Control of immunity via nutritional interventions.

Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.

Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.

The Molecular Link from Diet to Cancer Cell Metabolism.

Malignant cells remodel their metabolism to meet the demands of uncontrolled cell proliferation. These demands lead to differential requirements in energy, biosynthetic precursors, and signaling intermediates. Both genetic programs arising from oncogenic events and transcriptional programs and epigenomic events are important in providing the necessary metabolic network activity. Accumulating evidence has established that environmental factors play a major role in shaping cancer cell metabolism. For metabolism, diet and nutrition are the major environmental aspects and have emerged as key components in determining cancer cell metabolism. In this review, we discuss these emerging concepts in cancer metabolism and how diet and nutrition influence cancer cell metabolism.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Determinant factors for first-line treatment choice and effectiveness in pediatric eosinophilic esophagitis: an analysis of the EUREOS EoE CONNECT registry.

This study compared short-term effectiveness of proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), and dietary therapies in reversing clinical and histological features in pediatric patients with eosinophilic esophagitits (EoE). Determinants for treatment choice and PPI therapy effectiveness were also assessed.  A cross-sectional study analysis of patients under 18 years old recruited onto the multicenter EoE CONNECT registry was performed. Clinico-histological response was defined as symptomatic improvement plus a peak eosinophil count below 15 per high-power field after treatment. Effectiveness of first-line options used in monotherapy was compared. Overall, 393 patients (64% adolescents) receiving PPI, STC, or dietary monotherapy to induce EoE remission were identified. PPI was the preferred option (71.5%), despite STC providing the highest clinico-histological response rates (66%) compared to PPI (44%) and diet (42%). Logistic regression identified fibrotic features and recruitment at Italian sites independently associated to first-line STC treatment; age under 12 associated to dietary therapy over other options. Analysis of 262 patients in whom PPI effectiveness was evaluated after median (IQR) 96 (70-145) days showed that this effectiveness was significantly associated with management at pediatric facilities and use of high PPI doses. Among PPI responders, decrease in rings and structures in endoscopy from baseline was documented, with EREFS fibrotic subscore for rings also decreasing among responders (0.27 ± 0.63 vs. 0.05 ± 0.22, p < 0.001). Conclusion: Initial therapy choice for EoE depends on endoscopic phenotype, patient's age, and patients' origin. High PPI doses and treatment in pediatric facilities significantly determined effectiveness, and reversed fibrotic endoscopic features among responders. What is Known: • Proton pump inhibitors are widely used to induce and maintain remission in EoE in real practice, despite other first-line alternative therapies possibly providing higher effectiveness. What is New: • Proton pump inhibitors represent up to two-thirds of first-line monotherapies used to induce EoE remission in pediatric and adolescent patients with EoE. The choice of STC as first-line treatment for EoE was significantly associated with fibrotic features at baseline endoscopy and recruitment in Italian centers; age less than 12 years was associated with dietary therapy. • PPI effectiveness was found to be determined by use of high doses, attendance at pediatric facilities, presenting inflammatory instead of fibrotic or mixed phenotypes, and younger age. Among responders, PPI therapy reversed both inflammatory and fibrotic features of EoE after short-term treatment.

Quantifying the subjective cost of self-control in humans.

Since Odysseus committed to resisting the Sirens, mechanisms to limit self-control failure have been a central feature of human behavior. Psychologists have long argued that the use of self-control is an effortful process and, more recently, that its failure arises when the cognitive costs of self-control outweigh its perceived benefits. In a similar way, economists have argued that sophisticated choosers can adopt "precommitment strategies" that tie the hands of their future selves in order to reduce these costs. Yet, we still lack an empirical tool to quantify and demonstrate the cost of self-control. Here, we develop and validate an economic decision-making task to quantify the subjective cost of self-control by determining the monetary cost a person is willing to incur in order to eliminate the need for self-control. We find that humans will pay to avoid having to exert self-control in a way that scales with increasing levels of temptation and that these costs appear to be modulated both by motivational incentives and stress exposure. Our psychophysical approach allows us to index moment-to-moment self-control costs at the within-subject level, validating important theoretical work across multiple disciplines and opening avenues of self-control research in healthy and clinical populations.

Gut microbiome contributions to altered metabolism in a pig model of undernutrition.

The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, we developed a feature-selection algorithm to identify representative characteristics distinguishing DR fecal microbiomes from those of full-fed (FF) pigs as both groups consumed a common sequence of diets during their growth cycle. Gnotobiotic mice were then colonized with DR and FF microbiomes and subjected to controlled feeding with a pig diet. DR microbiomes have reduced representation of genes that degrade dominant components of late growth-phase diets, exhibit reduced production of butyrate, a key host-accessible energy source, and are causally linked to reduced hepatic fatty acid metabolism (ß-oxidation) and the selection of alternative energy substrates. The approach described could aid in the development of guidelines for microbiome stewardship in diverse species, including farm animals, in order to support their healthy growth.

New approaches to diet therapy for eosinophilic esophagitis.

PURPOSE OF REVIEW: An empiric step-up (2-4-6) elimination diet remains the most common dietary approach in clinical practice when treating eosinophilic esophagitis (EoE). However, research in this field has fallen behind pharmacological therapy. This review aims to summarize novel approaches to dietary therapy for EoE. RECENT FINDINGS: A first prospective multicenter study in 41 pediatric patients (mean age 9 years) has evaluated the efficacy of a cow's milk elimination diet. This dietary approach led to histological remission in 51% of patients, albeit a caveat is that up to 80% of patients were receiving concomitant therapy with proton pump inhibitors. In a series of 18 adult patients with documented milk-induced EoE, ingestión of 400 ml of sterilized milk (boiled for up to 20 min) daily for 8 weeks did not induce histologic relapse in two-thirds of patients. SUMMARY: Milk elimination diet is effective in one-half of pediatric EoE patients and should likely be the first choice in children with EoE (within a step-up dietary approach). Promising data on tolerance of sterilized milk in adults with milk-induced EoE (66%) merit further replication in children, which may radically improve quality of life for patients and their caregivers.

Predicting insulin use among women with gestational diabetes diagnosed in oral glucose tolerance test.

BACKGROUND: Gestational diabetes mellitus (GDM) is one of the most common complications affecting pregnant women. While most women will achieve adequate glycemic levels with diet and exercise, some will require pharmacological treatment to reach and maintain glucose levels between the desired thresholds. Identifying these patients early in pregnancy could help direct resources and interventions. METHODS: This retrospective cohort of women with GDM diagnosed with an abnormal 75g-OGTT presents data from 869 patients (724 in the diet group and 145 in the insulin group). Univariate logistic regression was used to compare the groups, and multivariable logistic regression was used to identify independent factors associated with the need for insulin. A log-linear function was used to estimate the probability of requiring pharmacological treatment. RESULTS: Women in the insulin group had higher pre-pregnancy BMI index (29.8 vs 27.8 kg/m2, odds ratio [OR] 1.06, 95% confidence interval [CI] 1.03-1.09), more frequent history of previous GDM (19.4% vs. 7.8%, OR 2.84, 95% CI 1.59-5.05), were more likely to have chronic hypertension (31.7% vs. 23.2%, OR 1.54, 95% CI 1.04-2.27), and had higher glucose levels at all three OGTT points. Multivariable logistic regression final model included age, BMI, previous GDM status, and the three OGTT values as predictors of insulin requirement. CONCLUSIONS: We can use regularly collected data from patients (age, BMI, previous GDM status, and the three OGTT values) to calculate the risk of a woman with GDM diagnosed in OGTT needing insulin. Identifying patients with a greater risk of requiring pharmacological treatment could help healthcare services to better allocate resources and offer closer follow-up to high-risk patients.

Fruit and Vegetable Intake and Mortality: Results From 2 Prospective Cohort Studies of US Men and Women and a Meta-Analysis of 26 Cohort Studies.

BACKGROUND: The optimal intake levels of fruit and vegetables for maintaining long-term health are uncertain. METHODS: We followed 66 719 women from the Nurses' Health Study (1984-2014) and 42 016 men from the Health Professionals Follow-up Study (1986-2014) who were free from cardiovascular disease (CVD), cancer, and diabetes at baseline. Diet was assessed using a validated semiquantitative food frequency questionnaire at baseline and updated every 2 to 4 years. We also conducted a dose-response meta-analysis, including results from our 2 cohorts and 24 other prospective cohort studies. RESULTS: We documented 33 898 deaths during the follow-up. After adjustment for known and suspected confounding variables and risk factors, we observed nonlinear inverse associations of fruit and vegetable intake with total mortality and cause-specific mortality attributable to cancer, CVD, and respiratory disease (all Pnonlinear<0.001). Intake of ≈5 servings per day of fruit and vegetables, or 2 servings of fruit and 3 servings of vegetables, was associated with the lowest mortality, and above that level, higher intake was not associated with additional risk reduction. In comparison with the reference level (2 servings/d), daily intake of 5 servings of fruit and vegetables was associated with hazard ratios (95% CI) of 0.87 (0.85-0.90) for total mortality, 0.88 (0.83-0.94) for CVD mortality, 0.90 (0.86-0.95) for cancer mortality, and 0.65 (0.59-0.72) for respiratory disease mortality. The dose-response meta-analysis that included 145 015 deaths accrued in 1 892 885 participants yielded similar results (summary risk ratio of mortality for 5 servings/d=0.87 [95% CI, 0.85-0.88]; Pnonlinear<0.001). Higher intakes of most subgroups of fruits and vegetables were associated with lower mortality, with the exception of starchy vegetables such as peas and corn. Intakes of fruit juices and potatoes were not associated with total and cause-specific mortality. CONCLUSIONS: Higher intakes of fruit and vegetables were associated with lower mortality; the risk reduction plateaued at ≈5 servings of fruit and vegetables per day. These findings support current dietary recommendations to increase intake of fruits and vegetables, but not fruit juices and potatoes.

AGA Clinical Practice Update on Medical Management of Colonic Diverticulitis: Expert Review.

Colonic diverticulitis is a painful gastrointestinal disease that recurs unpredictably and can lead to chronic gastrointestinal symptoms. Gastroenterologists commonly care for patients with this disease. The purpose of this Clinical Practice Update is to provide practical and evidence-based advice for management of diverticulitis. We reviewed systematic reviews, meta-analyses, randomized controlled trials, and observational studies to develop 14 best practices. In brief, computed tomography is often necessary to make a diagnosis. Rarely, a colon malignancy is misdiagnosed as diverticulitis. Whether patients should have a colonoscopy after an episode of diverticulitis depends on the patient's history, most recent colonoscopy, and disease severity and course. In patients with a history of diverticulitis and chronic symptoms, alternative diagnoses should be excluded with both imaging and lower endoscopy. Antibiotic treatment can be used selectively rather than routinely in immunocompetent patients with mild acute uncomplicated diverticulitis. Antibiotic treatment is strongly advised in immunocompromised patients. To reduce the risk of recurrence, patients should consume a high-quality diet, have a normal body mass index, be physically active, not smoke, and avoid nonsteroidal anti-inflammatory drug use except aspirin prescribed for secondary prevention of cardiovascular disease. At the same time, patients should understand that genetic factors also contribute to diverticulitis risk. Patients should be educated that the risk of complicated diverticulitis is highest with the first presentation. An elective segmental resection should not be advised based on the number of episodes. Instead, a discussion of elective segmental resection should be personalized to consider severity of disease, patient preferences and values, as well as risks and benefits.

Comments on the Discussion Forum: Oromucosal immunomodulation as clinical spectrum mitigating factor in SARS-CoV-2 infection.

The mammalian lactoperoxidase system, consisting of lactoperoxidase and the H2 O2 -producing enzyme duox, is our first line of defence against airborne microbes. This system catalyses the production of hypoiodite and hypoiodous acid in the presence of sufficient iodine. These products are highly efficient at destroying the H1N1 virus and the respiratory syncytial virus (RSV). Japan has not been affected as much as other nations during the COVID-19 pandemic (death rate about 10% of the United States), and we think this is due to a diet high in iodine. With this in mind, we suggest four actions to prevent SARS-CoV-2 infections. First, health professionals should study the preventative effect of increasing iodine in the diets of the aged, institutionalized, diabetics andsmokers. Second, the recommended daily intake (RDI) for iodine should be significantly increased, to at least double, the current RDI. Governments should encourage the use and distribution of cheap iodized salts, kelp and seaweed. Third, more research should be done around the physiology and the protective effects of the lactoperoxidase system. Finally, the degradation products of the SARS-CoV-2 viral particle by hypoiodite and hypoiodous acid should be characterized; portions of the damaged particle are likely to elicit stronger immunity and better vaccines.

Nutritional Modulation of the Microbiome and Immune Response.

The evolution of the immune system, diet, and the microbiome are interconnected. Dietary metabolites modulate the cells of the immune system both directly and indirectly via shifts in the composition of the intestinal microbiota and its products. As a result, overconsumption and malnutrition can have substantial effects on immune responses and inflammation. In resource-rich nations, diets high in processed foods, fat, and sugar can contribute to chronic inflammatory conditions, which are on the rise worldwide. Conversely, in resource-poor countries, malnutrition associated with food insecurity can lead to immunodeficiencies and shifts in the microbiome that drive intestinal inflammation. Developing a deeper understanding of the relationship between diet, microbiota, and the immune system is of huge importance, given its impact on inflammatory diseases and its potential as an easily modifiable mediator of immunomodulation.

Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss.

Given the increasing prevalence of diabetes and obesity worldwide, the deleterious effects of non-alcoholic fatty liver disease (NAFLD) are becoming a growing challenge for public health. NAFLD is the most common chronic liver disease in the Western world. NAFLD is closely associated with metabolic disorders, including central obesity, dyslipidaemia, hypertension, hyperglycaemia and persistent abnormalities of liver function tests.In general NAFLD is a common denominer for a broad spectrum of damage to the liver, which can be due to hepatocyte injury, inflammatory processes and fibrosis. This is normally seen on liver biopsy and can range from milder forms (steatosis) to the more severe forms (non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and liver failure). In these patients, advanced fibrosis is the major predictor of morbidity and liver-related mortality, and an accurate diagnosis of NASH and NAFLD is mandatory. Histologic evaluation with liver biopsy remains the gold standard to diagnose NAFLD. Diagnosis of NAFLD is defined as presence of hepatic steatosis, ballooning and lobular inflammation with or without fibrosis. Weight loss, dietary modification, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established. Dietary recommendations and lifestyle interventions, weight loss, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established with promising results but are difficult to maintain. Pioglitazone and vitamin E are recommended by guidelines in selected patients. This review gives an overview of NAFLD and its treatment options.

Impact of a Pilot Structured Mobile Technology Based Lifestyle Intervention for Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Lifestyle modification is the main treatment for nonalcoholic fatty liver disease (NAFLD), but remains challenging to implement. The aim of this pilot was to assess the acceptability and feasibility of a mobile-technology based lifestyle program for NAFLD patients. METHODS: We enrolled adult patients with NAFLD in a 6-month mobile-technology based program where participants received a FitBit with weekly tailored step count goals and nutritional assessments. Anthropometrics, hepatic and metabolic parameters, Fibroscan, physical function and activity, and health-related quality of life measures were obtained at enrollment and month 6. Semi-structured exit interviews were conducted to assess patient's experience with the program. RESULTS: 40 (63%) eligible patients were enrolled. Median age was 52.5 with 53% males, 93% whites, 43% with diabetes and median BMI 33.9. On baseline Fibroscan, 59% had F0-2 fibrosis and 70% had moderate-severe steatosis. 33 patients completed the study. Median percentage of days with valid FitBit data collection was 91. 4 patients increased and maintained, 19 maintained, and 8 increased but subsequently returned to baseline weekly step count. 59% of patients reported Fitbit was easy to use and 66% felt step count feedback motivated them to increase their activity. Roughly 50% of patients had reduction in weight, triglycerides and Fibroscan liver stiffness, and 75% had improvement in controlled attenuation parameter and physical function. CONCLUSIONS: A 6-month mobile-technology based pilot lifestyle intervention was feasible and acceptable to NAFLD patients. The program promoted physical activity and was associated with improvement in clinical parameters in some patients.

What non-pharmacological treatments do people with polymyalgia rheumatica try: results from the PMR Cohort Study.

Polymyalgia rheumatica (PMR) is common. The mainstay of treatment, glucocorticoids, are associated with significant adverse effects and many patients remain on high doses for a number of years. Little is known about the use of other, non-pharmacological therapies as adjuncts in PMR. The PMR Cohort Study is an inception cohort study of patients diagnosed with PMR in primary care. This analysis presents data on the use and perceived impact of non-pharmacological therapies from a long-term follow-up survey. Non-pharmacological treatments were classified as either diet, exercise, or complementary therapies. Results are presented as adjusted means, medians, and raw counts where appropriate. One hundred and ninety-seven participants completed the long-term follow-up questionnaire, of these 81 (41.1%) reported using non-pharmacological therapy. Fifty-seven people reported using a form of complementary therapy, 35 used exercise and 20 reported changing their diet. No individual non-pharmacological therapy appeared to be associated with long-term outcomes. The use of non-pharmacological therapies is common amongst PMR patients, despite the paucity of evidence supporting their use. This suggests that people perceive a need for treatment options in addition to standard glucocorticoid regimens. Further research is needed to understand patients' aims when seeking additional treatments and to strengthen the evidence base for their use so that patients can be guided towards effective options.

Effectiveness of system-based intervention in reducing incidence of type 2 diabetes and to improve the postnatal metabolic profiles in women with gestational diabetes mellitus: a randomized controlled study.

AIM: The objective of this study was to determine the effectiveness of system-based intervention in reducing the incidence of diabetes and to improve the postnatal metabolic profiles among women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: For women in the intervention arm (n = 130), they received one session of individualized health education at 36 gestational weeks, a booklet of diabetes prevention, five-session of postpartum booster educational program which were conducted including 1 session of dietary and exercise counseling by dietician and physiotherapist at 6 weeks postpartum. For women in the control group (n = 168), standard treatment whereby they had received group therapy on diet and physical activity modification by dietician and staff nurses during the antenatal period. RESULTS: There were no significant differences in baseline characteristics between groups for most of the variables examined except for educational level which the control group had a higher education than the intervention group. The women assigned to system-based intervention have a significant difference to GDM women who were assigned to the control group for LDL and HDL but not in anthropometric measurements, blood pressure, glucose index, total cholesterol, and triglyceride. In addition, it was found that the incidence of Type 2 diabetes mellitus (T2DM) 2 years after delivery was 20% in the intervention arm compared to 17% in the control arm. CONCLUSION: The system-based intervention was not statistically superior to the control intervention as there is no difference in terms of incidence of T2DM between the intervention and control group. We, therefore, suggested that more intensive interventions are needed to prevent GDM from developing into T2DM.

Therapeutic Food Development from Maize Grains, Pulses, and Cooking Banana Fruits for the Prevention of Severe Acute Malnutrition.

In children under five years of age, severe acute malnutrition is a complex and challenging problem, especially those living in poor communities. Therefore, this study aimed to formulate ready-to-use therapeutic foods from affordable, locally available cereals, pulses, and banana fruits to overcome the problem of severe acute malnutrition. Maize grains, pulses (soybeans), and cooking banana fruits were ingredients used in formulations of ready-to-use therapeutic foods (RUTF). A completely randomized design was done with two replicates. Data were analyzed using analysis of variance. A significant difference existed in the appearance and consistency for RUTF1, RUTF2, and RUTF3 samples (P < 0.05). The study findings revealed that the moisture content varied from 6.7 to 13.4%, energy from 513.2 to 642.41 kcal/100 g, protein from 13.9 to 19.34%%, and crude fat from 24.12 to 35.54%. The calcium content ranged from 225 to 302 g/100 mg, iron from 10.34 to 12.26 g/100 mg, and zinc from 10 to 20 g/100 mg. In this study, the phytate content varied from 314.74 to 369.3 µg/g and crude tannin, from 101.36 to 153.25 µg/g. This study concluded that the ingredients used in the RUTF1, RUTF2, and RUTF3 formulations met the standard ready-to-use therapeutic foods. Therefore, it is important to prescribe ready-to-use dietary supplements made from inexpensive, locally available, and culturally acceptable foods to prevent severe acute malnutrition in infants.

Food allergy across the globe.

The prevalence of food allergy (FA) is increasing in some areas of the globe, highlighting the need for better strategies for prevention, diagnosis, and therapy. In the last few decades, we have made great strides in understanding the causes and mechanisms underlying FAs, prompting guideline updates. Earlier guidelines recommended avoidance of common food allergens during pregnancy and lactation and delaying the introduction of allergenic foods in children aged between 1 and 3 years. Recent guidelines for allergy prevention recommend consumption of a healthy and diverse diet without eliminating or increasing the consumption of allergenic foods during pregnancy or breast-feeding. Early introduction of allergenic foods is recommended by most guidelines for allergy prevention after a period of exclusive breast-feedng (6 months [World Health Organization] or 4 months [European Academy of Allergy and Clinical Immunology]). New diagnostics for FA have been developed with varied availability of these tests in different countries. Finally, the first oral immunotherapy drug for FA was approved by the US Food and Drug Administration and European Medicines Agency in 2020. In this review, we will address the global prevalence of FA, our current understanding of the causes of FA, and the latest guidelines for preventing, diagnosing, and treating FA. We will also discuss similarities and differences between FA guidelines.

Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. Design, Setting, and Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). Main Outcomes and Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. Conclusions and Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04074161.