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Background Insulin resistance (IR) increases vascular risk in individuals with Type 1 Diabetes (T1D). We aimed to investigate the relationship between dietary intake and IR, as well as vascular biomarkers in T1D. Methods Baseline data from three randomised controlled trials were pooled. Estimated glucose disposal rate (eGDR) was used as an IR marker. Employing multivariate nutrient density substitution models, we examined the association between macronutrient composition and IR/vascular biomarkers (tumour necrosis factor-α, fibrinogen, tissue factor activity, and plasminogen activator inhibitor-1). Results Of the 107 patients, 50.5% were male with mean age of 29 ± 6 years. Those with lower eGDR were older with a longer diabetes duration, higher insulin requirements, and an adverse vascular profile (p p p β = 0.103, 95% CI 0.044–0.163). In contrast, increased dietary fat at the expense of dietary protein intake was associated with lower eGDR (β = − 0.119, 95% CI − 0.199 to − 0.040). Replacing fat with 5% isoenergetic amount of carbohydrate resulted in decreased vascular biomarkers (p Conclusion Higher fat, but not carbohydrate, intake is associated with increased IR and an adverse vascular profile in patients with T1D.

The age-related decline in skeletal muscle mass and function is known as sarcopenia. Sarcopenia progresses based on complex processes involving protein dynamics, cell signaling, oxidative stress, and repair. We have previously found that 8-week treatment with elamipretide improves skeletal muscle function, reverses redox stress, and restores protein S-glutathionylation changes in aged female mice. This study tested whether 8-week treatment with elamipretide also affects global phosphorylation in skeletal muscle consistent with functional improvements and S-glutathionylation. Using female 6–7-month-old mice and 28–29-month-old mice, we found that phosphorylation changes did not relate to S-glutathionylation modifications, but that treatment with elamipretide did partially reverse age-related changes in protein phosphorylation in mouse skeletal muscle.

Consumption of chickpea attenuates postprandial glycaemic response and enhances satiety independent of food processing.

The pathology of aging impacts multiple organ systems including the kidney, skeletal, and cardiac muscle. Long-term treatment with the mitochondrial targeted peptide elamipretide has previously been shown to improvein vivomitochondrial function in aged mice that is associated with increased fatigue resistance and treadmill performance, improved cardiovascular diastolic function, and glomerular architecture of the kidney. However, elamipretide is a short tetrameric peptide that is not orally bioavailable limiting its routes of administration. This study tested whether twice weekly intermittent injections of elamipretide could recapitulate the same functional improvements as continuous long-term infusion. We found that intermittent treatment with elamipretide for 8 months preserved endurance running in mice, skeletal muscle force production, and left ventricular mass but did not affect heart or kidney function as previously reported using continuous treatment.

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction that occurs during aging. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low-frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue- and mutation type-dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age suggests a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.

SUMMARYAging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment,in vivoheart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.Abstract FigureGraphical Abstract.ELAM Binds Directly to ANT and ATP Synthase and ELAM Treatment Improves ADP Sensitivity, Increases ATP Production, and Improves Physiological Function in Old Muscles.ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (Adenine nucleotide translocator), H+(proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2(flavin adenine dinucleotide), O2(oxygen), ELAM (elamipretide), −SH (free thiol), −SSG (glutathionylated protein).

The use of permeabilized muscle fibers (PMF) has emerged as a gold standard for assessing skeletal muscle mitochondrial function. PMF provide an intermediate approach between in vivo strategies and isolated mitochondria that allows the mitochondria to be maintained in close to their native morphology in the myofiber while allowing greater control of substrate and inhibitor concentrations. However, like mitochondrial isolation, the primary drawback to PMF is disruption of the cellular environment during the muscle biopsy and preparation. Despite all the benefits of permeabilized muscle fibers in evaluating mitochondrial respiration and dynamics one of the major drawbacks is increased variability introduced during a muscle biopsy as well as intrinsic variation that exists due to sex and age. This study was designed to evaluate how age, sex, and biopsy preparations affect mitochondrial respiration in extensor digitorum longus, soleus, and gastrocnemius muscle of mice. Here we detail a modified approach to skeletal muscle biopsy of the gastrocnemius muscle of mice focused on maintenance of intact fibers that results in greater overall respiration compared to cut fibers. The improved respiration of intact fibers is sex specific as are some of the changes in mitochondrial respiration with age. This study shows the need for standard practices when measuring mitochondrial respiration in permeabilized muscle and provides a protocol to control for variation introduced during a typical mouse muscle biopsy.

Kounis syndrome is the concurrence of acute coronary syndrome or coronary vasospasm with conditions associated with the release of inflammatory cytokines through mast cell activation in the setting of allergic or anaphylactic reactions. Many identified triggers have been identified in paediatric patients including exposures, drugs, and immunisations; however, to our knowledge this is the first case report of Kounis syndrome linked to immunotherapy. We present a case of a 9-year-old with seasonal allergies presenting with clinical symptoms of Kounis syndrome following her weekly subcutaneous injection of allergens. Clinicians need a high index of suspicion for Kounis syndrome in patients who develop systemic signs of anaphylaxis with clinical, laboratory, electrocardiographic, and echocardiographic findings of acute coronary syndrome to help direct therapy and improve outcomes.

The invasion of lionfish (Pterois spp.) into the Gulf of Mexico has been well documented but to date few studies have presented analysis on abundance trends to evaluate population status and trends. We used trawl and reef fish video survey data to analyze abundance trends from 2010 to 2019. The trawl and camera survey data evaluated show a rapid increase of lionfish through 2016–2017 with subsequent stabilization or decreases in 2018 and 2019. Lionfish occupied multiple natural habitats across the northern Gulf of Mexico, have a strong affinity for hard bottom habitats with sponge, but no preference relative to low versus high relief reef types. Population growth trends indicated faster population growth in trawl surveys as compared to video indices. Incidental catch of sponge in trawls, which primarily occurred in the eastern Gulf of Mexico, was a significant variable explaining lionfish catch. Interestingly, there were few lionfish captured in the western Gulf of Mexico suggesting that the low-relief soft-bottom in that region is less suitable for lionfish. Artificial habitats in the western Gulf of Mexico could be providing necessary hard-bottom habitat for lionfish, however, survey data analyzed in this study cannot provide inference as these surveys are not conducted on those habitats. Careful consideration must be taken when implementing lionfish removal programs given a potential for increased population growth when harvest does not achieve overfishing. In addition monitoring of community level effects will be needed as predation and indirect competition for resources could potentially negatively impact native species.

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) during aging has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue and mutation type dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with Elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age indicates a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.

Background and aims Postprandial responses are influenced not only by the type and amount of fat ingested, but also lipid droplet size distribution. However, little research has investigated the impact of differential lipid size distributions within a mixed-macronutrient meal context on postprandial vascular health. Therefore, we examined whether manipulating the lipid droplet size distribution within a mixed-macronutrient meal impacts vascular-inflammatory and thrombotic parameters. Methods and results In a randomised and counterbalanced fashion, sixteen adults (8 males; age 34 ± 7 years; BMI of 25.3 ± 4.5 kg/m2) completed three separate fasted morning-time feeding challenges, each separated by a minimum washout of 7-days. On each occasion, test-meals matched for carbohydrate and protein content differing only in fat amount and the lipid droplet size distribution were administered, such that participants consumed (1) a low-fat meal (LF) with negligible fat content, (2) an emulsified-high-fat meal with a fine lipid droplet size (FE), or (3) an emulsified-high-fat meal with a coarse lipid droplet size (CE). Periodic blood samples were retrospectively analysed for plasma triglycerides, tumour necrosis factor alpha (TNFα), tissue factor (TF), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1). Triglyceride concentrations increased rapidly overtime under FE (P-time0.05) and was comparable to LF (P-condition>0.05). Similarly, FE induced a significant rise in TNFα, TF, fibrinogen, and PAI-1 (P-time0.05). Conclusion A high-fat mixed-macronutrient meal with a larger lipid droplet size distribution ameliorates the associated rise in vascular-inflammatory and thrombotic parameters. Trial registration ISRCTN88881254.

Sea cucumber populations around the globe are experiencing marked declines caused by overexploitation and habitat degradation. Fisheries-independent data used to manage these ecologically and economically important species are frequently collected using diver- or snorkeler-based surveys, which have a number of limitations, including small spatial coverage and observer biases. In the present study, we explored how pairing traditional transect surveys with unmanned aerial vehicles (UAVs) and machine learning could improve sea cucumber density estimation in shallow environments. In July 2018, we conducted 24 simultaneous snorkeler–UAV transects in Tetiaroa, French Polynesia. All UAV images were independently reviewed by three observers and a convolution neural network (CNN) model: ResNet50. All three methods (snorkelers, manual review of UAV images, and ResNet50) produced similar counts, except at relatively high densities (∼75 sea cucumber 40 m−2), where UAVs and CNNs began to underestimate. Using a UAV-derived photomosaic of the study site, we simulated potential transect locations and determined a minimum of five samples were required to reliably estimate densities, while sample variance plateaued after 25 transects. Collectively, these results illustrate UAVs’ ability to survey small invertebrate species, while saving time, money, and labour compared to traditional methods, and highlights their potential to maximize efficiency when designing transect surveys.

Background Severe hypoglycaemia may pose significant risk to individuals with type 2 diabetes (T2D), and evidence surrounding strategies to mitigate this risk is lacking. Methods Data was re-analysed from a previous randomised controlled trial studying the impact of nurse-led intervention on mortality following severe hypoglycaemia in the community. A Cox-regression model was used to identify baseline characteristics associated with mortality and to adjust for differences between groups. Kaplan-Meier curves were created to demonstrate differences in outcome between groups across different variables. Results A total of 124 participants (mean age = 75, 56.5% male) were analysed. In univariate analysis, Diabetes Severity Score (DSS), age and insulin use were baseline factors found to correlate to mortality, while HbA1C and established cardiovascular disease showed no significant correlations. Hazard ratio favoured the intervention (0.68, 95% CI: 0.38–1.19) and in multivariate analysis, only DSS demonstrated a relationship with mortality. Comparison of Kaplan-Meier curves across study groups suggested the intervention is beneficial irrespective of HbA1c, diabetes severity score or age. Conclusion While DSS predicts mortality following severe community hypoglycaemia in individuals with T2D, a structured nurse-led intervention appears to reduce the risk of death across a range of baseline parameters.

The use of permeabilized muscle fibers (PMF) has emerged as a gold standard for assessing skeletal muscle mitochondrial function. PMF provide an intermediate approach between in vivo strategies and isolated mitochondria that allows the mitochondria to be maintained in close to their native morphology in the myofiber while allowing greater control of substrate and inhibitor concentrations. However, like mitochondrial isolation, the primary drawback to PMF is disruption of the cellular environment during the muscle biopsy and preparation. Despite all the benefits of permeabilized muscle fibers in evaluating mitochondrial respiration and dynamics one of the major drawbacks is increased variability introduced during a muscle biopsy as well as intrinsic variation that exists due to sex and age. This study was designed to evaluate how age, sex, and biopsy preparations affect mitochondrial respiration in extensor digitorum longus, soleus, and gastrocnemius muscle of mice. Here we detail a modified approach to skeletal muscle biopsy of the gastrocnemius muscle of mice focused on maintenance of intact fibers that results in greater overall respiration compared to cut fibers. The improved respiration of intact fibers is sex specific as are some of the changes in mitochondrial respiration with age. This study shows the need for standard practices when measuring mitochondrial respiration in permeabilized muscle and provides a protocol to control for variation introduced during a typical mouse muscle biopsy.

Funder: University of Leeds, PURPOSE: Findings from randomized controlled trials (RCTs) evaluating the effect of pulse intake on glycemic control are inconsistent and conclusive evidence is lacking. The aim of this study was to systematically review the impact of pulse consumption on post-prandial and long-term glycemic control in adults with and without type 2 diabetes (T2D). METHODS: Databases were searched for RCTs, reporting outcomes of post-prandial and long-term interventions with different pulse types on parameters of glycemic control in normoglycemic and T2D adults. Effect size (ES) was calculated using random effect model and meta-regression was conducted to assess the impact of various moderator variables such as pulse type, form, dose, and study duration on ES. RESULTS: From 3334 RCTs identified, 65 studies were eligible for inclusion involving 2102 individuals. In acute RCTs, pulse intake significantly reduced peak post-prandial glucose concentration in participants with T2D (ES - 2.90; 95%CI - 4.60, - 1.21; p ≤ 0.001; I2 = 93%) and without T2D (ES - 1.38; 95%CI - 1.78, - 0.99; p ≤ 0.001; I2 = 86%). Incorporating pulse consumption into long-term eating patterns significantly attenuated fasting glucose in normoglycemic adults (ES - 0.06; 95%CI - 0.12, 0.00; p ≤ 0.05; I2 = 30%). Whereas, in T2D participants, pulse intake significantly lowered fasting glucose (ES - 0.54; 95%CI - 0.83, - 0.24; p ≤ 0.001; I2 = 78%), glycated hemoglobin A1c (HbA1c) (ES - 0.17; 95%CI - 0.33, 0.00; p ≤ 0.05; I2 = 78) and homeostatic model assessment of insulin resistance (HOMA-IR) (ES - 0.47; 95%CI - 1.25, - 0.31; p ≤ 0.05; I2 = 79%). CONCLUSION: Pulse consumption significantly reduced acute post-prandial glucose concentration > 1 mmol/L in normoglycemic adults and > 2.5 mmol/L in those with T2D, and improved a range of long-term glycemic control parameters in adults with and without T2D. PROSPERO REGISTRY NUMBER: (CRD42019162322).

BackgroundRecent evidence suggests severe hypoglycaemia may pose a risk of premature mortality to individuals with type 2 diabetes. Evidence surrounding strategies to mitigate this risk is currently lacking as is evidence regarding risk stratification of such patients. MethodsWe performed a post-hoc analysis from a previously published RCT studying the impact of a structured nurse led intervention following severe hypoglycaemia. A Cox regression model was used to identify baseline characteristics associated with increased mortality and to adjust for differences between study groups. Kaplan Meier (KM) curves were created to demonstrate differences in outcome between study groups across a number of variables.Results124 participants (mean age 75, 57% male) were included in analysis. Diabetes severity score, age and insulin use were found to correlate with mortality, while other variables including HbA1c and presence of established cardiovascular disease showed no correlations. When comparing KM curves between study groups, the intervention appeared to be beneficial irrespective of glycaemic control, presence of vascular disease, diabetes severity score or age.ConclusionIn this analysis, only diabetes severity score, age and insulin use were significantly associated with death following severe hypoglycaemia in the community. A structured nurse-led intervention appears to reduce the risk of death irrespective of age, co-morbidities or type of treatment. Trial registrationData is taken from a previously published randomised controlled trial with trial registration NCT04422145.

BackgroundMutations in the mitochondrial genome (mtDNA) can cause devastating maternally inherited diseases, while the accumulation of somatic mtDNA mutations is linked to common diseases of aging. Although mtDNA mutations impact human health, the process(es) that give rise to these mutations are unclear and are under considerable debate. We analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing to provide clues to the mechanism by which de novo mutations arise as well as how the genome is replicated.ResultsWe observe two distinct mutational gradients in G→A and T→C transitions, but not their complements, that are delimited by the light-strand origin and the control region (CR). The gradients increase with age and are lost in the absence of DNA polymerase γ proofreading activity. A nearly identical pattern is present in human mtDNA somatic mutations. The distribution of mtDNA single nucleotide polymorphisms (SNPs) in the human population and genome base composition across >3,000 vertebrate species mirror this gradient pattern, pointing to evolutionary conservation of this phenomenon. Lastly, high-resolution analysis of the mtDNA control region highlights mutational ‘hotspots’ and ‘cold-spots’ that strongly align with important regulatory regions.ConclusionsCollectively, these patterns support an asymmetric strand-displacement mechanism with key regulatory structures in the CR and argue against alternative replication models. The mutational gradient is a fundamental consequence of mtDNA replication that drives somatic mutation accumulation and influences inherited polymorphisms and, over evolutionary timescales, genome composition.

This study offers an analysis of teacher attrition patterns at charter schools in Nashville and Memphis, Tennessee. Using survey data from 121 teachers, the study reports teacher opinion regarding four common causes of teacher attrition, examines the role of demography and school organization on future attrition plans, and offers various regression models in an attempt to predict future plans for the teachers within the sample. Overall, teachers reported lukewarm feelings regarding common causes of teacher attrition, and no background characteristic or school organizational structure held significance for future plans.

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Purpose The exact contribution of daily glucose exposure to HbA1c in people with type 1 diabetes (T1D) remains controversial. We examined the contribution of pre- and postprandial glycaemia, nocturnal and early-morning glycaemia, and glycaemic variability to HbA1c levels in T1D. In this analysis, we used clinical data, namely age, BMI and HbA1c, as well as glycaemic metrics (24-h glycaemia, postprandial, nocturnal, early-morning glycaemia, wake-up glucose, and glycaemic variability) obtained over a four-week period of continuous glucose monitoring (CGM) wear in thirty-two males with T1D. Methods The trapezoid method was used estimate the incremental area under the glucose curve (iAUC) for 24-h, postprandial (3-h period following breakfast, lunch, and dinner, respectively), nocturnal (between 24:00–04:00 AM), and early-morning (2-h period 2-h prior to wake-up) glycaemia. Linear regression analysis was employed whereby CGM-derived glycaemic metrics were explanatory variables and HbA1c was the outcome. Results Thirty-two T1D males (mean ± SD: age 29 ± 4 years; HbA1c 7.3 ± 0.9% [56 ± 13 mmol/mol]; BMI 25.80 ± 5.01 kg/m2) were included in this analysis. In linear models adjusted for age and BMI, HbA1c was associated with 24-h mean glucose (r2 = 0.735, p r2 = 0.643, p = 0.039), and dinner iAUC (r2 = 0.711, p = 0.001). CGM-derived metrics and non-glycaemic factors explained 77% of the variance in HbA1c, in which postprandial glucose accounted for 32% of the variance explained. The single greatest contributor to HbA1c was dinner iAUC resulting in 0.6%-point (~7 mmol/mol) increase in HbA1c per SD increase in dinner iAUC. Conclusions Using comprehensive CGM profiling, we show that postprandial glucose, specifically evening-time postprandial glucose, is the single largest contributing factor to HbA1c in T1D. Trial registration number NCT02204839 (July 30th 2014); NCT02595658 (November 3rd 2015).

We tested the efficacy of a stereo camera (SC) system adapted for use with a remotely operated vehicle (ROV) to estimate fish length distributions at reef sites in the northern Gulf of Mexico. A pool experiment was conducted to test the effect of distance (1, 2, 3 or 5 m), angle of incidence (AOI; 0° to 40° at 5° increments), and SC baseline distance (BD; BD1 = 406, BD2 = 610, and BD3 = 762 mm camera separation) on the accuracy and precision of fish model length (288, 552, or 890 mm fork length) estimates compared to a red laser scaler (RLS). A field experiment was then conducted at 20 reef sites with SCs positioned at BD1 to compare fish length distribution estimates between the SC and RLS systems under in situ conditions. In the pool experiment, mean percent errors were consistently within the a priori selected threshold of ±5% at AOIs ≤10° at all distances with all four systems. However, SCs produced accurate estimates at AOIs up to 30° at all distances tested; 2–3 m was optimal. During reef site surveys, SCs collected 10.4 times as many length estimates from 4.3 times as many species compared to the RLS. Study results demonstrate that, compared to laser scalers, ROV-based SC systems can substantially increase the number of available fish length estimates by producing accurate length estimates at a wider range of target orientations while also enabling measurements from a greater portion of the cameras’ field of view.

Harmful algal blooms (HABs) caused by the dinoflagellate Karenia brevis on the West Florida Shelf have become a nearly annual occurrence causing widespread ecological and economic harm. Effects range from minor respiratory irritation and localized fish kills to large-scale and long-term events causing massive mortalities to marine organisms. Reports of hypoxia on the shelf have been infrequent; however, there have been some indications that some HABs have been associated with localized hypoxia. We examined oceanographic data from 2004 to 2019 across the West Florida Shelf to determine the frequency of hypoxia and to assess its association with known HABs. Hypoxia was present in 5 of the 16 years examined and was always found shoreward of the 50-meter bathymetry line. There were 2 clusters of recurrent hypoxia: midshelf off the Big Bend coast and near the southwest Florida coast. We identified 3 hypoxic events that were characterized by multiple conductivity, temperature, and depth (CTD) casts and occurred concurrently with extreme HABs in 2005, 2014, and 2018. These HAB-hypoxia events occurred when K. brevis blooms initiated in early summer months and persisted into the fall likely driven by increased biological oxygen demand from decaying algal biomass and reduced water column ventilation due to stratification. There were also four years, 2011, 2013, 2015, and 2017, with low dissolved oxygen located near the shelf break that were likely associated with upwelling of deeper Gulf of Mexico water onto the shelf. We had difficulty in assessing the spatiotemporal extent of these events due to limited data availability and potentially unobserved hypoxia due to the inconsistent difference between the bottom of the CTD cast and the seafloor. While we cannot unequivocally explain the association between extreme HABs and hypoxia on the West Florida Shelf, there is sufficient evidence to suggest a causal linkage between them.