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1.
Comparative Analysis of Taxonomic and Functional Gut Microbiota Profiles in Relation to Seroconversion of Thyroid Peroxidase Antibodies in Euthyroid Participants.
Fenneman, AC, Boulund, U, Collard, D, Galenkamp, H, Zwinderman, AH, van den Born, BH, van der Spek, AH, Fliers, E, Rampanelli, E, Blaser, MJ, et al
Thyroid : official journal of the American Thyroid Association. 2024;(1):101-111
Abstract
Background: Previous studies have reported gut microbiome alterations in Hashimoto's autoimmune thyroiditis (HT) patients. Yet, it is unknown whether an aberrant microbiome is present before clinical disease onset in participants susceptible to HT or whether it reflects the effects of the disease itself. In this study, we report for the first time a comprehensive characterization of the taxonomic and functional profiles of the gut microbiota in euthyroid seropositive and seronegative participants. Our primary goal was to determine taxonomic and functional signatures of the intestinal microbiota associated with serum thyroid peroxidase antibodies (TPOAb). A secondary aim was to determine whether different ethnicities warrant distinct reference intervals for accurate interpretation of serum thyroid biomarkers. Methods: In this cross-sectional study, euthyroid participants with (N = 159) and without (N = 1309) TPOAb were selected from the multiethnic (European Dutch, Moroccan, and Turkish) HEalthy Life In an Urban Setting (HELIUS) cohort. Fecal microbiota composition was profiled using 16S rRNA sequencing. Differences between the groups were analyzed based on the overall composition (alpha and beta diversity), as well as differential abundance (DA) of microbial taxa and functional pathways using multiple DA tools. Results: Overall composition showed a substantial overlap between the two groups (p > 0.05 for alpha-diversity; p = 0.39 for beta-diversity), indicating that TPOAb-seropositivity does not significantly differentiate gut microbiota composition and diversity. Interestingly, TPOAb status accounted for only a minor fraction (0.07%) of microbiome variance (p = 0.545). Further exploration of taxonomic differences identified 138 taxa nominally associated with TPOAb status. Among these, 13 taxa consistently demonstrated nominal significance across three additional DA methods, alongside notable associations within various functional pathways. Furthermore, we showed that ethnicity-specific reference intervals for serum thyroid biomarkers are not required, as no significant disparities in serum thyroid markers were found among the three ethnic groups residing in an iodine-replete area (p > 0.05 for thyrotropin, free thyroxine, and TPOAb). Conclusion: These findings suggest that there is no robust difference in gut microbiome between individuals with or without TPOAb in terms of alpha and beta-diversity. Nonetheless, several taxa were identified with nominal significance related to TPOAb presence. Further research is required to determine whether these changes indeed imply a higher risk of overt HT.
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2.
Adherence and impact of an oral nutritional supplement enriched in leucine, EVOO, EPA and DHA, and beta-glucans on the coverage of energy and protein requirements in patients with cancer and malnutrition: Alisenoc study.
Milla, SP, Luna, PPG, Casariego, AV, González, FV, Folgueras, TM, Jáuregui, OI, Rey, SG, Fernández, AC, Plaza, BL, Quintana, TC, et al
Nutrition (Burbank, Los Angeles County, Calif.). 2024;:112355
Abstract
OBJECTIVE The aim of this study was to evaluate the impact of an enhanced ONS (enriched in EPA, DHA, leucine, and beta-glucans) on the dietary intake of cancer patients. METHODS A randomized, double-blind, parallel, controlled, and multicenter clinical trial was conducted in patients with cancer and malnutrition. The trial compared prescribed dietary advice and two packs per day, for 8 weeks, of a hypercaloric (400 kcal/pack) and hyperproteic ONS (20 g/pack) with fiber and specific ingredients (leucine, EPA and DHA, and beta-glucans) (enhanced-ONS) versus an isocaloric and isoproteic formula (standard-ONS) without specific ingredients. Food intake was assessed with a 3-day dietary survey, and adherence to the supplement with a patient self-completed diary. RESULTS Thirty-seven patients completed the intervention period. The combined intervention of dietary advice and ONS managed to increase the energy intake of the overall cohort by 792.55 (378.57) kcal/day, protein by 40.72 (19.56) g/day. Increases in energy and nutrient intakes were observed in both groups, both in dietary intake and associated exclusively with the supplement. The group that received the enhanced-ONS ingested a greater volume of product when there was a greater severity of malnutrition; a tumor location in the head, neck, upper digestive area, liver, or pancreas; more advanced stages of the tumor; or the receipt of more than one antineoplastic treatment. CONCLUSION The use of an enhanced-ONS helps meet the nutritional requirements of cancer patients, especially those who have a more compromised clinical condition, with high adherence, good tolerance, and acceptance.
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3.
Engineering of glycoside hydrolase family 7 cellobiohydrolases directed by natural diversity screening.
Brunecky, R, Knott, BC, Subramanian, V, Linger, JG, Beckham, GT, Amore, A, Taylor, LE, Vander Wall, TA, Lunin, VV, Zheng, F, et al
The Journal of biological chemistry. 2024;(3):105749
Abstract
Protein engineering and screening of processive fungal cellobiohydrolases (CBHs) remain challenging due to limited expression hosts, synergy-dependency, and recalcitrant substrates. In particular, glycoside hydrolase family 7 (GH7) CBHs are critically important for the bioeconomy and typically difficult to engineer. Here, we target the discovery of highly active natural GH7 CBHs and engineering of variants with improved activity. Using experimentally assayed activities of genome mined CBHs, we applied sequence and structural alignments to top performers to identify key point mutations linked to improved activity. From ∼1500 known GH7 sequences, an evolutionarily diverse subset of 57 GH7 CBH genes was expressed in Trichoderma reesei and screened using a multiplexed activity screening assay. Ten catalytically enhanced natural variants were identified, produced, purified, and tested for efficacy using industrially relevant conditions and substrates. Three key amino acids in CBHs with performance comparable or superior to Penicillium funiculosum Cel7A were identified and combinatorially engineered into P. funiculosum cel7a, expressed in T. reesei, and assayed on lignocellulosic biomass. The top performer generated using this combined approach of natural diversity genome mining, experimental assays, and computational modeling produced a 41% increase in conversion extent over native P. funiculosum Cel7A, a 55% increase over the current industrial standard T. reesei Cel7A, and 10% improvement over Aspergillus oryzae Cel7C, the best natural GH7 CBH previously identified in our laboratory.
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4.
Comparing the efficacy of glucocorticoids and anti-VEGF in treating diabetic macular edema: systematic review and comprehensive analysis.
Cheng, Z, Liu, X
Frontiers in endocrinology. 2024;:1342530
Abstract
INTRODUCTION The aim of this study was to better understand the efficacy of various drugs, such as glucocorticoids and anti-vascular endothelial growth factors (VEGF), in the treatment of diabetic macular edema (DME), and to evaluate various clinical treatment regimens consisting of different therapeutic measures. METHODS This study included randomized controlled trials up to February 2023 comparing the efficacy of corticosteroid-related therapy and anti-VEGF therapy. PubMed, the Cochrane Library, and Embase were searched, and the quality of the studies was carefully assessed. Finally, 39 studies were included. RESULTS Results at 3-month followup showed that intravitreal injection of bevacizumab (IVB) + triamcinolone acetonide (TA) was the most beneficial in improving best-corrected visual acuity and reducing the thickness of macular edema in the center of the retina in patients with DME. Results at 6-month follow-up showed that intravitreal dexamethasone (DEX) was the most effective in improving patients' bestcorrected visual acuity and reducing the thickness of central macular edema. DISCUSSION Overall, IVB+TA was beneficial in improving best-corrected visual acuity and reducing central macular edema thickness over a 3-month follow-up period, while DEX implants had a better therapeutic effect than anti-VEGF agents at 6 months, especially the patients with severe macular edema and visual acuity impaired. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=397100, identifier CRD42023397100.
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5.
Effects of 12 Months' Treatment with Testosterone Undecanoate on Markers for Erythropoietic Activity and Safety Aspects in Transgender and Cisgender Hypogonadal Men.
Lethin, K, Aardal, E, Lood, Y, Ekman, B, Wahlberg, J
The journal of applied laboratory medicine. 2024;(2):223-236
Abstract
BACKGROUND To investigate the erythropoietic activity and safety aspects of testosterone undecanoate (TU) injections in transgender men, assigned female at birth. METHODS Twenty-three men (13 hypogonadal cisgender men and 10 transgender men) who initiated TU at the study start (naïve) and 15 men (10 hypogonadal cisgender men and 5 transgender men) on steady-state treatment with TU (non-naïve) were included in this prospective 1-year observational study. A control group of 32 eugonadal cisgender men was investigated once at baseline. Complete blood count, testosterone in serum and saliva, and plasma lipids, and liver enzymes were assessed. RESULTS For naïve transgender men, a significant increase in hemoglobin concentration was noted (mean (SD)), 141 (8) g/L to 151 (13) g/L, while no increase was seen in naïve hypogonadal cisgender men. At the end of the study, naïve transgender men exhibited comparable levels of hemoglobin, hematocrit, and testosterone levels in serum and saliva to hypogonadal cisgender men, as well as to the eugonadal cisgender men. During the study, HDL-cholesterol decreased significantly in naïve transgender men, 1.4 (0.4) mmol/L to 1.2 (0.4) mmol/L, P = 0.03, whereas no significant change was noted in naïve hypogonadal cisgender men. Liver enzymes remained unchanged in all groups. CONCLUSIONS After 12 months of treatment with TU in naïve transgender men, hemoglobin and hematocrit increased to levels within the cisgender male reference range. A slight decrease in HDL-cholesterol was seen in naïve transgender men but liver enzymes remained unchanged.
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6.
A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
Harrison, SA, Bedossa, P, Guy, CD, Schattenberg, JM, Loomba, R, Taub, R, Labriola, D, Moussa, SE, Neff, GW, Rinella, ME, et al
The New England journal of medicine. 2024;(6):497-509
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).
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7.
Predictors of racial differences in weight loss: the PROPEL trial.
Newton, RL, Zhang, D, Johnson, WD, Martin, CK, Apolzan, JW, Denstel, KD, Brantley, PJ, Davis, TC, Arnold, C, Sarpong, DF, et al
Obesity (Silver Spring, Md.). 2024;(3):476-485
Abstract
OBJECTIVE Studies have consistently shown that African American individuals lose less weight in response to behavioral interventions, but the mechanisms leading to this result have been understudied. METHODS Data were derived from the PROmoting Successful Weight Loss in Primary CarE in Louisiana (PROPEL) study, which was a cluster-randomized, two-arm trial conducted in primary care clinics. In the PROPEL trial, African American individuals lost less weight compared with patients who belonged to other racial groups after 24 months. In the current study, counterfactual mediation analyses among 445 patients in the intervention arm of PROPEL were used to determine which variables mediated the relationship between race and weight loss. The mediators included treatment engagement, psychosocial, and lifestyle factors. RESULTS At 6 months, daily weighing mediated 33% (p = 0.008) of the racial differences in weight loss. At 24 months, session attendance and daily weighing mediated 35% (p = 0.027) and 66% (p = 0.005) of the racial differences in weight loss, respectively. None of the psychosocial or lifestyle variables mediated the race-weight loss association. CONCLUSIONS Strategies specifically targeting engagement, such as improving session attendance and self-weighing behaviors, among African American individuals are needed to support more equitable weight losses over extended time periods.
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8.
Comparison between ultrasonography and computed tomography for measuring skeletal muscle mass in critically ill patients with different body mass index.
Peres, LM, Luis-Silva, F, Menegueti, MG, Lovato, WJ, Espirito Santo, DAD, Donadel, MD, Sato, L, Malek-Zadeh, CH, Basile-Filho, A, Martins-Filho, OA, et al
Clinical nutrition ESPEN. 2024;:214-224
Abstract
BACKGROUND & AIM: Among critical patients, there is an early onset of changes in both the quantity and quality of muscle mass. It is essential to find tools that promptly identify this muscle mass loss. The aim of this study was to compare the ultrasonography of the quadriceps femoris to the gold standard, thigh computed tomography (CT) for assessing the musculature of critically ill patients with different body mass index who have suffered traumatic brain injury. METHODS This is a prospective validation study in an Intensive Care Unit (ICU) specialized in trauma care, located at a tertiary teaching hospital. Our study involved a convenience sample of patients. Sequential ultrasound and CT scans were performed at three distinct time intervals: upon admission, between 24 and 96 h' post-admission, and finally, between 96 and 168 h' post-admission. For all ultrasound measurements, we conducted simultaneous quadriceps CT measurements. The correlation between measurements obtained by ultrasound and computed tomography at three different times and in three BMI ranges was analyzed, in individuals with normal weight, overweight and obese. RESULTS Results: We analyzed 252 images in 49 patients in time 1, 40 patients in time 2, and 37 in time 3 to compare the thickness quadriceps muscle using US and CT. Of these, 18 patients had a BMI ≤ 24.9 kg/m2 (normal weight), 18 patients from 25 to 29.9 kg/m2 (overweight), and 8 patients had a BMI ≥ 30 kg/m2 (obese). The mean age was 37 years, the majority (94%) were male and the main comorbidities were: hypertension 12%, diabetes 4% and 14% smoking. The results revealed minor discrepancies between measurements obtained through the two methods, these changes were not influenced by the body mass index, with these variations being practically insignificant in the context of clinical application. Thus, the correlation and concordance between the values obtained found a strong positive correlation with good limits of agreement. The Spearman's correlation coefficients obtained were r = 0.89, 0.91 and 0.88, p < 0.01 at T1, T2 and T3 respectively for normal weight, r = 0.91, 0.80 and 0.81, p < 0.01 at T1, T2 and T3 respectively for overweight and r = 0.89, 0.94 and 0.84, p < 0.01 at T1, T2 and T3 respectively for obesity. In addition to a positive correlation, we observed a high agreement between the methods. The Bland & Altman analysis at time 1 showed, respectively, the bias of 1.46, 2.03 and 0.76. At time 2, the bias was 0.42, 3.11 and 2.12. At time 3, the bias was 2.26, 3.38 and 2.11 mm. CONCLUSION Our findings suggest that measure femoral quadriceps muscle thickness ultrasound-based exhibits a comparable performance to thigh CT. This conclusion stems from the excellent correlation and good agreement observed between ultrasound and CT, which is considered the gold standard for muscle assessment in critically ill patients. TRIAL REGISTRATION This clinical trial is registered at REBEC https://ensaiosclinicos.gov.br/ identifier: RBR-2bzspnz. The protocol was approved, on July 30, 2019, by the Research Ethics Committee of the Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto - Trial Registration Number: 3,475,851.
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9.
Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia.
Packer, M
American journal of nephrology. 2024;(2):255-259
Abstract
Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6-0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.
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10.
Intermittent fasting regimens for metabolic dysfunction-associated steatotic liver disease: a systematic review and network meta-analysis of randomized controlled trials.
Abuelazm, MT, Mohamed, I, Naeem, A, Khlidj, Y, Tanashat, M, Katamesh, BE, Abusuilik, H, Altobaishat, O, Abdelnabi, M, Abdelazeem, B
European journal of gastroenterology & hepatology. 2024;(4):371-381
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by excessive hepatic fat accumulation. Intermittent fasting (IF) has emerged as a potential therapeutic strategy with the ability to induce weight loss, improve insulin sensitivity and reduce hepatic steatosis. We aim to compare the efficacy of different IF regimens for MASLD management. A systematic review and network meta-analysis of randomized controlled trials investigating different IF regimens for MASLD. PubMed , EMBASE , WOS , SCOPUS and Cochrane Central Register of Controlled Trials were searched until 10 April 2023. Analysis was performed using R software with the meta and netmeta packages. Mean difference (MD) was used to pool continuous outcomes with 95% confidence intervals (CIs). Our meta-analysis was registered in PROSPERO (CRD42023418467). Our meta-analysis included eight randomized controlled trials with a total of 635 participants. The 5 : 2 diet significantly improved liver stiffness (MD, -0.32; 95% CI, -0.55 to -0.09; P < 0.01). Time-restricted feeding significantly improved liver steatosis (controlled attenuation parameter score) (MD, -39.83; 95% CI, -64.78 to -14.87; P < 0.01). No significant changes were observed in asparate aminotransferase, gamma-glutamyl transpeptidase, low-density lipoproteins cholesterol, total cholesterol, triglyceride levels, basal metabolic index, blood pressure, Homeostatic Model Assessment of Insulin Resistance, fasting blood sugar, lean body mass or waist circumference across all IF regimens. However, alternate-day fasting showed positive results in anthropometric measures, including significant improvements in lean body mass, waist circumference, fat mass and weight reduction ( P < 0.05). IF regimens showed various positive effects on clinical outcomes in MASLD patients; however, these effects were not consistent. Therefore, a patient-tailored IF regimen should be considered.