Vutrisiran: A Review in Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis.

Silencing the transthyretin (TTR) gene is an effective strategy in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis. Vutrisiran (Amvuttra®), an RNA interference (RNAi) therapeutic targeting TTR mRNA, is approved in the USA and EU for the treatment of adults with polyneuropathy of hATTR amyloidosis. N-acetylgalactosamine conjugation and enhanced stabilisation chemistry are utilised to target vutrisiran to the liver and increase stability, respectively, allowing for subcutaneous administration once every 3 months. In a pivotal phase 3 study in patients with hATTR amyloidosis with polyneuropathy, subcutaneous vutrisiran 25 mg every 3 months significantly reduced neuropathy impairment versus external placebo. Vutrisiran was also associated with significant improvements in neuropathy-specific quality of life, gait speed, nutritional status and disability scores. Vutrisiran was generally well tolerated; the only common adverse events to occur at a greater incidence than with external placebo were pain in extremity and arthralgia. Vutrisiran reduces serum vitamin A levels and vitamin A supplementation is recommended. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, which has the potential advantage of infrequent subcutaneous dosage.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive and disabling disease caused by variants in the transthyretin (TTR) gene, which cause destabilisation and misfolding of the TTR protein. Deposition of misfolded TTR protein (amyloid) around nerves causes a range of neuropathic symptoms. Vutrisiran (Amvuttra^®) silences the TTR gene via RNA interference (RNAi). Vutrisiran, administered subcutaneously once every 3 months, is approved in the USA and EU for the treatment of polyneuropathy of hATTR amyloidosis in adults. In a phase 3 study in patients with hATTR amyloidosis with polyneuropathy, vutrisiran significantly reduced neuropathy impairment and improved other disease-related outcomes versus external placebo. Vutrisiran was generally well tolerated, with most adverse events being mild or moderate in severity. As vutrisiran decreases vitamin A levels, patients undergoing vutrisiran treatment should supplement with vitamin A. In conclusion, vutrisiran is an efficacious and generally well-tolerated alternative option for the treatment of polyneuropathy of hATTR amyloidosis, with a convenient dosage regimen.

A study on the effect of nutrition education based on the goal attainment theory on oral nutritional supplementation after colorectal cancer surgery.

OBJECTIVE: To investigate their compliance with postoperative oral nutritional supplementation and nutritional outcomes. METHODS: A total of 84 patients with colorectal cancer surgery with NRS-2002 risk score ≥ 3 who were treated with oral nutritional supplementation were selected and divided into control and observation groups according to the random number table method, with 42 cases in each group. The control group received conventional oral nutritional supplementation and dietary nutrition education; the observation group established a nutrition intervention group based on the Goal Attainment Theory and carried out individualized nutrition education based on the Goal Attainment Theory. The nutritional indicators at 1 day postoperative, 7 days postoperative, oral nutritional supplementation adherence scores at 7 and 14 days postoperative, and the attainment rate of trans-oral nutritional intake at 21 days postoperative were compared between the 2 groups of patients. RESULTS: There was no statistically significant difference between the nutritional status indexes of the 2 groups of patients before the intervention, p > 0.05; when comparing the prealbumin of the 2 groups of patients at 7 days postoperatively, the prealbumin level of the patients in the observation group at 7 days postoperatively (200.25 ± 53.25) was better than that of the control group (165.73 ± 43.00), with a p value of 0.002, and the difference was statistically significant (p < 0.05). Comparison of oral nutritional supplementation adherence scores at 7 and 14 days postoperatively showed that ONS treatment adherence scores were better than those of the control group, with statistically significant differences (p < 0.05). When comparing the attainment rate of oral nutritional intake at 21 days after surgery, the difference was statistically significant (p < 0.05). CONCLUSION: Nutritional education based on the Goal Attainment Theory can effectively improve the adherence to oral nutritional supplementation therapy and protein intake attainment rate of colorectal cancer patients after surgery and effectively improve the nutritional status of patients.

Effect of intradialytic oral nutritional supplementation on nutritional markers in malnourished chronic hemodialysis patients: prospective randomized trial.

BACKGROUND AND OBJECTIVES: Malnutrition is prevalent in chronic hemodialysis (HD) patients. It increases mortality and negatively affects quality of life. This study aimed to assess the effect of intradialytic oral nutritional supplement (ONS) on nutritional markers in chronic HD patients with protein energy wasting (PEW). METHODS: This 3-month prospective, open-label, randomized controlled trial included 60 chronic HD patients with PEW. The intervention group (30 patients) received intradialytic ONS and dietary counseling, whereas the control group (30 patients) received only dietary counseling. Nutritional markers were measured at the beginning and end of the study. RESULTS: The mean age of the patients was 54 ± 12.7 years, and that of the HD vintage was 64 ± 49.3 months. Compared to the control group, the intervention group showed a significant increase in serum albumin (p < 0.001), prealbumin (p < 0.001), cholesterol (p = 0.016), body mass index (BMI) (p = 0.019), serum creatinine/body surface area (BSA) (p = 0.016), and composite French PEW score (p = 0.002), as well as a significant decrease in high-sensitivity C-reactive protein (hs-CRP) (p = 0.001). The total iron binding capacity, normalized protein nitrogen appearance, and hemoglobin levels increased significantly in both groups. CONCLUSION: Intradialytic ONS and dietary counseling for three months were more effective than dietary counseling alone in terms of improving nutritional status and inflammation in chronic HD patients, as evidenced by increases in serum albumin, prealbumin, BMI, serum creatinine/BSA, composite French PEW score, and a decrease in hs-CRP.

Effects of taurine on metal cations, transthyretin and LRP-1 in a rat model of Alzheimer's disease.

BACKGROUND: Researches on diagnosis and treatment of Alzheimer's disease, the most common type of dementia, are still ongoing. Taurine is frequently used in Alzheimer's disease models due to its protective effects. Metal cation dyshomeostasis is an important etiological factor for Alzheimer's disease. Transthyretin protein is thought to act as a transporter for the Aß protein that accumulates in the brain and is eliminated in the liver and kidneys via the LRP-1 receptor. However, the effect of taurine on this mechanisms is not fully known. METHODS: 30 male rats, aged 28 ± 4 months, were divided into 5 groups (n = 6) as follows: control group, sham group, Aß 1-42 group, taurine group and taurine+Aß 1-42 group. Oral taurine pre-supplementation was given as 1000 mg/kg-body weight/day for 6 weeks to taurine and taurine+Aß 1-42 groups. RESULTS: Plasma copper, heart transthyretin and Aß 1-42, brain and kidney LRP-1 levels were found to be decreased in the Aß 1-42 group. Brain transthyretin was higher in taurine+Aß 1-42 group and brain Aß 1-42 was higher in Aß 1-42 and taurine+Aß 1-42 groups. CONCLUSION: Taurine pre-supplementation maintained cardiac transthyretin levels, decreased cardiac Aß 1-42 levels and increased brain and kidney LRP-1 levels. Taurine may have a potential to be used as a protective agent for aged people at high risk for Alzheimer's disease.

Protein Supplementation in a Prehabilitation Program in Patients Undergoing Surgery for Endometrial Cancer.

Enhanced recovery after surgery (ERAS) and prehabilitation programs are multidisciplinary care pathways to reduce stress response and improve perioperative outcomes, which also include nutritional interventions. The aim of this study is to assess the impact of protein supplementation with 20 mg per day before surgery in a prehabilitation program in postoperative serum albumin, prealbumin, and total proteins in endometrial cancer patients undergoing laparoscopic surgery. METHODS: A prospective study including patients who underwent laparoscopy for endometrial cancer was conducted. Three groups were identified according to ERAS and prehabilitation implementation (preERAS, ERAS, and Prehab). The primary outcome was levels of serum albumin, prealbumin, and total protein 24-48 h after surgery. RESULTS: A total of 185 patients were included: 57 in the preERAS group, 60 in the ERAS group, and 68 in the Prehab group. There were no basal differences in serum albumin, prealbumin, or total protein between the three groups. After surgery, regardless of the nutritional intervention, the decrease in the values was also similar. Moreover, values in the Prehab group just before surgery were lower than the initial ones, despite the protein supplementation. CONCLUSIONS: Supplementation with 20 mg of protein per day does not impact serum protein levels in a prehabilitation program. Supplementations with higher quantities should be studied.

Association between prealbumin, all-cause mortality, and response to nutrition treatment in patients at nutrition risk: Secondary analysis of a randomized controlled trial.

BACKGROUND: Because of the shorter half-life as compared with albumin, serum prealbumin concentrations have been proposed to be useful nutrition biomarkers for the assessment of patients at nutrition risk. In a post hoc analysis of patients at nutrition risk from a randomized controlled nutrition trial, we tested the hypothesis that (1) prealbumin is associated with higher all-cause 180-day mortality rates and that (2) individualized nutrition support compared with usual-care nutrition more effectively improves survival at 30 days in patients with low prealbumin levels compared with patients with normal prealbumin levels. METHODS: We performed a prespecified cohort study in patients included in the pragmatic, Swiss, multicenter randomized controlled EFFORT trial comparing the effects of individualized nutrition support with usual care. We studied low prealbumin concentrations (<0.17 g/L) in a subgroup of 517 patients from one participating center. RESULTS: A total of 306 (59.2%) patients (mean age 71.9 years, 53.6% men) had low admission prealbumin levels (<0.17 g/L). There was a significant association between low prealbumin levels and mortality at 180 days (115/306 [37.6%] vs 47/211 [22.3%], fully adjusted hazard ratio [HR]=1.59, 95% CI 1.11-2.28; P = 0.011). Prealbumin levels significantly improved the prognostic value of the Nutritional Risk Screening total score regarding mortality prediction at short- and long-term. The difference in mortality between patients receiving individualized nutrition support and usual-care nutrition was similar for patients with low prealbumin levels compared with patients with normal prealbumin levels (HR=0.90 [95% CI=0.51-1.59] vs HR=0.88 [95% CI=0.35-2.23]) with no evidence for interaction (P = 0.823). CONCLUSION: Among medical inpatients at nutrition risk, low admission prealbumin levels correlated with different nutrition markers and higher mortality risk, but patients with low or high prealbumin levels had a similar benefit from nutrition support. Further studies should identify nutrition markers that help further personalize nutrition interventions.

Association between Serum Biomarkers with Postoperative Complications and Delay of Adjuvant Chemotherapy Initiation in Ovarian Cancer Patients Undergoing Primary Cytoreductive Surgery: A Pilot Study.

This study sought to describe and relate the factors associated with complications and delays in adjuvant chemotherapy in patients with ovarian cancer treated with primary cytoreductive surgery. Serum from patients diagnosed with ovarian cancer scheduled for primary cytoreductive surgery were analyzed for prealbumin, 25-OH Vitamin D, intracellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), monocyte chemoattractant protein 2 (MCP-2), macrophage derived chemokine (MDC). Postoperative complications were identified using common terminology criteria for adverse events 4.0 and 30 day after surgery. Delays in adjuvant chemotherapy were defined as >1 week interval between surgery and initiation. Patients with postoperative complications (39.6%) were significantly older, had lower serum prealbumin levels, and higher serum IL-6 and IL-8 than those without. Univariate logistic regression found that age (OR: 1.12, 95%CI: 1.00-1.35) and IL-6 (OR: 1.02, 95%CI: 0.99-1.05) were associated with postoperative complications, whereas age remained significant after multivariate analysis (OR:1.14, 95%CI: 1.00-1.29). Patients with delays in chemotherapy exhibited greater BMI and lower 25-OH Vitamin D than those without. Multivariate analysis found that increasing levels of 25-OH Vitamin D were associated with a lower risk of delayed chemotherapy initiation after controlling for age, body mass index, and tumor grade (OR: 0.93, 95%CI:0.87-0.99). This work suggests that in addition to age being predictive of postoperative complications, serum 25-OH Vitamin D may a provide insight into a patient's risk for postsurgical delays in chemotherapy initiation. These findings should, however, be confirmed in a larger study including robust survival analysis.

In a small cohort, increasing age was associated with postsurgical complications in patients with ovarian cancer following primary cytoreductive surgery.In patients with ovarian cancer following primary cytoreductive surgery delays in adjuvant chemotherapy initiation were inversely associated with serum 25-OH vitamin D status.

[A prospective randomized controlled study on the curative effects of enteral immunonutrition support therapy in adult burn patients at nutritional risk].

Objective: To explore the effects of enteral immunonutrition support therapy on nutritional metabolism, immune function, and inflammatory response in adult burn patients at nutritional risk as assessed by the modified 2nd nutrition risk screening (NRS) 2002. Methods: A prospective randomized controlled study was conducted. From December 2019 to January 2022, 500 adult patients who were admitted to the Affiliated Huaihai Hospital of Xuzhou Medical University and had nutritional risk assessed by the modified 2nd NRS 2002 were recruited into the study. According to burn severity, the patients were divided into common burn patients (n=450) and severe burn patients (n=50). According to the random number table, the patients with common burn were divided into common burn diet nutrition group and common burn diet enteral immunonutrition group, with 225 patients in each group, and the patients with severe burn were divided into severe burn diet enteral non-immunonutrition group and severe burn diet enteral immunonutrition group, with 25 patients in each group. The patients in each group were given the corresponding nutritional support therapies on the basis of routine burn treatment. On post injury day (PID) 1, 3, 7, 14, and 21, the total energy intake and total protein intake of the patients in 4 groups were recorded, the plasma prealbumin, albumin, transferrin, serum immunoglobulin A (IgA), IgG, IgM, peripheral blood CD3 positive T cell percentage, CD4 positive T cell count, CD8 positive T cell count, the ratio of CD4 positive T cells to CD8 positive T cells, natural killer cell percentage, plasma interleukin-6 (IL-6), free mitochondrial DNA (mtDNA) copy number, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) of the patients in 4 groups were detected, and the nitrogen balance of the patients in 4 groups on the day was calculated. On PID 7, 14, and 21, the modified 2nd NRS 2002 scores of the patients in 4 groups were reassessed. The sepsis incidence during treatment and the length of hospital stay of the patients in 4 groups and the length of intensive care unit (ICU) stay of the patients in the 2 severe burn groups were recorded. Data were statistically analyzed with chi-square test, Fisher's exact probability test, Mann-Whitney U test, independent sample t test, analysis of variance for repeated measurement, and Bonferroni correction. Results: A total of 476 patients completed the trial, with 213 patients in common burn diet nutrition group (112 males and 101 females, aged (37±19) years), 218 patients in common burn diet enteral immunonutrition group (115 males and 103 females, aged (42±16) years), 22 patients in severe burn diet enteral non-immunonutrition group (11 males and 11 females, aged (35±8) years), and 23 patients in severe burn diet enteral immunonutrition group (12 males and 11 females, aged (35±8) years). Compared with those in common burn diet nutrition group, the patients in common burn diet enteral immunonutrition group had significantly higher total energy intake on PID 1 (t=6.06, P<0.01), significantly lower total energy intake on PID 7 and significantly lower total protein intake on PID 1 (with t values of 6.17 and 4.59, respectively,P<0.01). On PID 21, the total energy intake of patients in severe burn diet enteral immunonutrition group was significantly lower than that in severe burn diet enteral non-immunonutrition group (t=2.70, P<0.01). The total protein intake of patients in severe burn diet enteral immunonutrition group and severe burn diet enteral non-immunonutrition group were similar at each time point post injury (P>0.05). Compared with those in common burn diet nutrition group, the patients in common burn diet enteral immunonutrition group had significantly higher level of prealbumin on PID 3, 7, 14, and 21 (with t values of 2.05, 2.33, 2.45, and 2.11, respectively, P<0.05), significantly higher level of albumin on PID 7, 14, and 21 (with t values of 2.30, 2.56, and 2.15, respectively, P<0.05), significantly higher level of transferrin on PID 7 and 14 (with t values of 1.99 and 2.27, respectively, P<0.05), significantly higher nitrogen balance on PID 14 and 21 (with t values of 2.51 and 2.07, respectively, P<0.05), and significantly lower modified 2nd NRS 2002 score on PID 21 (t=1.99, P<0.05). Compared with those in severe burn diet enteral non-immunonutrition group, the patients in severe burn diet enteral immunonutrition group had significantly higher level of prealbumin on PID 3, 7, 14, and 21 (with t values of 2.50, 2.64, 2.18, and 2.39, respectively, P<0.05), significantly higher level of albumin​on PID 7, 14, and 21 (with t values of 2.27, 2.39, and 2.69, respectively, P<0.05), significantly higher level of transferrin and nitrogen balance but significantly lower modified 2nd NRS 2002 score on PID 14 and 21 (with t values of 2.30, 2.35, 2.41, 2.16, 2.31, and 2.73, respectively, P<0.05). Compared with those in common burn diet nutrition group, patients in common burn diet enteral immunonutrition group had significantly higher level of IgA and IgG on PID 7, 14, and 21 (with t values of 2.19, 2.36, 2.17, 2.49, 1.97, and 2.24, respectively, P<0.05), significantly higher level of IgM on PID 21 (t=2.06, P<0.05), significantly higher percentage of CD3 positive T cells and ratio of CD4 positive T cells to CD8 positive T cells on PID 3, 7, 14, and 21 (with t values of 2.49, 2.25, 2.33, 2.41, 2.39, 2.24, 2.46, and 2.18, respectively, P<0.05), significantly higher CD4 positive T cell count (with t values of 2.15 and 2.27, respectively, P<0.05) but significantly lower CD8 positive T cell count on PID 14 and 21 (with t values of 2.58 and 2.35, P<0.05), and significantly higher percentage of natural killer cells on PID 7, 14, and 21 (with t values of 2.53, 2.21, and 2.36, respectively, P<0.05). Compared with those in severe burn diet enteral non-immunonutrition group, patients in severe burn diet immunonutrition group had significantly higher level of IgA on PID 7 and 14 (with t values of 2.15 and 2.03, respectively, P<0.05), significantly higher level of IgG on PID 7, 14, and 21 (with t values of 2.09, 2.56, and 2.15, respectively, P<0.05), significantly higher level of IgM on PID 21 (t=2.08, P<0.05), significantly higher percentage of CD3 positive T cells, CD4 positive T cell count, and percentage of natural killer cells on PID 14 and 21 (with t values of 2.52, 2.14, 2.14, 2.39, 2.56, and 2.19, respectively, P<0.05), significantly lower CD8 positive T cell count but significantly higher ratio of CD4 positive T cells to CD8 positive T cells on PID 7, 14, and 21 (with t values of 2.27, 2.81, 2.01, 2.11, 2.69, and 2.05, respectively, P<0.05). Compared with those in common burn diet nutrition group, patients in common burn diet enteral immunonutrition group had significantly lower level of IL-6 (with t values of 2.34 and 2.32, respectively, P<0.05) and significantly lower free mtDNA copy number on PID 14 and 21 (with Z values of -2.28 and -2.34,respectively, P<0.05), significantly lower level of sTREM-1 on PID 7, 14, and 21 (with t values of 2.02, 2.94, and 3.72, respectively, P<0.05). Compared with those in severe burn diet enteral non-immunonutrition group, patients in severe burn diet enteral immunonutrition group had significantly lower level of IL-6 and sTREM-1 on PID 7, 14, and 21 (with t values of 2.15, 2.29, 2.47, 2.43, 2.07, and 2.32, respectively, P<0.05), and significantly lower free mtDNA copy number on PID 14 and 21 (with Z values of -2.49 and -2.21, respectively, P<0.05). During treatment, the sepsis incidences of patients in 2 common burn groups were similar (P>0.05), the sepsis incidences of patients in 2 severe burn groups were similar (P>0.05). The length of ICU stay of patients in severe burn diet enteral immunonutrition group was (11±3) d, which was significantly shorter than (14±3) d in severe burn diet enteral non-immunonutrition group (t=3.12, P<0.01). The length of hospital stay of patients in common burn diet enteral immunonutrition group was significantly shorter than that in common burn diet nutrition group (t=3.11, P<0.01). The length of hospital stay of patients in severe burn diet enteral non-immunonutrition group was similar to that in severe burn diet enteral immunonutrition group (P>0.05). Conclusions: Enteral immunonutrition support therapy for adult burn patients at nutritional risk assessed by the modified 2nd NRS 2002 can better improve the nutritional status and the immune function of patients, reduce inflammatory response of the body, and shorten the length of hospital stay in common burn patients and the length of ICU stay in severe burn patients.

[Influencing factors of nutritional status and change in 50 patients with oral squamous cell carcinoma during treatment].

PURPOSE: To investigate the changes of nutritional status in patients with oral squamous cell carcinoma(OSCC) and analyze the influencing factors during treatment. METHODS: Anthropometry (weight, BMI, waistline, middle circumference of left and right upper arms) and laboratory index(serum prealbumin, serum albumin, transferrins, 25-hydroxyvitamin D) were measured to represent the nutritional status of 50 patients with OSCC before operation, two days, one month and three months after operation. SPSS 24.0 software package was used for statistical analysis of the data, and influencing factors of nutrition risk in OSCC patient were analyzed with binary logistic regression model. RESULTS: Univariate and multivariate analysis showed that advanced age(OR=1.127,95%CI: 1.053-1.207), low educational level (OR=5.250, 95%CI: 1.147-21.796), smoking(OR=6.182, 95%CI: 1.631-23.433), alcohol use(OR=5.227, 95%CI: 1.336-20.450), chemoradiotherapy (OR=3.984, 95%CI: 1.199-13.242), free flap surgery (OR=8.000, 95%CI: 2.060-31.068), tracheostomy(OR=3.960, 95%CI: 1.069-14.671), cervical lymph node metastasis(OR=4.821, 95%CI: 1.418-16.399), buccal carcinoma(OR=9.000, 95%CI:1.140-71.038), tongue cancer(OR=7.200, 95%CI: 1.081-47.962), tumor stage T3-4(OR=3.542, 95%CI: 1.066-11.771) were independent influencing factors of the nutritional status of patients with OSCC. CONCLUSIONS: Aging, low educational level, smoking history and drinking history in the general demographic characteristics of patients, and chemoradiotherapy, free flap surgery, tracheostomy during treatment, as well as buccal carcinoma, tongue cancer, advanced stage and cervical lymph node metastasis are clinical characteristics, which affect the nutrition level during the treatment for OSCC patients.

Arginine and glutamine supplementation on transthyretin levels in severely burned patients: A systematic review.

OBJECTIVE: The aim of this study was to investigate the influence of supplementation with the immunomodulators arginine and glutamine on transthyretin levels in burn patients. METHODS: This systematic review followed the protocol proposed and registered in PROSPERO (CRD42021239526) and was carried out following the PRISMA checklist for systematic reviews. Forty-four studies were evaluated. Of the 44, we included 6 for complete analysis. RESULTS: In five of the six clinical trials, glutamine was the most used immunomodulator (0.5 g·kg·d-1 or 12-14 g/d), followed by arginine in three of the clinical trials (10-14 g/d in adults or 2% of total energy value in children). The findings of the studies were that the patients who received either of these supplements presented the following results: increased transthyretin, lymphoproliferative response, and serum glutamine values, as well as shorter stay in the intensive care unit, a significant reduction in C-reactive protein values, and a tendency toward a faster healing of the burns compared with the control groups. CONCLUSION: In view of the content in the present review, it is possible to affirm that the supplementation of immunomodulators in burn patients is an effective strategy for their treatment, and that the adequate nutritional offer may be a predictor of a favorable outcome. However, regarding the increase in transthyretin values, this finding needs to be considered with reservations as the values can be altered by the inflammatory activity, and not necessarily related to the use of a supplement.

Pediatric Patients With Sickle Cell Disease at a Public Hospital: Nutrition, Compliance and Early Experience With L-Glutamine Therapy.

BACKGROUND/AIM: Hydration and hydroxyurea (HU) can modify sickle cell disease (SCD) severity. Optimal nutrition and L-glutamine (Gln) may provide further amelioration. PATIENTS AND METHODS: Reviews of medical records and nutrition surveys were used to investigate severity of pediatric patients with SCD in relation to nutrition, growth, hematologic parameters, and diseasemodifying agents. RESULTS: Among 25 females and 25 males (9.1±7 years), beta-globin genotypes were: HbSS/Sß°, 60%; HbSC, 32%; HbSß+, 8%. The mean number of annual pain crises (APC) was 0.97±1.1. APCs increased ≥2-fold as HbF dropped to <10% with age. Proper hydration and nutrition correlated with younger ages and fewer APCs. Height and weight Z-scores were ≤-1SD in 20% of 35 surveyed patients (12±7.8 years), who had more APCs (2.5±2.5 vs. 1±1.3, p=0.03). Prealbumin levels were overall low. Twenty-two of 28 patients on HU reported ≥90% adherence - with higher mean corpuscular volume (92±9.6 vs. 74±10 f/l, p<0.01). Seventy percent of Gln prescriptions were filled. Compliance over 23 months was ≥70% in 12 patients, including 2 on chronic transfusion. Of 10 evaluable patients, 6 (8.8±2.2 years) had fewer APCs with Gln (mean 0.2 vs. 0.9, p=0.016), with increasing prealbumin levels (14.1 to 15.8 mg/dl, p=0.1). CONCLUSION: Younger, and well-nourished, well-hydrated patients have a milder clinic course. Disease severity was the worse in undernourished teenagers with suboptimal compliance. L-Glutamine with prealbumin monitoring should be considered for further evaluation in pediatric SCD.

Evidence From Human Placenta, Endoplasmic Reticulum-Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia.

BACKGROUND: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several aggregated proteins in the circulation of preeclampsia patients, the most prominent of which is the serum protein TTR (transthyretin). However, the mechanisms that underlie protein aggregation remain poorly addressed. METHODS: We examined TTR aggregates in hypoxia/reoxygenation-exposed primary human trophoblasts (PHTs) and the preeclampsia placenta using complementary approaches, including a novel protein aggregate detection assay. Mechanistic analysis was performed in hypoxia/reoxygenation-exposed PHTs and Ttr transgenic mice overexpressing transgene-encoded wild-type human TTR or Ttr-/- mice. High-resolution ultrasound analysis was used to measure placental blood flow in pregnant mice. RESULTS: TTR aggregation was inducible in PHTs and the TCL-1 trophoblast cell line by endoplasmic reticulum stress inducers or autophagy-lysosomal disruptors. PHTs exposed to hypoxia/reoxygenation showed increased intracellular BiP (binding immunoglobulin protein), phosphorylated IRE1α (inositol-requiring enzyme-1α), PDI (protein disulfide isomerase), and Ero-1, all markers of the unfolded protein response, and the apoptosis mediator caspase-3. Blockade of IRE1α inhibited hypoxia/reoxygenation-induced upregulation of Ero-1 in PHTs. Excessive unfolded protein response activation was observed in the early-onset preeclampsia placenta. Importantly, pregnant human TTR mice displayed aggregated TTR in the junctional zone of the placenta and severe preeclampsia-like features. High-resolution ultrasound analysis revealed low blood flow in uterine and umbilical arteries in human TTR mice compared with control mice. However, Ttr-/- mice did not show any pregnancy-associated abnormalities. CONCLUSIONS: These observations in the preeclampsia placenta, cultured trophoblasts, and Ttr transgenic mice indicate that TTR aggregation is an important causal contributor to preeclampsia pathophysiology.

Pharmacotherapy review: Emerging treatment modalities in transthyretin cardiac amyloidosis.

PURPOSE: This review aims to summarize the evidence and pharmacological characteristics of treatment options for transthyretin amyloid cardiomyopathy (ATTR-CM). Additionally, this review highlights the role of clinical pharmacists in helping to secure newly introduced therapies. SUMMARY: ATTR-CM, a disease characterized by misfolded protein that is deposited in the myocardium and disrupts cardiac functioning, has historically been underdiagnosed due to the need for invasive biopsy and an illusion of rarity. Once diagnosed, limited treatment modalities for ATTR-CM have led providers to rely on nonpharmacological remedies or off-label use of medications with limited evidence of benefit. However, recent noninvasive diagnostic advancements and heightened disease state awareness have revealed increased prevalence of ATTR-CM. This has led to the introduction of several first-in-class pharmaceuticals with actions targeted at inhibiting the various phases of amyloidosis: TTR stabilizers include diflunisal and Food and Drug Administration (FDA)-approved tafamidis; TTR silencers include patisiran and inotersen; fibril disrupters include doxycycline with tauroursodeoxycholic acid; and alternative agents include green tea extract and curcumin. CONCLUSION: ATTR-CM treatments have emerged and, despite current limited data, are continuing to evolve. Tafamidis, the only agent approved by FDA for ATTR-CM, shows promise to improve survival and quality of life in patients with ATTR-CM. Pharmacists can play a key role in assisting with agent selection for this disease state, as well as providing knowledge about current and future clinical trials evaluating the safety and efficacy of the available treatment modalities.

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases.

Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.

Transthyretin Amyloid Cardiomyopathy-Current and Future Therapies.

OBJECTIVE: To describe the clinical presentation of transthyretin amyloid cardiomyopathy (ATTR-CM) and discuss current treatments and investigational products and their effect on patient outcomes. DATA SOURCES: A literature search was performed in PubMed (September 2018 to December 2020) using the following keywords: transthyretin amyloidosis, cardiomyopathy, polyneuropathy and transthyretin amyloid cardiomyopathy, monoclonal light-chain, tafamidis, cardiac amyloidosis, ATTR cardiomyopathy, green tea and inhibition of cardiac amyloidosis, AG10, tolcapone, tolcapone and leptomeningeal ATTR, PRX004, NI006, patisiran, inotersen, vutrisiran, AKCEA-TTR-LRx, and NTLA-2001. STUDY SELECTION AND DATA EXTRACTION: Clinical trials were evaluated for evidence supporting pharmacology, safety, efficacy, and measured outcomes. DATA SYNTHESIS: Until 2019, there were no approved treatments for ATTR-CM. Treatment consisted of symptom management and organ transplant. Nonpharmacological and pharmacological treatments focused on the symptoms of heart failure (HF) associated with ATTR-CM. However, there are several emerging therapies recently approved or in development to address the underlying pathophysiology. Treatment classes for ATTR-CM include transthyretin stabilizers, human monoclonal antibodies, gene silencers, and CRISPR/Cas9 gene editing. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: ATTR-CM is a complex disease in which amyloidosis causes cardiomyopathy. Underdiagnosis is attributed to the clinical presentation being heterogeneous, indistinguishable from HF caused by other etiologies, and the need for invasive testing modalities, including endomyocardial biopsy. Improved diagnostic approaches along with targeted therapies can slow disease progression and enhance patient quality of life. CONCLUSION: Diagnostic modalities along with biomarker and genetic testing could detect disease earlier and target therapy more accurately. Novel therapies demonstrate potential treatment benefits and can help shape the standard of care for these patients.

Efficacy of alanyl glutamine in nutritional support therapy for patients with sepsis: A protocol for systematic review and meta-analysis.

BACKGROUND: Sepsis is a systemic inflammatory response caused by infection, which is a common complication after severe infection, trauma, shock, and surgery, and is also an important factor in inducing septic shock and multiple organ dysfunction syndrome (MODS), and has become one of the important causes of death in critically ill patients. Septic patients with gastrointestinal transport function weakened, are prone to malnutrition, resulting in decreased immune function, thereby affecting the therapeutic effect. Clinical practice shows that the nutritional metabolism and immune response of patients with sepsis can be effectively improved by giving alanyl glutamine nutritional support treatment, but there is no evidence of evidence-based medicine. The study carried out in this protocol aims to evaluate the effectiveness of alanyl glutamine in nutritional support therapy for patients with sepsis. METHODS: The Cochrane Library, PubMed, Embase, Web of Science, WHO International Clinical Trials Registry Platform, CNKI, CBM, VIP, and Wanfang databases were searched by computer, to retrieve all randomized controlled trials (RCTs) on nutritional support for the treatment of sepsis with alanyl glutamine from the date of database establishment to December 2020. Two researchers independently selected the study, extracted and managed the data. RevMan5.3 software was used to analyze the included literature. RESULTS: This study observed the changes of serum albumin (ALB), prealbumin (PAB), hemoglobin (Hb), C-reactive protein (CRP), immunoglobulin (IgG, IgA, and IgM), APACHE II score before and after treatment to evaluate the efficacy of alanyl glutamine in nutritional support therapy for patients with sepsis. CONCLUSION: This study will provide reliable evidence for the application of alanyl glutamine in nutritional support therapy for patients with sepsis. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/VRZPJ.

[A real-world study to evaluate a peptidic oral supplement in adults with altered intestinal function after parenteral nutrition]. / Un estudio en la vida real para evaluar un suplemento oral peptídico en adultos con alteración de la función intestinal tras la nutrición parenteral.

INTRODUCTION: Objectives: in routine clinical practice many disorders are found that can disrupt the sequence of reactions in digestion and absorption, leading to malnutrition and requiring the use of oral nutritional supplements (ONS). The objective of our study was to evaluate in a real world setting the use of and compliance with a peptide-based ONS in malnourished adult patients with intestinal compromise after more than 14 days of parenteral nutrition. Material and methods: the study was carried out in 44 malnourished patients who required total parenteral nutrition for at least 14 days without using the oral route during their hospital stay. All patients were administered, on an outpatient basis, 1 brick per day of Vital 1.5® for 12 weeks. At the beginning of treatment and after the intervention period evaluated, the following variables were collected: weight, height, body mass index (BMI), global subjective assessment test, nutritional biochemistry, 3-day nutritional survey, adverse effects generated by the formula, and completion rate. Results: 44 patients were enrolled. Mean age was 70.4 ± 10.4 years (20 women & 24 men). After the intervention the following parameters had increased: BMI (0.51 ± 0.1 kg/m2; p = 0.02), weight (1.4 ± 0.3 kg; p = 0.03), prealbumin (3.5 ± 4.1 mg/dl; p = 0.01), albumin (1.3 ± 0.1 mg/dl; p = 0.03), and transferrin (71.5 ± 24.1 mg/dl; p = 0.02). Dietary intake of the ONS represented 14.4 % of the diet's total caloric intake at 3 months, 17.5 % of carbohydrates, 12.9 % of proteins, and 12.3 % of fats. Mean compliance was 87.7 ± 7.2 % of the prescribed intakes. In relation to the nutritional situation, at the beginning of the study, 52.3 % (n = 23) of patients were in the global subjective assessment test in category B (moderate malnutrition or nutritional risk), and 47.7 % (n = 21) in category C (severe malnutrition). After the intervention, 75 % of patients were in category A (n = 33), 13.6 % (n = 6) in category B, and 11.4 % (n = 5) in category C. Conclusions: the use of a peptide-based ONS with short-chain triglycerides in outpatients showed a beneficial effect on biochemical and anthropometric parameters, and improved the nutritional status of patients with high compliance and good tolerance rates.

INTRODUCCIÓN: Objetivos: en la práctica clínica habitual existen multitud de situaciones y patologías que pueden interrumpir la digestión y la absorción intestinal, cursando con desnutrición y requiriendo el uso de suplementos orales nutricionales (SON). El objetivo de nuestro estudio fue evaluar, en el contexto de la vida real, el uso de un SON basado en péptidos, y el cumplimiento con el mismo, en pacientes adultos desnutridos con compromiso intestinal tras más de 14 días de nutrición parenteral. Material y métodos: el estudio se realizó en 44 pacientes desnutridos que requirieron nutrición parenteral total al menos 14 días, sin utilización de la vía oral durante el ingreso hospitalario. Se les administró de manera ambulatoria 1 brik al día de Vital 1.5® para su consumo durante 12 semanas. Al inicio del tratamiento y tras el periodo de intervención se les recogieron las variables siguientes: peso, talla, IMC, test de valoración subjetiva global, bioquímica nutricional, encuesta nutricional, efectos adversos generados por la fórmula y cumplimentación. Resultados: se incluyeron 44 pacientes con una edad media de 70,4 ± 10,4 años (20 mujeres/24 hombres). Tras la intervención aumentaron el IMC (0,51 ± 0,1 kg/m2; p = 0,02), el peso (1,4 ± 0,3 kg; p = 0,03), la prealbúmina (3,5 ± 4,1 mg/dl; p = 0,01), la albúmina (1,3 ± 0,1 mg/dl; p = 0,03) y la transferrina (71,5 ± 24,1 mg/dl; p = 0,02). La toma del SON represento a los 3 meses un 14,4 % del aporte calórico total de la dieta, un 17,5 % de los hidratos de carbono, un 12,9 % de las proteínas y un 12,3 % de las grasas. La cumplimentación media del grupo fue del 87,7 ± 7,2 % de las tomas prescritas. En relacion a la situacion nutricional, a la entrada del estudio un 52,3 % (n = 23) de los pacientes presentaban en el test de valoración subjetiva global la categoría B (malnutrición moderada o riesgo nutricional) y un 47,7 % (n = 21) la categoría C (desnutrición severa). Tras la intervención, un 75 % de los pacientes presentaban la categoría A (buena situación nutricional (n = 33), un 13,6 % (n = 6) de los pacientes presentaban la categoría B y un 11,4 % (n = 5) la categoría C. Conclusiones: la utilización de un suplemento peptídico con triglicéridos de cadena corta en pacientes ambulatorios tras haber recibido una nutrición parenteral total muestra un efecto beneficioso sobre los parametros bioquímicos y antropométricos, y la situación nutricional, con una alta cumplimentación y buena tolerancia.

Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities.

Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.