Pernicious anemia (B12 deficiency)

This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of pernicious anemia

Acute effects of exercise on appetite, food intake and circulating concentrations of gastrointestinal hormones

Recent years have witnessed significant research into the acute effects of exercise on appetite, energy intake and gut hormone responses. The experiments in this thesis have further investigated this topic by examining the appetite, acylated ghrelin, peptide YY and energy intake responses to energy deficits induced via different exercise protocols and food restriction. To achieve this, 48 young healthy males (mean (SD): age 23 (3) years, body mass index 23.7 (2.7) kg.m-2, maximum oxygen uptake 52.9 (9.8) mL.kg 1.min-1) were recruited into four studies. In study one, 60 min of treadmill running at 70% of VO2 max did not stimulate any increases in appetite or daily energy intake regardless of whether the exercise was performed after breakfast or in the fasted state. In study two, six 30 s Wingate tests stimulated increases in appetite during the subsequent hours compared with 60 min of cycling at 68% of VO2 max. Differences in appetite appeared to be unrelated to changes in plasma acylated ghrelin concentrations and did not influence ad libitum energy intake. Subsequently, endurance exercise resulted in a significantly greater negative daily energy balance than sprint exercise due to a larger exercise energy expenditure. Study three revealed that appetite and energy intake did not differ from a resting control trial after either ten, 4 min cycling bouts at 85 90% of VO2 max separated by 2 min of rest or 60 min of constant cycling at 60% of VO2 max. This occurred despite elevated PYY3-36 concentrations during the hours after exercise. Finally, study four showed that an energy deficit of ~1475 kJ stimulated increases in appetite when induced via food restriction but not when achieved by an acute bout of exercise. This was associated with differences in plasma PYY3-36 concentrations but did not appear to be related to changes in circulating levels of acylated ghrelin and did not influence energy intake. This thesis has shown that appetite perceptions do not differ from a resting control trial during the hours after continuous endurance exercise. Alternatively, supramaximal cycling exercise and subtle reductions in food intake stimulated increases in appetite during the subsequent hours. Such increases in appetite do not appear to be related to changes in acylated ghrelin but may be influenced by plasma PYY3-36 concentrations. Despite differences in appetite, daily energy intake was unaffected by all interventions

Creating an acute energy deficit without stimulating compensatory increases in appetite: is there an optimal exercise protocol?

Recent years have witnessed significant interest from both the scientific community and the media regarding the influence of exercise on subsequent appetite and energy intake responses. This review demonstrates a consensus among the majority of scientific investigations that an acute bout of land-based endurance exercise does not stimulate any compensatory increases in appetite and energy intake on the day of exercise. Alternatively, preliminary evidence suggests that low volume, supramaximal exercise may stimulate an increase in appetite perceptions during the subsequent hours. In accordance with the apparent insensitivity of energy intake to exercise in the short term, the daily energy balance response to exercise appears to be primarily determined by the energy cost of exercise. This finding supports the conclusions of recent training studies that the energy expenditure of exercise is the strongest predictor of fat loss during an exercise programme

Test-meal palatability is associated with overconsumption but better represents preceding changes in appetite in non-obese males

Single course ad libitum meals are recommended for the assessment of energy intake within appetite research. This represents the first investigation of the comparative sensitivity of two single course ad libitum meals designed to differ in palatability. Two experiments were completed using a preload study design. All protocols were identical except for the energy content of the preloads (Experiment one: 579kJ and 1776kJ; Experiment two: 828kJ and 4188kJ). During each experiment, 10 healthy men completed four experimental trials constituting a low or high energy preload beverage, a 60 min intermeal interval, and consumption of a pasta-based or porridge-based ad libitum meal. Appetite ratings were measured throughout each trial and palatability was assessed after food consumption. Preload manipulation did not influence appetite (P=0.791) or energy intake (P=0.561) in experiment one. Palatability and energy intake were higher for the pasta meal than the porridge meal in both experiments (palatability P≤0.002; energy intake P≤0.001). In experiment two, consumption of the high energy preload decreased appetite (P=0.051) and energy intake (P=0.002). Energy compensation was not significantly different between pasta and porridge meals (P=0.172) but was more strongly correlated with preceding changes in appetite at the pasta meal (r=-0.758; P=0.011) than the porridge meal (r=-0.498; P=0.143). The provision of a highly palatable pasta-based meal produced energy intakes that were more representative of preceding appetite ratings but the moderately palatable porridge-based meal produced more ecologically valid energy intakes. Ad libitum meal selection and design may require a compromise between sensitivity and ecological validity

Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions.

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: 1) MIE-normoxia, 2) MIE-hypoxia, 3) HIIE-normoxia, and 4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake ( 2max) and during HIIE performed 6 x 3 min running at 90% 2max interspersed with 6 x 3 min active recovery at 50% 2max with a 7 min warm-up and cool-down at 70% 2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2,980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants’ daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality

Appetite, energy intake, and PYY3-36 responses to energy-matched continuous exercise and submaximal high-intensity exercise.

High-intensity intermittent exercise induces physiological adaptations similar to energy-matched continuous exercise, but the comparative appetite and energy balance responses are unknown. Twelve healthy males (mean ± SD: age, 22 ± 3 years; body mass index, 23.7 ± 3.0 kg·m(-2); maximum oxygen uptake, 52.4 ± 7.1 mL·kg(-1)·min(-1)) completed three 8 h trials (control, steady-state exercise (SSE), high-intensity intermittent exercise (HIIE)) separated by 1 week. Trials commenced upon completion of a standardized breakfast. Exercise was performed from hour 2 to hour 3. In SSE, 60 min of cycling at 59.5% ± 1.6% of maximum oxygen uptake was performed. In HIIE, ten 4-min cycling intervals were completed at 85.8% ± 4.0% of maximum oxygen uptake, with a 2-min rest between each interval. A standardized lunch and an ad libitum afternoon meal were provided at hours 3.75 and 7, respectively. Appetite ratings and peptide YY3-36 concentrations were measured throughout each trial. Appetite was acutely suppressed during exercise, but more so during HIIE (p < 0.05). Peptide YY3-36 concentrations increased significantly upon cessation of exercise in SSE (p = 0.002), but were highest in the hours after exercise in HIIE (p = 0.05). Exercise energy expenditure was not different between HIIE and SSE (p = 0.649), but perceived exertion was higher in HIIE (p < 0.0005). Ad libitum energy intake did not differ between trials (p = 0.833). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in the SSE and HIIE trials than in the control trial (control, 4759 ± 1268 kJ; SSE, 2362 ± 1224 kJ; HIIE, 2523 ± 1402 kJ; p < 0.0005). An acute bout of energy-matched continuous exercise and HIIE were equally effective at inducing an energy deficit without stimulating compensatory increases in appetite

Exercise, appetite and weight control: are there differences between men and women?

Recent years have witnessed significant research interest surrounding the interaction between exercise, appetite and energy balance which has important implications for health. The majority of exercise and appetite regulation studies have been conducted in males. Consequently, opportunities to examine sex-based differences have been limited, but represent an interesting avenue of inquiry considering postulations that men experience greater weight loss after exercise interventions than women. This article reviews the scientific literature relating to the acute and chronic effects of exercise on appetite control in men and women. The consensus of evidence demonstrates that appetite, appetite-regulatory hormone and energy intake responses to acute exercise do not differ between the sexes, and there is little evidence indicating compensatory changes occur after acute exercise in either sex. Limited evidence suggests women respond to the initiation of exercise training with more robust compensatory alterations in appetite-regulatory hormones than men, but whether this translates to long-term differences is unknown. Current exercise training investigations do not support sex-based differences in appetite or objectively assessed energy intake, and increasing exercise energy expenditure elicits at most a partial energy intake compensation in both sexes. Future well-controlled acute and chronic exercise studies directly comparing men and women are required to expand this evidence base

Approaches to Selecting "Time Zero" in External Control Arms with Multiple Potential Entry Points: A Simulation Study of 8 Approaches

Background: When including data from an external control arm to estimate comparative effectiveness, there is a methodological choice of when to set “time zero,” the point at which a patient would be eligible/enrolled in a contemporary study. Where patients receive multiple lines of eligible therapy and thus alternative points could be selected, this issue is complex. Methods: A simulation study was conducted in which patients received multiple prior lines of therapy before entering either cohort. The results from the control and intervention data sets are compared using 8 methods for selecting time zero. The base-case comparison was set up to be biased against the intervention (which is generally received later), with methods compared in their ability to estimate the true intervention effectiveness. We further investigate the impact of key study attributes (such as sample size) and degree of overlap in time-varying covariates (such as prior lines of therapy) on study results. Results: Of the 8 methods, 5 (all lines, random line, systematically selecting groups based on mean absolute error, root mean square error, or propensity scores) showed good performance in accounting for differences between the line at which patients were included. The first eligible line can be statistically inefficient in some situations. All lines (with censoring) cannot be used for survival outcomes. The last eligible line cannot be recommended. Conclusions: Multiple methods are available for selecting the most appropriate time zero from an external control arm. Based on the simulation, we demonstrate that some methods frequently perform poorly, with several viable methods remaining. In selecting between the viable methods, analysts should consider the context of their analysis and justify the approach selected. There are multiple methods available from which an analyst may select “time zero” in an external control cohort. This simulation study demonstrates that some methods perform poorly but most are viable options, depending on context and the degree of overlap in time zero across cohorts. Careful thought and clear justification should be used when selecting the strategy for a study

Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

Follicular lymphomaLimfoma fol·licularLinfoma folicularIn the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.Was provided by Kite Pharma, a Gilead company, for this study