Effects of Dietary Acid Load on Exercise Metabolism and Anaerobic Exercise Performance

Dietary acid load, quantified as the potential renal acid load (PRAL) of the diet, affects systemic pH and acid-base regulation. In a previous cross-sectional study, we reported that a low dietary PRAL (i.e. alkaline promoting diet) is associated with higher respiratory exchange ratio (RER) values during maximal exercise. The purpose of the present study was to confirm the previous findings with a short-term dietary intervention study. Additionally, we sought to determine if changes in PRAL affects submaximal exercise RER (as a reflection of substrate utilization) and anaerobic exercise performance. Subjects underwent a graded treadmill exercise test (GXT) to exhaustion and an anaerobic exercise performance test on two occasions, once after following a low-PRAL diet and on a separate occasion, after a high-PRAL diet. The diets were continued as long as needed to achieve an alkaline or acid fasted morning urine pH, respectively, with all being 4-9 days in duration. RER was measured during the GXT with indirect calorimetry. The anaerobic performance test was a running time-to-exhaustion test lasting 1-4 min. Maximal exercise RER was lower in the low-PRAL trial compared to the high-PRAL trial (1.10 ± 0.02 vs. 1.20 ± 0.05, p = 0.037). The low-PRAL diet also resulted in a 21% greater time to exhaustion during anaerobic exercise (2.56 ± 0.36 vs. 2.11 ± 0.31 sec, p = 0.044) and a strong tendency for lower RER values during submaximal exercise at 70% VO₂max (0.88 ± 0.02 vs. 0.96 ± 0.04, p = 0.060). Contrary to our expectations, a short-term low-PRAL (alkaline promoting) diet resulted in lower RER values during maximal-intensity exercise. However, the low-PRAL diet also increased anaerobic exercise time to exhaustion and appears to have shifted submaximal exercise substrate utilization to favor lipid oxidation and spare carbohydrate, both of which would be considered favorable effects in the context of exercise performance.

Key points

• Short-term (4-9 days) changes in the acid or alkaline promoting qualities of the diet, quantified as potential renal acid load (PRAL), alter systemic pH, as evidenced in the present study by changes in fasted morning urine pH. Low-PRAL (alkaline promoting) diets are characterized by high intakes of vegetables and fruits with limited consumption of meats, cheeses, and grains while high-PRAL diets are characterized by the opposite dietary pattern.
• An alkaline promoting (low-PRAL) diet increases anaerobic exercise performance, as evidenced by greater time-to-exhaustion during high-intensity treadmill running.
• Preliminary evidence suggests that an alkaline promoting (low-PRAL) diet increases lipid oxidation and may have a carbohydrate-sparing effect during submaximal endurance exercise, although further studies are needed.
• In contrast to what has been observed in response to habitual/long-term dietary patterns, a short-term low-PRAL diet does not increase maximal exercise respiratory exchange ratio and even appears to lower it. This suggests that short-term and long-term alterations in PRAL have different physiologic effects on this parameter.

Key words: Renal acid load, alkaline diet, substrate oxidation, respiratory exchange ratio     

Trends in the Timing and Clinical Context of Maintenance Dialysis Initiation

Whether secular trends in eGFR at dialysis initiation reflect changes in clinical presentation over time is unknown. We reviewed the medical records of a random sample of patients who initiated maintenance dialysis in the Department of Veterans Affairs (VA) in fiscal years 2000–2009 (n=1691) to characterize trends in clinical presentation in relation to eGFR at initiation. Between fiscal years 2000–2004 and 2005–2009, mean eGFR at initiation increased from 9.8±5.8 to 11.0±5.5 ml/min per 1.73 m² (P<0.001), the percentage of patients with an eGFR of 10–15 ml/min per 1.73 m² increased from 23.4% to 29.9% (P=0.002), and the percentage of patients with an eGFR>15 ml/min per 1.73 m² increased from 12.1% to 16.3% (P=0.01). The proportion of patients who were acutely ill at the time of initiation and the proportion of patients for whom the decision to initiate dialysis was based only on level of kidney function did not change over time. Frequencies of documented clinical signs and/or symptoms were similar during both time periods. The adjusted odds of initiating dialysis at an eGFR of 10–15 or >15 ml/min per 1.73 m² (versus <10 ml/min per 1.73 m²) during the later versus earlier time period were 1.43 (95% confidence interval [95% CI], 1.13 to 1.81) and 1.46 (95% CI, 1.09 to 1.97), respectively. In conclusion, trends in eGFR at dialysis initiation at VA medical centers do not seem to reflect changes in the clinical context in which dialysis is initiated.     

Evaluation of expressive writing for postpartum health: a randomised controlled trial

Pregnancy, birth and adjusting to a new baby is a potentially stressful time that can negatively affect the health of women. There is some evidence that expressive writing can have positive effects on psychological and physical health, particularly during stressful periods. The current study aimed to evaluate whether expressive writing would improve women’s postpartum health. A randomized controlled trial was conducted with three conditions: expressive writing (n?=?188), a control writing task (n?=?213), or normal care (n?=?163). Measures of psychological health, physical health and quality of life were measured at baseline (6–12 weeks postpartum), 1 and 6 months later. Ratings of stress were taken before and after the expressive writing task. Intent-to-treat analyses showed no significant differences between women in the expressive writing, control writing and normal care groups on measures of physical health, anxiety, depression, mood or quality of life at 1 and 6 months. Uptake and adherence to the writing tasks was low. However, women in the expressive writing group rated their stress as significantly reduced after completing the task. Cost analysis suggest women who did expressive writing had the lowest costs in terms of healthcare service use and lowest cost per unit of improvement in quality of life. Results suggest expressive writing is not effective as a universal intervention for all women 6–12 weeks postpartum. Future research should examine expressive writing as a targeted intervention for women in high-risk groups, such as those with mild or moderate depression, and further examine cost-effectiveness.Clinical trial registration number ISRCTN58399513 www.isrctn.com     

Virus-Specific T Cells: Broadening Applicability

Virus infection remains an appreciable cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although pharmacotherapy and/or antibody therapy may help prevent or treat viral disease, these drugs are expensive, toxic, and often ineffective due to primary or secondary resistance. Further, effective treatments are limited for many infections (eg, adenovirus, BK virus), which are increasingly detected after alternative donor transplants. These deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders, leading to adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs), which can rapidly reconstitute antiviral immunity post-transplantation without causing graft-versus-host disease. This review will explore how the VST field has improved outcomes for many patients with life-threatening viral infections after HSCT, and how to broaden applicability beyond the “patient-specific” products, as well as extending to other viral diseases even outside the context of HSCT.     

Consequences,conditions and caveats: a qualitative exploration of the influence of undergraduate health professions students at distributed clinical training sites

Background

Traditionally, the clinical training of health professionals has been located in central academic hospitals. This is changing. As academic institutions explore ways to produce a health workforce that meets the needs of both the health system and the communities it serves, the placement of students in these communities is becoming increasingly common. While there is a growing literature on the student experience at such distributed sites, we know less about how the presence of students influences the site itself. We therefore set out to elicit insights from key role-players at a number of distributed health service-based training sites about the contribution that students make and the influence their presence has on that site.

Methods

This interpretivist study analysed qualitative data generated during twenty-four semi-structured interviews with facility managers, clinical supervisors and other clinicians working at eight distributed sites. A sampling grid was used to select sites that proportionally represented location, level of care and mix of health professions students. Transcribed data were subjected to thematic analysis. Following an iterative process, initial analyses and code lists were discussed and compared between team members after which the data were coded systematically across the entire data set.

Results

The clustering and categorising of codes led to the generation of three over-arching themes: influence on the facility (culturally and materially); on patient care and community (contribution to service; improved patient outcomes); and on supervisors (enriched work experience, attitude towards teaching role). A subsequent stratified analysis of emergent events identified some consequences of taking clinical training to distributed sites. These consequences occurred when certain conditions were present. Further critical reflection pointed to a set of caveats that modulated the nature of these conditions, emphasising the complexity inherent in this context.

Conclusions

The move towards training health professions students at distributed sites potentially offers many affordances for the facilities where the training takes places, for those responsible for student supervision, and for the patients and communities that these facilities serve. In establishing and maintaining relationships with the facilities, academic institutions will need to be mindful of the conditions and caveats that can influence these affordances.

     

From the Cover: PNAS Plus: The essential gene set of a photosynthetic organism

Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ∼250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism’s 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlap with well-conserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA^Leu, which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism’s physiology and defines the essential gene set required for the growth of a photosynthetic organism.Determining the sets of genes necessary for survival of diverse organisms has helped to identify the fundamental processes that sustain life across an array of environments (1). This research has also served as the starting point for efforts by synthetic biologists to design organisms from scratch (2, 3). Despite the importance of essential gene sets, they have traditionally been challenging to gather because of the difficulty of observing mutations that result in lethal phenotypes. More recently, the pairing of transposon mutagenesis with next generation sequencing, referred to collectively as transposon sequencing (Tn-seq), has resulted in a dramatic advance in the identification of essential gene sets (4–7). The key characteristic of Tn-seq is the use of high-throughput sequencing to screen for the fitness of every transposon mutant in a pooled population to measure each mutation’s impact on survival. These data can be used to quantitatively ascertain the effect of loss-of-function mutations at any given locus, intragenic or intergenic, in the conditions under which the library is grown (8). Essential gene sets for 42 diverse organisms distributed across all three domains have now been defined, largely through the use of Tn-seq (9). A recently developed variation on Tn-seq, random barcode transposon site sequencing (RB-TnSeq) (10), further minimizes the library preparation and sequencing costs of whole-genome mutant screens.Despite the proliferation of genome-wide essentiality screens, a complete essential gene set has yet to be defined for a photosynthetic organism. A collection of phenotyped Arabidopsis thaliana mutants has been created but extends to only one-tenth of Arabidopsis genes (11). In algae, efforts are underway to produce a Tn-seq–like system in Chlamydomonas reinhardtii; however, the mutant library currently lacks sufficient saturation to determine gene essentiality (12). To date, the essential genes for photoautotrophs have only been estimated by indirect means, such as by comparative genomics (13). The absence of experimentally determined essential gene sets in photosynthetic organisms, despite their importance to the environment and industrial production, is largely because of the difficulty and time required for genetic modification of these organisms.Cyanobacteria comprise an extensively studied and ecologically important photosynthetic phylum. They are responsible for a large portion of marine primary production and have played a foundational role in research to decipher the molecular components of photosynthesis (14, 15). Synechococcus elongatus PCC 7942 is a particularly well-studied member of this phylum because of its genetic tractability and streamlined genome (16). As a result, it has been developed as a model photosynthetic organism and a production platform for a number of fuel products and high-value chemicals (17). Despite the importance of S. elongatus for understanding photosynthesis and industrial production, 40% of its genes have no functional annotation, and only a small portion of those that do have been studied experimentally.Here, we use RB-TnSeq, a method that pairs high-density transposon mutagenesis and pooled mutant screens, to probe the S. elongatus genome for essential genes and noncoding regions. We categorized 96% of 2,723 genes in S. elongatus as either essential (lethal when mutated), beneficial (growth defect when mutated), or nonessential (no phenotype when mutated) under standard laboratory conditions. Furthermore, we determined the genome-wide essentiality of noncoding RNAs (ncRNAs), regulatory regions, and intergenic regions. Our investigation has produced an extensive analysis of the loci essential for the growth of a photosynthetic organism and developed a powerful genomic tool that can be used for additional screens under a wide array of ecologically and industrially relevant growth conditions.