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Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Transthyretin amyloidosis is largely caused by synthesis of mutant transthyretin in the liver and deposition of transthyretin in other organs. A therapeutic approach mediated by RNA interference resulted in reduced transthyretin levels in affected patients and in controls. Transthyretin amyloidosis is a life-threatening disorder caused by the deposition of hepatocyte-derived transthyretin amyloid in various tissues and organs. 1 , 2 Circulating transthyretin is derived from the liver 3 and can form amyloid deposits in peripheral nerves and in the gastrointestinal tract, heart, and kidneys. Transthyretin is also synthesized by the retina and choroid plexus, 4 , 5 which can lead to vitreal and leptomeningeal deposits. More than 100 genetic variants of the gene encoding transthyretin ( TTR ) are associated with autosomal dominant forms of the disease, known as familial amyloidotic polyneuropathy 6 – 8 and familial amyloidotic cardiomyopathy. 9 – 11 The most common mutation associated . . .

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p  = 0.60) and TQOL (from −0.03 to 0.25; p  = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p  = 0.01), as did TQOL score (from 0.61 to −0.16; p  < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

This focused review will highlight the results of HELIOS-B, the first randomized outcomes trial evaluating a gene silencing treatment for transthyretin cardiac amyloidosis (ATTR-CM). In HELIOS-B, vutrisiran was tested against placebo and demonstrated a 28% reduction in the composite of all-cause mortality and recurrent cardiovascular events. Additionally, there were clinically significant benefits on the 6-min walk test, Kansas City Cardiomyopathy Questionnaire, and NYHA class. Discontinuation rates and adverse events were similar between treatment and control arms, suggesting that vutrisiran is well tolerated. In this review, these promising results are explored and compared with other treatment trials in ATTR-CM.

The objective of this study was to investigate the efficacy and safety of intradialytic parenteral nutrition (IDPN) using ENEFLUID ® (310 kcal, 550 mL) in mild-moderate malnutrition patients receiving maintenance hemodialysis. A total of 40 adult patients with a Nutritional Risk Index-Japanese Hemodialysis (NRI-JH) score of 5–10 were enrolled in this multicenter, randomized, open-label study. Patients in the intervention group received IDPN using ENEFLUID ® via the dialysis circuit 3 times a week for 12 weeks; those in the control group did not. The primary endpoint was change in serum transthyretin (TTR). The secondary endpoints were changes in nutritional laboratory tests, nutritional parameters, food intake, plasma amino acids, and blood glucose. For both groups, mean age (72.1±11.4 years) and BMI (20.3±3.0), and median NRI-JH score [7.0 (interquartile range, 6–8)], did not differ. One patient withdrew before intervention, leaving 20 intervention and 19 control patients. Mean (95% confidence interval) change in serum TTR (mg/dL) at 12 weeks did not differ between groups: Intervention, 1.0 (-1.1–3.2); Control, -0.3 (-2.4–1.9); Intragroup difference, 1.3 (-1.7–4.3); P = 0.41. The values reflecting protein intake at 12 weeks compared to those on the study initiation day increased in the intervention group [the changes of blood urea nitrogen, 9.4 (2.6–16.2) mg/dL; P = 0.007, and normalized protein catabolic rate, 0.10 (0.02–0.18) g/kg/day; P = 0.02]. Mean food protein intake (g/kg/day) at 12 weeks increased in the intervention group and decreased in the control group, and differed between groups: Intervention, 0.12 (-0.03–0.28); Control, -0.18 (-0.43–0.08); Inter-group difference, 0.30 (0.00–0.60); P = 0.050. No adverse events occurred. In patients with mild to moderate malnutrition receiving ENEFLUID ® for 12 weeks as IDPN, serum TTR was not improved, decreases in protein intake was mitigated, no adverse events occurred. Trial registration Name of the registry: Japan Registry of Clinical Trials Registration number: jRCTs031220296 .

Abstract Rationale Hyperglycemia and insulin resistance have been shown to increase morbidity and mortality in severely burned patients, and glycemic control appears essential to improve clinical outcomes. However, to date no prospective randomized study exists that determines whether intensive insulin therapy is associated with improved post-burn morbidity and mortality. Objectives To determine whether intensive insulin therapy is associated with improved post-burn morbidity. Methods A total of 239 severely burned pediatric patients with burns over greater than 30% of their total body surface area were randomized (block randomization 1:3) to intensive insulin treatment (n = 60) or control (n = 179). Measurements and Main Results Demographics, clinical outcomes, sepsis, glucose metabolism, organ function, and inflammatory, acute-phase, and hypermetabolic responses were determined. Demographics were similar in both groups. Intensive insulin treatment significantly decreased the incidence of infections and sepsis compared with controls (P < 0.05). Furthermore, intensive insulin therapy improved organ function as indicated by improved serum markers, DENVER2 scores, and ultrasound (P < 0.05). Intensive insulin therapy alleviated post-burn insulin resistance and the vast catabolic response of the body (P < 0.05). Intensive insulin treatment dampened inflammatory and acute-phase responses by deceasing IL-6 and acute-phase proteins compared with controls (P < 0.05). Mortality was 4% in the intensive insulin therapy group and 11% in the control group (P = 0.14). Conclusions In this prospective randomized clinical trial, we showed that intensive insulin therapy improves post-burn morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00673309).

First-in-class drug that inhibits protein misfolding approved in Europe for the treatment of familial amyloid polyneuropathy. In November 2011, tafamidis (Vyndaqel; Pfizer), a small molecule that inhibits the dissociation of transthyretin tetramers, was granted marketing authorization by the European Commission for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurological impairment.

Background and aims Mechanically ventilated patients in intensive care units frequently require enteral nutrition. The choice of an appropriate feeding method may significantly influence nutritional status and clinical outcomes. Among biomarkers used for nutritional assessment, serum albumin, and prealbumin are widely accepted as reliable indicators for evaluating the effectiveness of nutritional interventions. This study aimed to compare the effects of two common enteral feeding methods—bolus and continuous feeding—on serum albumin and prealbumin levels in mechanically ventilated ICU patients. Methods This parallel, single-blind clinical trial was conducted at Imam Khomeini Hospital in Tehran, Iran, with 34 ICU patients receiving mechanical ventilation. Participants were randomly assigned to either the continuous feeding group (Intervention, n  = 17) or the bolus feeding group (Control, n  = 17). Enteral feeding was delivered via a nasogastric tube for one week. Serum albumin and prealbumin levels were measured before and one week after the intervention. Data were analyzed using SPSS version 16, and hypotheses were tested using paired and independent t-tests. Results No significant changes were observed in serum albumin levels within or between the groups over the intervention period. However, patients in the continuous feeding group (Intervention group) showed a statistically significant increase in serum prealbumin levels (from 0.11 ± 0.06 to 0.15 ± 0.02 g/L, p  = 0.004). In contrast, the change in the Bolus feeding group (Control group) was not significant (from 0.10 ± 0.04 to 0.12 ± 0.06 g/L, p  = 0.39). The between-group comparison of post-intervention prealbumin levels approached significance in favor of the continuous feeding group ( p  = 0.08). Conclusion Continuous enteral feeding may have a positive effect on serum prealbumin levels in mechanically ventilated patients, while bolus feeding showed no such impact. However, due to the small sample size and short duration of the intervention, these findings should be interpreted cautiously. Further research with larger sample sizes and longer follow-ups is needed to confirm these results (Fig. 1). Trial registration The protocol of this clinical trial has been registered in the Iranian Clinical Trial Registration Center (registration code: IRCT20190128042528N1). Registered 18 January 2020- Retrospectively registered, date of first recruitment: 6 October 2018, https://www.irct.ir/ . Highlight Continuous enteral feeding significantly increased serum prealbumin levels in mechanically ventilated ICU patients. No significant changes in serum albumin were observed in either feeding method. Continuous feeding showed potential short-term nutritional benefits over bolus feeding. Prealbumin should be considered a sensitive early marker in comprehensive nutritional assessments in ICU settings.

Limited evidence is available on the associations of high-quality protein and energy intake, serum transthyretin (TTR), serum amino acids and serum insulin-like growth factor-1 (IGF-1) with linear growth of young children. Data collected during the baseline of a randomized control trial involving rural Ethiopian children aged 6–35 months (n = 873) were analyzed to evaluate the associations among height/length-for-age z-scores, dietary intakes, and these biomarkers (i.e., serum level of TTR, IGF-1, tryptophan and lysine, and inflammation). The prevalence of stunting was higher for children >23 months (38%) than ≤23 months (25%). The prevalence of inflammation was 35% and of intestinal parasites 48%. Three-quarters of the children were energy deficient, and stunted children had lower daily energy intake that non-stunted children (p < 0.05). Intakes of tryptophan, protein, and energy, and serum levels of tryptophan and IGF-1 were positively correlated with the linear growth of children. Controlling for inflammation, intestinal parasites, and sociodemographic characteristics, daily tryptophan (b = 0.01, p = 0.001), protein (b = 0.01, p = 0.01) and energy (b = 0.0003, p = 0.04) intakes and serum TTR (b = 2.58, p = 0.04) and IGF-1 (b = 0.01, p = 0.003) were positively associated with linear growth of children. Linear growth failure in Ethiopian children is likely associated with low quality protein intake and inadequate energy intake. Nutrition programs that emphasize improved protein quantity and quality and energy intake may enhance the linear growth of young children and need to be further investigated in longitudinal and interventional studies.

(1) Background: Chlorogenic acids (CGAs) have been attracting interest of late, owing to their health benefits. Here, we performed a randomized, double-blind, placebo-controlled trial to investigate whether CGAs improved cognitive function in humans. (2) Methods: Thirty-eight healthy participants were assigned to either the CGA group, which was given CGA-added beverage daily for 16 weeks, or the placebo group. Cognitive functions were assessed using the Japanese version of the CNS Vital Signs (Cognitrax). (3) Results: The CGA group showed significant increase in the Cognitrax domain scores for motor speed, psychomotor speed, and executive function compared with the placebo group, as well as an improvement in the shifting attention test scores. In blood analysis, the CGA group showed increased levels of apolipoprotein A1 and transthyretin, both of which are putative biomarkers for early-stage cognitive decline. (4) Conclusions: These results suggest that CGAs may improve some cognitive functions, which would help in the efficient performance of complex tasks.