Pig True Ileal Digestible Amino Acid Contents of Individual Ingredients are Additive in Mixed Meals and Allow Accurate Predictions of Digestible Indispensable Amino Acid Score Values.

BACKGROUND: Although not every food protein contributes sufficient quantities of all of the indispensable amino acids (AAs) required for human health, the human diet is a mixture of foods. It is therefore important to evaluate protein quality in mixed meals. OBJECTIVES: The hypothesis was that the true ileal digestible AA content of mixed meals can be predicted from the amounts of digestible AA determined for individual food ingredients, allowing further prediction of the digestible indispensable amino acid score (DIAAS) for meals. METHODS: Four diets contained either pea protein isolate (PPI), whey protein concentrate (WPC), or mixtures of PPI:WPC at a ratio of 25:75 (PP25) or 75:25 (PP75). Six ileal cannulated pigs were allocated to a 4 × 6 Latin Square design. Experimental diets at 10% protein and a protein-free diet were fed for 7 d with ileal digesta collection on days 6 and 7. True ileal digestibility (TID) of AA, amount of digestible AA, and DIAAS were calculated for each diet and predicted for the 2 mixed meals. RESULTS: Predicted and determined digestible AA contents of the mixed diets were not different. The predicted values fell within the confidence interval (95%) of the determined values. DIAAS for PPI was 61% and for WPC it was 96%. DIAAS calculated based on the predicted amounts of digestible AA for PP25 was 104% and for PP75 83%. These values were nearly identical to the determined values of 104% and 84% for PP25 and PP75, respectively. CONCLUSIONS: The amount of digestible AA and DIAAS can be accurately predicted in mixtures of PP and WPC from the AA digestibility values for the individual ingredients.

Similar In Vitro Ileal Fermentation Outcomes Validate the Use of a Pig Ileal Inoculum in an In Vitro Fermentation Assay for the Adult Human.

BACKGROUND: An in vivo/in vitro ileal fermentation assay using growing pigs has shown important fermentability and organic acid production. This assay could be used to study human foods but needs validation. OBJECTIVES: A pig inoculum for studying human ileal fermentation was used to compare the in vitro fermentation of fiber substrates using ileal inocula prepared from growing pigs or human ileostomates. METHODS: Ten pigs (19 ± 4.5 kg bodyweight, mean ± standard deviation) received a diet containing human foods. After 2 wk, ileal digesta were collected 5 h postmeal. Five recruited human ileostomates incorporated the same human foods into their diet for a week before consuming 2 meals similar to the pigs' diet. Ileal effluents were then collected from 2 to 6 h postmeal. The porcine ileal digesta and human ileal effluents were used for microbial analysis and in vitro fermentation of arabinogalactan, fructooligosaccharides, and pectin. RESULTS: The in vitro organic matter fermentability of arabinogalactan, fructooligosaccharides, and pectin was similar (P > 0.05) between the pig and human ileal inocula (34 ± 2.13% on average). Regardless of substrates, the propionic and lactic acid production was similar between humans and pigs (P > 0.05). Ninety percent of the ileal bacterial genera were found in similar (P > 0.05) numbers in pigs and human ileostomates, which accords with the similar (P > 0.05) Shannon diversity index and predicted metabolic activity. However, some of the most abundant genera were different between species, such as Granulicatella which had 83-fold greater (P ≤ 0.05) numbers in human ileostomates, and Lactobacillus had 272-fold greater (P ≤ 0.05) numbers in pigs. CONCLUSIONS: The in vitro ileal fermentation patterns were similar across species despite some ileal microbial compositional differences, suggesting that the growing pig could be used as a model to provide an ileal inoculum for studying ileal fermentation in adult humans. This trial was registered at the Australian New Zealand Clinical Trials registry as ACTRN12622000813785.

Effects of Different Protein Sources on Amino Acid Absorption and Plasma Appearance of Tryptophan, Large Neutral Amino Acids, and Tryptophan Metabolites in Pigs.

BACKGROUND: Absorption of tryptophan (TRP) across the gut epithelium is potentially modulated by competing large neutral amino acids (LNAAs), which could affect the appearance of TRP and its metabolites in the bloodstream. OBJECTIVES: This study aimed to determine, in a growing pig model of an adult human, the absorption of TRP and other LNAAs from the gastrointestinal tract, and plasma appearance of TRP, LNAAs, and TRP metabolites, in response to dietary proteins varying in TRP content. METHODS: Pigs were adapted for 7 d to each of 4 diets that differed in their protein source and TRP content: 1) alpha-lactalbumin (AL; 9.95 mg TRP/g diet DM), 2) whey protein (6.59 mg TRP/g), 3) casein (3.73 mg TRP/g), or 4) zein (0.14 mg TRP/g). On day 8, pigs were euthanised after a 12-h fast (baseline), or 1, 2, 3, 4, or 6 h after they received a test meal consisting of 45 g protein, or a protein-free meal (n = 6 pigs at each time in each meal group). Tryptophan and LNAA absorption from the small intestine, and appearance of TRP, LNAAs, and TRP metabolites (melatonin, serotonin, kynurenine pathway metabolites), in the portal vein and systemic circulation, were determined. RESULTS: AL intake resulted in sustained elevated plasma TRP concentrations after an overnight fast. The amount of TRP absorbed was dose-dependently related to protein TRP content (P = 0.028), with fastest rates for pigs fed AL (371 mg/h). Portal and systemic plasma TRP, TRP/LNAA, and the TRP metabolites were highest (P ≤ 0.05) after AL intake, and remained above baseline levels for ∼4 h postprandially. Absorption rates of TRP correlated with postprandial plasma TRP and TRP metabolites (P ≤ 0.05). CONCLUSIONS: In adult humans, postprandial plasma TRP and TRP metabolite concentrations can likely be modulated by the TRP content of the meal.

Effectiveness of cladribine compared to fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting multiple sclerosis.

BACKGROUND: Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking. OBJECTIVES: To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS. METHODS: Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab were identified in the global MSBase cohort and two additional UK centres. Patients were followed for ⩾6/12 and had ⩾3 in-person disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARRs) and disability outcomes. RESULTS: The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab) or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (0.07 vs. 0.12, p = 0.006) and a higher ARR than natalizumab (0.10 vs. 0.06, p = 0.03), ocrelizumab (0.09 vs. 0.05, p = 0.008) and alemtuzumab (0.17 vs. 0.04, p < 0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.47-2.47) or alemtuzumab (HR 0.73, 95% CI 0.26-2.07), but was lower for patients treated with natalizumab (HR 0.35, 95% CI 0.13-0.94) and ocrelizumab (HR 0.45, 95% CI 0.26-0.78). There was no evidence for a difference in disability improvement. CONCLUSION: Cladribine is an effective therapy that can be viewed as a step up in effectiveness from fingolimod, but is less effective than the most potent intravenous MS therapies.

The kinetics of amino acid disappearance in the small intestine is related to the extent of amino acids absorbed in growing pigs.

This study evaluated the importance of a correction for amino acids (AA) released into the hindgut on a measure of AA absorption kinetics and tested whether AA absorption kinetics are related to the extent of AA absorption using the growing pig as a model for humans. Thirty-six nine-week-old pigs (22·3 kg) received a diet containing whey protein as the sole protein source for 8 d. Pigs received their last meal containing the indigestible marker titanium dioxide before being euthanised at 1, 2, 3, 4, 6 and 12 h post-feeding. The entire content of each gastrointestinal tract (GIT) region was collected to determine AA released into the hindgut, and the kinetics and extent of AA absorption (uncorrected and corrected for AA entering the hindgut). Amounts of AA released into the hindgut increased over time (e.g. 33 and 180 mg of Glu for 4 and 6 h post-feeding). The corrected apparent amount of each AA absorbed from the GIT lumen after 4 h post-feeding was generally lower (P ≤ 0·05) than the uncorrected counterpart. Differences in both the kinetics and extent of AA absorption were observed across AA. For example, the time to reach half of the apparent AA absorption (T50) was 1·5 and 3·4 h for Met and Arg, respectively, whereas their extent of apparent absorption was 93 and 73 %. Negative correlations between parameters related to kinetics and the extent of apparent absorption were observed (e.g. for T50 r = -0·81; P < 0·001). The kinetics of AA absorption is related to the extent of AA absorption.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

Available Lysine in Foods as Determined in Adult Ileostomates.

BACKGROUND: When foods are subjected to heat and pressure, a proportion of lysine is structurally altered and some will revert to lysine because of acid hydrolysis during amino acid analysis. Altered lysine molecules may be partly absorbed but are not utilized post-absorption. OBJECTIVES: A guanidination-based bioassay has been developed to determine true ileal digestible reactive lysine but it was only used in animal models (pig and rat). The objective of this study was to apply the assay and determine whether there is a difference between true ileal digestible total lysine and true ileal digestible reactive lysine in adult human ileostomates. METHODS: Six cooked or processed foods were analyzed for total lysine and reactive lysine. Six adults with a fully functioning ileostomy (4 women and 2 men; age range: 41-70 y; BMI: 20.8-28.1) participated. Foods for which total lysine > reactive lysine (cooked black beans, toasted wheat bread, and processed wheat bran), as well as a protein-free diet, were consumed by the ileostomates (n = 5 to 8; test food meals contained 25 g protein) and ileal digesta was collected. Each food was ingested twice by each participant, and the digesta was pooled. The order of foods for each participant was determined according to a Youden square. True ileal digestible total lysine and true ileal digestible reactive lysine were determined and a 2-way ANOVA model was used to analyze data. RESULTS: True ileal digestible reactive lysine was significantly lower than true ileal digestible total lysine for cooked black beans, toasted wheat bread, and processed wheat bran by 89%, 55%, and 85%, respectively (P< 0.05). CONCLUSIONS: True ileal digestible reactive lysine was lower than true ileal digestible total lysine, similar to that previously reported in pigs and rats, demonstrating the importance of determining the true ileal digestible reactive lysine contents of processed foods.

Type and Amount of Dietary Fiber Influence the Hindgut Synthesis of Organic Acids from Fermentable Material of Both Total and Nondietary Origin in a Pig Model of the Adult Human.

BACKGROUND: Organic acid synthesis by the hindgut microbiota is commonly believed to be mainly of fermentable material of dietary origin. OBJECTIVE: This study aimed to determine the hindgut organic acid synthesis from fermentable material of dietary (mainly fiber) or nondietary origin for different types and amounts of dietary fiber in growing pigs used as a model for adult humans. METHOD: Seven fiber-containing diets were formulated: 4 fiber types (cellulose, gum acacia, oligofructose, and pectin) at 6% of the diet and 3 (gum acacia, oligofructose, and pectin) at 3% as the sole fiber source. Ileal cannulated female pigs (n = 14; Landrace/Large white) were fed the fiber-containing diets (n = 6 pigs/diet) for 11 days (fiber phase) followed by 3 days on a fiber-free diet (fiber-free phase), using a replicated Youden square. Ileal digesta for each phase were collected and fermented in vitro with a pooled fecal microbial inoculum prepared from feces collected during the fiber phase to determine the organic acids synthesized from fermentable material of dietary (fiber phase) and nondietary (fiber-free phase) origins. RESULTS: The total amount of each individual organic acid synthesized during in vitro hindgut fermentation differed (P ≤ 0.05) across the types and amounts of dietary fiber intake. For example, the amount of acetate was 3.6-fold higher (P ≤ 0.05) for pigs fed the 6% pectin-containing diet than those fed the 6% oligofructose-containing diet. The nondietary substrate contributed between 36% (hexanoate) and 70% (succinate) to the total hindgut organic acid synthesis. The adaptation to the different fiber-containing diets led to different amounts of some organic acids of nondietary origin. CONCLUSIONS: The total amount of organic acids synthesized in the hindgut by the resident microbes is influenced by the type and amount of dietary fiber consumed. This study quantifies the interaction between both dietary and nondietary fermentable materials in hindgut fermentation.

Cooked Rice-Based and Wheat-Based Food Structure Influenced Digestion Kinetics and Glycemic Response in Growing Pigs.

BACKGROUND: How starch-based food structure can affect the rate and extent of digestion in the small intestine and resulting glycemic response is not properly understood. One possible explanation is that food structure influences gastric digestion, which subsequently determines digestion kinetics in the small intestine and glucose absorption. However, this possibility has not been investigated in detail. OBJECTIVES: Using growing pigs as a digestion model for adult humans, this study aimed to investigate how physical structure of starch-rich foods affects small intestinal digestion and glycemic response. METHODS: Male growing pigs (21.7 ± 1.8 kg, Large White × Landrace) were fed one of the 6 cooked diets (250-g starch equivalent) with varying initial structures (rice grain, semolina porridge, wheat or rice couscous, or wheat or rice noodle). The glycemic response, small intestinal content particle size and hydrolyzed starch content, ileal starch digestibility, and portal vein plasma glucose were measured. Glycemic response was measured as plasma glucose concentration collected from an in-dwelling jugular vein catheter for up to 390 min postprandial. Portal vein blood samples and small intestinal content were measured after sedation and euthanasia of the pigs at 30, 60, 120, or 240 min postprandial. Data were analyzed with a mixed-model ANOVA. RESULTS: The plasma glucose Δmaxoverall and iAUCoverall for couscous and porridge diets (smaller-sized diets) were higher than that of intact grain and noodle diets (larger-sized diets): 29.0 ± 3.2 compared with 21.7 ± 2.6 mg/dL and 5659 ± 727 compared with 2704 ± 521 mg/dL⋅min, for the smaller-sized and larger-sized diets, respectively (P < 0.05). Ileal starch digestibility was not significantly different between the diets (P ≥ 0.05). The iAUCoverall was inversely related to the starch gastric emptying half-time of the diets (r = -0.90, P = 0.015). CONCLUSIONS: Starch-based food structure affected the glycemic response and starch digestion kinetics in the small intestine of growing pigs.

An Accurate Estimate of the Amino Acid Content of Human Milk Collected from Chinese Women Adjusted for Differences in Amino Acid Digestibility.

BACKGROUND: The amino acid (AA) composition of human milk is used to define the AA requirements of the infant. Thus, it is important that estimates of composition be as complete and accurate as possible. When determining AA composition using standard hydrolysis methods, some AAs are progressively destroyed while others are incompletely released. For accuracy, AA composition needs to be determined using multiple hydrolysis times. The true ileal digestibility of AAs also needs to be taken into consideration. OBJECTIVE: The objective was to bring together AA compositional (determined using multiple hydrolysis intervals) and digestibility data determined using the piglet to give an estimate of the absorbed AA profile of human milk with reference in particular to Asian females. METHODS: Mature milk was collected from Chinese females. AA analysis using multiple hydrolysis intervals and a nonlinear regression model was used to accurately estimate AA composition. Human milk, as well as a protein-free diet, were fed to piglets (n = 6), and ileal digesta were collected (piglet age, 21 d) to determine the true ileal AA digestibility of AAs in human milk. RESULTS: True ileal AA digestibility coefficients ranged from (mean ± standard error of the mean) 0.61 ± 0.081 for tyrosine to 1.01 ± 0.030 for tryptophan, with a digestibility for total nitrogen of 0.90 ± 0.013. Convergence criteria were met for the modeling for each AA, and the model had a level of significance of P < 0.0001 for each AA. The amount of available AAs (total AA content as per the model prediction multiplied by the true ileal AA digestibility coefficient determined in the piglet) are reported. CONCLUSIONS: An estimate of the absorbed AA profile of mature milk collected from Chinese females is provided. For the first time, data is presented for cysteine.

Prediction of relapse activity when switching to cladribine for multiple sclerosis.

BACKGROUND: Patients with relapsing-remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. OBJECTIVE: To determine predictors of relapse hazard when switching to cladribine. METHODS: Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. RESULTS: Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03-5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01-4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65-14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35-12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91-0.99). CONCLUSION: Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard.

Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry.

BACKGROUND: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. OBJECTIVES: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. METHODS: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). RESULTS: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. CONCLUSION: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

The role of holistic nutritional properties of diets in the assessment of food system and dietary sustainability.

Advancing sustainable diets for nutrition security and sustainable development necessitates clear nutrition metrics for measuring nutritional quality of diets. Food composition, nutrient requirements, and dietary intake are among the most common nutrition metrics used in the current assessment of sustainable diets. Broadly, most studies in the area classify animal-source foods (ASF) as having a substantially higher environmental footprint in comparison to plant-source foods (PSF). As a result, much of the current dietary advice promulgates diets containing higher proportions of PSF. However, this generalization is misleading since most of these studies do not distinguish between the gross and bioavailable nutrient fractions in mixed human diets. The bioavailability of essential nutrients including ß-carotene, vitamin B-12, iron, zinc, calcium, and indispensable amino acids varies greatly across different diets. The failure to consider bioavailability in sustainability measurements undermines the complementary role that ASF play in achieving nutrition security in vulnerable populations. This article critically reviews the scientific evidence on the holistic nutritional quality of diets and identifies methodological problems that exist in the way the nutritional quality of diets is measured. Finally, we discuss the importance of developing nutrient bioavailability as a requisite nutrition metric to contextualize the environmental impacts of different diets.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis.

BACKGROUND: To compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing-remitting multiple sclerosis switching from fingolimod. METHODS: Using data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab. RESULTS: Overall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine; the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation. CONCLUSION: After fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences.

Comparison of True Ileal Amino Acid Digestibility between Adult Humans and Growing Pigs.

BACKGROUND: It is not feasible to determine the true ileal amino acid (AA) digestibility of protein sources in humans on a routine basis, and the growing pig has been recommended as an animal model for this purpose but requires further validation. OBJECTIVES: To determine and compare true ileal AA digestibility between adult human ileostomates and growing cannulated pigs for a range of food proteins. METHODS: Seven protein sources (black beans, bread, collagen, pigeon peas, wheat bran, whey protein isolate, and zein) that spanned the range of digestibilities typically seen in foods were evaluated. Six female growing pigs received each of the protein sources, as well as a protein-free diet, and digesta were collected via ileal T-cannula. Adult human ileostomates consumed the same protein sources (5-8 ileostomates, depending on the protein source), as well as a protein-free diet, and digesta were collected. Titanium dioxide and celite were included in the diets as indigestible markers. True ileal AA digestibility coefficients were determined. RESULTS: There was a significant effect of protein source (P ≤ 0.001) for all AAs. The effect of species was not significant (P > 0.05) except for total lysine (but not for available lysine). When analyzed within diets, the statistically significant species effect for true lysine digestibility was found for black beans only. Pig and human digestibility values were generally highly and significantly (P ≤ 0.05) correlated. A linear regression equation derived for true ileal AA digestibility (given as coefficients) determined in the human and pig for the overall mean of all AAs was (y = human, x = pig) y = 1.00x - 0.010, with the slope not statistically significant (P > 0.05) from unity and the intercept not different (P > 0.05) from zero. CONCLUSIONS: True ileal AA digestibility values determined in the growing pig can be directly used for predicting digestibility in adult humans.

Prediction of multiple sclerosis outcomes when switching to ocrelizumab.

BACKGROUND: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. OBJECTIVE: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. METHODS: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). RESULTS: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64, p = 0.006). CONCLUSION: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.