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Systemic amyloidosis is a rare but increasingly recognised disease that is heterogeneous in presentation. Early diagnosis, whilst imperative, remains challenging but can improve prognosis and limit organ dysfunction. An increased repertoire of diagnostic imaging and histological techniques are becoming mainstream and promise to aid early diagnosis. Better risk stratification, via biomarkers and cytogenetics, has improved multidisciplinary treatment decisions. The use of novel agents has improved treatment efficacy, which translates into survival benefit. Newer strategies targeting pre-deposited amyloidogenic protein are under investigation. The current paper reviews available data relating to the most recent advances in the field of systemic amyloidosis.

ObjectivesWild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM.MethodsThis is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression.ResultsChange in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively.ConclusionChange in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.

ObjectivesIn AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is required. We aimed to evaluate the prognostic impact of the 6MWT at baseline and change following chemotherapy.MethodsThis study evaluated the outcomes of patients who enrolled in a prospective observational study at the UK National Amyloidosis Centre (2012–2017). Patients underwent comprehensive assessments inclusive of blood testing, echocardiogram and 6MWT at baseline and annually thereafter.ResultsIn total, 799 patients were included within the study. Median baseline 6 min walk distance (6MWD) was 362 m (IQR: 231 m). 6MWD progressively decreased with worsening cardiac disease stage (458 m, 404 m, 331 m and 168 m for cardiac Mayo stages I, II, IIIa and IIIb, respectively (p<0.0001)). In patients with a baseline 6MWT of ≥350 m, the median overall survival was not reached (vs 30.0 (95% CI 23.2 to 36.8) months if <350 m and 5.0 (95% CI 2.8 to 7.2) months if unable to attempt 6MWT (p<0.0001). Following chemotherapy, only patients in a complete haematological response improved their 6MWD by 12 months (p=0.001). Improvement in 6MWD prolonged survival in patients with cardiac amyloidosis (p=0.005).ConclusionThe 6MWT is prognostic in AL amyloidosis. A baseline distance of ≥350 m independently predicts better survival. These data suggest that 6MWT has utility in AL amyloidosis for baseline prognosis and assessing response.

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p < 0.005). At 1-month, patients with CR and iFLC < 20 mg/l had a significantly better survival compared to CR and iFLC > 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.

Aims Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course. Methods and results We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P < 0.001; Stage III vs. II, HRs 1.64–2.25; P < 0.001–0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow‐up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58–3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86–4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I‐hATTR‐CM than in wtATTR‐CM (43% vs. 27% at 12 months of follow‐up; P = 0.003). Conclusions National Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR‐CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow‐up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I‐hATTR‐CM than in wtATTR‐CM.

Effective systemic therapies suppress toxic light chain production leading to an increased proportion of patients with light chain (AL) amyloidosis who survive longer albeit with end-stage renal disease. There is a critical need to identify patients in this population who benefit from renal transplantation. This multicenter, observational study from five countries includes 237 patients with AL amyloidosis who underwent renal transplantation between 1987 and 2020. With a median follow-up of 8.5 years, the median overall survival from renal transplantation was 8.6 years and was significantly longer in patients with complete and very good partial hematologic responses (CR + VGPR) compared to less than VGPR (9 versus 6.8 years; HR: 1.5, P = 0.04 [95% CI: 1–2.1]) at renal transplantation. Median graft survival was 7.8 years and was better in the CR + VGPR group (8.3 vs 5.7 years, HR: 1.4, P = 0.05 [95% CI: 1–2]). The frequency and time to amyloid recurrence in the graft was also lower (16% vs 37%, p = 0.01) and longer (median time not achieved vs 10 years, p = 0.001) in the CR + VGPR group. Comparing CR vs. VGPR there was no difference in overall or graft survival. Although 69 patients (29%) experienced hematologic relapse, treatment effectively prevented graft loss in the majority (87%). Renal transplantation in selected AL amyloidosis patients is associated with extended overall and renal graft survival. Patients with hematologic CR or VGPR have the most favorable outcomes, and these patients should be considered for renal transplantation.

Jeanson, M.; Dolique, F.; Sedrati, M.; Cohen, O.; Bertier, J.; Cavalin, A.; Charpentier, J, and Anthony E.J., 2016. Wave modification across a coral reef: Cap Chevalier, Martinique Island. In: Vila-Concejo, A.; Bruce, E.; Kennedy, D.M., and McCarroll, R.J. (eds.), Proceedings of the 14th International Coastal Symposium (Sydney, Australia). Journal of Coastal Research, Special Issue, No. 75, pp. 582–586. Coconut Creek (Florida), ISSN 0749-0208. Waves exert a major influence on hydrodynamic processes and on sediment transport over shallow submerged coral reefs, as well as on reef-bound beaches. This study describes results from a field experiment conducted at Cape Chevalier in the southeast of Martinique Island (Lesser Antilles, French West Indies), and investigates spatial and temporal variations in wave characteristics across a microtidal coral reef and lagoon. Measurements of wave pressure fluctuations were obtained using three pressure sensors deployed across the reef from 28 to 30 November, 2011. Analysis of the measured data shows that wave characteristics were strongly influenced by water depth and reef geometry. Calculations of energy dissipation indicate an average energy reduction of 91.5% between the fore-reef and back-reef (86% at high tide and 98% at low tide). The mean energy reduction between the fore-reef and the beach was 95.5% (92% and 99% respectively at high and low tide). The incident waves measured at the fore-reef during the experiment were predominantly trade wind-generated with peak periods between 7 and 10 s. Depending on tidal elevation and water depth, back-reef waves were characterized by an energy distribution dominated by the peak 7–10 s gravity waves at high tide and by infragravity frequencies (>20 s) at low tide. Wave energy at the beach was dominated by infragravity frequencies during both high tide and low tide. Wave spectral analysis indicates, thus, significant filtering of peak period energy as waves traveled across the reef.

We consider conditions under which an isolated quantum system approaches a microcanonical equilibrium state. A key component is the eigenstate thermalisation hypothesis, which proposes that all energy eigenstates appear thermal. We introduce a weaker version of this requirement, applying only to the average distinguishability of eigenstates from the thermal state, and investigate its necessity and sufficiency for thermalisation.