Neurological 64%, Mixed 27% Cardiac: predominant
Neurological and Mixed: Unknown
History of CTS,% 25% - 33% 14% - 30% ~ 30%
Time from CTS and AC diagnosis 15.5 years 13 years Unknown
AF,% 65 - 70% 30 ~ 50%
Low QRS voltages,% 30 - 45% Early-onset: 7.5%
Adams D.
Koike H.
Slama M.
Coelho T
Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease.
Nat Rev Neurol. 2019; https://doi.org/10.1038/s41582-019-0210-4
Late-onset: 4%
~ 45%
Median LV Wall Thickness, mm 18 ± 3 17 ± 4 16 +−34 mm
Restrictive filling pattern,% 40% < 20 - 25% ~ 55%
LVEF,% 51 ± 12 Early- and late-onset: 70 ± 7 40 ± 14%
LA diameter, mm 50 ± 10 43 ± 6 46 ± 6 mm
AV Valve Thickening,% 50% Early- and late-onset: 10% ~40%
Pericardial effusion,% ~40% ~55% –
Median Survival ~3.5 - 6 years 12 years (Early-onset)
7 years (Late-onset)
~2.5 years (without therapy)
Legend: AC, Amyloid Cardiomyopathy; AF, Atrial Fibrillation; AV, Atrio-Ventricular; CTS, Carpal Tunnel Syndrome; LA, Left Atrium; LVEF, Left Ventricular Ejection Fraction; TTR, Transthyretin. Epidemiologic data, including the prevalence of clinical and echocardiographic characteristics, derive from those available in literature [
Quarta C.C.
Obici L.
Salvi F.
Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective.
Eur Heart J. 2013; 34: 520-528https://doi.org/10.1093/eurheartj/ehs123
Farioli A.
Curti S.
Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies.
Eur J Heart Fail. 2020; 22: 507-515https://doi.org/10.1002/ejhf.1742
Arvanitis M.
Koch C.M.
Chan G.G.
Torres-Arancivia C.
LaValley M.P.
Jacobson D.R.
Identification of Transthyretin Cardiac Amyloidosis Using Serum Retinol-Binding Protein 4 and a Clinical Prediction Model.
JAMA Cardiol. 2017; 2: 305https://doi.org/10.1001/jamacardio.2016.5864
Ruberg F.L.
Kelly J.W.
Maurer M.S
Transthyretin Amyloid Cardiomyopathy.
In recent years, specific clinical presentations of ATTR-AC have been identified [
Manolis A.S.
Manolis A.A.
Manolis T.A.
Melita H
Cardiac amyloidosis: an underdiagnosed/underappreciated disease.
Eur J Intern Med. 2019; 67: 1-13https://doi.org/10.1016/j.ejim.2019.07.022
]. In particular, elderly patients with HF and preserved EF admitted to cardiology or internal medicine departments may harbour amyloid in their hearts. This may also be the case for patients with valvular heart disease due to aortic valve stenosis referred because of syncope or transcatheter aortic valve implantation (TAVI), particularly in relation to 'paradoxical' LF-LG disease. When encountering these peculiar profiles, some of which are common in everyday practice, experienced clinicians should maintain a high index of suspicion [
Witteles R.M.
Elliott P.M.
Fine N.M.
Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice.
JACC Hear Fail. 2019; 7: 709-716https://doi.org/10.1016/j.jchf.2019.04.010
] and look for specific signs of cardiac infiltration (Fig. 1, Fig. 2). Therefore, a major shift in mental attitude is essential to recognize suggestive findings and prompt further testing to confirm or rule out the disease.
Fig. 1Echocardiographic findings indicating high suspicion of cardiac amyloidosis. Diffuse, concentric cardiac hypertrophy of both ventricles with bi-atrial enlargement and thickened IAS. Power Doppler showing restrictive LV filling pattern. Severely impaired LV global longitudinal strain with apical sparing pattern upon speckle-tracking analysis. Global severe reduction of regional myocardial deformation of the basal inferior septum < 5 cm/s, suggesting advanced cardiac infiltration. Legend: LV, Left Ventricle; IAS, Interatrial Septum.
Fig. 2A 66-year-old man diagnosed with supposed hypertensive heart disease. Severe, concentric biventricular hypertrophy with granular sparkling appearance of the myocardium, thickened papillary muscles, bi-atrial enlargement and pericardial effusion. The regular size of the aortic root and the ascending aorta should have called into question the initial diagnosis of hypertensive heart disease. Thickened AV valves and IAS suggest long-standing infiltration. Legend: AV, atrioventricular; IAS, Interatrial Septum.
The 'red flag' diagnostic approach [
Vergaro G., Aimo A., Barison A., Genovesi D., Buda G., Passino C., et al. Keys to early diagnosis of cardiac amyloidosis: red flags from clinical, laboratory and imaging findings. Eur J Prev Cardiol 2019:204748731987770. 10.1177/2047487319877708.
] has proven to be effective in spotting core clinical clues that point clinicians towards the diagnosis of ATTR amyloidosis, even before overt LV hypertrophy (Table 2). Of these clues, specific osteo-articular disorders—such as atraumatic rupture of biceps tendons, lumbar spine stenosis and hip disease—might prompt further testing for AC [
]. Patients with these disorders frequently undergo scintigraphy with bone tracers, and incidental cardiac retention might sometimes occur (Fig. 3). This finding is consistent with cardiac amyloid infiltration and warrants a comprehensive cardiac evaluation focused on AC (Table 2).
Table 2The comprehensive 'red flag' approach to TTR-AC.
Cardiological Evaluation
Findings of high suspicion for amyloid disease
HCM diagnosed after the sixth decade of life
Supposed 'hypertensive cardiomyopathy' in elderly patients with normal BP values and no valvular disease
Recurrent syncope
Need for down-titration or discontinuation of antihypertensive therapy due to poor tolerability
Intolerance of ẞ-blockade in newly diagnosed HF
Bowel dysfunction (constipation, diarrhoea)
Clinical Signs HF with systemic venous congestion
Aortic valve stenosis in the elderly
Periorbital purpura
Bilateral CTS, atraumatic rupture of biceps tendon and LS stenosis
Unexplained neuropathic pain, mostly in non-diabetic patients
Orthostatic hypotension and erectile dysfunction due to autonomic neuropathy
Vitreous deposits
Laboratory Persistent elevation in serum troponin values
Increased NT-proBNP values (> 5000 pg/mL), disproportional to the clinical severity of HF
Monoclonal gammopathy of undetermined significance (frequently coexisting)
ECG Low QRS voltages (peripheral and/or precordial leads)
Discrepancies between severity of LV wall thickness and QRS voltages
AV delay and/or blocks
Pseudonecrosis
Echocardiography Diffuse LV cardiac hypertrophy with non-dilated LV
Coexisting RV hypertrophy
Restrictive diastolic filling pattern
Paradoxical low-flow low-gradient aortic valve stenosis
Increased thickness of the interatrial septum and AV valves
Granular sparkling appearance of the myocardium
Reduced LV longitudinal strain with 'apical sparing' pattern
Bold identifies the most specific red flags of disease according to [
]. Legend: AC, Amyloid Cardiomyopathy; AF, Atrial Fibrillation; AV, Atrio-Ventricular; BP, Blood Pressure; CA, Cardiac Amyloidosis; CAD, Coronary Artery Disease; CTS, Carpal Tunnel Syndrome; CV, Cardioversion; ECG, Electrocardiogram; EF, Ejection Fraction; HCM, Hypertrophic Cardiomyopathy; HF, Heart Failure; LS, Lumbar Spine; LV, Left Ventricle; NT-proBNP, N- terminal pro Brain Natriuretic Peptide; RV, Right Ventricular; TTR, Transthyretin.
Fig. 3A 62-year-old man diagnosed with hypertrophic cardiomyopathy. The patient underwent a cardiological evaluation due to palpitations and a family history of sudden death (father died at 78). An ECG revealed low-voltage QRS in the peripheral leads, Q waves in the inferior leads and poor R wave progression in the precordial leads ('pseudonecrosis'). A Holter ECG revealed paroxysmal AF and 3 consecutive ectopic ventricular beats >120 bpm. The echocardiogram and CMR showed LV hypertrophy (interventricular septum > 15 mm), left atrial dilatation and pericardial and bilateral pleural effusion. A diagnosis of hypertrophic cardiomyopathy was made, and the patient was implanted with an ICD for primary prevention of SCD. After 2 years, he was referred to our Cardiovascular Department for unexplained syncopal episodes. No arrhythmias were detected by the ICD. The patient complained of a one-year history of symptomatic bilateral carpal tunnel syndrome and discontinued anti-hypertensive drugs due to poor tolerability. An endomyocardial biopsy revealed diffuse amyloid fibrils upon Congo red staining (courtesy of Professor Rossana Bussani, MD, Institute of Pathological Anatomy and Histology, University of Trieste, Italy). Scintigraphy revealed high-grade (Perugini 3) cardiac accumulation of bone tracers, and after excluding a monoclonal component a diagnosis of ATTR-CA was made. Genetic testing revealed wild type transthyretin, and the patient was started on Tafamidis. Legend: AF, Atrial Fibrillation; CMR, Cardiac Magnetic Resonance; ECG, Electrocardiogram; ICD, Implantable Cardioverter Defibrillator; SCD, Sudden Cardiac Death.
Interestingly, carpal tunnel syndrome, particularly if bilateral at onset, can precede the diagnosis of ATTR-AC by many years (from 5 to 9 years) [
].These patients might exhibit normal wall thickness upon echocardiography; however, they have recently been reported to be at higher cardiovascular risk [
Fosbøl E.L.
Leicht B.P.
Schou M.
Kristensen S.L.
Association of Carpal Tunnel Syndrome With Amyloidosis, Heart Failure, and Adverse Cardiovascular Outcomes.
J Am Coll Cardiol. 2019; 74: 15-23https://doi.org/10.1016/j.jacc.2019.04.054
] and could benefit from regular cardiological evaluations.
The definite diagnosis of ATTR-AC does not rely upon specific biomarkers, but different parameters are currently under evaluation to aid in the identification of the disease and to monitor response to new disease-modifying drugs, including plasmatic concentration of TTR, retinol-binding protein-4 (RBP4), measurements of TTR kinetic stability and non-antibody peptide probes [
Pregenzer-Wenzler A.
Abraham J.
Barrell K.
Kovacsovics T.
Nativi-Nicolau J
Utility of Biomarkers in Cardiac Amyloidosis.
Hendren N.S.
Roth L.R.
Grodin J.L
Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis.
Curr Heart Fail Rep. 2020; 17: 77-83https://doi.org/10.1007/s11897-020-00457-z
TTR serum levels tend to be lower than normal in subjects with destabilizing mutations and patients with ATTRwt amyloidosis. Notably, treatment with the new disease-modifying drugs has opposite effects on circulating TTR (decreased by gene silencers and increased by stabilizers), that can be used to monitor the response to therapy. RBP4 has been recently demonstrated a useful tool to detect V122I ATTR amyloidosis in elderly African Americans with HF, especially when integrated in a multi-parametric prediction model [
Novel markers of TTR stability (still under evaluation) include peptide probes that selectively bind to misfolded pathogenic oligomers in the serum and measurements of the rate of subunit exchange with the TTR tetramer [
2.3 The contribution of genetics
Many experts consider ATTRv-AC a model of genotype–phenotype correlation. Exclusively or mainly 'cardiogenic' or 'neurologic' mutations in the TTR gene have been described [
]. Val30Met substitution is associated with isolated progressive polyneuropathy (early-onset phenotype), cardiomyopathy and mixed phenotypes. Val122Ile is the most common cause of late-onset ATTRv-AC in the United States, while severe AC most commonly results from Val122Ile and Thr60Ala (early-onset phenotypes) or Ile68Leu (late-onset phenotype) in Italy and from Leu111Met (early-onset phenotype) in Denmark [
Understanding the phenotypic heterogeneity of ATTR amyloidosis is challenging because many other non-genetic determinants are often involved, such as gender, geographical distribution and endemic/non-endemic aggregation [
]. The highly variable penetrance of mutations in the TTR gene and ageing are other elements of heterogeneity [
]. Therefore, it is strongly advocated that future research investigate the role of genetic mutation in driving disease phenotype and natural history.
2.4 Prognostic stratification
Amyloidosis is considered an ominous disease carrying a high mortality burden, but recent diagnostic advances and novel treatments will change the natural history of disease [
Porcari A.
Falco L.
Lio V.
Merlo M.
Fabris E.
Bussani R.
Cardiac amyloidosis: do not forget to look for it.
Eur Hear J Suppl. 2020; 22: E142-E147https://doi.org/10.1093/eurheartj/suaa080
]. Prognostic stratification remains challenging, as the diagnosis is made at different stages of the disease and the risk conferred by ATTR-AC is dynamic over time due to progressive cardiac infiltration. Patients are frequently diagnosed many years after disease onset and have commonly been managed as having hypertrophic cardiomyopathy or other phenocopies.
Some TTR mutations have been associated with more favourable or more adverse outcomes [
]. However, the presence and extent of cardiac involvement is by far the main prognostic factor, regardless of the specific amyloid precursor [
]. Therefore, dedicated staging systems have been developed to predict the outcome of ATTR-AC patients. The Mayo Clinic model validated the use of NT-proBNP and troponin T in ATTRwt-AC (cut off values of > 3000 ng/L and > 0.05 ng/mL, respectively). The estimated median overall survival when both values are above the cut-offs is 20 months [
]. More recently, Gillmore et al. have proposed another staging system based on NT-proBNP and the estimated glomerular filtration rate (eGFR) (cut off values of > 3000 ng/L and < 45 ml/min/m2, respectively), validated for both ATTRwt-AC and ATTRv-AC. The estimated median overall survival when both criteria are satisfied is 24 months [
]. The above-mentioned staging system includes only biomarkers of HF, cardiac damage and renal function. More parameters are relevant in the natural history of ATTR-CA, and a combination of blood tests and imaging parameters from echocardiography and cardiac magnetic resonance might potentially improve outcome estimation. In addition, most patients are elderly with multiple comorbidities (i.e. neoplasms) and significant competing risks of events.
Knowing the real prevalence of ATTR-AC and the natural history of disease from the initial stages of cardiac infiltration is critical to accurately predict long-term prognosis. Furthermore, the staging systems appear to perform adequately when the cardiac phenotype is apparent, but their predictive power at the initial stages of disease is currently unknown.
2.5 Disease-modifying therapies
No evidence-based treatment was available until recently, as ATTR-AC was largely underdiagnosed and frequently served as exclusion criteria in clinical trials testing HF medications. However, advances in knowledge about the 'amyloidogenic cascade' led to novel strategies targeting TTR synthesis and circulating TTR tetramers [
]. After years of unsuccessful pharmacological research, a stabilizer of circulating TTR called Tafamidis reduced all-cause mortality and cardiovascular hospitalization in patients with HF due to ATTR-AC [
Schwartz J.H.
Gundapaneni B.
Waddington-Cruz M.
Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.
N Engl J Med. 2018; 379: 1007-1016https://doi.org/10.1056/NEJMoa1805689
]. In the wake of this discovery, additional drugs, such as Patisiran and Inotersen, have been tested. These are able to directly interfere with TTR synthesis via the liver, resulting in a considerable drop in circulating levels of TTR protein (approaching 80%) [
]. These drugs are promising disease-modifying approaches that have been demonstrated to promote clinical amelioration of and beneficial changes in infiltrated cardiac muscle [
Solomon S.D.
González-Duarte A.
Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis.
Circulation. 2019; 139: 431-443https://doi.org/10.1161/CIRCULATIONAHA.118.035831
Dasgupta N.R.
Rissing S.M.
Smith J.
Jung J.
Benson M.D
Inotersen therapy of transthyretin amyloid cardiomyopathy.
Amyloid. 2020; 27: 52-58https://doi.org/10.1080/13506129.2019.1685487
]. The choice amongst different therapeutic approaches does not rely only on the assessment of drug safety and efficacy in different patient populations, such as those with cardiac and/or neuropathic involvement, but also on approval by regulatory authorities and the possibility of reimbursement. When therapy with Tafamidis, Patisiran or Inotersen is started, there are no defined criteria for early identification of responders and non-responders. Therefore, the decision to continue a therapy, to switch from one therapy to another or to combine two therapies is empirical. The identification of early criteria for response to treatment is an important goal of future research, particularly considering that these drugs greatly exceed conventional cost-effectiveness thresholds, as formally demonstrated for Tafamidis [
Kazi D.S.
Bellows B.K.
Baron S.J.
Cohen D.J.
Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy.
Currently, Tafamidis is the only approved treatment for ATTR-AC in the United States, while Patisiran and Inotersen are approved for ATTRv amyloidosis with neuropathy [
] (Table 3). Other drugs are being evaluated in clinical or pre-clinical studies, including:
AG-10, an oral drug that effectively stabilizes TTR tetramers (NCT03860935, NCT04418024);
AKCEA-TTR-LRx, an antisense oligonucleotide administered subcutaneously every 4 weeks that targets hepatocytes much more selectively than Inotersen, thus being more effective in silencing TTR gene expression and having less systemic adverse effects. A dedicated trial is evaluating its safety and efficacy in patients with peripheral neuropathy (NCT04136184);
Vutrisiran, a small-interfering RNA (similar to Patisiran) that can be administered subcutaneously every 3 months (NCT04153149);
Specific antibodies inducing the removal of tissue amyloid deposits. The monoclonal antibody PRX004 is able to specifically bind tissue TTR deposits, but the phase 1 trial (NCT03336580) has been prematurely terminated because of COVID 19 pandemic.
Table 3Focus on available treatments in TTR-AC and novel drugs under investigation.
Results in TTR-AC
Approved indications (FDA/EMA; June 2020)
Tafamidis (ATTR-ACT, 2018)
TTR stabilizer Multicentre, double-blind, placebo controlled
2:1:2 randomization 80 mg vs. 20 mg vs. placebo for 30 months TTR cardiomyopathy (TTRv and TTRwt) (n = 441) Reduced all-cause mortality (HR 0.70) and CV hospitalization (RR 0.68);
Less decline in 6MWT and KCCQ-OS score (both p <0.001) FDA: not approved
EMA: Stage I TTRv-related polyneuropathy
AG-10 (2019)
Judge D.P.
Heitner S.B.
Shah S.J.
Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy.
1:1:1 randomization 1600 mg vs. 800 mg vs. placebo for 28 days TTR cardiomyopathy (TTRv and TTRwt) (n = 49) Near-complete stabilization of TTR with restoration of normal serum levels. More effective at higher doses (average increase of 36±21% and 51±38% at 400 and 800 mg (both p<0.001) FDA: not approved.
EMA: not approved.
Patisiran (APOLLO, 2018)
Gonzalez-Duarte A, O'Riordan WD, Yang C-C, Ueda M, Kristen A V., et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.
N Engl J Med. 2018; 379: 11-21https://doi.org/10.1056/NEJMoa1716153
SiRNA Multicentre, double-blind, placebo controlled
2:1 randomization 0.3 mg/kg iv vs. placebo once every 3 weeks for 18 months TTRv-related polyneuropathy
Subgroup with cardiomyopathy (n = 126, 56%) Slower LV functional deterioration and promotion of favourable remodelling: decreased LV volumes, wall thickness, RWT, mass and NT-proBNP. FDA: TTRv-related polyneuropathy
EMA: Stages I–II TTRv-related polyneuropathy
Inotersen (2018)
Benson M.D.
Berk J.L.
Polydefkis M.
Dyck P.J.
Wang A.K.
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.
ASO Multicentre, double-blind, placebo controlled
2:1 randomization 300 mg sc vs. placebo for 64 weeks TTRv-related polyneuropathy – Stages I–II
Subgroup with cardiomyopathy (n = 108, 63%)
Slower progression in neuropathy, no effect on echocardiographic parameters (including GLS) FDA: TTRv-related polyneuropathy
PRX004 (NCT03336580) mAb Phase I, single centre, open-label, dose escalation 0.1 mg/kg iv once every 28 days TTRv amyloidosis (estimated n = 36) Aim: determine the safety, tolerability, PK, PD and MTD Prematurely terminated because of COVID 19 pandemic
Ab-A (2020)
George J.
Rappaport M.
Shimoni S.
Goland S.
Voldarsky I.
Fabricant Y.
A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.
mAb Single centre, open label, murine model 10 mg/kg vs. 5 mg/kg vs. 0.1 mg/kg vs. sham TTRwt amyloidosis Promoting clearance and degradation of aggregated TTR by cardiac macrophages
Protecting cardiomyocytes from aggregated TTR- mediated toxicity –
Legend: 6MWT, Six Minute Walking Test; AC, Amyloid Cardiomyopathy; ASO, Antisense Oligonucleotide; CV, Cardiovascular; EMA, European Medicine Agency; FDA, Food and Drug Administration; GLS, Global Longitudinal, Strain; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire Overall Summary; LV, Left Ventricular; mAb, Monoclonal Antibody; MTD, Maximum Tolerated Dose; NT-proBNP, N- terminal Brain Natriuretic Peptide; PD, Pharmacodynamics; PK, Pharmacokinetics; RWT, Relative Wall Thickness, siRNA, small interfering RNA; TTR, Transthyretin; TTRv, mutated Transthyretin; TTRwt, wild-type Transthyretin.
3. To treat or not to treat … and when?
The increasing availability of potential therapies for ATTR-AC highlights the fundamental issue of the accurate selection of candidates. In exploring uncharted horizons, relevant unsolved issues and challenging scenarios are emerging (Table 4) [
Vergaro G.
Giannoni A.
Spini V.
Passino C.
Management of complications of cardiac amyloidosis: 10 questions and answers.
Eur J Prev Cardiol. 2020; 204748732092075https://doi.org/10.1177/2047487320920756
TTR amyloid in the heart: disease or incidental finding of amyloid deposits? The prolongation of the average lifespan in the recent decades has been paralleled by the rise of degenerative disorders [
]. TTR amyloidosis is part of this phenomenon as a result of the failure of protein homoeostasis associated with ageing [
]. However, the mere presence of amyloid deposits in the myocardium does not directly involve a definite pathogenic role. TTR amyloidosis has been reported in the atria of > 91% of subjects over 65 years and in the aorta of ≥ 95% of those aged ≥ 80 years [
Kawamura S.
Takahashi M.
Ishihara T.
Uchino F
Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts.
Pathol Int. 1995; 45: 335-342https://doi.org/10.1111/j.1440-1827.1995.tb03466.x
Iwata T.
Kamei T.
Uchino F.
Mimaya H.
Yanagaki T.
Etoh H
Pathological study on amyloidosis -relationship of amyloid deposits in the aorta to aging.
]. At present, cardiac retention of bone tracers on scintigraphy can reveal TTR amyloid deposits even before a detectable increase in ventricular wall thickness on echocardiography [
]. This approach can considerably reduce diagnostic delay, allowing the identification of subjects at an asymptomatic stage [
]. However, the clinical relevance of such deposits is undetermined, being potentially the consequence of age-related physiological disruptions. Therefore, such information should be evaluated in combination with the clinical picture and cardiologic findings to avoid misdiagnosis and the initiation of unnecessary therapies. Although severe and widespread amyloid accumulation is reasonably detrimental, the amount of amyloid burden to be considered 'disease-related' and prompting treatment initiation remains to be established. Furthermore, amyloid localization should be considered, as even small amounts in vulnerable areas (i.e. the atrio-ventricular node) can have major consequences.
Table 4Grey zones and knowledge gaps in the current management of TTR-AC.
Reasonably indicated treatments and grey zones
Anti-neurohormonal therapy No survival benefit is demonstrated in TTR-AC.
Beta-blockers and ACE-i/ARB can be poorly tolerated, especially in advanced stages due to vasodilatation and reduced CO.
Atrial fibrillation and anticoagulation Anticoagulation with VKAs and DOACs should be administered based on the usual indications and contraindications.
Patients with TTR-AC in sinus rhythm can harbour thrombi in the left atrial appendage, especially when atrial function is severely impaired. Therefore, TEE should be routinely performed before a planned cardioversion.
Atrial fibrillation, rate or rhythm control and catheter ablation There is no specific recommended strategy for the management of arrhythmias.
Digoxin should be avoided or used at low dosages due to concerns about potential enhanced toxicity caused by binding to amyloid fibrils. Drugs with a negative inotropic effect should be avoided (i.e. verapamil and diltiazem).
The efficacy of catheter ablation seems limited, but future studies are required.
Transcatheter aortic valve implantation Percutaneous or surgical aortic valve replacement should not be denied only because of coexistent AC. Definitive PM implantation may be required due to a higher risk of persistent AV blocks.
Ventricular arrhythmias and implantable cardioverter defibrillator Sudden death is not infrequent in patients with advanced HF, but it is generally due to electromechanical dissociation.
The role of ICD for the purpose of:
- primary prevention is currently limited;
- secondary prevention can be considered in select non-advanced cases with sustained VT/VF.
Cardiac resynchronization therapy Very limited data are available on this topic.
CRT should be considered in patients eligible for PM implantation with an estimated time of RV pacing >40%.
Heart transplantation Highly selected HF patients with TTRwt or TTRv and predominant cardiac phenotype without extra-cardiac organ damage could be eligible. Combined heart and liver transplantation could be considered in very selected cases with mixed phenotype and limited neurological involvement.
Legend: AC, Amyloid Cardiomyopathy; ACE-i, Angiotensin Converting Enzyme Inhibitors, ARBs, Angiotensin Receptor Blockers; AV, Atrio-Ventricular; CO, Cardiac Output; DOACs, Direct Oral Anticoagulants; HF, Heart Failure; LBBB, Left Bundle Branch Block; LVEF, Left Ventricular Ejection Fraction; PM, Pacemaker; RV, Right Ventricular; SCD, Sudden Cardiac Death; TEE, Transoesophageal Echocardiography; TTR-AC, Transthyretin Amyloid Cardiomyopathy; TTRv, variant Transthyretin; TTRwt, wild-type Transthyretin, VF, Ventricular Fibrillation; VKAs, Vitamin K Antagonists; VT, Ventricular Tachycardia.
Whether and when asymptomatic patients with incidental cardiac retention of bone tracers on scintigraphy, no signs of HF, normal biomarker levels, no evidence of cardiac hypertrophy or neurological manifestations should be started on disease-modifying medications is unclear. A tailored strategy—also considering the presence of TTR mutations—seems reasonable in light of the variable natural history of disease. Some patients might never progress to subsequent stages of disease or might experience only neurological manifestation without cardiac involvement [
]. Accordingly, a cardiologic screening looking for red flags and suggestive echocardiographic features would allow prompt recognition of initial cardiac involvement and treatment initiation.
Advanced stages of the disease and comorbities. Considerable grey areas remain to be clarified in the clinical management and prognosis of ATTR-AC with advanced infiltration revealed by severe biventricular hypertrophy, a restrictive diastolic pattern and systolic dysfunction.
If present at all, the survival advantage provided by TTR stabilizers in advanced ATTR-AC seems minimal. In the "Tafamidis in Patients With Transthyretin Cardiomyopathy" trial [
], HF patients with New York Heart Association (NYHA) class IV or eGFR <25 ml/min/m2 were excluded, and Tafamidis provided greater benefits in those with early-stage ATTR-AC (NYHA I–II). Furthermore, although functional capacity and quality of life were significantly ameliorated at 6 months, the consistent mortality benefit was evident only after 18–20 months of therapy [
]. These findings raise the question of whether subjects with a lower estimated life expectancy (<6–12 months) should be treated, as they might derive no survival advantage while potentially experiencing side effects.
Prolonging the life expectancy of these patients will result in dealing with challenging scenarios not previously faced (Table 1). For instance, these patients could be eligible for implantable cardioverter defibrillator (ICD) therapy to prevent sudden arrhythmic death, cardiac resynchronization therapy to act on dyssynchrony due to left bundle branch block, percutaneous treatment of severe mitral regurgitation or aortic valve stenosis [
Scully P.R.
Patel K.P.
Treibel T.A.
Thornton G.D.
Hughes R.K.
Chadalavada S.
Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation.
Eur Heart J. 2020; 41: 2759-2767https://doi.org/10.1093/eurheartj/ehaa170
] or coronary artery revascularization. However, the prognostic benefit of these treatments is unknown, as are the effects of anti-neurohormonal therapies with proven impact in HF due to non-amyloidotic aetiologies [
Castiglione V.
Emdin M
Safety and Tolerability of Neurohormonal Antagonism in Cardiac Amyloidosis.
Eur J Intern Med. 2020; https://doi.org/10.1016/j.ejim.2020.05.015
], even in combination with novel specific treatments.
The prevention of sudden cardiac death and percutaneous aortic valve implantation are crucial issues and deserves further discussion. Although secondary prevention is a strong indication for ICD implantation also in patients with AC [
Ponikowski P.
Voors A.A.
Anker S.D.
Bueno H.
Cleland J.G.F.
Coats A.J.S.
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of.
Eur Heart J. 2016; 37: 2129-2200https://doi.org/10.1093/eurheartj/ehw128
] the benefits of this therapy for the purpose of primary prevention remain uncertain. Sudden cardiac death in AC, in fact, frequently results from pulseless electric activity or elettro-mechanical dissociation (non-defibrillable rhythms) rather than tachy-arrhythmias [
Kristen A V.
Dengler T.J.
Hegenbart U.
Schonland S.O.
Goldschmidt H.
Sack F.-.U.
Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death.
Hear Rhythm. 2008; 5: 235-240https://doi.org/10.1016/j.hrthm.2007.10.016
]. In a single-centre retrospective experience, appropriate ICD shocks accounted for only 32% of cases at one-year follow up [
Brady P.A
Implantable Cardioverter Defibrillators in Patients with Cardiac Amyloidosis.
J Cardiovasc Electrophysiol. 2013; 24: 793-798https://doi.org/10.1111/jce.12123
]. Furthermore, ICD therapy did not provide any overall survival benefit. Both ATTRv- and ATTRwt-AC patients experience lower rates of appropriate ICD shocks compared to AL-AC, suggesting that the risk of life-threatening arrhythmias may change in different forms of AC and highlighting the need for accurate patients selection.
Recent studies have shown that ATTR-AC frequently coexists with severe degenerative aortic stenosis (AS) (prevalence ranging from 8 to 16%) due to the shared epidemiologic substrate and the possible effect of increased myocardial strain of aortic stenosis acting on an underlying amyloidogenetic substrate [
Rosenblum H.
Masri A.
Narotsky D.L.
Goldsmith J.
Hamid N.
Hahn R.T.
Unveiling Outcomes in Coexisting Severe Aortic Stenosis and Transthyretin Cardiac Amyloidosis.
Eur J Heart Fail. 2020; (ejhf.1974)https://doi.org/10.1002/ejhf.1974
]. The first anecdotic reports have questioned the usefulness of aortic valve replacement, even when performed by TAVI. More recent prospective studies in relatively large cohorts of patients with severe AS in the elderly with or without ATTR-AC undergoing TAVI have shown similar short and medium term results regarding overall survival (with a higher risk of hospitalization for HF amongst patients with ATTR-AC) [
]. Waiting for further randomized studies, these results suggest that TAVI should not be denied only on the basis of the coexistence of ATTR-AC.
Genotype-positive phenotype-negative relatives. The clinical management of relatives carrying disease-related TTR gene mutations without evidence of cardiac and neurological diseases represents a major gap in knowledge. These patients might potentially be at higher risk of developing amyloid deposition over time and could benefit from dedicated screening programs. No official recommendations are available in this field. Asymptomatic carriers have been proposed to start regular monitoring up to 10 years before the predicted mutation-specific age of onset of symptomatic disease, most commonly between 40 and 55 years [
Conceição I.
Romero M.
Galán L.
Attarian S.
Luigetti M.
Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations*.
Amyloid. 2019; 26: 3-9https://doi.org/10.1080/13506129.2018.1556156
]. Early recognition of ATTRv amyloidosis is crucial to initiate orientated clinical evaluation and tailored treatments, genetic counselling and familial screening [
]. Cardiac scintigraphy with bone tracers and deformation imaging might play a future role in revealing initial cardiac infiltration in asymptomatic carriers [
Finally, several TTR variants exist. For example, non-pathogenic genetic variants have been found, the so-called TTR stabilizing mutations (i.e. Thr119Met and Arg104His). These variants slow the dissociation of the TTR tetramer acting as a trans-suppressor of amyloid fibril formation and result in a more stable TTR protein [
Hammarstrom P.
Jiang X.
Hurshman A.R.
Powers E.T.
Kelly J.W
Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity.
Proc Natl Acad Sci. 2002; 99: 16427-16432https://doi.org/10.1073/pnas.202495199
]. Therefore, the determinants of the clinical profile and the prognostic implications of specific TTR mutations are only partially known (also for TTRwt-AC), and further research is required.
3.1 Future directions and conclusions
Recent years have witnessed significant advances in the epidemiology, pathophysiology and diagnosis of amyloidosis [
]. ATTR-AC is increasingly recognized due to heightened awareness of the disease, more accurate aetiological characterization, the 'red flag' integrated approach and cardiac scintigraphy with bone tracers. Nevertheless, important issues in clinical research still need to be addressed, including:
Understanding the real prevalence of ATTR amyloidosis, particularly with the cardiac phenotype, in the various clinical scenarios and differentiating indolent cardiac accumulation of the 'senile' form from the authentic infiltrative disease;
The use of diphosphonate single photon emission computed tomography to better characterize patients with Perugini score 1 (by detecting localized but intense amyloid deposition, thus allowing an early diagnosis [
Grigoratos C.
Genovesi D.
Barison A.
Aquaro G.D.
Diphosphonate single-photon emission computed tomography in cardiac transthyretin amyloidosis.
Int J Cardiol. 2020; https://doi.org/10.1016/j.ijcard.2020.02.030
]) and possibly to quantify the amyloid burden;
Investigating the potential role of PET imaging with amyloid tracers (alone or in combination with bone tracer scintigraphy) for the differential diagnosis between AL and ATTR amyloidosis [
Giorgetti A.
Marzullo P.
Scipioni M.
Santarelli M.F.
[18F]-Florbetaben PET/CT for Differential Diagnosis Among Cardiac Immunoglobulin Light Chain, Transthyretin Amyloidosis, and Mimicking Conditions.
JACC Cardiovasc Imaging. 2020; https://doi.org/10.1016/j.jcmg.2020.05.031
Defining the minimal disease threshold to justify the initiation of novel treatments with high costs and potential side effects;
Defining the degree of cardiac involvement to be considered so advanced that no significant benefit is expected from the administration of disease-modifying drugs;
Identifying the most appropriate tool to quantify the global amyloid burden and to monitor its changes under specific treatment;
Defining baseline and early on treatment criteria to identify 'responders' and 'non-responders' to disease-modifying therapies in order to guide the decision to discontinue, change or possibly associate drugs;
Defining potential parameters at baseline to predict response to treatment and consequently identifying criteria to discontinue current drugs in favour of other medications or to start on combination therapy.
All this information will be crucial to address proper clinical management and more accurate prognostic stratification through a multiparametric approach integrating clinical evaluation with imaging-derived parameters and specific genetic information. A wide horizon of possibilities is unfolding and awaits discovery.
Funding and disclosures
The authors declare they have no conflict of interest.
We would like to thank Fondazione CariGO and Fondazione per la Cardiologia e le Scienze Multidisciplinari Livia e Vittorio Tonolli and all the healthcare professionals for the continuous support to the clinical management of patients affected by cardiomyopathies, followed in Heart Failure Outpatient Clinic of Trieste, and their families.
Accepted: September 26, 2020


First day is only 6 days from now.
Thought a little Raktacino Black might get things reved up.
That is a very cool photo, Douglas!
I'm ready guys! This should be fun!!
I am ready as I ever am!
Blade needs no sharpening on mine as I don't think I have ever used the blade?
Very good, ezdog! That'll make it all the easier to do the challenge.
Glad you're joining us in the MMCDMC.
Looks like your CD has the Glow of Romulan Ale, ezdog.
You'ld have a whole nickle.
Well, if he already has one nickel, then he'll now have two nickels to rub together.
Gotta practice the book learnin next maybe?
I don't want to learn to read and write.
You can have yiur reed'n an rite'n. I don't want nun o dat der rith-a-matic! It makes my head hurt.
-1. Dun wond thadt eethur.
Romulan Ale pacs'es a punchhh.
I'm about to go make a cappuccino.
That it does laddie, that it does!
Glad you're joining us, Antti! Should be a fun challenge too.
The time is fast approaching! Still time to get in before the launch!


A sturdy yet elegant design. This oval frame basket is a beautiful centre piece, fruit basket & even a useful gardening basket for all your bits & bobs. Woven in a lush rouge willow with beautiful diamond details on the finishing of the elegant bough handles.


If an event simply can't work anymore or maybe is cancelled for some reason, it can be deleted! Read on for information on how to delete an event in Infoodle.
If the event is part of a recurring series, infoodle will give the option to make changes to the single event, or all events in that series.
Infoodle will bring up the Edit Event panel. Click the Delete button on the panel.
Infoodle will then delete the event.
Note: Once it's gone, it's gone! You may need to contact infoodle to retrieve it or else create the event again from scratch.


Everybody knows that a well-balanced workout and diet program is required to lose weight and stay fit. You don't always need fancy exercise equipment to burn calories and stay fit. The RipDeck app for iPhone happens to be a simple app that provides you with a deck of workout cards on your smartphone to help you reach your fitness goals.
RipDeck provides you with bodyweight workouts to help you burn more calories at home. You can use it for timed sessions or get the pro version to create your own custom workouts and track history. The app lets you share workouts with others. The Apple Watch app helps you get started with your workout faster.
RipDeck is available for free at this time. To get the most out of it, you need to upgrade though.


text:
Value theory involves various approaches that examine how, why, and to what degree humans value things and whether the object or subject of valuing is a person, idea, object, or anything else.
Within philosophy, it can be known as ethics or axiology. Early philosophical investigations sought to understand good and evil and the concept of "the good". Today, much of value theory aspires to the scientifically empirical, recording what people do value and attempting to understand why they value it in the context of psychology, sociology, and economics.[1]
In ecological economics value theory is separated into two types: donor-type value and receiver-type value. Ecological economists tend to believe that 'real wealth' needs a donor-determined value as a measure of what things were needed to make an item or generate a service (H. T. Odum, Environmental Accounting: Emergy and environmental decision-making, 1996).
In other fields, theories positing the importance of values as an analytical independent variable (including those put forward by Max Weber, Émile Durkheim, Talcott Parsons, and Jürgen Habermas). Classical examples of sociological traditions which deny or downplay the question of values are institutionalism, historical materialism (including Marxism), behaviorism, pragmatic-oriented theories, postmodern philosophy and various objectivist-oriented theories.
At the general level, there is a difference between moral and natural goods. Moral goods are those that have to do with the conduct of persons, usually leading to praise or blame. Natural goods, on the other hand, have to do with objects, not persons. For example, the statement "Mary is a good person" uses 'good' very differently than in the statement "That is good food".
Ethics is mainly focused on moral goods rather than natural goods, while economics has a concern in what is economically good for the society but not an individual person and is also interested in natural goods. However, both moral and natural goods are equally relevant to goodness and value theory, which is more general in scope.
Main article: Value (ethics)
In sociology, value theory is concerned with personal values which are popularly held by a community, and how those values might change under particular conditions. Different groups of people may hold or prioritize different kinds of values influencing social behavior.
Methods of study range from questionnaire surveys to participant observation. Values can be socially attributed. What the community perceives as of paramount significance to them denotes or decipher their social attributes.
Main article: Theory of value (economics)
Economic analysis emphasizes goods sought in a market and tends to use the consumer's choices as evidence (revealed preference) that various products are of economic value. In this view, religious or political struggle over what "goods" are available in the marketplace is inevitable, and consensus on some core questions about body and society and ecosystems affected by the transaction, are outside the market's goods so long as they are unowned.[2]
However, some natural goods seem to also be moral goods. For example, those things that are owned by a person may be said to be natural goods, but over which a particular individual(s) may have moral claims. So it is necessary to make another distinction: between moral and non-moral goods. A non-moral good is something that is desirable for someone or other; despite the name to the contrary, it may include moral goods. A moral good is anything which an actor is considered to be morally obligated to strive toward.
When discussing non-moral goods, one may make a useful distinction between inherently serviced and material goods in the marketplace (or its exchange value), versus perceived intrinsic and experiential goods to the buyer. A strict service economy model takes pains to distinguish between the goods and service guarantees to the market, and that of the service and experience to the consumer.
Sometimes, moral and natural goods can conflict. The value of natural "goods" is challenged by such issues as addiction. The issue of addiction also brings up the distinction between economic and moral goods, where an economic good is whatever stimulates economic growth. For instance, some claim that cigarettes are a "good" in the economic sense, as their production can employ tobacco growers and doctors who treat lung cancer. Many people would agree that cigarette smoking is not morally "good", nor naturally "good," but still recognize that it is economically good, which means, it has exchange value, even though it may have a negative public good or even be bad for a person's body (not the same as "bad for the person" necessarily – consider the issue of suicide.)
In ecological economics value theory is separated into two types: donor-type value and receiver-type value. Ecological economists tend to believe that 'real wealth' needs a donor-determined value as a measure of what things were needed to make an item or generate a service (H. T. Odum, Environmental Accounting: Emergy and environmental decision-making, 1996). An example of receiver-type value is 'market value', or 'willingness to pay', the principal method of accounting used in neo-classical economics. In contrast, both Marx's labour theory of value and the emergy concept are conceived as donor-type value. Emergy theorists believe that this conception of value has relevance to all of philosophy, economics, sociology and psychology as well as Environmental Science.
Silvio Gesell denied value theory in economics. He thought that value theory is useless and prevents economics from becoming science and that a currency administration guided by value theory is doomed to sterility and inactivity.[3]
Ethics and axiology
Intuitively, theories of value must be important to ethics. A number of useful distinctions have been made by philosophers in the treatment of value.
Intrinsic and instrumental value
Main article: Instrumental and intrinsic value
Discreetness can be established by distinguishing between instrumental value and intrinsic values by giving value intrinsic and extrinsic properties. First introduced by Plato in the "Republic": an instrumental value is worth having as a means towards getting something else that is good (e.g., a radio is instrumentally good in order to hear music). An intrinsically valuable thing is worth having for itself, not as a means to something else.
Intrinsic and instrumental goods need not define mutually exclusive categories. As some things can be found to be both good (in themselves) while also simultaneously good for getting other things that are good. A concept of: "Understanding science" may be one such a good, by being a means as achieving other goods as well as worthwhile in and of itself.
A prominent argument in environmental ethics, made by writers like Aldo Leopold and Holmes Rolston III, is that wild nature and healthy ecosystems have intrinsic value, prior to and apart from their instrumental value as resources for humans, and should therefore be preserved. This line of argument has been articulated further in recent years by Canadian philosopher John McMurtry within the Encyclopedia of Life Support Systems published by UNESCO.
Pragmatism and contributory goodness
Further information: Pragmatic ethics
John Dewey (1859-1952), in his book Theory of Valuation,[4] sees goodness as the outcome of ethic valuation, a continuous balancing of "ends in view". An end in view is said to be an objective potentially adopted, which may be refined or rejected based on its consistency with other objectives or as a means to objectives already held.
Dewey's empiricist approach evinces absolute intrinsic value denial; i.e. not accepting intrinsic value as an inherent or enduring property of things. Instead, Dewey sees the appearance of intrinsic value as an illusory product of our continuous valuative activity as purposive beings. In addition to denying categorically that there is anything like intrinsic value, Dewey held the same position with regard to moral values - for Dewey, moral values are also based on a learning process, and are never intrinsic or absolute.
Another contribution of pragmatism to value theory is the idea of contributory goods with a contributory conditionality. These have the same qualities as the good thing, but need some emergent property of a whole state-of-affairs in order to be good. For example, salt is food on its own, but is far better as part of a prepared meal. In other words, such goods are only "good" when certain conditions are met. This is in contrast to other goods, which may be considered "good" in a wider variety of situations.
Kant: hypothetical and categorical goods
The thinking of Immanuel Kant greatly influenced moral philosophy. He thought of moral value as a unique and universally identifiable property, as an absolute value rather than a relative value. He showed that many practical goods are good only in states-of-affairs described by a sentence containing an "if" clause, e.g., in the sentence, "Sunshine is only good if you do not live in the desert." Further, the "if" clause often described the category in which the judgment was made (art, science, etc.). Kant described these as "hypothetical goods", and tried to find a "categorical" good that would operate across all categories of judgment without depending on an "if-then" clause.
An influential result of Kant's search was the idea of a good will being the only intrinsic good. Moreover, Kant saw a good will as acting in accordance with a moral command, the "Categorical Imperative": "Act according to those maxims that you could will to be universal law.[5]" but should not be confused with the Ethic of Reciprocity or Golden Rule, e.g. Mt. 7:12. Whereas the golden rule states that "One should treat others as one would like others to treat oneself," Kant asks us to analyze whether an act can be performed simultaneously by everyone without exception. For example, murder cannot be performed simultaneously by everyone, one set of people would have to live and the other die. That disparity is an exception. The act cannot be performed without exception, therefore it fails the categorical imperative. Contrast this with the golden rule which is subjective to the individual. Following the logic of the golden rule, if I wanted someone to kill me, then it would be acceptable for me to kill others, because I would be doing to others what I would want done to me. This is very important to keep in mind, because Kant's categorical imperative avoids this flaw. From this, and a few other axioms, Kant developed a moral system that would apply to any "praiseworthy person".[6]
Kantian philosophers believe that any general definition of goodness must define goods that are categorical in the sense that Kant intended.
Anthropological theories of value
Cultural Institutions Studies
Graded absolutism
Intuitionism
Labor theory of value
Law of value
Pirsig's metaphysics of Quality
Rationality and power
Thick concept
Ultimate importance
Value-added theory
David Detmer (1988). Freedom as a Value: A Critique of the Ethical Theory of Jean-Paul Sartre. Open Court Publishing. ISBN 978-0812690835.
Debreu, G (1972). Theory of Value: An Axiomatic Analysis of Economic Equilibrium. Cowles Foundation - Yale University. ISBN 978-0300015591.
biblio.wiki https://web.archive.org/web/20171210232654/https://biblio.wiki/wiki/The_Natural_Economic_Order/Part_III/Chapter_3i. Missing or empty |title= (help)
Dewey, J (1939). Theory of Valuation. University of Chicago USA. ISBN 978-0226575940.
Immanuel Kant & Gary Banham (Authors) plus other contributors (1787–2007). The Critique of Pure Reason. Macmillan. ISBN 978-0230013384.
Kant, Immanuel. Groundlaying toward the Metaphysics of Morals.
Nicholas Rescher. 2010. Axiogenesis: An Essay in Metaphysical Optimalism. Lexington Books.

redpajama_set_name: RedPajamaCommonCrawl


a Data from EPA, Compilation of Air Pollutant Emission Factors, AP-42, Fifth ed., U.S. Environmental Protection Agency, U.S. Government Printing Office, Washington, D.C., January 1995. All condensable PM is assumed to be less than 1.0 ^m in diameter.
bNo data are available for cyclone boilers; for cyclone boilers, use the factors provided for pulverized-coal-fired boilers and applicable controls. cFGD, flue gas desulfurization.
d CPM-TOT, total condensable particulate matter; CPM-IOR, inorganic condensable particulate matter; CPM-ORG, organic condensable particulate matter; ND, no data.
eFactors should be multiplied by fuel rate on a heat input basis (MMBtu), as fired. To convert to lb/short ton of lignite, multiply by 16 MMBtu/short ton.
f S = wt.% coal sulfur, as fired; for example, if the sulfur percent is 1.04, then S = 1.04. If the coal sulfur percent is 0.4 or less, use a default emission factor of 0.01 lb/MM Btu rather than the emission equation.


No pictures, but some interesting follow-up. I've been aware of the chemtrail situation for a few years now and living in the West Hills here in Portland, I have a ringside seat for the daily show. Every clear day and recently every clear night, they bombard us with chemtrails – every day without fail for at least the last three years; that is, until you posted the recent article. The day after that story appeared on your site was the first clear day in three years that they haven't sprayed Porland Or. The following day they did a relatively light spray, apparently realising just how quickly the brainwashed minions forget.
But now, we have a brand new situation. The last couple days they have again quit. Sitting here on a Sunday morning, now afternoon, on a perfectly beautiful and clear day they aren't spraying us – how come? Have you heard the news? There is a skin rash epidemic hitting our public schools. A couple schools have been closed – I believe they may be re-opened on Monday – while many, I think in the hundreds, of kids have come down with this'mystery rash'. It was the lead news story for a few nights. No one has been able to discover the cause, but since americans don't like the unknown, the local medical folks have come up with the concept of a "psychosomatic" rash. Can you believe that Jeff, the children in Portland Or. are so screwed up psychologically that they're all having a psychosomatic rash. All the local talking heads are pushing this 'theory'.
This rash looks just like those I've seen pictures of where those affected claim them to be chemtrail related. I'm not a doctor, I just play one on-line, but I'll bet you a cool million this rash is caused by our daily dose of chemtrails and the 'authorities' are afraid the minions may actually look up and somehow put two and two together. Personally, I don't think those in charge have anything to worry about, the people of Portland will never have the courage to face this issue.
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Handles the MouseDoubleClick event of the Label control.
Handles the OnChecked event of the ShowDistinguishedNamesCheckbox control.
Handles the OnUnchecked event of the ShowDistinguishedNamesCheckbox control.


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Q: Equivalent of include() in HTML I was wondering wether there is a way to include some html content inside another html using only html?
A replacement to PHP's
<?php include("file.php"); ?>

Is this possible?
EDIT:
This has brought up some confusion, what I needed was "almost an html tag" that had the functionality of including a html document in another.

A: HTML does not have a feature to include additional content natively.  However most web servers do have server-side include statements:
SSI in Apache
SSI in IIS

A: the only thing would be an iframe which is pure html. but you also can use javascript to get the page via ajax and include it into your dom hirarchy

A: Yes there is but you need to enable it in your config or .htaccess:
Options +Includes
AddType text/html .shtml
AddHandler server-parsed .shtml

Of course with that youd need to rename any file doing the including to .shtml... or you could jsut use:
Options +Includes
AddType text/html .html
AddHandler server-parsed .html

the syntax itself is similar to comment:

A: Have you tried:
<object type="text/html" data="file.html"></object>

A: There's no such thing. You'd have to use a server-side scripting language or JavaScript to do something like this.

A: If you're using Apache, you can try Server Side Includes.

A: It cannot be done purely by HTML. (There are iframes, however, but I don't think that qualifies in this case.)
It can be done using JavaScript. You get the other file via Ajax, and place its contents inside an HTML element on the current page.

A: This might be a few years late but this is how i did it !
in the first line after  put this line !

redpajama_set_name: RedPajamaStackExchange


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Chiiild Drops 'Sleepwalking' & 'Awake' Featuring Mahalia Ahead Of Debut Album
April 5, 2021 | 6:00 pm
Following the release of his 2020 EP Synthetic Soul and the "Bonafide" collaboration with Emotional Oranges at the top of this year, Montreal-bred singer-songwriter Chiiild gifts his growing fanbase with a soulful two-piece. He kicked off the rollout for his forthcoming debut album with the release of his surreal single "Sleepwalking" and its dreamy Daniel Regan-directed visual. Chiiild describes the song as a "self-reflective song about reclaiming agency over your life" noting, "We all have something that makes us special, that nurtured can create something beautiful." For the abstract visual, we watch as folks of all ages and from different walks of life travel backwards on a beach. Chiiild continues, "With Dan Regan at the helm, the sleepwalking video enters a new dimension. Aiming to create a future nostalgia."
As a well-suited follow-up, Chiiild dropped "Awake," a sexy mid-tempo bop featuring British songstress Mahalia. The two take turns professing their anticipation for a bit of private time and their sensual energy is palpable. Their vocals blend effortlessly over the lustful track, punctuated with a penetrating bass line and groovy guitar work, making it the perfect addition for your adult time playlist.
Vibe out to his new singles and watch Chiiild's "Sleepwalking" video below. Be sure to add the track, along with "Awake" featuring Mahalia, to your collection from your preferred digital platform. While the release date for his debut album Hope For Sale has not yet been revealed, we're already locked-in for more as part of the project's rollout.
TAGS: audio, Chiiild, Daniel Regan, Emotional Oranges, Mahalia
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Kai Lenny Breaks Down the "Day of Days" at Mavericks This Month
As all things 2020 have been trending, so was the winter forecast for the big-wave season ahead. Surfers anticipated less-than-good conditions courtesy of La Niña weather patterns impacting the Northern Hemisphere, generally resulting in less swell and colder water.
However, on Dec. 8, and seemingly out of nowhere, Mavericks awakened from a lengthy slumber and began firing on all cylinders.
Located just outside of Half Moon Bay, CA, the storied wave has a reputation for consequence that precedes it. But despite its distinction, the spot is finicky and typically only works during a big swell coming from the west to west-northwest, with minimal wind.
According to Kai Lenny, recent men's winner of the WSL's XXL Biggest Wave Award, the swell was coming from a different direction than normal. Lenny, who flew in from Maui for the conditions, says the swell was filling in from the north, causing the waves to break over the reef—a spot that hadn't yielded such ideal conditions in a decade. Additionally, the sun was out and the wind remained light, maxing out around 1.5 mph in the afternoon, allowing for surfable 30- to 50-foot faces all day.
Photo Credit: Fred Pompermayer
"From all accounts, it was one of the best days ever," says Lenny. "They were calling it the 'day of days'. This was a swell where you could surf maybe the biggest wave you've ever paddled into from sunup to sundown."
Lenny wasn't the only out-of-towner who flew in for the swell. In addition to a number of boats and jet ski safety crew, the lineup was stacked with legendary big-wave chargers such as Grant "Twiggy" Baker, Ian Walsh, and Peter Mel. The majority started out the morning doing tow-ins. Once the light hit, however, they swapped out tow-in boards for their guns and spent the remainder of the day paddling in.
Lenny clocked 12 hours in the water that day, only breaking for 15 minutes to down a burrito before paddling back out.
"When those days come around it's almost impossible for me to not want to maximize it because I know how quickly it will go by," says Lenny. "I'd rather push myself as hard as I possibly can and then rest later."
As Lenny frames it, Mavericks is a proving ground for the young guns trying to make a name for themselves. In addition to a number of big-wave veterans, there were a few groms out, pushing their limits. A particular standout was 18-year-old Luca Padua, a Half Moon Bay local who is leading the charge for Californians, sure to be a regular in the Mavericks lineup for years to come.
"I remember being there myself: keen and hungry but also scared and nervous," says Lenny. "It's fun to share sessions with these guys and watch them learn, grow, and experience what big-wave riding's all about."
Lenny predicts that paddle-in big-wave surfing will continue to progress to a point where surfers approach giant waves with more comfort and ease: riding the barrel and executing dynamic turns more typical on mortal-sized waves. For tow-in surfing, he imagines surfers will cover the wave canvas like professional snowboarder Travis Rice charges massive lines in Alaska, blending speed with freestyle tricks.
When the next big swell will hit Mavericks is anyone's guess. Although the early December conditions for the books only held for two days, many called that Big Tuesday a "career day," agreeing they scored some of their lives' best waves.
"I got a really big wave early in the morning and I was bottom-turning and could see a lot of my friends in the channel with their arms up in the air," says Lenny. "They were so far away that I was kind of alone, but they were with me as well. Big-wave surfing is a lot of camaraderie, and on this swell at Mavericks, everybody just wanted to see each other get some big waves."
This article originally appeared on mensjournal.com and was republished with permission.
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Welcome to Foil Days: Foiling & Wing Foiling on the Canary Islands


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Ships Go Gender-Neutral at Maritime Museum
By Bay Bulletin / April 25, 2019
For centuries, boats and ships have been referred to as "she." But it appears that some people take offense to using the female gender to refer to a vessel.
The Scottish Maritime Museum posted photos on Facebook of the acts of vandalism by an offended museum visitor.
Across the Atlantic Ocean, the Scottish Maritime Museum has set off a firestorm with its decision to make all of its future signs gender-neutral. The museum acted in response to vandals, who not once, but twice, scratched out "she" and "her" on the museum's exhibit plaques.
The Scottish Maritime Museum posted a photo of the most recent vandalism last week, with the following caption:
"2nd time in a year our signs referring to vessels as she/her have been vandalised. We are a charity and our signs are very expensive! We can't afford to replace all signs but new signs are gender neutral. Get in a touch, we would love to discuss it!"
The museum's director, David Mann, told Scottish media that the museum is simply keeping up with the times:
"Like other maritime museums and institutions, we recognise the changes in society and are committed to introducing gender neutral interpretation," said Mann.
The vandalism and the museum's response has sparked anger from some in the UK, who argue the museum has a responsibility to keep references historically accurate. Others say the female pronoun is a sign of reverence, and that dropping it would be disrespectful to the people who have served on the ships.
The former head of the Royal Navy, Admiral Lord Alan West, told BBC Radio 4's Today that the decision was "stark staring bonkers" and "political correctness gone mad".
"The ships are seen almost like a mother," he said. "They preserve us from the dangers of the sea and, indeed, also the violence of the enemy. To change it in this trite fashion is just absolutely stupid."
The Scottish Maritime Museum, which has locations in Irvine and Dumbarton, Scotland, holds the world's first commercial ship testing facility, as well as historic vessels and shipbuilding artifacts.
-Meg Walburn Viviano
The Ships of Kiptopeke
Judge May Block Carnival Cruise Ships from Docking…
Annapolis Author's New Book Makes Case for Autonomous Ships
Oral History Grant to Preserve Annapolis Maritime Past
SLIDESHOW: New Annapolis Hotel Pays Tribute to…
Folk Singer Kicks off Tour of Bay's Maritime Museums
For the Love of St Michaels…
Crisfield Students Present History at Tawes Musem Open House


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Q: Rotating labels in feyn Is there any way to rotate labels in feynmp? I want the dots in this picture to run from k_1 to k_n, so I need to rotate the labels by about 80 degrees clockwise. Thanks!
MWE:
\documentclass[amsmath,amssymb,aps,12pt,eqsecnum]{revtex4}
\usepackage[a4paper]{geometry}
\linespread{1}
\usepackage{slashed}
\usepackage{simplewick}
\usepackage{feynmp-auto}
\usepackage[pdftex]{graphicx}
\usepackage{textcomp}
\usepackage{gensymb}
\begin{document}

\begin{fmffile}{graph41}
   \begin{fmfgraph*}(120,120)
    \fmfcmd{input vbloboval;}
    \fmfleftn{i}{9}
    \fmfright{o1,o2}
    \fmfblobOval{0.16w}{v1}
    \fmf{fermion}{o1,v1}
    \fmf{fermion,label=$p'$}{v1,i7}
    \fmffreeze
    \fmf{photon}{v1,i1}
    \fmf{photon}{v1,i2}
    \fmf{photon}{v1,i3}
    \fmfv{label=$k_1$}{i3}
    \fmfv{label=$\cdots$}{i2}
    \fmfv{label=$k_n$}{i1}
    \end{fmfgraph*}
 \end{fmffile}

\end{document}

A: You may have to play with the angles and labels a bit, but this shows how to use \rotatebox to achieve a rotated label.
For those not familiar with feynmp protocol, one must first pdflatex the file; then mpost graph41.mp; and finally pdflatex it again.
EDITED to attempt to lower labels into alignment, though the algorithm of fmfgraph seems to want to restrict the label relocation somewhat. REEDITED to use \rule as the label-realignment mechanism.
\documentclass[amsmath,amssymb,aps,12pt,eqsecnum]{revtex4}
\usepackage[a4paper]{geometry}
\linespread{1}
\usepackage{slashed}
\usepackage{simplewick}
\usepackage{feynmp-auto}
\usepackage[pdftex]{graphicx}
\usepackage{textcomp}
\usepackage{gensymb}
\begin{document}

\begin{fmffile}{graph41}
   \begin{fmfgraph*}(120,120)
%    \fmfcmd{input vbloboval;}
    \fmfleftn{i}{9}
    \fmfright{o1,o2}
%    \fmfblobOval{0.16w}{v1}
    \fmf{fermion}{o1,v1}
    \fmf{fermion,label=$p'$}{v1,i7}
    \fmffreeze
    \fmf{photon}{v1,i1}
    \fmf{photon}{v1,i2}
    \fmf{photon}{v1,i3}
    \fmfv{label=\rotatebox{-65}{\rule{0pt}{10pt}{$k_1$}}}{i3}
    \fmfv{label=\rotatebox{-70}{\rule{0pt}{7pt}{$\cdots$}}}{i2}
    \fmfv{label=\rotatebox{-65}{$k_n$}}{i1}
    \end{fmfgraph*}
 \end{fmffile}

\end{document}


Guest Blog: Are Distressed Malls Worth Saving?
Today's post comes from (and contains the analysis and opinions of) guest blogger Scott Hounsel, J.D., AICP. Scott can be contacted at scott@scotthounsel.com or by phone at 214.536.3421.
According to the Urban Land Institute, "The shopping mall is the quintessential American contribution to the world's consumer culture… [b]ut the conditions that led to the creation of shopping malls and sustained them for decades are changing rapidly." The International Council of Shopping Centers says that currently there are 1,500 malls in the U.S. Due to economic and demographic changes, many older shopping malls are dead (see www.deadmalls.com) and the survival of distressed malls has become an increasingly public question, as the original developer has departed with its anticipated profit and the deteriorating site is unattractive to re-developers without public financial assistance. A source in a recent Wall Street Journal article said that there are 84 dead malls in the U.S., with more casualties expected during the current recession. General Growth Properties, owner of 200 malls, filed for bankruptcy in April 2009, although it claimed that its mall business would be unaffected.
Arguing that certain financial institutions were "too big to fail," many commentators feel that the federal government acted appropriately in providing astronomical amounts of assistance to those institutions. Generally speaking, no one in the real estate community considers any development project too big to fail, but the credit crunch has increased the pressure on all levels of government to step in and assist distressed real estate, not because the owner/developer deserves help, but because certain real estate projects (including some malls) provide positive externalities (social/cultural/economic) to the greater urban area that many feel must be preserved. Shopping malls, unlike big box centers, can serve a social functional beyond mere economic consumption; this is an attractive feature in a healthy mall, but can become a negative feature contributing to a death spiral for a distressed property.
Public assistance for distressed real estate usually is a local decision, and a very contentious one politically at a time when many localities are cash-strapped. Thus, for example, while General Motors is given the unique opportunity to reinvent itself (albeit through bankruptcy), the City of Detroit, heavily impacted by many of the same economic issues that have plagued GM, is 30% vacant; some areas of the city have almost returned to a natural state. A full description of the shrinking of Detroit is provided in a recent on-line article at The Map Scroll. This process is unlikely to be reversed, whatever happens with the U.S. auto industry.
Closer to my home, I have been intrigued by the reinvention discussion surrounding the Southwest Center Mall in southern Dallas. Formerly known as Red Bird Mall, this large shopping mall, built in 1975, has suffered from the construction of newer commercial developments that successfully targeted population growth from suburban cities further south and west. Economic Darwinists would have an easy case that this mall should go "the way of Detroit," as the mall cannot survive on its own despite its three major anchor tenants (two anchors have left for greener suburban pastures) and the fact that the population in the immediate area has remained constant (unlike Detroit). Yet the City of Dallas, in part due to political concerns generated over the distressed mall, brought in a research team from the Urban Land Institute to see if absolute failure could be prevented.
After a week of study, the ULI report (as presented to City staff in June 2009) gives a dire prognosis: the situation is so bad that only the City can take the first steps to save it. The ULI report gives no recommendation for the best possible re-use for the "mostly-dead" mall; any community planning process to determine a particular re-use strategy would be viable only after the City of Dallas steps in to buy the empty anchor sites (mixed ownership of the land has been a contributing factor to the decline of Southwest Center Mall). The ULI recommendation can be summarized in three steps: (1) City assembles the vacant tracts of land, (2) City engages local community as part of writing the redevelopment plan, and (3) City recruits a developer to build according to the plan. The idea that the City should literally buy into the mall (an estimated $4 million for the two empty anchors) comes at a time when the City is facing its biggest budget deficit in ten years. Although hardly a conventional plan for the redevelopment of distressed property, the suggestion that the City of Dallas has to be the first to put up new money is what bailout politics are all about in 2009.
Unfortunately, cities increasingly are on the frontline to help "preserve" distressed real estate when its decline threatens the health of the larger urban community. As for Dallas and Southwest Center Mall, some soul searching and perhaps some investigation into other deteriorating malls around the country are needed before the City opens its checkbook.
The following comes from guest blogger Scott Hounsel, one of my colleagues in the T&K real estate group. For more information, please contact Scott at 214.969.1281 or scott.hounsel@tklaw.com.
On February 25, 2009, the Dallas City Council approved an amendment to the Dallas Development Code (Chapter 51A) to permit "Form-Based Zoning" as an alternative to the traditional zoning (which is "use-based") currently in place. The new amendment added Article XIII to the Code without replacing the existing standards. As the term "Form-Based Zoning" is not particularly insightful to what changes have been made, I thought I would share a general summary of the amendments.
By emphasizing building form over building use, the goal of Article XIII is to create an easier path for developers to get City zoning approval for mixed-use, pedestrian-friendly developments of any size. Before, there was no baseline of requirements for what a mixed-use development would or could be in the City. Developers who wanted to do a sophisticated mixed-use project had to apply for the creation of a new Planned Development district (a "PD"), which involved a lot of heavy negotiating by consultants, staff, and the City Council.
For now, no property in Dallas has been rezoned; the amendments have created a "tool kit" that owners can apply for. If the tool kit works for the particular site, a zoning change would still be requested, but (in theory) this type of zoning change would not be contentious since the developer would be asking for the baseline tools instead of particular changes that would trigger greater scrutiny. In the future, the City may work with neighborhoods in formulating area plans that may then implement form-based zoning, but only by adopting zoning amendment(s) for the neighborhood through standard channels.
New Article XIII created three new zoning districts: (1) walkable mixed use (WMU), (2) walkable residential (WR), and (3) residential transition (RTN). The first two have variations in permitted building heights. On top of those three, there are overlay zoning districts for shopfronts, height variations, and parking management. There are only ten types of permitted uses, not all of which are available in each district. For example, a single family house (that is not a townhouse) is a permitted use ONLY in a residential transition district; apartments are permitted in WMU and WR. The ten types of uses are: mixed use shopfront, single-story shopfront, general commercial, apartment, townhouse stacked, townhouse, manor house, single-family house, civic, and open space.
Based on my discussions with some of the zoning consultants who assisted the City staff in writing Article XIII, it appears that Form-Based Zoning has not been well received, so inertia may be the biggest hurdle before widespread use. I have also heard the some attorneys told the City that they are advising their clients against using the new amendment.


The Moocall Heat is the newest product from the innovative bovine IoT company, Moocall. Unlike existing bovine fertility monitoring systems; Moocall Heat is a world first, where the focus of fertility management is on the Bull.
Moocall Heat uses a smart collar fitted to a bull's neck in conjunction with specially designed ear tags to alert farmers to when a cow is in heat, anywhere in the world. Moocall's innovation was to harness nature, and the bull's natural tendency to exhibit an interest in a cow in heat, to develop a radically new approach to fertility management.
It was also a significant design challenge as bulls' are not known for being fond of wearing man made technology. This was 'design for extreme environments' taken to the limit.


text:
Attorney (High Court)
A majority of the Danish parliament has decided that carbon capture and storage (CCS) and utilization (CCUS) is to be an important element in achieving Denmark's climate policy objectives. The decision was a part of the climate agreement of June 2020 and prompted the setting up of funds (the CCUS funds) of DKK 16 billion, which are scheduled for deployment between 2024-2048.
The Danish Energy Agency (DEA) is responsible for the deployment of the CCUS funds. The funds are intended to ensure the capture, transport and storage of 0.4 million tonnes of CO2 per year from 2025 and an additional 0.5 million tonnes of CO2 per year from 2030.
The Danish Energy Agency issued a call for tender, however the tender round was cancelled on 3 June 2022 and the tender notice for the re-tender has now been sent for publication on 9 June. This will once again start the tender process for the first phase of the CCUS pool, which will be Denmark's first support pool for capture, transport and storage of CO2. The deadline for applications for pre-qualification is 7 July 2022.
The Danish Energy Agency has updated the tender material with a view to ensuring that municipally owned waste heat plants can participate in the tender, cf. the political agreement on the CCS strategy.
The contract for financial support will be entered into between the successful bidder and the Danish authorities. The contract contains a number of elements that are interesting for anyone involved in CCS and CCUS, such as the definitions of the operator's overall obligations. Obligations include but are not limited to:
a) establishing a solution that enables the capture of CO2 at the source(s);
b) ensuring transportation of the CO2 to the permanent storage site, including, if relevant, any intermediate storage;
c) ensuring the permanent storage of the CO2 captured:
d) ensuring compliance with the CCS Directive's requirements as implemented in national law and any other applicable law; and
e) establishing and operating all systems, tools, procedures etc. necessary to document and report accurately the reductions and storage of CO2 achieved and provide such documentation and reporting to the DEA as required by the Contract.
Furthermore the contract contains definitions of the project phases and provisions on time of performance, quality, HSE, IPR, performance guarantees, financial security, confidentiality, payment, non-compliance and remedies and dispute resolution.
WSCO has for many years advised operators and suppliers and contractors within CCS and CCUS and related industries. We also continue to monitor developments in this area and are available for further discussions with interested parties within energy and infrastructure.
Read the whole article/document here


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World Cup 2022: Ex Premier League Star Names One Senegal Player Who Will Trouble England
Saturday, December 03, 2022 at 8:13 PM by Edwin Kiplagat
Troy Deeney has said former Watford teammate Ismaila Sarr will give England a lot of problems when they play Senegal in the Round of 16
Sarr has scored one goal in Qatar so far and has played a key role in the absence of Sadio Mane for the Senegalese
With Senegal's lack of depth in the attacking areas, Sarr will be required by Aliou Cisse to step up and lead the reigning African champions to the promised land
Former Premier League striker Troy Deeney has said that Ismaila Sarr will give England plenty of problems when England play Senegal in the Round of 16 on Sunday.
Sarr played with Deeney, who left5 Watford last year after 11 years. Sarr has made a name for himself in the Premier League and stepped up in Sadio Mane's absence for the Lions of Teranga.
Deeney was Sarr's captain at Watford. Photo by Charlotte Wilson.
Sarr has played an influential role for Senegal so far in Qatar and will be required to up the ante against England. The Three Lions are considered one of the favourites for the tournament and will seriously test Senegal.
Aliou Cisse's side began with a loss but bounced back with two wins over hosts Qatar and an impressive Ecuador side.
The Three Lions reached the semi-final in the 2018 edition and are fancied to win it again this time. Senegal will need to be at their best to stop them.
Sarr main player for Senegal?
According to an exclusive from the Sun, Deeney said he has seen first-hand what Sarr can do to fullbacks and warned England about the 24-year-old winger.
"He will cause a lot of problems for England out wide, especially their full-backs. I remember a match at Vicarage Road against Manchester United in December 2019."
Sarr of Senegal celebrates after scoring their team's first goal off a penalty during the FIFA World Cup Qatar 2022 Group A match between Ecuador and Senegal. Photo by Maddie Meyer.
Deeney was Sarr's captain at Watford before he left his boyhood club last year. The Senegal winger has scored 30 goals and provided 21 assists in 130 appearances for the Hornets, according to Transfermarkt.
With Mane absent for Senegal, the Round of 16 encounter with England is the game for Sarr to rise to the occasion and inspire his country to a famous victory.
Furthermore, Sarr has demonstrated that he has the ability to trouble any defender.
Sarr no-look penalty
Sports Brief earlier reported on Sarr scoring a no-look penalty against Ecuador in their final Group A match.
Against Ecuador, Sarr was brought down in the opposition's 18-yard box, leading the referee to award Senegal a penalty in the 44th minute.
Sarr stepped up in style and scored without even looking at the ball on the ground. Interestingly, although his teammates and likely most fans focused on the ball, the 24-year-old did not.
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